Physical Health Conditions in Psychiatry

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

THE MAUDSLEY GUIDELINES

Other books in the Maudsley Prescribing Guidelines series include:
The Maudsley Prescribing Guidelines in Psychiatry, 14th edition (coming in 2021) David M. Taylor, Thomas R.E. Barnes, Allan H. Young.
The Maudsley Guidelines on Advanced Prescribing in Psychosis Paul Morrison, David M. Taylor, Phillip McGuire.

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

David M. Taylor BSc, MSc, PhD, FcMHP, FFRPS, FRPharmS, FRcP (Edin)

Director of Pharmacy and Pathology, Maudsley Hospital;
and Professor of Psychopharmacology, King’s College, London, UK

Fiona Gaughran MD, FRcP(I), FRcP (Lon), FRcP (Edin), FRcPsych, FHEA

Lead Consultant Psychiatrist, National Psychosis Service (Bethlem Royal Hospital);
Director of Research and Development, South London and Maudsley NHS Foundation Trust; Reader in Psychopharmacology and Physical Health, King’s College, London, UK

Toby Pillinger MA (Oxon), BM Bch, MRcP, PhD

Academic Clinical Fellow, South London and Maudsley NHS Foundation Trust
and the Institute of Psychiatry, Psychology and Neuroscience, Kings College, London, UK

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The right of David M. Taylor, Fiona Gaughran and Toby Pillinger to be identified as the authors of this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication Data

Names: David M. Taylor, 1963– editor. | Gaughran, Fiona, editor. | Pillinger, Toby, editor.

Title: The Maudsley practice guidelines for physical health conditions in psychiatry / [edited by] David M. Taylor, Fiona Gaughran, Toby Pillinger.

Description: Hoboken, NJ : John Wiley & Sons, Inc., 2021. | Includes index. Identifiers: LCCN 2020025468 (print) | LCCN 2020025469 (ebook) |

ISBN 9781119554202 (paperback) | ISBN 9781119554219 (adobe pdf) |

ISBN 9781119554240 (epub)
Subjects: MESH: Mental Disorders–complications | Patient Care–methods |

Diagnostic Techniques and Procedures | Referral and Consultation |

Evidence-Based Practice | Practice Guideline
Classification: LCC RC454 (print) | LCC RC454 (ebook) | NLM WM 140 | DDC

616.89–dc23
LC record available at https://lccn.loc.gov/2020025468
LC ebook record available at https://lccn.loc.gov/2020025469

Cover Design: Wiley
Cover Image: © SciePro/Shutterstock

Set in 10/12pt Sabon by SPi Global, Pondicherry, India 10 9 8 7 6 5 4 3 2 1

For Aloysius, welcome to the world.

Contents

Preface xxiii List of Abbreviations xxv

Part 1 Cardiology 1

Chapter 1

Tachycardia 3

Guy Hindley, Eromona Whiskey, Nicholas Gall

Sinus tachycardia 3 Atrial fibrillation 4 Supraventricular tachycardia 4 Ventricular tachycardia 6 Diagnostic principles 6 Management 10 References 14

Bradycardia 17

Eleanor Croft, Nicholas Gall

Diagnosis 19 Management and when to refer to a specialist 21 References 22

QT Interval Prolongation 23

Guy Hindley, Nicholas Gall

Prescribing QTc‐prolonging medication 27 Diagnostic principles 28 Management 29 References 32

Syncope 35

Luke Vano, Nicholas Gall

Causes of syncope 35

Chapter 2

Chapter 3

Chapter 4

viii Contents

Chapter 5

Chapter 6

Chapter 7

Chapter 8

Chapter 9

Chapter 10

Syncope and serious mental illness 36 Diagnostic principles 36 Diagnosis and management 38 References 39

Hypertension 41

Luke Vano, Toby Pillinger, J. Kennedy Cruickshank

Diagnostic principles 43 Diagnosis 44 Management 45 References 48

Postural Hypotension 51

Toby Pillinger, Ian Osborne, Thomas Ernst, J. Kennedy Cruickshank

Diagnostic principles 53 Management 54 References 58

Peripheral Oedema 59

Thomas Whitehurst, Theresa McDonagh

Diagnostic principles 60 Management 66 References 67

Myocarditis 71

Thomas Whitehurst, Theresa McDonagh

Diagnostic principles 71 Management 75 Clozapine‐induced myocarditis 75 References 77

Hypercholesterolaemia 79

Dipen Patel, Toby Pillinger, Narbeh Melikian

Diagnostic principles 80 Diagnostic criteria 81 Management 81 References 84

Physical Activity 85

Garcia Ashdown-Franks, Brendon Stubbs

Physical activity and serious mental illness 85 How much physical activity and exercise should people be doing? 86 Practical tips 87 Messages to include in discussions with patients 87 References 88

Part 2 Endocrinology 91

Chapter 11

Chapter 12

Diabetes Mellitus 93

Yuya Mizuno, Toby Pillinger, Dan Siskind, Sophie Harris

Diagnostic principles 93 Management 97 References 102

Thyroid Disease 105

Harriet Quigley, Jackie Gilbert

Hypothyroidism 105 Diagnostic principles 107 Management 110 Hyperthyroidism 111 Diagnostic principles 112 Management 113 References 114

Hyperprolactinaemia 117

John Lally, Toby Pillinger, Olubanke Dzahini, Sophie Harris

Diagnostic principles 119 Management and when to refer to a specialist 121 Hyperprolactinaemia and osteoporosis risk in serious mental illness 122 Hyperprolactinaemia and cancer risk 123 References 123

Obesity 125

Yuya Mizuno, Toby Pillinger, Dan Siskind, Ian Osborne,
Kate Moffat, Donal O’Shea
Monitoring 127 Prevention and treatment of weight gain 129 References 134

Chapter 13

Chapter 14

Part 3 Chapter 15

Chapter 16

Haematology 137

Anaemia 139

Sanjena Mithra, Aleksander Mijovic

Diagnostic principles 140 Management and referral pathways 143 References 145

Neutropenia 147

John Lally, Toby Pillinger, Aleksander Mijovic

Drug‐induced neutropenia and agranulocytosis 149 Diagnostic principles 150 Management 151 References 153

Contents ix

x Contents

Chapter 17

Chapter 18

Thrombocytopenia 155

Sanjena Mithra, Aleksander Mijovic

Diagnostic principles 156 Management and when to refer 158 References 158

Venous Thromboembolism and Anticoagulation 159

Helen Doolittle, Lara Roberts, Roopen Arya

Risk factors 159 Prophylaxis 161 Diagnosis 162 Management 164 References 168

Part 4 Chapter 19

Chapter 20

Chapter 21

Chapter 22

Chapter 23

Gastroenterology 169

Gastro‐oesophageal Reflux and Peptic Ulcer Disease 171

Luke Vano, Seema Varma, John O’Donohue

Gastro‐oesophageal reflux disease 171 Peptic ulcer disease 176 References 178

Gastrointestinal Bleeding 181

Douglas Corrigall, David Dewar

Diagnostic principles 183 Management 185 References 188

Nausea and Vomiting 191

Mary Denholm, Matthew Cheetham

Diagnostic principles 193 Management 195 References 198

Dysphagia 199

Mary Denholm, Jason Dunn

Causes of dysphagia in the general population 199 Diagnostic principles 200 Management 203 Oesophageal cancer in psychiatric populations 203 Dysphagia in the elderly 204 References 204

Deranged Liver Function Tests 207

John Lally, Aisling Considine, Kosh Agarwal

Diagnostic principles 207 Management 212 References 213

Part 5 Chapter 29

Chapter 30

Renal and Urology

Urinary Retention

Atheeshaan Arumuham, Vimoshan Arumuham

Urinary retention and serious mental illness Diagnostic principles
Management
References

Urinary Incontinence

Atheeshaan Arumuham, Vimoshan Arumuham

Diagnostic principles Management References

Contents xi

Chapter 24

Chapter 25

Chapter 26

Chapter 27

Chapter 28

Alcohol and Physical Health

Musa Sami, Joseph Cooney, Michael Heneghan

What is harmful use?
Physical complications of alcohol use
Approach to the patient with suspected alcohol misuse Management
References

Unintentional Weight Loss

Mary Denholm, John O’Donohue

Diagnostic principles Management References

Dry Mouth

Enrico D’Ambrosio, Andrea Falsetti, Stephen Challacombe

Diagnostic principles Management References

Hypersalivation

Enrico D’Ambrosio, Andrea Falsetti, Toby Pillinger, Stephen Challacombe
Diagnostic principles
Management

References

Constipation

John Lally, Toby Pillinger, Kalliopi Vallianatou, Immo Weichert
Diagnostic principles
Management

References

215

215

216

217

220

222

223

225 227 227

229

231 231 232

235

235 236 239

241

243 244 249

251

253

253

254

256

259

261 262 264

xii Contents

Chapter 31

Chapter 32

Chapter 33

Chapter 34

Polyuria 267

Atheeshaan Arumuham, Toby Pillinger, Benjamin Whitelaw

Diagnostic principles 268 Management 269 References 271

Sodium Derangement 273

Atheeshaan Arumuham, Peter Conlon

Diagnostic principles 274 Management 276 References 277

Potassium Derangement 279

Ellis Onwordi, Peter Conlon

Hyperkalaemia 279 Hypokalaemia 282 References 285

Chronic Kidney Disease 287

Ellis Onwordi, Toby Pillinger, Anne Connolly, Peter Conlon

Diagnostic principles 289 Management 291 References 295

Part 6 Sexual and Reproductive Health 297

Chapter 35

Chapter 36

Chapter 37

Sexual Dysfunction 299

Rudiger Pittrof

Assessment of a patient with sexual dysfunction 299 Management 301 References 304

Contraception 307

Neha Pathak, Usha Kumar

Clinical approach 308 Contraceptive options 308 Ethical and legal considerations 312 When to refer 313 Special considerations in patients with serious mental illness 313 References 314

Infertility 317

Rudiger Pittrof

Addressing infertility in psychiatric practice 317 Onward referral and further tests for infertility 318 Infertility treatments 318 References 318

Part 7 Chapter 39

Chapter 40

Chapter 41

Chapter 42

Chapter 43

Chapter 44

Infectious Diseases

Pneumonia

Emma McGuire, Loren Bailey, Peter Saunders, Meera Chand

Pneumonia and serious mental illness Diagnostic principles
Management
References

Influenza

Anna Riddell, Eithne MacMahon

Diagnostic principles Management
Preventing spread of influenza References

Urinary Tract Infection

Sian Cooper, Conor Maguire

Urinary tract infection and serious mental illness Diagnostic principles
Management
References

Gastroenteritis

Maria Krutikov, Luke Snell

Diagnostic principles Management References

Viral Hepatitis

Klara Doherty, Aisling Considine, Kosh Agarwal

Hepatitis B Hepatitis C References

Tuberculosis

Sakib Rokadiya, Adrian R. Martineau

Diagnostic principles Management References

Contents xiii

Chapter 38

Sexually Transmitted Infection

Harriet Le Voir, Rudiger Pittrof

History
STI testing in psychiatry
Determining urgency of clinical action/referral Referral to sexual health services
References

319

319

320

321

322

324

325 327

329

332

335

337

338

339

341

342

343

344

347

350

351

351 354 356

357

357 361 364

365

366 369 371

xiv Contents

Chapter 45

Human Immunodeficiency Virus 373

Rebecca Marcus, Jessica Gaddie, Toby Pillinger, Ben Spencer,
Kalliopi Vallianatou, Rudiger Pittrof
Testing for HIV 374 HIV and the central nervous system 374 Antiretroviral therapy 375 References 380

Part 8 Chapter 46

Chapter 47

Chapter 48

Chapter 49

Respiratory 383

Smoking Cessation 385

Harriet Quigley, Mary Yates, John Moxham

Identifying those who want to stop smoking and degree
of nicotine dependence 385 Approaches to smoking cessation 387 References 392

Chronic Obstructive Pulmonary Disease 395

Mary Docherty, Jenny Docherty, Peter Saunders

Common causes of COPD in the general population and patients
with serious mental illness 395 The asthma–COPD overlap 396 Diagnostic principles 397 Management 400 References 403

Asthma 405

Mary Docherty, Jenny Docherty, Peter Saunders

Causes in the general population and people with serious
mental illness 405 Diagnostic principles 406 Management 409 References 412

Obstructive Sleep Apnoea 413

Nicholas Meyer, Hugh Selsick, Kai Lee

Diagnostic principles 414 Management 415 References 416

Part 9 Neurology 419

Chapter 50 Delirium 421

Luke Jelen, Sean Cross

Diagnostic principles 421 Management 426 References 429

Chapter 51

Chapter 52

Chapter 53

Autoimmune Encephalitis

Adam Al-Diwani, Julia Thompson, Sarosh Irani

Autoimmune disease mechanisms Clinical approach
Management
References

Catatonia

Jonathan P. Rogers, Ali Amad

Diagnostic principles Management References

Seizure Disorders

Emanuele F. Osimo, Brian Sweeney

Acute seizure
Psychiatric comorbidity in people with epilepsy Psychiatric side effects of antiepileptic drugs Psychiatric drug therapy in people with epilepsy Psychogenic non‐epileptic seizures
Epilepsy surgery
Epilepsy and learning disability
References

Headache

Ines Carreira Figueiredo, Nazia Karsan, Peter Goadsby

Diagnostic principles Management References

Disorders of Sleep and Circadian Rhythm

Nicholas Meyer, Hugh Selsick

Definitions of common sleep disorders in psychiatric populations Diagnostic principles
Management
References

Extrapyramidal Side Effects

Graham Blackman, R. John Dobbs, Sylvia Dobbs

Clinical approach Management References

Tardive Dyskinesia

Graham Blackman, Toby Pillinger, R. John Dobbs, Sylvia Dobbs

Clinical approach Management References

431

431

432

437

439

441

442 444 448

451

452

455

457

458

459

461

463 466 468

471

471

474

476

477

479

480 482 483

485

486 487 489

Chapter 54

Chapter 55

Chapter 56

Chapter 57

Contents xv

xvi Contents

Chapter 58 Tremor 491

Graham Blackman, R. John Dobbs, Sylvia Dobbs

Clinical approach 491 Management 494 References 496

Part 10 Rheumatology and Musculoskeletal Health 497

Chapter 59

Chapter 60

Low Back Pain 499

Jennifer Ireland, Matthew Cheetham

Diagnostic principles 500 Management 502 References 503

Arthritis 505

Sarah Griffin, Joseph Nathan, Richard Campbell

Clinical approach 510 Management 512 References 512

Part 11 Ophthalmology 515

Chapter 61

Eye Disease 517

Ernest Iakovlev, Radwan Almousa

Clinical approach to a patient with visual disturbance or
orbital/periorbital disorders 517 Disorders of the eyelids 522 Disorders of the conjunctiva 526 Disorders of the cornea 529 References 533

Part 12 Chapter 62

Chapter 63

Obstetrics and Gynaecology 535

Pregnancy 537

Katherine Beck, Ruth Cochrane, Louise M. Howard

The pre‐conception period 538 During pregnancy 539 Psychiatric medication in pregnancy 543 Postpartum psychosis 547 Electroconvulsive therapy in pregnancy 547 References 548

Menopause 551

Deirdre Lundy

Physiology and symptoms of perimenopause 551 Clinical approach 552 Treatment 553 References 556

Part 13 Dermatology 559

Chapter 64

Chapter 65

General Dermatology 561

Jonathan Kentley, Ruth Taylor, Anthony Bewley

Infectious skin disease 561 Non‐infectious skin disease 564 References 566

Psychodermatology 569

Jonathan Kentley, Ruth Taylor, Anthony Bewley

Psychiatric disorders with skin manifestations 569 Psychophysiological conditions 571 Secondary psychological disorders 571 Cutaneous sensory disorders 572 References 572

Part 14 Chapter 66

Part 15 Chapter 67

Chapter 68

Chapter 69

Electroconvulsive Therapy 573

Electroconvulsive Therapy 575

James Kelly, Mariese Cooper, Mario Juruena

Indications and contraindications 575 The ECT procedure 576 Physiological effects of ECT 576 Pre‐ECT assessment 578 Safety of ECT 579 ECT prescribing 579 Guidance for the doctor administering ECT 579 Side effects of ECT 580 Special patient groups 581 References 581

Emergencies 583

Chest Pain 585

Luke Vano, Immo Weichert

Diagnostic principles 586 Management 590 Information to provide in a ‘chest pain’ referral to medical services 591 References 591

Acute Shortness of Breath 593

Martin Osugo, Toby Pillinger, Vivek Srivastava

Diagnostic principles 593 Management 595 References 596

Acute Coronary Syndrome 597

Laura O’Sullivan, Narbeh Melikian

Diagnostic principles 598 Management 602 References 603

Contents xvii

xviii Contents

Chapter 70

Chapter 71

Chapter 72

Chapter 73

Chapter 74

Chapter 75

Chapter 76

Arrhythmia 605

Martin Osugo, Nicholas Gall

Tachycardia 605 Bradycardia 605 Reference 608

Hypertensive Crisis 609

Luke Vano, J. Kennedy Cruickshank

Diagnostic principles 609 Management 610 References 611

Sepsis 613

Laura O’Sullivan, Immo Weichert

When to think sepsis 613 Septic shock 614 Management 614 Post‐sepsis syndrome 615 References 616

Acute Kidney Injury 617

Phillipa Brothwood, Toby Pillinger, Anne Connolly, Peter Conlon

Categorisation of acute kidney injury 617 Diagnostic principles 620 Management 622 Psychiatric medication and acute kidney injury 622 References 623

Diabetic Emergencies 625

Toby Pillinger, Yuya Mizuno, Sophie Harris

Hypoglycaemia 625 Diabetic ketoacidosis 626 Hyperosmolar hyperglycaemic state 627 References 627

Acute Upper Gastrointestinal Bleeding 629

Douglas Corrigall, David Dewar

Signs of acute upper gastrointestinal bleeding 629 Waiting for transfer 629 Handing over to the acute medical team 630

Status Epilepticus 631

Emanuele F. Osimo, Brian Sweeney

Chapter 77

Chapter 78

Chapter 79

Chapter 80

Chapter 81

Chapter 82

Anaphylaxis

James Kelly, Immo Weichert

Management References

Reduced Consciousness and Coma

James Kelly, Immo Weichert

Clinical approach References

Thyroid Emergencies

Harriet Quigley, Jackie Gilbert

Hypothyroid crisis/myxoedema coma Hyperthyroid crisis/thyroid storm References

Head Injury

Susie Bradwell, Sophie Williams, Joanna Manson

Clinical approach
Types of intracranial haemorrhage References

Acute Meningitis and Infective Encephalitis

Hina Khan, Brian Sweeney

Meningitis
Infective encephalitis References

Stroke and Transient Ischaemic Attack

Toby Pillinger, James Teo

Stroke
Diagnostic principles Management
Transient Ischaemic Attack Diagnostic principles Management
References

Overdose

Stephen Kaar, Immo Weichert

General principles
Information gathering
Emergency assessment and management

633

633 636

637

637 640

641

641 642 643

645

645 649 650

651

651 653 655

657

657

658

659

660

661

663

663 664 664

Chapter 83

Contents xix

xx Contents

Chapter 84

Chapter 85

Chapter 86

Chapter 87

Specific scenarios 667 Management of a person who refuses admission to hospital
after an overdose 670 References 670

Acute Dystonia 673

Jonathan P. Rogers, R. John Dobbs, Sylvia Dobbs

Diagnostic principles 673 Management 675 References 677

Neuroleptic Malignant Syndrome 679

Robert A. McCutcheon, James Kelly, Toby Pillinger

Diagnostic principles 679 Management 680 References 681

Serotonin Syndrome 683

Robert A. McCutcheon, James Kelly, Toby Pillinger

Diagnostic principles 683 Management 684 References 685

Emergencies in Obstetrics and Gynaecology 687

Hanine Fourie, Ruth Cochrane

Maternal collapse 689 Pre‐eclampsia 689 Major obstetric haemorrhage 691 Amniotic fluid embolism 691 Ectopic pregnancy 691 Miscarriage 693 Hyperemesis gravidarum 694 Ovarian cyst accidents 695 Pelvic inflammatory disease 697 References 697

The Acute Abdomen 699

Sophie Williams, Joanna Manson

History 699 Causes of the acute abdomen based on pain location 702 Examination 705 Investigations 706 Onward referral 706 References 707

Chapter 88

Contents xxi

Chapter 89

The ABCDE Approach

Toby Pillinger, Immo Weichert

First steps Airway (A) Breathing (B) Circulation (C) Disability (D) Exposure (E) References

Index

709

709

711

712

713

Preface

It is well documented that people with severe mental illness have elevated mortality rates compared with the general population, with physical health conditions the pre- dominant cause. There are several potential mechanisms underlying this mortality gap. First, lifestyle factors such as poor diet, reduced exercise levels, and higher rates of smoking play a role. Second, psychiatric medications are associated with physical side effects, and can contribute to progressive impairment of multiple organ systems. Third, individuals with serious mental illness are less likely to present to a general practitioner or medical hospital with a physical complaint, thereby allowing conditions to progress without treatment. Fourth, when physical conditions are identified while under the care of psychiatric services, practitioners may lack the knowledge and confidence to act.

This, the first edition of The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry, aims to bridge the gap between psychiatric and physical health services which are usually geographically and organisationally separate. A key objective is to enhance the clinical confidence of psychiatric practitioners by providing these individuals with a practical and evidence‐based ‘toolkit’ with which to assess, investigate, and potentially initiate treatment for common physical health conditions seen in patients with serious mental illness. It is hoped that co‐working relationships between psychiatrists and general practitioners, physicians, and surgeons alike will be enhanced owing to improved quality of referrals. Furthermore, it is anticipated that the standard of clinical care delivered to patients with serious mental illness will improve by expediting appropriate investigation and management of physical comorbidity. Finally, we hope that the patient–practitioner relationship will be enhanced as psychi- atric patients become aware that both body and mind are being considered as part of their holistic care.

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry con- sists of 89 chapters, covering 14 different organ systems, alongside emergency presenta- tions. Although The Guidelines are predominantly based on UK practice, we have made efforts to acknowledge the anticipated international readership, and as such have also included references to psychiatric and medical drugs not currently licensed in the UK. However, the reader should be aware that no guideline can take into account every drug available across the world, so omissions are inevitable.

xxiv Preface

This text may be seen as a sister volume to the The Maudsley Prescribing Guidelines in Psychiatry. Like that book, the The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry is the product of a group of local and international experts; we are indebted to the 125 individuals from across medicine, surgery, and psychiatry who have contributed. At present, the world’s attention is centred on the COVID‐19 pandemic and never has there been a greater need for clinicians from across specialties to work together for the greater good of patients. We hope that The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry will go some way to facilitate this, not only in the current climate but for years to come.

Toby Pillinger London, UK September 2020

Abbreviations

ABPM ambulatory blood pressure monitoring ACE angiotensin‐converting enzyme
ACOS asthma–COPD overlap syndrome
ACS acute coronary syndrome

ADH antidiuretic hormone
ADR adverse drug reaction
AE autoimmune encephalitis
AED antiepileptic drug
AF atrial fibrillation
AFB acid‐fast bacilli
AKI acute kidney injury
ALP alkaline phosphatase
ALT alanine aminotransferase
ANC absolute neutrophil count
ARB angiotensin II receptor blocker ART antiretroviral therapy
ASPD advanced sleep phase disorder AST aspartate aminotransferase
ATT antitubercular treatment
AUR acute urinary retention
BEN benign ethnic neutropenia
BMI body mass index
BNP brain natriuretic peptide
BP blood pressure
BPH benign prostatic hyperplasia CAP community‐acquired pneumonia CBT cognitive‐behavioural therapy CI confidence interval
CIM clozapine‐induced myocarditis CKD chronic kidney disease
CLD chronic liver disease

xxvi Abbreviations

CNS
COPD
COVID‐19 coronavirus disease 2019
CPAP continuous positive airway pressure CRP C‐reactive protein
CSF cerebrospinal fluid
CT computed tomography
CVD cardiovascular disease
DAA direct‐acting antiviral
DEXA dual‐energy X‐ray absorptiometry
DI diabetes insipidus
DKA diabetic ketoacidosis
DRE digital rectal examination
DSPD delayed sleep phase disorder
DVT deep vein thrombosis
ECT electroconvulsive therapy
EDS excessive daytime sleepiness
eGFR estimated glomerular filtration rate EPSE extrapyramidal side effect
ESC European Society of Cardiology
ESR erythrocyte sedimentation rate
ESRF end‐stage renal failure
FBC full blood count
FDA Food and Drug Administration
FEV1 forced expiratory volume in 1 s
FVC forced vital capacity
GABA gamma‐aminobutyric acid
GCS Glasgow Coma Scale
GGT gamma‐glutamyltransferase
GORD gastro‐oesophageal reflux disease
HAD HIV‐associated dementia
HAND HIV‐associated neurocognitive disorders HAP hospital‐acquired pneumonia
HBPM home blood pressure monitoring
HBV hepatitis B virus
HCG human chorionic gonadotrophin
HCV hepatitis C virus
HDL high‐density lipoprotein
HHS hyperosmolar hyperglycaemic state HMOD hypertension‐mediated organ damage HRT hormone replacement therapy
HSV herpes simplex virus
ICD implantable cardioverter‐defibrillator ICP intracranial pressure

central nervous system
chronic obstructive pulmonary disease

Abbreviations

xxvii

ICU intensive care unit
IGRA interferon gamma release assay
INR international normalised ratio
IOP intraocular pressure
IUD intrauterine device
LARC long‐acting reversible contraceptive
LBBB left bundle branch block
LDL low‐density lipoprotein
LFT liver function test
LLQ left lower quadrant
LMWH low‐molecular‐weight heparin
LOS lower oesophageal sphincter
LP lumbar puncture
LUQ left upper quadrant
LVH left ventricular hypertrophy
MAOI monoamine oxidase inhibitor
MCV mean corpuscular volume
MDD major depressive disorder
MOH major obstetric haemorrhage
MRI magnetic resonance imaging
MRSA methicillin‐resistant Staphylococcus aureus
MSU mid‐stream urine
NAFLD non‐alcoholic fatty liver disease
NICE National Institute for Health and Care Excellence NMDA N‐methyl‐d‐aspartate
NMS neuroleptic malignant syndrome
NNRTI non‐nucleoside reverse transcriptase inhibitor NRT nicotine replacement therapy
NSAID non‐steroidal anti‐inflammatory drug
NSTEMI non‐ST‐segment elevation myocardial infarction OD odds ratio
OGTT oral glucose tolerance test
OIC opioid‐induced constipation
OSA obstructive sleep apnoea
PA physical activity
PAMORA peripherally acting μ‐opioid receptor antagonist PCI percutaneous coronary intervention
PCR polymerase chain reaction
PE pulmonary embolism
PEF peak expiratory flow
PEFR peak expiratory flow rate
PEP post‐exposure prophylaxis
PHAP psychiatric hospital‐acquired pneumonia
PID pelvic inflammatory disease

xxviii Abbreviations

PLMS
PLWHIV people living with HIV
PNES psychogenic non‐epileptic seizures
POI premature ovarian insufficiency
PPI proton‐pump inhibitor
PPS psychogenic pseudosyncope
PUD peptic ulcer disease
PwE people with epilepsy
RAPD relative afferent pupillary defect
RID relative infant dose
RLS restless leg syndrome
RR relative risk
RUQ right upper quadrant
SARS‐CoV‐2 severe acute respiratory syndrome coronavirus 2
SD sexual dysfunction
SIADH syndrome of inappropriate antidiuretic hormone secretion SJS Stevens–Johnson syndrome
SLE systemic lupus erythematosus
SMI serious mental illness
SNRI serotonin/noradrenaline reuptake inhibitor
SPECT single photon emission computed tomography
SSRI selective serotonin reuptake inhibitor
STEMI ST‐segment elevation myocardial infarction
STI sexually transmitted infection
SVT supraventricular tachycardia
TD tardive dyskinesia
T2DM type 2 diabetes mellitus
TEN toxic epidermal necrolysis
TFT thyroid function test
TIA transient ischaemic attack
TIBC total iron‐binding capacity
TLE temporal lobe epilepsy
TLOC transient loss of consciousness
TNF tumour necrosis factor
TRH thyrotropin releasing hormone
TSH thyroid stimulating hormone
UA unstable angina
ULN upper limit of normal
UPSI unprotected sexual intercourse
UTI urinary tract infection
VGKC voltage‐gated potassium channel
VT ventricular tachycardia
VTE venous thromboembolism
WHO World Health Organization

periodic limb movements in sleep

Part 1

Cardiology

Chapter 1

Tachycardia

Guy Hindley, Eromona Whiskey, Nicholas Gall

In adults, tachycardia is defined as a heart rate faster than 100 beats per minute (bpm). This may represent a normal physiological response, a sign of systemic illness, or primary cardiac pathology [1]. There are several possible cardiac rhythms associated with tach- ycardia. Identifying the underlying rhythm is central to the diagnostic process and directs management. Classifying these rhythms according to the width of the QRS com- plex and the regularity of the rhythm (as seen on an ECG) helps to simplify this process (Table 1.1) [2].

SINUS TACHYCARDIA

Sinus tachycardia is the most commonly encountered rhythm disturbance. In the major- ity of cases, this is an appropriate physiological response mediated by the sympathetic nervous system to an identifiable cause, which may be benign or pathological (Box 1.1) [3]. In the context of mental health, sinus tachycardia may be experienced during epi- sodes of agitation, anxiety or panic. Sympathomimetic and anticholinergic drugs are also important causes to consider, including clozapine which causes a transient sinus tachycardia in 25% of patients, usually limited to the first six weeks of treatment [4]. Among pathological causes, people with serious mental illness (SMI) are at higher risk of sepsis [5] and pulmonary embolism [5,6], while sinus tachycardia is also associated with clozapine‐induced myocarditis [7], neuroleptic malignant syndrome, and seroto- nin syndrome [8]. Hyperthyroidism and, more rarely, phaeochromocytoma may pre- sent with both psychiatric symptoms and sinus tachycardia [9,10]. The reader is directed to other chapters for detailed information on sepsis (Chapter 72), venous thromboem- bolism (Chapter 18), myocarditis (Chapter 8), neuroleptic malignant syndrome (Chapter 85), serotonin syndrome (Chapter 86), and hyperthyroidism (Chapter 79).

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry, First Edition. David M. Taylor, Fiona Gaughran, and Toby Pillinger.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

4 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 1.1 Differential diagnosis of tachycardia according to the length of the QRS complex and regularity of rhythm [2].

CHAPTER 1

Regular

Irregular

Narrow QRS (≤120 ms)

Sinus tachycardia Supraventricular tachycardia Atrioventricular re‐entrant

tachycardia (AVRT) Atrioventricular nodal re‐entrant

tachycardia (AVNRT) Atrial flutter (with regular

atrioventricular block) Focal atrial tachycardia

Atrial fibrillation (AF) Atrial flutter with varying

atrioventricular block Multifocal atrial tachycardia

Broad QRS (>120 ms)

Monomorphic ventricular tachycardia (VT)
Any regular narrow‐complex tachycardia with aberrant conduction (e.g. bundle branch block/accessory pathway)

Torsade de pointes
Polymorphic VT
Ventricular fibrillation
AF with aberrant conduction (bundle branch block/accessory pathway)

ATRIAL FIBRILLATION

Atrial fibrillation (AF) is the second most prevalent rhythm disturbance, occur- ring in 0.4–1% of adults [11]. Risk increases significantly with age [11]. Alcohol and stimulant use, hyperthyroidism, heart failure, hypertension, and chronic lung disease are associated with AF, all of which are more prevalent in patients with SMI (Table 1.2) [12]. AF can cause acute cardiac decompensation presenting as pulmonary oedema or myocardial ischaemia (see Chapters 67 and 68), as well as longer‐term complications such as thromboembolic disease (e.g. stroke; see Chapter 82) [13].

SUPRAVENTRICULAR TACHYCARDIA

Conventionally, supraventricular tachycardia (SVT) refers to any tachycardia other than AF that originates above the level of the ventricles, i.e. involving the atria, the atrioventricular node, or the bundle of His [2]. Atrioventricular nodal re‐entrant tachy- cardia (AVNRT), atrioventricular re‐entrant tachycardia (AVRT), atrial flutter, and focal atrial tachycardia are the most common forms of SVT and each is associated with its own distinct pathophysiology and management [14]. Among people with SMI, alco- hol and stimulant use may precipitate SVT (see Box 1.1) [15]. Ischaemic heart disease is also an important risk factor [16], the incidence of which is higher in people with SMI [17]. Among the general population, SVT rates are higher in women and those older than 65, although in the absence of ischaemic heart disease, SVT tends to present in younger people with a mean age of 37 [16].

Tachycardia 5

Box 1.1 Common or important causes of tachycardia: those associated with serious mental illness are highlighted in italic

Sinus tachycardia

Emotional/physical arousal: anxiety/panic/agitation

Pain
Circulatory compromise:

Sepsis
Pulmonary embolism
Hypovolaemia including haemorrhage

Heart failure
Myocardial ischaemia
Anaemia
Hyperthyroidism
Electrolyte disturbance (hypokalaemia, hypomagnesaemia) Pregnancy
Postural orthostatic tachycardia syndrome
Inappropriate sinus tachycardia
Orthostatic intolerance
Alcohol/opiate/benzodiazepine withdrawal
Serotonin syndrome
Neuroleptic malignant syndrome
Drugs:

Salbutamol
Caffeine
Cocaine
Amphetamine Cannabis
Clozapine
Tricyclic antidepressants Carbamazepine Methylphenidate

Supraventricular tachycardia [2,15,16]

Wolff–Parkinson–White syndrome (AVRT)

Electrolyte disturbances (hypokalaemia/hyperkalaemia, hypomagnesaemia) Ischaemic heart disease
Drugs:

Alcohol Cocaine Amphetamine Caffeine

Atrial fibrillation [12]

Older age

Sepsis
Pulmonary embolism Heart failure
Valvular heart disease Hypertension

CHAPTER 1

Chronic lung disease and lung cancer
Hyperthyroidism
Electrolyte disturbance (hypokalaemia, hypomagnesaemia) Drugs:

Atropine

Alcohol Caffeine Cocaine Amphetamine

Ventricular tachycardia [23–26]

Myocardial infarction
Cardiomyopathy
Structural heart disease
Electrolyte disturbances (hypokalaemia/hyperkalaemia, hypomagnesaemia) Prolonged QTc interval (congenital or acquired)

Brugada syndrome (phenotype associated with antipsychotics) Eating disorders
Drugs:

Cocaine
Amphetamines
Tricyclic antidepressants
QTc prolonging medication including antipsychotics (see Chapter 3) Digoxin

6 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

VENTRICULAR TACHYCARDIA

Ventricular tachycardia (VT) is less common but is associated with high mortality and is the leading cause of sudden cardiac death [18]. The majority of cases are experienced in the context of structural heart disease, myocardial infarction or cardiomyopathy (both ischaemic and non‐ischaemic) [19]. Although a specific association between VT and SMI has not been investigated, sudden cardiac death is significantly more prevalent in the psychiatric population and particularly among those taking antipsychotic medi- cation and people with eating disorders [20,21]. Torsades de pointes (TdP), an irregular polymorphic VT, is of particular relevance due to its association with many antipsy- chotics and other psychotropic medications that prolong the QT interval (see Chapter 3). Despite this, TdP is still relatively rare, with an annual incidence of 0.16% in general hospital inpatients [22].

DIAGNOSTIC PRINCIPLES History

1 Define cardiac symptoms.
a Palpitations (Box 1.2): if these are paroxysmal (i.e. intermittent), ask the patient to

tap out the rhythm; this may provide information on the rate and the regularity of

CHAPTER 1

Tachycardia 7

Box 1.2 Clinical assessment of paroxysmal palpitations

▪ Palpitations are defined as the abnormal sensation of one’s own heartbeat.

▪ They may be associated with tachyarrhythmias but can also be experienced during other abnor-
mal cardiac rhythms such as ectopic beats or bradyarrhythmias (see Chapter 1.2) [28].

▪ Common causes include anxiety and somatisation (31%), paroxysmal atrial fibrillation (16%), and
paroxysmal supraventricular tachycardia (10%) [29].

▪ Although psychiatric symptoms are an important risk factor for a non‐cardiac cause of palpita-
tions, 13% of such patients have an underlying cardiac abnormality and so further investigation may be warranted in the presence of other cardiac symptoms or red flag features [30].

the heartbeat during the palpitations (if irregularly irregular, strongly suggestive of

paroxysmal AF).

. b Symptomsofhaemodynamiccompromise,e.g.chestpain,shortnessofbreath,syncope/
presyncope.

. c Symptoms of heart failure, e.g. orthopnoea (shortness of breath on lying flat), par-
oxysmal nocturnal dyspnoea (sensation of shortness of breath that wakes a patient
from their sleep), swollen ankles.

. d Symptoms of myocardial infarction (assessment of chest pain including character,
site, and radiation; nausea/vomiting, sweating).

. 2 Determine possible precipitants including exercise, stress, drugs, or alcohol.

. 3 Symptoms suggestive of systemic illness.

. a Sepsis: fever, rigors, presyncope/syncope, confusion, symptoms related to infective source.

. b Dehydration/hypovolaemia: recent evidence of volume loss (diarrhoea/vomiting, reduced oral intake, blood loss).

. c Hyperthyroidism: weight loss despite increased appetite, oligomenorrhoea, emo- tional lability, heat intolerance.

. d Anxiety/panic: paraesthesia, breathlessness, association with psychosocial stressors.

. 4 Medication history including any new medications or recent dose changes/with- drawal, paying particular attention to any sympathomimetic or anticholinergic drugs (e.g. clozapine).

. 5 Past medical history, including:

. a ischaemic, structural, or valvular heart disease or heart failure

. b chronic lung disease (e.g. chronic obstructive pulmonary disease/obstructive sleep
apnoea)

. c thyroid disease

. d diabetes mellitus

. e previous tachyarrhythmias

. f eating disorder (purging behaviour may be associated with electrolyte
disturbance)

. g panic attacks/anxiety.

CHAPTER 1

8 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

. 6 Family history of sudden cardiac death/unexplained death under 40 or tachyarrhyth- mias [27].

. 7 Social history including alcohol and tobacco use, illicit substance use, and consump- tion of caffeinated drinks (see Chapter 46).

. 8 Perform a mental state examination, exploring for any psychiatric symptoms that may be associated with autonomic activation, e.g. panic, anxiety, or fear in the con- text of delusional beliefs or hallucinatory experiences.

Examination

. 1 In an emergency (e.g. the unconscious patient), resuscitate using the ABCDE approach and refer to emergency medical services.

. 2 Observations: heart rate, blood pressure, temperature, respiratory rate, oxygen saturations.

. 3 In stable patients, perform a cardiovascular examination paying particular attention to the following.

. a Inspection: dyspnoea, raised jugular venous pressure, swollen ankles (evidence of
heart failure).

. b Palpation: examine pulse for rate, rhythm, character, and volume.

. c Auscultation: murmurs (valvular heart disease), S3/S4 (heart failure), pulse deficit
(additional heartbeats that do not correspond to a palpable pulse are a sign of AF),
chest (pulmonary oedema).

. d Palpation for sacral and pedal oedema (heart failure).

. 4 Focused examination if underlying cause suspected, as in the following examples.

. a If infection is suspected, focused examination for potential sources (e.g. chest).

. b If hyperthyroidism suspected: fine tremor, sweaty palms, exophthalmos/lid lag,
palpate for goitre (see Chapter 12 for focused examination).

. 5 Lying and standing blood pressure may elicit postural drop in blood pressure indica-
tive of haemodynamic compromise.

Investigations

. 1 ECG (see Box 1.3 for descriptions of ECGs for common or important tachyarrhyth- mias with examples).

. 2 Bloods:

. a full blood count (anaemia, high/low neutrophil count)

. b renal function (hypovolaemia, hypokalaemia/hyperkalaemia)

. c bone profile (hypomagnesaemia, hypocalcaemia)

. d C‐reactive protein (infection)

. e thyroid function (hyperthyroidism)

. f antipsychotic levels (toxicity)

. g troponin (if suspecting an ischaemic event or myocarditis)

. h D‐dimer (see Chapter 18 to guide use of this test)

. i brain natriuretic peptide (heart failure)

. j HbA1c (diabetes mellitus)

. k blood sugar (diabetic ketoacidosis/hyperosmolar hyperglycaemic state).

CHAPTER 1

Tachycardia 9

Box 1.3 ECG characteristics of different tachyarrhythmias [32]

▪ Sinus tachycardia: P waves preceding every QRS complex, QRS complex following every P wave.
II

▪ Atrial fibrillation: irregularly irregular rhythm without P waves II

▪ Atrial flutter: saw‐tooth pattern reflecting atrial contractions at 300 bpm best seen in leads II, III and aVF. Usually narrow QRS complexes at 150 bpm (2 , 1 AV node conduction, as shown here).
II

▪ Supraventricular tachycardia (atrioventricular re‐entrant tachycardia or atrioventricular nodal re‐entry tachycardia): regular tachycardia 140–300 bpm. Narrow QRS complexes (unless aberrant conduc- tion). ST depression and T‐wave inversion possible even in the absence of coronary artery disease.
II

▪ Wolff–Parkinson–White in sinus rhythm: short PR interval <120 ms. Delta wave: slowly rising QRS complex. QRS prolongation >110 ms. ST‐segment and T‐wave changes.
II

▪ Monomorphic ventricular tachycardia: regular rhythm, very broad QRS complexes (>160 ms) typically in the elderly or those with structural heart disease.
II

▪ Torsade de pointes: variable QRS complexes which ‘twist’ around isoelectric line.aVL aVL

CHAPTER 1

10 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

3 Urine toxicology (cocaine, amphetamines, cannabis).
4 Urine dipstick (urinary tract infection, ketonuria, glycosuria).
5 Chest X‐ray (cardiomegaly, pulmonary oedema, pneumonia, lung cancer).

Specialist investigations

. 1 Echocardiogram (valvular heart disease, systolic/diastolic dysfunction, structural heart disease).

. 2 A 24‐hour ECG (paroxysmal tachyarrhythmias, e.g. paroxysmal AF, SVTs) for symp- tomatic episodes that occur less than 24 hours apart, or suspected asymptomatic episodes.

. 3 Consider use of an event recorder if symptomatic episodes more than 24 hours apart and referral to cardiology [31].
MANAGEMENT

Sinus tachycardia

The management of sinus tachycardia depends entirely on the underlying cause. Indeed, since sinus tachycardia may represent a physiological response, attempts to slow the heart rate in this context may result in hypotension [33].

▪ If a specific cause is identified, management should focus on treatment of the underly- ing condition.

▪ In psychiatric inpatients, if agitation or panic is suspected but alternative diagnoses cannot initially be discounted (e.g. evolving infection), then increasing frequency of observations and clinical reviews may be indicated, even if only temporarily [8].

▪ The presence of red flag symptoms including persistent chest pain, syncope, hypoten- sion, pyrexia, tachypnoea or hypoxia may necessitate transfer to the accident and emergency department (A&E) for further investigation, higher levels of monitoring, and acute management [28].
Clozapine‐induced sinus tachycardia
Clozapine‐induced sinus tachycardia is very common in the early stages of treatment but is usually benign and may be dose related. For asymptomatic patients without signs of myocarditis (e.g. fever, chest pain), clozapine‐induced sinus tachycardia in the early stages of treatment can generally be managed conservatively with monitoring of clozapine levels, appropriate dose modification, and reassurance and daily observa- tions [34]. If symptomatic, then rate control with beta‐blockers such as bisoprolol (starting oral dose 1.25–2.5 mg once daily, titrate to response) may be used as first‐line medical therapy, although the evidence base for beta‐blockade in the context of clozapine use is limited [35], and may be associated with side effects such as fatigue, weight gain, postural hypotension and, in men, impotence. If beta‐blockers are

CHAPTER 1

contraindicated or not tolerated, ivabradine can be considered (5–7.5 mg, oral, twice daily) [36,37]. Seek advice from a cardiologist if first‐line treatment fails, as untreated tachycardia has been associated with cardiomyopathy [38]. Evidence is currently lack- ing to support the treatment of asymptomatic clozapine‐induced tachycardia, and therefore management should weigh the risks of rate‐control medication against the potential risk of long‐term tachycardia (i.e. cardiomyopathy). If pharmacological rate control is not pursued, ongoing monitoring of these patients is recommended, with consideration of annual echocardiograms to screen for cardiomyopathy, and where appropriate discussion with cardiology.

Atrial fibrillation

Guidelines published by the National Institute for Health and Care Excellence (NICE), the European Cardiac Society and the American College of Cardiology provide com- prehensive algorithmic approaches to the management of AF. A brief summary is pro- vided here, and readers are encouraged to consult the complete guidelines (accessed at https://pathways.nice.org.uk/pathways/atrial‐fibrillation, https://www.escardio.org/ Guidelines and https://www.acc.org/guidelines) [13]. General principles involve offer- ing symptomatic patients rate control (e.g. a beta‐blocker) and anticoagulation if the risk of thromboembolism is high (CHA2DS2VASc score ≥2; Table 1.2) but not out- weighed by the risk of major bleeding (calculated using the HAS‐BLED score; Table 1.3) [39,40]. Choice of anticoagulant should be made after a joint discussion of risks and benefits between doctor and patient. Options include warfarin or a direct oral

Table 1.2 CHA2DS2VASc score to assess risk of thromboembolic event in atrial fibrillation and need for anticoagu- lation [39].

Risk criteria Score

Congestive heart failure 1

Hypertension 1

Female sex 1

Age: 65–74 1

≥75

2 Diabetes 1 Stroke/TIA/thromboembolism 2 Vascular disease 1

Score = 0: anticoagulation not indicated
Score = 1: consider anticoagulation in men
Score ≥2: anticoagulate if it outweighs risk of bleeding

TIA, transient ischaemic attack.

Tachycardia 11

CHAPTER 1

12 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 1.3 HAS‐BLED score determines risk of major bleeding for people with atrial fibrillationa [40].

Risk criteria Score

Hypertension: uncontrolled, >160 mmHg systolic 1 Renal disease: dialysis, transplant, Cr >200 μmol/L 1 Liver disease: cirrhosis or bilirubin more than twice normal and AST/ALT/AP more than three times normal 1 Stroke history: prior major bleeding or predisposition to bleeding 1 Labile INR: unstable/high INRs, time in therapeutic range <60% 1 Age >65 years 1 Medication: aspirin, clopidogrel, NSAIDs 1 Alcohol: eight or more drinks per week 1

Score ≤0–1: low risk, consider anticoagulation Score = 2: moderate risk, consider anticoagulation Score ≥2: high risk, consider alternatives

a HAS‐BLED score does not relate directly to CHA2DS2VASc score and cannot be compared quantitatively.
ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; Cr, creatinine; INR, international normalised ratio; NSAIDs, non‐steroidal anti‐inflammatory drugs.

anticoagulant (e.g. apixaban, dabigatran, rivaroxaban, and edoxaban). Referral to car- diology is recommended if anticoagulation is contraindicated. Anticoagulation, rate control, and symptoms should be reviewed at least annually alongside an assessment of cardiovascular risk and potential complications such as heart failure. Referral to cardi- ology is indicated if pharmacological or electrical cardioversion is being considered.

Supraventricular tachycardia

Persistent new‐onset SVT requires immediate transfer to A&E due to risk of haemody- namic compromise [2]. Non‐pharmacological interventions such as the Valsalva manoeuvre or carotid sinus massage can be attempted and immediate transfer to hos- pital can be avoided for people with known SVT who revert to sinus rhythm.

Further acute management may involve intravenous adenosine administration, syn- chronised cardioversion or intravenous antiarrhythmics such as diltiazem or beta‐blockers [14]. Long‐term management should be directed by a cardiologist. Lifestyle advice on alcohol, caffeine, and illicit drug use as potential precipitants should be offered, as well as strict control of general cardiac risk factors (e.g. smoking cessation) [2].

Broad‐complex tachycardia

Any broad‐complex tachycardia should be managed as VT until proven otherwise [28,29,41]. For psychiatric inpatients or people in the community, this is likely to

CHAPTER 1

Tachycardia 13

Box 1.4 Driving and working advice for patients with arrhythmia in the UK
In the UK, if the arrhythmia has caused or is likely to cause incapacity (e.g. syncope or VT), the

patient should be advised to stop driving until:

▪ a satisfactory diagnosis is found

▪ the symptoms are controlled for at least 4 weeks (Group 1 entitlement: motor car or motorcycle)
or 3 months (Group 2 entitlement: lorries, buses or HGVs) [42].
Note that guidelines differ somewhat internationally [43]. Please refer to local guidelines if not UK‐based.
If the patient is working in potentially dangerous occupations (at height or with heavy machinery), they should be advised to:

▪ stop working until the condition is controlled

▪ notify their occupational health department if applicable [29].

require urgent transfer to A&E where further investigations and initial treatment can be enacted in a monitored environment, although immediate resuscitation will be required using the ABCDE approach if the patient loses cardiac output (see Chapter 70) [28,29,41]. Sinus tachycardia or AF in a patient with known bundle‐ branch block are the most likely exceptions to this rule. However, if in doubt, refer- ral to emergency services is recommended given the high mortality associated with VT [28,29,41].

Advice from the UK government regarding driving and working for patients with arrhythmia is shown in Box 1.4. We advise reviewing the guidance at source as it is updated monthly (https://www.gov.uk/guidance/cardiovascular‐disorders‐assessing‐ fitness‐to‐drive).

When to refer to a specialist

Urgent transfer to A&E is indicated for the following conditions [28,29,41].

▪ Any tachycardia with ‘red flag’ features:

▪ haemodynamic instability

▪ significant breathlessness

▪ chest pain

▪ syncope or near syncope

▪ family history of sudden cardiac death under 40

▪ symptoms precipitated by exercise.

▪ Suspected VT.

▪ Persistent SVT.

▪ AF with evidence of serious complication (e.g. stroke or heart failure).

▪ Evidence of concurrent illness that necessitates admission (e.g. sepsis).

CHAPTER 1

Box 1.5 Diagnostic summary for the tachycardic patient History

▪ Define cardiac symptoms

▪ Determine possible precipitants

▪ Assessment of palpitations (if paroxysmal)

▪ Screen for symptoms of systemic illness

▪ Past medical and psychiatric history: any cardiac disease, hypertension, diabetes, thyroid disease,
chronic lung disease, anxiety, panic

▪ Medication history

▪ Drug and alcohol history

▪ Family history of sudden cardiac death
Examination

▪ ABCDE assessment

▪ Cardiovascular examination

▪ Focused examination if systemic illness suspected
Investigations

▪ ECG

▪ Bloods

▪ Urine dipstick

▪ Consider echocardiogram or 24‐hour tape

14 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

What information to include in a referral to a specialist

Referral to a specialist should include any positive findings and salient negative findings from the history, examination and investigations (summarized in Box 1.5). Where pos- sible, include all relevant ECGs. In emergency situations, it may be possible to send scanned ECGs via secure email. Also include contact details of the patient’s mental healthcare team/support network, and if the appointment should be sent to anyone in addition to the patient. Finally, provide details of any reasonable adjustments needed for the patient (e.g. time or duration of appointment, carer/support worker in attendance).

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42. UK Driver and Vehicle Licensing Agency. Assessing Fitness To Drive: A Guide for Medical Professionals. https://www.gov.uk/government/
publications/assessing‐fitness‐to‐drive‐a‐guide‐for‐medical‐professionals

43. Banning AS, Ng GA. Driving and arrhythmia: a review of scientific basis for international guidelines. Eur Heart J 2012;34(3):236–244.

CHAPTER 1

Chapter 2

Bradycardia

Eleanor Croft, Nicholas Gall

Sinus bradycardia is defined as sinus rhythm at a rate of less than 60 beats per minute (bpm) [1] (Figure 2.1). However, sinus bradycardia is ‘normal’ for many young adults (particularly those who exercise regularly), some elderly patients [2], or during sleep (when rates may transiently drop to as low as 30 bpm). Therefore, in clinical practice it is usually more pragmatic to categorise the bradycardic patient as either symptomatic/ asymptomatic and appropriate/inappropriate for the circumstance, which will then guide appropriate assessment and management. Symptoms may be subtle, with some patients noticing only fatigue; however, other patients may present with light‐headed- ness or collapse (see Chapter 4) [3,4]. Although asymptomatic bradycardia may be a benign presentation reflecting normal physiology, it could signpost serious underlying pathology, and therefore a low threshold for further investigation or at least discussion with cardiology is recommended.

Figure 2.1 Sinus bradycardia, rate 50 bpm, as measured from lead II of the ECG.

18 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Common causes of bradycardia in the general and psychiatric population are docu- mented in Table 2.1. These can be divided into intrinsic disorders of the heart (e.g. ischaemic heart disease), systemic conditions (e.g. hypothyroidism), or extrinsic insults (e.g. medication) [5]. In the psychiatric patient population, bradycardia may be seen in the context of electrolyte imbalance or reduced body mass index (BMI) in those with eating disorders [6,7], neglect, alcohol dependence [8], as a consequence of psychiatric medication such as lithium [9] or chronic selective serotonin reuptake inhibitor (SSRI) treatment [10,11], or in association with physical health conditions that have neuropsy- chiatric sequelae (e.g. hypothyroidism) [12].

Table 2.1 Causes of bradycardia in the general and psychiatric population.

CHAPTER 2

General and psychiatric population Intrinsic disorders of the heart

Sinoatrial node dysfunction (‘sick sinus syndrome’): associated with age due to fibrotic/degenerative destruction of the sinus node and surrounding nerves [3–5]

Acute myocardial infarction (seen in up to 25% of patients) [3–5]

Genetic mutations associated with sinoatrial node dysfunction (e.g. HCN4 and SCN5A) [13]

Systemic conditions

Low BMI [5,6]

Hypothyroidism [4,5]

Hypothermia [4,5]

Infection, e.g. Lyme disease, Legionella, malaria [3–5]

Obstructive sleep apnoea (see Chapter 49) [14]

Exaggerated vagal activity (e.g. following coughing, micturition, or vomiting; see Chapter 4) [4,5]

Increased intracranial pressure following head injury [4,5]

Electrolyte disturbance [4,5]

Medication

Drugs that potentiate parasympathetic activity, e.g. acetylcholinesterase inhibitors [15]

Drugs that inhibit sympathetic activity, e.g. beta‐blockers, methyldopa [3–5]

Opioids and sedatives, e.g. benzodiazepines [4,16] Digoxin [3–5]
Calcium channel blockers (e.g. diltiazem) [3–5] Ivabradine [4]

Amiodarone [4]
BMI, body mass index; SSRI, selective serotonin reuptake inhibitor.

Special consideration in psychiatric population

N/A

Low BMI and electrolyte imbalance may be present in those with eating disorders [5,6] or alcohol dependence [7]

See Potassium derangement (Chapter 33), Acute kidney injury (Chapter 73), Chronic kidney disease
(Chapter 34), and Alcohol and physical health
(Chapter 24)

Lithium, both as a direct side effect or related to associated thyroid dysfunction [3,17]

SSRIs, e.g. fluoxetine [9,10], citalopram [18]

Individual case reports of antipsychotics, e.g. olanzapine [19]

Several drugs may cause bradycardia in overdose (see https://www.toxbase.org/)

Bradycardia 19

DIAGNOSIS

Bradycardia can represent a medical emergency. If there is evidence of haemodynamic compromise (e.g. low blood pressure, shortness of breath, or chest pain), then resuscitation and transfer to emergency services should be performed (see Chapter 70). In the absence of haemodynamic compromise, an approach to assessing a patient with bradycardia is described in the following sections and summarised in Box 2.1.

Box 2.1 Summary approach to assessment, investigation, and management of bradycardia History

▪ Symptoms typical of bradycardia, symptoms of ischaemic heart disease

▪ Risk factors for bradycardia from past medical history

▪ Psychiatric history (e.g. eating disorder)

▪ Medication history (medical and psychiatric)

▪ Family history of arrhythmia or sudden cardiac death

▪ Social history (alcohol consumption)
Examination

▪ If any concerns regarding haemodynamic stability, transfer to emergency services

▪ Check heart rate, blood pressure, temperature, oxygen saturation

▪ Calculate BMI

▪ Cardiac and respiratory examination for evidence of ischaemic heart disease and heart failure

▪ Consider thyroid examination if appropriate
Investigation

▪ ECG: confirm sinus bradycardia, rule out heart block

▪ Bloods: electrolytes, thyroid function, and if appropriate cardiac enzymes, BNP, drug levels (e.g.
lithium)
Management

▪ Asymptomatic patients may need no further investigation or treatment

▪ Address underlying reversible causes

▪ If possible, rationalise medication

▪ If medication rationalisation is not possible or there is intrinsic cardiac disease, patient may require
permanent pacing so refer to cardiology

History

Elicit symptoms

In most patients, sinus bradycardia will be asymptomatic. However, symptoms may emerge if bradycardia progresses to the extent of cerebral hypoperfusion, or in the con- text of comorbidity that may be exacerbated by the compromised cardiac output of

CHAPTER 2

20 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

bradycardia (e.g. in patients with ischaemic heart disease, bradycardia may result in angina). Specific symptoms that may be reported include:

▪ dizziness and light‐headedness (presyncope)

▪ syncope (see Chapter 4 for comprehensive syncope history)

▪ chest pain, shortness of breath

▪ fatigue

▪ reduced exercise tolerance.
Identify risk factors

▪ Advanced age.

▪ Ischaemic heart disease and associated risk factors (e.g. smoking, diabetes mellitus,
hypercholesterolaemia).

▪ Past medical history: thyroid disease (see Chapter 12), obstructive sleep apnoea (see
Chapter 49), recent infection.

▪ Previous cardiac surgery.

▪ Family history of cardiac disease, unexplained collapse, atrial fibrillation, or sudden
cardiac death.

▪ Eating disorder.

▪ Alcohol abuse.
Medication history
As described in Table 2.1. Note any recent medication changes, including dose changes.
Social history

▪ Alcohol use.

▪ Recreational drug use.
Examination
General inspection and observations

▪ Body habitus (calculate BMI) and nutritional status.

▪ Evidence of systemic disease (e.g. hypothyroidism).

▪ Heart rate, blood pressure, oxygen saturation, temperature.
Physical examination

▪ Cardiac and respiratory examination: examine for evidence of heart failure.

▪ If appropriate, consider a thyroid examination (see Chapter 12).

CHAPTER 2

Investigations

ECG

ECG is used to confirm the presence of sinus bradycardia. ECG can also be used to exclude other causes of bradyarrythmia such as atrioventricular block, which can be defined as follows.

▪ First‐degree heart block:

▪ defined as a PR interval >200 ms

▪ QRS can be narrow or wide depending on the site of the block.

▪ Second‐degree heart block:

▪ Mobitz type I (Wenckebach): progressively increasing PR interval until a P wave
does not conduct (the QRS is absent); the PR interval is then shorter again.

▪ Mobitz type II: there is no change to the PR interval, but some P waves are not conducted through to the ventricles (the QRS is absent); the QRS complex is usu-
ally broad in this circumstance.

▪ Third‐degree (complete heart block): P waves fail to conduct from the atria to the
ventricles and, as such, P waves and QRS complexes are not associated.
Blood tests

▪ Electrolytes (sodium, potassium, calcium, and magnesium).

▪ Cardiac enzymes (troponin) if there are ECG changes suggestive of ischaemia or if the
history is in keeping with a cardiac event.

▪ Brain natriuretic peptide (BNP) if there is evidence of heart failure.

▪ Thyroid function.

▪ If appropriate, consider checking lithium and digoxin levels.
Specialist investigations

▪ Echocardiography may be considered if there is suspicion of underlying structural cardiac disease.

▪ 24/48‐hour ECG monitoring may be considered if there is suspicion of paroxysmal bradyarrythmia (see Chapter 4).
MANAGEMENT AND WHEN TO REFER TO A SPECIALIST
Asymptomatic patients with sinus bradycardia do not necessarily require either intervention or treatment.
Addressing an underlying reversible cause may be sufficient to treat symptomatic bradycardia, for example electrolyte disturbance or hypothyroidism. Rationalisation of

Bradycardia 21

CHAPTER 2

22 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

medication may also be indicated. In the case of psychiatric medications such as lithium, a multidisciplinary approach involving input from psychiatry, cardiology, and of course the patient to determine the best therapeutic approach is advised (i.e. weighing up the risks and benefits of continuing lithium treatment).

In the case of intrinsic disease of the heart (e.g. sick sinus syndrome) or if a causative medication cannot be stopped, then a permanent pacemaker may be indicated, and referral to cardiology should be made.

References

1. Spodick DH, Raju P, Bishop RL, Rifkin RD. Operational definition of normal sinus heart rate. Am J Cardiol 1992;69(14):1245–1246.

2. Agruss NS, Rosin EY, Adolph RJ, Fowler NO. Significance of chronic sinus bradycardia in elderly patients. Circulation
1972;46(5):924–930.

3. Katritsis DG, Gersh BJ, Camm AJ. Bradyarrhythmias. In: Clinical Cardiology: Current Practice Guidelines. Oxford: Oxford University Press,
2013:537–557.

4. Olshansky B, Saha S, Gopinathannair R. Bradycardia. BMJ Best Practice. https://bestpractice.bmj.com/topics/en‐gb/832. Last updated:
January 2020.

5. Mangrum JM, DiMarco JP. The evaluation and management of bradycardia. N Engl J Med 2000;342(10):703–709.

6. Miller K, Grinspoon SK, Ciampa J, et al. Medical findings in outpatients with anorexia nervosa. Arch Intern Med 2005;165(5):561–566.

7. Misra M, Aggarwal A, Miller K, et al. Effects of anorexia nervosa on clinical, hematologic, biochemical and bone density parameters in
community‐dwelling adolescent girls. Pediatrics 2004;114(6):1574–1583.

8. Vamvakas S. Teschner M, Bahner U, Heidland A. Alcohol abuse: potential role in electrolyte disturbances and kidney diseases. Clin Nephrol
1998;49(4):205–213.

9. Rosenqvist M, Bergfeldt L, Aili H, Mathé AA. Sinus node dysfunction during long term lithium treatment. Br Heart J 1993;70:371–375.

10. Pacher P, Ungvari Z, Kecskemeti V, Furst S. Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants. Curr Med Chem 1998;5(5):381–390.

11. Enemark B. The importance of ECG monitoring in antidepressant treatment. Nordic J Psychiatry 1993;47:57–65.

12. Vaidya B, Pearce SH. Management of hypothyroidism in adults. BMJ 2008;337:a801.

13. Nof E, Glikson M, Antzelevitch C. Genetics and sinus node dysfunction. J Atr Fibrillation 2009;1(6):151.

14. Zwillich C, Devlin T, White D, et al. Bradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest 1982;69(6):1286–1292.

15. Hernandez RK, Farwell W, Cantor MD, Lawler EV. Cholinesterase inibitors and incidence of bradycardia in patients with dementia in the
Veterans Affairs New England Healthcare System. J Am Geriatr Soc 2009;57(11):1997–2003.

16. Chen A, Ashburn MA. Cardiac effects of opioid therapy. Pain Med 2015;16(Suppl 1):S27–S31.

17. Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab 2009;23(6):723–733.

18. Rasmussen S, Overø KF, Tanghø P. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin Psychopharmacol
1999;19(5):407–415.

19. Lee TW, Tsai SJ, Hwang JP. Severe cardiovascular side effects of olanzapine in an elderly patient: case report. Int J Psychiatry Med
2003;33(4):399–401.

CHAPTER 2

Chapter 3

QT Interval Prolongation

Guy Hindley, Nicholas Gall

Prolongation of the corrected QT interval (QTc) is an independent risk factor for torsade de points (TdP), a potentially fatal ventricular tachyarrhythmia, and sudden cardiac‐related death (SCD) (see Box 3.1). Definitions of QTc prolongation for men and women vary in the literature, often described as more than 440 ms for men and more than 470 ms for women [1]. However, the risk of TdP increases with increasing QTc, and the clearest evidence of an association is apparent when QTc is greater than 500 ms (for both men and women) [2].

QTc prolongation can be inherited or acquired. Inherited forms are rare (1 in 3000 to 1 in 5000) and predominantly caused by mutations in genes encoding sodium, potassium, and calcium channels present in the myocardium [5]. Acquired QTc prolon gation is particularly common among people with serious mental illness (SMI), with prevalence estimated as high as 8% among psychiatric inpatients [6].

Box 3.1 Understanding and measuring the QTc interval

▪ The QT interval measures the time between the start of ventricular depolarisation and the end of ventricular repolarisation.

▪ This is represented on an ECG by the beginning of the Q wave to the end of the T wave. QT intervals vary significantly between different ECG leads [3] and most normal reference ranges are based on measurements from lead II [4].

▪ Since QT varies with the length of the cardiac cycle, it is corrected for heart rate, most commonly using Bazett’s formula: QTc = QT/√RR, where QT is the interval in seconds and RR is cardiac cycle in seconds.

Q S

▪ Most ECG machines will calculate the QTc automatically. However, it may measure the RR or QT interval incorrectly, so it is important to check this.

▪ Bear in mind that Bazett’s formula may over‐correct if the patient is tachycardic and under‐correct if bradycardic.

▪ Alternatives to the Bazett formula exist for when patients present with tachycardia or bradycardia, e.g. the Fridericia, Hodges, and Framingham corrections. If there are uncertainties regarding QTc calculation, discuss with cardiology.

24 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Medication is the most frequently identified contributing factor to acquired QTc prolongation [7]. Table 3.1 provides an overview of the effects of commonly prescribed psychotropic medications on the QTc interval, while Box 3.2 lists some commonly encountered non‐psychotropic drugs associated with QTc prolongation. The associa tion between QTc prolongation and antipsychotics is particularly well characterised and their use is associated with increased rates of sudden cardiac death [8–11]. Risk is increased when given parenterally or in overdose [12,13]. Indeed, all antipsychotics given intravenously are considered to be high risk for TdP, and combinations of antipsychotics also confer increased risk. The effect of drugs on QTc interval is usually plasma level‐dependent [14], and therefore high doses and combination with cytochrome P450 inhibitors (e.g. fluvoxamine, fluoxetine, and paroxetine) may be causative [11].

For a comprehensive list of medications that increase the QTc and that is updated on a regular basis, please refer to crediblemeds.org or the CredibleMeds mobile phone application [12].

Despite the clear risk of certain medication regimens in prolonging the QTc interval, it is rare for medication to be the only identified risk factor in cases of TdP [15,16]. Furthermore, the association between risk of QTc prolongation and risk of TdP is unclear for several psychotropics. It is therefore important to consider other physiologi cal causes [7], summarised in Box 3.3 [17]. For example, in patients with anorexia nervosa, QTc alterations may be influenced by not only medication but also electrolyte abnormalities and bradycardia [18,19]. Cardiovascular disease (CVD) is also associated with QTc prolongation, and this should be considered in the psychiatric population, especially considering the increased rates of CVD in this group [20].

CHAPTER 3

Table 3.1 Effects of psychotropic medication on QTc [17].

Class

Antipsychotics [17]

No known effect

Brexpiprazole Cariprazine Lurasidone

Paroxetinea Fluvoxaminea Sertralinea

Carbamazepine Valproate Lamotrigine Benzodiazepines Gabapentin Pregabalin

Low effect

Aripiprazole Asenapine Clozapine Flupentixol Fluphenazine Loxapine Olanzapine Paliperidone Perphenazine Prochlorperazine Risperidone Sulpiride

Fluoxetinea Venlafaxine Bupropion Duloxetine Mirtazapine Amitriptyline Trazodone

Buprenorphine Lithium Promethazine Memantine Galantamine

Moderate effect

Amisulpride Chlorpromazine Haloperidol Iloperidone Levomepromazine Melperone Quetiapine Ziprasidone

Citalopram Escitalopram Clomipramine Trimipramine Nortriptyline Imipramine

Methadone (especially >100 mg/day)

High effect

Any intravenous antipsychotic Pimozide
Sertindole

Any drug or combination of drugs used in doses exceeding recommended maximum

Unknown effect

Pipotiazine Trifluoperazine Zuclopenthixol

Antidepressants [21–23]

Others [24–33]

a P450 inhibitor and so may prolong QTc if prescribed in combination with another QTc‐prolonging drug. High effect indicates significant average QTc prolongation at therapeutic doses (usually >20 ms). Moderate effect indicates moderate average QTc prolongation at therapeutic doses (10–20 ms).
Low effect indicates severe QTc prolongation only in overdose or small average increases (<10 ms).

No effect indicates no known QTc prolongation at therapeutic doses or in overdose.

Box 3.2 Common non‐psychotropic drugs associated with QTc prolongation [12] Cardiac

Amiodarone Dronedarone Flecainide Quinidine Sotalol

Antibiotics

Azithromycin Ciprofloxacin Clarithromycin Erythromycin

Other antimicrobials

Fluconazole Chloroquine

Other drugs

Domperidone
Ondansetron
Terfenadine
Ciclosporin
Tacrolimus
Tramadol
Bendroflumethiazide/loop diuretics (hypokalaemia)

26 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Box 3.3 Non‐pharmacological causes of acquired QTc prolongation: factors relevant to individuals with SMI are highlighted in italic [17,34,35]

Inherited

Long QT syndrome

Electrolyte abnormalities

Hypokalaemia Hypomagnesaemia Hypocalcaemia

Cardiac causes

Arrhythmia
Bradycardia
Ischaemic heart disease (left ventricular hypertrophy, heart failure) Hypertension

CHAPTER 3

QT Interval Prolongation 27

Metabolic/endocrine

Thyroid disease (hypothyroidism/hyperthyroidism) High body mass index
Diabetes
Hypercholesterolaemia

Other medical

Liver failure
Renal failure
Intracerebral haemorrhage

Psychiatric

Anorexia nervosa

Others

Extreme physical exertion Smoking
Extremes of age
Female gender

PRESCRIBING QTC‐PROLONGING MEDICATION

There is a lack of high‐quality evidence and consensus over the prescription and moni toring of QTc‐prolonging medication [17,36–38]. The list that follows describes six key considerations when prescribing [37]. The reader is also directed to the review by Brouillette and Nattel [39] which provides an algorithmic approach to minimising the risk of drug‐induced QTc prolongation.

. 1 Avoid using QTc‐prolonging medication where possible [38].

. 2 Avoid polypharmacy with other QTc‐prolonging drugs as the effect is likely
additive [15].

. 3 Use the lowest effective dose and avoid drugs that have significant metabolic interac
tions as QTc prolongation is likely dose‐dependent [14,17].

. 4 Assess cardiac risk (personal history, family history, cardiac symptoms, cardiovascu
lar risk factors) before commencing any drug with a possible risk of QTc prolonga
tion or arrhythmia (moderate or high risk in Table 3.1).

. 5 Consider ECG screening prior to commencing any QTc‐prolonging medication and
repeat once steady state has been achieved or in the presence of cardiovascular risk factors [37]. The National Institute for Health and Care Excellence (NICE) recom mendations for ECG screening prior to initiating antipsychotic therapy are summa rised in Box 3.4 [40].

. 6 ConsiderconsultingacardiologistbeforecommencinganyQTc‐prolongingdruginthe presence of cardiovascular risk factors or symptoms suggestive of arrhythmia [40].

CHAPTER 3

Box 3.4 NICE guidelines for ECG screening during antipsychotic treatment [40]
A screening ECG should be offered to patients before starting any antipsychotic medication

known to cause QTc prolongation if:

▪ specified in the drug’s summary of product characteristics

▪ a specific cardiovascular risk factor is identified during history or physical examination (e.g.
hypertension)

▪ personal history of cardiovascular disease

▪ patient is an inpatient/on admission.
Consider repeating the ECG once the therapeutic dose has been reached and yearly thereafter.

28 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES

The RISQ‐PATH risk score for QTc prolongation provides a system for predicting QTc prolongation, and can be used to guide the intensity of QTc monitoring that should be offered patients [41].

QTc prolongation should be suspected in any individual presenting with symptoms sug gestive of arrhythmia (e.g. palpitations or unexplained collapse), particularly if taking anti psychotics or any other QTc‐prolonging medication. The diagnosis may also be made on a screening ECG or as an incidental finding in the absence of any preceding symptoms [42].

A detailed clinical assessment is still essential following diagnosis in order to:

▪ screen for symptoms suggestive of arrhythmia

▪ identify pharmacological and physiological causes

▪ elicit other cardiovascular risk factors for TdP or sudden cardiac death.
History

. 1 Relevant cardiac symptoms, including palpitations, syncope, dizziness/light‐ headedness (to be distinguished from vertigo), chest pain, shortness of breath.

. 2 History suggestive of electrolyte disturbance, such as diarrhoea, vomiting, malnutri tion, and eating disorder.

. 3 Cardiovascular risk factors, including personal history and family history of CVD, smoking, obesity, diabetes mellitus, hypertension, and hypercholesterolaemia.

. 4 History of significant cardiac event, such as syncope, ventricular tachyarrhythmia, TdP, cardiac arrest, unexplained falls/car crashes.

. 5 Other relevant past medical history (see Table 3.1): a liver failure
b renal failure
c hyperthyroidism/hypothyroidism.

. 6 Detaileddrughistory(seeBox3.2),includingpossibledeliberateoraccidentaloverdose.

. 7 Family history of sudden cardiac death/unexplained death especially under 40 or long
QT syndrome.

. 8 Social history: smoking history, alcohol and substance use.

CHAPTER 3

Examination

. 1 Full cardiovascular examination paying special attention to the following.

. a Inspection: high or low BMI, peripheral oedema, raised jugular venous pressure
(heart failure).

. b Palpation: pulse (regularity plus rate).

. c Auscultation: murmurs or added sounds (heart failure/left ventricular hypertro
phy), pulmonary oedema.

. d Palpation for pedal/sacral oedema (heart failure, renal failure).

. 2 Lying and standing blood pressure if history of presyncope/syncope.

Investigations

. 1 Bloods:

. a full blood count

. b urea and electrolytes (renal failure, hypokalaemia, hypomagnesaemia, hypocalcaemia)

. c liver function tests (liver failure)

. d lipid profile (hypercholesterolaemia)

. e thyroid function tests (hyperthyroidism/hypothyroidism)

. f antipsychotic plasma levels (toxicity)

. g brain natriuretic peptide (BNP, if history suggestive of heart failure).

. 2 ECG [43]

. a Ischaemia: ST depression/elevation, T‐wave inversion, pathological Q waves.

. b Left ventricular hypertrophy (LVH): left axis deviation, increased amplitude R
waves in V4–V6 plus deep S waves in V1–V3. If LVH is suspected, refer patient for
transthoracic echocardiogram.

. c Hypokalaemia: PR prolongation, T‐wave flattening and inversion, ST depression,
U waves.

. d QTc interval (see Box 3.1).

. 3 Consider requesting an echocardiogram if history or examination is suggestive of heart failure, ischaemia or structural heart disease (following consultation with cardiology).

. 4 Consider 24‐hour ECG monitoring if history suggestive of arrhythmia (consult cardiologist).
MANAGEMENT

High‐quality evidence for the management of acquired QTc prolongation is lacking [37,44]. A history of significant cardiac events, such as syncope or tachyarrhythmias or severe prolongation greater than 500 ms, may necessitate emergency medical attention and management should be led by a cardiologist [17,37]. Table 3.2 describes the management of acquired QTc prolongation, while Box 3.5 summarises a general approach to QTc prolongation. For the management of tachyarrhythmias please refer to Chapter 1.

QT Interval Prolongation 29

CHAPTER 3

Box 3.5 Approach to QTc prolongation Prescribing, screening, and monitoring

▪ Avoid QTc prolonging medication if possible

▪ Use lowest effective dose

▪ Avoid polypharmacy

▪ Assess cardiovascular risk and consider need for screening ECG

▪ Consult cardiologist if in doubt
Assessment

▪ Screen for symptoms of arrhythmia

▪ Identify pharmacological and non‐pharmacological causes

▪ Assess cardiovascular risk

▪ Bloods plus ECG (with or without 24‐hour tape/echocardiogram)
Management

▪ Consider stopping or reducing dose of offending drugs

▪ Address non‐pharmacological risk factors

▪ Monitor proactively

▪ Refer to cardiologist if:

▪ >500 ms or >60 ms increase

▪ associated with history suggestive of arrhythmia

▪ prior cardiac event

▪ unable to stop or reduce medication

30 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 3.2 The management of acquired QTc prolongation [17,37,44].

QTc interval

440–500 ms (men) or 470–500 ms (women)

>500 ms or increase of >60 ms

Action

Consider dose reduction of presumed causative medication, or switch to alternative treatment with reduced risk

Address non‐pharmacological risk factors Repeat ECG in 1–2 weeks

Stop QTc‐prolonging medication and switch to lower‐risk alternative
(see Table 3.1)

Address non‐pharmacological risk factors Repeat ECG in 1–2 weeks or earlier

Discuss with cardiologist/senior medic

Immediately if associated with unexplained cardiac symptoms or clinically unable to reduce/stop QTc‐prolonging drug

Immediately

Initial management

Rationalising medication

1 Anydecisionregardingachangeinmedicationneedstoweighuptheriskofcontinuing treatment (i.e. the risk of QTc prolongation) against the risk of medication change (i.e. the risk of deterioration in mental state).

CHAPTER 3

QT Interval Prolongation 31

2 Where possible, stop or reduce the dose of the QTc‐prolonging medication, particu larly when QTc is greater than 500 ms.

3 Consider changing to treatment with lower risk of QTc prolongation. 4 When in doubt, discussion with cardiology is recommended [37].

Addressing non‐pharmacological risk factors (likely to be performed by medical practitioners rather than psychiatrists)

. 1 Replace electrolytes [37].

. 2 Optimise management of cardiovascular risk (hypertension, hypercholesterolaemia,
hyperlipidaemia, diabetes, smoking cessation, lifestyle advice) [37].

. 3 Optimise management of other relevant medical conditions (e.g. thyroid disease and
heart failure) [44].

Monitoring QTc interval

1 Repeat ECG in one to two weeks of any significant dose change [37]. 2 Monitoring every six months to one year thereafter [17,45].

When to refer to a specialist

Immediate referral to a cardiologist is indicated if:

▪ QTc >500 ms or change in QTc >60 ms since commencing QTc‐prolonging drug

▪ new unexplained cardiac symptoms plus QTc >440 ms (men) or QTc >470 ms (women)

▪ history suggestive of arrhythmia (see Chapters 1, 2 and 70).
Consider discussion with cardiology if planning to initiate QTc‐prolonging medication in a patient with:

▪ cardiovascular disease

▪ other significant non‐pharmacological risk factors

▪ already prescribed a QTc‐prolonging medication.
Information to include in a referral to cardiology
A comprehensive handover to a specialist should include, where possible, the history, examination, and investigation findings described in the preceding sections. In the scenario where a psychiatric medication is prescribed that may be responsible for QTc prolongation, explain the rationale behind its prescription, and the potential risks of stopping its prescription (this may aid a risk–benefit decision regarding continuation of a given treatment). Also include the contact details of the patient’s mental health care team/support network and clarify if the appointment should be sent to anyone in addition to the patient. Finally, document any reasonable adjustments needed for the patient, for example time or duration of appointment, carer/support worker in attendance.

CHAPTER 3

32 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Further management your patient may be offered by cardiology

Treatment of inherited QTc prolongation and high‐risk cases of acquired QTc prolon gation should be initiated and monitored by a cardiologist.

. 1 Persistently prolonged acquired QTc may indicate the need for genetic testing and family screening [46].

. 2 Beta‐blockers may be considered in severe or refractory cases or if associated with significant cardiac events, although they do not shorten the QTc interval and ran domised controlled trials are lacking. Meta‐analysis of observational studies has demonstrated a mortality benefit for beta‐blockade in congenital long QT syndrome [47]. However, they may be not be effective for acquired QTc prolongation and may in fact increase risk [48].

. 3 Implantable cardioverter‐defibrillators (ICDs) may be considered in patients who [49]:
a remain symptomatic despite beta‐blocker therapy b have a history of cardiac arrest
c present with QTc >550 msec
d are unable to be prescribed beta blockers.

. 4 Left cervicothoracic sympathectomy is a procedure which denervates the heart from its sympathetic input. This may be considered if an ICD is contraindicated or if an individual requires multiple ICD shocks [50].

References

1. Botstein P. Is QT interval prolongation harmful? A regulatory perspective. Am J Cardiol 1993;72:50B–52B.

2. Bednar MM, Harrigan EP, Anziano RJ, et al. The QT interval. Prog Cardiovasc Dis 2001;43(5 Suppl 1):1–45.

3. Cowan JC, Yusoff K, Moore M, et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988;61(1):83–87.

4. Lepeschkin E, Surawicz B. The measurement of the QT interval of the electrocardiogram. Circulation 1952;6(3):378–388.

5. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51(24):2291–2300.

6. Reilly JG, Ayis SA, Ferrier IN, et al. QTc‐interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet
2000;355(9209):1048–1052.

7. Van Noord C, Eijgelsheim M, Stricker BHC. Drug‐ and non‐drug‐associated QT interval prolongation. Br J Clin Pharmacol 2010;
70(1):16–23.

8. Jones ME, Campbell G, Patel D, et al. Risk of mortality (including sudden cardiac death) and major cardiovascular events in users of olan
zapine and other antipsychotics: a study with the General Practice Research Database. Cardiovasc Psychiatry Neurol 2013;2013:647476.

9. Liperoti R, Gambassi G, Lapane KL, et al. Conventional and atypical antipsychotics and the risk of hospitalization for ventricular arrhyth
mias or cardiac arrest. Arch Intern Med 2005;165(6):696–701.

10. Hennessy S, Bilker WB, Knauss JS, et al. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using
administrative data. BMJ 2002;325(7372):1070.

11. Barbui C, Bighelli I, Carrà G, et al. Antipsychotic dose mediates the association between polypharmacy and corrected QT interval. PLoS One
2016;11(2):e0148212.

12. crediblemeds.org. https://www.crediblemeds.org (accessed 30 January 2019).

13. Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics
2013;54(1):1–13.

14. Gupta A, Lawrence AT, Krishnan K, et al. Current concepts in the mechanisms and management of drug‐induced QT prolongation and tor
sade de pointes. Am Heart J 2007;153(6):891–899.

15. Hasnain M, Vieweg WVR. QTc interval prolongation and torsade de pointes associated with second‐generation antipsychotics and antide
pressants: a comprehensive review. CNS Drugs 2014;28(10):887–920.

16. Zeltser D, Justo D, Halkin A, et al. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine
(Baltimore) 2003;82(4):282–290.

17. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry, 13th edn. Chichester: Wiley Blackwell, 2018.

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QT Interval Prolongation 33

18. Westmoreland P, Krantz MJ, Mehler PS. Medical complications of anorexia nervosa and bulimia. Am J Med 2016;129(1):30–37.

19. Isner JM, Roberts W, Heymsfield S, Yager J. Anorexia nervosa and sudden death. Ann Intern Med 1985;102(1):49–52.

20. De Hert M, Correll CU, Bobes J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and dis
parities in health care. World Psychiatry 2011;10(1):52–77.

21. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother 2013;47(10):1330–1341.

22. Jasiak NM, Bostwick JR. Risk of QT/QTc prolongation among newer non‐SSRI antidepressants. Ann Pharmacother
2014;48(12):1620–1628.

23. van Noord C, Straus SMJM, Sturkenboom MCJM, et al. Psychotropic drugs associated with corrected QT interval prolongation. J Clin
Psychopharmacol 2009;29(1):9–15.

24. Wang D, Wu Y, Wang A, et al. Electrocardiogram changes of donepezil administration in elderly patients with ischemic heart disease. Cardiol
Res Pract 2018;2018:9141320.

25. Wedam EF, Bigelow GE, Johnson RE, et al. QT‐interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch
Intern Med 2007;167(22):2469–2475.

26. Mujtaba S, Romero J, Taub CC. Methadone, QTc prolongation and torsades de pointes: current concepts, management and a hidden twist
in the tale? J Cardiovasc Dis Res 2013;4(4):229–235.

27. Mehta N, Vannozzi R. Lithium‐induced electrocardiographic changes: a complete review. Clin Cardiol 2017;40(12):1363–1367.

28. Owczuk R, Twardowski P, Dylczyk‐Sommer A, et al. Influence of promethazine on cardiac repolarisation: a double‐blind, midazolam‐
controlled study. Anaesthesia 2009;64(6):609–614.

29. Saetre E, Abdelnoor M, Amlie JP, et al. Cardiac function and antiepileptic drug treatment in the elderly: a comparison between lamotrigine
and sustained‐release carbamazepine. Epilepsia 2009;50(8):1841–1849.

30. Venkatraman N, O’Neil D, Hall AP. Life‐threatening overdose with lamotrigine, citalopram, and chlorpheniramine. J Postgrad Med
2008;54(4):316–317.

31. Apfelbaum JD, Caravati EM, Kerns II WP, et al. Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med 1995;25(5):631–635.

32. Kurt E, Emul M, Ozbulut O, et al. Is valproate promising in cardiac fatal arrhythmias? Comparison of P‐ and Q‐wave dispersion in bipolar
affective patients on valproate or lithium–valproate maintenance therapy with healthy controls. J Psychopharmacol 2008;23(3):328–333.

33. Acciavatti T, Martinotti G, Corbo M, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T‐peak to T‐end
interval and QT dispersion. J Psychopharmacol 2017;31(4):453–460.

34. Vandael E, Vandenberk B, Vandenberghe J, et al. Risk factors for QTc‐prolongation: systematic review of the evidence. Int J Clin Pharm
2017;39(1):16–25.

35. Popescu D, Laza C, Mergeani A, et al. Lead electrocardiogram changes after supratentorial intracerebral hemorrhage. Maedica (Buchar)
2012;7(4):290–294.

36. Shah AA, Aftab A, Coverdale J. QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J Psychiatr Pract
2014;20(3):196–206.

37. Fanoe S, Kristensen D, Fink‐Jensen A, et al. Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management.
Eur Heart J 2014;35(20):1306–1315.

38. Zolezzi M, Cheung L. A literature‐based algorithm for the assessment, management, and monitoring of drug‐induced QTc prolongation in
the psychiatric population. Neuropsychiatr Dis Treat 2018;15:105–114.

39. Brouillette J, Nattel S. A practical approach to avoiding cardiovascular adverse effects of psychoactive medications. Can J Cardiol
2017;33(12):1577–1586.

40. National Institute for Health and Care Excellence. Psychosis and Schizophrenia in Adults: Prevention and Management. Clinical Guideline
CG178. London: NICE, 2014. Available at https://www.nice.org.uk/guidance/cg178

41. Vandael E, Vandenberk B, Vandenberghe J, et al. Development of a risk score for QTc‐prolongation: the RISQ‐PATH study. Int J Clin Pharm
2017;39(2):424–432.

42. Mahmud R, Gray A, Nabeebaccus A, Whyte MB. Incidence and outcomes of long QTc in acute medical admissions. Int J Clin Pract
2018;72(11):e13250.

43. Life in the Fastlane. https://litfl.com/ (accessed 2 February 2019).

44. Aktas MK, Daubert JP. Long QT syndrome. BMJ Best Practice. https://bestpractice.bmj.com/topics/en‐gb/829. Lasr updated: January 2018.

45. Krantz MJ. QTc interval screening in methadone treatment. Ann Intern Med 2009;150(6):387–395.

46. Giudicessi JR, Wilde AAM, Ackerman MJ. The genetic architecture of long QT syndrome: a critical reappraisal. Trends Cardiovasc Med
2018;28(7):453–464.

47. Ahn J, Kim HJ, Choi J‐I, et al. Effectiveness of beta‐blockers depending on the genotype of congenital long‐QT syndrome: a meta‐analysis.
PLoS One 2017;12(10):e0185680.

48. Barra S, Agarwal S, Begley D, Providência R. Post‐acute management of the acquired long QT syndrome. Postgrad Med J
2014;90(1064):348–358.

49. Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long‐QT syndrome patients who receive an implantable cardioverter‐defibrillator and
what happens to them? Data from the European Long‐QT Syndrome Implantable Cardioverter‐Defibrillator (LQTS ICD) Registry.
Circulation 2010;122(13):1272–1282.

50. Schneider HE, Steinmetz M, Krause U, et al. Left cardiac sympathetic denervation for the management of life‐threatening ventricular tachyar
rhythmias in young patients with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome. Clin Res Cardiol 2013;102(1):33–42.

CHAPTER 3

Chapter 4

Syncope

Luke Vano, Nicholas Gall

Syncope is defined as a transient loss of consciousness (TLOC) secondary to reduction in blood flow to the brain (i.e. cerbral hypoperfusion) [1]. It is rapid in onset, rarely lasts longer than two minutes, and recovery is spontaneous. Longer periods of uncon- sciousness are unlikely to be secondary to syncope or syncope alone (e.g. syncope resulting in head injury may result in a longer period of loss of consciousness).

Syncope is one of multiple causes of TLOC that also include seizure, intoxication, metabolic disturbance (e.g. hypoglycaemia or adrenal insufficiency*), and trauma [2]. As such, after consciousness is regained, a clinician must first differentiate syncope from other precipitants of TLOC, before then determining cause of syncope, which are similarly numerous.

CAUSES OF SYNCOPE

■ Cardiac syncope describes loss of consciousness secondary to reduced cardiac output. Common causes include arrhythmia (see Chapters 1–3 and 70) and structural heart disease (e.g. aortic stenosis and hypertrophic cardiomyopathy).

■ Reflex/neurally mediated syncope is the result of altered autonomic regulation of postural tone resulting in inappropriate bradycardia and/or vasodilation. Types of reflex syncope include vasovagal syncope, carotid sinus syncope, and micturition syncope.

* Patients with adrenal insufficiency (Addison’s disease) present with non‐specific symptoms including pos- tural hypotension and syncope, abdominal pain, nausea, vomiting, fatigue, weakness, and confusion. Adrenal insufficiency is a medical emergency, and as such the patient should be reviewed in the accident and emer- gency department.

36 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

■ Orthostatic syncope is caused by reduced cerebral perfusion on standing (see Chapter 6). Common causes include prescribed medication, volume loss, autonomic failure, and heart disease.

SYNCOPE AND SERIOUS MENTAL ILLNESS

Compared with the general population, people with mental illness are at higher risk of syncopal episodes [3,4]. Orthostatic hypotension can be a consequence of some psychi- atric treatment (see Chapter 6) [5] and may follow intravascular volume depletion in anorexia nervosa [6]. Some psychotropic medications prolong the QTc interval and predispose to torsades de pointes (see Chapter 4), thus increasing risk of cardiac syn- cope [7]. Those with a diagnosis of somatisation disorder are at increased risk of vas- ovagal syncope [8].

Psychogenic pseudosyncope (PPS) describes the appearance of TLOC in the absence of true loss of consciousness [9]. PPS is often secondary to conversion disorder, hypoth- esised to represent the physical manifestation of internal stressors [9]. Risk factors for PPS include being young, female, and having a comorbid psychiatric diagnosis [10,11]. People with conversion disorder are also more likely to experience psychogenic non‐ epileptic seizures (see Chapter 53) [12]. Cataplexy is a rare cause of TLOC, in which patients briefly lose voluntary muscle control and have associated rapid eye movement sleep. This typically occurs when people with narcolepsy experience a strong emotional reaction. There is some evidence of a link between narcolepsy–cataplexy and schizo- phrenia [13].

DIAGNOSTIC PRINCIPLES

The following sections are based on the UK National Institute for Health and Care Excellence (NICE) guidelines for assessing TLOC and syncope [14]. This guidance assumes recovery from the episode of unconsciousness. In the acute setting, the patient should be managed as per the ABCDE approach (see Chapter 78 on an approach to the unconscious patient) and, based on clinical judgement, a decision should be made regarding whether the patient requires immediate transfer to emergency services.

History

1 Ask the patient about the circumstances surrounding loss of consciousness. Ideally questions should also be directed at anyone who witnessed the event.

. a What was the patient doing at the time? Did the patient fall to the floor and/or
sustain injuries? Syncope during exercise suggests a cardiac arrhythmia (whereas
syncope after exercise is more likely to be vasovagal).

. b Was the event in association with a change in posture (e.g. on standing)?

. c Was there a clear provoking factor (e.g. pain)?

CHAPTER 4

Syncope 37

. d Did the patient experience any presyncopal symptoms (e.g. light‐headedness, pal- pitations, sweating)?

. e What did the patient look like during the episode (e.g. change in skin colour)?

. f Were there any associated symptoms that may indicate cardiac pathology (e.g.
chest pain)?

. g Were there any associated symptoms that might indicate seizure activity (e.g. limb‐
jerking during the episode, tongue biting)?

. h Was recovery rapid or was there a period of confusion after the event?

. i Was there any history of recent bleeding (e.g. melaena)? (See Chapter 20.)

. 2 Past medical history:
a previous syncopal episodes, including number and frequency
b cardiac history, if pacemaker/implantable cardioverter defibrillator in situ.

. 3 Medication history: any recent changes to medication or dose.

. 4 Family history, including history of cardiac disease, sudden cardiac death, or unex-
plained sudden death of a family member aged <40 years.

. 5 Social history, recording smoking status, alcohol and substance use.

Examination

. 1 Vital signs, including heart rate, blood pressure (lying and standing; see Chapter 6), and oxygen saturations.

. 2 General inspection: pallor (anaemia, blood loss), decreased skin turgor (plasma vol- ume depletion), presence of pacemaker.

. 3 Cardiac examination: pulse rate and rhythm, evidence of heart failure, murmurs.

. 4 Neurological examination: focal neurology that may suggest vascular event (see
Chapter 82).

. 5 Gastrointestinal examination: for evidence of an intra‐abdominal bleed (rigid tender
abdomen, abnormal rectal examination).

Investigations

. 1 ECG is needed in all patients. Examine for:

. a bradycardia

. b ventricular arrhythmia

. c prolonged QTc

. d Brugada sign (coved ST elevation >2 mm in more than one of V1–V3 followed by negative T wave)

. e ventricular pre‐excitation of Wolff–Parkinson–White syndrome (short PR interval and delta wave)

. f T‐wave inversion (ischaemia or cardiomyopathy)

. g pathological Q waves (myocardial infarction)

. h atrial arrythmia

. i paced rhythm.

. 2 Capillary glucose (hypoglycaemia; see Chapter 74).

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The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Further investigations may be indicated if other specific causes of TLOC are suspected, such as the following.

. a Full blood count to assess for anaemia.

. b Urea and electrolytes (including magnesium and calcium) to assess for dehydration or
electrolyte imbalance which may accompany metabolic disturbance (e.g. hyponatraemia
and hyperkalaemia of Addison’s disease) or cause cardiac arrythmia.

. c Creatine kinase (if patient obtunded).

. d Troponin if there are concerns regarding an acute coronary event (see Chapter 69).

. e EEG should not be ordered unless epilepsy is suspected (i.e. based on a high pretest
probability) and following discussion with neurology.

Other investigations may be requested by specialist care (e.g. cardiology).

. a If structural heart disease is suspected (e.g. hypertrophic obstructive myopathy),
perform echocardiogram.

. b Exercise testing, if the syncope is exercise‐induced.

. c If Brugada syndrome is suspected, an ajmaline study is performed, coordinated by
an inherited cardiac conditions clinic.

. d Tilt test if recurrent vasovagal syncope is suspected with associated detrimental
impact on quality of life and/or representing high risk of injury (assessing if syn-
cope is associated with severe cardioinhibitory response, usually asystole).

. e If carotid sinus syncope is suspected, or in unexplained syncope in patients aged >60, perform carotid sinus massage (only in a controlled environment, with ECG recording, with resuscitation equipment to hand as long as there is no carotid
stenosis >50% or recent stroke/transient ischaemic attack).

. f Ambulatory ECG if suspected cardiac arrhythmia (or if syncope unexplained):
i Holter monitoring if episodes occurring several times a week
ii external event recording if episodes occurring every one to two weeks
iii implantable event recorder if episodes occurring less than every two weeks.

DIAGNOSIS AND MANAGEMENT

CHAPTER 4

Where diagnosis is unclear, a referral to a specialist syncope clinic may be indicated, or where such services do not exist, cardiology. A diagnosis of uncomplicated vasovagal syncope (a faint) may be made if there are no features of an alternative diagnosis, and the events are associated with the ‘3 Ps’: posture (prolonged standing, prevented by sitting down), provoking factors (e.g. pain), and prodromal symptoms (presyncope: sweating, light‐headedness). Similarly, a diagnosis of situational syncope may be made if there are no features of an alternative diagnosis and there is a clear situational precipitant (e.g. micturition). For both uncomplicated and situational syncope, if there are no safety concerns then no further immediate management is required. Patients should be provided with information regarding their diagnosis and strategies to avoid syncopal episodes (e.g. to sit/lie down when presyncopal symptoms emerge).

Orthostatic syncope has a typical history and on testing of lying/standing blood pressure, postural hypotension should be observed. Postural hypotension has several potential causes (see Chapter 6), and medication represents a major differential. In such patients a medication review and where appropriate rationalisation may be required.

Syncope 39

Any suspicion of cardiac syncope should prompt referral to cardiology, urgently in the case of syncope associated with exercise. Suspect seizures if any of the following features are present: tongue biting, unusual posturing, prolonged rhythmic limb jerking (this can briefly accompany syncopal episodes), loss of bowel or bladder control, pos- tictal phase, prodromal déjà vu or jamais vu [14]. These patients will require a referral to neurology (see Chapter 53).

Patients should be provided with advice about driving in the context of syncopal episodes. Advise all people who are waiting for a specialist assessment that they must not drive. Those from the UK are directed to the Driver and Vehicle Licensing Agency (DVLA) website for the latest guidance [15].

References

1. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39(21):1883–1948.

2. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med 2002;347(12):878–885.

3. Kouakam C, Lacroix D, Klug D, et al. Prevalence and prognostic significance of psychiatric disorders in patients evaluated for recurrent
unexplained syncope. Am J Cardiol 2002;89(5):530–535.

4. Kapoor WN, Fortunato M, Hanusa BH, Schulberg HC. Psychiatric Illnesses in patients with syncope. Am J Med 1995;99(5):505–512.

5. Gugger JJ. Antipsychotic pharmacotherapy and orthostatic hypotension: identification and management. CNS Drugs 2011;25(8):659–671.

6. Sachs KV, Harnke B, Mehler PS, Krantz MJ. Cardiovascular complications of anorexia nervosa: a systematic review. Int J Eat Disord
2016;49(3):238–248.

7. Akhondzadeh S, Mojtahedzadeh V, Mirsepassi GR, et al. Diazoxide in the treatment of schizophrenia: novel application of potassium channel
openers in the treatment of schizophrenia. J Clin Pharm Ther 2002;27(6):453–459.

8. Alhuzaimi A, Aljohar A, Alhadi AN, et al. Psychiatric traits in patients with vasovagal and unexplained syncope. Int J Gen Med
2018;11:99–104.

9. Raj V, Rowe AA, Fleisch SB, et al. Psychogenic pseudosyncope: diagnosis and management. Auton Neurosci 2014;184:66–72.

10. Iglesias JF, Graf D, Forclaz A, et al. Stepwise evaluation of unexplained syncope in a large ambulatory population. Pacing Clin Electrophysiol 2009;32(Suppl 1):S202–S206.

11. Wiener Z, Shapiro NI, Chiu DT, Grossman SA. The prevalence of psychiatric disease in emergency department patients with unexplained syncope. Intern Emerg Med 2013;8(5):427–430.

12. Gelauff J, Stone J, Edwards M, Carson A. The prognosis of functional (psychogenic) motor symptoms: a systematic review. J Neurol Neurosurg Psychiatry 2014;85(2):220–226.

13. Sansa G, Gavalda A, Gaig C, et al. Exploring the presence of narcolepsy in patients with schizophrenia. BMC Psychiatry 2016;16:177.

14. Alphs L, Bossie CA, Fu DJ, et al. Onset and persistence of efficacy by symptom domain with long‐acting injectable paliperidone palmitate in
patients with schizophrenia. Expert Opin Pharmacother 2014;15(7):1029–1042.

15. Driver and Vehicle Licensing Agency (DVLA). Neurological disorders: assessing fitness to drive. https://www.gov.uk/guidance/neurological‐
disorders‐assessing‐fitness‐to‐drive. Last updated: 4 March 2020.

CHAPTER 4

Chapter 5

Hypertension

Luke Vano, Toby Pillinger, J. Kennedy Cruickshank

Previous American and current European guidelines define hypertension as a systolic blood pressure (BP) above 140 mmHg or a diastolic pressure exceeding 90 mmHg [1,2], while recent American guidelines are more aggressive, defining hypertension as systolic BP above 130 mmHg and diastolic BP above 80 mmHg [3]. Irrespective of defi- nitions, the higher a patient’s BP, the greater the risk of hypertensive‐associated compli- cations, including [4,5] myocardial infarction, stroke, left ventricular hypertrophy (LVH), heart failure, chronic kidney disease, and cognitive decline [6,7]. Moreover, all‐cause mortality increases with worsening BP control [2]. Globally, hypertension has a prevalence of over 25% [2,5]. Patients with serious mental illness (SMI) are 12% more likely to be hypertensive compared with the general population [8–11], and are more likely to have hypertension untreated [12]. (Readers are referred to Chapter 71 on hypertensive crisis if the patient’s BP is ≥180/≥110 mmHg.)

Essential hypertension describes raised BP when no direct cause can be identified, which occurs in approximately 90% of cases [13]. Risk factors for essential hyperten- sion are described in Box 5.1 [13]. Secondary hypertension describes increased BP in the setting of a causative comorbidity or drug (Box 5.2) [14]. Many of the risks for both primary and secondary hypertension are shared between the general population and those with SMI. However, lifestyle factors such as reduced levels of physical activity, poor diet, and increased rates of metabolic syndrome and smoking increase the likelihood of essential hypertension in people with SMI [11,15–17]. Also, certain antidepressants and catecholaminergic medications (see Box 5.2) have been shown to worsen hypertension [18–22], thereby increasing the risk of secondary hypertension in this group.

Box 5.1 Common risk factors for essential hypertension [1–7,13] Past medical history

▪ Diabetes mellitus

▪ Obstructive sleep apnoea

▪ Dyslipidaemia
Modifiable (lifestyle) risk factors

▪ Obesity

▪ Aerobic exercise less than three times a week

▪ Alcohol

▪ Salt intake over 5 g daily [2]

▪ Low fruit and vegetable intake

▪ Stimulants (e.g. caffeine, nicotine)
Non‐modifiable risk factors

▪ Age

▪ Family history of hypertension or cardiovascular disease

▪ Black ethnicity

42 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Box 5.2 Causes of secondary hypertension in the general and psychiatric patient population [1–7,13,18–23]

Medication

▪ Non‐steroidal anti‐inflammatory drugs

▪ Corticosteroids

▪ Anabolic steroids

▪ Ciclosporin and tacrolimus

▪ Erythropoietin

▪ Oral contraceptives, particularly oestrogen‐containing agents

▪ Decongestants (e.g. phenylephrine)

▪ Tricyclic antidepressants (e.g. amitriptyline)

▪ Serotonin/noradrenaline reuptake inhibitors (e.g. venlafaxine)

▪ Monoamine oxidase inhibitors (e.g. selegiline)

▪ Catecholaminergic medications (e.g. methylphenidate, bupropion)

▪ Atypical antipsychotics
Renal disease

▪ Glomerulonephritis

▪ Polyarteritis nodosa

▪ Systemic sclerosis

▪ Polycystic kidney disease

▪ Renovascular disease (renal artery stenosis)

CHAPTER 5

Hypertension 43

Endocrine disease

▪ Conn’s syndrome

▪ Cushing’s syndrome

▪ Phaeochromocytoma

▪ Hypothyroidism/hyperthyroidism

▪ Acromegaly

▪ Hyperparathyroidism
Lifestyle factors

▪ Stimulants (e.g. cocaine, amphetamines)

▪ Excessive liquorice ingestion

DIAGNOSTIC PRINCIPLES

History, examination, and investigations are performed to look for secondary causes of hypertension, assess for related risk factors, and to identify hypertension‐mediated organ damage (HMOD). HMOD include any established cardiovascular disease (CVD), renal disease, advanced retinopathy, and LVH on ECG or echocardiogram.

History

. 1 Hypertension, unless severe, is usually asymptomatic. However, headaches, neuro- logical symptoms, visual symptoms, and nose bleeds may herald a hypertensive emergency (see Chapter 71). Secondary causes of hypertension (see Box 5.2) may have characteristic presenting complaints depending on the underlying cause, for example weight loss, palpitations, excessive sweating, and disturbed sleep in hyperthyroidism.

. 2 Past medical history (Box 5.2).

. 3 Medication history (Box 5.2).

. 4 Family history of hypertension or CVD.

. 5 Social history, including smoking, alcohol, and substance misuse history.

Examination

1 Blood pressure measurement (Box 5.3). Ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM) measurements have been shown to be a greater predictor of HMOD and CVD outcomes than office readings [24,25]. They can and therefore should be used, where possible, in clinical practice. ABPM involves the use of a wearable cuff for 24 hours that automatically takes BP measurements every 15–60 minutes throughout the day, usually hourly at night (which does disturb sleep and BP meas- urement in some people) [26], whilst HBPM involves the patient taking their own BP using an automated device four times a day for at least 4 days [26]. The average of these measurements is then used to calculate an average BP value.

CHAPTER 5

Box 5.3 Blood pressure measurement technique

If this is the patient’s first measurement, then both arms should be tested. If there is a significant difference in readings, then the arm providing the highest value should be used for future measurements. This difference in measurements is usually due to atheromatous vascular disease.

When performing office BP measurements, automated and manual BP methods may be used, though the manual technique is required if the patient has an active arrhythmia (e.g. atrial fibrillation). Ensure the patient has been seated in a relaxed environment for five minutes prior to measurement. An appropriately sized cuff should be used and placed around the arm at the level of the patient’s heart. After three measurements have been taken, with ideally one minute between each, the average of the final two readings should be calculated and used as the recorded value. If there is a discrepancy of over 10 mmHg, then further measurements should be taken.

44 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

2 Measure height and weight and calculate body mass index (BMI).
3 Physical examination may be indicated to examine for signs of end‐organ damage secondary to hypertension. This will include cardiovascular (left ventricular heave of hypertrophy, raised jugular venous pressure, ankle oedema), respiratory (pulmonary oedema), and neurological (focal signs secondary to stroke) examination, including

(if possible) ophthalmoscopy to examine for hypertensive retinopathy.

Investigations

. 1 ECG: examine for LVH or evidence of previous myocardial infarction.

. 2 Urinalysis: proteinuria, haematuria, glycosuria.

. 3 Bloods: urea and electrolytes, fasting blood glucose and HbA1c, lipid levels, liver
function tests, bone profile.

. 4 Consider sending a urine sample to quantify proteinuria (albumin/creatinine ratio).

. 5 Echocardiogram may be considered to further assess for LVH.
DIAGNOSIS

Hypertension is most often diagnosed on routine testing. No other investigations are needed for the diagnosis, unless there is reason to believe a secondary cause is present (see section on when to refer to a specialist). The algorithm in Figure 5.1 details how to diagnose hypertension as per National Institute for Health and Care Excellence (NICE) guidelines [26]. Management is determined by the degree of hypertension (in mmHg based on clinic readings: stage 1, 140–159/90–99; stage 2, 160–179/100–109; severe, ≥180/≥110), the age of the patient, comorbidities, and the presence of end‐ organ damage.

CHAPTER 5

Normotensive <140/90 mmHg <135/85 mmHg (ABPM/HBPM)

Offer ABPM, HBPM or repeated clinic measurements
Access cardiovascular risk (QRISK3) and for end organ damage

Stage 1 Hypertension ≥140/≥90 mmHg ≥135/≥85 mmHg (ABPM/HBPM)

If under 40 years old

Consider specialist referral

Check BP at least annually

If presence of end organ damage, established CVD, renal disease, DM or 10-year cardiovascular risk >20%

Figure 5.1 Criteria for diagnosis of hypertension. ABPM, ambulatory blood pressure monitoring; HBPM, home blood pressure monitoring; CVD, cardiovascular disease; DM, diabetes mellitus.

MANAGEMENT Non‐pharmacological therapy

Lifestyle advice should be provided to all hypertensive patients, including:

▪ salt restriction (5 g/day) [2]

▪ Dietary Approaches to Stop Hypertension (DASH) diet [3,27] with emphasis on
low‐fat proteins, whole grains, low sodium, five servings of fruit and five servings of
vegetables daily [27]

▪ smoking cessation (see Chapter 46)

▪ weight loss (see Chapter 14)

▪ increase levels of exercise (see Chapter 10) [28]

▪ reducing alcohol consumption.

Offer non-pharmacological therapy

Review treatment and BP at least annually

Hypertension 45

Clinic BP <140/90 mmHg Normotensive

Clinic BP ≥140/≥90 mmHg Hypertensive range

Clinic BP >180/110 mmHg Severe Hypertension

Start antihypertensive medication immediately (see Chapter 71)

If acute onset hypertension or suspected secondary cause

Same day referral for specialist care

Stage 2 Hypertension ≥160/≥100 mmHg ≥150/≥95 mmHg (ABPM/HBPM)

Offer antihypertensive drug treatment

CHAPTER 5

46 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Consider rationalising psychiatric medication

Serotonin/noradrenaline reuptake inhibitors [18,20], tricyclic antidepressants [19], and monoamine oxidase inhibitors may contribute to hypertension; in patients prescribed these medications, switching to a selective serotonin reuptake inhibitor, which as a class has been shown to have at most only a very slight effect on BP, may be considered [18,19]. Sertraline is considered safe in patients with ischaemic heart disease [29].

Pharmacological therapy

There is robust evidence that pharmacological management of hypertension is associ- ated with significant reduction in CVD and improves mortality rates [30]. For example, compared with placebo, pharmacological antihypertensive therapy in the general popu- lation reduces the risk of heart failure, stroke and myocardial infarction by 20–50% [30]. Figure 5.1 defines when pharmacological treatment should be offered. Please note that American guidelines recommend that BP is treated if >130/>80 mmHg [3].

Target readings

▪ Aim for a target clinic BP below 140/90 mmHg in people aged under 80 years, or those of any age with diabetes mellitus, with treated hypertension.

▪ Aim for a target clinic BP below 150/90 mmHg in people aged 80 years and over with treated hypertension.
Prescribing algorithm
When prescribing antihypertensives, start at a low dose and titrate as necessary. Follow the algorithm in Figure 5.2 to guide additional treatment [26].
Angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers
Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) act therapeutically by reducing levels of circulating angiotensin II or its action at angiotensin receptors. This relaxes blood vessels and reduces fluid retention, result- ing in a fall in BP. An example prescription for an ACE inhibitor is ramipril at a starting dose of 2.5 mg once daily (oral), increasing to 10 mg total, starting twice‐daily dosing when the total dose reaches 5 mg. If an ACE inhibitor is not tolerated (ACE inhibitors can be associated with development of a cough), then switch to an ARB, for example losartan 50 mg once daily (oral) up to a maximum dose of 100 mg daily. Do not pre- scribe an ACE inhibitor and ARB in combination. Start with half the dose if elderly, if using a diuretic, or in the presence of chronic kidney disease. Do not start ACE inhibi- tors or ARBs without specialist advice if estimated glomerular filtration rate (eGFR) is below 30 mL/min per 1.73 m2. Urea and electrolytes should be checked prior to initia- tion, at week 1 and at week 4, and also after each titration, every 1–2 weeks. ACE inhibitors reduce lithium clearance, and therefore plasma lithium levels should be checked following initiation.

CHAPTER 5

Step 1 Step 2 Step 3 Step 4

A C

A + C

A + C + D

Resistant hypertension

A + C + D + consider further diuretic or
Alpha-blocker
or
Beta-blocker
Consider seeking expert advice

A- ACE inhibitor or angiotension II receptor blocker (ARB) C- Calcium-channel blocker D- Thiazide-like diuretic

Aged under 55 years

Aged under 55 years or person of black ethnicity, of any age

Figure 5.2 National Institute for Health and Care Excellence (NICE) algorithm for prescribing in hypertension [26].

Calcium channel blockers

Calcium channel blockers act on arterial vascular smooth muscle to relax blood vessels, resulting in a fall in BP. An example prescription for a calcium channel blocker is amlodipine starting at a dose of 5 mg daily (oral), increasing to 10 mg daily, as required. The most common side effect is ankle swelling.

Thiazide‐like diuretics

Thiazide diuretics work by inhibiting reabsorption of sodium and chloride ions in the distal convoluted tubules in the kidneys thereby causing diuresis, reducing intravascular volume, and by association BP. An example prescription is indapam- ide 2.5 mg once daily (1.5 mg if SR preparation), taken in the morning. Higher doses are rarely required. Urea and electrolytes are required prior to and during treatment owing to risk of hypokalaemia and/or hyponatraemia. Thiazide diuretics can dramatically increase plasma lithium levels: use together with caution and check lithium levels.

Hypertension 47

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48 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

When to refer to a specialist

If the patient has a blood pressure ≥180/≥110 mmHg and evidence of end‐organ dam- age, please refer to Chapter 71. In case of hypertensive emergency, the patient may need to be seen immediately by emergency/acute medical services.

It is important to refer to a specialist, ideally a specialist hypertension clinic, if there is any suspicion of a secondary cause (including patients aged under 40 with BP ≥160/≥100 mmHg). If specialist hypertension clinics are not available, then discuss with cardiology or endocrinology colleagues to clarify to whom a referral should be made. Patients with treatment‐resistant hypertension (i.e. poorly controlled BP despite adher- ence to three antihypertensives of different classes) or those with sudden onset of hyper- tension should also be referred.

When writing a referral letter to secondary care, it is important to include the follow- ing information: a detailed history of any symptoms that may indicate a secondary cause of hypertension, past medical history, current medication along with allergy sta- tus, a brief social history and any findings from clinical examination, remembering to include information on previous BP readings and treatment. Ensure that the patient’s psychiatric history is included in the letter.

References

1. James PA, Oparil S, Carter BL, et al. 2014 evidence‐based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311(5):507–520.

2. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39(33):3021–3104.

3. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the pre- vention, detection, evaluation, and management of high blood pressure in adults: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018;71(6):1269–1324.

4. Lewington S, Clarke R, Qizilbash N, et al. Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903–1913.

5. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365(9455):217–223.

6. Arboix A. Cardiovascular risk factors for acute stroke: risk profiles in the different subtypes of ischemic stroke. World J Clin Cases
2015;3(5):418–429.

7. Rahimi K, Emdin CA, MacMahon S. The epidemiology of blood pressure and its worldwide management. Circ Res 2015;116(6):925–936.

8. Carroll D, Phillips AC, Gale CR, Batty GD. Generalized anxiety and major depressive disorders, their comorbidity and hypertension in middle‐
aged men. Psychosom Med 2010;72(1):16–19.

9. Leboyer M, Soreca I, Scott J, et al. Can bipolar disorder be viewed as a multi‐system inflammatory disease? J Affect Disord
2012;141(1):1–10.

10. Goff DC, Sullivan LM, McEvoy JP, et al. A comparison of ten‐year cardiac risk estimates in schizophrenia patients from the CATIE study and
matched controls. Schizophr Res 2005;80(1):45–53.

11. Vancampfort D, Stubbs B, Mitchell AJ, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related
psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta‐analysis. World Psychiatry
2015;14(3):339–347.

12. Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the
CATIE schizophrenia trial sample at baseline. Schizophr Res 2006;86(1–3):15–22.

13. Bolivar JJ. Essential hypertension: an approach to its etiology and neurogenic pathophysiology. Int J Hypertens 2013;2013:547809.

14. Charles L, Triscott J, Dobbs B. Secondary hypertension: discovering the underlying cause. Am Fam Physician 2017;96(7):453–461.

15. Vancampfort D, Probst M, Knapen J, et al. Associations between sedentary behaviour and metabolic parameters in patients with schizophre-
nia. Psychiatry Res 2012;200(2–3):73–78.

16. Bly MJ, Taylor SF, Dalack G, et al. Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the
general population. Bipolar Disord 2014;16(3):277–288.

17. Dickerson F, Stallings CR, Origoni AE, et al. Cigarette smoking among persons with schizophrenia or bipolar disorder in routine clinical
settings, 1999–2011. Psychiatr Serv 2013;64(1):44–50.

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Hypertension 49

18. Licht CM, de Geus EJ, Seldenrijk A, et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 2009;53(4):631–638.

19. Zhong Z, Wang L, Wen X, et al. A meta‐analysis of effects of selective serotonin reuptake inhibitors on blood pressure in depression treatment: outcomes from placebo and serotonin and noradrenaline reuptake inhibitor controlled trials. Neuropsychiatr Dis Treat 2017;13:2781–2796.

20. Thase ME. Effects of venlafaxine on blood pressure: a meta‐analysis of original data from 3744 depressed patients. J Clin Psychiatry 1998;59(10):502–508.

21. Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004;25(1–2):215–221.

22. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention‐deficit/
hyperactivity disorder. J Clin Psychiatry 2005;66(2):253–259.

23. De Hert M, Dekker JM, Wood D, et al. Cardiovascular disease and diabetes in people with severe mental illness: position statement from the
European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society
of Cardiology (ESC). Eur Psychiatry 2009;24(6):412–424.

24. Banegas JR, Ruilope LM, de la Sierra A, et al. Relationship between clinic and ambulatory blood‐pressure measurements and mortality. N
Engl J Med 2018;378:1509–1520.

25. Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the
general population: follow‐up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation
2005;111:1777–1783.

26. National Institute for Health and Care Excellence. Hypertension in Adults: Diagnosis and Management. NICE Guideline NG136. London:
NICE, 2019. https://www.nice.org.uk/guidance/ng136

27. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop
Hypertension (DASH) diet. DASH‐Sodium Collaborative Research Group. N Engl J Med 2001;344(1):3–10.

28. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a meta‐analysis of randomized, controlled trials. Ann Intern
Med 2002;136(7):493–503.

29. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA
2002;288(6):701–709.

30. Blood Pressure Lowering Treatment Trialists Collaboration, Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood
pressure on major cardiovascular events in older and younger adults: meta‐analysis of randomised trials. BMJ 2008;336(7653):1121–1123.

CHAPTER 5

Chapter 6

Postural Hypotension

Toby Pillinger, Ian Osborne, Thomas Ernst, J. Kennedy Cruickshank

Postural (orthostatic) hypotension is defined as a fall in systolic blood pressure of at least 20 mmHg or diastolic pressure of at least 10 mmHg within two to five minutes of standing after a five‐minute period lying flat [1]. Postural hypotension has several causes, including impairment in autonomic reflexes (which may occur naturally with ageing), medication or depletion in intravascular volume. Common causes in the gen- eral population, and specifically in an individual with serious mental illness (SMI), are summarised in Table 6.1.

Specific considerations for psychiatric patients include a psychiatric medication review, as well as a drug and alcohol history (Box 6.1). Eating disorders may be associ- ated with volume loss secondary to vomiting/diarrhoea in the context of diuretic, laxa- tive or emetic use. Neurodegenerative diseases with psychiatric sequelae may be associated with inherent autonomic disturbance, or involve treatment with medica- tions which impact autonomic function. Higher rates of type 2 diabetes mellitus in psychiatric patients should lead to consideration of autonomic neuropathy. Other con- ditions that present with both psychiatric symptomatology and autonomic instability include vitamin deficiencies (e.g. B12/folate), thyroid disease, renal failure/uraemia, porphyria, and infection (e.g. syphilis and HIV). In old‐age psychiatry, the impact of ageing is important to consider; the prevalence of postural hypotension in those aged over 65 is 18% [2].

Box 6.1 Diagnostic summary for postural hypotension History

▪ Define symptoms

▪ Define symptoms suggestive of neuropathy/autonomic dysfunction

▪ Exclude volume loss (e.g. diarrhoea)

▪ Past medical history: diabetes, heart disease, malignancy, rheumatological and autoimmune dis-
orders, renal failure

▪ Medication history

▪ Drug and alcohol history

▪ Family history of similar presentation

52 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 6.1 Common causes of postural hypotension in the general and psychiatric patient population.

Medication

General population

Alpha‐adrenergic antagonists (mainly used for high blood pressure/enlarged prostate, e.g. doxazosin)
α2‐Agonists (e.g. clonidine, lofexidine)
Antihypertensives (e.g. amlodipine)

Anti‐parkinsonian drugs (e.g. levodopa) Beta‐blockers (e.g. bisoprolol)
Diuretics (e.g. furosemide)
Muscle relaxants (e.g. baclofen) Opioids

Phosphodiesterase inhibitors (e.g. sildenafil) Vasodilators (e.g. isosorbide mononitrate)

Vomiting/diarrhoea Fever
Fluid restriction Anaemia

Adrenal insufficiency Thyroid disease

Neurodegenerative disease (e.g. Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy) Neuropathies (e.g. diabetes, alcohol, amyloid, sarcoid, B12/ folate deficiency, infection, renal failure, porphyria, paraneoplastic, autoimmune, familial)

Heart failure Valve disease Cardiomyopathy Myocarditis Cardiomyopathy Arrhythmia

Individual with SMI

Antidepressants (see Table 6.2) Antipsychotics Anti‐parkinsonian drugs (e.g. levodopa)

Diuretics/laxative abuse (eating disorders)
Opioids

Vomiting/diarrhoea (eating disorders)
Dehydration (poor self‐care, catatonia)

Thyroid disease

Neurodegenerative disease (e.g. Parkinson’s disease and dementia with Lewy bodies)
Neuropathies (e.g. diabetes mellitus, alcohol, B12/folate deficiency, porphyria, syphilis, and HIV)

Myocarditis/cardiomyopathy secondary to psychotropic medication
Ischaemic cardiomyopathy

Volume loss

Autonomic failure

Heart disease

Ageing
Alcohol
Sympathicotonic orthostatic hypotension refers to orthostatic hypotension seen in individuals with excessive sympathetic discharge. This can be due to chronic stress from any cause. A rare but important medical cause includes phaeochromocytoma [3]

CHAPTER 6

Postural Hypotension 53

Examination

▪ Lying and standing blood pressure

▪ Neurologial examination

▪ Cardiovascular examination
Investigations

▪ Bloods

▪ ECG

▪ Urine dip

DIAGNOSTIC PRINCIPLES History

. 1 Symptoms of postural hypotension are a consequence of cerebral hypoperfusion, and include dizziness/light‐headedness, visual disturbances (e.g. blurring), and potentially (but rarely) syncope (see Chapter 4). Dizziness should be distinguished from vertigo, i.e. the illusion of movement, most commonly a spinning sensation. Symptoms typi- cally occur on standing but may also arise following a meal (more commonly in the elderly), on exertion, or following prolonged standing.

. 2 Medication history, specifically asking if there has been a recent change in medica- tion (see Table 6.1).

. 3 Recent evidence of volume loss (diarrhoea/vomiting/infection).

. 4 Associated symptoms that may point towards a peripheral neuropathy or autonomic dysfunction, e.g. constipation, erectile dysfunction, urinary incontinence, abnormal
sweating.

. 5 Family history of similar symptoms, suggestive of familial neuropathy.

. 6 Past medical history, including screening for malignancy, heart disease, diabetes
mellitus, autoimmune disease, renal failure, amyloid, sarcoid, and porphyria.

. 7 Social history, including a quantification of alcohol intake.

Examination

. 1 Lying/sitting and standing blood pressure. Blood pressure should be taken manually with a stethoscope (oscillometric devices can take a prolonged period of time to inflate, during which the postural episode may already have settled).

. 2 Neurological examination, specifically examining for evidence of Parkinsonism, ataxia (as a consequence of alcohol abuse/multiple system atrophy), peripheral neuropathy, autonomic dysfunction (e.g. pupillary changes, sweating abnormalities).

. 3 Cardiovascular examination (evidence of heart failure, valve disease).

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54 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Investigations

. 1 Bloods:
(a) full blood count (evidence of pernicious anaemia)
(b) renal function (renal failure, uraemia or dehydration)
(c) liver function (alcohol abuse)
(d) bone profile/calcium (hypercalcaemia is osmotic diuretic which will contribute to
hypovolaemia)
(e) glucose and HbA1c levels (diabetic neuropathy)
(f) thyroid function
(g) B12/folate levels
(h) autoimmune screen
(i) infection screen (syphilis, HIV)
(j) brain natriuretic peptide levels if there are clinical features suggestive of heart
failure
(k) morning cortisol* (adrenal insufficiency).

. 2 ECG to examine for cardiac disease.

. 3 Urine dip for glucose and proteinuria (diabetes mellitus).

. 4 In selected cases with features of strong sympathetic excess, consider 24‐hour
urine metanephrines.
MANAGEMENT

Up to one‐third of patients in the general population with postural hypotension may have no identifiable cause [4]. In the psychiatric patient population, psychotropic medi- cations are potentially responsible, and rationalising pharmacotherapy may be key to providing symptomatic relief.

Rationalising psychiatric and non‐psychiatric medication

Several antidepressants and antipsychotics cause postural hypotension, although the risk profile is diverse (Tables 6.2 and 6.3). In patients who are well established on an efficacious antipsychotic or antidepressant regimen and where there is a reluctance to change medication, consider dose reduction. Rationalisation of hypnotic use should also be considered. With general medical advice, rationalisation of non‐ psychiatric medication may also be indicated; for example, in the case of benign prostatic hypertrophy, switching doxazosin to tamsulosin, or for hypertension, switching non‐dihydropridine calcium channel blockers to dihydropyridines (e.g. amlodipine).

* Indicated if there are concerns regarding adrenal insufficiency (i.e. if the patient is ‘Addisonian’). These patients present with non‐specific symptoms including postural hypotension, abdominal pain, nausea, vomit- ing, fatigue, weakness, and confusion. If there are acute concerns about Addison’s, patients should be seen and reviewed in the accident and emergency department.

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Postural Hypotension 55

Table 6.2 Approximate relative hypotensive severity of antidepressants. Antidepressant Hypotension Tricyclics

Amitriptyline +++

Clomipramine +++

Dosulepin +++

Doxepin ++

Imipramine +++

Lofepramine +

Nortriptyline ++

Trimipramine +++

Monoamine oxidase inhibitors (MAOIs)

Isocarboxazid +++

Phenelzine +++

Tranylcypromine +++

Reversible inhibitor of monoamine oxidase A (RIMA)

Moclobemide –

Selective serotonin reuptake inhibitors (SSRIs)

Citalopram –

Escitalopram –

Fluoxetine –

Fluvoxamine –

Paroxetine –

Sertraline –

Vortioxetinea +

Other antidepressants

Agomelatine –

Duloxetineb –

Mianserin –

Mirtazapine +

Reboxetineb –

Trazodone +

Venlafaxineb –

a Vortioxetine classed as an SSRI for convenience here; it has several other pharmacologi- cal effects.
b Usually increase blood pressure.
+++, high incidence/severity; ++, moderate; +, low; –, very low.

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56 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 6.3 Approximate relative hypotensive severity of antipsychotics. Antipsychotic Hypotension Amisulpride –

Aripiprazole –

Asenapine –

Benperidol +

Brexpiprazole –

Cariprazine –

Chlorpromazine +++

Clozapine +++

Flupentixol +

Fluphenazine +

Haloperidol +

Iloperidone +

Loxapine ++

Lurasidone –

Olanzapine +

Paliperidone ++

Perphenazine +

Pimozide +

Pipotiazine ++

Promazine ++

Quetiapine ++

Risperidone ++

Sertindole +++

Sulpiride –

Trifluoperazine +

Ziprasidone +

Zuclopenthixol +

+++, high incidence/severity; ++, moderate; +, low; –, very low.

Non‐pharmacological therapy

1 Lifestyle modification.
(a) Sitting up slowly in stages from supine to standing. (b) Maintain hydration.

CHAPTER 6

Postural Hypotension 57

(c) Increased salt and water intake: a target daily ingestion of 1.5–3 L of water and 6–10 g of sodium has been recommended [5–8].

(d) Meal modification may be suggested if there is a clear postprandial association with hypotensive episodes. Advice includes reducing meal size, reducing alcohol intake with meals, and increasing water intake with meals.

. 2 Anti‐embolism elastic stockings that extend to the waist reduce peripheral blood pooling [9]. These are contraindicated in patients with peripheral vascular disease; if unsure, measurement of ankle–brachial pressure index should be sought first. Ensure regular foot inspection in patients with peripheral neuropathy.

. 3 Physical manoeuvres, e.g. isometric handgrip when standing [10].

. 4 Mild to moderate exercise and evidence‐based stress reduction programmes (e.g. mindfulness‐based stress reduction, Tai Chi) are recommended in individuals with
identified high stress burden.

Pharmacological therapy

Use of medication specifically targeting symptoms of postural hypotension should be accompanied by regular blood pressure monitoring by the patient at home.

. 1 Fludrocortisone is a synthetic mineralocorticoid that may be considered for patients whose postural hypotension does not respond to lifestyle modification [11]. Three randomised controlled trials examining use of fludrocortisone for postural hypoten- sion have provided conflicting outcomes [11–13], with two demonstrating improve- ment [11,12] and one no benefit [13], although the studies investigated diverse populations (diabetic neuropathy [11], Parkinson’s disease [12], and chronic fatigue syndrome [13]) with small numbers of participants and potentially subtherapeutic fludrocortisone doses. Fludrocortisone works primarily to increase extracellular vol- ume and thereby blood pressure. The dose of fludrocortisone starts at 100 μg daily in the morning, with an incremental increase in dose (if necessary) by 100 μg every week, to a maximum dose of 400 μg daily. Monitor for peripheral oedema (leg swelling), hypertension, and hypokalaemia (low potassium). Because fludrocortisone is a ster- oid, if it is taken for more than 3 weeks the dose should be gradually reduced when it is stopped. People taking fludrocortisone should carry a steroid treatment card. This card should always be carried with them and shown to anyone who treats them.

. 2 Ifthepatientremainssymptomaticordoesnottoleratefludrocortisone,asympathomi- metic agent such as midodrine (a selective α1 agonist) can be added/substituted [14–16]. Midodrine increases arterial resistance thereby increasing blood pressure. It does not cross the blood–brain barrier, which means the sympathomimetic side effects that can accompany the use of adrenergic agents (e.g. anxiety and tachycardia) do not occur. The dose should be increased from 2.5 mg three times daily up to 10 mg three times daily at weekly intervals. Midodrine should not be used in patients with heart disease, urinary retention or uncontrolled hypertension. Monitor for hypertension, urinary retention, gastro‐oesophageal reflux, and pruritis. Midodrine should be given at or just before ris- ing in the morning, a further dose 4 hours after the first, and a further dose 4 hours after the second dose. Avoid a dose of midodrine within 4 hours of going to bed.

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58 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

3 There is evidence for the use of pyridostigmine [17], non‐steroidal anti‐inflammatories [18], caffeine [19], and erythropoietin [20] as adjunctive agents in patients who remain symptomatic with the above regimen.

4 In the case of clozapine‐associated postural hypotension, reduce dose or slow down rate of increase. Increase fluid intake as described in the section on non‐pharmaco- logical therapy. Alongside fludrocortisone, there is evidence for the use of moclobe- mide (a reversible monoamine oxidase inhibitor, 150 mg three times daily) given together with one measure (12 g) of Bovril up to three times daily [21].

When to refer to a specialist

Postural hypotension can usually be managed in primary care, although referral to a medical subspecialty may be appropriate if investigations demonstrate an underlying condition, for example heart disease requiring a cardiology opinion. Frequent falls or persistent symptomatic orthostatic hypotension despite adhering to the advice in this chapter would warrant referral to a specialist ‘falls prevention’ clinic.

References

1. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21(2):69–72.

2. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension 1992;19(6 Pt 1):508–519.

3. Schatz IJ. Orthostatic hypotension. I. Functional and neurogenic causes. Arch Intern Med 1984;144(4):773–777.

4. Sathyapalan T, Aye MM, Atkin SL. Postural hypotension. BMJ 2011;342:d3128.

5. Nwazue VC, Raj SR. Confounders of vasovagal syncope: orthostatic hypotension. Cardiol Clin 2013;31(1):89–100.

6. Fedorowski A, Melander O. Syndromes of orthostatic intolerance: a hidden danger. J Intern Med 2013;273(4):322–335.

7. Shibao C, Lipsitz LA, Biaggioni I. ASH position paper: evaluation and treatment of orthostatic hypotension. J Clin Hypertens (Greenwich)
2013;15(3):147–153.

8. Lanier JB, Mote MB, Clay EC. Evaluation and management of orthostatic hypotension. Am Fam Physician 2011;84(5):527–536.

9. Henry R, Rowe J, O’Mahony D. Haemodynamic analysis of efficacy of compression hosiery in elderly fallers with orthostatic hypotension.
Lancet 1999;354(9172):45–46.

10. Clarke DA, Medow MS, Taneja I, et al. Initial orthostatic hypotension in the young is attenuated by static handgrip. J Pediatr
2010;156(6):1019–1022.e1.

11. Campbell IW, Ewing DJ, Clarke BF. 9‐Alpha‐fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropa-
thy. Diabetes 1975;24(4):381–384.

12. Schoffer KL, Henderson RD, O’Maley K, O’Sullivan JD. Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic
hypotension in Parkinson’s disease. Mov Disord 2007;22(11):1543–1549.

13. Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a rand-
omized controlled trial. JAMA 2001;285(1):52–59.

14. Izcovich A, Gonzalez Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review.
Neurology 2014;83(13):1170–1177.

15. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double‐blind, placebo‐controlled study with midodrine. Am J

Med 1993;95(1):38–48.

16. Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double‐blind
multicenter study. JAMA 1997;277(13):1046–1051.

17. Singer W, Sandroni P, Opfer‐Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol
2006;63(4):513–518.

18. Kochar MS, Itskovitz HD. Treatment of idiopathic orthostatic hypotension (Shy–Drager syndrome) with indomethacin. Lancet
1978;i(8072):1011–1014.

19. Onrot J, Goldberg MR, Biaggioni I, et al. Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for
postprandial hypotension. N Engl J Med 1985;313(9):549–554.

20. Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 1993;329(9):611–615.

21. Taylor D, Reveley A, Faivre F. Clozapine‐induced hypotension treated with moclobemide and Bovril. Br J Psychiatry 1995;167(3):409–410.

CHAPTER 6

Chapter 7

Peripheral Oedema

Thomas Whitehurst, Theresa McDonagh

Fluid accumulation in the interstitial compartment is termed oedema. This chapter discusses only palpable oedema found in distal dependent areas, i.e. peripheral oedema. In ambulant patients, peripheral oedema accumulates mostly in the lower limbs, but also occasionally in the distal upper limbs and, in bedbound patients, the sacrum.

Oedema occurs when the rate at which fluid filters from the capillaries is greater than the rate at which it is drained by the lymphatic system or reabsorbed into the capillaries [1]. Causes of oedema divide into those effecting an increase in capillary filtration, and those that decrease lymphatic drainage. Capillary filtration is dependent on several fac- tors. Firstly, increased capillary pressure increases filtration. This may occur in associa- tion with right ventricular failure, deep vein thrombosis (DVT) or use of vasodilators. Furthermore, capillary permeability increases in inflamed areas, thereby increasing fil- tration. Finally, reduced capillary osmotic pressure, a common consequence of low albumin in association with malnutrition, nephrotic syndrome or liver disease, can also lead to oedema [1]. In developed countries, reductions in lymphatic drainage are mainly due to infiltration/compression by cancer, or secondary to cancer treatments such as lymphadenectomy or radiotherapy. However, worldwide, the most common cause is infection, with filariasis accounting for most cases [2].

Special considerations in the psychiatric population fall into three categories. Firstly, some psychotropic medications cause oedema directly (Table 7.1 and Box 7.1). Secondly, some may increase the risk of systemic illnesses that cause oedema. For example, the complications of lithium include hypothyroidism and renal disease, both of which can cause peripheral oedema. Thirdly, subsets of the psychiatric population may be at increased risk of systemic illness independent of medication effects, for example malnu- trition occurring in severe depression or anorexia may lead to hypoalbuminaemia and oedema. A degree of interaction between these categories is also possible, as illustrated by the example of an acutely unwell person with a diagnosis of schizoaffective disorder

60 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

who is prescribed sodium valproate. Sodium valproate can cause acute bilateral oedema, which is reversible upon discontinuation, perhaps mediated by the effect of γ‐aminobu- tyric acid (GABA) on capillary permeability [3]. Alternatively, valproate can induce hepatotoxicity, manifesting as peripheral oedema, jaundice, and ascites [4]. Furthermore, heart failure is more common in schizoaffective disorder (indeed it is more common in patients with serious mental illness in general) [5,6] and may present with shortness of breath on exertion and peripheral oedema [7].

DIAGNOSTIC PRINCIPLES

A clinical approach to assessment of peripheral oedema should first aim to rule out acute or life‐threatening causes (e.g. DVT; see Chapter 18), followed by a systematic assessment aiming to examine for drug‐induced or other causative systemic/localised conditions. Figure 7.1 presents an algorithmic approach to assessing a patient with peripheral oedema.

History

History of presenting complaint

. 1 Enquire as to the site, whether bilateral, unilateral or asymmetric. Bilateral oedema generally implies a systemic cause, whereas unilateral oedema suggests local venous obstruction, infection or lymphatic blockage. Swelling of the lower limb, sparing the feet and arising at puberty, is characteristic of lipoedema, mostly found in young women [27].

. 2 Define speed of onset and course of the swelling, and whether it is intermittent or persistent. Oedema developing over less than three days is generally considered acute, and chronic if developing over more than three days.

. 3 Enquire as to associated pain, redness or loss of function.

. 4 Enquire if there is a history of injury. Excluding DVT, the commonest cause of uni-
lateral leg swelling is muscle strain or tear [82].

. 5 Enquire if there are any risk factors for DVT, including recent paralysis, immobility,
orthopaedic surgery, pregnancy or malignancy (see Chapter 18).

. 6 Enquire if dietary intake has recently reduced significantly.

. 7 Enquire as to any symptoms suggestive of specific organ failure.
a Heart: reduced exercise tolerance and fatigue, progressing to orthopnoea, short- ness of breath at rest, and peripheral oedema.
b Liver: jaundice, right upper quadrant pain, abdominal swelling, pale stools, bleeding (see Chapter 23).
c Kidney: reduced urine output, confusion, muscle weakness (see Chapters 34 and 73).
d Thyroid: intolerance to heat, hair loss, weight gain (see Chapter 12).

8 Foreign travel: other than long‐haul flights increasing risk of DVT, travel to

sub‐Saharan Africa or Southeast Asia will increase risk of filariasis.

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Peripheral Oedema 61

Table 7.1 Common causes of oedema in the general and psychiatric population.

Systemic illness

General population

Heart disease

Liver disease

Kidney disease

Thyroid disease

Malnutrition/malabsorption

Obstructive sleep apnoea (OSA) may lead to oedema secondary to pulmonary hypertension [25]

Antihypertensive drugs (especially calcium channel blockers and vasodilators, but also beta‐blockers), steroids, hormone replacement (e.g. oestrogens, testosterone), non‐ steroidal anti‐inflammatory drugs (NSAIDs), antidiabetics (e.g. glitazones) [8,27]

Individuals with serious mental illness (SMI)

Those with SMI are at increased risk of heart failure and death from coronary heart disease [5–7]. Antipsychotic use may underlie part of this increased risk, either through direct cardiotoxicity or by exacerbation of metabolic risk factors [10,11]. Myocarditis is more common in those taking clozapine (see Chapter 8) [12]. Abuse of alcohol, nicotine, and stimulants is more common in SMI [13] and increases risk of heart disease [14–16]

Higher rates of chronic liver disease are observed in schizophrenia [17]. SMI is associated with higher rates of substance misuse, including alcoholism. There are higher rates of blood‐ borne viruses in those with schizophrenia and substance use disorders [18,19]. Deliberate overdose of commonly available medications often has a primary pathological effect on the liver, e.g. paracetamol

Kidney disease is a recognised adverse effect of lithium treatment [20] (see Chapter 34 for more information)

Thyroid disease is increased with the use of first‐generation antipsychotics [21]. Second‐ generation antipsychotics seem to have less propensity to cause hypothyroidism [22]. Prevalence of lithium‐induced hypothyroidism is around 15% in women, around threefold the rate in men [23,24] (see Chapter 12 for more information

Starvation occurs in anorexia nervosa, catatonia, and severe depression. Malabsorption and malnutrition may occur in the context of alcohol abuse or excessive use of laxatives

OSA is more common in SMI compared to the general population [26] (see Chapter 49)

Medication

See Box 7.1

(continued )

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62 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 7.1 (Continued)

Deep vein thrombosis

Cellulitis

Trauma or muscle strain

Chronic venous insufficiency

Lymphoedema (oedema caused by blockage of lymphatic drainage)

Complex regional pain syndrome

Lipoedema

Physiological states

General population

Cancer, thrombotic disorder, inflammatory or infectious condition, obesity, pregnancy, hormone replacement or combined oral contraceptives, paralysis, dehydration

Immunocompromise, injury or cut, diabetes, chronic skin conditions (e.g. eczema), obesity, intravenous drug use

History of injury or assault, competitive sport, high BMI, older age [35,36]

Hypertension, obesity, older age, family history, smoking, phlebitis, venous thromboembolism, standing occupation, possibly female sex [38]

Either primary (inherited) or secondary. Most often due to cancer, radiotherapy or lymphadenectomy. In developing world, helminth infection (filariasis) is most important cause

Initiated by trauma or immobility (usually a fracture in the upper limb). More common in elderly females

Individuals with serious mental illness (SMI)

Meta‐analysis has found that antipsychotic medication is a risk factor for DVT, especially in the elderly and those prescribed atypical antipsychotics, in particular clozapine [28]. Immobility in catatonia or depressive stupor, or secondary to seclusion and restraint, is associated with DVT [29,30] (see Chapter 18)

Increased risk of bacterial infection in schizophrenia [31]
Intravenous drug use is more common in SMI [32]

Uncontrolled HIV infection is more common in SMI [33]
Clozapine may reduce immune response, thereby increasing vulnerability to infection [34]

High psychiatric distress is a risk factor for musculoskeletal problems [37]

Many risk factors, including smoking, hypertension and obesity, are more common in SMI [39–41]

While cancer is no more common in SMI, those with SMI have lower cancer survival rates, likely due to later presentation with more advanced disease [42,43]. Therefore, infiltration of tumours into lymph nodes and vessels may be more likely. Cancer patients with SMI may be less likely to receive surgery or radiotherapy [43].

Repeated application of ligatures or tourniquets in those who self‐harm can produce lymphoedema [44,45]

There is contradictory evidence as to whether this syndrome is more common in any particular psychiatric or psychological condition, although it is possible that anxiety, depression, and somatisation are associated [46]

Genetic, possibly X‐linked condition, arising in puberty, almost always in females. Distinguishable from obesity by pain and discomfort in affected areas, as well as ease of bruising. Diet and exercise have no effect on swelling [47]

Peripheral oedema occurs in almost half of all healthy pregnancies, and is a non‐ specific sign of pre‐eclampsia, although the latter can be investigated with a urine dipstick, testing renal function, and blood pressure monitoring (see Chapter 62) [48,49]

Oedema is a well‐described element of the premenstrual syndrome, although the most common sites are the breasts, upper arms, abdomen, and pelvis [50]

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Peripheral Oedema 63

Box 7.1 Psychiatric medication and risk of peripheral oedema Antipsychotics

▪ Over half of a study of 49 outpatients taking olanzapine had oedema, although found with lower frequency in clinical trials (3%) [51]. There are case reports for quetiapine [52], risperidone [53], ziprasidone [54], paliperidone [55], clozapine [56], and amisulpiride [57]. A recent systematic review of self‐limiting oedema associated with atypical antipsychotics reported such reactions had a mean onset in the fifth decade, were more common in females and usually occurred in the first four weeks of treatment [58]. There were more case reports for olanzapine, risperidone, and quetiapine than other atypicals.

▪ Pimavanserin, used for the treatment of Parkinson’s psychosis, caused oedema in 7% of patients in phase III clinical trials (vs. 3% for placebo) [59].

▪ Antidepressants (monamine oxidase inhibitors): phenelzine (up to 10%) [60] and rasagiline (7% vs. 4% in placebo group) [61] are the most likely to cause oedema. Tranylcypromine [62] and isocarboxazid [63] have been found to cause oedema, albeit less frequently [64].

▪ Prescribing information for most selective serotonin reuptake inhibitors lists peripheral oedema as an ‘infrequent side effect’ (0.1–1% of patients), and oedema is not a common side effect of tricyclics [65–68].

▪ Trazodone [69] and venlafaxine [70] both have several cases reported.

▪ Mirtazapine has at least four cases reported as well as having oedema listed as a possible side
effect in product literature, with an incidence of about 1% greater than placebo [71–73].

▪ Oedema occurs in bupropion treatment at a rate above 1% [74].

▪ Duloxetine was less likely to cause peripheral oedema than placebo in a large trial [75].
Mood stabilisers

▪ Sodium valproate [3], carbamazepine [76] and, very rarely, lamotrigine [77] can cause self‐limiting peripheral oedema.

▪ Oedema in a patient treated with lithium should prompt assessment for systemic disease, particu- larly renal, cardiac and thyroid [78].
Others

▪ Pregabalin and gabapentin caused oedema in 5–15% of patients in clinical trials [64,79,80].

▪ Peripheral oedema is a recognised side effect of granulocyte colony‐stimulating factor (GCSF), which may be used to increase neutrophil count during clozapine treatment (see Chapter 16) [81].

Past medical history

Record any history of systemic conditions that may predispose an individual to periph- eral oedema, especially cardiac, kidney or liver disease (see Table 7.1). As already described, important risk factors for DVT include active cancer, cancer treated in the last six weeks, or previous history of DVT.

Medication history

See Table 7.1 and Box 7.1.

Family history

Thrombotic disorders, cancer, and familial lymphoedema.

CHAPTER 7

Asymmetric

How long did the swelling take to emerge?

Do clinical examination and baseline investigations suggest systemic disease?

How long did the swelling take to emerge?

Well’s score 2 or more?

History of trauma, cancer, pelvic surgery or trauma?

Proximal vein ultrasound

Positive

Consider lymphoedema, chronic venous insufficiency or lipoedema

Consider ultrasound to test for chronic venous insufficiency

Negative

Consider referral for pelvic imaging for tumour or venous obstruction

Negative

Treat DVT

Proximal vein ultrasound

Consider alternative diagnoses, e.g. cellulitis, lymphoedema, injury, chronic venous insufficiency

Consider referral for pelvic imaging for tumour or venous obstruction, or other diagnosis

Review medication and consider stopping any added recently

Further investigation of the implicated system, and referral to the relevant specialist

Treat DVT

Unilateral, bilateral or asymmetric?

Unilateral

Yes

Bilateral

Over 3 days Yes

Over 3 days

Under 3 days Yes

No Yes

D-dimer? Positive

Negative Positive

Under 3 days

Figure 7.1 Algorithmic diagnostic approach to peripheral oedema. Source: adapted from diagrams in Trayes et al. [8] to re ect National Institute for Health and Care Excellence (NICE) guidelines on investigation for venous thrombosis [9].

CHAPTER 7

Peripheral Oedema 65

Social history

. 1 Intravenous drug use is associated with both lymphatic blockage and chronic venous insufficiency, as well as systemic disease [83].

. 2 Quantify alcohol and nicotine use.

Examination

. 1 Basic observations: heart rate, blood pressure, respiratory rate, oxygen saturations, and temperature.

. 2 Measure weight and calculate body mass index (BMI).

. 3 Note whether the oedema is bilateral, unilateral or asymmetric.

. 4 Extent (to ankle, calf, thigh or entire leg) which may help assessment of progression
of oedema over time.

. 5 Pitting or non‐pitting (i.e. leaving no indentation when removing a finger after five
seconds of pressure). Non‐pitting oedema is associated with lymphoedema, although early lymphoedema may still exhibit pitting [84]. Checking for pitting oedema may be uncomfortable for the patient, and therefore give warning prior to performing this assessment.

. 6 Measure the circumference of the calves 10 cm below the tibial tuberosity. A differ- ence of more than 3 cm between the two measurements is considered significantly asymmetric.

. 7 Skin changes: in cellulitis, skin may be red, hot, and tender; in chronic venous insuf- ficiency, there is hardening, pigmentation, ulcers or prominent superficial veins; in pretibial myxoedema, thick, dry, ‘orange peel’ skin.

. 8 Dilated superficial veins or tenderness along the deep veins.

. 9 Note whether you can pinch and lift the skin over the dorsum of the second toe
(negative Stemmer’s sign). Positive Stemmer’s sign is associated with
lymphoedema.

. 10 Palpate for lymph nodes.

. 11 If leg oedema is present, check the arms and sacrum.

. 12 Cardiovascular and respiratory examination: signs of heart failure may include
‘gallop’ rhythm on auscultation, raised jugular venous pressure, and basal crackles
on auscultation of the chest (pulmonary oedema).

. 13 Abdominal examination: ascites, jaundice, spider naevi, ascites or hepatomegaly in
liver failure.

. 14 Examine the neck for signs of thyroid disease, and eyes for proptosis (see Chapter 12
for full thyroid examination).

. 15 Perform a general examination/inspection looking for skin folds indicating rapid
weight loss, pallor in the conjunctiva or nails indicating malnutrition or anaemia, clubbing, palmar erythema, and evidence of intravenous injection.

If there is unilateral leg swelling, based on history and examination, calculate the revised Wells score for suspected DVT [9] (see Chapter 18).

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66 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Investigations

Bloods

. 1 Full blood count.

. 2 Urea and electrolytes.

. 3 Liver function tests.

. 4 C‐reactive protein.

. 5 If DVT suspected but Well’s score is less than 2, send for a D‐dimer [85] (see
Chapter 18).

. 6 Thyroid function tests (if indicated by above assessment).

. 7 B‐type natriuretic peptide (BNP) or N‐terminal pro‐hormone BNP (NTproBNP) if
heart failure is suspected.

. 8 Addition of troponin if there is suspicion of acute heart failure.

. 9 Mid‐stream urine dipstick to test for protein (renal disease).

. 10 ECG and chest X‐ray may be useful if cardiac disease and/or pulmonary oedema is suspected.

For bilateral oedema, further investigation depends on history, examination, and ini- tial investigation results. Where these indicate acute involvement of a particular organ system, refer to the relevant chapters (Chapter 73 for acute kidney injury, Chapter 23 for deranged liver function tests, Chapter 68 for shortness of breath, and Chapter 69 for acute coronary syndrome), and involve the relevant medical specialist. When initial assessment does not suggest systemic disease, lipoedema or chronic venous insuffi- ciency, review medication. Calculating a Naranjo score may be helpful, by determining the likelihood of an adverse drug reaction (e.g. oedema) indeed being secondary to a drug [86].

In acute‐onset unilateral oedema, proximal leg vein ultrasound is recommended if DVT is expected [9] (refer to Chapter 18 for further information). In unilateral oedema occurring over a longer time period, also consider pelvic imaging to exclude lymphatic obstruction and venous Doppler to assess for venous insufficiency [8].

MANAGEMENT

For peripheral oedema associated with chronic kidney disease, liver disease, and thy- roid disease, the reader is directed to Chapters 34, 23 and 12, respectively. In the case of acute onset of heart failure with shortness of breath, transfer immediately to an emergency unit as immediate supportive care is necessary for these patients. A specialist heart failure multidisciplinary team should diagnose chronic heart failure, with first‐ line treatments including angiotensin‐converting enzyme (ACE) inhibitors and beta‐ blockers, and diuretic therapy recommended to treat oedema [87].

The general approach to the treatment of peripheral oedema is the slow removal of excess fluid using diuretic therapy [88]. Daily weights and fluid input–output charts are used to monitor treatment progress. For heart failure and renal disease, the suggested rate of removal is between 1 and 3 l per day. In cirrhotic patients, removal of oedema

CHAPTER 7

Peripheral Oedema 67

from ascites at a rate of over 500 ml daily may lead to intravascular volume depletion, as peritoneal capillaries cannot absorb ascites any faster [89].

Thiazide diuretics, such as bendroflumethiazide and indapamide, reduce renal excre- tion of lithium, increasing serum lithium concentrations, and as such should be avoided in these patients [20]. Loop diuretics such as furosemide seem to have less effect on lithium concentration. The effect of diuretic treatment on lithium concentration is apparent in the first month [20]. Caution is advised in the use of lithium in heart failure. ACE inhibitors reduce lithium clearance, and plasma lithium levels should therefore be checked following initiation.

Diuretics all have the potential to cause electrolyte imbalance, which can exacerbate QTc prolongation if co‐prescribed with other causative agents (see Chapter 3). Diuretics are also associated with orthostatic hypotension, exacerbating the effects of agents such as clozapine and olanzapine (see Chapter 6) [90].

Those with oedema secondary to chronic venous insufficiency should be referred to a vascular surgery service, where the mainstays of treatment are leg elevation, exercise to build calf strength, and compression stockings. Novel venoactive drugs may be of use [88,91,92]. Cellulitis may be managed in primary care with antibiotics, provided there are no signs of sepsis (see Chapter 72).

The prognosis is poor for lymphoedema, with progressive impairment likely [84,93]. Complex decongestive therapy performed by trained physiotherapists combines spe- cialised massage techniques and compressive bandages to reduce swelling [84]. General measures such as limb elevation, keeping to a healthy weight, patient education, and psychosocial support may improve quality of life [94]. Diuretic therapy, once the diag- nosis of lymphoedema is confirmed, is of little benefit and may cause harm (e.g. via electrolyte imbalance) [84].

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CHAPTER 7

Chapter 8

Myocarditis

Thomas Whitehurst, Theresa McDonagh

Myocarditis (inflammation of the heart muscle) may be caused by a variety of infectious and non‐infectious conditions (Table 8.1). In the general population, the most common cause of myocarditis in the northern hemisphere is viral infection. Worldwide, infection with HIV and Trypanosoma cruzi (Chagas disease) are responsible for most cases of myocarditis [1,2]. In the adult population, autopsy studies indicate that myocarditis is more common in males and in those aged under 40 [3,4]. The Global Burden of Diseases Study estimates the yearly prevalence as 22 per 100,000 [5].

Among patients with serious mental illness (SMI), myocarditis represents a rare but serious complication of clozapine treatment. Other considerations in this group are increased rates of risk factors for myocarditis such as substance abuse, exposure to infectious diseases, malnutrition, and exposure to toxins and unusual pathogens due to poor living conditions (see Table 8.1).

DIAGNOSTIC PRINCIPLES

International definitions of myocarditis generally specify that a diagnosis is based on immunohistochemical changes, although in clinical practice endomyocardial biopsy is rarely performed [6,32,33]. Diagnosis therefore relies on a combination of clinical pres- entation, biochemistry, electrocardiography (ECG), echocardiography and, potentially, cardiac magnetic resonance imaging (MRI) [6]. Myocarditis may be asymptomatic [4,34–36]. When symptoms occur, the most common is shortness of breath, followed by chest pain, flu‐like symptoms, cough, and gastrointestinal disturbance [37]. Clinicians should view any presentation of acute‐onset chest pain or shortness of breath as an emergency (see Chapters 67–69 for more information). The most common signs are

72 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 8.1 Causes of myocarditis in the general population and special considerations in patients with serious mental illness.

Viral

General population

RNA viruses: enterovirsues, especially cocksackie B [3], but also coxsackie A, and polio. Also influenza, respiratory syncytial virus, mumps, rubella, dengue, yellow fever [6]

DNA viruses: adenovirus, varicella, human herpes virus 6, cytomegalovirus, Epstein–Barr virus, varicella‐zoster, HIV, hepatitis B and C [6]

Tuberculosis, Streptococcus Group A, Staphylococcus, Legionella, Streptococcus pneumoniae, gonorrhoea, Chlamydia, syphilis, Bartonella

Trypanosoma cruzi (most common cause in those living in Central and South America), Toxoplasma, Aspergillus, Cryptococcus, Candida [6]

Chemotherapy (e.g. fluorouracil, anthracyclines), Herceptin [6], antibiotics (e.g. penicillins, cephalosporins, sulfonamides, amphotericin B) [6], digoxin [15], antiepileptics [16]

Individuals with serious mental illness (SMI)

Elevated rates of HIV and blood‐borne viruses in those with schizophrenia [7,8]. Higher rates of infection with blood‐borne viruses in those with substance use disorders [7,9]. Lower adherence to antiretrovirals and higher viral load in those with SMI [10,11]

Those with SMI are more likely to have any kind of bacterial infection, including a doubled risk of tuberculosis [12]. Intravenous drug use increases risk of bacterial myocardial infection. There is some evidence that clozapine may reduce immune response, thereby increasing vulnerability to infection [13]

Immunocompromise occurs in starvation, e.g. anorexia nervosa, catatonia, or depression in old age. Uncontrolled HIV more common in SMI [14]

Clozapine, lithium, dopamine analogues used in Parkinson’s disease, barbiturates, and carbamazepine. Chlorpromazine, fluphenazine, haloperidol, and risperidone all associated with myocarditis in data‐ mining study of WHO adverse reactions [17]. Quetiapine [18] and olanzapine [19] in case reports only

Bacterial

Protozoal, fungal

Medication

Substances of abuse

Systemic disorders

Physiological states

Toxins

Stimulants (e.g. cocaine [20,21], amphetamines [22], mephedrone [23], alcohol [24], cannabis [25–27], and inhalants [28])

Diabetes mellitus, connective tissue disease, giant cell myocarditis, sarcoidosis, granulomatosis with polyangiitis, thyrotoxicosis, other autoimmune diseases

Increased risk in peripartum women [29,30]

For example, iron, lead, arsenic Smallpox vaccine [6]

Diabetes mellitus secondary to psychotropic use. Thyroid disease in use of antipsychotics and lithium

Tendency toward poorer living conditions and homeless in SMI. High prevalence of mental illness in those who have served in armed forces (who may have received smallpox vaccine) [31]

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Myocarditis 73

tachycardia and fever. More severe cases show evidence of heart failure, such as tachypnoea, peripheral oedema, orthopnoea (breathlessness on lying down) and raised jugular venous pressure [6].

History

History of presenting complaint

. 1 Most often non‐specific symptoms, feeling generally unwell, flu‐like illness.

. 2 Fever, with or without rigors.

. 3 Chest pain is present in about one‐third of cases and has symptoms similar to those of
ischaemic chest pain (heavy, central, crushing with radiation to the arm or jaw), atypical
chest pain or pleuritic pain (sharp, worse on breathing deeply or leaning forward).

. 4 Symptoms of heart failure, starting with reduced exercise tolerance and fatigue, pro-
gressing to orthopnoea, shortness of breath at rest, and peripheral oedema.

. 5 Palpitations, sensation of fast heart rate and syncope.

. 6 Viral illness within the preceding weeks, which may have resolved prior to the onset
of other symptoms. Gastroenteritis or upper respiratory tract infection are common
forerunners of myocarditis.

. 7 Menstrual history (risk increases with pregnancy).

. 8 Associated symptoms may point to a systemic inflammatory/autoimmune condition:
muscle aches and pains, joint pain, lymphadenopathy.

. 9 Recent travel history, especially to rural South America (Chagas disease).

Past medical history

. 1 Risk factors for myocarditis: autoimmune disease, infection screen (if HIV positive, assess concordance with treatment and last CD4 count; see Chapter 45).

. 2 Cardiovascular risk factors, e.g. hypertension, diabetes mellitus.

Medication history

1 See Table 8.1.
2 Check compliance, especially with potentially causative medication.

Family history

. 1 Similar symptoms in family members may suggest a familial cardiomyopathy.

. 2 Recent similar symptoms in family might suggest shared exposure to viral outbreak
or environmental toxins.

Social history

1 Recreational drug use, especially cocaine, amphetamines, inhalants or barbiturates. 2 Quantify alcohol and nicotine use.

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74 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Examination

. 1 Basic observations, including heart rate, blood pressure, respiratory rate, oxygen saturations, and temperature.

. 2 Cardiovascular and respiratory examination: signs of heart failure may include ‘gal- lop’ rhythm on auscultation, raised jugular venous pressure, peripheral oedema, bibasal crackles on auscultation of the chest (pulmonary oedema).

. 3 Neurological: altered consciousness indicating delirium, focal signs indicating central nervous system (CNS) infection as possible cause.

. 4 General: note height and weight (obesity is a poor prognostic factor) [34]. Evidence of arthritis (swelling or redness in the joints) or lymphadenopathy indicates an auto- immune cause. Evidence of liver disease (e.g. ascites, jaundice, spider naevi) might indicate alcohol/blood‐borne viral cause.

Investigations

Bloods

. 1 C‐reactive protein (CRP) and troponin are the most sensitive, if non‐specific, tests for myocarditis.

. 2 Full blood count (FBC) may show raised white cell count and eosinophilia, the latter particularly prevalent in clozapine‐induced myocarditis (CIM).

. 3 Urea and electrolytes.

. 4 Liver function tests.

. 5 B‐type natriuretic peptide (BNP) or N‐terminal pro‐hormone BNP (NTproBNP) may
help diagnose heart failure where there is ambiguity.

. 6 Where facilities allow, perform a viral screen including adenovirus, coxsackievirus A
and B, cytomegalovirus, echovirus, influenza, respiratory syncytial virus, mumps, rubella, adenovirus, varicella, human herpes virus 6, Epstein–Barr virus, varicella‐ zoster, HIV, and hepatitis B and C.

ECG

Often normal, and not required to diagnose myocarditis. Mostly used to exclude other causes of the clinical presentation such as ischaemia. However, changes seen in myocar- ditis may include the following.

. 1 Sinus tachycardia is the most common finding in CIM [37] but is also a common benign side effect at clozapine initiation [38].

. 2 Of those with CIM, 24% display T‐wave inversion, mostly in inferior and lateral leads (aVF, II, III, V4–V6) [37].

. 3 ST elevation, often in the anterior leads (V1–V3), is also common in myocarditis.

. 4 High‐grade atrioventricular block is common in myocarditis caused by Lyme disease or sarcoidosis.

CHAPTER 8

Chest X‐ray

May display cardiomegaly, pulmonary oedema, and bilateral pleural effusions if heart failure presents. Also helps to exclude other causes of raised inflammatory markers and chest pain, such as pneumonia.

Echocardiography

1 Left ventricular dysfunction.
2 Left ventricular dilation and wall motion abnormalities.

Specialist examinations

1 CardiacMRI(examiningforinflammatoryhyperaemiaandoedema,lategadolinium enhancement examining for scar formation).

2 Endomyocardial biopsy.

MANAGEMENT

Treat those with chest pain and ECG changes consistent with ischaemia as a medi- cal emergency; patients should be transferred as an emergency to acute medical services (see Chapter 69). Similarly, acute rises in troponin alongside chest pain (even in the absence of ECG changes) merit immediate transfer of the patient for medical review.

The European Society of Cardiology (ESC) states that those suspected of having myocarditis who are ‘haemodynamically unstable’ should be managed in high depend- ency units [6]. For those patients awaiting transfer to such a unit, immediate supportive care is necessary and should include oxygen therapy to keep saturations above 94%, cardiac monitoring, analgesia, constant pulse oximetry, and iterative measurement of vital signs.

The ESC also recommends the hospitalisation of haemodynamically stable patients suspected as having myocarditis, because of the fast changing nature of this clinical presentation, and the potential for rapid development of arrhythmia and heart failure [6]. Those responsible for the care of psychiatric patients suspected of having myocar- ditis should involve cardiologists early and develop a plan of investigation and treat- ment together. Medical treatment includes angiotensin‐converting enzyme inhibitors, diuretics, and beta‐blockers [2]. Psychiatrists should review medication and consider stopping or switching treatments also known to contribute to myocarditis risk.

CLOZAPINE‐INDUCED MYOCARDITIS

Myocarditis is an established complication of clozapine treatment [37]. CIM most often occurs within the first two weeks of treatment [37,39]. Some estimates of the

Myocarditis 75

CHAPTER 8

Box 8.1 Recommended monitoring for myocarditis on starting clozapine

▪ Daily measurement of pulse, temperature, and respiratory rate.

▪ Baseline measurement of FBC, CRP, troponin, ECG, and echocardiography.

▪ Weekly troponin and CRP (for first four weeks).

▪ Stop clozapine if CRP rises above 100 mg/L and troponin double the upper limit of normal. Refer
for echocardiography.

▪ Switch to daily troponin and CRP monitoring if there is fever, tachycardia plus either CRP or tro-
ponin above normal limits [49].

76 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

prevalence of CIM are up to two orders of magnitude greater than the lowest estimates, with the highest estimates coming from studies conducted in Australia [34,40,41]. Kilian and colleagues [42] estimated that the rate of myocarditis is 2000 times higher in the first month of treatment with clozapine than it is in the general population. CIM is associated with significant mortality, although estimates vary greatly [43]. Many countries have established national monitoring protocols for CIM, and subsequent reporting of non‐fatal suspected CIM to national databases in these countries has increased dramatically, without an increase in fatal cases or a comparable increase in prescription of clozapine [44,45]. Contrary to the Australian data, a 2017 retrospective study of over 800 patients commenced on clozapine at a UK institution using a similar monitoring protocol found an incidence of only 0.11% [38].

Despite the wide range of incidence estimates, most authors agree on several key points. Clozapine is an effective antipsychotic shown to reduce all‐cause mortality [46]. The better the treatment of the psychiatric symptoms of those with schizophrenia, the better treated their physical health problems [38]. Clozapine is underused and discon- tinued too often, denying many people with schizophrenia optimum treatment [47,48]. Testing of troponin and CRP during clozapine titration is a reasonable way of monitor- ing for myocarditis, although there is no direct evidence that such protocols reduce mortality [38,44,45]. A recommended monitoring regimen for emergent myocarditis during the first four weeks of treatment is shown in Box 8.1.

Clozapine re‐challenge post myocarditis

There have been reports of 19 patients being re‐challenged with clozapine following CIM [37]; seven developed CIM for a second time, while re‐challenge was successful in the remaining 12. National Institute for Health and Care Excellence (NICE) guidelines recommend that the clinician ‘discontinue permanently’ clozapine in those diagnosed with CIM [37]. In patients where clozapine represents the only viable treatment option for severe psychotic symptoms, a risk–benefit decision needs to be made regarding re‐ challenge and must involve multidisciplinary discussion involving both psychiatry and cardiology. Considering the significant risk of myocarditis reoccurring, clozapine re‐ challenge after CIM should be carried out in an inpatient setting (ideally a specialist psychiatric setting) in collaboration with cardiology colleagues, with vigilant monitoring of CRP and troponin and echocardiography [39].

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Myocarditis 77

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Chapter 9

Hypercholesterolaemia

Dipen Patel, Toby Pillinger, Narbeh Melikian

Hypercholesterolaemia describes elevated total or low‐density lipoprotein (LDL) cholesterol levels in the blood. Dyslipidaemia is a broader term used to describe hyper- cholesterolaemia accompanied by low levels of high‐density lipoprotein (HDL) choles- terol and/or raised triglycerides. Dyslipidaemia plays a significant role in the development of atherosclerosis (a condition where deposition of cholesterol‐rich particles in the wall of arteries results in progressive narrowing of vessels). Along with smoking, type 2 dia- betes mellitus and hypertension, dyslipidaemia is a key modifiable risk factor for car- diovascular disease (CVD) [1]. It is now well recognised that reducing cholesterol levels improves cardiovascular prognosis (including reducing rates of myocardial infarction and death) in individuals with (secondary prevention) and without (primary preven- tion) established CVD [2,3].

Compared with the general population, people with serious mental illness (SMI) have a significantly reduced life expectancy [2]. The majority of this excess mortality is sec- ondary to physical health conditions, in particular CVD. Mortality from CVD is approximately three times greater in people with SMI compared with the general popu- lation [3]. People with SMI have a higher prevalence of CVD risk factors, including obesity, hypertension, diabetes mellitus, and dyslipidaemia [4]. This is driven in part by physical inactivity, unhealthy dietary choices, high rates of smoking, and antipsychotic medication [5]. Common causes of hypercholesterolaemia in the general and psychiat- ric population are documented in Box 9.1.

Box 9.1 Causes of hypercholesterolaemia Primary (unmodifiable) causes

▪ Congenital (e.g. familial hypercholesterolaemia and familial combined hyperlipidaemia)

▪ Increasing age

▪ Male gender
Secondary (modifiable) causes

▪ Dieta

▪ Smokinga

▪ Alcohola

▪ Medical conditions (e.g. diabetes mellitus,a chronic liver or kidney disease,a hypothyroidisma)

▪ Obesitya

▪ Medications: ciclosporin, glucocorticoids, antiretrovirals, retinoic acid derivatives, oral contraceptive
pill, atypical antipsychotics,a some mood stabilisersa (e.g. sodium valproate and lithium), and antidepressantsa
a Factors more common in patients with SMI compared with the general population.

80 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES History

Hypercholesterolaemia is asymptomatic and usually identified during routine blood screening or when an individual presents with a clinical complication of established CVD disease (such as a myocardial infarction or stroke).

Therefore, the history should focus on (i) identifying evidence of underlying risk fac- tors for hypercholesterolaemia (which may then be modified); (ii) identifying physical comorbidity, the presence of which may influence the management plan (e.g. presence of CVD should prompt secondary CVD prevention initiatives); and (iii) identifying symptoms suggestive of CVD which may have been hitherto undiagnosed (which will require further investigation).

As such, the following should be elucidated.

. 1 SymptomsindicativeofCVD,forexampleangina(chestdiscomfortduringexertion or stress) or intermittent arterial claudication (calf discomfort during exertion).

. 2 Past medical history:

. a established CVD and/or presence or classical risk factors for CVD

. b alternative risk factors for raised cholesterol, e.g. type 2 diabetes mellitus, chronic
liver disease, chronic kidney disease, hypothyroidism, polycystic ovary syndrome, specific medication (such as selective immunosuppressants) that can elevate choles- terol levels (Box 9.1).

. 3 Social history:
a excess alcohol b smoking status

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c diet (cholesterol‐rich diet such as excess consumption of all dairy products, shell- fish, red meat, and fried food)

d amount of exercise engaged in on a weekly basis.
4 Family history of premature CVD (defined as diagnosis of CVD in first‐degree

relative below the age of 55 years for men and 65 years for women) and hypercholesterolaemia.

Examination

Check basic observations to examine for comorbid hypertension and calculate body mass index (BMI) to guide need for weight loss. Examination may be unremarkable. However, in the case of familial hypercholesterolaemia, corneal arcus (white or grey opaque ring in margin of cornea) or tendon xanthomata (nodules attached to tendons in hands, feet, and Achilles tendon) may be observed. If history suggests presence of CVD, a cardiovascular and peripheral vascular examination is indicated (the results of which may be included in a referral to cardiology/vascular services).

Investigations

. 1 Blood tests:

. a fasting full lipid profile including total cholesterol, LDL cholesterol, HDL choles-
terol, and triglycerides

. b urea and electrolytes

. c liver function tests

. d HbA1c

. e thyroid function tests.

. 2 Urine dipstick: proteinuria (suggestive of kidney disease) or glucosuria (suggestive of diabetes mellitus).

. 3 ECG: evidence of ischaemic heart disease.
DIAGNOSTIC CRITERIA

The European Society of Cardiology (ESC) guideline considers patients in terms of dif- ferent levels of risk and targets reflect the different level of risk (readers are directed to this resource for further information). However, the guidance states that in general total plasma cholesterol should be less than 5 mmol/L (<190 mg/dL) and LDL cholesterol should be less than 3 mmol/L (<115 mg/dL) (for low‐risk individuals) [6]. If total cho- lesterol is above 7.5 mmol/L and/or there is a family history of premature heart disease, consider a diagnosis of familial hypercholesterolaemia.

MANAGEMENT

The aim of treating hypercholesterolaemia is to reduce the risk of mortality and morbidity from CVD. Management approaches should always, where possible, include non‐pharmacological approaches. Of note, although raised triglyceride is a

Hypercholesterolaemia 81

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82 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

risk factor for CVD, there is currently insufficient evidence to support the practice of pharmacologically lowering triglyceride levels for CVD risk reduction.

Lifestyle modification

There is clear evidence that lifestyle modification reduces the risk of developing CVD. A recent meta‐analysis found that, compared with usual care, lifestyle interventions (specifically dietary modification and exercise) achieved significant improvements in total cholesterol [7]. Patients should be advised to follow a diet that is low in fatty food, to replace saturated fats with unsaturated fats (e.g. olive oil), to limit total calorific intake (2000 kcal/day for women, 2500 kcal/day for men; see Chapter 14), and to reduce alcohol intake. Patients should also be advised to undertake at least 150 minutes of moderate‐intensity aerobic activity or 75 minutes of vigorous intensity aerobic activ- ity weekly (see Chapter 10 for further details) [8].

Rationalisation of antipsychotic medication

Clozapine, olanzapine, and quetiapine are associated with increased risk of weight gain and lipid disturbance compared with other antipsychotics [9,10]. Similarly, certain mood stabilisers and antidepressants increase risk of weight gain (see Chapter 14), and therefore by association hypercholesterolaemia. As such, where hypercholesterolaemia is identified in a patient with SMI taking a psychiatric medication that may be at least partially causative, a multidisciplinary discussion is indicated involving the psychiatrist, primary care doctor, and ideally the patient to discuss the most appropriate course of action. This will involve a risk–benefit discussion weighing up the benefits of ongoing treatment (improved mental state) versus the risks (increased CVD risk), and where appropriate consideration of alternative treatments with more benign CVD risk (see Chapter 14).

Pharmacological treatment

Lipid modification therapy should be offered to all patients with established CVD as part of secondary prevention initiatives. A high‐intensity statin treatment (e.g. atorvas- tatin 80 mg once daily) is recommended (Box 9.2). The initial target is to achieve a 40% or greater reduction in non‐HDL cholesterol after 3 months [8].

In the primary prevention of CVD, where lifestyle interventions fail to bring choles- terol levels to within optimal range, statin therapy should be considered. National Institute for Health and Care Excellence (NICE) guidelines advocate the use of the Q‐RISK2 calculator to guide the need for lipid‐modifying therapy. This tool estimates the risk of heart attack or stroke for a given individual over a 10‐year period based on various CVD risk factors (e.g. age, ethnicity, comorbidity, and cholesterol levels). We would however advocate the use of the updated Q‐RISK3 tool [11], which factors in a diagnosis of SMI and prescription of second‐generation antipsychotics as part of its CVD risk calculation. Patients should be offered lipid‐modification therapy (e.g. ator- vastatin 20 mg daily) if they present with a 10‐year CVD risk of 10% or greater. As in

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Hypercholesterolaemia 83

Box 9.2 Intensities of statin therapy available

All doses are once daily by mouth

High‐intensity statin therapy

Atorvastatin 20–80 mg Rosuvastatin 10–20 mg Simvastatin 80 mg

Moderate‐intensity statin therapy

Atorvastatin 10 mg Rosuvastatin 5 mg Simvastatin 10–40 mg Pravastatin 40–80 mg Lovastatin 40 mg

secondary prevention, the initial target is to achieve a 40% or greater reduction in non‐HDL cholesterol after 3 months [8]. NICE also advises considering statin therapy for patients with type 1 diabetes who are over the age of 40, patients who have had diabetes mellitus for more than 10 years, or those with chronic kidney disease or other CVD risk factors.

In the USA, the American College of Cardiology (ACC)/American Heart Association (AHA) recommend treating those with an estimated 10‐year CVD risk of 7.5% or more with ‘moderate‐to‐high intensity’ statin therapy, and those with a risk of 5–7.5% with ‘moderate‐intensity’ therapy (see Box 9.2 for intensities of statin therapy avail- able) [12]. Muscle/joint discomfort, indigestion, and deranged liver function tests are common side effects of treatment with statins. Serious or life‐threatening side effects such as myositis, rhabdomyolysis, and liver dysfunction are rare. Discuss the risks and benefits of statin treatment so that the patient can make an informed choice about their treatment. Counsel regarding the clear cardiovascular benefits of reduc- ing cholesterol levels using a statin. Also outline that the adverse effects of statins are generally mild, reversible, and not medically serious. Myositis and rhabdomyolysis are rare, with estimated incidences of 5 per 100,000 person‐years and 1.6 per 100,000 person‐years, respectively [8]. In the context of risk of myositis, if a patient has per- sistent generalized unexplained muscle pain (whether associated with previous lipid‐ lowering therapy or not) measure creatine kinase (CK) levels. If CK or liver function tests are abnormal, then stop the statin and discuss with general medical colleagues if there are concerns regarding renal or hepatic function. If tests correct after stopping the statin, then the culprit is clear, and lipid clinic advice should be sought. In the case of symptom resolution after myositis, options include switching to a moderate‐inten- sity statin (e.g. pravastatin) if side effects occurred with a high‐intensity statin, or dose reduction if the patient was on a moderate‐intensity statin. Ezetimibe, which inhibits intestinal absorption of cholesterol, may be used where statin treatment is inappropriate or not tolerated (10 mg once daily by mouth). PCSK9 inhibitors

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84 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

(e.g. evolocumab and alirocumab), given as subcutaneous injections every two to four weeks, can also be used where statins are not tolerated [13].

When to refer

Hypercholesterolaemia can normally be managed by primary care physicians. However, a lipid clinic referral is indicated for any patient who may have a diagnosis of familial hypercholesterolaemia, if desired cholesterol level is not achieved despite appropriate intervention, or where there may be contraindications/side effects to statin therapy (e.g. persistently raised CK levels). A cardiology referral should be made in any patient where hitherto undiagnosed CVD has been identified (e.g. via a rapid‐access chest pain clinic).

References

1. Helkin A, Stein JJ, Lin S, et al. Dyslipidemia Part 1. Review of lipid metabolism and vascular cell physiology. Vasc Endovascular Surg 2016;50(2):107–118.

2. Chesney E, Goodwin GM, Fazel S. Risks of all‐cause and suicide mortality in mental disorders: a meta‐review. World Psychiatry 2014;13(2):153–160.

3. Osborn DPJ, Levy G, Nazareth I, et al. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s General Practice Research Database. Arch Gen Psychiatry 2007;64(2):242–249.

4. Mitchell AJ, Vancampfort D, Sweers K, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders: a systematic review and meta‐analysis. Schizophr Bull 2013;39(2):306–318.

5. Baller JB, McGinty EE, Azrin ST, et al. Screening for cardiovascular risk factors in adults with serious mental illness: a review of the evidence. BMC Psychiatry 2015;15:55.

6. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (con- stituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33(13):1635–1701.

7. Zhang X, Devlin HM, Smith B, et al. Effect of lifestyle interventions on cardiovascular risk factors among adults without impaired glucose tolerance or diabetes: a systematic review and meta‐analysis. PLoS One 2017;12(5):e0176436.

8. National Institute for Health and Care Excellence. Lipid modification: CVD prevention. Last revised: August 2019. https://cks.nice.org.uk/ lipid‐modification‐cvd‐prevention

9. Rummel‐Kluge C, Komossa K, Schwarz S, et al. Head‐to‐head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta‐analysis. Schizophr Res 2010;123(2–3):225–233.

10. Pillinger T, McCutcheon R, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta‐analysis. Lancet Psychiatry 2020;7:64–77.

11. ClinkRisk. The QRISK3‐2018 risk calculator. https://qrisk.org/three/.

12. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Circulation 2014;129(25 Suppl 2):S46–S48.

13. Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol 2017;9(2):76–91.

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Chapter 10

Physical Activity

Garcia Ashdown-Franks, Brendon Stubbs

Physical activity (PA) is defined as ‘any bodily movement produced by skeletal muscles requiring energy expenditure’ [1]. As such, PA involves a range of activities such as light workplace or leisure‐time activity including housework, moving around at work, sport, leisure activities, or exercise. Exercise is a planned and structured form of PA, with the objective of improving or maintaining physical fitness [1].

In the general population, higher levels of PA are associated with healthier ageing [2], improved quality of life [3], and reduced risk of developing both psychiatric disorders [4,5] and physical health conditions such as diabetes mellitus [6] and cardiovascular disease [7]. PA has the potential to play an important role in the successful management of both the physical and mental health of patients with cancer, cardiovascular disease, chronic respiratory disease, and chronic musculoskeletal conditions [8–12]. For exam- ple, a recent network meta‐analysis of 391 randomised controlled trials suggested that PA may have comparable efficacy to many common pharmacological agents in the management of hypertension [13].

PHYSICAL ACTIVITY AND SERIOUS MENTAL ILLNESS

Individuals with severe mental illness (SMI) die up to 20 years earlier than members of the general population [14], with 60% of this premature mortality attributed to physi- cal health conditions, in particular cardiovascular disease [15,16]. Given that PA is effective in the prevention [3,6,7] and management [8–12] of various physical morbidi- ties in the general population, there is potential for translation of PA interventions to the management of physical health conditions in people with SMI [17]. There is also potential for PA to play a role in the management of psychiatric symptoms, even those historically poorly controlled by traditional pharmacological and psychological interventions.

86 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

For example, in the general population, PA has a protective cognitive effect [18], with efficacy also observed in patients with Alzheimer’s disease [19]. In major depressive disorder (MDD), 12–16 weeks of PA improves symptoms compared to control condi- tions, with greatest effect sizes observed when PA is delivered at moderate to vigorous intensity (e.g. cycling, running, or playing football) [17]. The beneficial effects of exer- cise on mood also persist over time; a recent 12‐month study comparing the influence of aerobic exercise, internet‐delivered cognitive‐behavioural therapy (iCBT), and treat- ment as usual on the symptoms of MDD found that both PA and iCBT improved depressive symptoms more than usual care, with no significant difference observed between the PA and iCBT groups [20]. For schizophrenia spectrum disorder, there is evidence that aerobic PA delivered over 12–16 weeks can reduce positive, negative, and cognitive symptoms as well as improving cardiorespiratory fitness [17]. Furthermore, PA, as in the general population, has been observed to improve the quality of life of patients with schizophrenia [21].

HOW MUCH PHYSICAL ACTIVITY AND EXERCISE SHOULD PEOPLE BE DOING?

Current PA guidelines recommend a weekly combination of regular aerobic (cardiovas- cular training such as a brisk walk or playing a sport) and strength/resistance PA (using muscles against resistance such as using weights in a gym) [22]. Specifically, it is recom- mended that adults achieve at least 150 minutes per week of moderate aerobic PA (an activity that leads to the person becoming slightly short of breath, such as cycling or brisk walking), or 75 minutes per week of vigorous PA (where the person struggles to talk and breathe at the same time, such as running fast). Moreover, it is recommended that adults include strength training on two or more days each week. It is often recom- mended that adults participate in 30 minutes of moderate aerobic activity on five days each week, but the 150 minutes can be spread out however the individual chooses. Recent American guidelines have suggested that adults should seek to achieve 150–300 of moderate and 75–150 minutes of vigorous PA per week [23]. However, the guide- lines recognise that groups with chronic physical or mental disorders may struggle to achieve such targets and emphasise that engaging in even small amounts of PA is of worth. PA can of course take the form of various activities, such as organised sport, gardening, housework, and dancing. People should be encouraged to find a PA that they enjoy, to set goals over time to increase PA levels, and to engage with PA through- out their life [24].

Individuals with SMI are significantly more sedentary and engage in lower levels of PA compared with the general population [25]; psychiatric patients are 50% less likely to meet recommended guidelines of 150 minutes of moderate to vigorous PA per week [25]. Barriers to PA in the SMI population include symptoms of psychiatric illness (e.g. low mood, negative symptoms such as amotivation, and paranoia), lack of confidence in engaging in PA, physical comorbidity, side effects of psychiatric medication (e.g. sedation or extrapyramidal side effects), and lack of support and knowledge about PA [26,27]. In a recent systematic review, up to 63% of people with SMI reported that they

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would exercise more if given appropriate advice by their physician [28]. Psychiatric practitioners are thus uniquely positioned to provide guidance which should increase PA levels in this population.

PRACTICAL TIPS

PA is relatively safe and inexpensive, with evidence of benefits to both mental and physical health in SMI [17]. As such, it is recommended that psychiatric practitioners discuss and encourage engagement in PA as part of routine clinical reviews with patients. One approach is to use ‘physical activity vital sign’ (PAVS) questions to assess the amount of activity engaged in by the patient on a weekly basis [29]. This involves ask- ing the following questions.

1 On average, how many days per week do you engage in moderate to vigorous physi- cal activity such as a brisk walk?

2 On those days, on average how many minutes do you engage in physical activity at this level?

The clinician can then calculate the minutes of moderate to vigorous PA completed per week and establish if the patient complies with the recommendation of 150 minutes. This provides an entry point to discuss PA and, if appropriate, how to incorporate more activity into the patient’s life. PAVS scores can also act as a convenient screening tool for cardiometabolic health; low PAVS scores (i.e. fewer PA minutes per week) are asso- ciated with increased cardiometabolic risk in both schizophrenia [30] and bipolar dis- order [31].

MESSAGES TO INCLUDE IN DISCUSSIONS WITH PATIENTS

▪ Emphasise that any activity is better than none. Advise the patient to ‘start small’ and to increase incidental activity in daily life. Walking has numerous recognised health benefits in SMI [32].

▪ Help the patient determine ways to incorporate activity into their lifestyle in simple ways. Practical examples include:

▪ getting off the bus one stop early and walking the remainder of the journey

▪ taking the stairs instead of elevator

▪ standing up and moving around for a short walk every 30 minutes.

▪ Have the person find an activity that they enjoyed doing in the past [24].

▪ Social support is key; the patient should be encouraged to engage in PA with a friend,
relative, or trainer [33,34].

▪ Ultimately, patients should be aiming to complete two to three sessions every week
of supervised aerobic and/or aerobic and resistance training of moderate intensity for 45–60 minutes, which is associated with optimal mental and physical health benefits [20].

Physical Activity 87

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88 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Psychiatric multidisciplinary teams should seek to include exercise professionals such as exercise physiologists or physiotherapists. Where access to such professionals exists, patients interested in increasing PA levels should be referred: optimal beneficial impact of PA on cardiorespiratory fitness in SMI is achieved when PA is supervised by these personnel [17]. For teams who do not have access to exercise professionals, an effort to forge links with community exercise specialists is recommended.

References

1. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health‐related research. Public Health Rep 1985;100(2):126–131.

2. Daskalopoulou C, Stubbs B, Kralj C, et al. Physical activity and healthy ageing: a systematic review and meta‐analysis of longitudinal cohort studies. Ageing Res Rev 2017;38:6–17.

3. Gill DL, Hammond CC, Reifsteck EJ, et al. Physical activity and quality of life. J Prev Med Public Health 2013;46(Suppl 1):S28–S34.

4. Schuch FB, Vancampfort D, Firth J, et al. Physical activity and incident depression: a meta‐analysis of prospective cohort studies. Am J
Psychiatry 2018;175(7):631–648.

5. McDowell CP, Gordon BR, MacDonncha C, Herring MP. Physical activity correlates among older adults with probable generalized anxiety
disorder: results from the Irish Longitudinal Study on Ageing. Gen Hosp Psychiatry 2019;59:30–36.

6. Smith AD, Crippa A, Woodcock J, Brage S. Physical activity and incident type 2 diabetes mellitus: a systematic review and dose–response
meta‐analysis of prospective cohort studies. Diabetologia 2016;59(12):2527–2545.

7. Naci H, Ioannidis JP. Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ
2013;347:f5577.

8. Wong P, Muanza T, Hijal T, et al. Effect of exercise in reducing breast and chest‐wall pain in patients with breast cancer: a pilot study. Curr
Oncol 2012;19(3):e129–e135.

9. Eisele A, Schagg D, Kramer LV, et al. Behaviour change techniques applied in interventions to enhance physical activity adherence in patients
with chronic musculoskeletal conditions: a systematic review and meta‐analysis. Patient Educ Couns 2019;102(1):25–36.

10. Billinger SA, Mattlage AE, Ashenden AL, et al. Aerobic exercise in subacute stroke improves cardiovascular health and physical performance.
J Neurol Phys Ther 2012;36(4):159–165.

11. Lahham A, McDonald CF, Holland AE. Exercise training alone or with the addition of activity counseling improves physical activity levels in
COPD: a systematic review and meta‐analysis of randomized controlled trials. Int J Chron Obstruct Pulmon Dis 2016;11:3121–3136.

12. Welch WA, Alexander NB, Swartz AM, et al. Individualized estimation of physical activity in older adults with type 2 diabetes. Med Sci Sports
Exerc 2017;49(11):2185–2190.

13. Naci H, Salcher‐Konrad M, Dias S, et al. How does exercise treatment compare with antihypertensive medications? A network meta‐analysis
of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. Br J Sports Med 2019;53(14):
859–869.

14. Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease burden implications: a systematic review and meta‐
analysis. JAMA Psychiatry 2015;72(4):334–341.

15. Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific
severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 2017;16(2):163–180.

16. Gardner‐Sood P, Lally J, Smith S, et al. Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses:
baseline data from the IMPaCT randomized controlled trial. Psychol Med 2015;45(12):2619–2629.

17. Stubbs B, Vancampfort D, Hallgren M, et al. EPA guidance on physical activity as a treatment for severe mental illness: a meta‐review of the
evidence and Position Statement from the European Psychiatric Association (EPA), supported by the International Organization of Physical
Therapists in Mental Health (IOPTMH). Eur Psychiatry 2018;54:124–144.

18. Blondell SJ, Hammersley‐Mather R, Veerman JL. Does physical activity prevent cognitive decline and dementia? A systematic review and
meta‐analysis of longitudinal studies. BMC Public Health 2014;14:510.

19. Du Z, Li YW, Li JW, et al. Physical activity can improve cognition in patients with Alzheimer’s disease: a systematic review and meta‐analysis
of randomized controlled trials. Clin Interv Aging 2018;13:1593–1603.

20. Hallgren M, Helgadottir B, Herring MP, et al. Exercise and internet‐based cognitive‐behavioural therapy for depression: multicentre ran-
domised controlled trial with 12‐month follow‐up. Br J Psychiatry 2016;209(5):416–422.

21. Dauwan M, Begemann MJH, Heringa SM, Sommer IE. Exercise improves clinical symptoms, quality of life, global functioning, and depres-
sion in schizophrenia: a systematic review and meta‐analysis. Schizophr Bull 2016;42(3):588–599.

22. Bouchard C, Blair DT, Haskell WL (eds). Physical Activity and Health, 2nd edn. Champaign, IL: Human Kinetics, 2012.

23. Piercy KL, Troiano RP, Ballard RM, et al. The physical activity guidelines for Americans. JAMA 2018;320(19):2020–2028.

24. Ekkekakis P, Parfitt G, Petruzzello SJ. The pleasure and displeasure people feel when they exercise at different intensities: decennial update
and progress towards a tripartite rationale for exercise intensity prescription. Sports Med 2011;41(8):641–671.

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Physical Activity 89

25. Vancampfort D, Firth J, Schuch FB, et al. Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta‐analysis. World Psychiatry 2017;16(3):308–315.

26. Firth J, Rosenbaum S, Stubbs B, et al. Preferences and motivations for exercise in early psychosis. Acta Psychiatr Scand 2016;134(1):83–84.

27. Firth J, Rosenbaum S, Stubbs B, et al. Motivating factors and barriers towards exercise in severe mental illness: a systematic review and
meta‐analysis. Psychol Med 2016;46(14):2869–2881.

28. Farholm A, Sorensen M. Motivation for physical activity and exercise in severe mental illness: a systematic review of intervention studies. Int
J Ment Health Nurs 2016;25(3):194–205.

29. Coleman KJ, Ngor E, Reynolds K, et al. Initial validation of an exercise ‘vital sign’ in electronic medical records. Med Sci Sport Exerc
2012;44(11):2071–2076.

30. Vancampfort D, Stubbs B, Probst M, et al. Physical activity as a vital sign in patients with schizophrenia: evidence and clinical recommenda-
tions. Schizophr Res 2016;170(2–3):336–340.

31. Vancampfort D, Probst M, Wyckaert S, et al. Physical activity as a vital sign in patients with bipolar disorder. Psychiatry Res
2016;246:218–222.

32. Ashdown‐Franks G, Williams J, Vancampfort D, et al. Is it possible for people with severe mental illness to sit less and move more? A system-
atic review of interventions to increase physical activity or reduce sedentary behaviour. Schizophr Res 2018;202:3–16.

33. Gross J, Vancampfort D, Stubbs B, et al. A narrative synthesis investigating the use and value of social support to promote physical activity
among individuals with schizophrenia. Disabil Rehabil 2016;38(2):123–150.

34. Cohrdes C, Bretschneider J. Can social support and physical activity buffer cognitive impairment in individuals with depressive symptoms?
Results from a representative sample of young to older adults. J Affect Disord 2018;239:102–106.

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Part 2

Endocrinology

Chapter 11

Diabetes Mellitus

Yuya Mizuno, Toby Pillinger, Dan Siskind, Sophie Harris

Diabetes mellitus is an umbrella term describing a group of metabolic disorders charac- terised by high blood glucose. It is associated with relative or total impairment in pan- creatic insulin secretion, and with varying degrees of peripheral insulin resistance [1]. It is a major risk factor for both microvascular disease (retinopathy, nephropathy, and neuropathy) and macrovascular disease (coronary heart disease, peripheral arterial dis- ease, and stroke) [2]. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes in adults (>90%) and forms the focus of this chapter (see Box 11.1 for a description of type 1 diabetes mellitus and its relevance in the context of psychiatric illness). People with severe mental illness (SMI) are twice as likely to develop T2DM compared with the general population [3], with prevalence estimated at around 11% [4,5]. Furthermore, approximately three in five people with diabetes mellitus report low mood as a consequence of their condition [6]. People with SMI and T2DM receive poorer quality of diabetes management compared to people without mental illness [7,8]. Diagnosis and management of T2DM is thus important in preventing physical disability and premature mortality in this high‐risk population.

DIAGNOSTIC PRINCIPLES

Although the classical symptoms of raised blood glucose are polydipsia, polyuria, blurred vision, and weight loss [9], the majority of patients with T2DM are asympto- matic and diagnosis follows routine blood screening. Emergency presentations of diabetes are discussed in Chapter 74.

Box 11.1 Type 1 diabetes mellitus and implications for the psychiatric population

▪ Type 1 diabetes mellitus (T1DM) is characterised by autoimmune destruction of pancreatic beta cells, leading to total impairment of insulin secretion. As such, patients require immediate insulin therapy.

▪ In the psychiatric population, T1DM can pose various therapeutic challenges. Erratic use of insu- lin, potentially in the context of chaotic behaviour secondary to cognitive or negative symptoms of schizophrenia, can predispose to hypoglycaemic episodes or diabetic ketoacidosis with associ- ated acute risk to life, or chronic hyperglycaemia with associated comorbidity and premature mortality.

▪ Insulin, at higher doses, is lethal and this needs to be considered in patients at risk of deliberate self‐harm.

▪ Diabulimia is an eating disorder in which people with T1DM deliberately give themselves less insulin than they need for the purpose of weight loss.

▪ Patients with comorbid T1DM and SMI can be highly complex, and a multidisciplinary team approach to management, involving psychiatrists, psychologists, and diabetologists, is essential.

94 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

History

History of presenting complaint

Although the signs and symptoms of hyperglycaemia (polydipsia, polyuria, blurred vision, and weight loss) may be mild or absent, they should be screened for [9]. Other symptoms that may indicate complications of T2DM (generally in advanced disease) include visual symptoms of retinopathy (blurred vision, ‘floaters’, progressive loss of visual acuity), sensory/motor symptoms of a peripheral neuropathy (typically symmet- rical and distal: numbness/reduced ability to feel pain/temperature in fingers/toes), passing of foamy urine (proteinuria of nephropathy), impotence, acanthosis nigricans (dark velvety discoloration of body folds/creases), and frequent infections (particularly candidiasis, urinary tract infection, and abscesses) [9].

Past medical history

Sociodemographic factors such as advancing age and ethnicity (particularly South Asian, Hispanic, or African‐Caribbean decent) predispose to T2DM [10]. Furthermore, obesity (body mass index, BMI ≥30) [11] and increased waist circumference (>80 cm for all women; >94 cm for most men; >90 cm for South Asian men) [12,13] are important risk factors for T2DM. Screen for comorbid metabolic (i.e. hypertension, hypercholesterolae- mia) and cardiovascular disease (CVD), and for medical conditions that predispose indi- viduals to T2DM (e.g. polycystic ovary syndrome). Cushing’s disease and Wilson’s disease represent causes of T2DM that may also present with neuropsychiatric symptoms.

Drug history

Several psychiatric medications can predispose patients to T2DM, including antipsychot- ics, mood stabilisers, and antidepressants [14–16]. Non‐psychiatric drugs that can increase risk of T2DM include corticosteroids, thiazide diuretics, beta‐blockers, and statins.

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Diabetes Mellitus 95

Family history

There is a hereditary component to T2DM. Identifying family history of premature CVD may provide greater impetus to targeting other modifiable CVD risk factors alongside glucose control.

Social history

Modifiable risk factors for T2DM include levels of physical activity, dietary habits, smoking, and alcohol use [17]. Targeting these factors may form part of treatment (see Chapters 10, 14, 24, and 46).

Examination

Examination may be normal, unless the patient is presenting with a hyperglycaemic emergency (see Chapter 74) or, in patients with advanced chronic disease (which may be seen in patients with SMI presenting late to medical services), damage to multiple organ systems may be apparent. A set of basic observations may identify comorbid hypertension. General inspection should note body habitus, evidence of dehydration, and presence of skin alterations typical of T2DM (e.g. acanthosis nigricans). Consider performing cardiovascular and neurological examinations (with fundoscopy) to screen for complications of T2DM.

Investigations

The diagnostic glucose concentrations defined by the World Health Organization (WHO) are those above which it is recognised that an individual will be at high risk of developing microvascular complications [18]. Diagnosis may be made using random/ fasting plasma glucose, plasma glucose following the oral glucose tolerance test (OGTT), or HbA1c. Various international and national criteria exist (Box 11.2) [18–20]. These are all broadly similar, save for the UK (NICE) guidelines [20] that provide a more narrow definition of pre‐diabetes compared with the definitions of the American Diabetic Association [19] and WHO [18]. In symptomatic patients, only one glucose assessment is required to confirm diagnosis, whereas in asymptomatic patients two confirmatory glucose assessments are required. In psychiatric practice, fasting glucose assessments may be unrealistic (e.g. in patients who may not comply with fasting requirements), and the OGTT often unfeasible. As such, the HbA1c represents the sim- plest method of glucose assessment, and two separate HbA1c measurements of 6.5% or above in an asymptomatic patient will confirm diagnosis. However, clinicians should be aware that in patients with high red blood cell turnover (e.g. sickle cell anaemia, preg- nancy), use of HbA1c is inappropriate [21], and diagnosis will instead require assess- ment of plasma glucose levels.

Pre‐diabetes is a condition where blood glucose levels are higher than normal but do not yet meet the criteria for diabetes mellitus. About 30% of people with pre‐diabetes will progress to T2DM within 10 years. This provides opportunity to offer interven- tions to reduce risk of progression [22].

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Box 11.2 Diagnostic criteria for diagnosis of type 2 diabetes mellitus

World Health Organization [18]

Diabetes mellitus

HbA1c ≥48 mmol/mol (6.5%) or
FPG ≥7.0 mmol/L (126 mg/dL) or
2‐hour PG after 75 g OGTT ≥11.1 mmol/L (200 mg/dL) or Random PG ≥11.1 mmol/L (200 mg/dL)

Pre‐diabetes

42 ≤ HbA1c < 48 mmol/mol (6.0–6.4%) or
5.5 ≤ FPG < 7.0 mmol/L (100–125 mg/dL) or
7.8 ≤ 2‐hour PG after 75 g OGTT < 11.1 mmol/L (140–199 mg/dL)

American Diabetic Association [19]

Diabetes mellitus

HbA1c ≥48 mmol/mol (6.5%) or
FPG ≥7.0 mmol/L (126 mg/dL) or
2‐hour PG after 75 g OGTT ≥11.1 mmol/L (200 mg/dL) or Random PG ≥11.1 mmol/L (200 mg/dL)

Pre‐diabetes

39 ≤ HbA1c < 48 mmol/mol (5.7–6.4%) or
5.5 ≤ FPG < 7.0 mmol/L (100–125 mg/dL) or
7.8 ≤ 2‐hour PG after 75 g OGTT <11.1 mmol/L (140–199 mg/dL)

National Institute for Health and Care Excellence [20]

Diabetes mellitus

HbA1c >48 mmol/mol (6.5%) or
Random PG ≥11.1 mmol/L (200 mg/dL) or FPG ≥7.0 mmol/L (126 mg/dL)

Pre‐diabetes

42 ≤ HbA1c < 48 mmol/mol (6.0–6.4%) or
FPG ≥7.0 mmol/L (126 mg/dL) or
6.1 ≤ FPG < 7.0 mmol/L (110–125 mg/dL) or
7.8 ≤ 2-hour PG after 75 g OGTT < 11.1 mmol/L (140–199 mg/dL)

FPG, fasting plasma glucose (defined as no caloric intake for at least eight hours); OGTT, oral glucose tolerance test; PG, plasma glucose.

96 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Other investigations may be performed to screen for diabetes‐related complications and cardiovascular risk. These should be performed at least yearly and are described in more detail in the section on annual diabetic review.

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Drug class

Biguanide (metformin)

Dipeptidyl peptidase‐4 (DPP‐4) inhibitor (e.g. sitagliptin)

Glucagon‐like peptide‐1 receptor (GLP1R)‐agonists (e.g. exenatide)

Sulphonylureas (e.g. gliclazide)

Sodium glucose transporter 2 (SGLT2) inhibitors (e.g. dapagliflozin)

Mechanism

Increases insulin sensitivity, reduces hepatic synthesis and release of glucose, and increases peripheral glucose uptake

Inhibits action of DPP‐4 which acts to break down incretins (e.g. GLP‐1). This increases incretin effect, as seen in GLP1R agonists

Incretin mimetic: stimulates release of insulin, reduces glucagon release, delays gastric emptying, reduces appetite

Increases endogenous production of insulin

Inhibits SGLT2 in the proximal renal tubule, thereby reducing glucose reabsorption of glucose promoting glucosuria

Risk

Lactic acidosis
B12 deficiency
If gastrointestinal upset try modified‐ release formulation Contraindicated if eGFR <30 mL/min per 1.73 m3

Possible increased hospitalisations for heart failure with alogliptin and saxagliptin Possible increased pancreatitits risk

Subcutaneous administration (oral now becoming available) Nausea/vomiting Possible increased pancreatitis risk

Hypoglycaemia Weight gain

Polyuria
Postural hypotension Urinary tract infection
DKA can occur in stress settings
Mild fracture risk

Benefit

Weight loss (3 kg) Low risk of hypoglycaemia

Weight neutral Low risk of hypoglycaemia

Weight loss (3–4.5 kg)
Low risk of hypoglycaemia Liraglutide FDA approved for prevention of major cardiac events

Weight loss (2–3 kg)
Low risk of hypoglycaemia Empagliflozin FDA approved to reduce CV mortality Canagliflozin reduces cardiac events

Evidence base in SMI

Good evidence for use in SMI, and should be considered first line [31] Consider in patients with pre‐diabetes receiving olanzapine and clozapine [32]

Trial data lacking in SMI

Current evidence base suggests should be considered second line therapy in SMI Evidence for exenatide use in patients treated with antipsychotics, particularly olanzapine and clozapine
[33, 34]

Trial data lacking in SMI

(continued )

Diabetes Mellitus 97

MANAGEMENT

Management of T2DM is multifaceted, requiring a combination of patient education to facilitate lifestyle modification and pharmacological approaches. The overarching goals are to achieve normoglycaemia and manage/prevent vascular complications. Improving glycaemic control clearly improves outcomes in T2DM [23]. However, any approach needs to be individualised, balancing the benefits of HbA1c reduction against drug side effects such as hypoglycaemia and weight gain (see Table 11.1) [24]. A recent

Table 11.1 Risks, benefits and evidence base for diabetes treatments in serious mental illness (SMI).

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98 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 11.1 (Continued)

Drug class

Thiazolidinediones (glitazones, e.g. pioglitazone)

Mechanism

Improve insulin sensitivity by promoting adipogenesis and reducing circulating fatty acid and lipid availability

Supplements insufficient endogenous production of insulin

Risk

Weight gain Heart failure Oedema
Bone fractures

Benefit

May reduce stroke risk
Low risk of hypoglycaemia

Evidence base in SMI

Rosiglitazone improves glucose homeostasis in patients treated with olanzapine [35] and clozapine [36]. However, in the UK, rosiglitazone has been withdrawn owing to risk of myocardial infarction Pioglitazone remains available as an antidiabetic medication. However, due to concerns regarding the risk of cardiovascular disease, along with their propensity to cause weight gain, they are not preferred choices in SMI

Trial data lacking in SMI

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Insulin

Hypoglycaemia Weight gain

In poorly controlled diabetes may be only effective treatment in stabilising glucose

DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate.

consensus statement by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) set out the principles by which manage- ment of hyperglycaemia in T2DM should be approached, summarised in Box 11.3 [25]. An algorithm for approaching management of T2DM in the SMI population is shown in Figure 11.1.

Non‐pharmacological therapy: lifestyle modification

All patients and carers should be offered access to structured diabetes education around the time of diagnosis. In the general population, lifestyle interventions which target diet and physical activity have been effective in improving glycaemic control compared with standard treatment (see Ward et al. [26] for review). Efforts should be made to identify and improve lifestyle factors that may underlie poor glycaemic control, and address coexisting risk factors for cardiovascular disease (e.g. smoking and obesity). The reader is directed to Chapters 10, 14, and 46 for more details on weight gain, physical activity, and smoking cessation.

Pharmacological therapy

There are no diabetic treatment algorithms specific for psychiatric populations so phar- macological management should follow guidelines used in the general population. In

Diabetes Mellitus 99

Box 11.3 Approach to glycaemic control in type 2 diabetes mellitus [25]

. 1 Assess key patient characteristics

. a Current lifestyle

. b Comorbidities (e.g. cardiovascular disease)

. c Clinical characteristics (e.g. BMI)

. d Comorbid psychiatric diagnoses and socioeconomic/cultural context

. 2 Consider specific factors that impact choice of treatment

. a HbA1c target for that individual

. b Comorbid obesity or risk of hypoglycaemia

. c Side effects of medication

. d Complexity of regimen and likelihood of adherence

. 3 Shared decision‐making

. a Educate patient and family/caregivers

. b Consider patient preference

. 4 Agree on management plan: ‘SMART’ goals

. a Specific

. b Measurable

. c Achievable

. d Realistic

. e Time limited

. 5 Implement management plan

a Review patient at least every 3 months

. 6 Ongoing monitoring and support

. a Emotional well‐being

. b Check tolerability of medication

. c Monitor glycaemic status

. 7 Review and agree on management plan

. a Review above decision cycle and management plan at least once/twice a year

. b Mutual agreement on any changes

. c Ensure any changes implemented in a timely manner

the absence of specific guidance for SMI, the prescriber should consider an individual’s risk and the side effects of their psychiatric drugs to tailor prescribing accordingly.

Where possible, rationalisation of psychiatric medications is recommended. Male sex and elevated body weight at baseline increase the risk of antipsychotic‐induced glucose dysregulation [27]. Where there are concerns regarding diabetic risk in such patients, medications such as lurasidone and partial agonists (e.g. aripiprazole) are recommended [27]. However, the choice of antipsychotic treatment should be made on an individual basis, considering the clinical circumstances and preferences of patients and clinicians.

A selection of international guidelines for use in the general population are summa- rised in Box 11.4. The first‐line pharmacological therapy for T2DM is metformin mon- otherapy. Second‐line therapies generally involve the addition of an oral medication including dipeptidyl peptidase (DPP)‐4 inhibitor, thiazolidinedione (TZD), sulphonylu- rea (SU), or sodium‐glucose cotransporter 2 (SGLT2) inhibitor and, outside of the UK, glucagon‐like peptide‐1 receptor agonists (GLP1RA).

There are two considerations when selecting medications specifically for patients with SMI. As obesity is common in SMI, choosing medications which can aid in weight loss

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Raised fasting glucose or HbA1c?

Yes

Yes No

MDT approach involving psychiatry, primary care +/– secondary care:

1. Lifestyle modification and rationalise psychiatric medication

2. Start pharmacological therapy. Metformin first- line. Consider other weight- neutral drugs: GLP1RA, SGLT2i, DDP4i

3. Engage in annual diabetic monitoring

NB if evidence of diabetic complications or poor glucose control refer to secondary care

Discuss with and/or refer to emergency medical services

1. Lifestyle modification and rationalise psychiatric medication

2. Consider early use of metformin in patients receiving psychiatric medication that increase risk of T2DM

Continue routine monitoring for T2DM and broader metabolic dysregulation (at least annually in SMI)

100 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Criteria met for T2DM? (Box 11.2)

Acutely Unwell? (see Chapter 74)

Criteria met for pre-diabetes? (Box 11.2)

Figure 11.1 Approach to management of type 2 diabetes mellitus (T2DM) in patients with serious mental illness. DPP4i, dipeptidyl peptidase‐4 inhibitor; GLP1RA, glucagon‐like peptide‐1 receptor agonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

or are at least weight neutral are preferable (e.g. metformin, GLP1RAs, SGLT2 inhibi- tors, DPP‐4 inhibitors). Furthermore, in patients with SMI characterised by disorganised behaviour or at significant risk of deliberate self‐harm, medications which can result in hypoglycaemia may not be preferred (e.g. SU and insulin). Injectable agents such as insulin and GLP1RAs may require community nursing (although note that oral GLP1RAs are now emerging on the market). Multidisciplinary discussion between psychiatry and diabetology is recommended to ensure a patient receives appropriate treatment.

Pharmacological therapy should generally be initiated when the threshold is met for T2DM. A subgroup of patients whose HbA1c levels are close to threshold may however choose to attempt a duration of lifestyle modification (e.g. for three to six months) to see if their diabetes can be managed without use of medication. Early prescription of metformin reduces the risk of transition from pre‐diabetes to T2DM [28,29], and as

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Diabetes Mellitus 101

Box 11.4 A selection of international guidelines for use in the general population: algorithms for pharmacotherapy of type 2 diabetes mellitus

National Institute for Health and Care Excellence [1]

First line: metformin
Second line: dual therapy with metformin plus one of DPP4i, pioglitazone, SUa, SGLT2i Third line: triple therapy with one of the following combinations:

Metformin + DPP4i + SUa
Metformin + pioglitazone + SUa
Metformin + (pioglitazone or SUa) + SGLT2i

Fourth line: option for GLP1 mimetic alongside metformin and SUa if certain criteria are met:

BMI >35 kg/m2 and obesity‐related medical/psychological complications BMI <35 kg/m2 and insulin therapy has significant occupational implications If weight loss would benefit obesity‐related comorbidities

After exhausting the first four steps, consider insulin therapy

Scottish Intercollegiate Guidelines Network (SIGN) [37]

First line: metformin (or SUa if osmotic symptoms or intolerant of metformin)
Second line: dual therapy with metformin and one of SUa, SGLT2i, DPP4i, pioglitazone
Third line: add either an additional oral agent from a different class (SUa, SGLT2i, DPP4i, pioglita- zone) or an injectable agent (GLP1RA or insulin)
Fourth line: review adherence, add additional agent(s) from third line with specialist input

American Diabetes Association [38]

First line: metformin
Second line: dual therapy with metformin plus one of DPP‐4i, TZD, SUa, GLP1 agonist, SGLT2i, insulin Third line: triple therapy with one of the following combinations:

Metformin + SUa + TZD/DDP4i/SGLT2i/GLP1RA/insulin Metformin + TZD + SUa/DDP4i/SGLT2i/GLP1RA/insulin Metformin + DPP4i + SUa/TZD/SGLT2i/insulin Metformin + SGLT2i + SUa/TZD/DPP4i/GLP1RA/insulin Metformin + GLP1RA + SUa/TZD/SGLT2i/insulin Metformin + insulin + TZD/DDP4i/SGLT2i/GLP1RA

Fourth line: combination injectable therapya

SU, sulphonylurea; TZD, thiazolidinedione; DPP4i, dipeptidyl peptidase‐4 inhibitor; GLP1RA, gluca- gon‐like peptide‐1 receptor agonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.

a Medicationswhichcanresultinhypoglycaemia(e.g.SU)maynotbepreferredinsomepatientswith serious mental illness where there are concerns regarding risk of overdose, or chaotic behaviour.

such recent guidelines recommend considering use of metformin in certain patients to slow progression, especially in those who are under 60 years old, have a BMI over 35 kg/m2, or have a history of gestational diabetes [30]. We recommend considering early use of metformin in pre‐diabetic patients with SMI who are receiving psychiatric treatment recognised to increase diabetic risk (e.g. second‐generation antipsychotics).

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102 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Management of other comorbidities

To reduce the risk of microvascular/macrovascular complications, other cardiovascular risk factors alongside T2DM should be treated. Thus, smoking cessation, weight loss, and pharmacological treatment of hypertension and hypercholesterolaemia may be indicated (see Chapters 5, 9, 14, and 46).

Annual diabetic review

In the UK, patients with T2DM should be offered an annual diabetic review, which is generally coordinated by primary care services. This involves review of blood glucose via HbA1c, blood pressure, cholesterol, renal function, retinal screening, neurological assessment (foot/leg), education (dietary and medication advice), smoking cessation, influenza vaccination, support if experiencing sexual side effects, psychological sup- port, and specialist care if planning pregnancy [39].

When to refer to a specialist

T2DM can usually be managed in primary care. However, patients who have recurrent or unpredictable hypoglycaemia, suboptimal HbA1c, or diabetic complications (e.g. neu- ropathy, nephropathy, or foot ulcerations) may benefit from referral to secondary care.

Information in a referral should include the following:

▪ brief summary of symptoms and rationale behind referral

▪ comorbid psychiatric diagnosis and current treatment

▪ any psychosocial issues that may impact on diabetic control

▪ summary of any potential impact of mental health on accessing/engaging with inves-
tigations/follow‐up, and on concordance with recommended diabetic treatment

▪ contact details of the patient’s mental healthcare team/support network, and if the
appointment should be sent to anyone in addition to the patient

▪ any reasonable adjustments needed for the patient (e.g. time or duration of appoint-
ment, carer/support worker in attendance).
References

1. National Institute for Health and Care Excellence. Type 2 Diabetes in Adults: Management. NICE Guideline NG28. London: NICE, 2015. Available at nice.org.uk/guidance/ng28 (accessed 7 April 2019).

2. The Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta‐analysis of 102 prospective studies. Lancet 2010;375(9733):2215–2222.

3. Firth J, Siddiqi N, Koyanagi A, et al. The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness. Lancet Psychiatry 2019;6(8):675–712.

4. Osborn DP, Wright CA, Levy G, et al. Relative risk of diabetes, dyslipidaemia, hypertension and the metabolic syndrome in people with severe mental illnesses: systematic review and metaanalysis. BMC Psychiatry 2008;8:84.

5. Vancampfort D, Correll CU, Galling B, et al. Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta‐analysis. World Psychiatry 2016;15(2):166–174.

6. Diabetes UK. Three in five people with diabetes experience emotional or mental health problems. https://www.diabetes.org.uk/about_us/ news/three‐in‐five‐people‐with‐diabetes‐experience‐emotional‐or‐mental‐health‐problems. 2017.

7. Frayne SM, Halanych JH, Miller DR, et al. Disparities in diabetes care: impact of mental illness. Arch Intern Med 2005;165(22):2631–2638.

8. Goldberg RW, Kreyenbuhl JA, Medoff DR, et al. Quality of diabetes care among adults with serious mental illness. Psychiatr Serv 2007;58(4):536–543.

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9. Vijan S. In the clinic. Type 2 diabetes. Ann Intern Med 2015;162(5):ITC1–16.

10. Public Health England. Adult Obesity and Type 2 Diabetes. London: PHE, 2014. Available at https://assets.publishing.service.gov.uk/
government/uploads/system/uploads/attachment_data/file/338934/Adult_obesity_and_type_2_diabetes_.pdf (accessed 7 April 2019).

11. Abdullah A, Peeters A, de Courten M, Stoelwinder J. The magnitude of association between overweight and obesity and the risk of diabetes:
a meta‐analysis of prospective cohort studies. Diabetes Res Clin Pract 2010;89(3):309–319.

12. Rush E, Plank L, Chandu V, et al. Body size, body composition, and fat distribution: a comparison of young New Zealand men of European,
Pacific Island, and Asian Indian ethnicities. N Z Med J 2004;117(1207):U1203.

13. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome: a new world‐wide definition. A consensus statement from the international diabetes
federation. Diabetic Med 2006;23(5):469–480.

14. Smith M, Hopkins D, Peveler RC, et al. First‐ v. second‐generation antipsychotics and risk for diabetes in schizophrenia: systematic review
and meta‐analysis. Br J Psychiatry 2008;192(6):406–411.

15. Svendal G, Fasmer OB, Engeland A, et al. Co‐prescription of medication for bipolar disorder and diabetes mellitus: a nationwide popula-
tion‐based study with focus on gender differences. BMC Med 2012;10:148.

16. Barnard K, Peveler RC, Holt RIG. Antidepressant medication as a risk factor for type 2 diabetes and impaired glucose regulation: systematic
review. Diabetes Care 2013;36(10):3337–3345.

17. Mozaffarian D, Kamineni A, Carnethon M, et al. Lifestyle risk factors and new‐onset diabetes mellitus in older adults: the Cardiovascular
Health Study. Arch Intern Med 2009;169(8):798–807.

18. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation.
Part 1. Diagnosis and classification of diabetes mellitus. Geneva: WHO, 1999.

19. Cefalu WT, Berg EG, Saraco M, et al. Classification and diagnosis of diabetes: standards of medical care in diabetes 2019. Diabetes Care
2019;42:S13–S28.

20. National Institute for Health and Care Excellence. Diabetes – type 2. https://cks.nice.org.uk/diabetes‐type‐2#!diagnosisSub. Last revised:
September 2019.

21. KilpatrickES,AtkinSL.UsinghaemoglobinA1ctodiagnosetype2diabetesortoidentifypeopleathighriskofdiabetes.BMJ2014;348:g2867.

22. NHS England. NHS Diabetes Prevention Programme (NHS DPP). https://www.england.nhs.uk/diabetes/diabetes‐prevention/ (accessed 11
August 2019).

23. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood‐glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837–853.

24. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients
with type 2 diabetes. N Engl J Med 2008;358(24):2560–2572.

25. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American
Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;61(12):2461–2498.

26. Ward MC, White DT, Druss BG. A meta‐review of lifestyle interventions for cardiovascular risk factors in the general medical population:
lessons for individuals with serious mental illness. J Clin Psychiatry 2015;76(4):e477–e486.

27. Pillinger T, McCutcheon R, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia,
predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta‐analysis. Lancet
Psychiatry 2020;7(1):64–77.

28. Knowler WC, Barrett‐Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N
Engl J Med 2002;346(6):393–403.

29. Diabetes Prevention Program Research Group. Long‐term effects of lifestyle intervention or metformin on diabetes development and micro-
vascular complications over 15‐year follow‐up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol
2015;3(11):866–875.

30. Professional Practice Committee for the Standards of Medical Care in Diabetes‐2016. Diabetes Care 2016;39(Suppl 1):S107–S108.

31. Jarskog LF, Hamer RM, Catellier DJ, et al. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia
and schizoaffective disorder. Am J Psychiatry 2013;170(9):1032–1040.

32. Siskind DJ, Leung J, Russell AW, et al. Metformin for clozapine associated obesity: a systematic review and meta‐analysis. PLoS One
2016;11(6):e0156208.

33. Siskind DJ, Russell AW, Gamble C, et al. Treatment of clozapine‐associated obesity and diabetes with exenatide in adults with schizophrenia:
A randomized controlled trial (CODEX). Diabetes Obes Metab 2018;20(4):1050–1055.

34. Siskind D, Hahn M, Correll CU, et al. Glucagon‐like peptide‐1 receptor agonists for antipsychotic‐associated cardio‐metabolic risk factors: a
systematic review and individual participant data meta‐analysis. Diabetes Obes Metab 2019;21(2):293–302.

35. Baptista T, Rangel N, El Fakih Y, et al. Rosiglitazone in the assistance of metabolic control during olanzapine administration in schizophrenia:
a pilot double‐blind, placebo‐controlled, 12‐week trial. Pharmacopsychiatry 2009;42(1):14–19.

36. Henderson D, Fan X, Sharma B, et al. A double‐blind, placebo‐controlled trial of rosiglitazone for clozapine‐induced glucose metabolism
impairment in patients with schizophrenia. Acta Psychiatr Scand 2009;119(6):457–465.

37. Scottish Intercollegiate Guidelines Network (SIGN). Pharmacological Management of Glycaemic Control in People with Type 2 Diabetes.
SIGN 154. Available at https://www.sign.ac.uk/assets/sign154.pdf (accessed 15 April 2019).

38. American Diabetes Association. Standards of medical care in diabetes‐2017. Diabetes Care 2017;40(Suppl 1):S64–S74.

39. Diabetes UK. Annual diabetes checks. https://www.diabetes.org.uk/guide‐to‐diabetes/managing‐your‐diabetes/15‐healthcare‐essentials
(accessed 11 August 2019).

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Chapter 12

Thyroid Disease

Harriet Quigley, Jackie Gilbert

The thyroid is a butterfly‐shaped gland located at the front of the neck in front of the larynx (voice box). It produces three hormones: thyroxine (T4), triiodothyronine (T3), and calcitonin. T4 is inactive and is converted to active T3 peripherally. These hormones control the metabolic rate of the body. Calcitonin acts to reduce blood calcium.

T3 and T4 are released by the thyroid in response to thyroid stimulating hormone (TSH) which itself is produced by the pituitary gland. The pituitary gland releases TSH in response to thyrotropin releasing hormone (TRH), which is produced by the hypo- thalamus. Most T3/T4 in the circulation is bound to protein, and only free thyroid hormone is metabolically active. Free thyroid hormone feedbacks negatively to the hypothalamus and pituitary gland to reduce TRH and TSH production, respectively.

The three main clinical conditions arising from the thyroid gland in the general popula- tion are hypothyroidism, hyperthyroidism, and thyroid malignancy. This chapter provides an overview of the clinical presentation and management of hypothyroidism and hyper- thyroidism, as well as their specific relevance to severe mental illness (SMI).

HYPOTHYROIDISM

Hypothyroidism describes the clinical state resulting from underproduction of the thyroid hormones T4 and T3. Most cases (95%) are due to an inability of the thyroid gland to produce thyroid hormones, termed primary hypothyroidism. The most common cause of primary hypothyroidism worldwide is iodine deficiency, while autoimmune thyroiditis and iatrogenic hypothyroidism (i.e. secondary to medical interventions) are common causes in regions where iodine deficiency is less prevalent. Secondary hypothyroidism accounts for the remaining 5% of cases and is due to disorders of the pituitary or hypothalamus. Other causes of hypothyroidism are described in Table 12.1.

106 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 12.1 Primary and secondary causes of hypothyroidism and hyperthyroidism.

Hypothyroidism

Primary Autoimmune hypothyroidism: Hashimoto’s thyroiditis and atrophic thyroiditis

Iatrogenic: radioiodine treatment, surgery, radiotherapy to the neck Iodine deficiency

Congenital defects (e.g. absence of thyroid gland or dyshormonogenesis)

Infiltration of the thyroid (e.g. amyloidosis, sarcoidosis and haemochromatosis)

Medications (see Table 12.3)

Secondary Isolated TSH deficiency
Hypopituitarism: neoplasm, infiltrative, infection, radiotherapy Hypothalamic disorders: neoplasms and trauma

Hyperthyroidism

Graves’ disease

Toxic nodular goitre

Thyroiditis

Solitary thyroid nodule

Follicular carcinoma of the thyroid gland

Medications (see Table 12.3)

TSH‐secreting pituitary adenoma Gestational thyrotoxicosis
Thyroid hormone resistance syndrome hCG‐secreting tumour

Table 12.2 Common signs and symptoms of hypothyroidism and hyperthyroidism.

Hypothyroidism

Loss of outer third of eyebrows Dry skin
Brittle hair, hair loss Myxoedema

Tiredness, lethargy, cold intolerance Deep hoarse voice
Weight gain, decreased appetite Constipation

Bradycardia
Delayed tendon reflex relaxation
Carpal tunnel syndrome
General slowing, physically and mentally Myalgia
Arthralgia
Menorrhagia, oligomenorrhoea, amenorrhoea

Hyperthyroidism

Weight loss
Increased or decreased appetite Irritability
Weakness and fatigue Sweating, heat intolerance Tremor
Diarrhoea
Loss of libido Oligomenorrhoea/amenorrhoea Palmar erythema
Tachycardia, atrial fibrillation Hair thinning/diffuse alopecia Brisk reflexes
Goitre
Proximal myopathy
Lid lag

CHAPTER 12

Hypothyroidism often has an insidious onset but can be associated with significant morbidity. It disproportionately affects females and the elderly [1], and occurs in 2.5% of pregnant women (see Chapter 62) [2]. Clinical features are often subtle and non‐ specific, and may be wrongly attributed to other illnesses. Common signs and symptoms are summarised in Table 12.2. The first biochemical irregularity observed is an increase

in serum TSH concentration with normal serum free T4 and free T3 (subclinical hypothyroidism). This is followed by a decrease in serum free T4, at which stage most patients have symptoms and require treatment (overt hypothyroidism). The severest form of hypothyroidism is a myxoedema or hypothyroid crisis, a severe life‐threatening form of decompensated hypothyroidism associated with multiorgan failure (see Chapter 79).

DIAGNOSTIC PRINCIPLES History

. 1 Symptoms of hypothyroidism: weakness, lethargy, cold sensitivity, constipation, weight gain, low mood, myalgia, menstrual irregularity, dry or coarse skin, thick tongue, eyelid/facial oedema, deep voice.

. 2 Past medical history:

. a iodine deficiency

. b autoimmune disorders (including type 1 diabetes and multiple sclerosis)

. c Graves’ disease, and other autoimmune diseases of the thyroid

. d Turner’s and Down’s syndromes (both associated with increased risk of
hypothyroidism)

. e primarypulmonaryhypertension(associatedwithincreasedriskofhypothyroidism)

. f radiotherapy to the neck

. g infiltrative disease such as sarcoidosis (see Chapter 60) and haemochromatosis.

. 3 Medication history: see Table 12.3.

. 4 Family history: autoimmune thyroiditis.

. 5 Social history: history of working in the textile industry [3].
Table 12.3 Medications that cause hypothyroidism and hyperthyroidism. Hypothyroidism

Hyperthyroidism

Levothyroxine Amiodarone Interferon‐alpha

Thyroid Disease 107

General medications

Methimazole
Carbimazole
Propylthiouracil
Amiodarone
Iodide
Minocycline and other tetracyclines Interferon‐α

Other cytokines (interferon‐β, interleukin‐2) Propranolol
Glucocorticoids
Metformin

Lithium Anticonvulsants

Psychiatric medication

Lithium

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Box 12.1 The thyroid examination

Make sure that the neck is appropriately exposed.

General inspection

▪ Evidence of obesity or recent rapid weight loss.

▪ Exophthalmos (Graves’ disease).

▪ Dry skin (hypothyroidism).

▪ Hair (brittle and dry in hypothyroidism).

▪ Level of agitation (hyperthyroidism). Examination of the hands

▪ Check pulse (bradycadia in hypothyroidism, tachycardia and atrial fibrillation in hyperthyroidism).

▪ Check for presence of sweating and increase in temperature (hyperthyroid).

▪ Onycholysis (separation of the nail from its bed).

▪ Thyroid acropachy: phalangeal bone overgrowth (Graves’ disease).

▪ Ask the patient to extend his or her arms and hold hands with palms facing down; look for any tremor (hyperthyroidism).
Examination of the thyroid gland
Inspection

▪ Ask the patient to swallow; a thyroid mass will rise on swallowing.

▪ Note any asymmetry or scars from previous surgery.
Palpation

▪ Stand behind the patient with thumbs on the back of the neck and patient’s head slightly flexed.

▪ Gently palpate the neck for any abnormality.

▪ Have the patient swallow and feel the gland move under your fingers; ask patient to protrude
tongue.

▪ Palpation of both lobes and the isthmus: palpate again with patient swallowing. If thyroid tissue
is palpable, describe size (feel for the lower border to rule out retrosternal extension), shape (uniformly enlarged or nodular), consistency (soft, rubbery or hard), tenderness (thyroiditis), and mobility (malignant neoplasm: fixed).

▪ Palpate lymph nodes.

▪ Assess tracheal position.
Percussion
■ Percuss for retrosternal dullness, which may indicate retrosternal extension.
Auscultation
■ Bruit is a sign of increased blood flow and can be present in thyrotoxicosis.

108 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Examination

See Box 12.1.

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Thyroid Disease 109

Examination of the eyes

▪ Look for lid lag and exophthalmos (Graves’ disease).

▪ Check eye movements by asking the patient to follow your finger movements without moving
their head (restricted in Graves’ disease due to abnormal connective tissue deposition).

▪ Visual fields: bitemporal hemianopia may be suggestive of a sellar mass causing chiasmal com-
pression (secondary hypothyroidism).
Other

▪ Check reflexes (slow relaxing in hypothyroidism).

▪ Proximal myopathy.

▪ Examine for pretibial myxoedema.

▪ Cardiovascular examination (signs of cardiac failure).

Investigations

. 1 Thyroid function tests (TFTs): must include measurement of serum TSH and free T4 (Table 12.4). TSH is elevated in primary hypothyroidism, and free T4 is low. In second- ary hypothyroidism, free T4 is low and TSH may be low, normal, or minimally elevated. In subclinical disease, TSH is mildly elevated but free T4 normal.

. 2 Anti‐thyroid peroxidase (anti‐TPO) antibodies and anti‐thyroglobulin antibodies are found in 90–95% of patients with autoimmune thyroiditis.

. 3 Lipid profile, creatine kinase (CK), urea and electrolytes, full blood count (FBC), and fasting blood glucose. Untreated hypothyroidism may be associated with raised cholesterol and triglycerides, a raised CK, hyponatraemia, and anaemia (normocytic or macrocytic). These abnormalities usually resolve with treatment.

. 4 Where secondary hypothyroidism is suspected, investigations will be guided by endocrinology, and may involve:
a tests of pituitary function, including morning (9 a.m.) serum cortisol, prolactin,
testosterone, gonadotrophins, estradiol, and insulin‐like growth factor (IGF)‐1 b pituitary CT/MRI.

Table 12.4 Biochemical findings in hypothyroidism and hyperthyroidism.

Condition

Primary hypothyroidism

Secondary hypothyroidism

Subclinical hypothyroidism

Primary hyperthyroidism

Secondary hyperthyroidism

Subclinical hyperthyroidism

TSH

Raised

Lowered, normal or minimally elevated

Raised

Lowered

Raised

Lowered

Free T4

Lowered

Normal

Raised

Normal

Free T3

Lowered or normal

Normal

Raised or normal

Normal

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110 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

MANAGEMENT
Clinical primary hypothyroidism

▪ Guidance recommends use of thyroxine (T4) alone in the treatment of hypothyroid- ism, commonly prescribed as levothyroxine. For adults aged over 18 years without ischaemic heart disease, the initial dose of levothyroxine is based on the patient’s body weight, i.e. 1.6 μg/kg with repeat TFT assessment after 8 weeks. The usual mainte- nance dose is 100–200 μg daily. There are certain patients (those with cardiac disease, the elderly) for whom the recommended initial dose of levothyroxine is 25–50 μg once daily, adjusted in steps of 25 μg every 14–21 days according to response.

▪ Prescribing additional T3 is currently not recommended.

▪ TSH should be monitored annually.
Subclinical hypothyroidism
Some patients with subclinical hypothyroidism, especially those whose TSH level is greater than 10 mU/L and who have positive anti‐TPO or anti‐thyroglobulin antibod- ies, may achieve symptomatic benefit from treatment with levothyroxine. The treat- ment of patients with TSH values between 4.5 and 10 mU/L is controversial, especially in older patients [4,5].
Secondary hypothyroidism
First‐line treatment is levothyroxine, with adjunctive treatment for the underlying disorder.
Hypothyroidism and serious mental illness
Overt hypothyroidism can present with neuropsychiatric symptoms including cognitive deficits and depressive symptoms, and it is paramount that a diagnosis of hypothyroid- ism is excluded in such presentations. Moreover, there are case reports of severely hypo- thyroid patients presenting with frank psychotic symptoms, referred to as ‘myxoedema madness’ [6].
Depressive symptoms
Depression is the most common neuropsychiatric symptom in hypothyroidism, with an estimated prevalence of 60% [7]. The prevalence of overt hypothyroidism in individu- als with a depressive diagnosis has been estimated to be 0.5–8% [8], and 4–10% may have subclinical hypothyroidism [9]. Most studies report an improvement in depressive symptoms in individuals with overt thyroid disease treated with thyroid hormone replacement [10–12]. However, randomised, placebo‐controlled, blinded studies of thyroid hormone replacement therapy in individuals with subclinical hypothyroidism

CHAPTER 12

have not observed reliable improvement in depression or psychological distress scores [5,13,14].

Cognitive deficits

Overt hypothyroidism can affect a range of cognitive domains, including attention and concentration, memory, language, and executive functioning [15]. Memory is the most consistently affected; specific deficits in verbal memory are reported [16]. Thyroid hormone replacement is effective in treating these decrements, although there may not be complete reversal. Subclinical hypothyroidism is not associated with widespread or severe cognitive symptoms, though subtle deficits have been reported in memory and executive functioning. It is reasonable to initiate treatment for such patients, but realistic expectations should be set regarding symp- tom resolution.

Lithium

Lithium is associated with hypothyroidism. Up to 33% of patients treated with lithium have anti‐thyroid antibodies; lithium also has a direct toxic effect on the thyroid gland [17]. Regular monitoring of TFTs (every 6 months) is recommended for patients on lithium therapy. When lithium‐induced hypothyroidism occurs, treatment with levothy- roxine is indicated as already described.

HYPERTHYROIDISM

Thyrotoxicosis describes disorders of excess thyroid hormone with or without increased synthesis of thyroid hormone (hyperthyroidism). The most common cause of primary hyperthyroidism is Graves’ disease, an autoimmune disorder mediated by antibodies that stimulate the TSH receptor, accounting for approxi- mately 75% of cases in iodine‐replete areas. Toxic nodular disease accounts for 50% of cases in iodine‐depleted areas. Other causes of thyrotoxicosis include thyroiditis (autoimmune, viral infection, drug induced) and excess ingestion of thyroid hormone (see Table 12.1). A hyperthyroid crisis or thyroid storm is an acute life‐threatening hypermetabolic state caused by excessive release of thyroid hormone (see Chapter 79).

The prevalence of hyperthyroidism is 0.8% in Europe [18] and 1.3% in the USA [19]. Hyperthyroidism can be overt or subclinical. Overt hyperthyroidism is character- ised by low serum TSH concentrations and raised serum concentrations of T4, T3, or both. Subclinical hyperthyroidism is characterised by low serum TSH, but normal serum T4 and T3 concentrations. Excess thyroid hormone affects many different organ systems (see Table 12.1). Commonly reported symptoms are palpitations, fatigue, tremor, anxiety, disturbed sleep, weight loss, heat intolerance, sweating, and polydipsia. Frequent physical findings are tachycardia, tremor of the extremities, and weight loss (see Table 12.2).

Thyroid Disease 111

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112 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES History

. 1 Symptoms of hyperthyroidism: heat intolerance, sweating, weight loss, palpitations, tremor, irritability, scalp hair loss.

. 2 Symptoms related to size of goitre: anterior pressure sensation, dyspnoea, dysphagia.

. 3 Past medical history:
a radiation of the neck
b autoimmune disease
c trauma to thyroid gland (including surgery).

. 4 Medication history: see Table 12.3.

. 5 Drug and alcohol: tobacco use (strongly associated with Graves’ hyperthyroidism,
risk factor for orbitopathy) [20].

. 6 Family history: autoimmune thyroid disease.

. 7 Social history: stress may be associated with onset or relapse of Graves’ disease [21].

Examination

See Box 12.1.

▪ Graves’ disease: diffuse goitre, ophthalmopathy (proptosis, periorbital oedema, diplopia), thyroid dermopathy (pigmented thickened skin primarily involving the pretibial area), and thyroid acropachy (clubbing of the fingers and toes).

▪ Nodular thyroid disease: palpable thyroid nodule(s).

▪ Subacute thyroiditis: anterior neck pain.
Investigations

. 1 TFTs: TSH is the initial screening test, with reduced levels suggesting hyperthyroid- ism. Confirm the diagnosis with free T4 levels. If TSH is suppressed but free T4 levels are normal then, if not previously supplied, free T3 level is needed (T3 toxicosis). See Table 12.4.

. 2 Autoantibodies are most commonly seen in Graves’ disease: TSH receptor antibodies have a sensitivity of 98% and specificity of 99% for Graves’ disease [22].

. 3 Imaging.
a Thyroid ultrasound scan to characterise palpable nodule(s).
b Thyroid isotope scan (technetium‐99m) to identify autonomously functioning
nodule(s) (focal increased uptake); very low or absent uptake is seen in thyroiditis,
factitious ingestion of thyroid hormone, or iodine‐induced thyrotoxicosis.

. 4 Inflammatory markers: in patients with subacute thyroiditis, C‐reactive protein
(CRP) and erythrocyte sedimentation rate (ESR) are often raised.

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Thyroid Disease 113

MANAGEMENT
Clinical primary hyperthyroidism

. 1 Consider starting a beta‐blocker or calcium channel blocker to control symptoms driven by the sympathetic nervous system, especially in older patients and those with cardiovascular disease.

. 2 Anti‐thyroid medication.

. a Two methods are used (i) ‘block and replace’, where thionamides (e.g. carbima-
zole, methimazole, and propylthiouracil) are given with thyroxine replacement over a period of 6 months; and (ii) ‘dose titration’, where thionamides are used alone over 12–18 months and doses are titrated to achieve normalisation of thyroid hormone production. A Cochrane review suggests that both methods achieve long‐term remission rates of approximately 35% [23]. Some clinicians utilise the block and replace approach when thyroid function has demonstrated marked fluctuation during treatment.

. b Propylthiouracil can cause liver failure, particularly in children [24]. As such, its use is reserved for pregnancy and thyroid storm.

. c TFTs are repeated every 4‐6 weeks.

. d Thionamides can cause agranulocytosis (1–3 per 1000). It is more frequently seen early
in treatment and with higher doses (>40 mg carbimazole). It is important to advise
patients to stop thionamide and present for an FBC if they develop a sore throat or fever.

. e Thyrotoxicosis associated with thyroiditis is transient and resolves spontaneously;
anti‐thyroid drugs are not effective and should therefore be avoided.

. 3 Radioactive iodine.

. a Iodine‐131 is the treatment of choice for toxic nodular disease and in many cases of relapsed Graves’ disease. It can take three to four months to take effect.

. b Contraindicated in pregnant or breastfeeding women. Individuals are advised to avoid conception for six months.

. c Hypothyroidism is a common sequela.

. 4 Surgical.

. a Total thyroidectomy achieves a 98% cure rate. It is usually considered for patients who have a large goitre, compressive symptoms, significant ophthalmopathy, or who require rapid cure before pregnancy.

. b Patients should be returned to the euthyroid state with anti‐thyroid drugs before surgery to avoid thyroid storm.

. c Complications are rare (<1%) but include haemorrhage, hypoparathyroidism, and vocal cord paralysis.

Subclinical hyperthyroidism

Treatment of subclinical hyperthyroidism is recommended in elderly patients due to an increased risk of atrial fibrillation, osteoporosis, bone fractures, and progression to overt disease [25].

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114 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Hyperthyroidism and serious mental illness

Neuropsychiatric symptoms of overt hyperthyroidism include anxiety, dysphoria, emo- tional lability, intellectual dysfunction, and mania [9]. A subset of hyperthyroid patients, typically the elderly population, may present with depression, lethargy, pseudodemen- tia, and apathy, with what is termed ‘apathetic thyrotoxicosis’ [26]. Psychotic symp- toms including unusual presentations such as delusional parasitosis are rare in hyperthyroid patients, but have been reported [27,28]. Severe hyperthyroidism can result in thyroid storm, a condition that ranges in neuropsychiatric presentation from hyperirritability, anxiety, and confusion to apathy and coma.

Subclinical hyperthyroidism may be associated with agitation, irritability, and changes in mood [9]. There are no clear recommendations for treatment based on reversing neuropsychiatric symptoms associated with subclinical hyperthyroidism.

Hyperthyroidism may occur with long‐term lithium treatment, though is less com- mon than hypothyroidism. Lithium‐induced hyperthyroidism is characterised by a transient and painless thyroiditis, thought to be secondary to a direct toxic effect of lithium on the thyroid gland, or through lithium‐induced autoimmunity [17]. Regular monitoring of TFTs (every six months) is recommended for patients who are on lithium therapy.

Specialist input

All patients with new‐onset thyrotoxicosis should be referred for assessment in second- ary care to establish the aetiology and agree a management plan [29].

Consider referral for urgent admission if there is:

▪ atrial fibrillation or cardiac failure

▪ dehydration (secondary to diarrhoea). Consider urgent referral to a thyroid surgeon if:

▪ symptoms of tracheal compression are present

▪ hyperthyroid patients present with thyroid swelling associated with voice changes,
previous neck irradiation, family history of endocrine tumour, extremes of age (pre‐ puberty, >65).
References

1. Boelaert K, Franklyn JA. Thyroid hormone in health and disease. J Endocrinol 2005;187(1):1–15.

2. Lazarus JH, Premawardhana LD. Screening for thyroid disease in pregnancy. J Clin Pathol 2005;58(5):449–452.

3. Roberts FP, Wright AL, O’Hagan SA. Hypothyroidism in textile workers. J Soc Occup Med 1990;40(4):153–156.

4. Franklyn JA. The thyroid: too much and too little across the ages. The consequences of subclinical thyroid dysfunction. Clin Endocrinol
2013;78(1):1–8.

5. Parle J, Roberts L, Wilson S, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community‐
living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab
2010;95(8):3623–3632.

6. Easson WM. Myxedema with psychosis. Arch Gen Psychiatry 1966;14(3):277–283.

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Thyroid Disease 115

7. Bathla M, Singh M, Relan P. Prevalence of anxiety and depressive symptoms among patients with hypothyroidism. Indian J Endocrinol Metab 2016;20(4):468–474.

8. Radhakrishnan R, Calvin S, Singh J, et al. Thyroid dysfunction in major psychiatric disorders in a hospital based sample. Indian J Med Res 2013;138(6):888–893.

9. Feldman AZ, Shrestha RT, Hennessey JV. Neuropsychiatric manifestations of thyroid disease. Endocrinol Metab Clin North Am 2013;42(3):453–476.

10. Yu J, Tian A‐J, Yuan X, Cheng X‐X. Subclinical hypothyroidism after 131I‐treatment of Graves’ disease: a risk factor for depression? PLoS One 2016;11(5):e0154846.

11. Davis JD, Tremont G. Neuropsychiatric aspects of hypothyroidism and treatment reversibility. Minerva Endocrinol 2007;32(1):49–65.

12. Gulseren S, Gulseren L, Hekimsoy Z, et al. Depression, anxiety, health‐related quality of life, and disability in patients with overt and subclini-
cal thyroid dysfunction. Arch Med Res 2006;37(1):133–139.

13. Waterloo K, Jorde R, Nyrnes A, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect
of thyroxine treatment. J Clin Endocrinol Metab 2006;91(1):145–153.

14. Kong WM, Sheikh MH, Lumb PJ, et al. A 6‐month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism.
Am J Med 2002;112(5):348–354.

15. Samuels MH. Psychiatric and cognitive manifestations of hypothyroidism. Curr Opin Endocrinol Diabetes Obes 2014;21(5):377–383.

16. Miller KJ, Parsons TD, Whybrow PC, et al. Verbal memory retrieval deficits associated with untreated hypothyroidism. J Neuropsychiatry
Clin Neurosci 2007;192:132–136.

17. Kibirige D, Luzinda K, Ssekitoleko R. Spectrum of lithium induced thyroid abnormalities: a current perspective. Thyroid Res 2013;6(1):3.

18. Garmendia Madariaga A, Santos Palacios S, Guillen‐Grima F, Galofre JC. The incidence and prevalence of thyroid dysfunction in Europe: a
meta‐analysis. J Clin Endocrinol Metab 2014;99(3):923–931.

19. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994):
National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87(2):489–499.

20. Perros P, Krassas GE. Graves orbitopathy: a perspective. Nat Rev Endocrinol 2009;5(6):312–318.

21. Mizokami T, Wu Li A, El‐Kaissi S, Wall JR. Stress and thyroid autoimmunity. Thyroid 2004;14(12):1047–1055.

22. Tozzoli R, Bagnasco M, Giavarina D, Bizzaro N. TSH receptor autoantibody immunoassay in patients with Graves’ disease: improvement of
diagnostic accuracy over different generations of methods. Systematic review and meta‐analysis. Autoimmun Rev 2012;12(2):107–113.

23. Abraham P, Avenell A, McGeoch SC, et al. Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev
2010;(1):CD003420.

24. British National Formularly (online). Propylthiouracil. http://www.medicinescomplete.com (accessed 23 February 2019).

25. Biondi B. Natural history, diagnosis and management of subclinical thyroid dysfunction. Best Pract Res Clin Endocrinol Metab
2012;26(4):431–446.

26. Arnold BM, Casal G, Higgins HP. Apathetic thyrotoxicosis. Can Med Assoc J 1974;111(9):957–958.

27. Özten E, Tufan AE, Cerit C, et al. Delusional parasitosis with hyperthyroidism in an elderly woman: A case report. J Med Case Rep 2013;7:17.

28. Lazarus A, Jaffe R. Resolution of thyroid‐induced schizophreniform disorder following subtotal thyroidectomy: case report. Gen Hosp
Psychiatry 1986;8(1):29–31.

29. Vaidya B, Pearce SHS. Diagnosis and management of thyrotoxicosis. BMJ 2014;349:g5128.

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Chapter 13

Hyperprolactinaemia

John Lally, Toby Pillinger, Olubanke Dzahini, Sophie Harris

Prolactin, a protein secreted from the anterior pituitary gland, is a multifunctional hormone with more than 300 direct or indirect actions reported, including effects on water and salt balance, growth and development, energy metabolism, stress adaptation, neurogenesis and neuroprotection, reproduction, and immune activity [1]. A compre- hensive description of the actions of prolactin is beyond the scope of this chapter, which focuses on common causes of hyperprolactinaemia in patients with serious mental ill- ness (SMI), the typical presentation of a patient with hyperprolactinaemia, recom- mended investigations, and management.

Normal prolactin levels are gender‐dependent, with higher levels seen in females [2]. Normal prolactin levels are generally reported as 210–420 mIU/L for men (approxi- mately 10–20 ng/mL), and 210–530 mIU/L for women (approximately 10–25 ng/mL) [3]. The causes of hyperprolactinaemia are listed in Box 13.1. In patients with SMI, psychiatric medication, most often antipsychotics, are implicated in most cases of hyperprolactinaemia. Prolactin secretion is tonically inhibited by dopamine released from the hypothalamus into the tuberoinfundibular system acting at D2 dopamine receptors on lactotroph cells of the anterior pituitary. Thus, antipsychotic‐mediated D2 receptor blockade removes tonic inhibition of prolactin secretion. There is heterogene- ity in the relative degree to which different antipsychotics affect prolactin levels (Table 13.1). As such, antipsychotics have historically been subcategorised into ‘prolactin‐ raising’ agents (so‐called first‐generation antipsychotics plus risperidone, paliperidone, and amisulpride) and ‘prolactin‐sparing’ agents (so‐called second‐generation antipsy- chotics, except for risperidone, paliperidone, and amisulpride). Some antipsychotics can increase blood prolactin levels within hours of treatment initiation [4]. Prolactin levels generally fall to normal range within two to four days of stopping oral antipsychotics, although this is influenced by the half‐life of the antipsychotic and the formulation in

Box 13.1 Causes of hyperprolactinaemia Pituitary disorders

▪ Prolactinomas:
Microadenomas (<10 mm): 90% Macroadenomas (>10 mm): 10%

▪ Cushing’s disease

▪ Acromegaly

▪ Empty sella syndrome

▪ Cranial irradiation
Systemic disorders

▪ Hypothyroidism

▪ Chronic renal failure

▪ Liver failure

▪ Seizures

▪ Sarcoidosis

▪ Polycystic ovary disease

▪ Oestrogen‐secreting tumours

▪ Chest wall lesions
Physiological

▪ Pregnancy

▪ Breastfeeding

▪ REM sleep

▪ Stress
Medication

▪ Antipsychotics (see Table 13.1)

▪ Tricyclic antidepressants

▪ Monoamine oxidase inhibitors

▪ Metoclopramide

▪ Reserpine

▪ Verapamil

▪ Methyldopa

118 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

which it is delivered. Some antipsychotics take up to three weeks for prolactin levels to normalise post discontinuation [4], and slower decline is seen after discontinuation of medication given in long‐acting injectable form [5]. Other psychiatric medications, including tricyclic antidepressants and monoamine oxidase inhibitors, can also result in hyperprolactinaemia (see Box 13.1). Psychosocial stress can cause elevations in prolac- tin [6,7], a potential explanation for why hyperprolactinaemia occurs more frequently in patients with first‐episode psychosis compared with healthy controls, even prior to use of antipsychotics [8].

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Hyperprolactinaemia 119

Table 13.1 Relative risk of hyperprolactinaemia with different antipsychotics [3,9]. Amisulpridea +++

Aripiprazole – Asenapine –/+ Blonanserin + Brexpiprazole – Cariprazine – Chlorpromazine +++ Clozapine – Flupentixol +++ Fluphenazine +++ Haloperidol ++ Lurasidone + Molindone +++ Olanzapine + Paliperidonea +++ Perphenazine +++ Pimozide +++ Pipothiazine +++ Quetiapine –/+ Risperidonea +++ Sertindole + Sulpiridea +++ Trifluoperazine +++ Ziprasidone + Zuclopenthixol +++

a Amisulpride, sulpiride, risperidone, and paliperidone are generally associated with more severe prolactin changes. +++, high risk; ++, moderate; +, low; –, very low.

DIAGNOSTIC PRINCIPLES

Although prolactin is a multifunctional hormone, the signs and symptoms of hyper- prolactinaemia generally derive from the role of prolactin in stimulating the mam- mary glands to produce milk, and via its influence on oestrogen levels in women and testosterone levels in men. As such, hyperprolactinaemia may be associated with hypogonadism, sexual dysfunction, acne, hirsutism, galactorrhoea (secretion of milk

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120 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

from nipples), and rarely gynaecomastia (the excessive growth and development of the male mammary glands) [3,10]. Sexual dysfunction due to hyperprolactinaemia in males and females may be characterised by reduced libido, and impaired arousal and orgasm [10]. Men may develop erectile dysfunction. Galactorrhoea is much more common in women than men with hyperprolactinaemia [11], and is estimated to occur in 10–20% of women treated with first‐generation antipsychotics [12]. Prolonged hyperprolactinaemia, via its influence on gonadotrophin levels, can also reduce bone mineral density (therefore resulting in osteopenia/osteoporosis) in both men and women.

The degree of hyperprolactinaemia will generally influence the type and severity of clinical symptoms experienced, and the following is a guide with regard to premeno- pausal women [13].

▪ Serum prolactin levels above 2120 mIU/L (99.6 ng/mL) are associated with hypog- onadism and menstrual dysfunction, including amenorrhoea and galactorrhoea.

▪ Serum prolactin levels between 1081 and 1590 mIU/L (50.8–74.7 ng/mL) are associ- ated with oligomenorrhea (infrequent menstrual periods).

▪ Serum prolactin levels between 657 and 1060 mIU/L (30.9–49.8 ng/mL) are associ- ated with reduced libido.
History and investigation
Many psychiatric patients with hyperprolactinaemia are asymptomatic, with raised prolactin noted on routine blood screening. However, a history should still be taken for evidence of hypogonadism, galactorrhoea, or gynaecomastia, as already detailed. Any patient presenting spontaneously to clinic with these symptoms should be investigated with a serum prolactin level.
Although the long‐term consequences of raised prolactin in asymptomatic patients are yet to be clearly defined, chronically raised levels are likely to be associated with comorbidity, and as such it is recommended that prolactin levels in patients receiving antipsychotic treatment are tested routinely.
General principles regarding serum prolactin testing are as follows.

▪ Check serum prolactin levels in patients before starting an antipsychotic and before switching to a new antipsychotic. Consider rechecking once optimal antipsychotic dose has been reached, and annually in patients on established antipsychotic treatment.

▪ Since stress can elevate prolactin levels, where elevations are modest (<1000 mIU/L) repeat testing is recommended to confirm presence of hyperprolactinaemia.

▪ In women of childbearing age, rule out pregnancy.

▪ Enquire about headache or visual disturbance (pituitary adenoma) or symptoms of
hypothyroidism (see Chapter 12). Physical examination may be indicated to confirm
presence of a bitemporal hemianopia or evidence of hypothyroidism.

▪ Consider also checking thyroid, renal, and liver function (see Box 13.1).

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▪ Where prolactin levels remain persistently elevated without an obvious cause, discussion with endocrinology and pituitary MRI is indicated (see section on management).

▪ Since persistent hyperprolactinaemia is associated with osteoporosis, enquire about fracture history, and family history of fractures. Also consider checking vitamin D levels and enquire about exercise levels, smoking status, and alcohol intake.
MANAGEMENT AND WHEN TO REFER TO A SPECIALIST

▪ Prolactin levels above 1000 mIU/L prior to antipsychotic initiation should prompt further investigations (see section History and investigation) and discussion with endocrinology.

▪ Hyperprolactinaemia with levels below 2500 mIU/L in asymptomatic patients where antipsychotic treatment is felt to be the most likely cause does not necessarily require further investigation or treatment. The patient should be informed and may be fol- lowed up with regular enquiry regarding emergent symptoms. Development of hypo- gonadism, galactorrhoea, or gynaecomastia would indicate the need for repeat serum prolactin testing and intervention. Where it is unclear whether to intervene in such
patients, discussion with endocrinology is recommended.

▪ Where hyperprolactinaemia of less than 2500 mIU/L is likely secondary to antipsy-
chotic treatment and the decision is made to intervene (e.g. in the case of hypog- onadism), dose reduction may be considered, although whether antipsychotic‐induced hyperprolactinaemia is dose dependent is unclear [14]. Alternatively, treatment can be switched to an antipsychotic with a reduced propensity to cause hyperprolactinae- mia (see Table 13.1). However, this may not always be possible due to the risk of deterioration in the patient’s mental state. The use of the partial dopamine agonist aripiprazole (5–10 mg daily; often 5 mg is sufficient) as an adjunctive agent is effec- tive in reducing hyperprolactinaemia, with almost 80% of patients with antipsy- chotic‐induced hyperprolactinaemia experiencing normalisation of prolactin levels [15]. However, aripiprazole augmentation is generally ineffective in amisulpride‐ induced hyperprolactinaemia [16]. Low‐dose dopamine receptor agonists (e.g. bro- mocriptine and cabergoline) can be considered as third‐line treatments, although this requires close monitoring for psychotic relapse and should only be used following endocrinology input as part of a multidisciplinary approach.

▪ Hypogonadism may be treated with hormone replacement. Males can be treated with testosterone administered via transdermal patches. In females, the use of a combined oral contraceptive will offset oestrogen deficiency and associated complications including bone mineral density loss [17]. However, this will not ameliorate other hyperprolactinaemia‐related symptoms. Hormonal treatment should only be used following endocrinology input as part of a multidisciplinary approach.

▪ Prolactin levels above 2500 mIU/L should, after history and examination of the patient (see section History and investigation), prompt discussion with endocrinol- ogy regardless of whether the patient is receiving antipsychotic treatment as these levels may indicate a prolactinoma [4]. Pituitary adenomas can generally be managed

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122 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

pharmacologically using dopamine agonists, although caution should be exer- cised in the use of such agents in the psychiatric patient population, and a multi- disciplinary approach involving both psychiatry and endocrinology is advised. Where drug treatment is not indicated, transsphenoidal surgery may be considered.

▪ There are currently no guidelines that stipulate which patients with hyperprolactinae- mia should be assessed with dual‐energy X‐ray absorptiometry (DEXA). Persistent hypogonadism (e.g. amenorrhoea for over six months) is an indication to measure bone mineral density. DEXA scans are also recommended if a patient experiences a broken bone after only a minor fall, if the patient has received prolonged (more than three months) glucocorticoid treatment, if the patient has experienced early meno- pause, if the patient has a low body mass index (<19 kg/m2), or if the patient has any other comorbid medical/psychiatric condition that can lead to low bone density (e.g. malabsorption syndromes, chronic renal failure, eating disorders) [18].

▪ The Fracture Risk Assessment Tool (FRAX) is validated for fracture risk prediction in those greater than 50 years of age [19] and can be used in people with psychotic disorders, although a diagnosis of a psychotic disorder or the use of antipsychotic medication is not currently included in the FRAX algorithm. Indeed, the FRAX cal- culator has been found to significantly underestimate 10‐year fracture risk associated with use of psychotropic medication [20].
HYPERPROLACTINAEMIA AND OSTEOPOROSIS RISK IN SERIOUS MENTAL ILLNESS
Hyperprolactinaemia suppresses the hypothalamic–pituitary–gonadal axis which, when prolonged, reduces bone mineral density and increases risk of osteoporosis. People with schizophrenia are 2.5 times more likely to have osteoporosis and have a 72% increased risk of fracture compared to the general population [21]. The mechanisms underlying reduced bone mineral density in schizophrenia are poorly understood and multifactorial, with lifestyle factors such as increased rates of smoking, alcohol intake, low vitamin D levels, and sedentary behaviour, alongside the side effects of antipsychotic medication likely contributing [22–25]. Schizophrenia and related psychotic disorders are usually diagnosed between the ages of 16 and 30, often prior to the patient reaching peak bone mass [26]. Exposure to prolactin‐raising medications at an early age, alongside the lifestyle factors, may therefore prevent development of optimum peak bone mass, thus reducing lifelong bone mineral density and predisposing patients to osteoporosis [21]. However, it is important to note that while antipsychotic‐induced hyperprolactinaemia could play a role in the development of reduced bone mineral density in people with schizo- phrenia [27,28], there is currently insufficient evidence to be certain that antipsychotic‐ induced hyperprolactinaemia, in the absence of hypogonadism, constitutes an independent risk factor for the development of osteoporosis in patients with schizophrenia [29].

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Hyperprolactinaemia 123

HYPERPROLACTINAEMIA AND CANCER RISK

Hyperprolactinaemia has been implicated in an increased risk of malignancy, particu- larly breast cancer [30]. Female patients with schizophrenia are at increased risk of breast cancer, although the contribution of antipsychotic‐induced hyperprolactinaemia is unclear. Furthermore, studies not taking into account parity may overestimate the risk for breast cancer in schizophrenia [31]. Further work is required to determine if moderating hyperprolactinaemia in this cohort will reduce malignancy rates [32].

References

1. Bole‐Feysot C, Goffin V, Edery M, et al. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 1998;19(3):225–268.

2. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guide- line. J Clin Endocrinol Metab 2011;96(2):273–288.

3. Peuskens J, Pani L, Detraux J, De Hert M. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014;28(5):421–453.

4. Haddad PM, Wieck A. Antipsychotic‐induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004;64(20):2291–2314.

5. Wistedt B, Wiles D, Kolakowska T. Slow decline of plasma drug and prolactin levels after discontinuation of chronic treatment with depot neuroleptics. Lancet 1981;317(8230):1163.

6. Fitzgerald P, Dinan TG. Prolactin and dopamine: what is the connection? A review article. J Psychopharmacol 2008;22(2 Suppl):12–19.

7. Lennartsson A‐K, Jonsdottir IH. Prolactin in response to acute psychosocial stress in healthy men and women. Psychoneuroendocrinology
2011;36(10):1530–1539.

8. Gonzalez‐Blanco L, Greenhalgh AM, Garcia‐Rizo C, et al. Prolactin concentrations in antipsychotic‐naive patients with schizophrenia and
related disorders: a meta‐analysis. Schizophr Res 2016;174(1–3):156–160.

9. Huhn M, Nikolakopoulou A, Schneider‐Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treat-
ment of adults with multi‐episode schizophrenia: a systematic review and network meta‐analysis. Lancet 2019;394(10202):939–951.

10. Bobes J, Garc APMP, Rejas J, et al. Frequency of sexual dysfunction and other reproductive side‐effects in patients with schizophrenia treated
with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study. J Sex Marital Ther 2003;29(2):125–147.

11. Wieck A, Haddad PM. Antipsychotic‐induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Br J Psychiatry
2003;182:199–204.

12. Windgassen K, Wesselmann U, Schulze Monking H. Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: fre-
quency and etiology. Neuropsychobiology 1996;33(3):142–146.

13. Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and management of hyperprolactinemia. Can Med Assoc J 2003;169(6):575–581.

14. Lally J, Ajnakina O, Stubbs B, et al. Hyperprolactinaemia in first episode psychosis: a longitudinal assessment. Schizophr Res
2017;189:117–125.

15. Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic‐induced hyperprolactinemia: meta‐analysis of randomized
controlled trials. PLoS One 2013;8(8):e70179.

16. Paulzen M, Grunder G. Amisulpride‐induced hyperprolactinaemia is not reversed by addition of aripiprazole. Int J Neuropsychopharmacol
2007;10(1):149–151.

17. Inder WJ, Castle D. Antipsychotic‐induced hyperprolactinaemia. Aust N Z J Psychiatry 2011;45(10):830–837.

18. Compston J, Cooper A, Cooper C, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos
2017;12(1):43.

19. Fracture Risk Assessment Tool (FRAX). https://www.sheffield.ac.uk/FRAX/index.aspx (accessed 6 October 2019).

20. Bolton JM, Morin SN, Majumdar SR, et al. Association of mental disorders and related medication use with risk for major osteoporotic
fractures. JAMA Psychiatry 2017;74(6):641–648.

21. Stubbs B, Gaughran F, Mitchell AJ, et al. Schizophrenia and the risk of fractures: a systematic review and comparative meta‐analysis. Gen
Hosp Psychiatry 2015;37(2):126–133.

22. De Hert M, Detraux J, Stubbs B. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic frac-
tures in patients with schizophrenia: a critical literature review. Expert Opin Drug Saf 2016;15(6):809–823.

23. de Leon J, Diaz FJ. A meta‐analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors.
Schizophr Res 2005;76(2–3):135–157.

24. Lally J, Ajnakina O, Singh N, et al. Vitamin D and clinical symptoms in first episode psychosis (FEP): a prospective cohort study. Schizophr
Res 2019;204:381–388.

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25. Lally J, Gardner‐Sood P, Firdosi M, et al. Clinical correlates of vitamin D deficiency in established psychosis. BMC Psychiatry 2016;16(1):1–9.

26. Heaney RP, Abrams S, Dawson‐Hughes B, et al. Peak bone mass. Osteoporos Int 2000;11(12):985–1009.

27. Tseng PT, Chen YW, Yeh PY, et al. Bone mineral density in schizophrenia: an update of current meta‐analysis and literature review under
guideline of PRISMA. Medicine (Baltimore) 2015;94(47):e1967.

28. Gomez L, Stubbs B, Shirazi A, et al. Lower bone mineral density at the hip and lumbar spine in people with psychosis versus controls: a
comprehensive review and skeletal site‐specific meta‐analysis. Curr Osteoporos Rep 2016;14(6):249–259.

29. Lally J, Bin Sahl A, Murphy KC, et al. Serum prolactin and bone mineral density in schizophrenia‐ a systematic review. Clin Psychopharmacol
Neurosci 2019;17(3):333–342.

30. Bernichtein S, Touraine P, Goffin V. New concepts in prolactin biology. J Endocrinol 2010;206(1):1–11.

31. Oksbjerg Dalton S, Munk Laursen T, Mellemkjaer L, et al. Schizophrenia and the risk for breast cancer. Schizophr Res
2003;62(1–2):89–92.

32. Chou AIW, Wang YC, Lin CL, Kao CH. Female schizophrenia patients and risk of breast cancer: a population‐based cohort study. Schizophr
Res 2017;188:165–171.

CHAPTER 13

Chapter 14

Obesity

Yuya Mizuno, Toby Pillinger, Dan Siskind, Ian Osborne, Kate Moffat, Donal O’Shea

The World Health Organization (WHO) defines overweight and obesity as abnormal or excessive fat accumulation that presents a risk to health [1]. A crude measure of obesity is the body mass index (BMI), with a BMI greater than or equal to 25 and 30 respectively considered overweight and obese (Box 14.1) [1]. Waist circumference and waist‐to‐height ratio are other indices that may be used to assess central obesity (Box 14.2). Recent global estimates indicate that 39% and 13% of adults aged 18 years and older are respectively overweight and obese [1]. In the UK, approximately 60% of adults are either overweight or obese [11]; in the USA, approximately 70% of adults meet these criteria [13]. Obesity is robustly associated with various medical conditions, including cardiometabolic disease [13,14], musculoskeletal disorders (especially osteo- arthritis), and cancer [9,11]. Accordingly, in 2014–2015 the NHS spent approximately £6 billion on overweight and obesity‐related ill‐health [15]. In the USA, annual medical spending attributable to obesity was approximately $150 billion in 2014 [16].

Box 14.1 Calculating body mass index and definitions of overweight and obesity [1]

Body mass index (BMI) may be calculated using the following formula:

mass kg height m 2

BMI kg /m2
As a general principle, the following applies for adults.

▪ Ideal weight: BMI within the range 18.5–24.9.

▪ Overweight: BMI within the range 25.0–29.9.

▪ Obese: BMI greater than or equal to 30.0.

In the UK, a lower BMI cut‐off value of 23 is used for black, Asian, and other minority groups due to greater risk of diabetes mellitus at lower BMI relative to white populations [2,3]. However, note that people with high muscle mass may be categorised as overweight despite having a healthy body weight. Similarly, BMI calculations will be inaccurate in patients with oedema, ascites, or who are pregnant. Furthermore, in older adults (≥65 years) being over- weight is not associated with an increased risk of mortality (indeed, risk of mortality increases in those with a low‐normal and low BMI) [4]. As such, an ‘ideal’ BMI range for older adults is 23.0–29.9 kg/m2.

A BMI classified as overweight (except for older adults) or obese should prompt the healthcare professional to seek permission to discuss the individual’s weight and its implications with them. This discussion should explore readiness and motivation for lifestyle change to manage weight. If ready, possible interventions should be discussed (see section Prevention and treatment of obesity).

Obesity is divided into three classes.

▪ Class 1: BMI 30–34.9.

▪ Class 2: BMI 35–39.9.

▪ Class 3: BMI 40+ (‘extreme’ or ‘severe’ obesity).

Box 14.2 Measurement and significance of waist circumference and waist‐to‐height ratio

Waist circumference is an index of intra‐abdominal fat mass [5]. This is important as excessive abdominal fat is associated with greater risk for cardiovascular disease, type 2 diabetes, and cancer [6]. Measure waist circumference as follows [7].

▪ Find the bottom of the patient’s ribs and the top of the patient’s hips (see Figure 14.1).

▪ Wrap a tape measure around the patient’s waist, midway between these points.

▪ Have the patient breath out naturally before taking the measurement.
As a general principle, the following cut‐off values apply for waist circumference, independent of height or BMI [7].

▪ At waist circumferences of 94 cm (37 inches) for men and 80 cm (31.5 inches) for women, losing weight should be considered.

▪ Waist circumferences above 102 cm (40 inches) for men and 88 cm (34.5 inches) for women are associated with a high risk of serious health conditions; these patients should be reviewed by a clinician and intervention (see section Prevention and treatment of weight gain) strongly recommended.
The waist‐to‐height ratio is calculated as waist circumference divided by height. A simple cut‐ off value of 0.5 or greater has been proposed as an indicator of increased health risk, regardless of differences in sex or ethnicity (i.e. ‘keep your waist circumference to less than half your height’) [8,9].
Despite the utility of waist circumference and waist‐to‐height ratio in assessing risk of obesity‐ related ill‐health, it can be measured inaccurately. For example, locating anatomical landmarks may be challenging in individuals who have obesity, and tape measures can be wrapped too tightly or loosely around the waist. Furthermore, there is no universally accepted protocol for measuring waist circumference, with the World Health Organization (WHO) and National Institutes of Health having different protocols. Figure 14.1 shows the anatomical landmarks recommended by WHO for measuring waist circumference in men and women [10].

126 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

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Obesity 127

Figure 14.1 Waist circumference measurement sites for men and women based on World Health Organization recommendations. The measure is taken from midway between the highest point on the iliac crest and the bottom of the ribcage. Source: adapted from Patry‐Parisien et al. [10].

Obesity is more prevalent in people with severe mental illness (SMI) compared to the general population [17,18]; for example, a 2010 North American study observed that 80% of a sample of over 10,000 people with diagnoses of schizophrenia, bipolar disor- der, and depression were either overweight or obese [19]. The cause of weight gain in this population is multifactorial, including high caloric intake, genetic factors, seden- tary behaviour, social isolation, and negative discrimination [20,21]. Furthermore, many antipsychotic medications [22,23], as well as some antidepressants [24] and mood stabilisers [25], are recognised to induce weight gain. In addition to the burden of physical comorbidities, obesity reduces self‐worth, is associated with reduced quality of life [26] and poor concordance with psychotropic treatment [27], and is an inde- pendent predictor of psychiatric readmission [28].

Tackling obesity as a modifiable risk factor for all‐cause and cardiovascular mortal- ity represents a key component of the holistic care provided to people with SMI [29]. There is evidence that some patients with SMI (e.g. those with first‐episode psychosis) present with metabolic dysregulation from illness onset and prior to psychotropic pre- scription [30–32]. Thus, risk of obesity and broader metabolic disturbance in this patient population should be considered from first contact with psychiatric services.

MONITORING

There are multiple guidelines focusing on the monitoring of weight gain and cardio- metabolic risk in patients with schizophrenia (see De Hert et al. [33] for review). Key guidelines in the UK include the National Institute for Health and Care Excellence

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128 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 14.1 Monitoring protocol for weight gain, metabolic disturbance, and cardiovascular risk in patients with serious mental illness initiating psychotropic medication (all antipsychotics, consider with some antidepres- sants and mood stabilisers; see text).

Parameters

When to evaluate

+4 +8 Baselinea weeks weeks

+12 +6 Annually
weeks months thereafterb Comments

Body weight, BMI ✓✓

Waist circumference ✓✓

Waist‐to‐height ratio (✓)

Fasting glucose, HbA1c, ✓ and lipid profileb

Blood pressure ✓

Personal/family history ✓ of cardiovascular disease

History of tobacco and ✓✓ alcohol use

✓ ✓ ✓

(✓) (✓)

✓ ✓

✓ Ideally weekly for first 4–6 weeks, then every
2–4 weeks up to 12 weeks

✓ Not mandatory, but recommended

(✓) Not mandatory

✓ HbA1c is preferable for monitoring long‐term blood glucose control

✓ ✓ ✓

✓ ✓ ✓ ✓

a Before starting psychotropic, or as soon as possible after starting.
b Increase frequency if clinically indicated (e.g. more than 5% weight gain after a one‐month period). Source: adapted from Cooper et al. [35].

(NICE) guidelines [34] and the British Association for Psychopharmacology (BAP) guidelines [35]. The monitoring protocol recommended by the BAP forms the basis of Table 14.1. Increased monitoring frequency should be considered in certain clinical situations. For example, psychotropic‐naive adults and paediatric patients are at increased risk of antipsychotic‐induced weight gain [36]. Rapid weight gain following initiation of psychotropic medications (more than 5% weight gain after a one‐month period) is a strong predictor of long‐term weight gain and should prompt both enhanced monitoring and preventative or remedial strategies (see section Lifestyle modification) [37]. It is recommended that patients with bipolar disorder and major depressive disor- der undergo the same baseline assessments as those with schizophrenia when initiating treatment [38,39]. Weight gain has been described in patients receiving antidepressants (especially mirtazapine, mianserin, tricyclics, and monoamine oxidase inhibitors) [38] and mood stabilisers (especially sodium valproate and lithium) [39]. We recommend that patients receiving those antidepressants and mood stabilisers with recognised risk of weight gain (i.e. those listed in this section) should be monitored as per the monitor- ing protocol shown in Table 14.1. However, this guidance is flexible, and whenever psychiatric patients appear to be gaining weight, they should be monitored closely.

As part of an assessment of a patient’s weight, consider quantifying 10‐year cardio- vascular risk using the QRISK3 calculator [40,41]. This tool incorporates various

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Obesity 129

cardiovascular risk factors detailed in Table 14.1, as well as a diagnosis of SMI and antipsychotic prescription. The QRISK3 outcome can not only be used to guide subse- quent management (see Chapter 9) but also to engage with the patient on the topic of weight gain and cardiovascular risk.

PREVENTION AND TREATMENT OF WEIGHT GAIN

Figure 14.2 summarises an approach to management of weight gain in patients with SMI. As a general principle, clinicians should proactively manage weight gain before it becomes an issue.

Baseline screening

OVERWEIGHT?

Yes

Inform and work alongside primary care

2. 3.

Non-pharmacological interventions

• Dietary advice (see Box 14.3); consider
referral to dietetic services

• Increase physical activity

• Improve sleep hygiene
Rationalise psychiatric medication Consider use of metformin, especially if pre-diabetic
Manage comorbidities (e.g, hypertension, diabetes mellitus, dyslipidaemia)

BECOME OVERWEIGHT

Monitor as per Table 14.1

REMAIN OVERWEIGHT?

Yes

1. Liaise with primary care and refer to specialist service if indicated 2. Consider use of pharmacological agents with evidence of aiding

weight loss in psychiatric patients (e.g, add-on aripiprazole for

olanzapine/clozapine-induced weight gain)
3. Consider referral for bariatric surgery (See Box 14.4)

Figure 14.2 Flowchart to manage weight gain in patients with severe mental illness.

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Box 14.3 Dietary advice for weight loss

▪ Having a bowl of soup or a sugar‐free drink before a main meal can help fill you up and so eat less.

▪ Aim to eat three regular balanced meals a day.

▪ A healthy weight loss plate is half vegetables/salad and the other half split equally between starch
(preferably high fibre: wholemeal bread, rice, pasta, potatoes, yam, plantain chapatti) and protein
(e.g. pulses, nuts, seeds, eggs, fish, poultry, or red meat).

▪ Increase fruit and vegetable intake, aiming for five to ten portions per day and more vegetables
than fruit.

▪ Choose food and snacks that are low in fat, sugar, and salt.

▪ When reading traffic light food labels, choose those with more green and amber and fewer red.

▪ Choose drinks that are sugar‐free/‘diet’ and low fat or fat‐free.

▪ Restrict fruit juice and smoothie intake to 150 mL/day: more can cause weight gain and tooth decay.

▪ Take care with portion sizes: aim for a ‘small’ or ‘medium’ size when given the option.

▪ When having a takeaway have one main dish, one side dish, and a sugar‐free drink.

▪ When eating aim to eat at a table rather than on the couch or in bed.

▪ When eating make this the only activity you are doing, i.e. no TV, no social media, no phones.

▪ Eat slowly, take your time, and enjoy your food.

▪ It takes at least 15–20 minutes for your brain to register that your stomach is full, so wait and give
yourself time to feel full before considering second portions.

▪ A healthy dessert such as fruit and low‐fat low sugar yoghurts are a better choice than second
portions and can help ensure your diet is balanced.

▪ If you find that when taking psychiatric medication you are getting hungry very soon after having
eaten a main meal, choose high‐fibre, low‐calorie nutritious foods such as fruits, vegetables,
salad, wholegrain bread, and cereals.

▪ If you find that you need to eat a lot to feel full, limit eating to three main meals per day. Avoid
snacking and drink water and sugar‐free drinks between meals instead.

130 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Non‐pharmacological interventions to combat weight gain

Lifestyle modification

Preventative strategies that aim to help patients achieve healthy lifestyles should be offered to everyone. These include avoiding/stopping smoking, addressing alcohol and substance misuse, improving diet, improving sleep, and increasing physical activity [29] (see Chapters 10, 24, 46, and 55). There is evidence that combined lifestyle interventions including behavioural interventions, nutrition, and exercise are effective in attenuating weight gain when introduced during early phase of antipsychotic treatment [42,43].

An individual is more likely to be successful in managing their weight if they feel ready and motivated to make the necessary lifestyle changes. Thus, if possible, explore whether weight loss is important to the individual, any motivating factors, and any potential barriers. For those who feel ready to make lifestyle changes, it is important to set realistic goals; success increases confidence and motivates further success. Make only one to three small lifestyle changes at once (selecting those that the person feels are most likely to be successful) and increase over time. In terms of weight loss targets, recommend losing 5–10% of current body weight at a rate of 0.5 kg per week, and 4 cm from around the waist.

Box 14.3 provides dietary advice/tips for weight loss. Where accessible and appropri- ate, consider referring to a dietician ideally with experience in treating patients with

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SMI. Other factors that can aid weight loss include using a food diary and regularly monitoring progress, for example weighing oneself weekly and measuring waist cir- cumference monthly.

Rationalising psychiatric medication

When prescribing psychotropic medication, the propensity for weight gain and other metabolic adversities associated with treatments should be carefully considered. Figure 14.3 summarises the relative risk of weight gain associated with acute treatment with 18 antipsychotics relative to placebo (see Pillinger et al. [23] for ranking of antip- sychotics based on other metabolic disturbance). Since all marketed antipsychotics are more effective than placebo in treating acute psychotic episodes, and drug‐naive patients are particularly susceptible to weight gain, antipsychotics with high risk of weight gain should generally be avoided as first‐line treatments [44]. Based on broader metabolic dysfunction associated with different antipsychotics, the following agents are thought to be safer options: aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasi- done [23]. For patients already established on an antipsychotic, there is evidence that switching treatment to aripiprazole or lurasidone is associated with weight loss (with low risk of relapse) [45,46].

For mood stabilisers, lamotrigine likely has the most benign metabolic profile [47,48]. For antidepressants, selective serotonin reuptake inhibitors (SSRIs) and serotonin/ noradrenaline reuptake inhibitors (SNRIs) are reasonable options although paroxetine may be associated with a greater risk of weight gain [24]. Agomelatine is reported to

Olanzapine
Clozapine
Zotepine
Sertindole
Iloperidone
Quetiapine Rispridone/paliperidone Asenapine

Flupentixol Brexpiprazole Amisulpride Fluphenazine Cariprazine Lurasidone Aripiprazole Ziprasidone Haloperidol

Figure 14.3 Propensity of 18 antipsychotics to induce weight gain in the acute treatment of psychosis relative to placebo [23].

Obesity 131

Weight Gain

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132 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

have a low incidence of weight gain [49], and bupropion may have potential to induce weight loss in individuals with obesity [50].

Early use of metformin

In the general population, there is evidence that early use of metformin in patients with pre‐diabetes delays progression to type 2 diabetes mellitus [51]. Metformin is also associated with weight loss in patients with schizophrenia receiving clozapine or olanzapine [52]. Therefore, in individuals who are overweight or have pre‐diabetes and are receiving olanzapine or clozapine, where lifestyle interventions have not been effective, consider early prescription of metformin (aiming to reach a dose of 2 g daily in two to three divided doses, or once daily if using a modified‐release preparation).

Management of comorbidities

Other components of the metabolic syndrome (hypertension, type 2 diabetes mellitus, and dyslipidaemia) should be managed to reduce cardiovascular risk. The reader is directed to the chapters on these topics (Chapters 5, 9, and 11).

Pharmacological interventions

As already described, the best evidence for pharmacological management of weight gain in patients with SMI is for the use of metformin. There are however various other agents available, which are summarised in Table 14.2. Of note, most of the evidence for these agents is based on patients with schizophrenia receiving clozapine or olanzapine. Therefore, it is unclear if the evidence is directly translatable for patients with other psychiatric diagnoses receiving other medications. When using pharmacological strate- gies, the risk–benefit with regard to potential side effects needs to be considered. Comorbidities may also guide prescription decisions (e.g. use of metformin or GLP1R agonists in the context of type 2 diabetes mellitus). If patients present with sedation from medications such as clozapine or olanzapine, then add‐on aripiprazole or betahis- tine may be appropriate choices.

When to refer to a specialist

Primary care practitioners should be informed from the onset and should be involved in multidisciplinary discussions regarding the patient’s weight and associated metabolic disturbance. Where available, referral to a dietician should be consid- ered as well as supporting improved access to physical activity. Bariatric surgery may be considered for patients with morbid obesity who struggle to lose weight despite undertaking both non‐pharmacological and pharmacological strategies (Box 14.4).

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Obesity 133

Table 14.2 Pharmacological interventions to counteract weight gain.

Drug

Metformin (500–2000 mg/day)

Glucagon‐like peptide‐1 receptor (GLP1R) agonists (e.g. liraglutide 3 mg/day subcutaneously)

Aripiprazole (5–15 mg/day)

Amantadine (100–300 mg/day)

Bupropion (150 mg twice daily)

Betahistine (48 mg/day, although trial data suggests doses up to 144 mg/day)

Methylcellulose (1500 mg before meals)

Orlistat (120 mg thrice daily with meals)

Reboxetine (4–8 mg once daily)

Topiramate (up to 300 mg daily)

Zonisamide (100–600 mg/day)

Risks/side effects

Lactic acidosis, vitamin B12 deficiency, GI disturbance (then try immediately after meals, if still not tolerated try modified‐release formulation), contraindicated with eGFR

<30 mL/min per 1.73 m2

Nausea/vomiting, possible increased pancreatitis risk.

Sleep disturbance, akathisia, GI disturbance

Theoretical risk of exacerbating psychosis

GI side effects reported. Potent inhibitor of cytochrome P450 isoenzyme CYP2D6 [62], so may alter other psychiatric medication levels, including clozapine

Reports of headache and hypersensitivity reactions

Can be difficult to swallow, bloating, laxative effect

A fatty diet will result in steatorrhoea and potential malabsorption of oral medication

Difficulty sleeping, GI disturbance, dizziness, excessive sweating

Sedation, cognitive impairment

Sedation, diarrhea, cognitive impairment

Comment

First line for psychotropic‐induced weight gain [52–56]

Effective in patients treated with olanzapine or clozapine [57,58]. Weekly formulations available

Evidence for use in conjunction with clozapine or olanzapine [52,59]

Some evidence for use in olanzapine‐induced weight gain [60,61]

Evidence for use in the general population, including combination therapy with naltrexone [63]. Data lacking in severe mental illness and psychotropic‐ induced weight gain, although some evidence in depression alongside calorie restriction [64]

Evidence for use in olanzapine‐induced weight gain [65,66]

Data lacking in severe mental illness and psychotropic‐induced weight gain

Evidence for use in clozapine‐ and olanzapine‐induced weight gain [67–72]. Consider referral to a dietician to support a low‐fat diet

Evidence for use in olanzapine‐induced weight gain, and in combination with betahistine [52]

Evidence for use in psychotropic‐induced weight gain, also for preventing weight gain [73,74]

Evidence for use in second‐generation antipsychotic induced weight gain [75]

eGFR, estimated glomerular filtration rate; GI, gastrointestinal.

CHAPTER 14

Box 14.4 Overview of bariatric surgery [76]

Bariatric surgery (also referred to as weight loss surgery) refers to a group of surgical interventions designed to reduce body weight and improve obesity‐related conditions. Common types of bariatric surgery include the following.

▪ Gastric bypass: the top part of the stomach is joined to the small intestine.

▪ Sleeve gastrectomy: some of the stomach is removed.

▪ Gastric banding was previously commonly performed but is no longer recommended.
Bariatric surgery is available on the NHS for people who meet the following criteria.

▪ BMI of 40 or more, or a BMI between 35 and 40 and an obesity‐related condition that may improve if the person lost weight (e.g. type 2 diabetes mellitus, hypertension).

▪ Attempted all other weight loss methods including lifestyle change and pharmacotherapies but have not lost significant weight.

▪ Agree to long‐term follow‐up after surgery (e.g. making healthy lifestyle changes, attending regu- lar check‐ups).
In the general population, bariatric surgery is associated with both weight loss and remission of diabetes mellitus in individuals living with obesity [77]. While there are still limited data in patients with schizophrenia, growing evidence suggests that bariatric surgery may improve short‐term weight status among patients with bipolar disorder, to a comparable degree with individuals in the general population [78].

134 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

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CHAPTER 14

Part 3

Haematology

Chapter 15

Anaemia

Sanjena Mithra, Aleksander Mijovic

The primary physiological function of haemoglobin (Hb) is to transport and deliver oxygen to body tissues. According to the World Health Organization, anaemia is defined as an Hb below 130 g/L for men and below 120 g/L for non‐pregnant women, with global prevalence rates of 12.7% and 30.2%, respectively [1]. Anaemia is com- mon in patients with serious mental illness (SMI), with observational studies estimating a prevalence of up to 35% [2], but it can also occur separately either due to an underly- ing condition or as a side effect of psychiatric medication [3]. It ultimately has the potential to exacerbate SMI if left untreated.

Several factors, including age, sex, nutrition, geography, ethnicity, and socioeconomic status, are known to contribute to anaemia and can therefore complicate physical or mental illness [4]. Nutritional deficiencies in eating disorders or neglect may contribute to reductions in Hb, and certain psychiatric medications are also associated with anae- mia [3]. Hb levels naturally reduce with age, and differ by gender [5], ethnicity (e.g. Hb is lower in African Americans compared with Caucasians) [6], and geography (Hb increasing with altitude) [7]. Other causes of anaemia in the general population and those with SMI are documented in Table 15.1.

140 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 15.1 Causes of anaemia in the general and psychiatric patient population.
General population Individual with serious mental illness

Medical comorbidity

Nutrition

Medication

Other

Anaemia of chronic disease (e.g. chronic kidney disease, hypothyroidism, malignancy, systemic lupus erythematosus, heart failure, infection)
Acute blood loss (e.g. trauma, GI bleed, deliberate self‐harm)
Chronic blood loss (e.g. GI bleed, urinary tract bleeding)

Haematological disorders (e.g. haemoglobinopathies, myelodysplasia, haematological malignancies)
Gynaecological causes (e.g. menorrhagia, fibroids)

Iron/B12/folate deficiency (e.g. old age, vegetarian diet, alcohol excess) Malabsorption (coeliac disease, Crohn’s disease, following bariatric surgery)

Phenytoin
Antibiotics (e.g. cephalosporins, trimethoprim)
Chemotherapy and radiation NSAIDs
Some antimalarial drugs (in glucose‐6‐phosphate dehydrogenase deficiency)

Pregnancy

Iron/B12/folate deficiency (eating disorders, chronic liver disease secondary to alcohol, poor oral intake as part of spectrum of altered behaviours in serious mental illness, neglect)

Mood stabilisers (e.g. carbamazepine) Antidepressants (e.g. fluoxetine, monoamine oxidase inhibitors, bupropion, duloxetine, mianserin) [8] Antipsychotics (e.g. aripiprazole, chlorpromazine, trifluoperazine) [9]
Levodopa
Donepezil, memantine
Chlordiazepoxide
Promethazine

DIAGNOSTIC PRINCIPLES

The signs and symptoms associated with anaemia are dependent on its severity. Untreated progressive anaemia can cause physical symptoms such as lethargy, headaches, palpitations, and even psychiatric symptoms such as cognitive deficits and depression [10] An approach to clinical assessment of anaemia is documented in Figure 15.1, and a glossary of terms provided in Table 15.2.

Acute bleeding should be managed as a medical emergency, with resuscitation and emergency referral/transfer of the patient to medical services.

History

A very slowly falling Hb allows for a degree of compensation and enhancement of oxygen‐carrying capacity of the blood, which means some patients may be asymptomatic. In general, elderly people tolerate anaemia less well and may present with non‐specific symptoms [13,14]. Key features from a history are as follows.

1 Symptoms of anaemia: dizziness, feeling faint, fatigue, shortness of breath (either at rest or exertion), palpitations, headache, or angina (if there is pre‐existing ischaemic heart disease) [5].

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BLOODS TESTS

As described in ‘Investigations’ section

Anaemia 141

INDICATIONS FOR TESTING

Fatigue, weakness, pallor, dizziness, palpitations

ANAEMIA PRESENT

NORMOCYTIC

(normal MCV)

MICROCYTIC

(low MCV)

MACROCYTIC

(high MCV)

• Malignancy

• Inflammation

• Autoimmune
disease

• Chronic disease

• Aplastic anaemia

• Iron deficiency (High TIBC/low iron/low ferritin)

• Thalassaemia

• B12 deficiency

• Folate deficiency

• Drug effect

• Excessive alcohol

• Hypothyroidism

• Myelodysplasia

NEXT STEPS

• Peripheral blood film evaluation

• Dietary and lifestyle modification as appropriate

• Rationalise medications (both psychiatric and non-psychiatric))

• Consider haematology opinion

Figure 15.1 An algorithmic approach to anaemia.

. 2 Evidence of blood loss (per rectum bleeding, dark stool, haematemesis).

. 3 Symptoms that may point towards an underlying comorbidity (see Table 15.1) such as peripheral neuropathy (B12 deficiency), abdominal distension (hepatosplenomeg- aly), or any ‘red flag’ symptoms suggestive of malignancy, e.g. unintentional weight
loss (see Chapter 25), smoking history, or change in bowel habit.

. 4 Past medical history including previous diagnoses of connective tissue disorders,
heart disease, haematological disorders, and chronic kidney disease.

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142 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 15.2 Haematological tests in the work‐up of anaemia.

Test

Mean corpuscular volume

Reticulocyte count

Lactate dehydrogenase (LDH)

Direct antiglobulin test (DAT)

Haptoglobin Iron studies

Peripheral blood film

Definition

The normal red cell has a volume of 80–96 femtolitres (fL) and the mean volume of red cells is called the mean corpuscular volume (MCV) [11,12]

Reticulocytes are young red blood cells and their presence or absence can help diagnose types of anaemia [11]
High count: increased red cell loss (bleeding), increased destruction (e.g. haemolytic anaemia) Low count: hypoproliferative anaemias (iron deficiency anaemia, aplastic anaemia, vitamin B12/folate deficiency, kidney disease, infection)

Enzyme that catalyses anaerobic respiratory reactions. Used as a marker for red cell breakdown in haemolysis

Also known as direct Coombs’ test. Used to diagnose autoimmune haemolytic anaemias by detecting antibodies on the red cell membrane

Binds to free haemoglobin. Reduced/undetectable in hemolytic anaemias. Reduced haptoglobin alongside raised reticulocytes indicates haemolysis (of any aetiology)

Total iron‐binding capacity (TIBC) is the total capacity of the blood to bind and transport iron. TIBC is increased in iron deficiency anaemia. Iron is transported through the blood bound to a protein called transferrin. Low transferrin saturation (expressed as a percentage) indicates reduced iron availability (e.g. in iron deficiency anaemia, or in anaemia of inflammation). Ferritin levels reflect intracellular iron stores. As such, low levels of ferritin represent low amounts of body iron. Ferritin levels below 20 μg/L are diagnostic of iron deficiency anaemia

A way to examine the components of blood (red and white cells) under the microscope. It is also used to look for blood parasites (e.g. malaria). Red cell abnormalities may accompany anaemia, e.g. spherocytes (round cells, seen in spherocytosis and immune haemolytic anaemias), target cells (e.g. thalassaemia, post splenectomy), red cell fragments (e.g. microangiopathic haemolytic anaemia)

. 5 Medicationhistory,specificallyrecentnon‐steroidalanti‐inflammatorydrug(NSAID) use (as prolonged treatment increases the risk of developing gastrointestinal bleed- ing), new medications, or antibiotic use.

. 6 Social and dietary history including vegan diets (iron/B12 deficiency), alcohol intake, socioeconomic status [10], poor diet, pregnancy. Urge to eat ice, clay, or dirt (pica) is a peculiar symptom occurring in iron deficiency anaemia.

. 7 Family history (hereditary anaemias: spherocytosis, sickle cell disease, thalassaemias).

. 8 A mental state examination should explore for evidence of symptoms of mental ill- ness that may be contributing to poor diet, either directly (eating disorders) or indi- rectly (e.g. poor self‐care in patients with dementia, or in those with severe depressive
or psychotic symptoms).

Examination

. 1 General examination: is there conjunctival pallor, yellow sclerae, jaundice, or glossitis?

. 2 Basic observations: is there a postural drop (this can occur in the event of acute blood
loss) or tachycardia?

CHAPTER 15

. 3 Examine for lymphadenopathy (cervical, axillary, inguinal).

. 4 Cardiovascular examination: is there evidence of heart failure?

. 5 Gastrointestinal examination: is there hepatosplenomegaly?

. 6 Neurological examination: is there peripheral neuropathy (suggestive of B12
deficiency), loss of balance, or gait disorder?

Investigations

Bedside

. 1 Urine dip (haematuria).

. 2 Pregnancy test.

. 3 ECG (anaemia may be associated with tachycardia or induce myocardial
ischaemia).

Blood tests

. 1 Full blood count: pay attention to Hb, mean corpuscular volume, and reticulocyte count.

. 2 Peripheral blood film (see Table 15.2).

. 3 Urea and electrolytes (upper gastrointestinal bleeding can be associated with raised
urea disproportionate to the accompanying creatinine).

. 4 Liver function tests: for side effects of medications, evidence of chronic liver disease
(e.g. secondary to alcohol abuse), and low albumin from poor nutrition.

. 5 C‐reactive protein (infection).

. 6 Blood group and antibody screen in case transfusion required.

. 7 Lactate dehydrogenase, direct antiglobulin test, and haptoglobin (markers of hae-
molysis; see Table 15.2).

. 8 Vitamin B12 and folate.

. 9 Iron studies (see Table 15.2).

. 10 Hepatitis B and C, HIV serology.

. 11 Autoimmune screen including antinuclear antibodies, erythrocyte sedimentation
rate (ESR), double‐stranded DNA, and extractable nuclear antigen (if suspicion of systemic lupus erythematosus).

Imaging/special tests

1 Chest X‐ray: is there any indication of pulmonary congestion or infection? 2 Cardiac echocardiogram: to evaluate myocardial function.

MANAGEMENT AND REFERRAL PATHWAYS

A blood transfusion should only be considered if there is severe acute anaemia or if the patient is particularly symptomatic (e.g. breathless or complaining of chest pain). If in doubt, discuss with general medical/haematology colleagues. Patients with acute blood loss should be assessed urgently by the on‐call medical team or emergency department.

Anaemia 143

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144 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Anaemia can usually be managed in primary care, although referral to a subspecialty may be appropriate if initial investigations reveal an underlying condition (e.g. if malig- nancy is suspected, if there is evidence of heart failure requiring cardiology input, or if a connective tissue disease is suspected requiring rheumatology input). If a psychiatric medication is thought to be causative, a risk–benefit decision will need to be made regarding ongoing treatment with a drug that is presumed to be responsible for the anaemia, balancing risk of continuing therapy (progressive anaemia) versus the risk of stopping treatment (deterioration in mental state). In this scenario, a multidisciplinary discussion involving psychiatry, haematology, and the patient is recommended. In the absence of a clear cause of anaemia, and where lifestyle/nutritional factors are thought to be responsible, the following approach is recommended.

Lifestyle modification

▪ Dietary advice (iron‐rich, dark leafy green vegetables, brown rice, white and red meat). Ascorbic acid enhances iron absorption, so drinking orange juice (or indeed any food/drink high in vitamin C) may increase iron absorption. Tea impairs iron absorption, although typically this only becomes clinically significant when con- sumed in large volumes.

▪ Reduce alcohol intake.
Psychosocial interventions to improve dietary intake

▪ Treat symptoms of mental illness that may be contributing to poor oral intake.

▪ Social interventions in cases of neglect.
Pharmacological therapy

▪ If appropriate, rationalise psychiatric medication or, in collaboration with medical colleagues, physical health medication.

▪ Iron deficiency: ferrous sulfate 200 mg two to three times daily or ferrous fumarate tablets 210 mg two to three times daily. (Note that these medications can cause dark stools and abdominal cramps, and can also cause constipation; be aware when used alongside clozapine.) Hb should rise by 10 g/L per week. If oral iron replacement is not tolerated, an intravenous iron infusion can be considered, usually given every three months.

▪ Folate/B12 deficiency: folic acid 5 mg once daily in combination with B12 injections (unless normal B12) as low levels of vitamin B12 may precipitate subacute combined degeneration of the cord. If the reason for B12 deficiency is purely poor dietary intake, oral supplements are appropriate. However, if compliance with oral treatment is poor or there is the risk of malabsorption, then parenteral vitamin B12 is preferred, as an intramuscular injection (1 mg three times per week for two weeks). If there is evidence of neuropathy, give B12 injections, and thereafter as a maintenance dose of 1 mg once a month. For all other cases give maintenance doses of 1 mg intramuscularly every three months (the typical maintenance dose for pernicious anaemia or post‐total gastrectomy).

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Anaemia 145

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9. Stübner S, Grohmann R, Engel R, et al. Blood dyscrasia induced by psychotropic drugs. Pharmacopsychiatry 2004;37(Suppl 1):S70–S78.

10. Mazaira S. Haematological adverse effects caused by psychiatric drugs. Vertex 2008;19(82):378–386.

11. Provan D, Hickin S. Haematology. In: Longmore M, Wilkinson IB, Baldwin A, Wallin E (eds) Oxford Handbook of Clinical Medicine,
9th edn. Oxford: Oxford University Press, 2014:316–336.

12. Frewin R, Henson A, Provan D. ABC of Clinical haematology. Iron deficiency anaemia. BMJ 1997;314(7077):360–363.

13. Boksa P. Smoking, psychiatric illness and the brain. J Psychiatry Neurosci 2017;42(3):147–149.

14. Smith JR, Landaw SA. Smokers’ polycythemia. N Engl J Med 1978;298:6–10.

CHAPTER 15

Chapter 16

Neutropenia

John Lally, Toby Pillinger, Aleksander Mijovic

The neutrophil is the most abundant type of white blood cell in the body. Neutrophils are the first line of defence against invading microbes by employing phagocytosis of pathogens and/or release of antimicrobial factors contained within specialised granules. They also represent a key role in the interface between innate and adaptive immunity. Neutropenia is defined as an absolute neutrophil count (ANC) below 1.5 × 109/L. Based on ANC, neutro- penia can be categorised as mild (1.0–1.5 × 109/L), moderate (0.5–1.0 × 109/L), and severe (<0.5 × 109/L). Agranulocytosis is commonly defined as an ANC less than 0.5 × 109/L.

Neutropenia is generally caused by decreased granulocyte production or increased peripheral destruction of neutrophils. Neutrophil pooling leading to neutropenia occurs in specific settings, e.g. splenomegaly and haemodialysis. Common causes of neutropenia are listed in Box 16.1.

Box 16.1 Causes of neutropenia in the general population Nutritional

■ Vitamin and mineral deficiencies (e.g. B12, folate, copper): in the SMI population, consider this differential in those with eating disorders or alcohol dependency.

Infection

■ Viral (e.g. HIV, infectious mononucleosis), bacterial (e.g. brucellosis, tuberculosis), parasitic (e.g. malaria, kala‐azar), and rickettsial infections.

Rheumatological/autoimmune

■ Primary autoimmune neutropenia.
■ Secondary, e.g. in rheumatoid arthritis, systemic lupus erythematosus, common variable

immunodeficiency.

Chronic idiopathic neutropenia

■ Long‐standing neutropenia of unknown cause. Usually runs a benign course, but patients may be prone to bacterial/fungal infections. Exact mechanism is unknown, but there is a high degree of overlap with autoimmune neutropenia.

Congenital neutropenias

▪ Benign ethnic neutropenia (BEN) describes an inherited neutropenia in people of African ethnicity, but also in some Middle Eastern populations. It is not associated with increased risk of infection. Although its pathophysiology is unclear, BEN has a genetic basis, being associated with a polymorphism of the Duffy antigen receptor for chemokines (DARC) gene [11]. Unexplained mild familial neutropenia in ethnic groups not associated with BEN can also occur.

▪ Cyclic neutropenia (CyN) is a rare autosomal dominant disorder with an incidence of 1–2 per mil- lion. Heterozygous mutation of the ELANE (formerly ELA2) gene occurs in almost all cases of CyN [12]. Severe neutropenia typically recurs every two to four weeks, with fever, pharyngitis, and mouth sores. Prognosis is typically benign, but there are reports of overwhelming infection and death in association with CyN.

▪ Severe congenital neutropenia (SCN) is a genetically heterogeneous disorder, characterised by early‐onset severe neutropenia and bacterial infections, often requiring prolonged treatment with G‐CSF. SCN is a preleukaemic condition, regardless of treatment with G‐CSF.

▪ Other congenital neutropenias include rare entities such as Shwachman–Diamond syndrome and WHIM (warts, hypogammaglobulinaemia, immunodeficiency, and myelokathexis) syndrome, among others.
Haematological malignancies

▪ Myelodysplastic syndromes and acute myeloid leukaemia (although rarely present with isolated neutropenia).

▪ Neutropenia with large granular lymphocyte (LGL) proliferation, with its two subtypes: T lympho- cyte, and natural killer lymphocytes. Often associated with rheumatoid arthritis and sometimes indistinguishable from Felty’s syndrome.
Hypersplenism

■ Hypersplenism is due to an increase in the marginated granulocyte pool, a portion of which is located in the spleen. Non‐haematological causes of hypersplenism include liver cirrhosis, heart failure, infection, rheumatological disease (e.g. rheumatoid arthritis, systemic lupus erythemato- sus, and sarcoid), and infiltrative disease (e.g. amyloid). It can occur in haematological cancers with a bulky spleen, e.g. primary myelofibrosis.

Drugs

See Box 16.2.

148 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

A significant proportion of people of African heritage have neutrophil counts lower than the laboratory standard ranges [1]. This is often not pathological and a diagnosis of benign ethnic neutropenia (BEN) is made where a reduced ANC exists in the absence of secondary causes.

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Neutropenia 149

DRUG‐INDUCED NEUTROPENIA AND AGRANULOCYTOSIS

A wide range of medications, and in particular psychotropic agents, are associated with neutropenia (Box 16.2), with various pathoaetiological mechanisms pro- posed. All antipsychotics have been associated with neutropenia, although the highest risk is traditionally considered to be with clozapine (approximate fre- quency 3%). Mood stabilisers are also associated with disturbances of white cell count: the risk of neutropenia with carbamazepine is 0.5–2% [2,3] while sodium valproate is associated with leucopenia in approximately 1 in 400 patients [3]. A hospital‐based cohort study identified leucopenia in 0.3% of patients treated with tricyclic antidepressants [3].

Box 16.2 Medications associated with neutropenia/leucopenia/agranulocytosis

▪ Anti‐inflammatory agents (e.g. NSAIDs, sulfasalazine): time course unclear, occurs in <1% of users.

▪ Antibiotics (e.g. β‐lactams): typically occurs in patients receiving treatment for two weeks or
more.

▪ Antimalarials (e.g. chloroquine, quinine): time course unclear, rare.

▪ Diuretics (e.g. thiazides, furosemide, spironolactone): time course unclear.

▪ Cardiovascular agents (e.g. ACE inhibitors): risk of ACE inhibitor‐related neutropenia may be
higher risk in patients with renal failure, typically occurs in first 90 days.

▪ Antithyroid agents (e.g. carbimazole, propylthiouracil): with carbimazole, usually in first two
months of treatment.

▪ Chemotherapy (virtually all chemotherapy drugs): at any time, but usually within first few weeks
of treatment.

▪ Gastrointestinal agents (e.g. histamine H2 receptor antagonists): time course unclear, rare.

▪ Antipsychotics (e.g. clozapine, olanzapine, haloperidol, risperidone, paliperidone, chlorpromazine,
lurasidone, ziprasidone, fluphenazine, cariprazine, asenapine): with clozapine, usually in first three
months but may occur at any time.

▪ Anticonvulsants/mood stabilisers (e.g. sodium valproate, carbamazepine, lamotrigine): neutropenia
typically occurs in first few weeks to months of treatment.

▪ Antidepressants (e.g. mirtazapine, mianserin, sertraline, trazodone): usually within first few weeks
of treatment.

Drug‐induced agranulocytosis from any cause is rare, with an annual incidence of 3–12 per million population [4]. Agranulocytosis occurs in 0.2–0.9% of clozapine‐ treated patients [5–7], although incidence is reduced with more regular monitoring of neutrophil counts. The one‐year prevalence of clozapine‐induced neutropenia is 2.7% in the first year, with the peak incidence occurring at 6–18 weeks [8].

There are case reports of agranulocytosis with lamotrigine [9], and during clinical trials of mirtazapine, agranulocytosis was reported in three of 2796 patients (occurring in the first three months of treatment), with neutrophil counts recovering on discon- tinuation of mirtazapine in all cases [10]. Risk of mirtazapine‐induced agranulocytosis increases with age (>65 years) [10].

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150 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES

Neutropenia may be an incidental finding in an asymptomatic patient on routine blood testing, or instead may present as a clinical emergency with neutropenic sepsis. The urgency with which a patient is examined and investigated will therefore be defined by the patient’s presenting complaint, and the severity of neutropenia.

Neutropenic patients with evidence of sepsis (e.g. fever, rigors, shortness of breath, confusion, hypotension, tachycardia, or low urine output) should be managed as a medical emergency. Resuscitation and referral to emergency services is indicated (see Chapter 72).

History

A history should screen for the common causes of neutropenia described in Boxes 16.1 and 16.2. This will include clarifying the patient’s ethnicity, enquiring about recent/ ongoing infection, recurrent infections, episodic aphthous ulcers (may suggest cyclic neutropenia), previous haematological malignancy, recent weight loss/other ‘red flag’ signs for malignancy, history of malabsorption or conditions that predispose to malabsorption (e.g. inflammatory bowel disease), liver disease, rheumatological/autoimmune disease, family history of neutropenia, alcohol intake, diet, travel history, and medication history.

Examination

. 1 Check temperature, blood pressure, pulse, respiratory rate, and oxygen saturation.

. 2 Examine for evidence of infection, including the oral cavity (gingivitis, mouth ulcers),
skin (cellulitis), nails (paronychia), lungs, and perirectal area.

. 3 Examine for evidence of conditions that might underlie neutropenia: joint swelling
of rheumatological disease, hepatomegaly/jaundice, lymphadenopathy suggestive of haematological malignancy, splenomegaly suggestive of haematological/liver disease, or parasitic infection (e.g. leishmaniasis).

Investigations

The following blood tests are recommended in the neutropenic patient.

. 1 Full blood count (FBC) for comparison with previous FBCs if available; blood film for examination of neutrophil morphology and for other haematological diagnoses.

. 2 If concerns regarding infection, consider collecting blood, urine, stool, or sputum samples (as appropriate) for microscopy, culture, and sensitivity. Nose, mouth, and skin swabs are also required.

. 3 Urea and electrolytes (renal function).

. 4 Liver function tests.

. 5 C‐reactive protein (CRP).

. 6 HIV serology, hepatitis B and C serology, hepatitis C RNA.

. 7 Rheumatoid factor, antinuclear antibodies, autoimmune screen.

CHAPTER 16

8 Serum vitamin B12/folate.

9 Thyroid function tests.
10 Serum protein electrophoresis and immunoglobulins.

MANAGEMENT

Management of neutropenic sepsis will involve urgent admission under acute medical services for appropriate supportive care and antimicrobial treatment. Any presumed causative agent(s) should also be discontinued.

Patients with an ANC below 0.5 × 109/L, even if systemically well, should be reviewed medically. The urgency of this medical referral will be guided by the patient’s clinical presentation, the severity of neutropenia, and the results of screening blood tests described in the preceding section.

Asymptomatic incidental neutropenia with an ANC above 1.0 × 109/L can be moni- tored on an outpatient basis. If there is resolution over the following weeks, the most likely diagnosis is a transient neutropenia secondary to viral infection or medication. No further investigations will likely be required.

Stable mild neutropenia is usually secondary to BEN, familial neutropenia, diet, rheuma- tological conditions, or an indolent haematological malignancy. In cases of systemic condi- tions resulting in neutropenia, appropriate targeted therapy may improve blood counts.

In systemically well patients, and where a psychiatric drug is felt to be causative, a risk–benefit decision will need to be made regarding ongoing treatment with a drug that is presumed to be responsible for the neutropenia, balancing risk of continuing therapy (worsened neutropenia and infection liability) versus the risk of stopping treat- ment (e.g. deterioration in mental state). In this scenario, a multidisciplinary discussion involving psychiatry, haematology, and the patient is recommended.

Neutropenia and clozapine

During clozapine treatment, transient fluctuations in neutrophil counts can occur that may not necessarily progress to agranulocytosis; however, even if clozapine is contin- ued, current UK licensing requires discontinuation [13] at a neutrophil count of less than 1.5 × 109/L (or <1.0 × 109/L in patients with BEN). In the USA, a lower neutrophil count (<1.0 × 109/L) is allowed (or <0.5 × 109/L in patients with BEN).

Differentiating between a clozapine‐induced neutropenia and a transient natural dip in neutrophils can be difficult. Where possible, all cases of neutropenia with clozapine should be assessed as described in the Diagnostic principles section, which will serve to identify any intercurrent conditions (e.g. infections) or co‐administered drugs (e.g. val- proate) [14] that may be causative. Specific considerations that suggest a neutropenic episode was related to clozapine are as follows:

■ if the decrease in neutrophil count was inconsistent with previous counts (i.e. not in a patient who presents with labile ANCs which often ‘naturally’ dip in to neutropenia territory)

Neutropenia 151

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152 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ if ANC dropped below 0.5 × 109/L

▪ if neutropenia was prolonged for longer than 10 days

▪ if neutropenia occurred within 18 weeks of clozapine initiation

▪ if no alternative causes for the neutropenia/agranulocytosis, such as concurrent medi-
cation or infection, were identified [15,16].
Re‐challenge with clozapine after neutropenia is ‘off licence’ but has been observed to be successful in approximately 70% of cases, although this figure includes re‐challenge in some cases where clozapine was not the likely cause [17]. There are some non‐pharmacological and pharmacological strategies that can be employed to avoid recurrent modest dips in neutrophil counts that may result in extra blood tests or temporary interruption in clozapine administration. For example, some people have a marked circadian rhythm in their neutrophil count, with higher levels in the afternoon compared to the morning, and thus venepuncture later in the day may be associated with higher ANCs. Moderate to heavy exercise can also increase ANCs. Lithium can be used to promote granulopoiesis, with evidence of serum levels above 0.4 mmol/L promoting neutrophil proliferation in the absence of left shift (i.e. the increased ANC is not a consequence of excessive numbers of immature neutrophils; the neutrophils are mature and function normally) [18]. However, caution with these approaches is required, as neither will prevent drug‐induced agranulocytosis from occurring.
In some cases, granulocyte colony‐stimulating factor (G‐CSF) may be used to sup- port clozapine re‐challenge and maintenance following neutropenia. These agents are more typically administered during chemotherapy to reduce the incidence or duration of neutropenia [19,20]. They stimulate proliferation and differentiation of committed myeloid progenitor cells in the bone marrow [21]. Filgrastim and lenograstim are the most commonly used G‐CSFs, and are administered by subcutaneous injection. A systematic review providing the largest synthesis of clozapine re‐challenge follow- ing neutropenia to date reported relatively high success but highlighted the likelihood of publication bias [16]. Consultation with a haematologist is recommended before considering the use of lithium and certainly before use of G‐CSF in the context of clozapine‐associated neutropenia. It is important to note that while G‐CSF will help maintain an adequate baseline ANC to allow administration within licensing guide- lines, it is unlikely to prevent progression from neutropenia to a true clozapine‐related agranulocytosis.
Management of clozapine‐induced agranulocytosis
As with any drug, if clozapine is considered the causative agent in the context of agranulocytosis, it should be stopped and clinical review conducted as described. Following cessation, G‐CSF shortens time to neutrophil recovery from a median of 12 days to 7 days, and may therefore be considered [22]. Because of the high risk of recurrence, re‐challenge following clozapine‐induced agranulocytosis, with or without lithium or G‐CSF, and certainly outside of specialist care settings, is not recommended.

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Neutropenia 153

References

1. Shoenfeld Y, Alkan ML, Asaly A, et al. Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol 1988;41(3):273–277.

2. Duggal HS, Singh I. Psychotropic drug‐induced neutropenia. Drugs Today (Barc) 2005;41(8):517–526.

3. Tohen M, Castillo J, Baldessarini RJ, et al. Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228
patients at risk. Am J Psychiatry 1995;152(3):413–418.

4. Andres E, Noel E, Kurtz JE, et al. Life‐threatening idiosyncratic drug‐induced agranulocytosis in elderly patients. Drugs Aging
2004;21(7):427–435.

5. Myles N, Myles H, Xia S, et al. Meta‐analysis examining the epidemiology of clozapine‐associated neutropenia. Acta Psychiatr Scand
2018;138(2):101–109.

6. Honigfeld G, Arellano F, Sethi J, et al. Reducing clozapine‐related morbidity and mortality: 5 years of experience with the Clozaril National
Registry. J Clin Psychiatry 1998;59:3–7.

7. Tang YI, Mao PX, Jiang F, et al. Clozapine in China. Pharmacopsychiatry. 2008;41(1):1–9.

8. Munro J, O’Sullivan D, Andrews C, et al. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance.
Br J Psychiatry 1999;175:576–580.

9. Ahn YM, Kim K, Kim YS. Three cases of reversible agranulocytosis after treatment with lamotrigine. Psychiatry Investig 2008;5(2):
121–123.

10. Remeron (mirtazapine). Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 1996:1878–1881.

11. Reich D, Nalls MA, Kao WHL, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen
receptor for chemokines gene. PLoS Genet 2009;5(1):e1000360.

12. Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia:genetics and pathophysiology.
Hematol Oncol Clin North Am 2013;27(1):19–41, vii.

13. Ingimarsson O, MacCabe JH, Haraldsson M, et al. Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus
other antipsychotics: an observational study in Iceland. BMC Psychiatry 2016;16(1):441.

14. Malik S, Lally J, Ajnakina O, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr
Res 2018;195:267–273.

15. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry, 13th edn. Chichester: Wiley Blackwell, 2018.

16. Lally J, Malik S, Krivoy A, et al. The use of granulocyte colony‐stimulating factor in clozapine rechallenge: a systematic review. J Clin
Psychopharmacol 2017;37(5):600–604.

17. Manu P, Sarpal D, Muir O, et al. When can patients with potentially life‐threatening adverse effects be rechallenged with clozapine? A sys-
tematic review of the published literature. Schizophr Res 2012;134(2–3):180–186.

18. Meyer N, Gee S, Whiskey E, et al. Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis. J Clin Psychiatry
2015;76(11):e1410–e1416.

19. Renner P, Milazzo S, Liu JP, et al. Primary prophylactic colony‐stimulating factors for the prevention of chemotherapy‐induced febrile neu-
tropenia in breast cancer patients. Cochrane Database Syst Rev 2012;10:CD007913.

20. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony‐stimulating factor on febrile neu-
tropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25(21):3158–3167.

21. Lieschke GJ, Burgess AW. Granulocyte colony‐stimulating factor and granulocyte‐macrophage colony‐stimulating factor. N Engl J Med
1992;327(1):28–35.

22. Lally J, Malik S, Whiskey E, et al. Clozapine‐associated agranulocytosis treatment with granulocyte colony‐stimulating factor/granulocyte‐
macrophage colony‐stimulating factor: a systematic review. J Clin Psychopharmacol 2017;37(4):441–446.

CHAPTER 16

Chapter 17

Thrombocytopenia

Sanjena Mithra, Aleksander Mijovic

Platelets are tiny cell fragments within the blood that, along with coagulation factors, allow blood to clot. They are shed from the cytoplasm of megakaryocytes and circulate for a lifespan of 7–10 days or until they are activated by a specific trigger [1]. A normal platelet count is 150–400 × 109/L, but levels can vary depending on several factors including menstrual cycle, pregnancy (gestational thrombocytopenia), and in response to inflammation [2]. Thrombocytopenia can be subdivided into mild (platelet count 100–150 × 109/L), moderate (50–100 × 109/L), and severe (<50 × 109/L) [3]. Risk of bleeding is highest in patients with severe thrombocytopenia.

Thrombocytopenia may occur due to accelerated destruction, ineffective production, or splenic sequestration of platelets (Table 17.1) [4]. Patients with serious mental illness (SMI) are at increased risk of various conditions that may in turn result in thrombocy- topenia, such as vitamin B12/folate deficiency [5,6] and splenomegaly secondary to cir- rhosis of the liver and portal hypertension [7]. Certain medications, including psychiatric medication, are associated with development of thrombocytopenia (Box 17.1). Indeed, alongside immune thrombocytopenic purpura (ITP), medication is the most common cause of thrombocytopenia [4]. Drug‐induced thrombocytopenia is thought to be due to the actions of drug‐dependent antibodies [8], and generally occurs within one to two weeks of starting a new drug. If the drug is stopped, there is usually resolution within 5–10 days. In addition, some foods and drink have been implicated in causing throm- bocytopenia, such as tonic water (which contains quinine) [9], herbal remedies [10], walnuts [11], and even cows’ milk [12].

Box 17.1 Medications associated with thrombocytopenia

▪ Methotrexate (and other cytotoxic drugs, including chemotherapy)

▪ Histamine H2 receptor antagonists (ranitidine, cimetidine)

▪ Heparin (occurs within five days)

▪ Antibiotics (e.g. penicillin, quinine, trimethoprim, ciprofloxacin) [8,13]

▪ Antifungals (e.g. fluconazole) [8,13]

▪ Antiplatelet drugs: can occur after first administration (e.g. tirofiban and abciximab) [8]

▪ Mood stabilisers (carbamazepine, phenytoin, valproic acid, lamotrigine) [13,14]

▪ Antidepressants (tricyclic antidepressants, escitalopram, venlafaxine, buproprion, duloxetine,
fluoxetine, mirtazapine, sertraline) [13,14]

▪ Antipsychotics (haloperidol, chlorpromazine, clozapine, fluphenazine, olanzapine, quetiapine, ris-
peridone/paliperidone, trifluoperazine, ziprasidone)

▪ Benzodiazepines

▪ Donepezil

▪ Recreational drugs (e.g. alcohol, cocaine)

▪ Miscellaneous (gold, furosemide) [8]

156 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 17.1 Causes of isolated thrombocytopenia.

Mechanism

Accelerated destruction

Decreased production

Splenic sequestration

Pathology

Immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP) and related disorders Disseminated intravascular coagulation (DIC)
Systemic lupus erythematosus, antiphospholipid syndrome Medication (see Box 17.1)

Congenital thrombocytopenias
Vitamin B12/folate deficiency
Haematological disorders (e.g. leukaemia, aplastic anaemia, myelodysplastic syndrome) Sepsis
Medication (see Box 17.1)

Portal hypertension with splenomegaly: cirrhosis due to viral disease or alcohol, hepatic vein thrombosis (Budd–Chiari syndrome), splanchnic vein thrombosis, cardiac failure
Viral infections with splenomegaly (e.g. Epstein–Barr virus, cytomegalovirus)
Myelofibrosis

Gaucher’s disease (inherited lysosomal storage disease characterised by hepatosplenomegaly, pancytopenia, bone pain, and neurological symptoms)

DIAGNOSTIC PRINCIPLES

Mild to moderate thrombocytopenia is generally asymptomatic. Clinical signs and symptoms of thrombocytopenia generally start to manifest at platelet levels of approxi- mately 30 × 109/L [15]. Determining the aetiology of thrombocytopenia can be chal- lenging. Often, if a drug is suspected then the diagnosis is empirical and based on confirmation of platelet count recovery after discontinuation of the offending drug, or even following recurrence of thrombocytopenia following re‐exposure to the drug in question. To make a laboratory diagnosis of a drug‐induced thrombocytopenia would

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Thrombocytopenia 157

be time‐consuming and costly, involving the demonstration of drug‐dependent anti- platelet antibodies by methods such as flow cytometry, platelet immunofluorescence test, and ELISA [8].

History

Eliciting a full medical history is vital for determining the aetiology of thrombocytope- nia and whether this is accompanied by suppression of other cell lines (red and white blood cells).

. 1 Duration of symptoms (drug‐induced thrombocytopenia is associated with a shorter duration of symptoms, usually days to weeks).

. 2 Ask about any concurrent symptoms suggestive of infection.

. 3 Clinical signs: petechial rash, bruises or superficial bleeding after minor trauma (such
as shaving or brushing teeth), or prolonged menstrual bleeding.

. 4 Presentations suggestive of more severe bleeding: fatigue (due to blood loss and anae- mia), headache or fluctuating conscious level (which may suggest cerebral haemor-
rhage), haematemesis, or melaena (indicative of gastrointestinal bleeding).

. 5 Past medical history: red flag screening for haematological malignancy (uninten- tional weight loss, lymphadenopathy, night sweats), venous thromboembolism or
atrial fibrillation and stroke requiring anticoagulation.

. 6 Family history: bleeding disorders.

. 7 Medication history: new medications and antibiotics, as well as non‐steroidal anti‐
inflammatory drugs (NSAIDs), aspirin, or anticoagulants that could further increase likelihood of bleeding.

Examination

This should predominantly focus on determining the location and severity of any bleed- ing, although evidence of infection or hepatosplenomegaly may point towards an underlying pathology.

1 Observations including temperature (fever may signal underlying infection). 2 General: skin examination (looking for petechiae).
3 Abdominal examination for hepatosplenomegaly.
4 Neurological examination to assess conscious level and any focal neurology.

Investigations

. 1 Bedside: urine dip.

. 2 Blood tests:
a full blood count to determine if thrombocytopenia is isolated or associated with low haemoglobin and white cells
b blood film to confirm if the low count represents true thrombocytopenia or if there is any ‘clumping’, and also to assess platelet size (larger may suggest a hereditary cause)

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158 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

c coagulation screen (international normalised ratio, activated partial thromboplas- tin time)

d urea and electrolytes, liver function tests, C‐reactive protein. 3 Imaging/special tests:

a chest X‐ray if any suspicion of infection
b consider CT head if fluctuating conscious level or suspicion of intracranial bleed c mixing clotting studies are used to distinguish between clotting factor deficiency

and clotting factor inhibitors (e.g. antibodies such as ‘lupus anticoagulant’).

MANAGEMENT AND WHEN TO REFER

Acute bleeding should be managed as a medical emergency, with emergency transfer of the patient to medical services.

Finding the causative agent of thrombocytopenia is difficult and is made more so by polypharmacy and lack of specific laboratory tests. The mainstay of treatment is to stop the agent thought to have caused the thrombocytopenia. Drug‐induced thrombocytope- nia usually occurs within weeks of starting a new drug (within days in the case of hepa- rin), and the causative drug is usually the most recent drug to have been prescribed.

If a psychiatric medication is thought to be responsible, multidisciplinary discussion involving psychiatry, haematology, and the patient should be sought. If there is evidence of associated acute pathology or bleeding, the patient should be referred urgently to the emergency department or acute medical team for assessment. A platelet transfusion is considered if levels drop below 10 × 109/L, or below 20 × 109/L with evidence of bleed- ing [15]. Other interventions that may be considered following haematology input include intravenous immunoglobulin (e.g. for ITP), steroids (e.g. for immune‐mediated thrombocytopenia), or plasmapheresis (e.g. for TTP) [15]

References

1. Stasi R. How to approach thrombocytopenia. Hematology Am Soc Hematol Educ Program 2012;2012:191–197.

2. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence‐based practice guideline for immune thrombocy-
topenia. Blood 2011;117(16):4190–4207.

3. Williamson DR, Albert M, Heels‐Ansdell D, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk
factors, and outcomes. Chest 2013;144(4):1207–1215.

4. Izak M, Bussel JB. Management of thrombocytopenia. F1000Prime Rep 2014;6:45.

5. Carmel R, Gott PS, Waters CH, et al. The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and
electrophysiologic abnormalities. Eur J Haematol 1995;54(4):245–253.

6. Silver H. Vitamin B12 levels are low in hospitalized psychiatric patients. Israel J Psychiatry 2000;37(1):41–45.

7. Hsu JH, Chien IC, Lin CH, et al. Increased risk of chronic liver disease in patients with schizophrenia: a population‐based cohort study.
Psychosomatics 2014;55(2):163–171.

8. George JN, Aster RH. Drug‐induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ

Program 2009;2009:153–158.

9. Davies JK, Ahktar N, Ranasinge E. A juicy problem. Lancet 2001;358(9299):2126.

10. Royer DJ, George JN, Terrell DR. Thrombocytopenia as an adverse effect of complementary and alternative medicines, herbal remedies, nutritional supplements, foods, and beverages. Eur J Haematol 2010;84(5):421–429.

11. Achterbergh R, Vermeer HJ, Curtis BR, et al. Thrombocytopenia in a nutshell. Lancet 2012;379(9817):776.

12. Caffrey EA, Sladen GE, Isaacs PE, Clark KG. Thrombocytopenia caused by cows milk. Lancet 1981;318(8241):316.

13. Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug‐induced immune thrombocytopenia: pathogenesis, diagnosis, and management.
J Thromb Haemost 2009;7(6):911–918.

14. Song HR, Jung YE, Wang HR, et al. Platelet count alterations associated with escitalopram, venlafaxine and bupropion in depressive patients.

Psychiatry Clin Neurosci 2012;66(5):457–459.
15. Provan D, Hickin S. Haematology. In: Longmore M, Wilkinson IB, Baldwin A, Wallin E (eds) Oxford Handbook of Clinical Medicine, 9th

edn. Oxford: Oxford University Press, 2014:316–336.

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Chapter 18

Venous Thromboembolism and Anticoagulation

Helen Doolittle, Lara Roberts, Roopen Arya

The term ‘venous thromboembolism’ (VTE) comprises deep vein thrombosis (DVT), most commonly in the pelvic or deep leg veins, and the movement of the clot through the vasculature to the lungs, i.e. pulmonary embolism (PE). VTE is associated with significant morbidity and mortality. Venous thrombosis may occur in other sites, such as the intra‐abdominal veins, cavernous sinus, deep veins of the upper limbs, and superficial veins. There is some overlap between the provoking factors and management of these atypical thromboses, but these are beyond the scope of the guidance given here.

RISK FACTORS

There are many recognised risk factors for VTE. In psychiatric patients it is important to consider underlying medical conditions, features of the psychiatric illness (e.g. immobility), and psychiatric treatments (antipsychotics) which may all increase risk of developing VTE (Box 18.1).

Box 18.1 Risk factors for venous thromboembolism (VTE) Inherited

▪ Inherited thrombophilia (including protein C deficiency, protein S deficiency, antithrombin defi- ciency, prothrombin gene polymorphism, factor V Leiden)

▪ History of VTE in first‐degree relative

Acquired: persistent

General physical/lifestyle factors

▪ Increasing age

▪ Body mass index (BMI) >30 kg/m2

▪ Previous/current intravenous drug use
Medical conditions

▪ Cancer (active disease/receiving anticancer therapy)

▪ Chronic inflammatory/metabolic conditions

▪ Myeloproliferative disorders

▪ Paroxysmal nocturnal haemoglobinuria

▪ Antiphospholipid syndrome

▪ Previous personal history of VTE
Acquired: transient/reversible
General physical/lifestyle factors

▪ Pregnancy/postpartum

▪ Prolonged periods of immobility, including paresis, long‐distance travel
(>4 hours), catatonia, stupor
Medical conditions

▪ Post surgery

▪ Acute medical illness

▪ Hospitalisation

▪ Trauma/fracture especially to lower limbs
Medications

▪ Oestrogen‐containing/oestrogen receptor‐targeting medications (including com- bined hormonal contraception, oral hormone replacement therapy, tamoxifen)

▪ Antipsychotics (see text)

160 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Antipsychotics and venous thromboembolism

Studies have demonstrated an increased risk of VTE in patients treated with antipsy- chotic medications of 1.3 to 7‐fold [1]. The mechanism by which antipsychotics increase VTE risk is not clear but the risk appears to be highest in the first three months of treatment, in younger patients, and is probably dose related [1]. While clo- zapine was the first antipsychotic widely acknowledged to carry an increased VTE risk, a broad variety of antipsychotic medications have now been implicated [1,2]. Evidence is still lacking as to whether there are significant differences in the risk asso- ciated with different drugs or classes of antipsychotics [3,4].

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Venous Thromboembolism and Anticoagulation 161

PROPHYLAXIS

Prophylaxis has been shown to reduce the risk of VTE in selected patient groups, such as acutely unwell medical and postoperative patients. Prophylaxis includes mechanical and pharmacological measures. The decision regarding whether VTE prophylaxis is warranted during an acute hospital admission and the selection of the most appropriate prophylactic measure are based on assessing the patient’s risk of developing VTE along- side their bleeding risk.

Several international guidelines have been developed for the appropriate assess- ment of hospitalised patients and provision of VTE prophylaxis [5–7], although most do not specifically discuss assessment and management of psychiatric patients. However, the UK‐based National Institute for Health and Care Excellence (NICE) guidance (2018) recommends that acute psychiatric inpatients are assessed similarly to acutely unwell medical inpatients using the Department of Health VTE risk assessment tool (http://www.nice.org.uk/guidance/ng89/resources) or an equivalent published tool [5]. The initial assessment should take place as soon as possible after admission to hospital, with reassessment at the time of the patient’s consultant review and when the patient’s condition changes. Further work is required to determine if existing risk assessment tools need adaptation for psy- chiatric patients.

Before employing pharmacological VTE prophylaxis, the risk of bleeding should be also assessed; the IMPROVE bleeding assessment model is sometimes used to assess bleeding risk in medical patients [8]. Again, further work is required to see if such tools are valid for use in psychiatric patients. Where pharmacological VTE prophylaxis is indicated, the use of low‐molecular‐weight heparin (LMWH) is usually recommended. Fondaparinux can be considered if LMWH is contraindicated, such as inpatients wish- ing to avoid animal products or with hypersensitivity reactions to LMWH (especially thrombocytopenia). Dose adjustment, additional monitoring, or alternative drugs may be required in patients with renal impairment.

The use of mechanical thromboprophylaxis with graduated compression stock- ings has only been evaluated and demonstrated to benefit patients in the surgical setting. There is no evidence to support their use in medical or obstetric patients, or indeed psychiatric patients. The UK‐based NICE and Asian VTE guidelines there- fore no longer recommend the use of graduated compression stockings for acute medical patients, although the American Society of Hematology suggests they can be considered for medical patients where pharmacological prophylaxis is contrain- dicated [5–7]. If graduated compression stockings are used they should be fitted by staff trained in their use. They are not recommended for patients with peripheral arterial disease (suspected or known), peripheral arterial bypass grafting, peripheral sensory impairment, and local skin or soft tissue conditions (where stockings can cause further damage and severe leg oedema) [5]. In selected situations, intermittent pneumatic compression is recommended as an alternative form of mechanical VTE prophylaxis [5–7].

Early mobilisation and maintaining hydration are also proposed to reduce the risk of VTE.

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162 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSIS
Deep vein thrombosis

A diagnosis of DVT should be considered in a patient with unilateral calf swelling and/ or pain. The clinical assessment should be based around calculating the Revised Wells Score for suspected DVT [9] (Table 18.1) and considering other causes for the patient’s presentation such as cellulitis, trauma, or ruptured Baker’s cyst. This is usually done by a DVT clinic or following referral of the patient to the nearest emergency or medical team. An algorithm outlining the investigation and management of a suspected DVT is presented in Figure 18.1.

Table 18.1 Revised Wells Score for suspected deep vein thrombosis (DVT) [9].

Clinical characteristic Score

Active cancer (treatment for cancer within previous 6 months/ongoing palliative treatment) 1 Paralysis, paresis, or plaster immobilisation of lower limbs 1 Recently bedridden for ≥3 days, or major surgery within 12 weeks requiring general or regional anaesthesia 1 Localised tenderness along the distribution of the deep venous system 1 Entire leg swollen 1 Calf swelling ≥3 cm than asymptomatic side (measured at 10 cm below tibial tuberosity) 1 Pitting oedema in the symptomatic leg only 1 Collateral superficial veins (non‐varicose) 1 Previous DVT 1 Alternative diagnosis at least as likely as DVT –2

Score ≥2 indicates DVT likely; score <2 indicates DVT unlikely.

Pulmonary embolism

A diagnosis of PE should be considered in a patient with new or progressive hypoxia, pleuritic chest pain, unexplained tachycardia, or collapse (see Chapters 67 and 68). If such symptoms or signs are present, urgent assessment should be sought at the nearest acute medical or emergency unit. Direct admission to an acute hospital will be required if the patient has significant hypoxia or is haemodynamically unstable. Initial assess- ment of a patient with a suspected PE should include calculation of the Revised PE Wells Score [11] (Table 18.2) and consideration of other causes for the presentation such as pneumonia, chest wall pain (secondary to trauma or malignant disease), gastro‐ oesophageal reflux, cardiac chest pain (secondary to ischaemia, pericarditis, or aortic dissection/aneurysm rupture), as well as any neurological or other cardiovascular causes of collapse. An algorithm for the investigation and management of suspected PE is presented in Figure 18.2.

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Venous Thromboembolism and Anticoagulation 163

Negative D-Dimer

Clinical suspicion of DVT

Poximal leg vein USS

(if USS is delayed by >4 hours, give interim treatment dose of anticoagulation)

Positive D-Dimer

Proximal DVT not detected

Poximal leg vein USS

(if USS is delayed by >4 hours, give interim treatment dose of anticoagulation)

Request D-Dimer

Positive D-Dimer

Negative D-Dimer

Repeat Proximal leg vein USS 6–8 days later

Proximal DVT not detected

Proximal DVT detected

Proximal DVT not detected

Consider alternative diagnosis

Start management of DVT

Consider alternative diagnosis

Figure 18.1 Investigation of suspected deep vein thrombosis (DVT). CRP, C‐reactive protein; FBC, full blood count; USS, ultrasound scan. Source: adapted from National Institute for Health and Care Excellence [10].

Table 18.2 Wells Score for suspected pulmonary embolus (PE) [11].

Clinical characteristic Score

Clinical signs and symptoms of DVT (including leg swelling and pain over deep veins) 3 Alternative diagnosis less likely than PE 3 Heart rate >100 beats per minute 1.5 Immobilisation or surgery within previous 4 weeks 1.5 Previous DVT/PE 1.5 Haemoptysis 1 Active cancer (treatment for cancer within previous 6 months/ongoing palliative treatment) 1

Score >4 indicates PE likely; score ≤4 indicates PE unlikely.

Clinical assessment (including history, examination and bloods (including FBC, CRP, renal function, coagulation screen)

Revised Wells Score for suspected DVT

Score <2

DVT Unlikely

Score ≥ 2

DVT Likely

Request D-Dimer

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Score >4

PE Likely

Request CTPA

(if CTPA is delayed, give interim treatment dose of anticoagulation)*

Clinical suspicion of PE

Clinical assessment (including history, examination, bloods (including FBC, CRP, renal function, troponin, coagulation screen), ECG and CXR

Wells Score for suspected PE

Score ≤4

PE Unlikely

Request D-Dimer

Positive D-Dimer

Negative D-Dimer

Request CTPA

(if CTPA is delayed, give interim treatment dose of anticoagulation)*

Negative scan for PE

Positive scan for PE

Negative scan for PE

Start management of PE

Consider alternative diagnosis

164 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Figure 18.2 Investigation of suspected pulmonary embolus (PE). ECG, electrocardiogram; CXR, chest X‐ray; CTPA, computed tomography pulmonary angiogram. *If patient has renal impairment, allergy to contrast media or with high irradiation risk, ventilation–perfusion single photon emission computed tomography scan can be considered as an alternative to CTPA. Source: adapted from National Institute for Health and Care Excellence [10].

MANAGEMENT Anticoagulation

Anticoagulation is the recommended treatment of DVT or PE. The majority of patients with DVT and a significant proportion of patients with PE are now managed without hospital admission. The minimum duration of therapy is usually three months, with a minimum of six months recommended for those with active cancer. This allows resolu- tion of the VTE and prevention of early recurrent VTE. Anticoagulation may be extended beyond this, based on individual characteristics and particularly in the absence of provoking factors for VTE. The risk of bleeding will also need to be consid- ered in this decision‐making process, along with the patient’s preferences.

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Venous Thromboembolism and Anticoagulation 165

Initial management of VTE can be with LMWH, fondaparinux, or a direct oral anticoagulant (apixaban or rivaroxaban). Long‐term anticoagulants include direct oral anticoagulants, warfarin, LMWH, or fondaparinux. The characteristics of the dif- ferent agents are summarised in Table 18.3. These can all be used to manage VTE, and the choice should be made based on the patient’s medical comorbidities and concomi- tant medications. LMWH is generally recommended for use in patients with active cancer, at least in the initiation phase [12]. Selection of appropriate anticoagulation will usually be made by the DVT clinic or acute medical unit managing the patient. Patients with absolute or relative contraindications to anticoagulation should be dis- cussed with haematology for specialist guidance.

If VTE occurs in the context of prior therapeutic anticoagulation, a discussion regarding adherence to medication is needed. If compliance to prior anticoagulation therapy is established, the patient should be discussed with the haematology team. Increased intensity of anticoagulation may be indicated. Temporary inferior vena cava filters may also be considered.

Use of anticoagulants alongside antipsychotic drugs

If a patient requires treatment for VTE and is taking an antipsychotic drug, the role of that drug in causing the event requires consideration by the psychiatric and haematol- ogy teams involved in the patient’s care. This might have implications as to the choice of antipsychotic agent. This decision may also affect the duration of anticoagulation. If extended anticoagulation is required, low‐dose direct oral anticoagulants are a convenient option.

Since the co‐prescription of selective serotonin reuptake inhibitors (SSRIs) may increase risk of bleeding, SSRIs should generally be avoided alongside anticoagulation [13]. For patients taking SSRIs in whom anticoagulation is indicated, a multidiscipli- nary discussion involving both psychiatry and haematology should take place. If SSRI use cannot be avoided, monitor closely, avoid concomitant use of non‐steroidal anti‐ inflammatories or antiplatelet medications, and consider prescribing gastroprotection (e.g. a proton pump inhibitor). Given the bleeding risk associated with SSRIs is thought to be due to reduced serotonin uptake by platelets, reducing platelet function, caution is also recommended with the use of serotonin/noradrenaline reuptake inhibitors (SNRIs) [14]. Whether a true increased bleeding risk exists with SNRIs remains a point of debate and a selected population‐based study did not observe excess bleeding in SNRI users [15].

Follow‐up and referral to anticoagulation clinic

All patients started on anticoagulation should be given information about the treat- ment, its duration and side effects, and when to seek medical attention in the event of bleeding. It is best practice to provide written patient information and an anticoagu- lant alert card. Appropriate follow‐up in primary or secondary care should be arranged, with NICE recommending treatment‐duration review within three months for all

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Table 18.3 Anticoagulants for use in long‐term treatment of DVT/PE and prevention of recurrent DVT/PE in adults.

Drug group

Direct thrombin inhibitor

Direct factor Xa inhibitors

Drug

Dabigatran

Apixaban Edoxaban Rivaroxaban

Delivery

Oral

Note: rivaroxaban doses of 15 mg or more should be taken with food

Monitoring

Not routinely required

Reversal agent

Idarucizumab

Protocols using prothrombin complex concentrate often used in emergency situations

Andexanet (reversal of apixaban/ rivaroxaban) is not currently available in UK

Use in renal impairment

CrCl 30–50 mL/min: dose reduction to 110 mg b.d.

CrCl <30 mL/min: contraindicated

Apixaban

CrCl 15–30 mL/min: use with caution

CrCl <15 mL/min: contraindicated

Edoxaban

CrCl 15–50 mL/min: dose reduction to 30 mg

CrCl <15 mL/min: contraindicated

Rivaroxaban

CrCl 15–30 mL/min: use with caution and consider dose reduction

CrCl <15 mL/min: contraindicated

Drug interactions/ cautionsa

Amiodarone Antifungals Carbamazepine Ciclosporin Clarithromycin Phenytoin Protease inhibitors Rifampicin

St John’s Wort
Drugs associated with

bleeding riskb

Antifungals Carbamazepine Ciclosporin Erythromycin Phenytoin Protease inhibitors Rifampicin

St John’s Wort

Drugs associated with bleeding riskb

Initiation of treatment in acute VTE

Start after >5 days of parenteral anticoagulation with LMWH/UFH

Apixaban/rivaroxaban: no prior parenteral anticoagulation required

Edoxaban: start after >5 days of parenteral anticoagulation with LMWH/UFH

LMWH

Dalteparin Enoxaparin

Fondaparinux

Warfarin

Subcutaneous

Only required in selected patient groups as per haematology guidance (anti‐Xa level)

Not required

Required (INR)

Protamine partially effective

Not available

Vitamin K and prothrombin complex concentrate

Dalteparin

CrCl 15–30 mL/min: use with caution and adjust dose according to anti‐Xa monitoring

CrCl <15 mL/min: not recommended

Enoxaparin

CrCl 15–30 mL/min: dose reduction ± anti‐Xa monitoring

CrCl <15 mL/min: not recommended

CrCl 30–50 mL/min: use with caution

CrCl <30 mL/min: contraindicated

No renal excretion

Antihistamines

Cardiac glycosides

Tetracyclines

Ascorbic acid

Drugs associated with bleeding riskb

Many drugs and foods interact with warfarin, so care is required with all concomitant therapy. Clinicians should refer to drug SPC or BNF for individual details

Suitable for use in the initial management of acute VTE

Parenteral anticoagulation required for >5 days and until INR ≥2 for 24 hours (whichever is longer)

Fondaparinux

Vitamin K antagonists

Subcutaneous

Oral

a Underlined drugs are those which reduce the drug plasma concentrations.
b Drugs associated with bleeding risk include anticoagulants, antiplatelet agents, non‐steroidal anti‐inflammatory drugs, selective serotonin reuptake inhibitors, and serotonin/noradrenaline reuptake inhibitors.
BNF, British National Formulary; CrCl, creatinine clearance; INR, international normalised ratio; LMWH, low‐molecular‐weight heparin; SPC, summary of product characteristics; UFH, unfractionated heparin; VTE, venous thromboembolism.

168 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

patients with a new VTE diagnosis [10]. Other indications for referral to anticoagulation clinic include:

1 blood monitoring of warfarin (if this is not available with the patient’s general practitioner)

2 unprovoked proximal DVT/PE or recurrent VTE on anticoagulation for further investigation and counselling regarding anticoagulation dose and duration.

References

1. Jonsson AK, Schill J, Olsson H, et al. Venous thromboembolism during treatment with antipsychotics: a review of current evidence. CNS Drugs 2018;32(1):47–64.

2. Hagg S, Spigset O, Soderstrom TG. Association of venous thromboembolism and clozapine. Lancet 2000;355(9210):1155–1156.

3. Zhang R, Dong L, Shao F, et al. Antipsychotics and venous thromboembolism risk: a meta‐analysis. Pharmacopsychiatry
2011;44(5):183–188.

4. Barbui C, Conti V, Cipriani A. Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta‐analysis
of observational studies. Drug Saf 2014;37(2):79–90.

5. National Institute for Health and Care Excellence. Venous Thromboembolism in Over 16s: Reducing the Risk of Hospital‐acquired Deep
Vein Thrombosis or Pulmonary Embolism. NICE Guideline NG89. London: NICE, 2018. Available at https://www.nice.org.uk/guidance/
ng89/resources

6. Liew NC, Alemany GV, Angchaisuksiri P, et al. Asian venous thromboembolism guidelines: updated recommendations for the prevention of
venous thromboembolism. Int Angiol 2017;36(1):1–20.

7. Schunemann HJ, Cushman M, Burnett AE, et al. American Society of Hematology 2018 guidelines for management of venous thromboem-
bolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018;2(22):3198–3225.

8. Rosenberg DJ, Press A, Fishbein J, et al. External validation of the IMPROVE Bleeding Risk Assessment Model in medical patients. Thromb
Haemost 2016;116(3):530–536.

9. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D‐dimer in the diagnosis of suspected deep‐vein thrombosis. N Engl J Med
2003;349(13):1227–1235.

10. National Institute for Health and Care Excellence. Venous Thromboembolic Diseases: Diagnosis, Management and Thrombophilia Testing.
Clinical Guideline CG144. London: NICE, 2012.

11. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism:
increasing the models utility with the SimpliRED D‐dimer. Thromb Haemost 2000;83(3):416–420.

12. Watson HG, Keeling DM, Laffan M, et al. Guideline on aspects of cancer‐related venous thrombosis. Br J Haematol
2015;170(5):640–648.

13. Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors
and coumarins. Arch Intern Med 2008;168(2):180–185.

14. Maurer‐Spurej E, Pittendreigh C, Solomons K. The influence of selective serotonin reuptake inhibitors on human platelet serotonin. Thromb
Haemost 2004;91(1):119–128.

15. Cheng YL, Hu HY, Lin XH, et al. Use of SSRI, but not SNRI, increased upper and lower gastrointestinal bleeding: a nationwide popula-
tion‐based cohort study in Taiwan. Medicine (Baltimore) 2015;94(46):e2022.

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Part 4

Gastroenterology

Chapter 19

Gastro‐oesophageal Reflux and Peptic Ulcer Disease

Luke Vano, Seema Varma, John O’Donohue

GASTRO‐OESOPHAGEAL REFLUX DISEASE

As part of normal digestion, food is passed from the mouth to the stomach via the oesophagus. The lower oesophageal sphincter (LOS) is a ring of muscle that encircles the bottom end of the oesophagus where it meets the stomach. This sphincter helps to prevent stomach contents from refluxing back into the oesophagus.

In gastro‐oesophageal reflux disease (GORD), acidic stomach contents are refluxed back into the oesophagus, which is lined by squamous epithelium and, unlike the spe- cialised gastric mucosa, can be inflamed by acid. Exposure of the oesophagus to acid may lead to retrosternal discomfort and burning (‘heartburn’). Reflux may also cause other symptoms, including cough, wheeze, and hoarseness. GORD is a common condi- tion that affects up to 20% of the Western world [1]. Complications that may arise from GORD include erosive oesophagitis, oesophageal strictures, Barrett’s oesophagus (pre‐cancerous cell changes), and oesophageal cancer [2].

Table 19.1 documents common causes of GORD in the general and psychiatric popu- lation. If the LOS is weakened from previous surgery (e.g. for achalasia), anatomical abnormalities (e.g. hiatus hernia), or by use of medications that relax smooth muscle (e.g. calcium channel blockers or nitrates), the likelihood of GORD increases. Conditions that increase pressure on the stomach (e.g. obesity or pregnancy) can also lead to GORD as stomach contents are more readily refluxed. Diets high in fat have been observed to increase the risk of developing GORD, while diets high in fibre are protective [3].

In the psychiatric population, bulimia nervosa and binge eating disorder increase the risk of GORD [4]. Medications with anticholinergic effects (e.g. tricyclic antidepres- sants, anticholinergics, and antipsychotics) decrease LOS tone, which can lead to reflux. Depression, even in the absence of antidepressant use, is a risk factor for GORD [5–7]. It has been observed that people who score highly on psychosomatic symptom check- lists are at higher risk of GORD. Mechanistically, it has been postulated that people

172 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 19.1 Common causes of GORD in the general and psychiatric patient population [1–9].

Medication

Past medical history

Lifestyle factors

Non‐modifiable factors

Psychiatric conditions

General population

NSAIDs (e.g. ibuprofen)
Nitrates (e.g. isosorbide mononitrate) Calcium channel blockers (e.g. amlodipine) Bisphosphonates
Corticosteroids
Theophylline

Asthma
Previous oesophageal surgery
Hiatus hernia
Lower oesophageal sphincter dysfunction

Obesity
Alcohol consumption Overeating
Diet (high fat, low fibre) Smoking

Older age
Family history of GORD Male gender Pregnancy

N/A

Psychiatric population

As for general population Tricyclic antidepressants Anticholinergics Antipsychotics Benzodiazepines

As for general population

Bulimia nervosa
Binge eating disorder
Depression
Presence of psychosomatic symptoms

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with psychosomatic symptoms are more likely to take non‐steroidal anti‐inflammatory drugs (NSAIDs), a risk factor for GORD [8].

Diagnostic principles

An algorithm for approaching diagnosis and management of GORD is shown in Box 19.1.

History

1 Symptoms:

. a Typical: heartburn (burning feeling in the chest occurring after meals that is often
worse on lying or bending down), acid regurgitation (sour or bitter taste at the
back of mouth).

. b Atypical: belching, bloating, nausea, dyspepsia (indigestion), epigastric (upper
abdominal) pressure/pain, odynophagia (painful swallowing).

. c Extra‐oesophageal: nocturnal asthma (breathlessness and wheeze), laryngitis
(hoarse voice), sinusitis, chronic cough, dental erosions [1].

Gastro‐oesophageal Reflux and Peptic Ulcer Disease 173

Box 19.1 Approach to diagnosis and management of gastrointestinal oesophageal reflux disease History

▪ Screen for typical, atypical, extra‐oesophageal, and red flag symptoms

▪ Gastrointestinal history

▪ Past medical and surgical histories

▪ Medication history

▪ Social history

▪ Family history
Examination

▪ Gastrointestinal examination

▪ Height and weight measurements
Management
Where possible, rationalise psychiatric medication and offer non‐pharmacological interventions
Typical symptoms

▪ Start once‐daily PPI for four weeks then review

▪ If symptoms persist, increase PPI to twice daily and refer to gastroenterology

▪ If symptoms improve with four‐week trial PPI, continue for a further four weeks
before discontinuing

▪ Re‐prescribe PPI if symptoms return and refer to gastroenterology
Atypical symptoms present

▪ Start once‐daily PPI for four weeks, to be reviewed, and refer to gastroenterology

▪ If symptoms persist, then increase dose to twice daily and await gastroenterology
review
Red flag symptoms present

▪ Do not start a PPI

▪ Discuss with a medical doctor if any acute concerns

▪ Refer for urgent ‘two‐week wait’ upper gastrointestinal endoscopy and gastroen-
terology review

. 2 Ask about ‘red flag’ symptoms which may indicate a more serious condition: bleed- ing (haematemesis or melaena; see Chapter 20), symptoms of anaemia or unex- plained anaemia on full blood count (see Chapter 15), persistent vomiting (see Chapter 21), weight loss (see Chapter 25), dysphagia (difficulty swallowing; see Chapter 22), and cardiac sounding chest pain (see Chapter 67).

. 3 Medication history (see Table 19.1).

. 4 Any recent changes in diet or weight.

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174 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

. 5 Family history of any gastrointestinal disease, especially GORD or gastrointestinal cancer.

. 6 Past medical history (see Table 19.1).

. 7 Social history, including smoking and alcohol history.

Examination

. 1 Abdominal examination is often unremarkable in GORD. Halitosis (bad breath) is more likely in patients with GORD. There may be evidence of pallor (unusually pale skin) if anaemia is present.

. 2 Possible Russell’s sign (calluses on the back of hands) if patient has bulimia nervosa.

. 3 Height and weight measures.

Diagnosis

GORD is a clinical diagnosis. Typical symptoms of either heartburn or acid regurgita- tion are both highly specific, though low in sensitivity for GORD [1]. Treatment should therefore be started empirically if either of these symptoms are present and GORD is suspected (see section Management).

Differential diagnoses include coronary artery disease, peptic ulcer disease, achalasia, gastritis, dyspepsia, gastroparesis, and ‘functional’ heartburn. Red flag symptoms may indicate oesophagitis, peptic stricture, or malignancy.

Management

In patients with suspected GORD, rationalisation of medication, non‐pharmacological therapy, and pharmacological therapy should be considered. In the absence of atypical or red flag symptoms and where GORD is successfully treated with an eight‐week trial of a proton‐pump inhibitor, no further investigations are required. Where atypical or red flag symptoms are present, referral to specialist services are indicated.

Rationalising psychiatric medication

Tricyclic antidepressants have been shown to increase the risk of GORD, with clomi- pramine possibly having the greatest effect [6]. Selective serotonin reuptake inhibitors have little, if any, impact on risk of GORD [6,7]. If a patient with GORD is on a tricy- clic antidepressant, the prescriber may consider offering a switch to an alternative anti- depressant, having considered the risks and benefits of such a decision, and after discussion with the patient.

Anticholinergics have been shown to increase the number of reflux episodes in patients with pre‐existing GORD [10–12]. In patients with GORD who are experienc- ing acute extrapyramidal side effects, appropriate treatment with anticholinergics should not be withheld (see Chapter 56), but GORD treatment regimens may need to be intensified. If a patient receiving long‐term anticholinergic treatment develops

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Gastro‐oesophageal Reflux and Peptic Ulcer Disease 175

GORD, then a risk–benefit conversation should be engaged in with the patient to deter- mine whether continued anticholinergic treatment is necessary.

Antipsychotics may increase the risk of developing GORD [13,14], with clozapine associated with higher rates of GORD (up to five times the prevalence) compared with other antipsychotics [15,16]. However, it is considered safe to continue prescribing antipsychotics in patients with GORD.

Hypnotics and benzodiazepines may increase the risk of developing GORD, but the quality of this evidence is not strong enough to advise any changes to practice of pre- scribing these medications [17,18].

Non‐pharmacological: lifestyle modification [1,3,5,19]

▪ Avoid eating meals within three hours of bedtime.

▪ Raise the head of the bed.

▪ Weight loss.

▪ Smoking cessation.

▪ Reduce alcohol intake or, if safe, stop drinking alcohol entirely (see Chapter 24).

▪ Encourage a low‐fat, high‐fibre diet.

▪ If patient notices any relationship between certain foods (e.g. chocolate or caffeine)
and their symptoms, then a trial elimination of these foods from their diet may be considered.
Pharmacological
GORD is treated by suppressing stomach acid production. Proton‐pump inhibitors (PPIs), histamine H2‐receptor antagonists, and antacids can all be used; however, note that ranitidine was recently withdrawn from international markets owing to concerns regarding carcinogenicity. PPIs have been shown to be more effective at treating GORD than histamine H2‐receptor antagonists, but are also costlier [1,5,19,20].
Patients with no red flag or atypical symptoms but who are suspected of suffering with GORD should be given an eight‐week trial of a PPI. This provides rapid sympto- matic relief in 70–80% of patients [20]. All PPIs have been shown to be of roughly equal efficacy. They should be taken around 30–60 minutes prior to food for maximum benefit [1,5,19,20]. Doses of commonly prescribed PPIs are omeprazole 20 mg, lanso- prazole 30 mg, esomeprazole 20 mg, and pantoprazole 40 mg, all given orally once daily. If the patient does not fully respond to PPI treatment within four weeks, then the dose of PPI should be increased to twice daily, with doses being taken before breakfast and before dinner, and a referral to gastroenterology should be completed [20].
Long‐term PPI use has been associated with increased risk of various comorbid com- plaints, including pneumonia [21], osteoporosis and fractures [22], Clostridium difficile infection [23], and increased all‐cause mortality [24]. Although association does not imply causality, and confounding has been implicated in some of these population‐ based analyses [25], the judicious prescriber may consider limiting long‐term PPI use where possible. Moreover, PPIs may influence plasma levels of other medications (including psychiatric drugs), either through alterations in absorption secondary to changes in gut pH, or via cytochrome P450 interactions [26].

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176 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

When to refer to a specialist

Where atypical symptoms are present then treatment should be started as described, and the patient referred to gastroenterology. If any red flag symptoms are detected, then a ‘two‐week wait’ urgent referral for endoscopy should be made, alongside a referral to gastroenterology. Avoid PPIs and histamine H2‐receptor antagonists for two weeks prior to endoscopy.

In patients who experience a relapse of symptoms when the PPI is discontinued, the PPI should be reinstated and a referral to gastroenterology made [20]. Gastrointestinal endoscopy should be considered in those whose symptoms repeatedly recur after PPIs are stopped, or in those who require maintenance PPIs. This enables risk stratification of GORD (non‐erosive, erosive) and to exclude Barrett’s oesophagus.

Information to include in a referral letter

When writing a referral letter to either the two‐week wait service or the gastroenterol- ogy team, it is important to include the following information: gastrointestinal history, past medical and surgical histories, current medication along with allergy status, a brief social history, and any findings from clinical examination. Ensure that the patient’s psychiatric history is included in the letter.

PEPTIC ULCER DISEASE

The typical presentation of peptic ulcer disease (PUD) is of chronic epigastric pain asso- ciated with eating. There may also be pain on palpation of the epigastrium. It is most often caused by Helicobacter pylori infection or use of NSAIDs. PUD may coexist with GORD or may be difficult to distinguish from it, but should be suspected when epigas- tric pain is the primary presenting complaint, or if treatment for GORD has been inef- fective. If there are any red flag symptoms (as described for GORD), or the patient does not respond to treatment, then specialist advice from gastroenterology should be sought. An algorithm for approaching diagnosis and management of PUD is shown in Box 19.2.

Investigation of new symptoms of PUD

. 1 Full blood count: anaemia may indicate gastrointestinal bleeding.

. 2 If aged under 55 years, H. pylori breath or stool testing is the first‐line investiga- tion. Testing should not be performed if PPIs, bismuth or antibiotics have been used in the two weeks prior to testing in order to reduce the chance of a false‐nega-
tive result.

. 3 In those aged 55 years or older, and also in those (at any age) who have associated
weight loss, vomiting, anaemia or dysphagia, upper gastrointestinal endoscopy should be requested. If an ulcer is found, then H. pylori testing is indicated. In patients with no weight loss, H. pylori testing should be organised as the first‐line investigation.

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Gastro‐oesophageal Reflux and Peptic Ulcer Disease 177

Box 19.2 Approach to diagnosis and management of peptic ulcer disease History

▪ Gastrointestinal history including screen for red flag symptoms

▪ Past medical and surgical histories

▪ Medication history

▪ Social history

▪ Family history
Examination and investigations

▪ Gastrointestinal examination

▪ Full blood count

▪ Age <55: H. pylori testing

▪ Age ≥55 or with weight loss, anaemia, vomiting or dysphagia: endoscopy and H. pylori testing if
ulcer present
Management

▪ Stop NSAIDs if possible

▪ If NSAIDs to continue, offer long‐term PPI therapy

▪ Refer to specialists if red flag symptoms present or not responding to treatment
Active bleeding

■ Resuscitation and transfer to emergency services H. pylori test negative

■ Once‐daily PPI for four to eight weeks H. pylori test positive

▪ One‐ to two‐week course of triple therapy (PPI and antibiotics), as defined by local guidelines

▪ See local guidelines for alternative regimen if symptoms persist

▪ H. pylori testing four weeks after successful therapy to confirm eradication

Management

NSAIDs should be stopped unless the patient is using aspirin as an antiplatelet agent for primary/secondary prevention of cardiovascular disease [27]. In this instance, aspirin should be continued, and the patient started on long‐term acid suppression therapy (PPI) [27]. NSAIDs for pain management should be used at the lowest dose for the shortest period of time.

Active bleeding

Start resuscitation and call for ambulance/emergency assistance. Active bleeding will require endoscopy/surgery, PPI, and possible blood transfusion. PPI will be continued for around four to eight weeks post intervention but be guided by specialist advice.

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178 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

H. pylori test negative

Once daily PPI for four to eight weeks (see section on pharmacological management of GORD for medication and doses).

H. pylori test positive

A one‐ to two‐week period of triple therapy is needed, for example PPI twice daily (see section on pharmacological management of GORD for medication and doses), clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily (use metronidazole if allergic to penicillin). Most patients will not need continued PPI prescribing thereaf- ter. If symptoms persist, then an alternative treatment regimen may be trialled (refer to local guidelines). Testing for H. pylori should be repeated four weeks after the end of therapy to confirm eradication. This should ideally by performed using carbon‐14 urea breath testing which, unlike stool testing, is validated in the post‐eradication setting.

References

1. Badillo R, Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther 2014;5(3):105–112.

2. Chait MM. Gastroesophageal reflux disease: important considerations for the older patients. World J Gastrointest Endosc 2010;2(12):388–396.

3. El‐Serag HB, Satia JA, Rabeneck L. Dietary intake and the risk of gastro‐oesophageal reflux disease: a cross sectional study in volunteers. Gut 2005;54(1):11–17.

4. Denholm M, Jankowski J. Gastroesophageal reflux disease and bulimia nervosa: a review of the literature. Dis Esophagus 2011;24(2):79–85.

5. Keung C, Hebbard G. The management of gastro‐oesophageal reflux disease. Aust Prescr 2016;39(1):6–10.

6. van Soest EM, Dieleman JP, Siersema PD, et al. Tricyclic antidepressants and the risk of reflux esophagitis. Am J Gastroenterol
2007;102(9):1870–1877.

7. Martin‐Merino E, Ruigomez A, Garcia Rodriguez LA, et al. Depression and treatment with antidepressants are associated with the develop-
ment of gastro‐oesophageal reflux disease. Aliment Pharmacol Ther 2010;31(10):1132–1140.

8. Locke GR III, Talley NJ, Fett SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106(6):642–649.

9. Theodoropoulos DS, Lockey RF, Boyce HW Jr, Bukantz SC. Gastroesophageal reflux and asthma: a review of pathogenesis, diagnosis, and
therapy. Allergy 1999;54(7):651–661.

10. Ciccaglione AF, Grossi L, Cappello G, et al. Effect of hyoscine N‐butylbromide on gastroesophageal reflux in normal subjects and patients
with gastroesophageal reflux disease. Am J Gastroenterol 2001;96:2306–2311.

11. Koerselman J, Pursnani KG, Peghini P, et al. Different effects of an oral anticholinergic drug on gastroesophageal reflux in upright and supine
position in normal, ambulant subjects: a pilot study. Am J Gastroenterol 1999;94(4):925–930.

12. Lidums I, Checklin H, Mittal RK, Holloway RH. Effect of atropine on gastro‐oesophageal reflux and transient lower oesophageal sphincter
relaxations in patients with gastro‐oesophageal reflux disease. Gut 1998;43:12–16.

13. Dziewas R, Warnecke T, Schnabel M, et al. Neuroleptic‐induced dysphagia: case report and literature review. Dysphagia 2007;22(1):63–67.

14. Crouse EL, Alastanos JN, Bozymski KM, Toscano RA. Dysphagia with second‐generation antipsychotics: a case report and review of the
literature. Ment Health Clin 2017;7(2):56–64.

15. Taylor D, Olofinjana O, Rahimi T. Use of antacid medication in patients receiving clozapine: a comparison with other second‐generation
antipsychotics. J Clin Psychopharmacol 2010;30(4):460–461.

16. van Veggel M, Olofinjana O, Davies G, Taylor D. Clozapine and gastro‐oesophageal reflux disease (GORD): an investigation of temporal
association. Acta Psychiatr Scand 2013;127(1):69–77.

17. Rushnak MJ, Leevy CM. Effect of diazepam on the lower esophageal sphincter. A double‐blind controlled study. Am J Gastroenterol
1980;73:127–130.

18. Singh S, Bailey RT, Stein HJ, et al. Effect of alprazolam (Xanax) on esophageal motility and acid reflux. Am J Gastroenterol
1992;87:483–488.

19. Sandhu DS, Fass R. Current trends in the management of gastroesophageal reflux disease. Gut Liver 2018;12(1):7–16.

20. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol
2013;108(3):308–328.

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Gastro‐oesophageal Reflux and Peptic Ulcer Disease 179

21. Zirk‐Sadowski J, Masoli JA, Delgado J, et al. Proton‐pump inhibitors and long‐term risk of community‐acquired pneumonia in older adults. J Am Geriatr Soc 2018;66(7):1332–1338.

22. Andersen BN, Johansen PB, Abrahamsen B. Proton pump inhibitors and osteoporosis. Curr Opin Rheumatol 2016;28(4):420–425.

23. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium
difficile infection. JAMA Intern Med 2015;175(5):784–791.

24. Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States
veterans. BMJ Open 2017;7(6):e015735.

25. Othman F, Crooks CJ, Card TR. Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population
based study. BMJ 2016;355:i5813.

26. Frick A, Kopitz J, Bergemann N. Omeprazole reduces clozapine plasma concentrations. A case report. Pharmacopsychiatry
2003;36(3):121–123.

27. Cryer B, Mahaffey KW. Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment. J Multidiscip
Healthc 2014;7:137–146.

28. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med
2016;375(26):2519–2529.

29. Whittle BJ. COX‐1 and COX‐2 products in the gut: therapeutic impact of COX‐2 inhibitors. Gut 2000;47:320–325.

CHAPTER 19

Chapter 20

Gastrointestinal Bleeding

Douglas Corrigall, David Dewar

Gastrointestinal (GI) bleeding refers to blood loss from within the gastrointestinal tract. Upper GI bleeding is defined as bleeding occurring proximal to the ligament of Treitz; that is to say from the oesophagus, stomach, or duodenum. Lower GI bleeding is that originating from the small bowel or colon. Acute small bowel bleeding is rare, so we focus here on investigation and management of upper GI bleeds and colonic bleeding.

Acute upper GI bleeding can be life‐threatening, with mortality rates ranging between 10 and 50% in general medical inpatient settings [1,2], depending on severity and aeti- ology. This therefore is the focus of the chapter. Assessment of GI bleeding in a psychi- atric inpatient setting must focus on the rapid identification of patients who will require urgent medical interventions that necessitate transfer. We would advise timely discus- sion with medical/gastroenterological colleagues in the case of all suspected acute GI bleeds. As 70% of blood loss from the GI tract is due to upper GI causes, the usual approach is to rule these out before considering lower GI investigations [3].

Common causes in the general population and specific considerations in individuals with serious mental illness (SMI) are summarised in Box 20.1. Specific considerations for psychiatric patients include the fact that some selective serotonin reuptake inhibi- tors (SSRIs) have been shown in observational studies to increase the risk of both upper and lower GI bleeding (potentially via inhibition of platelet function; see Chapter 17) [4]. Variceal bleeding as a result of chronic liver disease is usually secondary to alcohol‐ related liver disease (see Chapter 24) or chronic viral hepatitis (consider this in patients with risk factors such as a history of intravenous drug misuse; see Chapter 43). Variceal bleeding is a medical emergency, with mortality rates approaching 50% [3]. Any signs of upper GI bleeding in patients with known liver disease should be treated as a variceal bleed until proven otherwise [5]. Patients with eating disorders such as bulimia with frequent vomiting/purging may develop Mallory–Weiss tears at the gastro‐oesophageal junction [6].

Box 20.1 Common causes/risk factors for GI bleeds in the general and psychiatric patient population

Upper GI tract

▪ Gastric/duodenal ulcer

▪ Varices (gastric or oesophageal)

▪ Mallory–Weiss tear

▪ Oesophagitis

▪ Arteriovenous malformations

▪ Gastrointestinal stromal tumours
Lower GI tract

▪ Anal fissures

▪ Angiodysplasia

▪ Colitis (radiation, ischaemic, infectious)

▪ Colonic polyps

▪ Colonic carcinoma

▪ Diverticular disease

▪ Inflammatory bowel disease

▪ Haemorrhoids
Small bowel (rare)

▪ Arteriovenous malformations

▪ Meckel’s diverticulum

▪ Tumours
Medication

▪ NSAID use can cause ulcers

▪ Bisphosphonates can cause oesophagitis
Infection

■ Helicobacter pylori can cause ulcers/gastritis Liver disease

▪ Variceal bleed

▪ Portal hypertensive gastropathy
Kidney disease
■ Angiodysplasia Malignancy

■ Blood loss from friable tumours or vessel invasion Alcohol

▪ Can cause oesophagitis, gastritis, ulcers

▪ Association with liver disease
Patients with SMI

▪ SSRI prescription

▪ Liver disease, portal hypertension and resultant varices

▪ Mallory–Weiss tear secondary to purging behaviours

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A further consideration for SMI patients, especially those who may be survivors of abuse, is that endoscopy is an invasive and for some unpleasant test which can pro- voke a great deal of anxiety [7]. The sedation typically given during endoscopy con- sists of an anxiolytic, usually 2–5 mg of midazolam, which can be given with a short‐acting opiate such as pethidine or fentanyl, so any interactions with other medications should also be considered and advice regarding interactions with psychiat- ric medications will be gratefully received. Furthermore, tolerance to benzodiazepines in those on long‐term benzodiazepine treatment may occur, potentially necessitating higher doses of sedation.

DIAGNOSTIC PRINCIPLES

Mortality from acute upper GI bleeds, even those occurring in hospital, remains high and this has not changed significantly for decades [8]. Therefore, when faced with a possible GI bleed in an inpatient setting it is important first to exclude this and patients must be assessed and triaged for early resuscitation and endoscopy [8]. The signs and symptoms of lower GI bleeding, including fresh blood per rectum, can be due to an acute upper GI source and this will need to be excluded (by upper GI endoscopy) in most cases before proceeding to further investigations [3]. As always, careful history and examination is vital in guiding appropriate investigations and avoiding unneces- sary tests. The aim is to identify those with acute bleeds who need urgent management, and those with chronic blood loss who can be managed on an outpatient basis. Most if not all patients with suspected GI blood loss will require an endoscopy; the question is how soon it should occur.

History

. 1 Ask about the timing of bleeding, estimated volume, the colour of any vomit (resist the temptation to mention coffee grounds; the patient will often describe the vomitus as this unprompted, which is useful in arriving at the diagnosis), and the frequency of haematemesis/melaena.

. 2 For lower GI blood loss ask about stool frequency, volumes of blood, and whether it is mixed in with the stool or fresh on the tissue (suggesting haemorrhoids).

. 3 Systemic symptoms such as weight loss, loss of appetite, dysphagia, or dypsepsia which may suggest malignancy.

. 4 Medication history, specifically non‐steroidal anti‐inflammatory drugs (NSAIDs) or bisphosphonates.

. 5 Any symptoms suggestive of volume loss, including dizziness or syncope.

. 6 Symptoms of anaemia: tiredness, fatigue, and shortness of breath.

. 7 Family history of gastrointestinal disease, liver disease, or malignancy.

. 8 Past medical history: previous ulcers/bleeding, liver disease.

. 9 Social history, including alcohol and smoking and any other non‐prescribed medications.

Gastrointestinal Bleeding 183

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184 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Signs of upper GI bleeding

. 1 Haematemesis(vomitingfreshblood;however,notethatoccasionallyregurgitationof bright red food or drink can be mistaken for haemetemesis). Frank haematemesis sug- gests moderate to severe bleed usually from stomach or oesophagus, which may be ongoing.

. 2 Coffee ground vomitus (altered blood from an upper GI source that has been in the stomach for a period of time): bleeding may still be ongoing.
Melaena (blood altered by passage through the GI tract):
a characteristic sickly sweet smell
b present in 70% of upper GI bleeds
c black tarry stool indicates at least 50 mL of blood loss
d generally means blood has been in GI tract for eight hours or more [9] e oral iron supplementation causes tarry black stool so beware.

. 3 Haematochezia (frank blood per rectum): can represent upper GI bleed [10].

Signs of lower GI bleeding

. 1 Blood per rectum can occur with any GI source of blood loss.

. 2 Haematochezia:
a can be frank blood or dark red stool
b can be due to large upper GI bleeds [11].

. 3 Blood in toilet/on tissue (suggests haemorrhoid source): toilet water can appear
bright red from only 5 mL of blood.

Examination

. 1 Basic observations: haemodynamic instability suggests a possible large upper GI bleed and should prompt rapid transfer to a resuscitation area.

. 2 Cardiovascular examination:

. a Look for signs of hypoperfusion such as increased capillary return time.

. b Flow murmur on auscultation can occur in high‐output states.

. c Young fit patients: resting tachycardia or postural tachycardia should be treated
with caution, since this can represent significant blood loss (with associated
physiological compensation).

. 3 Respiratory examination: listen for any crepitations which may suggest that aspi-
ration of vomit has occurred. Aspiration of blood can cause a severe
pneumonitis.

. 4 Abdominal examination:

. a Lookforsignsofchronicliverdiseaseandinparticularsignsofhepaticdecompensa- tion such as ascites or jaundice.

. b Per rectum examination to check for fresh blood or melaena. Ensure visual inspection for haemorrhoids.

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5 Neurological examination:
a Any signs of altered consciousness could be due to hypoperfusion or hepatic

encephalopathy in decompensated chronic liver disease.
b Check for asterixis (‘liver flap’), which is suggestive of hepatic encephalopathy.

Investigations

These will obviously be dependent on the facilities available. If results of tests are not immediately available, this may necessitate transfer to a medical environment.

. 1 ECG to check for any signs of cardiac ischaemia secondary to blood loss.

. 2 Bloods:

. a Full blood count: this may be misleadingly normal in the hyperacute situation before haemodilution has occurred.

. b Urea and electrolytes.

. c Clotting screen.

. d Liver function tests.

. e Iron studies: iron deficiency anaemia can represent chronic GI blood loss.

. f Blood cultures if signs of liver disease (infection is a frequent cause of decompen-
sating events).

. g Groupandsaveifaninpatient.Ifthereisasuggestionofalargebleed,cross‐matchat
least 4 units immediately. If in the psychiatric setting and group and save is being considered, urgent referral and transfer to medical services should have been requested.

. MANAGEMENT

If an inpatient, ensure the patient is kept nil by mouth until decisions about endoscopy have been made [4]. If there is frank active bleeding and haemodynamic instability, do not delay transfer by requesting investigations. This is a medical emergency which requires rapid transfer to a medical unit where resuscitation can continue. If possible and appropriate, ensure the following.

. 1 Airway patent and secure.

. 2 If facilities allow, gain intravenous access with two large‐bore cannulae.

. 3 If blood pressure is low, and if facilities allow, commence fluid resuscitation (e.g.
normal saline 0.9%) while rapid transfer is arranged.

. 4 If haemodynamically stable, there is no sign of ongoing bleeding, and blood results
can be obtained in a timely manner, it may after discussion with the medical/gastro- enterology teams be appropriate to await these and calculate the Blatchford score [12] (Table 20.1) before transfer.

The Blatchford score is a validated scoring system that can be used to predict clinical outcomes [12]. Low‐risk patients with a Blatchford score of zero can be considered for non‐urgent or outpatient endoscopy [4]. Those patients with higher risk scores can be prioritised for urgent (within 24 hours) or emergent inpatient endoscopy.

Gastrointestinal Bleeding 185

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186 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 20.1 Blatchford score for GI bleeds.

Risk marker

Haemoglobin (g/L)

Male

120–130 100–120
<100
Urea (mmol/L) 6.5–8

8–10
10–25
>25
Systolic blood pressure (mmHg) 100–109

90–99
<90
Other markers Pulse >100 Melaena Syncope Hepatic disease Cardiac failure

Non‐pharmacological therapy

Score

Female

100–120 1 3 <100 6

2 3 4 6

1 2 3

1 1 2 2 2

CHAPTER 20

Endoscopy is the definitive investigation and usually the definitive therapeutic modality in GI bleeds. Depending on what is seen at endoscopy, the risk of rebleeding can be estimated.

In cases of intractable bleeding, depending on the site, embolisation via interven- tional radiology to occlude the bleeding vessel can be attempted, or surgery such as partial gastrectomy can be attempted [13].

Pharmacological therapy

In an outpatient setting where the patient is stable, consider oral PPI therapy while waiting for gastroenterology review if you suspect reflux disease, gastritis, or peptic ulcer disease.

In inpatients, practice continues to vary widely around the use of intravenous PPI therapy prior to endoscopy [4,14]. You may be advised to commence intravenous PPIs in patients awaiting endoscopy, although some authorities feel there is little evidence for their benefit [4]. Similarly, while there is a paucity of high‐quality evi- dence for the use of tranexamic acid, this is sometimes given in an attempt to slow bleeding [15].

In the case of variceal bleeds, antibiotics are given along with terlipressin [4] or octreotide [16] infusions to attempt to reduce portal pressure. Terlipressin and octreotide require close monitoring so should not be given in the psychiatric setting.

When to refer to a specialist

In view of the high in‐hospital mortality and potential for deterioration it is important that all suspected inpatient acute GI bleeds are discussed immediately with the local medical or gastroenterological team and most should receive timely endoscopy within 24 hours [4] or on an emergent basis in the case of suspected variceal bleeds or if there is ongoing haemodynamic instability.

In stable patients in the community with a Blatchford score of zero, urgent outpatient management can be appropriate as outlined in Box 20.2 [8]. If there is any uncertainty at all, discuss with your local medical or gastroenterology on‐call team.

Gastrointestinal Bleeding 187

Box 20.2 When to consider outpatient management for suspected acute GI bleeds Consider for urgent outpatient management

▪ Age <60 years and

▪ Haemodynamically stable and

▪ No significant cardiac disease, liver disease, malignancy or other major comorbidity and

▪ Not currently an inpatient and

▪ No witnessed haematemesis/haematochezia
Consider admission/early endoscopy

▪ Age >60 years or

▪ Witnessed haematemesis/haematochezia or suspected continued bleeding or

▪ Haemodynamic instability or

▪ Liver disease/known varices or

▪ Current inpatient (medical or psychiatric)

Chronic GI bleeding generally presents with iron deficiency anaemia or a positive faecal test for occult blood (in the UK, a faecal immunochemical test). It can be man- aged on an outpatient basis and in the first instance urgent referral to gastroenterology outpatients or a medical consultation should be sought [17] and upper and lower GI endoscopy arranged. Anaemia is not a diagnosis and the cause must be established. Box 20.3 provides a diagnostic summary to guide investigation and management.

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Box 20.3 Diagnostic summary History

▪ Define symptoms: suggestive of acute or chronic blood loss?

▪ Explore risk factors/symptoms suggesting malignancy

▪ Past medical history, including previous GI bleeds and liver disease

▪ Medication history

▪ Alcohol/smoking

▪ Family history of malignancy
Examination

▪ Establish if any ongoing bleeding/haemodynamic instability

▪ Examine for signs of liver disease
Investigations
■ Bloods
■ Endoscopy
Management

▪ Stratify risk: does this patient need urgent/emergent endoscopy?

▪ Decide on urgent inpatient investigations or outpatient follow‐up

188 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

References

1. Rockall TA, Logan RF, Devlin HB, Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. BMJ 1995;311(6999):222–226.

2. Hearnshaw SA, Logan RFA, Lowe D, et al. Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011;60(10):1327–1335.

3. Oakland K, Chadwick G, East JE, et al. Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology. Gut 2019;68(5):776–789.

4. National Institute for Health and Care Excellence. Acute Upper Gastrointestinal Bleeding in Over 16s: Management. Clinical Guideline CG141. London: NICE, 2012. Available at https://www.nice.org.uk/guidance/cg141

5. Tripathi D, Stanley AJ, Hayes PC, et al. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015;64(11):1680–1704.

6. Forney KJ, Buchman‐Schmitt JM, Keel PK, Frank GKW. The medical complications associated with purging. Int J Eat Disord 2016;49(3):249–259.

7. Davy E. The endoscopy patient with a history of sexual abuse: strategies for compassionate care. Gastroenterol Nurs 2006; 29(3):221–225.

8. Scottish Intercollegiate Guidelines Network. Management of Acute Upper and Lower Gastrointestinal Bleeding: A National Clinical Guideline. SIGN Guideline 105, 2008.

9. Schiff L, Shapiro N, Stevens RJ. Observations on the oral administration of citrated blood in man. Am J Med Sci 1939;207(4):465–467.

10. Srygley FD, Gerardo CJ, Tran T, Fisher DA. Does this patient have a severe upper gastrointestinal bleed? JAMA 2012;307(10):1072.

11. Sittichanbuncha Y, Senasu S, Thongkrau T, et al. How to differentiate sites of gastrointestinal bleeding in patients with hematochezia by using
clinical factors? Gastroenterol Res Pract 2013;2013:265076.

12. Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper gastrointestinal haemorrhage. Lancet
2000;356(9238):1318–1321.

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Gastrointestinal Bleeding 189

13. Siau K, Chapman W, Sharma N, et al. Management of acute upper gastrointestinal bleeding: an update for the general physician. J R Coll Physicians Edinb 2017;47(3):218–230.

14. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol 2012;107(3):345–360.

15. Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev
2014;(11):CD006640.

16. LaBrecque D, Khan AG, Sarin SK, Le Mair AW. Esophageal varices. World Gastroenterology Organisation Global Guidelines, 2014. http://
http://www.worldgastroenterology.org/UserFiles/file/guidelines/esophageal‐varices‐english‐2014.pdf (accessed 21 May 2019).

17. Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. Gut 2011;60(10):1309–1316.

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Chapter 21

Nausea and Vomiting

Mary Denholm, Matthew Cheetham

Nausea is the unpleasant feeling of the need to vomit, which may be accompanied by additional autonomic symptoms (e.g. tachycardia and sweating). Vomiting, as distinct from expectoration or regurgitation, is expulsion of gastric contents through the mouth. Regurgitation is the return of substances from the oesophagus to the hypopharynx with minimal effort [1]. Clinically it is important to distinguish acute presentations from those of a more chronic nature. Both can indicate significant pathology, but some acute causes, such as bowel obstruction or acute pancreatitis, require immediate medical attention.

Nausea and vomiting are prompted by activation of specific ‘trigger areas’ within the body, some of which are located in the gastrointestinal tract and some in the central nervous system (CNS), in the latter mainly the floor of the fourth ventricle (the chemo- receptor trigger zone) and the medulla (the nucleus tractus solitarius) [2]. Afferent sig- nals can come from different locations, hence the association of nausea and vomiting with a wide range of conditions. Common causes are listed in Box 21.1 [1,3–8].

Nausea and/or vomiting in patients with serious mental illness (SMI) may be the feature of a primary psychiatric diagnosis (e.g. bulimia nervosa), a consequence of autonomic activation in the context of psychological symptoms (e.g. anxiety/panic), or secondary to psychiatric treatment. For example, nausea and vomiting is a recognised side effect of selective serotonin reuptake inhibitors (SSRIs), likely secondary to stimulation of 5‐HT3 receptors [9], and may also accompany SSRI discontinuation [10]. Although several antipsychotics have anti‐emetic activity, D2 dopamine receptor partial agonists such as aripiprazole may be associated with nausea, especially early during treatment [11]. Psychostimulants (e.g. methylphenidate) and mood stabilisers (e.g. sodium valproate and lithium) can also be associated with nausea. Indeed, nausea and vomiting in a patient receiving lithium treatment may herald toxicity. Functional disorders associated with nausea and vomiting (e.g. cyclic vomiting disorder) are diagnoses of exclusion.

Box 21.1 Common causes of nausea and vomiting Gastrointestinal

Gastric stasis, intestinal obstruction or pseudo‐obstruction/ileus, constipation, presence of ascites, gastritis, peptic ulceration, gastroenteritis, pyloric stenosis, acute pancreatitis, cholecystitis, gastric cancer, oesophageal reflux, appendicitis

Metabolic

Hypercalcaemia, renal failure/uraemia, hyponatraemia, Addisonian crisis, diabetic ketoacidosis

Neurological

Raised intracranial pressure, meningitis, encephalitis, migraine, Ménière’s disease, labyrinthitis, autonomic neuropathy, head injury, benign paroxysmal positional vertigo

Infection

Viral or bacterial gastrointestinal infections, mucocutaneous candidiasis, urinary tract infection, sepsis syndromes

Pain

Usually acute and severe pain

Pregnancy

First trimester but may persist

Alcohol and recreational drugs

For example, cannabis (cannabinoid hyperemesis syndrome)

Drugs

Opiates (e.g. codeine phosphate), chemotherapy, iron, antibiotics, NSAIDs, digoxin

Psychiatric drugs

Selective serotonin reuptake inhibitors
Dopamine D2 receptor partial agonists (e.g. aripiprazole)
Mood stabilisers (e.g. lithium, sodium valproate, and lamotrigine) Psychostimulants (e.g. methylphenidate)

Psychiatric

Anxiety, panic disorder, bulimia nervosa

Functional disorders

For example, cyclic vomiting disorder, chronic nausea and vomiting syndrome (diagnoses of exclusion)

192 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

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Nausea and Vomiting 193

Miscellaneous

Normal physiological response to stress, travel sickness, radiation therapy, hepatic and biliary disease (e.g. cirrhosis), testicular torsion, twisted ovarian cyst

Rumination syndrome

A chronic motility disorder commonly misdiagnosed as vomiting

DIAGNOSTIC PRINCIPLES

History, examination, and investigations are primarily performed to screen for acute underlying conditions that may require urgent medical attention (e.g. appendicitis), chronic but severe underlying conditions that may require expedited medical/surgical referral (e.g. malignancy), or complications secondary to vomiting/poor oral intake that may require urgent medical attention (e.g. electrolyte disturbance).

History [3,12]

▪ Duration (acute or chronic).

▪ Amount and frequency.

▪ Colour/contents (e.g. liquid, bile, feculent).

▪ Ask about any contacts or family members unwell with similar symptoms
(gastroenteritis).

▪ Presence or absence of blood: fresh red, dark ‘coffee ground’ (GI bleeding).

▪ Timing:

▪ Time of day: early morning (pregnancy) and with headaches (raised intracranial pressure, ICP).

▪ Relation to eating: few hours after food suggests gastric outlet obstruction.

▪ Systemic symptoms, e.g. fevers, unintentional weight loss (malignancy).

▪ Headaches: nausea/vomiting may be associated with migraine or raised ICP.

▪ Vertigo (possible acute viral labyrinthitis).

▪ Abdominal pain: right upper quadrant pain may suggest biliary colic or cholecystitis,
right iliac fossa pain may suggest appendicitis (see Chapter 88).

▪ ‘Red flag’ gastrointestinal symptoms that may point towards malignancy, e.g. dys-
phagia (see Chapter 22), weight loss, and melaena (see Chapter 20).

▪ Reflux symptoms and nausea might suggest gastro‐oesophageal reflux disease (see
Chapter 19).

▪ Abdominal bloating/distension.

▪ Bowel habit (diarrhoea suggestive of gastroenteritis).

▪ Past medical history: previous malignancy (intracranial metastases), diabetes mellitus
(autonomic neuropathy), active cancer treatment (chemotherapy‐induced nausea and vomiting, immunosuppression and risk of CNS infection).

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194 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ Medication history (see Box 21.1).

▪ Dietary history.

▪ Social history: alcohol use, recreational drug use.
Examination

▪ Basic observations including temperature, heart rate, and blood pressure to assess for hypovolaemia.

▪ Clinical hydration status: check mucous membranes, skin turgor, and jugular venous pressure; assess for pedal oedema.

▪ Abdominal examination: tenderness, distension, masses, bowel sounds for evidence of obstruction.

▪ Rectal/genital/pelvic examination if indicated to exclude faecal impaction, testicular/ ovarian cyst, torsion.

▪ Physical signs of self‐induced vomiting/bulimia: dental enamel erosion, calluses on the dorsal surface of the hands, enlargement of the parotid glands [13,14].

▪ Neurological: check fundi for papilloedema if concerned about raised ICP, although absence does not exclude raised ICP.

▪ In a patient receiving lithium therapy, examine for other clinical features that may suggest toxicity, e.g. coarse tremor, nystagmus, ataxia, and altered consciousness.
Investigations
For short‐lived causes of nausea and vomiting such as gastroenteritis, where the patient is clinically stable and able to tolerate oral fluids, generally symptoms will be self‐limit- ing, and no further investigations are required.
In cases of persistent vomiting, if signs/symptoms suggest severe systemic pathology (see Box 21.1), or where oral fluids are not tolerated, investigations that may be con- sidered are as follows.

▪ Bloods:

▪ urea and creatinine

▪ electrolytes including potassium and magnesium

▪ full blood count

▪ liver function tests

▪ C‐reactive protein

▪ serum amylase

▪ bone profile (to include corrected calcium)

▪ blood cultures if pyrexial

▪ glucose levels if patient is diabetic

▪ lithium levels if receiving lithium (possible toxicity).

▪ ECG: particularly in context of electrolyte disturbance, or to calculate QTc interval before initiation of an anti‐emetic which may interact with other prescribed medica- tions to cause prolongation.

▪ Urinalysis including pregnancy test.

▪ Stool cultures if associated prolonged diarrhoea.

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If the patient requires transfer from psychiatric to medical care (e.g. in the setting of acute infection/volume depletion), then the following investigations may be considered.

▪ Venous blood gas to check lactate (hydration status, indicators of ischaemia, e.g. some cases of bowel obstruction) and for acidosis (renal failure) or metabolic alkalo- sis (pyloric stenosis or gastric outlet obstruction).

▪ Abdominal X‐ray: look for signs of bowel obstruction or toxic megacolon.

▪ Ultrasound abdomen/pelvis.

▪ CT head if concerns over raised ICP.

▪ Lumbar puncture (bacterial meningitis/viral encephalitis).
MANAGEMENT [15]
Acute management of nausea and vomiting

▪ For acute cases where the patient can still tolerate oral fluids or diet, only support- ive management is required: oral fluids (ideally oral rehydration therapy), simple analgesia such as paracetamol for headache or abdominal pain, and anti‐emetics (Table 21.1).

▪ Referral to acute medical services may be necessary for the following.

▪ Severe gastroenteritis, hyperemesis gravidarum, or any cause where the patient is no longer able to tolerate oral fluids and requires intravenous fluids and electrolyte
replacement.

▪ Targeted management of the underlying cause, e.g. bowel obstruction, management
of underlying infections (e.g. meningitis, cholecystitis), steroids if raised ICP due to intracranial lesion.
Management of chronic nausea and vomiting
Rationalise medication

▪ Nausea in the context of psychiatric medication may be dose‐related. For example, SSRI‐related nausea may resolve with dose reduction [9]. Nausea can also be associ- ated with SSRI discontinuation, generally emerging within a week of discontinuing the drug and resolving within three weeks [10]. In this situation, consider slowing the rate of SSRI tapering.

▪ Nausea has also been reported as a side effect of dopamine D2 receptor partial ago- nists such as aripiprazole [11], brexpiprazole [16], and cariprazine [17]. This may be dose‐related (consider slowing dose titration rate) and usually occurs early in treat- ment, with most patients developing tolerance [11].

▪ Nausea has been reported in association with prescription of psychostimulants (e.g. methylphenidate) for attention deficit hyperactivity disorder, although a recent meta‐ analysis observed that the risk of nausea was not significantly increased in patients receiving methylphenidate compared with placebo [18].

Nausea and Vomiting 195

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196 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

■ Nausea and vomiting can be associated with prescription of mood stabilisers, such as sodium valproate [19], lamotrigine [20], and lithium. Indeed, nausea has been docu- mented in up to 20% of lithium‐treated patients, although it tends to be more likely early in treatment, with most patients developing tolerance [21]. Plasma lithium lev- els should be checked in a nauseated patient receiving lithium to rule out lithium toxicity. In the absence of toxicity, taking lithium after meals or using a sustained‐ release preparation may diminish associated nausea.

Table 21.1 Commonly prescribed anti‐emetics. Particular

Drug

Cyclizine

Ondansetron

Haloperidol

Prochlorperazine

Metoclopramide

Domperidone

Levomepromazine

Mechanism

Antihistamine

5‐HT3 antagonist

indications

Good general anti‐emetic

Opiate‐induced nausea and vomiting

Metabolic causes (see Box 21.1) Drug‐induced nausea and vomiting

Metabolic causes (see Box 21.1)

Delayed gastric emptying/ gastroparesis (prokinetic)

Metabolic causes (see Box 21.1) Useful in palliative care: also has anxiolytic properties

Dose

50 mg t.d.s. (IV/IM/SC/ PO)a

4–8 mg t.d.s. (PO/IV)

0.5–1.5 mg b.d. (PO/ SC/IM)

Oral: 5–10 mg t.d.s. Buccal: 3–6 mg b.d.

10 mg t.d.s. (PO/IV)

10 mg t.d.s. (PO)

6.25 mg b.d. initially (should not be used outside oncology and palliative care without specialist advice)

Side effects/cautions

Can cause acute reaction when given intravenously Dry mouth, drowsiness

Constipation: avoid in bowel obstruction
Headache

Sedation
EPSE
Caution using alongside ondansetron due to risk of QTc prolongation

Sedation
EPSE (although rare at this dose, risk increased in the elderly)

Do not give in bowel obstruction: can cause severe colic
EPSE (although rare at this dose)

EPSE rarer than with metoclopramide (reduced BBB permeability)
Increased risk of serious cardiac side effects, particularly if aged >60, with higher doses, and if taking other medication that prolong the QTc or inhibit CYP3A4 [24]

Sedation

Dopamine receptor antagonist

Prokinetic Dopamine antagonist 5‐HT4 agonist

Dopamine (D2) antagonist

Antagonist at muscarinic, histamine, 5HT2 and dopamine (D2) receptors

(D2)

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(D2) and

Nausea and Vomiting 197

Table 21.1 (Continued)

Drug

Hyoscine hydrobromide

Cinnarizine

Mechanism

Antimuscarinic

Antihistamine

Particular indications

Licensed for motion sickness, but also used (unlicensed) in treatment of clozapine‐ associated hypersalivation

Motion sickness, vestibular disorders (e.g. Ménière’s disease)

Dose

300 μg up to t.d.s. (PO) or as transdermal patch (1.5 mg every 72 hours)

30 mg t.d.s. (PO) for vestibular disorders, 30 mg 2 hours prior to travel if motion sickness, followed by 15 mg every 8 hours as required during journey

Side effects/cautions

Sedation

a IV, intravenous; IM, intramuscular; SC, subcutaneous; PO, by mouth. EPSE, extrapyramidal side effects; BBB, blood–brain barrier.

Other management options

■ Non‐pharmacological management:

▪ acupressure wrist bands

▪ small snacks instead of larger meals.

▪ Anti‐emetic therapy (see Table 21.1).

▪ Investigation and management of underlying causes: if malignancy is suspected
(weight loss, dysphagia, anaemia), consider an urgent referral for endoscopy and gastroenterology. In absence of red flag signs/symptoms, a routine referral can be made to gastroenterology.
Anti‐emetic therapy
The properties of commonly used anti‐emetics are listed in Table 21.1. Anti‐emetics should be given regularly for the duration of symptoms rather than on an as‐required basis for best efficacy. Haloperidol and levomepromazine are used most commonly in palliative care settings but are not first‐choice options for acute settings and should not be used without specialist advice. Of course, some patients with SMI may already be prescribed these drugs. Care must be taken over the risk of QTc prolonga- tion and risk of arrhythmia, particularly if patients are taking antipsychotics, antiarrhythmics (e.g. amiodarone, flecainide), antibiotics (macrolides such as clarithromycin, erythromycin and azithromycin, or fluoroquinolones such as ciprofloxacin), antifungal medication (e.g. fluconazole), or antimalarial medication (e.g. chloroquine) [4,22].

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198 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

In the SMI population, dopamine antagonists such as metoclopramide are more likely to cause acute movement disorders when used in patients already receiving antip- sychotic treatment. This risk increases in the elderly. Alternatives such as cyclizine and 5‐HT3 antagonists (e.g. ondansetron) may be preferred, although care should be taken over avoiding constipation with ondansetron [23].

References

1. American Gastroenterological Association. American Gastroenterological Association medical position statement: nausea and vomiting. Gastroenterology 2001;120(1):261–263.

2. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111(Suppl 8A):106S–112S.

3. Metz A, Hebbard G. Nausea and vomiting in adults: a diagnostic approach. Aust Fam Physician 2007;36:688–692.

4. Watson M, Lucas C, Hoy A, Wells J. Gastrointestinal symptoms: nausea and vomiting. In: Oxford Handbook of Palliative Care, 2nd edn.
Oxford: Oxford University Press, 2010:308–315.

5. Herrell HE. Nausea and vomiting of pregnancy. Am Fam Physician 2014;89:965–970.

6. Bollom A, Austrie J, Hirsch W, et al. Emergency department burden of nausea and vomiting associated with cannabis use disorder: US trends
from 2006 to 2013. J Clin Gastroenterol 2018;52(9):778–783.

7. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. Gastroenterology 2016;150:1380–1392.

8. Brzana RJ, Koch KL. Gastroesophageal reflux disease presenting with intractable nausea. Ann Intern Med 1997;126:704–707.

9. Goldstein BJ, Goodnick PJ. Selective serotonin reuptake inhibitors in the treatment of affective disorders: III. Tolerability, safety and pharma-
coeconomics. J Psychopharmacol 1998;12(3 Suppl B):S55–S87.

10. Haddad P. The SSRI discontinuation syndrome. J Psychopharmacol 1998;12:305–313.

11. Fleischhacker WW. Aripiprazole. Expert Opin Pharmacother 2005;6:2091–2101.

12. Scorza K, Williams A, Phillips JD, Shaw J. Evaluation of nausea and vomiting. Am Fam Physician 2007;76:76–84.

13. Harrington BC, Jimerson M, Haxton C, Jimerson DC. Initial evaluation, diagnosis, and treatment of anorexia nervosa and bulimia nervosa.
Am Fam Physician 2015;91:46–52.

14. Carney CP, Andersen AE. Eating disorders. Guide to medical evaluation and complications. Psychiatr Clin North Am 1996;19:657–679.

15. Singh P, Yoon SS, Kuo B. Nausea: a review of pathophysiology and therapeutics. Therap Adv Gastroenterol 2016;9:98–112.

16. Ishigooka J, Iwashita S, Tadori Y. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: a 6‐week, rand-
omized, double‐blind, placebo‐controlled study. Psychiatry Clin Neurosci 2018;72:692–700.

17. Campbell RH, Diduch M, Gardner KN, Thomas C. Review of cariprazine in management of psychiatric illness. Ment Health Clin
2017;7:221–229.

18. Holmskov M, Storebø OJ, Moreira‐Maia CR, et al. Gastrointestinal adverse events during methylphenidate treatment of children and ado-
lescents with attention deficit hyperactivity disorder: a systematic review with meta‐analysis and Trial Sequential Analysis of randomised
clinical trials. PLoS One 2017;12(6):e0178187.

19. Carpay JA, Aldenkamp AP, van Donselaar CA. Complaints associated with the use of antiepileptic drugs: results from a community‐based
study. Seizure 2005;14:198–206.

20. Mackay FJ, Wilton LV, Pearce GL, et al. Safety of long‐term lamotrigine in epilepsy. Epilepsia 1997;38:881–886.

21. Schou M, Baastrup PC, Grof P, et al. Pharmacological and clinical problems of lithium prophylaxis. Br J Psychiatry J Ment Sci
1970;116:615–619.

22. Goldstein EJC, Owens RC, Nolin TD. Antimicrobial‐associated QT interval prolongation: pointes of interest. Clin Infect Dis
2006;43:1603–1611.

23. Howard LM, Barley EA, Davies E, et al. Cancer diagnosis in people with severe mental illness: practical and ethical issues. Lancet Oncol
2010;11(8):797–804.

24. Medicines and Healthcare Products Regulatory Agency. Domperidone: risks of cardiac side effects. https://www.gov.uk/drug‐safety‐update/
domperidone‐risks‐of‐cardiac‐side‐effects (accessed 30 March 2019).

CHAPTER 21

Chapter 22

Dysphagia

Mary Denholm, Jason Dunn

Dysphagia is defined as the subjective sensation of difficulty or abnormality in swallowing. Odynophagia is defined as pain or discomfort on swallowing. Dysphagia is commonly subdivided into oropharyngeal dysphagia and oesophageal dysphagia [1]. Oropharyngeal dysphagia is characterised by difficulty initiating a swallowing action and with passage of food through the mouth or throat. Oesophageal dysphagia describes difficulty in movement of food or liquid down the oesophagus. Oesophageal dysphagia is the more common of the two, and accounts for most cases in the adult population. A comprehen- sive history has been shown to be able to differentiate between the two types in 80–85% of cases [2]. Dysphagia is common, with an estimated prevalence in adult populations of approximately 3% [3]. Dysphagia can be a ‘red flag’ for malignancy, and persistent dysphagia in almost all cases will require prompt assessment and referral for further investigation.

CAUSES OF DYSPHAGIA IN THE GENERAL POPULATION

Box 22.1 provides a list of non‐acute causes of oropharyngeal and oesophageal dyspha- gia. Both types of dysphagia can coexist in some neurological conditions including Parkinson’s disease and myotonic dystrophy, and in acute conditions including Candida infection. An acute presentation with sudden dysphagia and inability to swallow solids, liquids or, in some cases, even saliva suggests the presence of a foreign body in the oesophagus, usually a food bolus [4]. This requires immediate attention and referral to an acute hospital.

Box 22.1 Common causes of oropharyngeal and oesophageal dysphagia [5,6] Oropharyngeal dysphagia

Neuromuscular disturbance
Central nervous system, e.g. stroke, motor neurone disease or multiple sclerosis (bulbar palsy),

cranial nerve deficits
Myasthenia gravis, oculopharyngeal muscular dystrophy Drug induced (see Box 22.2)

Thyromegaly/goitre Lymphadenopathy
Infection
Cancer of the head and neck Strictures post surgery or radiotherapy Eosinophilic oesophagitis

Cervical osteophytes

Oesophageal dysphagia

Peptic stricture (benign) Oesophageal cancer Oesophageal webs and rings Eosinophilic oesophagitis Achalasia

Spastic motility disorders
Iatrogenic strictures, e.g. post surgery or radiotherapy Scleroderma
Functional dysphagia, e.g. globus (diagnosis of exclusion)

Rarer causes

Lymphocytic oesophagitis
Oesophageal involvement from Crohn’s disease Caustic injury from artificial substances

200 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Additional causes of dysphagia in patients with serious mental illness

Adults with serious mental illness (SMI) have higher rates of dysphagia and are consid- ered especially vulnerable to its complications, including asphyxiation and aspiration. This relates particularly to oropharyngeal dysphagia, with one study showing rates of up to 35% in an SMI cohort compared with 6% in the general population [7]. Box 22.2 summarises factors predisposing patients with SMI to dysphagia.

DIAGNOSTIC PRINCIPLES History [5]

▪ Is the onset of symptoms sudden or progressive?

▪ Is there difficulty swallowing solids, liquids or both? Did the symptoms start with
solids then progress to liquids?

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Dysphagia 201

Box 22.2 Additional causes of dysphagia in patients with serious mental illness [7,8] Medication

▪ Antipsychotics

▪ May affect the oral and pharyngeal phases of swallowing

▪ Acute dystonia

▪ Anticholinergic side effects, e.g. dry mouth (see Chapter 26)

▪ Benzodiazepines

▪ Anti‐seizure medication
Extrapyramidal symptoms
■ Drug‐induced

■ Disease‐related, e.g. Parkinson’s disease

Poor chewing skills and concentration in dementia patients

▪ Is there pain on swallowing?

▪ Are the symptoms constant or intermittent?

▪ Can the patient initiate and complete the swallowing action? Do they repeat the swal-
lowing action numerous times trying to initiate it?

▪ Is there a previous history of acid reflux, dyspepsia, or Barrett’s oesophagus?

▪ Is there a history of atopy (associated with eosinophilic oesophagitis)?

▪ Has there been associated weight loss?

▪ Has there been any recent change in bowel habit or melaena?

▪ Has there been any previous oesophageal treatment/intervention?

▪ Have there been episodes of coughing/choking, or nasal regurgitation?

▪ Has the patient had recurrent lower respiratory tract infections or pneumonia?
Key features in the history to suggest a particular cause

▪ Dysphagia starting with solids and progressively worsening to include softer foods and liquids is suspicious of a stricture/tumour.

▪ Dysphagia to both solids and liquids from the outset and which is not worsening may be more suggestive of a motility disorder.

▪ Accompanying chest pain/oesophageal spasm can be more suggestive of a motility disorder (but oesophageal spasm as a cause for acute chest pain must be a diagnosis of exclusion to avoid missing acute cardiac events and other serious causes).

▪ Patients with peptic (benign) strictures frequently have a long pre‐existing history of acid reflux symptoms, and usually do not exhibit weight loss.

▪ History of acid reflux or Barrett’s oesophagus is a risk factor for development of oesophageal cancer.

▪ History of smoking and excess alcohol use are risk factors for oesophageal cancer.

▪ Dysphagia that is intermittent and associated with instances of food impaction may
indicate eosinophilic oesophagitis.

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202 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Examination

▪ Halitosis: may suggest long‐standing obstruction.

▪ Evidence of recent weight loss.

▪ Oral Candida infection.

▪ Lymphadenopathy: cervical and supraclavicular nodes in particular.

▪ Umbilical nodule (Sister Mary Joseph nodule): underlying gastrointestinal
malignancy.

▪ Neurological examination including cranial nerves: look for diplopia, ptosis,
dysarthria.

▪ Features of Parkinson’s disease: rigidity, tremors, shuffling gait, autonomic dysfunc-
tion (e.g. postural hypotension).

▪ Features of systemic scleroderma: calcinosis, Raynaud’s phenomenon, sclerodactyly,
telangiectasia.
Investigations

▪ Bloods:

▪ full blood count

▪ haematinics, e.g. B12, folate, iron studies if anaemic

▪ creatinine, urea and electrolytes (including phosphate and magnesium)

▪ bone profile including calcium

▪ liver function tests including albumin.

▪ A bedside swallow test may be performed as an initial screening test [9].

▪ Chest X‐ray may be indicated if there are concerns regarding aspiration.
Further investigations that may be undertaken in hospital
Oropharyngeal dysphagia may be investigated using video fluoroscopy. Oesophageal dysphagia may be investigated using endoscopy, barium swallow, or oesophageal manometry. CT imaging may be indicated if malignancy is suspected.
Onward referral

▪ Patients with acute dysphagia should be referred as an emergency to hospital for urgent assessment.

▪ Patients with subacute symptoms that have progressed to complete dysphagia will also require admission for alternative nutrition and hydration while diagnostic inves- tigations are undertaken.

▪ New presentations of oesophageal dysphagia may warrant an urgent ‘two‐week wait’ referral to gastroenterology to rule out malignancy, and referral should certainly be made if dysphagia is accompanied by other red flag symptoms (Box 22.3).

▪ If in doubt regarding the correct referral route, liaise with your local gastroenterology service.

CHAPTER 22

Key information required for referral

▪ Full clinical details including comorbidities, current medication, nutritional status, degree of weight loss.

▪ Any recent blood results.

▪ Any imaging done to date.

▪ Functional status and ability to live independently/support required.

▪ Facilitates prompt organisation of support required to attend appointments.

▪ Allows specialty teams to consider further appropriate onward referrals and treat-
ment decisions

▪ All patients with a diagnosis of cancer will be discussed at a multidisciplinary team
meeting and functional status is key in deciding on appropriate treatments, e.g. radical surgery/chemoradiotherapy or palliative chemotherapy in the case of meta- static disease.
MANAGEMENT
Management will depend on the cause of the dysphagia (some examples are summa- rised in Box 22.4) [5,10]. Where nutritional intake is compromised, dietetic review is essential as well as consideration of alternative routes of feeding if indicated and appro- priate for the patient. Speech and language therapy review is a cornerstone of diagnosis and management, particularly for oropharyngeal dysphagia. In the SMI population, if psychiatric medication is felt to be contributing, consider rationalisation of treatment (reduce dose of causative agent or switch to alternative therapy). A multidisciplinary approach is recommended, involving as appropriate the psychiatrist, gastroenterology, and speech and language therapists.
OESOPHAGEAL CANCER IN PSYCHIATRIC POPULATIONS
The prognosis of oesophageal cancer remains poor for the general population, and this is potentially further exacerbated by delays to diagnosis in the SMI population. Patients with psychiatric illnesses have been shown to have delayed diagnosis of oesophageal

Dysphagia 203

Box 22.3 Red flag features indicating urgent referral to gastroenterology

▪ Symptom duration <4 months

▪ Unexplained weight loss

▪ Progression of symptoms from solids to liquids

▪ Anaemia

▪ Vomiting

▪ Evidence of gastrointestinal bleeding: haematemesis, melaena

▪ Age >50 years

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Box 22.4 Management of dysphagia Management of oropharyngeal dysphagia

Neurological causes (e.g. Parkinson’s disease): pharmacological management of underlying condition

Neoplastic causes
Surgical resection Chemotherapy/radiotherapy

Aftercare of stroke, post trauma, or post treatment complications
Rehabilitation
Techniques to increase safe oral intake or alternative feeding routes if not possible

Management of oesophageal dysphagia

Oesophageal cancer
Surgery/radical chemoradiotherapy for localised disease amenable to resection Palliative chemotherapy for metastatic disease
Stenting or palliative radiotherapy for local control if unsuitable for radical resection

Peptic stricture: antacid therapy (e.g. proton pump inhibitor), soft food, dilatation of stricture Eosinophilic oesophagitis: oral topical steroids (budesonide oro‐dispersible tablets), elimination

diets (removing food from diet that may be responsible), proton pump inhibitors
Achalasia: surgery (Heller’s myotomy), per oral endoscopic myotomy (POEM), pneumatic balloon

dilatation, botulinum toxin injections
Oesophageal spasm: nitrates, calcium‐channel blockers Infection: treatment of underlying infection, e.g. Candida

204 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

cancer, and more advanced presentations at diagnosis, thereby limiting therapeutic options. Even in those patients presenting earlier, psychiatric illness is associated with lower rates of curative surgery [11,12].

DYSPHAGIA IN THE ELDERLY

Dysphagia in the older patient population is increasingly recognised as complex and multi- factorial, as well as producing difficult ethical situations. It is common in those with demen- tia, as well as other acute illnesses and conditions such as cerebrovascular disease/stroke. It is estimated that the normal ageing process can cause mild abnormalities in oesophageal motility, but these are usually insufficient to cause symptoms, and dysphagia in older patients should not be attributed to ageing alone without appropriate investigation [13]. The British Geriatrics Society recommends a multidisciplinary approach to dysphagia, and emphasises need to assess capacity [14]: decisions to commence artificial enteral feeding in this population are highly complex and should not be taken in isolation.

References

1. Liu LWC, Andrews CN, Armstrong D, et al. Clinical practice guidelines for the assessment of uninvestigated esophageal dysphagia. J Can Assoc Gastroenterol 2018;1:5–19.

2. Hila A, Castell DO. Upper gastrointestinal disorders. In: Hazzard WR, Blass JP, Halter JB, et al. (eds) Principles of Geriatric Medicine and Gerontology. New York: McGraw‐Hill Professional, 2003:613–640.

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Dysphagia 205

3. Cho SY, Choung RS, Saito YA, et al. Prevalence and risk factors for dysphagia: a USA community study. Neurogastroenterol Motil 2015;27:212–219.

4. Ginsberg GG. Food bolus impaction. Gastroenterol Hepatol 2007;3:85–86.

5. Malagelada J‐R, Bazzoli F, Boeckxstaens G, et al. World Gastroenterology Organisation Global Guidelines: dysphagia. Global guidelines and
cascades update September 2014. J Clin Gastroenterol 2015;49:370–378.

6. Aziz Q, Fass R, Gyawali CP, et al. Functional esophageal disorders. Gastroenterology 2016;150(6):1368–1379.

7. Regan J, Sowman R, Walsh I. Prevalence of dysphagia in acute and community mental health settings. Dysphagia 2006;21:95–101.

8. Cicala G, Barbieri MA, Spina E, de Leon J. A comprehensive review of swallowing difficulties and dysphagia associated with antipsychotics
in adults. Expert Rev Clin Pharmacol 2019;12:219–234.

9. Martino R, Silver F, Teasell R, et al. The Toronto Bedside Swallowing Screening Test (TOR‐BSST): development and validation of a dysphagia
screening tool for patients with stroke. Stroke 2009;40:555–561.

10. Sami SS, Haboubi HN, Ang Y, et al. UK guidelines on oesophageal dilatation in clinical practice. Gut 2018;67:1000–1023.

11. Howard LM, Barley EA, Davies E, et al. Cancer diagnosis in people with severe mental illness: practical and ethical issues. Lancet Oncol
2010;11:797–804.

12. O’Rourke RW, Diggs BS, Spight DH, et al. Psychiatric illness delays diagnosis of esophageal cancer. Dis Esophagus 2008;21:416–421.

13. Shamburek RD, Farrar JT. Disorders of the digestive system in the elderly. N Engl J Med 1990;322:438–443.

14. British Geriatrics Society. Dysphagia management for older people towards the end of life. Good Practice Guide, 2012. https://www.bgs.org.
uk/resources/dysphagia‐management‐for‐older‐people.

CHAPTER 22

Chapter 23

Deranged Liver Function Tests

John Lally, Aisling Considine, Kosh Agarwal

Serum parameters traditionally termed as ‘liver function tests’ (LFTs) include the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma‐glutamyltransferase (GGT) alongside bilirubin and albu- min. Specifically, liver enzymes with bilirubin are markers of liver injury (with ALT and AST released from damaged hepatocytes), while albumin, bilirubin, and clotting (pro- thrombin time, international normalised ratio) are markers of liver function. There are many causes of deranged LFTs (Box 23.1), and partly owing to the frequency with which LFTs are routinely requested, deranged LFTs are a common observation in day‐to‐day clinical practice [1]. Patients with serious mental illness present with a number of risk fac- tors for liver injury, including increased rates of obesity (and therefore non‐alcoholic fatty liver disease, NAFLD), alcohol abuse, viral hepatitis [2], use of potentially hepatotoxic psychiatric drugs (Box 23.2), and deliberate self‐harm (e.g. paracetamol overdose) [3]. Thus, deranged LFTs will be a relatively frequent observation in psychiatric practice. This chapter provides an approach to the assessment, investigation, and management of a patient presenting with deranged LFTs. The reader is also directed to Chapters 24 and 43 for relevant information on alcohol and liver disease and on viral hepatitis, respectively.

DIAGNOSTIC PRINCIPLES

The clinical presentation of a patient with deranged LFTs will depend on the degree of liver injury and patient comorbidity. In mild cases, patients may be asymptomatic with normal clinical examination, while in severe cases patients may present with signs and symptoms of hepatic decompensation and haemodynamic instability. Severe cases should be managed as medical emergencies, potentially with early referral to a specialist hepatology provider (e.g. in cases where transplantation may be indicated). In the

Box 23.1 Causes of deranged liver function tests

Non‐alcoholic fatty liver disease Alcohol‐related liver disease Cirrhosis of any aetiology
Viral hepatitis

▪ Hepatitis A, B, C, D, and E

▪ Cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpesvirus, parvoviruses, varicella zoster virus
Ischaemic hepatitis

■ Systemic hypotension ■ Sepsis

▪ Primary cardiac, circulatory, respiratory failure

▪ Budd–Chiari syndrome
Reversible causes

■ Autoimmune hepatitis
■ Haemochromatosis
■ Leptospirosis, hepatic amoebiasis, malaria, rickettsial diseases

Pregnancy‐specific liver diseases

▪ Acute fatty liver of pregnancy

▪ HELLP syndrome (haemolysis, elevated liver enzymes, and a low platelet count)

▪ Pre‐eclampsia‐associated liver diseases
Miscellaneous

▪ Primary biliary cirrhosis

▪ Primary sclerosing cholangitis

▪ Wilson’s disease

▪ α1‐Antitrypsin deficiency

▪ Hypothyroidism

▪ Addison’s disease

▪ Coeliac disease

▪ Glycogen storage diseases

▪ Strenuous exercise

▪ Skeletal muscle damage/rhabdomyolysis

▪ Malignancy including hepatocellular carcinoma

▪ Toxin related

▪ Paracetamol overdose

▪ Recreational drugs including methamphetamine, cocaine

▪ Use of unregulated supplements/herbal remedies

▪ Associated with psychiatric/physical health prescription

▪ Medications associated with hepatoxicity, e.g. rifampicin, isoniazid, statins, efavirenz (see
Box 23.2)

▪ Alcohol

208 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

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Deranged Liver Function Tests 209

Box 23.2 Medications associated with liver injury and abnormal liver function tests [4,5]

Psychiatric medication

Antipsychotics

Clozapine, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, chlorpromazine

Antidepressants

Sertraline, paroxetine, fluoxetine, citalopram/escitalopram, fluvoxamine, venlafaxine, duloxetine, mirtazapine, agomelatine, bupropion, trazodone, imipramine, amitriptyline, iproniazid, phenelzine, moclobemide

Mood stabilisers

Carbamazepine, sodium valproate, lamotrigine, topiramate, pregabalin, lithium, benzodiazepines

Physical health medication

Antibiotics

Amoxicillin/clavulanic acid, flucloxacillin, erythromycin, ciprofloxacin, nitrofurantoin, minocycline, dapsone, doxycycline, trimethoprim

Antifungals

Ketoconazole

Antiretrovirals

Efavirenz, didanosine, abacavir

Anticonvulsants

Sodium valproate, phenytoin, carbamazepine

Analgesics

Paracetamol in doses in excess of maximum licenced daily dose for weight/age Non‐steroidal anti‐inflammatories

Anti‐tuberculosis drugs

Isoniazid, rifampicin, pyrazinamide

Miscellaneous

Propylthiouracil, statins, amiodarone, baclofen, methotrexate, methyldopa, lisinopril Herbal medicines, in particular Chinese herbal medicines
Khat

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210 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

non‐acute setting, there may be an opportunity for the psychiatric practitioner, in com- bination with input from pharmacy and/or dialogue with gastroenterology, to explore the aetiology of liver dysfunction. Such an approach is described in this chapter. Where medication‐induced liver injury is the most likely cause, removal of said treatment and subsequent normalisation of LFTs might avoid a referral to medical services. Even if a gastroenterology review is ultimately required, the referral will be strengthened by the history, examination, and investigations described here.

History

A history should screen for the common causes of abnormal LFTs described in Boxes 23.1 and 23.2. This will include the following.

. 1 History of presenting complaint:

. a Patients may present with malaise, fatigue, nausea, jaundice, abdominal pain, and
pruritus.

. b Red flag symptoms of malignancy (e.g. weight loss).

. c Associated symptoms that may suggest a causative comorbidity include:
i shortness of breath, peripheral oedema (heart failure)
ii skin pigmentation, diabetes mellitus, arthritis (haemochromatosis)
iii right upper quadrant pain (gallstones); cholestasis may be associated with dark urine and pale stool.

. 2 Past medical history:
a pre‐existing liver disease or autoimmune disorders
b metabolic syndrome
c inflammatory bowel disease (primary sclerosing cholangitis) d previous cholecystectomy.

. 3 Drug history:
a recent medication changes
b over‐the‐counter and herbal remedies.

. 4 Family history of liver or autoimmune disease.

. 5 Social history:

. a alcohol (see Chapter 24 for screening questions)

. b recreational drug use

. c other risk factors for viral hepatitis, e.g. tattoos or intravenous drug use (see
Chapter 43)

. d exposure to potential hepatotoxins.

. 6 As part of a mental state examination, enquire regarding deliberate self‐harm. Overdose should be managed as a medical emergency (see Chapter 83).

Examination

. 1 Basic observations: temperature, blood pressure, pulse, respiratory rate, and oxygen saturations.

. 2 Calculate body mass index (BMI).

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Deranged Liver Function Tests 211

. 3 On general inspection there may be evidence of chronic liver disease: finger clubbing, palmar erythema, spider naevi, telangectasia, ascites, and jaundice. If there is decom- pensated liver function, there may be signs of easy bruising. There may be evidence of routes of transmission such as tattoos or needle marks.

. 4 Hepatic encephalopathy may be accompanied by changes in mental state, e.g. fluctu- ating levels of consciousness, inattention, mood changes, irritability, drowsiness, leth- argy, and confusion.

. 5 A focused abdominal examination should look for asterixis, hepatosplenomegaly, ascites, and peripheral oedema.

Investigations

A key step in the interpretation of abnormal LFTs is to consider them in the context of historical blood test results in order to determine if this is an acute or chronic presenta- tion. The pattern of LFT derangement may provide insight into the underlying pathoae- tiology. For example, a predominant increase in ALT and AST points towards hepatocellular pathology, such as a viral or toxic (drugs/alcohol) hepatitis or a cirrhosis, while a predominant increase in ALP points towards cholestatic pathology (gallstones, stricture, or malignancy). Raised bilirubin may be seen in either hepatocellular or chole- static disease. An AST/ALT ratio above 2 is suggestive of alcoholic hepatitis, rather than other causes of hepatitis (e.g. viral). Raised GGT is a marker of recent alcohol use (24 hours to two weeks). Where LFTs are deranged, clotting should be requested to assess syn- thetic function. Other tests that may be requested, depending on history or examina- tion, are as follows.

Bloods

. 1 Routine bloods: full blood count, renal function, C‐reactive protein, HbA1c, lipid profile.

. 2 Viral hepatitis screen: hepatitis B surface antigen (HBsAg), IgM anti‐hepatitis B core antigen (anti‐HBc), antibody to HBsAg (anti‐HBs), anti‐hepatitis C virus antibody (HCV), hepatitis C viral RNA.

. 3 Autoantibody screen:

. a antinuclear antibody/anti‐smooth muscle antibody (autoimmune hepatitis)

. b anti‐liver/kidney microsomal antibody (autoimmune hepatitis)

. c anti‐mitochondrial antibody (primary biliary cirrhosis)

. d anti‐neutrophil cytoplasmic antibodies (consider if cholestatic picture: primary
sclerosing cholangitis).

. 4 Pregnancy test if a female of childbearing age.

. 5 Creatine kinase if considering a muscle disorder.

. 6 Toxicology screen including paracetamol (acetaminophen) level.

. 7 If Wilson’s disease is suspected: plasma ceruloplasmin level and urinary copper
quantitation.

. 8 If haemochromatosis is suspected: iron studies.

. 9 If hepatocellular carcinoma suspected: alpha‐fetoprotein.

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212 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Imaging

Abdominal ultrasound should be used to image the liver (masses, cirrhosis, or fatty liver) and biliary tract (obstruction), with Doppler imaging for vascular occlusion (Budd–Chiari syndrome). Liver biopsy may be considered if the diagnosis remains unclear after these tests, or to assess the degree of liver damage.

MANAGEMENT

Abnormal LFTs do not always indicate hepatitis or liver disease, and therefore may not require specific management. In members of the general population with abnormal LFTs, defined as ALT twice the upper limit of normal (ULN), one‐third of males and one‐quarter of females had no identifiable cause [6]. Furthermore, 20% of healthy vol- unteers treated with placebo in clinical trials have ALT increases of between one and three times ULN [7], and 12% of the general population have one abnormal LFT meas- ure [8]. When assessing abnormal LFTs it is important to consider the clinical context in which they have occurred and the pattern and degree of increase. If the increase in ALT/AST is less than three times ULN, and if the patient has evidence of obesity and/or the metabolic syndrome and no other clear risk factors for liver disease, then a diagno- sis of NAFLD is likely [9]. Lifestyle advice should be offered, with recommendations to reduce or discontinue alcohol use. Increased exercise and dietary changes to aid weight loss are recommended (see Chapter 14). LFTs should then be rechecked two to three months later. Increases in ALT/AST of more than three times ULN or raised ALP should prompt assessment for other causes, including a blood and imaging liver screen as described. When in doubt, discuss the case with general medical/gastroenterology col- leagues. Management will then depend on the underlying cause.

Drug‐induced liver injury

A number of drugs can cause LFT derangements. In the psychiatric patient population, psychotropic medications are potentially responsible, and rationalising pharmacotherapy may be required. Up to one‐third of people treated with antipsychotic medications have one or more abnormal LFTs recorded, and 4% have at least one LFT of more than three times ULN [4]. The time to onset of LFT changes after starting antipsychotic medications is generally short, with the majority occurring within one to six weeks [4,10]. However, antipsychotic‐induced liver injury is generally mild and transient [4], so stopping treatment is not always necessary. Clozapine is one of the psychotropic agents more frequently asso- ciated with abnormal LFTs. The median rate of clozapine‐associated hepatitis (defined as ALT more than twice ULN) is 17%, although for most patients this does not result in progression to severe liver injury [4], and LFTs will normalise in up to 60% of cases with continued treatment [11]. Hepatotoxicity is associated with all antidepressants and is more common in the elderly and with polypharmacy. Antidepressants are associated with mild transient increases in transaminases in 0.5–3% of patients treated [5]. Clinically significant liver impairment or damage is however rare.

Most episodes of drug‐induced hepatitis are benign and improve following discon- tinuation of the offending agent. Medications such as paracetamol cause a predictable

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Deranged Liver Function Tests 213

dose‐dependent liver toxicity. However, antipsychotic and other psychotropic medication‐ induced hepatitis are idiosyncratic reactions, being unpredictable and not dose depend- ent. Risk factors for drug‐induced hepatitis include older age, female gender, alcohol use, NAFLD, obesity, and pre‐existing liver disease. Although a transient and mild transaminitis may be seen with many antipsychotics and antidepressants, it is impor- tant to recognise progressive drug‐induced hepatitis to allow for the withdrawal of the medication and prevent progression to liver failure. As a guide, if serum ALT or AST is more than three times ULN, and serum total bilirubin is elevated to more than twice ULN [12] and there is a likely drug cause, then consider discontinuing the treatment. If ALT is increased more than five times ULN, then immediate discontinuation is indi- cated [13]. If ALT was already raised at baseline, then increases in ALT more than three times the baseline level should prompt consideration of discontinuing treatment. However, this is only a guide, and any decision should balance the risk of continuing treatment (progressive and potentially irreversible liver damage) against the risk of stopping treatment (deterioration in mental state). A multidisciplinary team (MDT) approach involving the patient is recommended. A similar MDT approach is recom- mended if re‐challenge of a potentially causative agent is being considered.

Some patients with drug‐induced liver injury may present with a more severe clinical picture, with features of systemic hypersensitivity, fever, raised inflammatory markers, eosinophilia, and cutaneous or multiorgan involvement. The patient should be trans- ferred to the care of medical colleagues. Management involves discontinuation of the medication and supportive management (i.e. there are no specific treatments for psy- chotropic‐induced hepatitis/liver failure). Monitoring of transaminases, bilirubin, and clotting should be initiated and continued until markers stabilise. Patients should be monitored for emerging clinical features of liver dysfunction, haemodynamic instabil- ity, or encephalopathy.

References

1. Pratt DS, Kaplan MM. Evaluation of abnormal liver‐enzyme results in asymptomatic patients. N Engl J Med 2000;342(17):1266–1271.

2. Hughes E, Bassi S, Gilbody S, et al. Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review
and meta‐analysis. Lancet Psychiatry 2016;3(1):40–48.

3. David S, Hamilton JP. Drug‐induced liver injury. US Gastroenterol Hepatol Rev 2010;6:73–80.

4. Marwick KF, Taylor M, Walker SW. Antipsychotics and abnormal liver function tests: systematic review. Clin Neuropharmacol
2012;35(5):244–253.

5. Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant‐induced liver injury: a review for clinicians. Am J Psychiatry
2014;171(4):404–415.

6. Ruhl CE, Everhart JE. Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology
2012;55(2):447–454.

7. Rosenzweig P, Miget N, Brohier S. Transaminase elevation on placebo during phase I trials: prevalence and significance. Br J Clin Pharmacol
1999;48(1):19–23.

8. Rosalki SB, Dooley JS. Liver function profiles and their interpretation. Br J Hosp Med 1994;51(4):181–186.

9. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the
American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328–357.

10. Lally J, Al Kalbani H, Krivoy A, et al. Hepatitis, interstitial nephritis, and pancreatitis in association with clozapine treatment: a systematic
review of case series and reports. J Clin Psychopharmacol 2018;38(5):520–527.

11. Hummer M, Kurz M, Kurzthaler I, et al. Hepatotoxicity of clozapine. J Clin Psychopharmacol 1997;17(4):314–317.

12. Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug‐induced liver
injury. Am J Gastroenterol 2014;109(7):950–966; quiz 967.

13. Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug‐induced liver injury. Clin Pharmacol Ther
2011;89(6):806–815.

CHAPTER 23

Chapter 24

Alcohol and Physical Health

Musa Sami, Joseph Cooney, Michael Heneghan

Alcohol (ethanol) is the most commonly used drug in the world [1]. For most people who consume it, alcohol causes little or no harm. However, alcohol is a toxin with the potential to damage multiple organ systems.

WHAT IS HARMFUL USE?

There is no global consensus on recommended maximum intake (or safe limits) of alcohol. In the UK, alcohol units can be quantified by multiplying volume (litres) by percentage alcohol concentration. A glass of red wine (175 mL, 12% alcohol) constitutes 0.175 × 12 = 2.1 units and a bottle of vodka (700 mL, 37.5%) 0.7 × 37.5 = 26.25 units. In the UK, current safe recommended intakes are less than 14 units of alcohol per week for both men and women [2].

Harmful use is that which causes damage to physical or mental health. Alcohol dependence is characterised by inability to control use (compulsion), priority given to drinking over other substances (salience), and persistence of use despite negative conse- quences. Craving and physical tolerance (needing increasing amounts to get the same effect) and withdrawal symptoms (tremor, tachycardia, sweats, anxiety, and nausea on cessation or reduction of use) may also be present. Alcohol use disorder refers to both harmful use and dependence. The terms ‘alcoholic’ and ‘alcoholism’ are used colloqui- ally, but they do not adequately distinguish between harmful use and dependence, can be stigmatising, and are best avoided by health professionals.

In pregnancy, alcohol crosses the placenta and there is a risk of fetal alcohol spectrum disorders (an umbrella term encompassing a spectrum of disorders that includes decreased IQ, distinctive facies, and attentional and behavioural difficulties). Pregnant women and those planning pregnancies should be advised there is no safe minimum level of alcohol intake and to minimise consumption (see Chapter 62) [2].

216 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

PHYSICAL COMPLICATIONS OF ALCOHOL USE Acute presentations

These will require immediate referral to emergency services.

▪ Delirium tremens: a severe form of alcohol withdrawal that usually occurs two to three days after alcohol cessation, characterised by severe tremor, perspiration, fever, and tachycardia. Can be associated with dramatic florid or bizarre visual/tactile hal- lucinations. Occasionally, hallucinations are predominant and physical signs less apparent, so the patient may present on a psychiatric ward before diagnosis is made. Main risks are of dehydration from increased perspiration or alcohol withdrawal seizures. Manage in a medical unit with a benzodiazepine detoxification regimen, fluids, and vitamin replacement (thiamine).

▪ Alcohol withdrawal seizures.

▪ Gastrointestinal bleeding: cirrhosis leads to portal venous hypertension and oesopha-
geal/gastric varices which may bleed (see Chapter 20). Often presents as haematem- esis (vomiting fresh red blood), ‘coffee ground’ vomiting, or melaena (black tarry stool indicating partially digested blood from stomach). Less severe is a Mallory– Weis tear of the mucous membrane of the upper gastrointestinal tract caused by vomiting often secondary to alcohol ingestion. Alcohol can also be associated with gastric ulcers (erosion in membrane of stomach; see Chapter 19).

▪ Pancreatitis: acutely presents with severe abdominal pain radiating to the back, often precipitated by an alcohol binge (see Chapter 88). Additional features include fever, tachycardia, and nausea. Raised serum amylase/lipase is diagnostic (although amyl- ase levels may be blunted in chronic pancreatitis). Can be life‐threatening, requiring supportive care and fluid resuscitation. Manage in hospital acutely. Surgical interven- tion may be required for debridement of peripancreatic necrosis.

▪ Hepatic encephalopathy.

▪ Spontaneous bacterial peritonitis: acute bacterial infection of ascitic fluid.

▪ Others: severe alcohol intoxication (ethanol poisoning) can cause respiratory and
central nervous depression. Surrogate alcohols (e.g. hand sanitiser, mouthwash) are sometimes consumed in the absence of commercially available alcohol, and owing to their especially high alcohol concentrations are particularly dangerous. Other substi- tutes such as antifreeze can cause methanol poisoning, presenting with abdominal pain, alterations in consciousness, and retinal toxicity.
Chronic presentations
These will merit outpatient referral for physician assessment (in the UK, usually via a general practitioner).

■ Alcoholic liver disease: alcohol is one of the most common causes of chronic liver disease (the others being non‐alcoholic fatty liver disease, NAFLD), viral hepatitis, autoimmune hepatitis, and idiopathic causes (see Chapters 23 and 43). There is a

CHAPTER 24

wide range of damage alcohol can cause to the liver, including inflammation, fibrosis, and cirrhosis. Severe alcohol damage can lead to portal venous hypertension and decompensation in liver synthetic function, including decreased plasma proteins and impaired clotting. End‐stage liver disease may lead to hepatic encephalopathy, a pic- ture of chronic confusion sometimes associated with asterixis (coarse shaking of the hands when the wrist is extended).

▪ Cardiac disease: there are a range of cardiac complications including arrhythmias (particularly atrial fibrillation, atrial flutter, and ventricular tachyarrhythmias; see Chapter 1). Alcoholic cardiomyopathy can present with dilation of heart muscle sec- ondary to heavy chronic alcohol ingestion leading to heart failure (see Chapter 7). Alcohol is a risk factor for cardiovascular disease, synergistic with other risk factors (including smoking, obesity, hypertension, and increased cholesterol; see Chapters 5, 9, 14, and 46 for details of all these presentations).

▪ Immune dysfunction: alcohol is associated with bone marrow suppression and altera- tion in cytokine expression [3]. This may lead to immunosuppression and predispose to infections. Alcohol abuse is associated with increased risk of pneumonia (consider tuberculosis or mycobacterial infection if chronic and there is evidence of poor nutri- tion and accommodation; see Chapters 39 and 44), cellulitis (particularly if periph- eral neuropathy and poor self‐care), and spontaneous bacterial peritonitis in association with ascites.

▪ Neurotoxicity: alcohol has a plethora of neurotoxic effects. Central nervous system effects include global atrophic changes, frontal degeneration and change in personal- ity, chronic subdural haemorrhage, Wernicke–Korsakoff syndrome (thiamine defi- ciency leading to triad of confusion, ataxia, and ophthalmoplegia), cerebellar degeneration (slurred speech, nystagmus, ataxia, hypotonia, intention tremor), reduc- tion in seizure threshold, and withdrawal seizures. Hepatic encephalopathy may occur secondary to chronic liver disease. Peripherally, alcohol can cause a symmetri- cal distal peripheral neuropathy.

▪ Cancer: heavy alcohol intake is associated with increased risk of cancers of the mouth, pharynx, larynx, oesophagus, breast, bowel, and liver [4].
APPROACH TO THE PATIENT WITH SUSPECTED ALCOHOL MISUSE
A brief assessment of problematic alcohol use can be undertaken by using the CAGE questionnaire, which is a series of four yes/no questions.

. 1 Have you ever felt you needed to Cut down on your drinking?

. 2 Have people Annoyed you by criticising your drinking?

. 3 Have you ever felt Guilty about drinking?

. 4 Have you ever felt you needed a drink first thing in the morning (Eye‐opener) to
steady your nerves or to get rid of a hangover?

▪ Two ‘yes’ answers indicates problematic alcohol use and should be investigated further.

Alcohol and Physical Health 217

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218 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Further freely available validated questionnaires include the following.

▪ Alcohol Use Disorders Identification Test (AUDIT): provides a more detailed measure over the previous year with a score of 8/40 or above indicating harmful use [5].

▪ Severity of Alcohol Drinking Questionnaire (SADQ): rates the severity of depend- ence [6].

▪ Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA‐Ar): assesses for presence of withdrawal symptoms (nausea/vomiting, tremor, sweating, anxiety, tactile/auditory/visual disturbances, headache, disorientation) and rates their severity [7,8].
History
Quantify the amount the individual is currently drinking. Enquiring about the daily pattern of drinking can be useful (‘Tell me how much you drink on a typical day…’). Establish harmful use and dependence criteria (‘Who has control – you or the drink?’). If appropriate, quantify severity of withdrawal using the CIWA‐Ar. Ask about any comorbid cardiac or liver conditions that can exacerbate comorbid pathology (e.g. hepatitis B and C, NAFLD). Ask about the presence of risk factors for cardiovascular disease (obesity, raised cholesterol, hypertension). Enquire about smoking status and use of illicit drugs.
Physical examination
Examine for evidence of the following.

▪ Alcohol misuse: signs of alcohol intoxication or withdrawal, including tremor, smell of alcohol, Dupuytren’s contracture.

▪ Evidence of organ disease:

▪ Liver: clubbing, pallor, cachexia, unsteadiness, telangiectasia, jaundice, spider naevi,
hepatomegaly, ascites.

▪ Cardiac: displaced apex beat, heaves and thrills, anaemia.

▪ Evidence of decompensated hepatic function: signs of easy bruising, signs of low body albumin such as pitting oedema and ascites, splenomegaly, and caput medusae.

If there is evidence of chronic liver disease, ensure that the patient is referred to general medical services.

In cases of acute bleeding (haematemesis or malaena), measure blood pressure (not- ing for hypotension and a postural drop) and heart rate and oxygen saturations if avail- able (see Chapter 20), resuscitate as necessary using the ABCDE approach, and ensure the patient is referred as an emergency to medical services.

CHAPTER 24

Alcohol and Physical Health 219

Liver failure can be associated with hypoglycaemia, and therefore regular blood sugar monitoring may be required (symptoms of hypoglycaemia include suddenly feel- ing trembly, increased anxiety, irritability, hunger, and blurring of vision), with treat- ment as necessary (see Chapter 74).

Investigations

Blood tests

. 1 Full blood count to check for anaemia, low platelets, and neutropenia. Raised mean corpuscular volume (MCV) is a marker of chronic alcohol use (more than three months).

. 2 Haematinic studies (iron deficiency anaemia may indicate chronic gastrointestinal bleeding).

. 3 Urea and electrolytes.

. 4 Liver function tests including aspartate aminotransferase (AST) and alanine ami-
notransferase (ALT): an AST/ALT ratio >2 is suggestive of alcoholic hepatitis, rather than other causes of hepatitis (e.g. viral). Raised gamma‐glutamyltransferase (GGT) is a marker of recent alcohol use (24 hours to two weeks).

. 5 Increased international normalised ratio (INR) and low albumin are tests of syn- thetic liver function and can help define the degree of hepatic failure.

. 6 C‐reactive protein (CRP) if infection suspected.

. 7 Serum amylase or lipase if suspected pancreatitis (amylase can normalise in
chronic pancreatitis). Testing for urine amylase may be useful in delayed pres- entations (hyperamylasuria occurs two to three days after an elevated serum level).

. 8 Serum ammonia if hepatic encephalopathy is a differential (liaise with laboratory before collection and deliver on ice).

Electrocardiogram

May show atrial fibrillation or flutter, evidence of cardiomyopathy (bizarre QRS com- plexes), or other arrhythmias. In case of an abnormal ECG, confirm haemodynamic stability and refer to general medical colleagues as appropriate.

Breathalyser

This is useful in detoxification settings. Wait until blood alcohol levels are in safe limits before commencing detoxification.

Urine drug sampling

May be useful in determining use of other drugs.

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220 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Specialist investigations

Other tests often undertaken by general medical doctors include abdominal ultrasound (to quantify the degree of cirrhosis, for evidence of ascites, and for evidence of portal venous hypertension such as splenomegaly). A needle aspiration can help determine the cause of ascites: a serum ascites albumin gradient in excess of 11 g/L is indicative of ascites secondary to portal hypertension [9]. Antibiotic prophylaxis should be offered alongside needle aspiration if the patient has a history of hepatic encephalopathy or spontaneous bacterial peritonitis (please refer to local guidelines).

Gastroenterologists and surgeons may undertake gastroscopy to investigate and treat gastrointestinal bleeding. Imaging of the brain with either CT or MRI may be required to rule out subdural haemorrhage. MRI may show evidence of Wernicke–Korsakoff syndrome with mammillary body and thalamic hyperintensities.

If dilated cardiomyopathy secondary to alcohol use is suspected, an echocardiogram can help diagnose and quantify the extent of heart failure.

MANAGEMENT

Patients with alcohol misuse are at high risk of physical health complications. There should be a low threshold for seeking help from general medical colleagues.

Refer patients to emergency services in the following instances: signs of haemody- namic instability (low blood pressure, high pulse rate, low oxygen saturations), vomit- ing of blood or melaena, sudden change of consciousness or evidence of hepatic encephalopathy (confusion, obtundation, tremor), severe acute abdominal pain, sei- zures, evidence of sepsis, evidence of developing Wernicke–Korsakoff syndrome (confu- sion, ophthalmoplegia, ataxia), acute pancreatitis (generally managed conservatively but may require surgical intervention), severe alcohol withdrawal, or delirium tremens that cannot be safely managed in the psychiatric setting.

If there is evidence of chronic organ damage such as ascites on physical examination, anaemia without frank bleeding, unexplained lethargy or weight loss, or abnormal ECG, seek advice from general medical colleagues and arrange for an outpatient refer- ral to gastroenterology.

Detoxification

Detoxification (when appropriate) is undertaken with long‐acting benzodiazepine sub- stitution therapy such as chlordiazepoxide or diazepam reduced over 5–14 days depend- ing on setting, combined with parenteral thiamine (see section Nutrition). Dose and regimen are titrated to severity and can be fixed dose or symptom triggered as appro- priate to knowledge and skills of your unit. Examples of fixed‐dose regimens for mod- erate (SADQ score 16–30) and severe (SADQ score >30) alcohol dependence are respectively provided in Tables 24.1 and 24.2 as a guide. These example regimens are not intended to be prescriptive, and regimens should be tailored to the individual patient. Symptom‐triggered therapy is generally used in patients without a history of

CHAPTER 24

Alcohol and Physical Health 221

Table 24.1 Moderate alcohol dependence: example of fixed‐dose chlordiazepoxide treatment regimen. Total daily dose (mg)

Day 1

Day 2

Day 3

Day 4

Day 5

20 mg q.d.s. 80

15 mg q.d.s. 60

10 mg q.d.s. 40

5 mg q.d.s. 20

5 mg b.d. 10

Table 24.2 Severe alcohol dependence: example of fixed‐dose chlordiazepoxide treatment regimen. Total daily dose (mg)

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

40 mg q.d.s.

30 mg q.d.s.

25 mg q.d.s.

20 mg q.d.s.

15 mg q.d.s.

10 mg q.d.s.

10 mg t.d.s.

5 mg q.d.s.

10 mg nocte

+ 40 mg p.r.n. 200

160

120

100

complications and should only be carried out by staff with experience of its delivery. In all detoxification regimens, monitor for signs of over‐sedation, ataxia, and signs of undertreatment (i.e. withdrawal). Daily doses can be adjusted accordingly.

Nutrition

Input from dieticians may be required to support the nutritional needs of patients with advanced liver disease. Heavy alcohol use is associated with depletion of thiamine (vita- min B1) and Wernicke–Korsakoff syndrome. Those with a history of heavy alcohol use should be prescribed prophylactic oral thiamine replacement therapy (300 mg daily). In detoxification settings, individuals with severe alcohol dependence (SADQ score >30 or alcohol consumption >30 units/day) and/or evidence of malnutrition should be pre- scribed parenteral (intramuscular or intravenous) thiamine as vitamin replacement due to inadequate enteral absorption of thiamine. Standard parenteral regimen is one pair

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222 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

of Pabrinex IMHP daily (containing thamine 250 mg/dose) for five days, followed by oral thiamine and/or vitamin B compound for as long as required (where diet is inade- quate or alcohol consumption is resumed) [10]. Where parenteral thiamine is used, facilities for treating anaphylaxis should be available. If Wernicke’s encephalopathy is suspected, the patient should be transferred to a medical unit where intravenous thia- mine can be administered (at least two pairs of Pabrinex IVHP, i.e. four ampoules) three times daily for three to five days followed by one pair of ampoules once daily for a further three to five days, or longer (until no further response is seen) [10]. Patients with encephalopathy should be prescribed laxatives, aiming to achieve bowels opening three to four times daily (example prescription: lactulose 10 mL four times daily).

Relapse prevention

Acamprosate and supervised disulfiram are licensed in the UK for the treatment of alcohol dependence and may be offered in combination with psychosocial treatment [11]. Treatment should be initiated by specialist services. Naltrexone is also recom- mended as an adjunct in the treatment of moderate and severe alcohol dependence [11]. Further details are provided in the Maudsley Prescribing Guidelines in Psychiatry [12].

Liver transplant

In the UK, approximately 600–800 people receive liver transplants every year, with alcohol‐related liver disease the most common precipitant [13]. Patients generally need to have demonstrated abstinence from alcohol for six months prior to the operation.

References

1. National Institute on Drug Abuse. Commonly used drugs charts. https://www.drugabuse.gov/drugs‐abuse/commonly‐abused‐drugs‐charts (accessed 5 May 2019).

2. UK Chief Medical Officers. UK Chief Medical Officers’ low risk drinking guidelines. https://www.gov.uk/government/publications/alcohol‐ consumption‐advice‐on‐low‐risk‐drinking (accessed 5 May 2019).

3. Cook RT. Alcohol abuse, alcoholism, and damage to the immune system: a review. Alcohol Clin Exp Res 1998;22(9):1927–1942.

4. Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and site‐specific cancer risk: a comprehensive dose‐response meta‐analysis. Br J
Cancer 2015;112(3):580–593.

5. World Health Organization. Alcohol Use Disorders Identification Test (AUDIT). https://www.drugabuse.gov/sites/default/files/files/AUDIT.
pdf (accessed 5 May 2019).

6. SMART. Severity of Alcohol Dependence Questionaire (SADQ‐C). https://www.smartcjs.org.uk/wp‐content/uploads/2015/07/SADQ.pdf
(accessed 5 May 2019).

7. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alco-
hol scale (CIWA‐Ar). Br J Addict 1989;84(11):1353–1357.

8. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA‐Ar). https://umem.org/files/uploads/1104212257_CIWA‐Ar.pdf
(accessed 5 May 2019).

9. Runyon BA, Montano AA, Akriviadis EA, et al. The serum–ascites albumin gradient is superior to the exudate–transudate concept in the
differential‐diagnosis of ascites. Ann Intern Med 1992;117(3):215–220.

10. Lingford‐Hughes AR, Welch S, Peters L, et al. BAP updated guidelines: evidence‐based guidelines for the pharmacological management of
substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012;26(7):899–952.

11. National Institute for Health and Care Excellence. Alcohol‐use Disorders: Diagnosis, Assessment and Management of Harmful Drinking and
Alcohol Dependence. Clinical Guideline CG115. London: NICE, 2011. https://www.nice.org.uk/guidance/cg115 (accessed 5 May 2019).

12. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry, 13th edn. Chichester: Wiley Blackwell, 2018.

13. National Health Service. Transplant Activity Report 2017–18. https://www.organdonation.nhs.uk/helping‐you‐to‐decide/about‐organ‐
donation/statistics‐about‐organ‐donation/transplant‐activity‐report/ (accessed 5 May 2019).

CHAPTER 24

Chapter 25

Unintentional Weight Loss

Mary Denholm, John O’Donohue

Clinically significant weight loss is defined as loss of more than 5% of a patient’s base- line body weight over a period of 6–12 months [1]. Unintentional weight loss that is progressive may be a sign of either significant physical or mental illness [2]. Unintentional weight loss is often associated with specific conditions (Box 25.1), but is also a general feature of ageing [3]. Weight loss is an important prognostic indicator of increased mortality in both the general population [4] and certain patient groups, for example people with chronic cardiorespiratory disease or nursing home residents [5]. A malig- nant cause of unexplained weight loss is found in 15–37% of patients [6,7]. Many serious illnesses are associated with the syndrome of cachexia, featuring a loss of mus- cle mass sometimes accompanied by a loss of adipose tissue, combined with a systemic inflammatory response [8]. For example, cancer cachexia, pulmonary cachexia, and cardiac cachexia are all well‐recognised syndromes [9,10]. In older patients, loss of muscle mass may lead to the syndrome of sarcopenia, also associated with weight loss. This is characterised by loss of muscle mass and strength with consequent reductions in functional ability/performance. It can be an important contributing factor to falls in this population [11].

In addition to eating disorders, individuals with other serious mental illness (SMI) may be at increased risk of weight loss and malnutrition, particularly if requiring inpa- tient care [12] and in those with coexisting substance abuse [13]. This has associated implications for physical health and increased mortality risk [14]. This risk is particu- larly pronounced in older patients [15]. Indeed, patients with dementia treated with acetylcholinesterase inhibitors are at increased risk of weight loss, over and above being a vulnerable population at baseline [16]. Unintentional weight loss may also be observed in patients who discontinue long‐term treatment with antipsychotics (e.g. chlorproma- zine and haloperidol) [17]. Significant life events including bereavement can also cause weight loss alongside psychological symptoms [18]. Weight loss is common in cancer

Box 25.1 Common causes of weight loss in the general and psychiatric patient population Gastrointestinal disease

▪ Malabsorption (e.g. coeliac disease, pancreatic insufficiency)

▪ Inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis)

▪ Peptic ulcer disease
Malignancy

▪ Haematological malignancy (e.g. lymphoma, leukaemia)

▪ Solid tumours, particularly gastrointestinal and lung cancers
Endocrine causes

▪ Hyperthyroidism

▪ Diabetes mellitus: acute presentation of type 1 diabetes (weight gain a more common presenting
feature for type 2), incorrect use of/omitting insulin treatment

▪ Adrenal causes: primary adrenal insufficiency (e.g. Addison’s disease)
Chronic systemic disease

▪ Chronic cardiac disease (e.g. heart failure)

▪ Chronic lung disease (e.g. chronic obstructive pulmonary disease)

▪ Chronic/end‐stage renal failure
Rheumatological/connective tissue diseases

▪ Rheumatoid arthritis

▪ Giant cell arteritis
Infection

▪ HIV

▪ Tuberculosis: can be a sign of active disease or reactivation of previous disease

▪ Hepatitis B and C

▪ Parasitic/helminth infections
Neurological disease

▪ Dementia

▪ Stroke

▪ Parkinson’s disease/Lewy body dementia (impaired cognition and physical factors, e.g.
dysphagia)
Psychiatric conditions

▪ Depression (particularly in the elderly/nursing home residents)

▪ Anxiety

▪ Eating disorders (weight loss distinguished as being intentional)

▪ As part of clinical spectrum of altered behaviours in serious mental illness

224 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

CHAPTER 25

Unintentional Weight Loss 225

Medication

▪ Thyroxine replacement for hypothyroidism

▪ Anti‐seizure medications (e.g. topiramate)

▪ GLP‐1 agonists (e.g. exenatide) used in management of diabetes

▪ Acetylcholinesterase inhibitors used in the treatment of dementia (e.g. donepezil, galantamine,
rivastigmine)

▪ Over‐the‐counter remedies (e.g. St John’s Wort)
Substance abuse

▪ Alcohol

▪ Recreational drugs (e.g. cocaine, amphetamines, cannabis)

▪ Tobacco

patients at presentation [19,20]. Cancer diagnoses are often delayed in the SMI population, and this group are known to have poorer cancer outcomes compared with the general population [19].

DIAGNOSTIC PRINCIPLES

History

▪ Record and assess amount of weight loss, time frame, and whether progressive/ ongoing.

▪ Patient’s weight patterns over previous years: stable or fluctuating.

▪ Constitutional symptoms (e.g. night sweats, fatigue, fevers).

▪ Evaluate for any intentional weight loss (e.g. dieting, increased exercise regimes, and
evidence of disordered eating behaviours).

▪ Screen for low mood/depression.

▪ Determine if the patient has noticed any new swellings/lymphadenopathy.

▪ Symptoms of hyperthyroidism: palpitations, sweating, tremor.

▪ Symptoms of adrenal insufficiency: nausea, vomiting, significant lethargy and fatigue.

▪ Respiratory symptoms: increasing breathlessness, chronic cough, haemoptysis.

▪ Abdominal pain, distension, nausea and vomiting, early satiety.

▪ Rectal bleeding or melaena, change in bowel habit, steatorrhoea.

▪ Extraintestinal manifestations of inflammatory bowel disease/coexisting conditions
(e.g. cholangitis, uveitis, skin complaints, arthritis, synovitis).

▪ Medication history (see Box 25.1).

▪ Comprehensive social history:

▪ recreational drugs

▪ alcohol and smoking

CHAPTER 25

226 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ accommodation

▪ travel history

▪ sexual history.

▪ Issues with purchasing or accessing food/any financial constraints.

▪ Problems with physical or mental capacity to coordinate or make meals.
Examination

▪ General: ill‐fitting clothes.

▪ Mouth: candidiasis, stomatitis (iron or B vitamin deficiencies).

▪ Neck for goitre (hyperthyroidism).

▪ Lymphadenopathy: neck nodes, axillae, groin (malignancy or tuberculosis).

▪ Cardiovascular and respiratory examination (evidence of chronic pulmonary disease
or cardiac failure).

▪ Abdominal examination:

▪ abdominal masses

▪ distension/presence of ascites

▪ tenderness

▪ hepatomegaly, splenomegaly

▪ extraintestinal manifestations of inflammatory bowel disease (e.g. pyoderma gan-
grenosum, erythema nodosum).

▪ Neurological examination: features of Parkinson’s disease/Lewy body dementia, tar-
dive dyskinesia, signs of bulbar/pseudobulbar palsy (motor neurone disease), sensory, motor or speech deficit to suggest previous stroke, peripheral neuropathy (malignant paraneoplastic syndromes, e.g. small cell lung cancer). Screening assessment of cogni- tion if concerns regarding dementia.
Investigations

▪ Blood tests:

▪ full blood count

▪ urea and creatinine

▪ electrolytes (sodium, potassium, calcium, magnesium, phosphate, especially if con-
cerns regarding refeeding syndrome)

▪ haematinics including B12, folate, iron studies

▪ liver function tests

▪ thyroid function tests

▪ C‐reactive protein

▪ fasting glucose, HbA1c

▪ HIV/hepatitis B and C serology

▪ if concerns over Addison’s, consider a 9 a.m. cortisol with or without proceed-
ing to short synacthen test (discussion with general medical colleagues first is
recommended).

▪ Urinalysis (haematuria, glucose).

▪ Chest X‐ray if concerns regarding underlying chest pathology.

CHAPTER 25

Unintentional Weight Loss 227

MANAGEMENT

Management will depend on the underlying cause.

▪ Correction of endocrine abnormalities, e.g. thyroid function, management of diabe- tes, steroid replacement in Addison’s disease.

▪ Identification and management of malignancy.

▪ Optimisation and management of underlying chronic illnesses and psychiatric
conditions.

▪ Assessment and management of substance abuse and its sequelae.
General points

▪ Dietician review (inpatient or community) should be considered for accurate dietetic assessment and advice about the optimal dietary management.

▪ Refeeding syndrome may occur with rapid correction of weight loss, especially if more than 10% or body weight has been lost. It results from rapid flux of electrolytes into cells from the circulation and may cause profound biochemical derangements including hypokalaemia, hypophosphataemia, hypomagnesaemia, and occasionally hypocalcaemia. Regular monitoring of electrolytes and blood sugars may be required under the guidance of a dietician to recognise and avoid this.

▪ Thiamine (vitamin B1) deficiency may also be present in malnourished individuals. If commencing feeding in a thiamine‐depleted patient, further depletion could result in Wernicke’s encephalopathy and Korsakov’s syndrome. Oral supplementa- tion with thiamine 300 mg once daily and one to two Vitamin B Compound Strong tablets three times daily may be indicated. Parenteral delivery of B vitamins may be required in patients with inadequate enteral absorption of thiamine (see Chapter 24).

▪ Control of symptoms due to underlying conditions (e.g. nausea and vomiting, consti- pation, and breathlessness) can help significantly in promoting oral intake.

▪ If there is any concern over safety of swallowing, then a speech and language therapy assessment should be obtained.
References

1. Wong CJ. Involuntary weight loss. Med Clin North Am 2014;98:625–643.

2. Malhi GS, Mann JJ. Depression. Lancet 2018;392:2299–2312.

3. Moriguti JC, Moriguti EK, Ferriolli E, et al. Involuntary weight loss in elderly individuals: assessment and treatment. Sao Paulo Med J
2001;119:72–77.

4. Sahyoun NR, Serdula MK, Galuska DA, et al. The epidemiology of recent involuntary weight loss in the United States population. J Nutr
Health Aging 2004;8:510–517.

5. Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42:583–585.

6. Hernández JL, Riancho JA, Matorras P, González‐Macías J. Clinical evaluation for cancer in patients with involuntary weight loss without
specific symptoms. Am J Med 2003;114:631–637.

7. Thompson MP, Morris LK. Unexplained weight loss in the ambulatory elderly. J Am Geriatr Soc 1991;39:497–500.

8. Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr 2008;27:793–799.

9. Kotler DP. Cachexia. Ann Intern Med 2000;133:622–634.

10. Graul AI, Stringer M, Sorbera L. Cachexia. Drugs Today (Barc) 2016;52:519–529.

11. Beaudart C, McCloskey E, Bruyère O, et al. Sarcopenia in daily practice: assessment and management. BMC Geriatr 2016;16:170.

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228 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

12. Haga T, Ito K, Ono M, et al. Underweight and hypoalbuminemia as risk indicators for mortality among psychiatric patients with medical comorbidities. Psychiatry Clin Neurosci 2017;71:807–812.

13. Jeynes KD, Gibson EL. The importance of nutrition in aiding recovery from substance use disorders: a review. Drug Alcohol Depend 2017;179:229–239.

14. Haga T, Ito K, Sakashita K, et al. Risk factors for death from psychiatric hospital‐acquired pneumonia. Intern Med 2018;57:2473–2478.

15. Kvamme J‐M, Grønli O, Florholmen J, Jacobsen BK. Risk of malnutrition is associated with mental health symptoms in community living
elderly men and women: the Tromsø Study. BMC Psychiatry 2011;11:112.

16. Soysal P, Isik AT, Stubbs B, et al. Acetylcholinesterase inhibitors are associated with weight loss in older people with dementia: a systematic
review and meta‐analysis. J Neurol Neurosurg Psychiatry 2016;87:1368–1374.

17. Mikkelsen EJ, Albert LG, Upadhyaya A. Neuroleptic‐withdrawal cachexia. N Engl J Med 1988;318:929.

18. Parkes CM. Bereavement in adult life. BMJ 1998;316:856–859.

19. Howard LM, Barley EA, Davies E, et al. Cancer diagnosis in people with severe mental illness: practical and ethical issues. Lancet Oncol
2010;11:797–804.

20. Zhu R, Liu Z, Jiao R, et al. Updates on the pathogenesis of advanced lung cancer‐induced cachexia. Thorac Cancer 2019;10:8–16.

CHAPTER 25

Chapter 26

Dry Mouth

Enrico D’Ambrosio, Andrea Falsetti, Stephen Challacombe

Xerostomia is defined as the subjective sensation of oral dryness, which a patient will typically describe as a dry mouth [1]. Hyposalivation is defined as the objective reduc- tion in the volume of saliva secreted measured with sialometry [2]. Approximately 20% of the adult population complain of xerostomia, though not all have salivary gland hypofunction [3]. Common causes of dry mouth are summarised in Box 26.1 [4–6]. Specific considerations for patients with a psychiatric disorder include a psychiatric medication review, with attention to drugs with a marked anticholinergic action (see http://www.medichec.com). Such drugs typically reduce salivary flow by approximately 30%, and their effects are additive [7]. Thus, any patient on two or more xerostomic medications (with a resultant reduction in salivary flow of up to 60%) may experience a significant degree of hyposalivation and resultant dry mouth [7]. While patients with depression may present with medication‐induced salivary hypofunction, depression is itself independently associated with dry mouth [5]. Chronic systemic conditions associ- ated with xerostomia (e.g. Sjögren’s syndrome and systemic lupus erythematosus) may be associated with psychiatric comorbidity. Parotid gland hypertrophy as a consequence of bulimia nervosa may result in impaired salivary secretion.

Box 26.1 Common causes of dry mouth

Medication (non‐psychiatric)

Xerostomia

■ Beta‐blockers

▪ Bronchodilators (e.g. tiotropium)

▪ Calcium channel blockers (e.g. verapamil)

▪ Muscle relaxants (e.g. baclofen)

▪ Ophthalmologic drugs (e.g. brimonidine)

▪ Opiates
Hyposalivation

▪ Anticholinergics (e.g. atropine)

▪ Antihypertensives (e.g. clonidine)

▪ Anti‐Parkinsonism drugs (e.g. rotigotine)

▪ Bisphosphonates (e.g. alendronate)

▪ Diuretics (e.g. thiazides)
Medication (psychiatric)
Xerostomia

▪ Anticonvulsants (e.g. gabapentin)

▪ Benzodiazepines (e.g. lorazepam)

▪ Benzodiazepine‐related drugs (e.g. zolpidem)
Hyposalivation

▪ Antidepressants (e.g. tricyclics)

▪ Antipsychotics (e.g. quetiapine)

▪ Mood stabilisers (e.g. lithium)
Recreational drugs
Hyposalivation

▪ Cannabis

▪ Methamphetamine (e.g. MDMA)

▪ Cocaine
Systemic disorders
Xerostomia

▪ Burning mouth syndrome

▪ Fibromyalgia

▪ Chronic renal failure

▪ Endocrine disorders (e.g. diabetes mellitus)
Hyposalivation

■ Chronic inflammatory disorders (e.g. Sjögren’s syndrome) Effects of treatment

Hyposalivation

■ Radiotherapy of head and neck cancer

230 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

CHAPTER 26

Dry Mouth 231

Other

Xerostomia

▪ Ageing

▪ Alcohol

▪ Mouth breathing

▪ Tobacco

▪ Oral infection (e.g. candidiasis/gingivitis)
Psychiatric disorders
Hyposalivation

▪ Eating disorders

▪ Autonomic activation associated with panic, anxiety and depression

DIAGNOSTIC PRINCIPLES

History and examination

After establishing the duration and severity of xerostomia, history should be directed to establish potential underlying causes. For example, nasal obstruction resulting in mouth breathing can cause dry mouth, similarly poor fluid intake and poor self‐care resulting in dehydration. A past medical history for rheumatoid conditions may raise suspicion for Sjögren’s syndrome. Take a thorough medication history, focusing on the drugs listed in Box 26.1 and calculate the anticholinergic burden using http://www.medichec. com. A mental state examination may identify comorbid anxiety or depression result- ing in autonomic hyperactivity and dry mouth. Examine the patient’s mouth for evi- dence of candidiasis or gingivitis. Examine under the tongue to check for masses blocking salivary excretion. Check the parotid glands for swelling. Investigations will be guided by the identification of any potential underlying conditions, although gener- ally diagnosis is a clinical one. The Clinical Oral Dryness Score (CODS) is a useful scale used to grade oral dryness [8]. The scoring system includes three levels of severity (mild, moderate, and severe dryness) and can guide the clinician in the choice of treatment [1].

MANAGEMENT

Reversible causes such as dehydration, infection, and nasal congestion leading to mouth breathing should be addressed, alongside any psychiatric comorbidity that may be leading to autonomic overactivity. Psychiatric medications may be responsible for hyposalivation, although the risk profile with different drugs is variable [9–13]. Nevertheless, rationalising

CHAPTER 26

232 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

pharmacotherapy may be key to providing symptomatic relief. In patients who are well established on an efficacious antipsychotic or antidepressant regimen and where there is a reluctance to change medication, consider dose reduction.

Non‐pharmacological therapy for dry mouth may involve lifestyle modification, such as avoiding alcohol and caffeine [14]. Betel nut, citric acid, and red pepper can stimu- late salivary secretion [2]. Regular sips of water during meals can facilitate chewing and swallowing. Saliva substitutes are available, including gums, gels, and sprays. Patients can also try natural lubricants, namely two drops of edible oil in the mouth every hour [1]. Dry mouth is associated with dental caries, so referral to a dentist may be required.

Sialogogic drugs are medications designed to stimulate salivary secretion. Pilocarpine and cevimeline (the latter not licensed in the UK) have been shown to be efficient in Sjögren’s syndrome; however, their role in treating dry mouth in patients on psychiatric medications has not been well explored [15] and side effects, especially with pilocarpine, can be considerable. Bethanechol has been studied in the treatment of dry mouth in patients taking antidepressant and antipsychotic drugs resulting in symptomatic improvement [2,16,17].

Pilocarpine is a non‐selective muscarinic agonist with a relatively high affinity for muscarinic receptors in the central nervous system. It is effective and well tolerated, administered at a dose of 5 mg four times a day [18]. It is contraindicated in patients with asthma, hypertension, and glaucoma. Cevimeline, a specific agonist of the M3 muscarinic receptor, is prescribed at a dose of 30 mg three times daily [19]. Because of its high selectivity, the use of cevimeline is associated with fewer neurological, cardiac, and gastrointestinal side effects when compared with pilocarpine. Bethanechol is a car- bamic ester of β‐methylcholine resistant to cholinesterase with a long duration of action that stimulates M3 receptors. It is effective at a dose of 25 mg three times daily [20]. It can cause lacrimation, frequent urination, diarrhoea, and nausea.

References

1. Piali D, Challacombe SJ. Dry mouth and clinical oral dryness scoring systems. Prim Dent J 2016;5:77–79.
2. Miranda‐Rius J, Brunet‐Llobet L, Lahor‐Soler E, Farré M. Salivary secretory disorders, inducing drugs, and clinical management. Int J Med

Sci 2015;12:811–824.

3. Furness S, Worthington HV, Bryan G, et al. Interventions for the management of dry mouth: topical therapies. Cochrane Database Syst Rev
2011;(12):CD008934.

4. Ying Joanna ND, Thomson WM. Dry mouth: an overview. Singapore Dent J 2015;36:12–17.

5. Saleh J, Figueiredo MAZ, Cherubini K, Salum FG. Salivary hypofunction: an update on aetiology, diagnosis and therapeutics. Arch Oral Biol
2015;60(2):242–255.

6. von Bültzingslöwen I, Sollecito TP, Fox PC, et al. Salivary dysfunction associated with systemic diseases: systematic review and clinical manage-
ment recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(Suppl):S57.e1–e15.

7. Singh ML, Papas A. Oral implications of polypharmacy in the elderly. Dent Clin North Am 2014;58(4):783–796.

8. Osailan SM, Pramanik R, Shirlaw P, et al. Clinical assessment of oral dryness: development of a scoring system related to salivary flow and
mucosal wetness. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114(5):597–603.

9. Wolff A, Joshi RK, Ekström J, et al A guide to medications inducing salivary gland dysfunction, xerostomia, and subjective sialor-
rhea: a systematic review sponsored by the World Workshop on Oral Medicine VI. Drugs R D 2017;17:1–28.

10. Marques LO, Lima MS, Soares BG. Trifluoperazine for schizophrenia. Cochrane Database Syst Rev 2004;(1):CD003545.

11. Kreinin A, Epshtein S, Sheinkman A, Tell E. Sulpiride addition for the treatment of clozapine‐induced hypersalivation: preliminary
study. Isr J Psychiatry Relat Sci 2005;42(1):61–63.

12. Lancaster SG, Gonzalez JP. Lofepramine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in
depressive illness. Drugs 1989;37(2):123–140.

CHAPTER 26

Dry Mouth 233

13. Szabadi E, Tavernor S. Hypo‐ and hypersalivation induced by psychoactive drugs: Incidence, mechanisms and therapeutic implications. CNS Drugs 1999;11:449–466.

14. Villa A, Connell CL, Abati S. Diagnosis and management of xerostomia and hyposalivation. Ther Clin Risk Manag 2014;11:45–51.

15. Swager LWM, Morgan SK. Psychotropic‐induced dry mouth: don’t overlook this potentially serious side effect. Curr Psychiatry
2011;10(12):54–58.

16. Everett HC. The use of bethanechol chloride with tricyclic antidepressants. Am J Psychiatry 1975;132(11):1202–1204.

17. Schubert DSP. Use of bethanechol chloride with phenothiazines: a case report. Am J Psychiatry 1979;136(1):110–111.

18. Wu CH, Hsieh SC, Lee KL, et al. Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sjögren’s sydrome in Taiwan: a
double‐blind, placebo‐controlled trial. J Formos Med Assoc 2006;105(10):796–803.

19. Leung KCM, McMillan AS, Wong MC, et al. The efficacy of cevimeline hydrochloride in the treatment of xerostomia in Sjögren’s syndrome
in southern Chinese patients: a randomised double‐blind, placebo‐controlled crossover study. Clin Rheumatol 2008;27(4):429–436.

20. Kavitha M, Mubeen K, Vijaylakshmi KR. A study on evaluation of efficacy of bethanechol in the management of chemoradiation‐induced
xerostomia in oral cancer patients. J Oral Maxillofac Pathol 2017;21:459–460.

CHAPTER 26

Chapter 27

Hypersalivation

Enrico D’Ambrosio, Andrea Falsetti, Toby Pillinger, Stephen Challacombe

Hypersalivation, sialorrhoea, ptyalism, and excessive drooling are interchangeable terms to describe excess production or decreased clearance of saliva from the mouth. Unstimulated whole saliva (UWS) flow rates have wide interindividual variability [1]. Although the diagnosis is mainly based on symptoms, a UWS rate higher than 0.8 mL/ min measured with sialometry is indicative of hypersalivation [2]. Common causes of hypersalivation are summarised in Box 27.1 [3–5]. The mechanisms by which different drugs induce hypersalivation are multiple, and for some agents poorly defined. They include direct agonism of muscarinic acetylcholine receptors (e.g. clozapine), indirect muscarinic agonism via acetylcholinesterase inhibition (e.g. rivastigmine), blockade of α2‐adrenergic receptors (e.g. clozapine), dopamine antagonism leading to extrapyrami- dal side effects such as orofacial dyskinesia and thus impaired clearance of saliva (all antipsychotics), and sedation leading to reduced clearance of saliva [3]. Hypersalivation is not only socially embarrassing and affects quality of life but may also increase risk of choking and aspiration pneumonia.

DIAGNOSTIC PRINCIPLES History and examination

Enquire about episodes of hypersalivation during the day and at night, for example waking up with a choking sensation, or noticing that the pillow is wet in the morning. A comprehensive drug history is recommended (see Box 27.1), although in the psychi- atric population the causative agent may be clear (e.g. hypersalivation in a patient recently started on clozapine). The age of the patient should be considered, as elderly patients may have altered positioning of the head and neck and/or dysphagia that

Box 27.1 Common causes of hypersalivation Medication (non‐psychiatric)

▪ Adrenergic antagonists (e.g. ephedrine)

▪ Antibiotics (e.g. doxycycline)

▪ Direct cholinergics (e.g. pilocarpine)

▪ Poisons and toxins (e.g. mercury, insecticides)
Medication (psychiatric)

▪ Acetylcholinesterase inhibitors (e.g. rivastigmine)

▪ Anticonvulsants

▪ Antipsychotics

▪ Stimulants (e.g. modafinil)
Recreational drug

■ Phencyclidine (PCP) ■ Ketamine

Increased production

▪ Gastro‐oesophageal reflux disease

▪ Infection (e.g. rabies)

▪ Oral inflammation

▪ Pregnancy
Impaired clearance

▪ Anatomical (e.g. macroglossia)

▪ Neuromuscular/sensory dysfunction (e.g. cerebral palsy, Down’s syndrome, Parkinson’s disease,
amyotrophic lateral sclerosis, dysphagia)

▪ Positional problems of the head/neck (e.g. in elderly)

236 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

compromise clearance of saliva. If aetiology is unclear, enquire about past medical his- tory of gastro‐oesophageal reflux disease, any orthodontic complaints or historical interventions, and any past/recent dental/gingival infections. A social history should include quantification of alcohol and illicit drug use. Examination of the oral cavity may be indicated, examining for evidence of gingival or dental infection. In the absence of infection, further investigations are not indicated; diagnosis of hypersalivation is a clinical one.

MANAGEMENT

If a clear reversible cause for hypersalivation is identified, such as poor oral hygiene, then appropriate referral to the relevant specialist should be made (e.g. a dentist). Non‐ pharmacological management of hypersalivation includes using chewing gum to increase swallowing, sleeping with extra pillows at night (at least two) to reduce risk of aspiration, and placing a towel on the pillow to prevent soaking of clothes.

CHAPTER 27

Several classes of psychiatric medication cause salivary dysfunction (see Box 27.1), although the risk profile is variable [4]. Since the hypersalivatory effects of some treat- ments may be dose‐related, in patients who are well established on an efficacious antip- sychotic regimen and where there is a reluctance to change medication, consider dose reduction.

Clozapine‐induced hypersalivation is well recognised, generally occurring early on in treatment and likely to be dose‐related [6]. A number of pharmacological agents are available to treat sialorrhoea associated with clozapine (Table 27.1); the evidence base supporting different agents is variable and treatment often based on clinical experience. Hyoscine (scopolamine) hydrobromide is probably the most commonly prescribed first‐line agent for clozapine‐induced hypersalivation. A recent randomised controlled trial observed a reduction in the severity of hypersalivation with oral hyoscine hydro- bromide 0.3 mg once daily [7]. It is generally used as an oral tablet (0.3 mg up to three times daily; in cases of predominantly nocturnal hypersalivation, doses of up to 0.9 mg at night can be trialed, sucked or chewed for local effect) or as a transdermal patch 1.5 mg per 72 hours. Clinicians should monitor for emergence of anticholinergic side effects, and where patients are already experiencing such side effects (especially consti- pation), use of hyoscine or indeed any other anticholinergic agent is not recommended. In this setting, metoclopramide is a reasonable alternative; a recent double‐blind ran- domised controlled trial observed that metoclopramide (dose 10–30 mg/day) signifi- cantly improved clozapine‐induced nocturnal hypersalivation [8]. There is also some evidence from China to support the use of antihistamines (e.g. diphenhydramine) [9]. Since there is some evidence that amisulpride/sulpiride augmentation can improve psy- chotic symptoms in patients with only a partial response to clozapine [10,11], addition of amisulpride/sulpiride in such patients who also present with hypersalivation may be considered [12–15]. Use of atropine eye drops (as a mouthwash) and botulinum toxin injections into the parotid salivary glands is an attractive strategy owing to their local

Table 27.1 Drug treatments for hypersalivation.

Treatment

Antimuscarinics

Amitriptyline [17,18]

Atropine [19,20]

Benzatropine + terazosin [21]

Glycopyrrolate [22–25]

Dose

25–100 mg/day

1% eye drops: three drops up to t.d.s. (or just at night if predominantly nocturnal hypersalivation). Use as mouthwash: put three drops in small amount of water, swill, then spit out

2 mg/day (benzatropine) 2 mg/day (terazosin)

0.5–4 mg b.d.

Comments

Limited literature to support

Contraindicated in narrow‐angle glaucoma, bladder obstruction, and gastrointestinal motility disorders. Although significant systemic absorption unlikely when used as described, still monitor for anticholinergic side effects

Combination shown to be better than either drug alone. Be wary of hypotension with terazosin (α1 antagonist)

RCT‐level evidence to support its efficacy over placebo and biperiden (another anticholinergic agent)

(continued )

Hypersalivation 237

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238 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 27.1 (Continued)

Treatment

Hyoscine hydrobromide [7,26]

Ipratropium nasal spray (0.03 or 0.06%) [27–29]

Oxybutynin [30]

Pirenzepine [31,32]

Propantheline [33]

Dose

Oral up to 300 μg t.d.s. or transdermal patch (1.5 mg/72 h). If predominant nocturnal hypersalivation can trial up to 900 μg at night. Suck tablets to obtain local effect

Two sprays 0.06% sublingually three times daily or one spray 0.03% intranasally daily

5–10 mg/day

50–150 mg/day

7.5 mg/day

Comments

Competitive muscarinic antagonist. Contraindicated in patients with severe constipation and paralytic ileus, pyloric stenosis, prostatic hyperplasia, and glaucoma. As with all anticholinergic agents, not advised in patients already experiencing anticholinergic side effects (e.g. constipation)

Non‐selective muscarinic receptor antagonist used in respiratory diseases. Limited evidence in literature including a negative RCT [29]. However, minimal side effects mean that a trial may be considered

Anticholinergic agent used for the treatment of urinary incontinence and overactive bladder syndrome. Very limited evidence (single case report) [30]

Anticholinergic with M1–M4 receptor antagonist action that does not cross the blood–brain barrier. The only RCT examining its efficacy was negative [32]

One positive and one negative RCT. Monitor for constipation

Presynaptic partial α2 agonist used in hypertension treatment. Addition to clozapine can lead to a worsening of postural hypotension. May exacerbate depression and psychosis. Limited data to support use

Presynaptic α2 agonist structurally similar to clonidine. Single case report. Can cause postural hypotension

Presynaptic α2 agonist used to treat hypertension and opioid withdrawal. Single case report. May exacerbate depression and psychosis

RCT level of evidence of efficacy versus placebo and moclobemide

Evidence base from treatment of hypersalivation associated with neurological disorders. Case‐report level of evidence in context of clozapine use

Noradrenaline/dopamine receptor antagonist antidepressant also used in smoking cessation. Lowers seizure threshold. Only single case report to support use

Supported by double‐blind placebo‐controlled RCT; use is generally well tolerated

Effective in a small open label study

Evidence of efficacy from a small RCT and supported by a Cochrane review

CHAPTER 27

Adrenoceptor agonists

Clonidine [34]

Guanfacine [35]

Lofexidine [36]

Others

Amisulpride [12,13]

Botulinum toxin [37,38]

Bupropion [39]

Metoclopramide [8]

Moclobemide [40]

Sulpiride [14,15]

0.1–0.2 mg patch weekly or oral 0.1 mg/day

1 mg/day

0.2 mg twice daily

100–400 mg/day

Bilateral parotid gland injections, 150 IU into each gland

100–150 mg/day

10–30 mg/day

150–300 mg/day

RCT, randomised controlled trial.

Hypersalivation 239

CLOZAPINE-INDUCED HYPERSALIVATION

• Clozapine dose reduction

• Lifestyle advice (e.g. sleep with at
least two pillows

Ongoing hypersalivation

Patient experiencing anticholinergic side effects? e.g. constipation

Yes

• Hyoscine hydrobromide 300 μg three times a day or up to 900 μg at night if predominantly nocturnal hypersalivation

• Ensure tablets are sucked (local effect)

• Monitor for anticholinergic side effects

Ongoing hypersalivation

Oral metoclopramide 10 mg up to three times a day (and stop hyoscine hydrobromide if ineffective)

Ongoing hypersalivation

• Stop metoclopramide if ineffective

• If ongoing psychotic symptoms, add
amisulpride 100–400 mg/day

• Add 1% atropine eye drops up to three drops up to three times a day (swill with
small amount of water then spit out)

Figure 27.1 Suggested treatment algorithm for clozapine‐induced hypersalivation.

action, thus avoiding/reducing the risk of systemic side effects. However, atropine use should be avoided (or at least supervised) in the context of chaotic or self‐harming behavior (i.e. where there is risk of overdose) [16] and it is recognised that there may be logistical barriers to arranging botulinum toxin injections (e.g. requiring a referral to interventional radiology). A suggested management algorithm for clozapine‐induced hypersalivation is presented in Figure 27.1; however, trials of various agents may be required.

References

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2. Edgar WM. Saliva and dental‐health: clinical implications of saliva. Report of a consensus meeting. Br Dent J 1990;169(3–4):96–98.

3. Miranda‐Rius J, Brunet‐Llobet L, Lahor‐Soler E, Farre M. Salivary secretory disorders, inducing drugs, and clinical management. Int J Med
Sci 2015;12(10):811–824.

4. Wolff A, Joshi RK, Ekstrom J, et al. A guide to medications inducing salivary gland dysfunction, xerostomia, and subjective sialorrhea: a
systematic review sponsored by the World Workshop on Oral Medicine VI. Drugs R D 2017;17(1):1–28.

5. von Bultzingslöwen I, Sollecito TP, Fox PC, et al. Salivary dysfunction associated with systemic diseases: systematic review and clinical man-
agement recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(Suppl):S57.e1–e15.

Consider referral for parotid salivary gland botulinum toxin injection

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240 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

6. Praharaj SK, Arora M, Gandotra S. Clozapine‐induced sialorrhea: pathophysiology and management strategies. Psychopharmacology 2006;185(3):265–273.

7. Segev A, Evans A, Hodsoll J, et al. Hyoscine for clozapine‐induced hypersalivation: a double‐blind, randomized, placebo‐controlled cross‐ over trial. Int Clin Psychopharmacol 2019;34(2):101–107.

8. Kreinin A, Miodownik C, Mirkin V, et al. Double‐blind, randomized, placebo‐controlled trial of metoclopramide for hypersalivation associ- ated with clozapine. J Clin Psychopharmacol 2016;36(3):200–205.

9. Chen SY, Ravindran G, Zhang Q, et al. Treatment strategies for clozapine‐induced sialorrhea: a systematic review and meta‐analysis. CNS Drugs 2019;33(3):225–238.

10. Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double‐ blind, placebo‐controlled study. Br J Psychiatry 1997;171:569–573.

11. Munro J, Matthiasson P, Osborne S, et al. Amisulpride augmentation of clozapine: an open non‐randomized study in patients with schizo- phrenia partially responsive to clozapine. Acta Psychiatr Scand 2004;110(4):292–298.

12. Kreinin A, Miodownik C, Sokolik S, et al. Amisulpride versus moclobemide in treatment of clozapine‐induced hypersalivation. World J Biol Psychiatry 2011;12(8):620–626.

13. Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine‐induced hypersalivation in schizophrenia patients: a randomized, double‐blind, placebo‐controlled cross‐over study. Int Clin Psychopharmacol 2006;21(2):99–103.

14. Kreinin A, Epshtein S, Sheinkman A, Tell E. Sulpiride addition for the treatment of clozapine‐induced hypersalivation: preliminary study. Isr J Psychiatry Relat Sci 2005;42(1):61–63.

15. Wang JJ, Omori IM, Fenton M, Soares B. Sulpiride augmentation for schizophrenia. Schizophr Bull 2010;36(2):229–230.

16. Stellpflug SJ, Cole JB, Isaacson BA, et al. Massive atropine eye drop ingestion treated with high‐dose physostigmine to avoid intubation. West
J Emerg Med 2012;13(1):77–79.

17. Copp PJ, Lament R, Tennent TG. Amitriptyline in clozapine‐induced sialorrhoea. Br J Psychiatry 1991;159:166.

18. Praharaj SK, Arora M. Amitriptyline for clozapine‐induced nocturnal enuresis and sialorrhoea. Br J Clin Pharmacol 2007;63(1):128–129.

19. Antonello C, Tessier P. Clozapine and sialorrhea: a new intervention for this bothersome and potentially dangerous side effect. J Psychiatry
Neurosci 1999;24(3):250.

20. Van der Poorten T, De Hert M. The sublingual use of atropine in the treatment of clozapine‐induced sialorrhea: a systematic review. Clin Case
Rep 2019;7(11):2108–2113.

21. Reinstein MJ, Sirotovskaya LA, Chasanov MA, et al. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of
hypersalivation secondary to clozapine. Clin Drug Invest 1999;17(2):97–102.

22. Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine‐induced sialorrhea. Ann Pharmacother 2011;45(5):667–675.

23. Blissit KT, Tillery E, Latham C, Pacheco‐Perez J. Glycopyrrolate for treatment of clozapine‐induced sialorrhea in adults. Am J Health Syst
Pharm 2014;71(15):1282–1287.

24. Qurashi I, Chu S, Husain N, et al. Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation
induced by clozapine (GOTHIC1): study protocol for a randomised controlled feasibility study. Trials 2016;17(1):553.

25. Robb AS, Lee RH, Cooper EB, et al. Glycopyrrolate for treatment of clozapine‐induced sialorrhea in three adolescents. J Child Adolesc
Psychopharmacol 2008;18(1):99–107.

26. Gaftanyuk O, Trestman RL. Scopolamine patch for clozapine‐induced sialorrhea. Psychiatr Serv 2004;55(3):318.

27. Calderon J, Rubin E, Sobota WL. Potential use of ipatropium bromide for the treatment of clozapine‐induced hypersalivation: a preliminary
report. Int Clin Psychopharmacol 2000;15(1):49–52.

28. Freudenreich O, Beebe M, Goff DC. Clozapine‐induced sialorrhea treated with sublingual ipratropium spray: a case series. J Clin
Psychopharmacol 2004;24(1):98–100.

29. Sockalingam S, Shammi C, Remington G. Treatment of clozapine‐induced hypersalivation with ipratropium bromide: a randomized, double‐
blind, placebo‐controlled crossover study. J Clin Psychiatry 2009;70(8):1114–1119.

30. Leung JG, Puri NV, Jacobson MJ. Immediate‐release oxybutynin for the treatment of clozapine‐induced sialorrhea. Ann Pharmacother
2011;45(9):e45.

31. Fritze J, Elliger T. Pirenzepine for clozapine‐induced hypersalivation. Lancet 1995;346(8981):1034.

32. Bai YM, Lin CC, Chen JY, Liu WC. Therapeutic effect of pirenzepine for clozapine‐induced hypersalivation: a randomized, double‐blind,
placebo‐controlled, cross‐over study. J Clin Psychopharmacol 2001;21(6):608–611.

33. Syed Sheriff RJ, Au K, Cahill C, et al. Pharmacological interventions for clozapine‐induced hypersalivation. Schizophr Bull
2008;34(4):611–612.

34. Grabowski J. Clonidine treatment of clozapine‐induced hypersalivation. J Clin Psychopharmacol 1992;12(1):69–70.

35. Webber MA, Szwast SJ, Steadman TM, et al. Guanfacine treatment of clozapine‐induced sialorrhea. J Clin Psychopharmacol
2004;24(6):675–676.

36. Corrigan FM, MacDonald S, Reynolds GP. Clozapine‐induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 1995;167(3):412.

37. Kahl KG, Hagenah J, Zapf S, et al. Botulinum toxin as an effective treatment of clozapine‐induced hypersalivation. Psychopharmacology
2004;173(1–2):229–230.

38. Steinlechner S, Klein C, Moser A, et al. Botulinum toxin B as an effective and safe treatment for neuroleptic‐induced sialorrhea.
Psychopharmacology 2010;207(4):593–597.

39. Stern RG, Bellucci D, Cursi‐Vogel N, et al. Clozapine‐induced sialorrhea alleviated by bupropion: a case report. Prog Neuropsychopharmacol
Biol Psychiatry 2009;33(8):1578–1580.

40. Kreinin A, Miodownik C, Libov I, et al. Moclobemide treatment of clozapine‐induced hypersalivation: pilot open study. Clin Neuropharmacol
2009;32(3):151–153.

CHAPTER 27

Chapter 28

Constipation

John Lally, Toby Pillinger, Kalliopi Vallianatou, Immo Weichert

Constipation is defined as infrequent and/or difficult defecation, characterised by excessive straining, hard stools (see the Bristol Stool Form Scale in Figure 28.1) [1], the sensation of incomplete evacuation, or the passage of fewer than three stools per week [2]. Constipation is either idiopathic or due to secondary causes (Box 28.1). Chronic idiopathic constipation has a pooled global prevalence of 14% [3]. There is increased

Figure 28.1 The Bristol Stool Form Scale. Source: adapted from Lewis and Heaton [1].

Type 1 Type 2 Type 3 Type 4 Type 5 Type 6 Type 7

Separate hard lumps, like nuts (hard to pass) Sausage-shaped but lumpy
Like a sausage but with cracks on the surface Like a sausage or snake, smooth and soft Soft blobs with clear-cut edges

Fluffy pieces with ragged edges, a mushy stool Water, no solid pieces. Entirely liquid

Box 28.1 Secondary causes of constipation

▪ Hypothyroidism (see Chapter 12)

▪ Electrolyte abnormalities (e.g. hypercalcaemia, hypokalaemia)

▪ Gastrointestinal obstruction (e.g. strictures or malignancy)

▪ Central neurological disorders (e.g. Parkinson’s disease, multiple sclerosis)

▪ Peripheral neurological disorders (e.g. diabetic autonomic neuropathy)

▪ Irritable bowel syndrome (may be associated with constipation)

▪ Previous abdominal surgery (adhesions)

▪ Inflammatory bowel disease (strictures)

▪ Anorexia nervosa

▪ Pregnancy

▪ Learning disability

▪ Medication (see Box 28.2)

Box 28.2 Medications that can cause constipation

▪ Some antihypertensive drugs, e.g. calcium channel blockers (reduce smooth muscle contractility)

▪ Any drugs with anticholinergic effects: antispasmodics, some antidepressants (tricyclics, paroxe- tine, reboxetine), anti‐Parkinsonian drugs, older sedating antihistamines (e.g. chlorphenamine), antipsychotics (especially clozapine). Venlafaxine and monoamine oxidase inhibitors such as
phenelzine and isocarboxazid also commonly cause constipation

▪ Serotonin antagonists (e.g. ondansetron)

▪ Diuretics

▪ Opioids

▪ Oral iron supplementation

▪ Calcium/aluminium antacids

242 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

prevalence in the elderly, females, and those with a sedentary lifestyle [4]. Risk of consti pation is increased in some psychiatric patient groups, in particular patients with schizophrenia and those with learning difficulties [5–7]. This can be related to psychi atric medication, decreased physical activity, and dietary factors [5,7].

The neural and hormonal control of colonic peristalsis is complex. Simplistically, serotonin, produced by enterochromaffin cells in response to gut wall distension by a food/stool bolus, is the major orchestrator of gut peristalsis and prompts enteric nerves to produce neurotransmitters such as acetylcholine and nitric oxide that respectively contract and relax gut wall smooth muscle in a coordinated fashion. Various drugs cause constipation by disrupting these neurochemical pathways (Box 28.2). Many psychiatric medications list constipation as a potential side effect, although for some agents this occurrence will be rare. Psychotropics where constipation is common include antidepressants (e.g. tricyclic antidepressants, paroxetine, and reboxetine) and antipsychotics with strong anticholinergic effects. There is also evidence that some ‘first‐generation’ antipsychotics (e.g. haloperidol, flupentixol, and pimozide) increase risk of constipation despite not having strong anticholinergic effects [5]; this is poten tially related to concurrently prescribed anticholinergic medication to manage extrap yramidal side effects.

CHAPTER 28

Of all the antipsychotics, clozapine is associated with the highest risk of causing con stipation; indeed, patients are three times more likely to be constipated when treated with clozapine compared with other antipsychotics [8]. Clozapine‐treated patients have, as a group, colonic transit times that are four times longer than expected in the general adult population [9], with constipation affecting approximately one‐third of patients [8]. This is believed to be secondary to a combination of anticholinergic, anti‐ histaminergic, and anti‐serotonergic properties of the drug, alongside its sedative effects and resultant sedentary behaviour which in itself increases risk of constipation [10]. Untreated constipation can lead to severe complications, including faecal impaction, colonic obstruction, bowel ischaemia and necrosis, perforation, and sepsis. The preva lence of life‐threatening constipation with clozapine is 0.3%, and case fatality as high as 28% [11]. A Danish nationwide study reported a 0.8% incidence of hospital admission as a consequence of ileus in clozapine‐treated patients [12]. Thus, constipation repre sents a greater threat to the physical health of patients who take clozapine compared with the risk of blood dyscrasias. Despite this, there is evidence that management of clozapine‐induced constipation is poor in certain patient groups, in particular men [13].

DIAGNOSTIC PRINCIPLES

Through history and examination one should aim to determine the severity of constipa tion and identify any secondary causes. If the patient presents with severe abdominal pain, vomiting, fever, tachycardia, or hypotension, have a low threshold for transferring care to emergency services (see Chapters 72 and 88). When in doubt, discuss with gen eral surgical/medical colleagues.

History

In the non‐acute setting, a directed history should cover the following.

. 1 History of presenting complaint.

. a Define bowel habits prior to onset of constipation.

. b Define stool frequency, consistency, and size (see Figure 28.1). Note that diarrhoea
may indicate constipation with overflow. On an inpatient ward, consider use of a
stool chart.

. c Recent change in bowel habit may be a feature of gastrointestinal malignancy.
Screen for other associated ‘red flag’ signs, symptoms, and investigation findings such as tenesmus (feeling of incomplete defecation), weight loss, gastrointestinal bleeding, and anaemia (see Chapters 15, 20, and 25 for more details on anaemia, gastrointestinal bleeding, and unexplained weight loss, respectively).

. d Document diet (including fluid intake) and amount of regular physical activity the patient engages in.

. 2 Past medical history: screen for disorders documented in Box 28.1.

. 3 Drug history: note laxative use and any potentially causative agents documented in
Box 28.2.

Constipation 243

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244 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Examination

Examination may be entirely normal. During abdominal examination, high‐pitched ‘tinkling’ bowel sounds on auscultation may indicate obstruction. Digital rectal exam ination may be performed to identify a faecally loaded rectum, masses, abnormal sphincter function (ask the patient to squeeze during examination), blood in stool, or fissures/hemorrhoids.

Investigations

Investigations may not be required if symptoms are mild or there is a clear pharmaco logical precipitant. If there are concerns regarding a secondary cause of constipation (Box 28.1), the following tests should be considered:

. 1 full blood count (for anaemia or evidence of infection)

. 2 C‐reactive protein (infection)

. 3 urea and electrolytes and bone profile (for evidence of dehydration, hypokalaemia,
or hypercalcaemia)

. 4 HbA1c

. 5 thyroid function tests (unless already performed in the last eight weeks)

. 6 if there is abdominal pain in a woman of childbearing age, perform a pregnancy test.
A plain abdominal X‐ray may be indicated if obstruction is suspected; in a psychiat

ric setting this will require a referral to emergency or surgical services. Other investiga tions that may be performed by medical/surgical services in such a context include an erect chest X‐ray (examining for air under the diaphragm in the context of bowel per foration) and computed tomography (CT) of the abdomen. Chronic constipation may require endoscopic investigation (flexible sigmoidoscopy/colonoscopy) to examine for strictures or masses. Endoscopy or CT pneumocolon is certainly indicated if the patient presents with any red flags for gastrointestinal malignancy; in patients who may be too frail or will not tolerate endoscopy, CT of the colon is an alternative option.

MANAGEMENT

Non‐pharmacological and pharmacological management of constipation are described here. An algorithm describing an approach to clozapine‐induced gastrointestinal hypomotility is provided in Figure 28.2.

Non‐pharmacological

All patients with constipation should be provided with dietary advice [14]. This includes increasing water intake (2 L/day) and fibre intake (25–30 g/day). Dietary fibre may be in the form of fruit (where appropriate including the skin), vegetables, legumes, and bran. Note that the effects of a high‐fibre diet may be seen in a few days but can take weeks. A referral to a dietician may be considered. Patients should also be encouraged to increase physical activity levels (see Chapter 10).

CHAPTER 28

Constipation 245

Clozapine-related constipation

Acute abdomen? Evidence of sepsis?

Manage as per ABCDE approach Emergency transfer to medical/surgical colleagues

YES

Non-pharmacological advice

• Increase water intake (2 L/day)

• Increase fibre intake (25–30 g/day)

• Increase physical activity Rationalise pharmacotherapy

• Where possible discontinue other
anticholinergic drugs

• Use minimum effective dose of clozapine

Alongside non-pharmacological advice have a low-threshold to start laxatives

If still constipated

*an osmotic laxative (not lactulose) e.g, Movicol (one sachet twice daily) would be a reasonable alternative to docusate sodium

It bowel function satisfactory

Continue treatment and monitoring

If diarrhoea develops

Gradually reverse steps e.g, reduce then stop macrogol, reduce docusate and senna (e.g, by one tablet every 2 days) until bowel function satisfactory

Senna two tablets at night
and
Docusate sodium (initial dose: 100 mg t.d.s)*

Review within 48-hours If still constipated

Increase docusate sodium (maximum dose 500 mg/24 h) and senna: increase dose by one to two tablets every 2 days; higher doses can be used under medical supervision e.g. 30 mg nocte (do not exceed 30 mg in a single dose)

Rectal examination to examine for impaction

• If impacted, will likely require glycerine suppository
(e.g, 4 g glycerine) or a phosphate enema.

• If glycerine suppository/phosphate enema ineffective,
or if no evidence of impaction, add macrogol one sachet twice daily (higher doses can be used in faecal impacton, see Figure 28.1)

If still constipated

Discuss with medical/surgical colleagues who may guide increased dose of macrogol and frequency of enemas, or consider use of a secretagogue (e.g, linaclotide) or prucalopride.

Figure 28.2 Management algorithm for clozapine‐related constipation. Source: based on the Porirua protocol (Every‐Palmer et al. [9]).

CHAPTER 28

Box 28.3 Commonly used laxatives and their doses for treatment of idiopathic constipation in adults Bulk‐forming laxatives

Bulk‐forming laxatives increase faecal mass and soften stool to stimulate a bowel motion. Onset of action is usually 48–72 hours. Examples include:

▪ Isphaghula husk (e.g. Fybogel), one sachet in water twice daily.

▪ Methylcellulose, three to six tablets twice daily.
Osmotic laxatives
Osmotic laxatives draw water into the bowel to soften stool. Onset of action is usually 24–72 hours. Examples include:

▪ Lactulose, dose adjusted according to response to 30–50 mL three times daily.

▪ Polyethylene glycol (also known as macrogol and Movicol). Dose for chronic constipation (non‐ proprietary ‘full‐strength sachets’ or Movicol oral powder), one to three sachets daily. Dose for faecal impaction (non‐proprietary ‘full‐strength sachets’ or Movicol oral powder): four sachets on first day then increased in steps of two sachets daily up to a maximum of eight sachets daily (drink
daily dose in 6 hours).

246 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Pharmacological

Where possible, rationalise use of medications that may be contributing to constipa tion. For psychiatric medications this might involve switching an antidepressant or antipsychotic to a treatment with lower anticholinergic burden. For example, avoid tricyclic antidepressants and consider switching to a selective serotonin reuptake inhibi tor (apart from paroxetine), and consider switching antipsychotic treatment to agents such as aripiprazole, amisulpride, or risperidone. Where treatment cannot be switched, aim to use the minimum effective dose; this advice also applies to patients treated with clozapine. Liaise with primary care practitioners or medical colleagues if physical health medications are thought to be causative. For example, if oral iron supplementation is playing a role, consider if the patient is in fact iron deficient (and therefore needs sup plementation), reducing the frequency of dosing, switching to an alternative iron salt, or switching to intravenous iron supplementation.

Laxatives

There are four main types of laxative, described in Box 28.3. For idiopathic constipation it is generally recommended to start with a bulk‐forming laxative; note that this approach may be ineffective in clozapine‐induced constipation (i.e. slow transit constipation; see sec tion Special considerations with clozapine). If this is ineffective, an osmotic laxative can be tried instead of or as well as the bulk‐forming laxative. Persistent constipation may require a stimulant laxative. It is essential to remember that long‐term use of stimulant laxatives does not cause damage to, or impair functioning of, the bowel [15]. Persistent severe consti pation may require use of glycerine suppositories (which helps to break down obstruction, with onset of efficacy in minutes) or a phosphate enema (onset of efficacy in minutes).

CHAPTER 28

Constipation 247

Emollient laxatives

Emollient laxatives are stool softeners. Onset of action is usually 24–72 hours. Examples include:

■ Docusate sodium, up to 500 mg daily (as oral solution or capsule) in divided doses, adjusted according to response.

Stimulant laxatives

Stimulant laxatives stimulate the muscles of the gut lining and generally take 6–12 hours to work. Examples include:

▪ Senna, 7.5–15 mg once daily (usually at night) but higher doses may be prescribed under medical supervision (e.g. 45 mg in two to three divided doses; do not give more than 30 mg in a single dose).

▪ Bisacodyl, 10 mg once daily, increased up to 20 mg if necessary (usually at night).

▪ Sodium picosulfate, 5–10 mg once daily (usually at night).

Newer pharmacological agents

Lubiprostone (a prostaglandin E1 analogue) functions as an osmotic agent, acting on intestinal epithelial chloride channels to increase intestinal fluid secretion, and was previously licensed in the UK for management of chronic idiopathic constipation [16]. There is case‐level evidence of its efficacy in the management of ‘treatment‐resistant constipation’ associated with clozapine use [17]. However, lubiprostone (Amitiza) mar keting in the UK was discontinued in 2018. Other secretagogues that are available include linaclotide (an oral guanylate cyclase C agonist licensed for the treatment of moderate to severe irritable bowel syndrome associated with constipation; dose 290 μg once daily) and plecanatide (also an oral guanylate cyclase C agonist licensed for treat ment of chronic idiopathic constipation; dose 3 mg once daily). Neither linaclotide nor plecanatide have published evidence of efficacy in the treatment of clozapine‐induced constipation, although absence of evidence is not evidence of absence [18]. Plecanatide is not currently available in the UK.

The prokinetic agent prucalopride is a selective 5‐HT4 receptor agonist that pro motes gut peristalsis and thus gastrointestinal transit and can be used in chronic constipation when other laxatives fail to provide an adequate response (2 mg once daily). There is case‐report level evidence supporting its use in the management of clozapine‐induced constipation [19].

Opioid‐induced constipation

Opioid‐induced constipation (OIC) affects 40–90% of patients on long‐term opioid therapy [20] but is also prominent in short‐term use of opioid analgesics [21]. Osmotic laxatives (but not non‐absorbable sugars like lactulose, which can ferment within the colon and exacerbate bloating and distension) and stimulants are first‐line choices in the management of OIC [22]. Bulk‐forming laxatives should be avoided due to an increased risk of bowel obstruction [23].

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248 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Peripherally acting μ‐opioid receptor antagonists (PAMORAs) such as naldemedine, naloxegol, and methylnaltrexone inhibit opioid binding in the gastrointestinal tract and as such decrease the constipating effects of opioids. Naloxegol and naldemedine should be used with caution alongside CYP3A4 inhibitors (e.g. fluvoxamine, diltiazem, verapamil, clarithromycin, systemic antifungals, and protease inhibitors) as resultant increased systemic levels of PAMORAs can antagonise the central effects of opioids and precipitate withdrawal. In such a scenario, the PAMORA dose may need to be reduced or indeed the drug stopped. As such, in patients with OIC who do not respond to standard laxatives and where PAMORAs are being considered, first discuss use with pharmacy, medical colleagues, or specialist pain services.

Special considerations with clozapine

The algorithm for management of clozapine‐induced gastrointestinal hypomotility in Figure 28.2 is based on the Porirua protocol, a stepwise approach taken from the only prospective study of colonic transit time changes in clozapine‐treated patients per formed to date [9]. This pharmacological approach reduced colonic transit time in patients from a median of 110 hours at baseline to 62 hours and reduced prevalence of gastrointestinal hypomotility from 86% before treatment to 50% after treatment. General principles regarding management of clozapine‐induced constipation are as follows.

▪ Pre‐existing constipation should be managed prior to starting clozapine, i.e. provide lifestyle advice and start laxatives to ensure regular bowel motions before clozapine initiation.

▪ There is an argument that people taking clozapine should be offered prophylactic laxative treatment to prevent constipation (i.e. proactive rather than reactive treatment) [24].

▪ Patients receiving clozapine should recognise the importance of presenting to medical services if they become constipated.

▪ Prescribing clinicians should ask about clozapine‐associated constipation at each clinical assessment [25].

▪ Where constipation occurs during clozapine initiation, a slow titration is recom mended and use of the minimum effective dose (colonic transit times correlate with plasma clozapine levels) [9].

▪ Bulk‐forming laxatives are not effective in slow‐transit constipation and should therefore be avoided [26]. In contrast, stimulant laxatives should be used early. There are similarities between clozapine‐induced and opioid‐induced consti pation in that they are both characterised by slow transit; therefore, osmotic laxatives such as macrogol (but not non‐absorbable sugars such as lactulose; see preceding section) are a reasonable choice and can be considered early (along side a stimulant laxative) instead of the emollient laxative docusate sodium (see Figure 28.2) [27].

CHAPTER 28

Constipation 249

When to refer to a specialist

Constipation can usually be managed by psychiatrists or in primary care, although a referral to medical/surgical colleagues may be necessary if investigations demonstrate a secondary cause, or if constipation persists despite the interventions described in this chapter. Early involvement of specialists may be necessary in the context of clozapine‐ induced gastrointestinal hypomotility.

References

1. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Gut 1997;41:A122–A123.

2. Drossman DA. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology
2016;150(6):1262–1279.

3. Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta‐analy
sis. Am J Gastroenterol 2011;106(9):1582–1591.

4. Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci 1989;34(4):606–611.

5. De Hert M, Dockx L, Bernagie C, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retro
spective descriptive study. BMC Gastroenterol 2011;11:17.

6. Jancar J, Speller CJ. Fatal intestinal obstruction in the mentally handicapped. J Intellect Disabil Res 1994;38(Pt 4):413–422.

7. Coleman J, Spurling G. Constipation in people with learning disability. BMJ 2010;340:c222.

8. Shirazi A, Stubbs B, Gomez L, et al. Prevalence and predictors of clozapine‐associated constipation: a systematic review and meta‐analysis.
Int J Mol Sci 2016;17(6):863.

9. Every‐Palmer S, Ellis PM, Nowitz M, et al. The Porirua protocol in the treatment of clozapine‐induced gastrointestinal hypomotility and
constipation: a pre‐ and post‐treatment study. CNS Drugs 2017;31(1):75–85.

10. De Hert M, Hudyana H, Dockx L, et al. Second‐generation antipsychotics and constipation: a review of the literature. Eur Psychiatry
2011;26(1):34–44.

11. Palmer SE, McLean RM, Ellis PM, Harrison‐Woolrych M. Life‐threatening clozapine‐induced gastrointestinal hypomotility: an analysis of
102 cases. J Clin Psychiatry 2008;69(5):759–768.

12. Nielsen J, Meyer JM. Risk factors for ileus in patients with schizophrenia. Schizophr Bull 2012;38(3):592–598.

13. Bailey L, Varma S, Ahmad N, et al. Factors predicting use of laxatives in outpatients stabilized on clozapine. Ther Adv Psychopharmacol
2015;5(5):256–262.

14. Tramonte SM, Brand MB, Mulrow CD, et al. The treatment of chronic constipation in adults. A systematic review. J Gen Intern Med
1997;12(1):15–24.

15. Wald A. Is chronic use of stimulant laxatives harmful to the colon? J Clin Gastroenterol 2003;36(5):386–389.

16. National Institute for Health and Care Excellence. Lubiprostone for treating chronic idiopathic constipation. Technology appraisal guidance
TA318. https://www.nice.org.uk/guidance/ta318.

17. Meyer JM, Cummings MA. Lubiprostone for treatment‐resistant constipation associated with clozapine use. Acta Psychiatr Scand
2014;130(1):71–72.

18. Altman DG, Bland JM. Absence of evidence is not evidence of absence. Aust Vet J 1996;74(4):311.

19. Thomas N, Jain N, Connally F, et al. Prucalopride in clozapine‐induced constipation. Aust N Z J Psychiatry 2018;52(8):804.

20. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid‐induced constipation in patients with noncancer pain. N Engl J Med
2014;370(25):2387–2396.

21. Nilsson M, Poulsen JL, Brock C, et al. Opioid‐induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI. Eur J
Gastroenterol Hepatol 2016;28(5):514–524.

22. Farmer AD, Drewes AM, Chiarioni G, et al. Pathophysiology and management of opioid‐induced constipation: European expert consensus
statement. United European Gastroenterol J 2019;7(1):7–20.

23. Kumar L, Barker C, Emmanuel A. Opioid‐induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res
Pract 2014;2014:141737.

24. Attard A, Iles A, Attard S, et al. Clozapine: why wait to start a laxative? BJPsych Advances 2019;25(6):377–386.

25. Cohen D, Bogers JP, van Dijk D, et al. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin
Psychiatry 2012;73(10):1307–1312.

26. Voderholzer WA, Schatke W, Muhldorfer BE, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol
1997;92(1):95–98.

27. Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J
Gastroenterol 2005;100(Suppl 1):S5–S21.

CHAPTER 28

Part 5

Renal and Urology

Chapter 29

Urinary Retention

Atheeshaan Arumuham, Vimoshan Arumuham

Urinary retention describes the difficulty to voluntarily void urine, a presentation that may be acute or chronic. Acute urinary retention (AUR) is the most common urological emergency [1] and as such will form the predominant focus of this chapter. Causes of AUR include outflow obstruction (e.g. benign prostatic hyperplasia or BPH, urethral stricture, or infection causing inflammation) and neurological disorders (e.g. Parkinson’s disease or diabetic neuropathy), with risk also increasing in postoperative and postpar- tum periods. AUR is up to 13 times more likely in males than females [2], with 86% of AUR episodes in the UK ascribed to men [3]. Within the general population, BPH is the most common cause of urinary retention [4].

Numerous drugs have been associated with urinary retention (Box 29.1) [5]. In par- ticular, drugs with anticholinergic ‘activity’ pose a higher risk of precipitating retention. The reader is directed to http://www.medichec.com, a web‐based application that provides an ‘anticholinergic score’ for individual drugs [6].

URINARY RETENTION AND SERIOUS MENTAL ILLNESS

Psychiatric medication represents a key cause of AUR in patients with serious mental illness (SMI). Furthermore, the prevalence of type 2 diabetes is higher in psychiatric patients [7]. The resultant autonomic neuropathy can precipitate urinary retention.

Control of micturition involves coordination of the autonomic, peripheral, and cen- tral nervous systems. The bladder receives direct autonomic input, with adrenorecep- tors in the detrusor and internal sphincter promoting storage, while muscarinic receptors in the detrusor muscle receiving cholinergic input induce contraction [8]. Both dopa- minergic and serotonergic signalling pathways have been implicated in central control of urinary voiding [9]. It is thus little surprise that various psychiatric medications, with

Box 29.1 Drugs associated with urinary retention [5]

Drugs with anticholinergic effects Antipsychotics
Antidepressants Antispasmodics Anti‐Parkinsonian agents Atropine

Class I antiarrhythmic agents
Histamine H1 receptor antagonists
Anticholinergics prescribed for treatment of overactive bladder, chronic obstructive pulmonary

disease, and asthma
Analgesia (opioids, non‐steroidal anti‐inflammatory drugs) Benzodiazepines
Calcium channel antagonists
α‐Adrenoreceptor agonists

254 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

their broad receptor‐binding profiles, can cause urinary retention. This risk may be compounded when multiple treatments are co‐prescribed.

Antipsychotics differ in terms of their anticholinergic activity, which may play a role in the relative associated risk of AUR. Inhibition of noradrenergic reuptake [10] and central serotonergic effects [11] have also been implicated in the mechanisms underly- ing antipsychotic‐induced AUR. Retention has been reported with phenothiazines (e.g. chlorpromazine) [12], haloperidol [13], olanzapine [12], quetiapine [12], risperidone [12], and ziprasidone at high doses (likely secondary to inhibition of noradrenergic reuptake) [14].

Of all the different antidepressants, tricyclics are more commonly associated with urinary retention [5], in particular amitriptyline and imipramine [15]. Episodes of AUR have been reported with the selective serotonin reuptake inhibitors sertraline [16] and escitalopram [17], potentially owing to central serotonergic effects [11].

There are reports of clonazepam [18], diazepam [19], and alprazolam [20] causing urinary retention, the proposed mechanism being a relaxant effect on the detrusor mus- cle that prevents voiding contraction.

DIAGNOSTIC PRINCIPLES

In AUR, the patient is typically in great discomfort and prompt catheterisation is required. This will not generally be possible in a psychiatric environment and if AUR is suspected the patient will need to be transferred to acute medical or urological services. In chronic pres- entations there may be an opportunity to take a history and perform basic examinations that will strengthen a referral to urology. This will almost certainly be required if the patient is a psychiatric inpatient where a urology review is being requested.

CHAPTER 29

Urinary Retention 255

History

. 1 History of presenting complaint

. a Onset (sudden or prolonged) and duration (minutes to hours or months to
years).

. b Nature of symptoms (painful or painless).

. c Characterise micturition:
i frequency ii urgency
iii hesitancy
iv strength of urinary stream
v post‐micturition dribbling vi nocturia.

. d Course of symptoms (worsening, improving, or fluctuating).

. e Associated symptoms:
i fever may suggest urinary tract infection ii constipation can result in AUR
iii recent trauma and neurological symptoms may suggest cauda equina.

. 2 Past medical history
a BPH/prostate cancer.
b Recurrent urinary tract infection (see Chapter 41). c Diabetes mellitus (see Chapter 11).
d Surgical history/postpartum.
e Pelvic malignancy.

. 3 Medication review: note any recent additions or dose changes (see Box 29.1).

. 4 Social history: history of recreational drug use.

Examination

. 1 Basic observations including temperature.

. 2 Abdominal examination: suprapubic tenderness, distension, and dullness to
percussion.

. 3 Neurological examination: in context of comorbid type 2 diabetes mellitus, the pres-
ence of a peripheral neuropathy may herald broader neurological dysfunction (i.e. an autonomic neuropathy). Spinal cord compression must be excluded in the presence of focal neurological deficits (saddle anaesthesia, lower limb motor weakness, and sensory deficits).

. 4 With a chaperone, consider examination of external genitalia: a Males: phimosis, balanitis, discharge.
b Females: prolapse, acute vulvovaginitis, discharge.

. 5 With a chaperone, consider digital rectal examination:
a Males: is the prostate enlarged?
b Males and females: is there a rectal mass? Is there faecal loading?

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256 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Investigations

. 1 Urinalysis:
a protein and glucose (diabetes mellitus)
b blood (infection, stones, malignancy, trauma)
c nitrites and leucocytes (infection)
d send sample for microscopy, culture and sensitivity.

. 2 Bloods:
a full blood count (white cell count for evidence of infection)
b renal function (acute and/or chronic kidney failure)
c inflammatory markers (C‐reactive protein for evidence of infection) d glucose and HbA1c (diabetes mellitus).

. 3 For inpatients, a bedside bladder scan (ultrasound), if available, can be useful in monitoring retention.
MANAGEMENT

As already discussed, acute management of AUR will require transfer of the patient to acute medical/urological services. Once retention has been relieved, focus will turn to deducing and treating the precipitant (e.g. infection, BPH).

Psychiatric input is indicated as part of a multidisciplinary approach if psychiatric treatment is felt to be causative. This may involve rationalisation of treatment, such as dose reduction or switching treatment to an agent with less anticholinergic activity. The reader is directed to http://www.medichec.com which may be used to guide treatment ration- alisation (i.e. defining which drugs have greater anticholinergic activity and may there- fore need switching).

If the effects of psychiatric treatment were indirect but still related to a drug that one wishes to continue (e.g. clozapine causing constipation which in turn precipitated AUR), then a management plan that better targets the side effects of treatment is indi- cated (in this case laxatives; see Chapter 28).

References

1. Marshall JR, Haber J, Josephson EB. An evidence‐based approach to emergency department management of acute urinary retention. Emerg Med Pract 2014;16(1):1–20; quiz 21.

2. Klarskov P, Andersen JT, Asmussen CF, et al. Acute urinary retention in women: a prospective study of 18 consecutive cases. Scand J Urol Nephrol 1987;21(1):29–31.

3. Cathcart P, van der Meulen J, Armitage J, Emberton M. Incidence of primary and recurrent acute urinary retention between 1998 and 2003 in England. J Urol 2006;176(1):200–204.

4. Rosenstein D, McAninch JW. Urologic emergencies. Med Clin North Am 2004;88(2):495–518.

5. Verhamme KMC, Sturkenboom MCJM, Stricker BHC, Bosch R. Drug‐induced urinary retention: incidence, management and prevention.
Drug Saf 2008;31(5):373–388.

6. Bishara D, Harwood D, Sauer J, Taylor DM. Anticholinergic effect on cognition (AEC) of drugs commonly used in older people. Int J Geriatr

Psychiatry 2017;32(6):650–656.

7. Mitchell AJ, Vancampfort D, Sweers K, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related
disorders: a systematic review and meta‐analysis. Schizophr Bull 2013;39(2):306–318.

8. Ochodnicky P, Uvelius B, Andersson KE, Michel MC. Autonomic nervous control of the urinary bladder. Acta Physiol (Oxf)
2013;207(1):16–33.

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Urinary Retention 257

9. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008;9(6):453–466.

10. Walker NF, Brinchmann K, Batura D. Linking the evidence between urinary retention and antipsychotic or antidepressant drugs: a systematic
review. Neurourol Urodynam 2016;35(8):866–874.

11. Ramage AG. The role of central 5‐hydroxytryptamine (5‐HT, serotonin) receptors in the control of micturition. Br J Pharmacol
2006;147:S120–S131.

12. Tueth MJ. Emergencies caused by side‐effects of psychiatric medications. Am J Emerg Med 1994;12(2):212–216.

13. Crawford GB, Meera AM, Quinn SJ, et al. Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium. J Palliat Med
2013;16(11):1335–1341.

14. Xomalis D, Bozikas VP, Garyfallos G, et al. Urinary hesitancy and retention caused by ziprasidone. Int Clin Psychopharmacol
2006;21(1):71–72.

15. Degner D, Grohmann R, Kropp S, et al. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance
program AMSP. Pharmacopsychiatry 2004;37(Suppl 1):S39–S45.

16. Lowenstein L, Mueller ER, Sharma S, FitzGerald MP. Urinary hesitancy and retention during treatment with sertraline. Int Urogynecol J
2007;18(7):827–829.

17. Ferentinos P, Margaritis D, Douzenis A. Escitalopram‐associated acute urinary retention in elderly men with known or latent benign prostatic
hyperplasia: a case series. Clin Neuropharmacol 2016;39(6):327–328.

18. Caksen H, Odabas D. Urinary retention due to clonazepam in a child with dyskinetic cerebral palsy. J Emerg Med 2004;26(2):244.

19. Maany I, Greenfield H, Dhopesh V, Woody G. Urinary retention as a possible complication of long‐term diazepam abuse. Am J Psychiatry
1991;148(5):685.

20. Aykut DS, Uysal RAE. Acute urinary retention after alprazolam use: a case report. Psychiatry Clin Psychopharmacol 2018;28(2):220–221.

CHAPTER 29

Chapter 30

Urinary Incontinence

Atheeshaan Arumuham, Vimoshan Arumuham

Urinary incontinence is the involuntary and inappropriate voiding of urine. Although prevalence estimates vary depending on the population studied, in the USA the age‐ standardised prevalence in the general population is approximately 51% in women and 14% in men [1]. There are various types and causes of urinary incontinence as described in Table 30.1.

Some risk factors for urinary incontinence, such as obesity [2], smoking [3], and excessive alcohol intake [4], are increased in patients with serious mental illness [5–7] and may play a role in the increased rates of incontinence (compared with the general population) in some patients with schizophrenia [8] and major depressive disorder [9]. It has also been proposed that there may be an overlap in the neurobio- logical/chemical aetiology of urinary incontinence and some psychiatric conditions [9–11]. Detrusor overactivity and resultant urinary incontinence has historically been proposed as a symptom of schizophrenia owing to putative disruption of neu- ral control of bladder voiding [10], and alterations in serotonergic signalling have been proposed as a cause of urinary incontinence in depression [9]. Indeed, the noradrenaline and serotonin reuptake inhibitor duloxetine can be effective in the treatment of stress incontinence [11].

Rates of incontinence are also increased in patients with dementia owing to several neurobiological factors (e.g. impaired sensory function to sense bladder fullness, impaired higher cortical function to provide inhibition of the desire to void) and envi- ronmental issues (e.g. poor access to the toilet, poor manual dexterity to undress) [12]. Of note, there is a bidirectional relationship between urinary incontinence and mental illness. Rates of anxiety and depression are increased in patients with pre‐existing uri- nary incontinence [13], and comorbid depression increases severity of urinary inconti- nence in patients with overactive bladder [14].

260 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 30.1 Types of urinary incontinence.

Incontinence type

Stress

Urge

Mixed

Overflow

Features

Urine leakage secondary to abrupt increase in intra‐abdominal pressure (e.g. cough, sneeze, laugh), combined with weakness of pelvic floor muscles

More common in older women

Involuntary voiding of urine, preceded by an urgent, irrepressible need to void

Often termed ‘overactive bladder’

Prevalent in both genders, and more common in older age

Accounts for 40–80% of male urinary incontinence [17]

Causes

Weakening of pelvic floor muscles (e.g. following pregnancy)

Anti‐adrenergic drugs (e.g. some antipsychotics, antihypertensives/treatments for prostatic enlargement, e.g. doxazosin, tamsulosin) leading to reduced urethral sphincter tone

Atrophic urethritis in postmenopausal women

Enlarged prostate in men (e.g. BPH or prostatitis) or after prostate surgery

Diuretics (including alcohol and caffeine) leading to rapid bladder filling may worsen urge incontinence

Infection (see Chapter 41)

A combination of both stress and urge incontinence

Urinary leaking secondary to urinary retention with bladder distension

Either caused by structural abnormality occluding normal flow of urine, or weakness of the detrusor muscles

Increased intra‐abdominal pressure may lead to exacerbation of leaking, so can be misdiagnosed as stress incontinence

Structural abnormalities (e.g. prostate enlargement, urethral narrowing)

Neuropathic denervation of detrusor (e.g. diabetes neuropathy, surgery)

Any drugs that can cause urinary retention, leading to overflow (see Chapter 29)

BPH, benign prostatic hypertrophy.

Antipsychotics have the potential to cause urinary incontinence, although the course is typically sporadic and self‐limiting [15,16]. However, there is a strong asso- ciation between urinary incontinence and clozapine; nocturnal enuresis (bed wetting) has been reported in up to 41% of clozapine‐treated patients [17–19]. The mecha- nisms by which antipsychotic‐induced urinary incontinence occurs are not clearly defined owing to the multiple physiological systems involved in the normal storage and excretion of urine that can be affected by these drugs. Nevertheless, there are several proposed mechanisms, including dopamine blockade in the basal ganglia leading to bladder hyperactivity, anticholinergic effects on the bladder wall causing retention and overflow incontinence, and anti‐adrenergic activity causing relaxation of the bladder outlet and stress incontinence [20–23]. For clozapine, it has been pos- tulated that although its anticholinergic effect should cause urinary retention (see Chapter 29), its strong serotonergic activity inhibits parasympathetic control of mic- turition leading to enuresis [24].

Antidepressants, namely selective serotonin reuptake inhibitors (SSRIs), have been associated with urinary incontinence, although this evidence is limited to case reports

CHAPTER 30

and in most cases antidepressants were used in combination with either antipsychotics or benzodiazepines [25–27]. Evidence to suggest that antidepressants are associated with urinary incontinence is further undermined by duloxetine’s efficacy in treating stress incontinence in women, putatively via increasing urethral sphincter tone [11]. Benzodiazepine use, especially in the elderly, has been associated with urinary inconti- nence [28].

DIAGNOSTIC PRINCIPLES History

. 1 Determine the nature of urinary incontinence using the features of stress and urge incontinence described in Table 30.1 as a guide. Ask if the patient is experiencing nocturnal enuresis. Incontinence that occurs without warning may point towards overflow.

. 2 Determine the speed of onset of incontinence and if there was a temporal relation- ship with medication change/dose adjustments.

. 3 Associated symptoms:

. a If there is increased urinary frequency, ask about symptoms of infection (see
Chapter 41).

. b In men, ask about other features of prostatic hypertrophy (e.g. increased urinary
frequency, nocturia, difficulty starting urination, weak urine stream, dribbling at
the end of urination, and inability to completely empty the bladder).

. c Enquire if there have been any concurrent neurological symptoms (e.g. weakness/
sensory disturbance in the legs or difficulty walking).

. d Ask if the patient is constipated (which can contribute to urinary incontinence) [29].

. 4 Past medical history:

. a Diabetes mellitus: poorly controlled disease may lead to increased urinary fre-
quency and increased risk of urinary tract infection.

. b Obstructive sleep apnoea: has been associated with overactive bladder and urge
incontinence [30,31].

. c Previous spinal cord injury/surgery (all patients), previous prostate surgery in men.

. 5 Social history:

. a Alcohol and smoking history.

. b Recreational drug use: chronic ketamine use can lead to sclerotic changes within
the bladder that reduce functional bladder capacity, leading to lower urinary tract
symptoms that include incontinence.

. 6 Medication review (see Table 30.1).

Examination

Weigh the patient and calculate body mass index (see Chapter 14). If there is evidence of infection, check basic observations including pulse, blood pressure, respiratory rate, oxygen saturation, and temperature (see Chapters 41 and 72).

Urinary Incontinence 261

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262 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Further examination may not be necessary. Abdominal examination may be indi- cated where retention and overflow are suspected (palpable bladder), and a neurologi- cal examination should be performed in patients with evidence of neurology.

Baseline investigations

In the psychiatric setting, the only laboratory investigation that will usually be per- formed in the context of urinary incontinence is urinalysis alongside sending urine for microscopy, culture, and sensitivity if infection is suspected (see Chapter 41). In inpa- tients where retention is suspected and potential hydronephrosis, check renal function.

Where there is diagnostic uncertainty and the patient is referred to urology, further investigations may include ultrasound examination of the kidneys, ureters, and bladder (e.g. examining for retention, obstruction, and hydronephrosis), a bladder stress test (where stress incontinence is suspected), measurement of post‐void residual (where retention is suspected), and urodynamic testing.

MANAGEMENT

Management of urinary incontinence is dependent on the cause, and the provision of most such interventions is clearly beyond the remit of the psychiatrist. However, psychiatrists are well placed to recommend and facilitate some non‐pharmacologi- cal interventions that may improve certain types of urinary incontinence and which can improve the physical health of patients more broadly. Furthermore, where psy- chotropic medications are implicated in the pathoaetiology of incontinence, the psychiatrist will play a central role in rationalising drug interventions. Also, treat- ment of comorbid anxiety and depression in patients with pre‐existing urinary incontinence improves physical health outcomes in these individuals [13,14]. A sug- gested management algorithm for clozapine‐induced nocturnal enuresis is provided in Figure 30.1.

Non‐pharmacological interventions

. 1 Where psychotropic medications are implicated in urinary incontinence, one approach is simply to observe the progression of symptoms: episodes of incontinence may be transient and resolve spontaneously.

. 2 Simple lifestyle modifications can be suggested. In cases of nocturnal enuresis, sug- gest reducing fluid intake in the evening (e.g. nothing to drink after 6 p.m.). If caf- feine/alcohol is related to episodes of incontinence, advise reducing the amount of caffeine/alcohol consumed or consider a trial of abstinence. If appropriate, recom- mend that the patient stops smoking (see Chapter 46) and loses weight (see Chapter 14). If the patient stops smoking, be aware that blood concentrations of some psychiatric drugs (e.g. olanzapine, clozapine, and tricyclic antidepressants) may be altered (see Chapter 46 for further information).

CHAPTER 30

NOCTURNAL ENURESIS

Likely to be clozapine-induced?

Yes No

Urinary Incontinence 263

Non-pharmacological interventions

• Reduce fluid intake in the evening

• Reduce (ideally stop) caffeine and alcohol
intake

• Stop smoking (if so, monitor clozapine
levels)

• Weight-loss
Pharmacological interventions: step 1

• Consider stopping any co-prescribed antipsychotics

• Reduce clozapine dose or, if during a titration, slow titration rate

• If present, treat constipation

Ongoing nocturnal enuresis

• Consider alternative diagnoses (see Table 30.1)

• Refer to primary care/urology

Pharmacological interventions: step 2

• •

Desmopressin nasal spray 10–20 μg at night (monitor sodium levels)
If desmopressin contraindicated, consider

trial of anticholinergic agent e.g, oxybutynin up to 5 mg three times a day (monitor for anticholinergic symptoms) or aripiprazole augmentation (10–15 mg daily)

Figure 30.1 Suggested management of clozapine‐induced nocturnal enuresis.

3 Some patients may need to be provided with absorbent pads or protective undergarments.

4 Pelvic floor/bladder training may be provided by specialist incontinence services, accessed either via primary care or urology [32].

Pharmacological interventions

1 Consider dose reduction/cessation of implicated psychotropic medications, having first weighed up the risks and benefits of such an action. If nocturnal enuresis occurs during a clozapine titration, consider the following: slow the rate of titration; take evening clozapine dose earlier (e.g. 6 p.m.) or, if tolerated, weight dose such that more is given in the morning; ideally stop any other co‐prescribed antipsychotics.

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264 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

. 2 Treat comorbid constipation (see Chapter 28).

. 3 For perimenopausal women with stress/urge incontinence, consider use of topical
vaginal oestrogen (see Chapter 63).

. 4 Duloxetine has been shown to be beneficial in the treatment of stress incontinence in
women [11].

. 5 Men with benign prostatic hypertrophy may benefit from anti‐adrenergic drugs (e.g.
doxazosin, tamsulosin).

. 6 Anticholinergic agents such as oxybutynin, tolterodine, and darifenacin can be used
in the treatment of urge incontinence as they reduce overactivity of bladder muscle and the feeling of urgency. However, caution should be taken in the prescription of such agents alongside psychotropic agents with their own anticholinergic effects; patients (especially those prescribed clozapine) should be monitored for the develop- ment of constipation among other anticholinergic symptoms (e.g. cognitive deficits). There is case report‐level evidence to support the use of anticholinergic agents in the treatment of clozapine‐induced nocturnal enuresis; in these reports, oral oxybutynin (up to 5 mg three times daily) [33] and oral trihexyphenidyl (up to 6 mg daily) [34] were reported as effective.

. 7 Desmopressin, which may be given orally, sublingually, or as a nasal spray, can be used to manage both urinary incontinence and nocturnal enuresis. There is case report‐level evidence for the efficacy of desmopressin in the treatment of clozapine‐ induced nocturnal enuresis (most commonly given as a nasal spray 10–20 μg at night) [33,35–37]. However, patients should be monitored for the development of hyponatraemia [35]. Check sodium levels at baseline (before desmopressin initia- tion), and then the week and month following treatment initiation.

. 8 In terms of other pharmacological agents used in the management of clozapine‐ induced nocturnal enuresis, one study has observed efficacy of the adrenergic agonist ephedrine (150 mg/day) [38] and there is some evidence that aripiprazole augmenta- tion (10–15 mg/day) can be effective [39]

When to refer to a specialist

Patients should be referred to primary care, urology, or a specialist incontinence service where incontinence is not clearly a consequence of psychotropic prescription, or where incontinence is persistent and chronic in nature despite attempts made to rationalise psychiatric medication. Beyond specialist investigations, urology colleagues will pro- vide access to other treatment modalities for specific presentations, including surgical interventions.

References

1. Markland AD, Richter HE, Fwu CW, et al. Prevalence and trends of urinary incontinence in adults in the United States, 2001 to 2008. J Urol 2011;186(2):589–593.

2. Subak LL, Richter HE, Hunskaar S. Obesity and urinary incontinence: epidemiology and clinical research update. J Urol 2009;182(6 Suppl):S2–S7.

3. Tahtinen RM, Auvinen A, Cartwright R, et al. Smoking and bladder symptoms in women. Obstet Gynecol 2011;118(3):643–648.

4. Lee AH, Hirayama F. Is alcohol consumption associated with male urinary incontinence? Low Urin Tract Symptoms 2011;3(1):19–24.

5. Dickerson FB, Brown CH, Kreyenbuhl JA, et al. Obesity among individuals with serious mental illness. Acta Psychiatr Scand
2006;113(4):306–313.

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Urinary Incontinence 265

6. Lasser KE, Boyd JW, Woolhandler SJ, et al. Smoking and mental illness: a population‐based prevalence study. JAMA 2000;284(20):2606–2610.

7. Petrakis IL, Gonzalez G, Rosenheck R, Krystal JH. Comorbidity of alcoholism and psychiatric disorders: an overview. Alcohol Res Health 2002;26(2):81–89.

8. Hsu WY, Muo CH, Ma SP, Kao CH. Association between schizophrenia and urinary incontinence: a population‐based study. Psychiatry Res 2017;248:35–39.

9. Zorn BH, Montgomery H, Pieper K, et al. Urinary incontinence and depression. J Urol 1999;162(1):82–84.

10. Bonney WW, Gupta S, Hunter DR, Arndt S. Bladder dysfunction in schizophrenia. Schizophr Res 1997;25(3):243–249.

11. Jost WH, Marsalek P. Duloxetine in the treatment of stress urinary incontinence. Ther Clin Risk Manag 2005;1(4):259–264.

12. Sakakibara R, Uchiyama T, Yamanishi T, Kishi M. Dementia and lower urinary dysfunction: with a reference to anticholinergic use in elderly
population. Int J Urol 2008;15(9):778–788.

13. Vrijens D, Drossaerts J, van Koeveringe G, et al. Affective symptoms and the overactive bladder: a systematic review. J Psychosom Res
2015;78(2):95–108.

14. Lai HH, Shen BX, Rawal A, Vetter J. The relationship between depression and overactive bladder/urinary incontinence symptoms in the clini-
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15. Berrios GE. Temporary urinary incontinence in the acute psychiatric patient without delirium or dementia. Br J Psychiatry
1986;149:224–227.

16. Ambrosini PJ, Nurnberg HG. Enuresis and incontinence occurring with neuroleptics. Am J Psychiatry 1980;137(10):1278–1279.

17. Harrison‐Woolrych M, Skegg K, Ashton J, et al. Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine:
comparative cohort study. Br J Psychiatry 2011;199(2):140–144.

18. Lin CC, Bai YM, Chen JY, et al. A retrospective study of clozapine and urinary incontinence in Chinese in‐patients. Acta Psychiatr Scand
1999;100(2):158–161.

19. Yusufi B, Mukherjee S, Flanagan R, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship
with clozapine dose and plasma concentration. Int Clin Psychopharmacol 2007;22(4):238–243.

20. Yoshimura N, Kuno S, Chancellor MB, et al. Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6‐hydroxy-
dopamine (6‐OHDA) lesion of the nigrostriatal pathway. Br J Pharmacol 2003;139(8):1425–1432.

21. Barnes TR, Drake MJ, Paton C. Nocturnal enuresis with antipsychotic medication. Br J Psychiatry 2012;200(1):7–9.

22. Tsakiris P, Oelke M, Michel MC. Drug‐induced urinary incontinence. Drugs Aging 2008;25(7):541–549.

23. Ambrosini PJ. A pharmacological paradigm for urinary incontinence and enuresis. J Clin Psychopharmacol 1984;4(5):247–253.

24. Torre DL, Isgro S, Muscatello MR, et al. Urinary incontinence in schizophrenic patients treated with atypical antipsychotics: urodynamic
findings and therapeutic perspectives. Int J Psychiatry Clin Pract 2005;9(2):116–119.

25. Votolato NA, Stern S, Caputo RM. Serotonergic antidepressants and urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct
2000;11(6):386–388.

26. Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug‐induced urinary retention: incidence, management and prevention. Drug Saf
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drugs: a critical review of the literature. Psychother Psychosom 2016;85(5):270–288.

28. Landi F, Cesari M, Russo A, et al. Benzodiazepines and the risk of urinary incontinence in frail older persons living in the community. Clin
Pharmacol Ther 2002;72(6):729–734.

29. Wood LN, Anger JT. Urinary incontinence in women. BMJ 2014;349:g4531.

30. Ipekci T, Cetintas G, Celik O, et al. Continuous positive airway pressure therapy is associated with improvement in overactive bladder symp-
toms in women with obstructive sleep apnea syndrome. Cent Eur J Urol 2016;69(1):78–82.

31. Kemmer H, Mathes AM, Dilk O, et al. Obstructive sleep apnea syndrome is associated with overactive bladder and urgency incontinence in
men. Sleep 2009;32(2):271–275.

32. Dumoulin C, Hay‐Smith J. Pelvic floor muscle training versus no treatment for urinary incontinence in women. A Cochrane systematic
review. Eur J Phys Rehabil Med 2008;44(1):47–63.

33. Lurie SN, Hosmer C. Oxybutynin and intranasal desmopressin for clozapine‐induced urinary incontinence. J Clin Psychiatry 1997;58(9):404.

34. Frankenburg FR, Kando JC, Centorrino F, Gilbert JM. Bladder dysfunction associated with clozapine therapy. J Clin Psychiatry
1996;57(1):39–40.

35. Sarma S, Ward W, O’Brien J, Frost AD. Severe hyponatraemia associated with desmopressin nasal spray to treat clozapine‐induced nocturnal
enuresis. Aust N Z J Psychiatry 2005;39(10):949.

36. Steingard S. Use of desmopressin to treat clozapine‐induced nocturnal enuresis. J Clin Psychiatry 1994;55(7):315–316.

37. Aronowitz JS, Safferman AZ, Lieberman JA. Management of clozapine‐induced enuresis. Am J Psychiatry 1995;152(3):472.

38. Fuller MA, Borovicka MC, Jaskiw GE, et al. Clozapine‐induced urinary incontinence: incidence and treatment with ephedrine. J Clin
Psychiatry 1996;57(11):514–518.

39. Rocha FL, Hara C. Benefits of combining aripiprazole to clozapine: three case reports. Prog Neuropsychopharmacol Biol Psychiatry
2006;30(6):1167–1169.

CHAPTER 30

Chapter 31

Polyuria

Atheeshaan Arumuham, Toby Pillinger, Benjamin Whitelaw

Polyuria in adults is defined as a urine output exceeding 3 L/day. It should be differenti- ated from other urinary complaints such as increased urinary frequency or nocturia, which are not associated with increased total urine output. Common causes of polyuria are shown in Table 31.1. Major causes that should be considered in patients with seri- ous mental illness (SMI) include the glucose‐induced osmotic diuresis of diabetes mel- litus, psychogenic polydipsia, and nephrogenic diabetes insipidus in the context of lithium use. Use of diuretics may also be considered in individuals with eating disor- ders. Primary polydipsia is present in more than 20% of inpatients with chronic psychi- atric conditions, and is commonly seen in individuals with schizophrenia, those with developmental disability, and anxiety disorders [1–3]. The underlying pathoaetiology is unclear.

Table 31.1 Causes of polyuria. Cause

Osmotic diuresis (e.g. diabetes mellitus)

Primary polydipsia
Central diabetes insipidus Nephrogenic diabetes insipidus

Mechanism

Water follows non‐reabsorbed solute (e.g. glucose) across the kidney tubules

Excessive water intake
Deficient pituitary antidiuretic hormone (ADH) secretion
Normal ADH secretion but renal resistance to its water‐retaining effect

Box 31.1 Key points in determining the aetiology of polyuria

▪ Distinguish true polyuria from increased urinary frequency.

▪ Evaluate sense of thirst and determine how much the patient is drinking.

▪ Paired (obtained at the same time) blood and urine samples for osmolality are often very useful.

▪ Serum tests to exclude diabetes mellitus and hypercalcaemia (HbA1c and bone profile) are
essential.

268 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES

Key points for determining the aetiology of polyuria are shown in Box 31.1.

History

. 1 Clarify if there is increased volume of urine or increased frequency of urination.

. 2 Determine if there is associated polydipsia.

. 3 Screen for associated symptoms:
a urinary symptoms that may point towards infection/prostatism
b weight loss may point towards diabetes mellitus, malignancy, or tuberculosis.

. 4 Past medical history:
a diabetes mellitus (osmotic diuresis)
b head trauma or pituitary surgery (central diabetes insipidus)
c history of any infiltrative conditions, e.g. sarcoid (central diabetes insipidus).

. 5 Social history:

. a alcohol inhibits pituitary secretion of antidiuretic hormone (ADH)

. b recreationaldruguse,e.g.3,4‐methylenedioxymethamphetamine(Ecstasy)increases
secretion of ADH and impact on serotonergic pathway causes polydipsia.

. 6 Family history of polyuria/excessive water drinking.

. 7 Medication review (e.g. diuretics, lithium).

Examination

. 1 Assessfluidstatus:checkpulse,capillaryrefilltime,skinturgor,assessfordrymucous membranes. Perform lying and standing blood pressure assessing for postural hypo- tension (see Chapter 6).

. 2 Assess body habitus: obesity may point towards diabetes mellitus, cachexia may point towards malignancy, tuberculosis, or an eating disorder.

. 3 Skin examination: hyperpigmented/hypopigmented lesions, ulcers, or subcutaneous nodules may suggest sarcoidosis (see Chapter 60). Lymphadenopathy may herald malignancy or infiltrative disorders.

Investigations

Urine

1 History alone will often distinguish polyuria from frequency, but occasionally a 24‐ hour urine collection may be required. The practicality of such an investigation in a psychiatric setting will be dependent on the patient’s mental state.

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Polyuria 269

Box 31.2 Interpretation of paired urine/serum osmolalities and sodium levels in the context of polydipsia and diabetes insipidus

▪ A low plasma sodium concentration (<137 mmol/L) with a low urine osmolality (e.g. less than half the plasma osmolality) is usually indicative of water overload due to psychogenic polydipsia.

▪ A high‐normal plasma sodium concentration (>142 mmol/L) in conjunction with a urine osmolal- ity that is lower than plasma osmolality points toward diabetes insipidus.

▪ A normal plasma sodium concentration is not helpful in diagnosis but, if associated with a urine osmolality of more than 600 mosmol/kg, excludes a diagnosis of diabetes insipidus.

. 2 Urine dip examining for evidence of infection (if so, send to the laboratory for microscopy, culture, and sensitivity), proteinuria (if concern about renal failure or diabetes mellitus), glucose, and ketones.

. 3 Urine osmolality and sodium levels paired with plasma osmolality and sodium levels (see Box 31.2 for interpretation).

Blood

. 1 Renal function, specifically:
a sodium levels (see Chapter 32)
b potassium levels (hypokalaemia may point towards diuretic use; see Chapter 33) c urea levels to assess for degree of dehydration
d creatinine levels to assess for evidence of renal failure (see Chapters 34 and 73).

. 2 Plasma osmolality paired with urine osmolality (see Box 31.2).

. 3 Serum calcium levels (hypercalcaemia can induce polyuria).

. 4 Fasting/random glucose and HbA1c levels.

. 5 If appropriate, lithium levels.
The gold standard test to differentiate between primary polydipsia and central and

nephrogenic diabetes insipidus is the water restriction test, followed by (if appropriate) administration of desmopressin. However, such tests should only be performed in a specialist clinic.

MANAGEMENT Diabetes mellitus

Uncontrolled diabetes mellitus results in an osmotic diuresis. Treatment involves opti- mising glycaemic control (see Chapter 11 for more details).

Psychogenic polydipsia

Treatment principles involve the following.

1 Optimum management of the underlying psychiatric disorder. 2 Fluid restriction to 1–1.5 L/day.

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270 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

. 3 Cognitive behavioural techniques and reinforcement schedules [4,5]. Most behav- ioural intervention studies are reported in hospitalised patients, often requiring close monitoring and a substantial time commitment from staff.

. 4 Pharmacological interventions:

. a clozapine has shown benefit in case reports and prospective trials [5–7]

. b risperidone and olanzapine improved polydipsia in case reports, but prospective
double‐blind studies have not shown any benefit with olanzapine [8–10]

. c demeclocycline (a tetracycline antibiotic) has historically been prescribed for poly- dipsia, although it has not been demonstrated to be effective in double‐blind,
placebo‐controlled trials [11].

. 5 Concomitantly giving loop diuretics (e.g. furosemide) to enhance water excretion
may be necessary, although should be discussed with medical colleagues first.

Nephrogenic diabetes insipidus

Central diabetes insipidus (DI) is associated with deficient secretion of ADH. Nephrogenic DI is characterised by normal ADH secretion but varying degrees of renal resistance to its water‐retaining effect. Nephrogenic DI is far more likely to be seen in psychiatric patients owing to the prescription of lithium. Polyuria due to impaired uri- nary concentrating ability occurs in up to 20% of patients chronically treated with lithium; an additional 30% have a subclinical impairment in concentrating ability. These adverse effects are mediated by lithium entry into the principal cells in the col- lecting tubule via the epithelial sodium channel [12]. At cytotoxic concentrations, lith- ium inhibits signalling pathways that involve glycogen synthase kinase type 3 β (GSK3β), resulting in dysfunction of the aquaporin‐2 water channel [12]. GSK3β knockout mice have a reduced response to vasopressin administration [13]. The effect is thought to be dose dependent and is usually reversible in the short to medium term, but may be irre- versible after long‐term treatment (>15 years) [12]. Treatment should be carried out alongside input from medical colleagues (e.g. renal/endocrine) and pharmacy; general principles are as follows.

. 1 Dose reduction of lithium, if possible.

. 2 Low‐sodium, low‐protein diet [15].

. 3 Thiazide diuretics in combination with a low‐sodium diet. A thiazide diuretic (e.g.
hydrochlorothiazide 25 mg once or twice daily) acts by inducing mild volume deple- tion. As little as 1–1.5 kg weight loss can reduce urine output by more than 50% (e.g. from 10 L/day to below 3.5 L/day in a study of patients with nephrogenic DI on a severely sodium‐restricted diet [9 mEq/day]) [16]. This effect is thought to be mediated by a hypovolaemia‐induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH‐sensitive sites in the collecting tubules and reducing urine output. However, thiazide diuretics can dramatically increase plasma lithium levels; use together with caution and check lithium levels regularly [17].

. 4 The potassium‐sparing diuretic amiloride can be used to decrease urine volume [18], with evidence for benefit in combination with thiazide diuretics in the context of lithium use [19].

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Polyuria 271

. 5 Non‐steroidal anti‐inflammatory drugs (NSAIDs) reduce urine output via inhibition of renal prostaglandin synthesis, thereby combating the antagonistic actions of pros- taglandins on ADH function. The net effect in patients with DI may be a 25–50% reduction in urine output [20,21], a response that is partially additive to that of a thiazide diuretic [21]. Indomethacin has a greater effect than ibuprofen in increasing ADH’s actions on the kidney. However, use of concomitant NSAIDs with lithium requires close monitoring of renal function tests and lithium levels; co‐prescription unpredictably increases risk of lithium toxicity with potentially fatal conse- quences [22]. NSAID use will also likely require gastroprotection, especially if a selective serotonin reuptake inhibitor is co‐prescribed (see Chapter 19).

. 6 Desmopressin (DDAVP) may be tried in patients who have persistent symptomatic polyuria after implementation of the above regimen, as there is likely only a partial rather than complete resistance to ADH in nephrogenic DI. One case report of a patient with lithium‐induced nephrogenic DI suggested that benefit may be more likely if desmopressin is combined with an NSAID (although note cautions regarding concomitant lithium and NSAID use already documented) [23].

Central diabetes insipidus

Central DI is generally treated with desmopressin (either orally or as a nasal spray) two to three times per day. If desmopressin is omitted there is a risk of dehydration; there have been cases of patients dying due to omission of desmopressin for 48 hours [24]. Thus, ensuring regular desmopressin administration in such patients is essential.

References

1. de Leon J, Verghese C, Tracy JI, et al. Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 1994;35(6):408–419.

2. de Leon J. Polydipsia: a study in a long‐term psychiatric unit. Eur Arch Psychiatry Clin Neurosci 2003;253(1):37–39.
3. Illowsky BP, Kirch DG. Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry 1988;145(6):675–683.
4. Bowen L, Glynn SM, Marshall BD Jr, et al. Successful behavioral treatment of polydipsia in a schizophrenic patient. J Behav Ther Exp

Psychiatry 1990;21(1):53–61.

5. Costanzo ES, Antes LM, Christensen AJ. Behavioral and medical treatment of chronic polydipsia in a patient with schizophrenia and diabetes
insipidus. Psychosom Med 2004;66(2):283–286.

6. Leadbetter RA, Shutty MS Jr. Differential effects of neuroleptic and clozapine on polydipsia and intermittent hyponatremia. J Clin Psychiatry
1994;55(Suppl B):110–113.

7. Lee HS, Kwon KY, Alphs LD, Meltzer HY. Effect of clozapine on psychogenic polydipsia in chronic schizophrenia. J Clin Psychopharmacol
1991;11(3):222–223.

8. Kruse D, Pantelis C, Rudd R, et al. Treatment of psychogenic polydipsia: comparison of risperidone and olanzapine, and the effects of an
adjunctive angiotensin‐II receptor blocking drug (irbesartan). Aust N Z J Psychiatry 2001;35(1):65–68.

9. Goldman MB, Hussain N. Absence of effect of olanzapine on primary polydipsia: results of a double‐blind, randomized study. J Clin
Psychopharmacol 2004;24(6):678–680.

10. Rao N, Venkatasubramanian G, Korpade V, et al. Risperidone treatment for polydipsia and hyponatremia in schizophrenia: a case report.

Turk Psikiyatri Derg 2011;22(2):123–125.

11. Alexander RC, Karp BI, Thompson S, et al. A double blind, placebo‐controlled trial of demeclocycline treatment of polydipsia‐hyponatremia
in chronically psychotic patients. Biol Psychiatry 1991;30(4):417–420.

12. Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009;5(5):270–276.

13. Rao R, Patel S, Hao C, et al. GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. J Am Soc Nephrol
2010;21(3):428–437.

14. Bowen RC, Grof P, Grof E. Less frequent lithium administration and lower urine volume. Am J Psychiatry 1991;148(2):189–192.

15. Wesche D, Deen PM, Knoers NV. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol
2012;27(12):2183–2204.

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16. Earley LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin‐ resistant diabetes insipidus. J Clin Invest 1962;41(11):1988–1997.

17. Kim GH, Lee JW, Oh YK, et al. Antidiuretic effect of hydrochlorothiazide in lithium‐induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin‐2, Na‐Cl co‐transporter, and epithelial sodium channel. J Am Soc Nephrol 2004;15(11):2836–2843.

18. Batlle DC, Vonriotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long‐term lithium‐therapy. N Engl J Med 1985;312(7):408–414.

19. Knoers N, Monnens LAH. Amiloride–hydrochlorothiazide versus indomethacin–hydrochlorothiazide in the treatment of nephrogenic diabe- tes insipidus. J Pediatr 1990;117(3):499–502.

20. Libber S, Harrison H, Spector D. Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. J Pediatr 1986;108(2):305–311.

21. Monnens L, Jonkman A, Thomas C. Response to indomethacin and hydrochlorothiazide in nephrogenic diabetes insipidus. Clin Sci 1984;66(6):709–715.

22. New Zealand Medicines and Medical Devices Safety Authority. Drug interactions with lithium and therapeutic drug monitoring. Prescriber Update 2017;38(3):36–38. Available at https://www.medsafe.govt.nz/Profs/PUArticles/September2017/Lithium.htm

23. Stasior DS, Kikeri D, Duel B, Seifter JL. Nephrogenic diabetes insipidus responsive to indomethacin plus DDAVP. N Engl J Med 1991;324(12):850–851.

24. NHS England. Patient Safety Alert (Stage One: Warning). Risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus. https://www.england.nhs.uk/patientsafety/wp‐content/uploads/sites/32/2016/02/psa‐desmopressin‐080216. pdf (8 February 2016).

CHAPTER 31

Chapter 32

Sodium Derangement

Atheeshaan Arumuham, Peter Conlon

Dysnatraemia is defined as serum sodium levels of either less than 135 mmol/L (hyponatraemia) [1] or more than 145 mmol/L (hypernatraemia) [2]. Hyponatraemia is one of the most frequently encountered electrolyte imbalances encountered in medi- cal practice [3]. Hypernatraemia is less common, with a reported incidence of 0.3% in general medical inpatients [4]. Both presentations, when severe, represent potentially life‐threating medical emergencies, resulting in seizure, coma, and death.

Common causes of dysnatraemia are summarised in Table 32.1. The most significant risk factor for derangements in sodium levels is increasing age [5]. Psychiatric patients represent a vulnerable cohort for both hyponatraemia and hypernatraemia. For exam- ple, abuse of laxatives and diuretics in patients with eating disorders may result in excessive gastrointestinal sodium losses [6,7]. These patients may also present with hypodipsia; compounding gastrointestinal losses with severe dehydration can result in either a rise or fall in serum sodium levels. Several psychiatric drugs, including antide- pressants (especially selective serotonin reuptake inhibitors, SSRIs), antipsychotics, and mood stabilisers, can cause syndrome of inappropriate antidiuretic hormone secretion (SIADH) resulting in hyponatraemia [8–17]. Nephrogenic diabetes insipidus, which occurs in up to 40% of patients prescribed lithium [18], can result in hypernatraemia; the reader is directed to Chapter 31 for further details on on polyuria. Furthermore, patients with serious forms of mental illness may present with psychogenic polydipsia, thus leaving them vulnerable to electrolyte imbalances [13]. Crucially, electrolyte imbal- ance itself may manifest as an organic cause of psychiatric symptoms such as depres- sion and anxiety [19].

274 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 32.1 Common causes of hyponatraemia and hypernatraemia.

Hypovolaemic

Euvolaemic

Hypervolaemic

Hyponatraemia

Cerebral salt wasting (e.g. head injury, intracranial haemorrhage)
Diuretics
Gastrointestinal losses (diarrhoea/vomiting) Primary (Addison’s), secondary (pituitary failure), and tertiary (hypothalamic failure) mineralocorticoid deficiency

Osmotic diuresis (e.g. diabetic ketoacidosis) Renal tubular acidosis
‘Third‐spacing’ (bowel obstruction/burns)

3,4‐Methylenedioxymethamphetamine (Ecstasy) consumption
Beer potomania
Glucocorticoid deficiency Hypothyroidism

Psychogenic polydipsia
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Water intoxication

Congestive cardiac failure Cirrhosis
Nephrotic syndrome
Renal failure (acute/chronic)

Hypernatraemia

Diuretics
Gastrointestinal losses (diarrhoea/vomiting) Osmotic diuresis

NB These presentations involve both a reduction in total body water and sodium, but with a relatively greater reduction in total body water

Diabetes insipidus (nephrogenic or central) Hypodipsia

Excess intravenous administration of sodium‐ containing fluids
Mineralocorticoid excess (e.g. Cushing’s, hyperaldosteronism)

DIAGNOSTIC PRINCIPLES History

Dysnatraemia is often asymptomatic, with symptoms generally only occurring in severe derangement. However, identifying precipitating factors is key to guiding management, and thus a detailed history and examination is necessary.

Aim to cover the following when exploring the history of the presenting complaint.

▪ Quantify recent water/fluid intake.

▪ Presence of thirst and/or a reduction in urine output.

▪ Recent diarrhoea, vomiting, or constipation.

▪ Weight loss or other red flags for malignancy, e.g. change in bowel habit, dysphagia
(malignancy is associated with SIADH).

▪ Assess for features of adrenal insufficiency such as hyperpigmentation, postural
hypotension. (If there are acute concerns about Addison’s disease, patients should be
seen and reviewed in the accident and emergency department.)

▪ The presence of neurological symptoms is suggestive of severe alterations in sodium
levels, and include lethargy, headache, dizziness, confusion, decreased consciousness, and seizures.

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Sodium Derangement 275

A past medical and psychiatric history should screen for comorbid conditions that may be associated with dysnatraemia, including thyroid dysfunction, congestive car- diac failure, chronic kidney disease, cirrhosis, diabetes mellitus, and malignancy. Psychogenic polydipsia can occur in the setting of serious mental illness.

A comprehensive drug history should screen for medications commonly associ- ated with derangements in sodium levels. These include diuretics, laxatives, steroids, and psychotropic or anticonvulsant drugs. A Danish register‐based study of over 600,000 individuals compared risk of hyponatraemia in those prescribed and not prescribed antidepressants [20]. Risk of hyponatraemia was increased with virtually all antidepressants examined (amitriptyline, clomipramine, nortriptyline, citalo- pram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, and mirtazapine); only mianserin did not increase risk. The strongest association between hyponatraemia and antidepressants was found in SSRIs, with highest risk within the first two weeks of treatment. These findings are complemented by a systematic review of the available literature published in 2014 which observed that risk of hyponatraemia during antidepressant treatment was highest with SSRIs and venlafaxine and lower with mirtazapine [21]. It was also observed that risk of antidepressant‐associated hyponatraemia increased with age and co‐prescription of a thiazide diuretic.

Social history should screen for recreational drug use such as 3,4‐methylenedioxym- ethamphetamine (Ecstasy) consumption and quantify alcohol intake (screening for beer potomania).

Examination

▪ Assess level of consciousness. If there are concerns regarding reduced consciousness, manage as per the ABCDE approach and transfer care to the emergency services (see Chapter 78).

▪ Check basic observations, assessing heart rate, blood pressure, respiratory rate, and oxygen saturation. Hypotension or orthostatic hypotension should raise concerns for hypovolaemia. Also check finger‐prick blood glucose (may identify hyperglycaemia in context of diabetic ketoacidosis).

▪ Derangements in sodium are most commonly associated with regulation of water balance rather than a derangement in sodium per se, so determining the fluid status of the patient can provide rapid insight into the underlying pathoaetiology (see Table 32.1). As such, assess if the patient is hypovolaemic, euvolaemic, or hypervol- aemic. Features of hypovolaemia include tachycardia, postural hypotension, pro- longed capillary refill time, reduced skin turgor, and dry mucous membranes. Features of hypervolaemia can include peripheral oedema, raised jugular venous pressure, and bibasal crackles on lung auscultation (pulmonary oedema).

▪ Cachexia may indicate underlying malignancy or an eating disorder.

▪ Perform an abdominal examination to assess for bowel obstruction/constipation, or for evidence of liver dysfunction. Chapter 24 describes an appropriate examination
where alcohol abuse is suspected.

▪ If appropriate, perform a thyroid examination (see Chapter 12).

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276 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Investigations

Bloods

▪ A general rule: when presented with any electrolyte abnormality, repeat the test. As such, take repeat blood for electrolytes (sodium, potassium), alongside urea and cre- atinine. Creatinine levels will provide insight into renal function.

▪ Check serum lipid and protein levels; severely raised triglyceride and protein levels can occasionally be responsible for incorrect laboratory calculation of sodium levels (pseudohyponatraemia).

▪ Check serum calcium (hypercalcaemia can induce diabetes insipidus and polydipsia).

▪ Check HbA1c to screen for diabetes mellitus.

▪ Check lithium levels if appropriate.

▪ Check brain natriuretic peptide levels if heart failure is suspected.

▪ Perform liver function tests.

▪ Checking serum osmolality paired with urine osmolality and sodium levels can pro-
vide insight into the underlying aetiology of dysnatraemia. Interpretation of paired urine/serum osmolalities in the setting of water overload and diabetes insipidus is discussed further in Chapter 31. SIADH is characterised by reduced plasma osmolal- ity (<275 mosmol/kg), increased urine osmolality (>100 mosmol/kg), and raised uri- nary sodium levels (>20 mmol/L). An early morning urine osmolality (after fasting for six to eight hours) is useful for diagnosing diabetes insipidus; if the urine osmolality is greater than 400 mosmol/kg, it excludes severe diabetes insipidus.
Urine

▪ History can often distinguish polyuria from increased urinary frequency, but occa- sionally a 24‐hour urine collection may be needed. Where diabetes insipidus is sus- pected, give the patient two collection jars as they may produce in excess of 8 L of urine. The practicality of such an investigation will depend on a patient’s mental state.

▪ Perform a urine dip examining for proteinuria (if concerns about renal failure or diabetes mellitus), glucose, and ketones.

▪ As already discussed, consider testing urine osmolality and sodium levels, paired with serum osmolality and sodium levels.
MANAGEMENT Hyponatraemia
It is recommended that management of acute hyponatraemia, severe hyponatraemia (<120 mmol/L), or symptomatic hyponatraemia occurs in a general medical setting [3]. These patients will require careful monitoring of electrolytes, controlled use of fluid resuscitation or diuresis, and management of the underlying pathology. When in doubt

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Sodium Derangement 277

regarding the appropriate setting for a patient’s management, discuss with medical colleagues.

Mild hyponatraemia in stable patients may be managed in a psychiatric setting according to the clinician’s experience. Any degree of hyponatraemia should prompt a medication review, and rationalisation of treatments performed where one or more agents are implicated. Where antidepressant treatment is necessary in the setting of hyponatraemia, strongly consider stopping concurrent use of thiazide diuretics (after consultation with medical colleagues). Compared with other antidepressants, mirtazap- ine and mianserin have lower hyponatraemia risk profiles. Alternatives are agomelatine or bupropion.

In patients with chronic hyponatraemia in association with underlying conditions (i.e. liver, heart, or kidney failure), referral to corresponding specialties may be of ben- efit in elucidating how these patients can be managed within mental health teams or whether they require specialist assessment. Psychogenic polydipsia may be managed using psychoeducation, fluid restriction, and treatment of the underlying psychiatric disorder. There is evidence that clozapine improves polydipsia [22].

Hypernatraemia

The most common cause of hypernatraemia is secondary to gastrointestinal losses or excessive use of diuretics [23]. Where intravenous replacement of fluids is required, the patient should be transferred to a general medical hospital; uncontrolled correction can result in cerebral oedema [24]. If nephrogenic diabetes insipidus is suspected secondary to lithium, it is important that the patient is given free access to water. Management of nephrogenic diabetes insipidus is covered in Chapter 31.

References

1. Henry DA. In the clinic: hyponatremia. Ann Intern Med 2015;163(3):ITC1–19.

2. Muhsin SA, Mount DB. Diagnosis and treatment of hypernatremia. Best Pract Res Clin Endocrinol Metab 2016;30(2):189–203.

3. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Intensive Care Med
2014;40(3):320–331.

4. Long CA, Marin P, Bayer AJ, et al. Hypernatraemia in an adult in‐patient population. Postgrad Med J 1991;67(789):643–645.

5. Chan TY. Drug‐induced syndrome of inappropriate antidiuretic hormone secretion. Causes, diagnosis and management. Drugs Aging
1997;11(1):27–44.

6. Mascolo M, Chu ES, Mehler PS. Abuse and clinical value of diuretics in eating disorders therapeutic applications. Int J Eat Disord
2011;44(3):200–202.

7. Tozzi F, Thornton LM, Mitchell J, et al. Features associated with laxative abuse in individuals with eating disorders. Psychosom Med
2006;68(3):470–477.

8. Letmaier M, Painold A, Holl AK, et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme.
Int J Neuropsychopharmacol 2012;15(6):739–748.

9. Lien YH. Antidepressants and hyponatremia. Am J Med 2018;131(1):7–8.

10. Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or parox- etine in elderly people. Br J Clin Pharmacol 1999;47(2):211–217.

11. Peterson JC, Pollack RW, Mahoney JJ, Fuller TJ. Inappropriate antidiuretic hormone secondary to a monamine oxidase inhibitor. JAMA 1978;239(14):1422–1423.

12. Kimelman N, Albert SG. Phenothiazine‐induced hyponatremia in the elderly. Gerontology 1984;30(2):132–136.

13. Spigset O, Hedenmalm K. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psycho-
tropic drugs. Drug Saf 1995;12(3):209–225.

14. Peck V, Shenkman L. Haloperidol‐induced syndrome of inappropriate secretion of antidiuretic hormone. Clin Pharmacol Ther
1979;26(4):442–444.

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15. Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994;35(1):181–188.

16. Miyaoka T, Seno H, Itoga M, et al. Contribution of sodium valproate to the syndrome of inappropriate secretion of antidiuretic hormone. Int Clin Psychopharmacol 2001;16(1):59–61.

17. Mewasingh L, Aylett S, Kirkham F, Stanhope R. Hyponatraemia associated with lamotrigine in cranial diabetes insipidus. Lancet 2000;356(9230):656.

18. Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009;5(5):270–276.

19. Gehi MM, Rosenthal RH, Fizette NB, et al. Psychiatric manifestations of hyponatremia. Psychosomatics 1981;22(9):739–743.

20. Leth‐Moller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register‐based population study.
BMJ Open 2016;6(5):e011200.

21. De Picker L, Van den Eede F, Dumont G, et al. Antidepressants and the risk of hyponatremia: a class‐by‐class review of literature.
Psychosomatics 2014;55(6):536–547.

22. Kirino S, Sakuma M, Misawa F, et al. Relationship between polydipsia and antipsychotics: a systematic review of clinical studies and case
reports. Prog Neuropsychopharmacol Biol Psychiatry 2020;96:109756.

23. Pfennig CL, Slovis CM. Sodium disorders in the emergency department: a review of hyponatremia and hypernatremia. Emerg Med Pract
2012;14(10):1–26.

24. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342(20):1493–1499.

CHAPTER 32

Chapter 33

Potassium Derangement

Ellis Onwordi, Peter Conlon

Derangements in potassium levels are common in the general medical patient popula- tion. Hypokalaemia occurs in approximately 2–3% of outpatients [1] and 20% of inpatients [2] while hyperkalaemia occurs in 0.2–0.7% of outpatients [1] and 1.4% of inpatients [3]. Rates of potassium abnormalities in patients with serious mental illness (SMI) are poorly defined. However, psychiatric patients represent a vulnerable cohort for renal disease that increases risk of hyperkalaemia (see Chapters 34 and 73). Furthermore, rhabdomyolysis, which can occur in the context of physical restraint or neuroleptic malignant or serotonin syndrome, can also result in hyperkalaemia. Some psychiatric disorders predispose to hypokalaemia owing to insufficient dietary potas- sium (e.g. in patients with eating disorders, catatonia, stupor, dementia, severe negative symptoms, or alcohol dependence). Severe derangements in potassium levels are medi- cal emergencies owing to the associated risk of cardiac arrhythmia and arrest. Where patients are prescribed psychiatric medications that prolong the QT interval (see Chapter 3), derangements in potassium levels further increase the risk of torsade de pointes [4].

HYPERKALAEMIA

While there is no universally accepted definition of abnormally elevated extracellular potassium levels (hyperkalaemia), it is often defined as a serum potassium concentration of 5.5 mmol/L or greater [5,6]. It can be categorised as mild (5.5–5.9 mmol/L), moder- ate (6.0–6.4 mmol/L), and severe (≥6.5 mmol/L) [5]. As shown in Box 33.1, hyperkalae- mia is caused by one or a combination of excessive potassium intake, reduced renal

Box 33.1 Common causes of raised potassium [8] Excessive intake

▪ Dietary (foods high in potassium, e.g. bananas, dried fruit)

▪ Excessive iatrogenic potassium supplementation or use of potassium‐containing laxatives (e.g.
Movicol and Fybogel)

▪ Red blood cell transfusion

▪ Pica
Insufficient excretion

▪ Acute kidney injury (AKI; see Chapter 73)

▪ Chronic kidney disease (CKD; see Chapter 34)

▪ Decreased renal blood flow (AKI/CKD, cirrhosis, congestive heart failure)

▪ Drugs: angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, non‐steroidal
anti‐inflammatories, spironolactone

▪ Primary renal tubular disorders:

▪ Sickle cell disease

▪ Obstructive uropathy

▪ Amyloidosis

▪ Systemic lupus erythematosus

▪ Tubular defects

▪ Hypoaldosteronism (e.g. Addison’s) Transcellular shift

▪ Insulin deficiency or resistance

▪ Metabolic acidosis

▪ Medications (e.g. beta‐blockers, digoxin)

▪ Cell breakdown (e.g. rhabdomyolysis, haemolysis)

▪ Genetic (e.g. hyperkalaemic periodic paralysis)

280 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

potassium excretion, or transcellular potassium shifts [7]. Pseudohyperkalaemia is where laboratory test results erroneously report hyperkalaemia; the most common cause is haemolysis of blood cells owing to poor blood‐drawing/handling technique or samples being left for prolonged periods before being analysed.

Diagnostic principles

Severe hyperkalaemia is a medical emergency. When a potassium level of ≥6.0mmol/L is recorded in a psychiatric inpatient setting, the patient should be immediately assessed using the ABC approach with an ECG performed. In an outpatient setting, and in the absence of facilities to allow appropriate clinical assessment, the patient will likely require assessment in an Accident and Emergency department. If possible, check previ- ous blood test results; chronic hyperkalaemia is generally better tolerated that an acute rise in potassium.

CHAPTER 33

History

. 1 Symptoms:

. a Many patients are asymptomatic. Severe hyperkalaemia can be associated with
weakness, flaccid paralysis, and paraesthesia. Arrhythmia may be accompanied by
palpitations, shortness of breath, and chest pain.

. b Screen for symptoms indicative of an underlying pathoaetiology, e.g. recent diar-
rhoea/vomiting if concerns regarding volume depletion, or fatigue, weight loss, and
abdominal pain that may accompany Addison’s disease.

. 2 Past medical history: screen for chronic kidney disease. If patients are receiving
dialysis, determine the time since last dialysis, any recent complications during dialysis
(e.g. insufficient duration), or non‐compliance with dialysis or a low‐potassium diet.

. 3 Drug history (see Box 33.1).

Examination

. 1 Check basic observations, assessing heart rate, blood pressure, respiratory rate, and oxygen saturation. Also check finger‐prick blood glucose.

. 2 Assess volume status and examine for potential causes of acute kidney injury (AKI)/ chronic kidney disease (CKD) (see Chapters 34 and 73). If creatinine is raised, the patient is a poor historian, previously not known to services, and with an unclear past medical history, examine for evidence of dialysis access (central venous catheter, peritoneal dialysis catheter, arteriovenous fistula). Assess for features of adrenal insufficiency (e.g. hyperpigmentation, postural hypotension).

. 3 Perform a cardiac examination for evidence of arrhythmia or cardiac failure (e.g. pulmonary oedema).

Investigations

. 1 Bloods that are generally available in a psychiatric setting:

. a repeat serum potassium (rule out pseudohyperkalaemia)

. b urea, electrolytes, and creatinine

. c creatine kinase (if rhabdomyolysis, neuroleptic malignant syndrome, or serotonin
syndrome suspected)

. d morning (9 a.m.) cortisol if suspicion of Addison’s (hyponatraemia alongside
hyperkalaemia may be indicative of adrenal insufficiency).*

. 2 Perform an ECG in all patients with potassium in excess of 6.0 mmol/L. ECG fea-
tures of hyperkalaemia include:
a tented T waves (larger than R wave in more than one lead) b flattened/absent P waves
c prolonged PR interval (>200 ms)
d ST depression
e widened QRS complex (>120 ms)

*If there are acute concerns about Addison’s, patients should be seen and reviewed in the accident and emergency department.

Potassium Derangement 281

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282 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

f QRS complexes merging with T waves (‘sine‐wave’ pattern) g sinus bradycardia
h ventricular tachycardia.

A widened QRS complex, sine‐wave pattern, bradycardia, and ventricular tachycardia are associated with a high risk of cardiac arrest. Of note, even in the presence of severe hyper- kalaemia, ECG changes may not occur. Thus, a normal ECG does not mean that escalation of care is not indicated. However, the presence of ECG changes should prompt urgent action.

Management [9]

The principles of the treatment of hyperkalaemia are as follows [10].

. 1 Protect the heart.

. 2 Shift potassium into cells.

. 3 Remove potassium from the body.

. 4 Assess medications. Most cases of hyperkalaemia result from use of angiotensin‐
converting enzyme inhibitors, angiotensin receptor blockers, or spironolactone. Assess dietary potassium intake and advise low potassium diet (no bananas, oranges, orange juice, or tomatoes).

. 5 Monitor potassium over time.

. 6 Prevent recurrence.
Realistically, only mild hyperkalaemia without ECG changes can be managed in a

psychiatric setting, and any treatment should be guided by the skillset of the clinician and available facilities. To reiterate, patients with more advanced hyperkalaemia and/ or associated ECG changes must be managed as a medical emergency and referred urgently to acute medical colleagues. In a psychiatric setting this will likely involve call- ing an ambulance. When in doubt, discuss with general medical colleagues.

The exchange resin oral calcium resonium (15 g q.d.s.), which shifts potassium across the intestinal wall, can be used to remove potassium from the body. Glucose/insulin intravenous infusion (50 mL 50% glucose containing 5–10 units of short‐acting insulin over 15 minutes) and nebulised salbutamol (10–20 mg) shift potassium into cells. Of these three options, only oral calcium resonium is likely to be available in an inpatient psychiatric setting. Such an intervention may be considered in patients with mild hyperkalaemia while also treating/ managing the underlying precipitant (e.g. stopping a causative drug; see Box 33.1).

Intravenous calcium salts (calcium chloride or calcium gluconate) antagonise cardiac membrane excitability and thus protect the heart. This intervention, alongside other interventions such as sodium bicarbonate infusion if the patient is acidotic and haemo- dialysis, may be considered by medical colleagues.

HYPOKALAEMIA

Hypokalaemia is the most common electrolyte disturbance in general medical patients [11]. It is defined as a serum potassium concentration below 3.5 mmol/L [12]. It can be categorised as mild (3.0–3.5 mmol/L), moderate (2.5–3.0 mmol/L), and severe (<2.5 mmol/L) [10]. As shown in Box 33.2, hypokalaemia is caused by one or a combination

CHAPTER 33

Potassium Derangement 283

Box 33.2 Causes of reduced serum potassium [8] Insufficient intake

▪ Anorexia

▪ Bulimia

▪ Starvation

▪ Dementia

▪ Alcohol excess

▪ Total parenteral nutrition
Excessive losses

▪ Medications:

▪ Diuretics

▪ Laxative abuse

▪ Enemas

▪ Corticosteroids

▪ Gastrointestinal losses

▪ Vomiting

▪ Diarrhoea

▪ Villous adenoma

▪ Intestinal fistula

▪ Ileostomy

▪ Renal losses

▪ Osmotic diuresis

▪ Mineralocorticoid excess

▪ Renal tubular acidosis

▪ Polydipsia

▪ Intrinsic renal transport defects

▪ Endocrine

▪ Cushing’s syndrome

▪ Hyperaldosteronism

▪ Conn’s syndrome

▪ Primary renal tubular disorders

▪ Sickle cell disease

▪ Obstructive uropathy

▪ Amyloidosis

▪ Systemic lupus erythematosus

▪ Hereditary tubular defects

▪ Dialysis (haemodialysis using a low potassium dialysate, peritoneal dialysis)

▪ Hypomagnesaemia
Transcellular shift

▪ Medication, e.g. insulin, β2 agonists (e.g. salbutamol)

▪ Refeeding syndrome

▪ Increased β2 adrenergic stimulation:

▪ Head injury

▪ Delirium tremens

▪ Myocardial ischaemia

▪ Hypothermia

▪ Thyrotoxicosis

▪ Alkalosis

▪ Genetic (e.g. familial hypokalaemic periodic paralysis)

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284 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

of excessive potassium loss, cellular shift of potassium out of the blood into cells, and decreased potassium intake. Most cases are due to medication and gastrointestinal dis- ease (e.g. diarrhoea).

Diagnostic principles

History

. 1 Symptoms:

. a Mild hypokalaemia is generally asymptomatic; however, as hypokalaemia becomes
more pronounced, patients can develop generalised weakness, fatigue, cramps,
paraesthesia, and constipation.

. b In severe hypokalaemia, cardiac arrhythmia, ascending paralysis, tetany, respira-
tory failure, ileus, and rhabdomyolysis may occur.

. c Screen for signs or symptoms associated with causative pathology, e.g. diarrhoea/
vomiting of gastroenteritis, presence of purging behaviour in the context of an eat-
ing disorder, evidence of thyrotoxicosis or of alcohol dependence.

. 2 Document past medical history for conditions associated with hypokalaemia (see Table 2). Furthermore, enquire as to a history of cardiovascular disease: the probabil- ity of symptoms associated with hypokalaemia increases in the presence of pre‐exist-
ing heart disease [12].

. 3 Drug history (see Box 33.2).

. 4 Social history: define quantity and frequency of alcohol consumption.

Examination

. 1 Check basic observations, assessing heart rate, blood pressure, respiratory rate, and oxygen saturation.

. 2 Perform a general examination assessing for cachexia (insufficient oral intake of potas- sium) or features of purging behaviour in eating disorders (e.g. calluses/scars on fingers).

. 3 If appropriate, perform a thyroid examination if concerns regarding thyrotoxicosis (see Chapter 12). Chapter 24 describes an appropriate examination where alcohol abuse is suspected.

. 4 Perform a cardiac examination for evidence of arrhythmia or cardiac failure (e.g. pulmonary oedema).

Investigations

1 Consider performing the following blood tests.

. a Repeat urea, electrolytes (sodium and potassium), and creatinine to confirm
hypokalaemia.

. b Also check serum magnesium (hypomagnesaemia is associated with hypokalae-
mia; low levels of both magnesium and potassium increase risk of cardiac arrhyth- mia) and thyroid function tests if concerns regarding thyrotoxicosis.

CHAPTER 33

Potassium Derangement 285

2 Perform an ECG in all patients with potassium below 3.5 mmol/L. ECG changes may be absent, but severe hypokalaemia may be associated with U waves (a small deflec- tion immediately following the T wave, usually in the same direction as the T wave), T‐wave flattening, or ST segment changes.

Management

Treatment is guided by the extent of hypokalaemia, the presence of symptoms, and associated ECG changes. The principles of treatment of hypokalaemia are as follows.

1 Replace potassium.
2 Identify and address underlying cause. 3 Prevent recurrence.

Stable patients with mild hypokalaemia typically require only oral potassium replace- ment therapy with potassium chloride, which may be provided in a psychiatric setting. Effervescent tablets (e.g. Sando‐K), which each contain 12 mmol of potassium and 8 mmol of chloride, are preferable over modified‐release tablets (e.g. SlowK) which may cause gastric irritation. For plasma potassium levels of 3.0–3.5 mmol/L, an appropriate starting dose is Sando‐K two tablets three times daily, accompanied by twice‐weekly monitoring of potassium. Once plasma potassium levels are stable or if potassium is above 4.5 mmol/L, reassess need for supplementation. Regardless of the preparation of potassium used (different countries may use different products), a dose of 20 mmol/day of potassium in oral form is generally sufficient for the prevention of hypokalaemia, and 40–100 mmol/day enough for its treatment [13]. It would be unwise to manage plasma potassium levels of 2.5–2.9 mmol/L using oral potassium prepara- tions as these patients typically have a total body deficit of potassium of between 100 and 200 mmol and will likely require intravenous supplementation. It is recommended that these patients are discussed with medical colleagues to assess need for intravenous potassium replacement. Severe hypokalaemia (<2.5 mmol/L) or any degree of hypoka- laemia with associated ECG changes should prompt urgent medical referral for intra- venous supplementation.

Efforts should also be made to identify and address the underlying cause of hypoka- laemia. This may be obvious in the case of malnutrition or diarrhoea/vomiting. Medications such as loop/thiazide diuretics may be implicated and need review, although changes to such treatment should not be attempted without prior discussion with medical colleagues. For persistent hypokalaemia, a diet high in potassium may be necessary (i.e. rich in bananas, oranges, and tomatoes).

References

1. Liamis G, Rodenburg EM, Hofman A, et al. Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med 2013;126(3):256–263.

2. Paice BJ, Paterson KR, Onyanga‐Omara F, et al. Record linkage study of hypokalaemia in hospitalized patients. Postgrad Med J 1986;62(725):187–191.

3. Paice B, Gray JM, McBride D, et al. Hyperkalaemia in patients in hospital. BMJ 1983;286(6372):1189–1192.

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286 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

4. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2010;55(9):934–947.

5. Soar J, Perkins GD, Abbas G, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation 2010;81(10):1400–1433.

6. Nyirenda MJ, Tang JI, Padfield PL, Seckl JR. Hyperkalaemia. BMJ 2009;339:b4114.

7. Evans KJ, Greenberg A. Hyperkalemia: a review. J Intensive Care Med 2005;20(5):272–290.

8. Viera AJ, Wouk N. Potassium disorders: hypokalemia and hyperkalemia. Am Fam Physician 2015;92(6):487–495.

9. Alfonzo A, Soar J, MacTier R, et al. Treatment of acute hyperkalaemia in adults. UK Renal Association: Clinical Practice Guidelines. Final
revision March 2014. https://renal.org/wp‐content/uploads/2017/06/hyperkalaemia‐guideline‐1.pdf

10. Alfonzo AV, Isles C, Geddes C, Deighan C. Potassium disorders: clinical spectrum and emergency management. Resuscitation
2006;70(1):10–25.

11. Rastegar A, Soleimani M. Hypokalaemia and hyperkalaemia. Postgrad Med J 2001;77(914):759–764.

12. Gennari FJ. Hypokalemia. N Engl J Med 1998;339(7):451–458.

13. Cohn JN, Kowey PR, Whelton PK, Prisant LM. New guidelines for potassium replacement in clinical practice: a contemporary review by the
National Council on Potassium in Clinical Practice. Arch Intern Med 2000;160(16):2429–2436.

CHAPTER 33

Chapter 34

Chronic Kidney Disease

Ellis Onwordi, Toby Pillinger, Anne Connolly, Peter Conlon

Chronic kidney disease (CKD) is defined as deterioration in kidney function or kidney damage lasting for at least three months [1]. Deterioration in kidney function is often identified as a reduction in glomerular filtration rate (GFR), usually estimated from blood creatinine (eGFR). eGFR is calculated from serum creatine, race, sex, and age; if eGFR is not provided by a laboratory, there are several online calculators.* From the eGFR, patients can be categorised into one of five stages of CKD (Table 34.1). Damage to the kidney may be identified indirectly by identification of blood or albumin (avail- able from urine dipstick or laboratory measurement) in the urine. End‐stage renal dis- ease is CKD requiring dialysis or transplantation.

CKD represents a heterogeneous group of disorders, with many causes (Box 34.1). It is common, with a global mean prevalence (accounting for all stages of the disease) of 13.4% [2]. Compared with the general population, there is a higher prevalence of CKD in patients with severe mental illness (SMI), in particular schizophrenia and bipolar affective disorder [3–6]. This is likely secondary to increased rates of physical comor- bidity associated with development of CKD such as diabetes mellitus and hypertension [7–10], as well as the nephrotoxic effects of some psychiatric drugs. Most notably, lithium is directly nephrotoxic [11], although case reports suggest that direct nephro- toxicity can (rarely) occur with other psychotropic agents [12–17]. Furthermore, the anticholinergic effects of some psychiatric drugs can cause urinary retention which, via

*Estimated glomerular filtration rate can be determined using various equations, including the Cockcroft– Gault formula (an online calculator is available at https://www.mdcalc.com/creatinine‐clearance‐cockcroft‐ gault‐equation) or the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula (https:// http://www.kidney.org/professionals/kdoqi/gfr_calculator). Note that the CKD‐EPI formula is more accurate; how- ever, the Cockcroft–Gault formula should usually be used to determine appropriate drug doses since this is the formula used in the literature to calculate most (but not all) current dose recommendations.

288 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 34.1 Stages of chronic kidney disease based on glomerular filtration rate (GFR) and degree of albuminuria (albumin excretion rate, AER) [1].

GFR stages

G3a

G3b

Albuminuria stages

GFR (mL/min per 1.73 m2)

≥90

60–89

45–59

30–44

15–29

<15

AER (mg/day)

<30

30–300

>300

Interpretation

Normal
Mildly decreased
Mildly to moderately decreased Moderately to severely decreased
Severely decreased
Kidney failure (‘5D’ if treated with dialysis)

Normal to mildly increased Moderately increased Severely increased

CHAPTER 34

hydronephrosis, may damage the kidneys [18,19]. Of note, the relationship between CKD and psychiatric disorders is bidirectional. For example, patients with CKD under- going renal replacement therapy exhibit high rates of depression and anxiety [20,21].

CKD is associated with increased all‐cause mortality, although the leading cause of death in this group is cardiovascular disease [22–24]. CKD is also associated with a number of other complications which reflect diminished endocrine and/or exocrine function. These include, depending on the severity of CKD, increased risk of acute kidney injury (see Chapter 73), anaemia (secondary to reduced renal erythropoietin synthesis capacity), hypertension, dyslipidaemia, mineral bone disorders, metabolic aci- dosis, electrolyte abnormalities most notably hyperphosphataemia and hyperkalaemia (see Chapter 33), hyperparathyroidism, infection, uraemia (symptoms/complications of which can include pruritis, restless legs syndrome, sleep disturbance, fatigue, sexual dysfunction, anorexia and cachexia, bleeding, pericarditis, and encephalopathy), thy- roid dysfunction (see Chapter 12), and increased risk of drug toxicity owing to accumu- lation of renally excreted agents [1,25–27].

There are various clinical scenarios in which a psychiatric practitioner may need to consider CKD as part of the holistic care they provide patients. The first scenario, usually encountered in an inpatient setting, is determining whether a patient with raised serum creatinine is presenting with an acute or a chronic kidney injury, as this will determine the urgency with which subsequent investigations are performed. The second scenario, again generally encountered in an inpatient setting, is dealing with the complications of CKD, such as electrolyte disturbance or the accumulation of renally excreted drugs such as lithium. The third scenario, which occurs in both inpa- tient and outpatient settings, is supporting patients with established CKD to reduce the risk of worsening renal disease via control of risk factors such as smoking, hyper- tension, and diabetes mellitus. The fourth scenario, again pertinent to all clinical

Chronic Kidney Disease 289

Box 34.1 Causes of chronic kidney disease Diabetes mellitus

▪ Hypertension

▪ Obesity

▪ Obstructive uropathy

▪ Glomerulonephritis

▪ Chronic interstitial nephritis

▪ Polycystic kidney disease

▪ Autoimmune disease

▪ Genetic

▪ Malignancy
Infections (examples)

▪ Human immunodeficiency virus

▪ Hepatitis B and C

▪ Malaria

▪ Schistosomiasis

▪ Leptospirosis

▪ Hantavirus

▪ Scrub typhus
Drug toxicity (examples)

▪ Lithium

▪ Non‐steroidal anti‐inflammatory drugs

▪ Chemotherapy

▪ Proton pump inhibitors

▪ Antimicrobial agents

▪ Some herbal medicines (e.g. Aristolochia species)

settings, is appropriate prescription of psychiatric medication in the context of CKD, be that drugs that are directly nephrotoxic (lithium) or those indirectly nephrotoxic (e.g. metabolic effects of some antipsychotics and mood stabilisers), drugs that are predominantly renally excreted and thus may accumulate (e.g. lithium, sulpiride, and amisulpride), or drugs with side effects that may be amplified in the context of reduced renal excretion (e.g. sedative effects of benzodiazepines or anticholinergic effects of tricyclic antidepressants).

DIAGNOSTIC PRINCIPLES

Promptly determining whether a blood test result represents an acute or chronic dete- rioration in kidney function is paramount. As such, it is recommended that previous blood test results, where available, are checked early. The reader is directed to Chapter 73 on acute kidney injury where such a presentation is suspected.

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290 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

History

Chronic kidney disease is usually asymptomatic, with signs and symptoms only arising in later stages of illness in the context of the complications detailed previ- ously. However, non‐specific symptoms such as lethargy, nausea and vomiting, anorexia, and pruritis may occur, and some symptoms may point to specific renal/ urinary pathology, such as loin pain, haematuria, changes in urinary frequency, and frothy urine.

In terms of past medical history, other than determining if there is pre‐existing CKD, enquire about the presence of other comorbidities and risk factors for CKD (see Box 34.1). Scrutinise medication lists for any agents that are associated with kidney damage (see Box 34.1), for drugs that may accumulate in the context of renal dysfunc- tion, and for drugs that may be harmful in CKD (e.g. metformin owing to risk of lactic acidosis; use is contraindicated when GFR <30 mL/min). In terms of drug accumula- tion, psychiatric medications to be particularly aware of are lithium, amisulpride, and sulpiride; however, the reader should be aware that a number of psychiatric drugs and their active metabolites can accumulate in CKD [28]. Take a family history for CKD and polycystic kidney disease, and a social history for smoking, alcohol intake, and recreational drug use; complications of the latter include glomerulonephritis and amy- loidosis in intravenous drug users, renal failure secondary to rhabdomyolysis with use of cocaine and amphetamines for example, and renal artery atherosclerosis with cocaine use [29].

Examination

The purpose of examination is to rule out complications secondary to CKD, and if aetiology is unclear to identify potential causes. A set of basic observations includ- ing blood pressure may identify comorbid hypertension, and low oxygen saturation may indicate pulmonary oedema. Abdominal, cardiac, and respiratory examina- tions should be performed. General inspection may provide evidence of fluid over- load (shortness of breath, peripheral oedema), anaemia (conjunctival pallor), or the accumulation of certain drugs (e.g. tremor in context of lithium). Cardiac and res- piratory examination will again screen for evidence of fluid overload (raised jugular venous pressure, crackles on auscultation of the lungs). Abdominal examination should inspect for masses, which may indicate polycystic kidney disease, or for a distended bladder in a male patient in chronic urinary retention. General inspection may identify features of other systemic illnesses associated with CKD (e.g. rheuma- tological disease).

Investigations

The following tests may be considered by a psychiatric team and will aid in ruling out acute life‐threatening presentations that may accompany CKD (e.g. hyperkalaemia), but will also strengthen a referral to renal colleagues, especially if the aetiology of the CKD has not previously been investigated.

CHAPTER 34

Bloods

▪ Urea, electrolytes (sodium and potassium), creatinine, and eGFR.

▪ Bone profile (check phosphate levels).

▪ Liver function.

▪ Full blood count (anaemia).

▪ HIV, hepatitis B and C (potential causes of CKD).

▪ HbA1c (diabetes mellitus).

▪ Autoimmune profile (autoimmune cause suspected).

▪ If appropriate, plasma levels of drugs that accumulate in renal failure (e.g. lithium,
amisulpride, and sulpiride).
Urine

▪ Dip urine for proteinuria and haematuria.

▪ Measure urinary albumin and calculate the albumin/creatinine ratio.

▪ Consider sending urine for microscopy (casts).
ECG
Examine for consequences (e.g. hyperkalaemia) or causes (e.g. left ventricular hypertro- phy of hypertension) of CKD.
Imaging and other specialist investigations
If this is a new presentation of CKD with no previous investigations, consider referring the patient for an ultrasound of the kidney and urinary tract, examining for any struc- tural abnormalities. If appropriate, renal physicians may request/perform specialist investigations such as MRI of the kidneys (examining for renal artery stenosis) and potentially renal biopsy if aetiology of CKD remains unclear
MANAGEMENT
Specific management of CKD is clearly beyond the remit of the psychiatrist; however, as already described, there are various clinical scenarios in which a psychiatric practi- tioner may need to consider CKD as part of the holistic care they provide their patient. The reader is directed to Chapter 73 on acute kidney injury where such a presentation is suspected, or indeed acute‐on‐chronic injury (where a renal insult occurs in the set- ting of already chronically impaired renal function). The reader is also directed to Chapter 33 on potassium disturbance, which provides advice on appropriate manage- ment of hyperkalaemia.
The general principles of management of CKD are summarised in Box 34.2. In the UK, patients with CKD stage 4 or above are generally managed in secondary care, with regular follow‐up to monitor for progression of disease. Specialist renal input should

Chronic Kidney Disease 291

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Box 34.2 General principles of chronic kidney disease management

▪ Manage reversible causes of renal impairment, e.g. nephrotoxic drugs (especially non‐steroidal anti‐inflammatory drugs), decreased perfusion, urinary tract obstruction

▪ Control risk factors, e.g. glycaemic control in diabetes, blood pressure control in hypertension, smoking cessation

▪ Manage complications, e.g. anaemia, but this should be managed with secondary care input. People with stage 3, 4 or 5 CKD are at increased risk of influenza and should be immunised (see Chapter 40)

292 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

also be sought where hereditary renal disease is suspected, or for persistent CKD‐ associated complications such as recurrent hyperkalaemia or recalcitrant hypertension.

Regardless of the cause of CKD, all patients should have risk factors for CKD and broader cardiovascular risk factors aggressively managed, including control of weight gain, hypertension, hypercholesterolaemia, and diabetes mellitus, and referral for smok- ing cessation. Psychiatrists may be in a unique position to facilitate management of these comorbidities and risk factors, particularly in patients who engage poorly with primary or secondary (renal) care. Thus, rationalisation of psychiatric medication may be indicated, switching to agents with fewer metabolic side effects (see Chapter 14) [30], as well as providing the patient with information on smoking cessation (see Chapter 46) and diet.

It is generally wise to assume mild renal impairment in all patients above 65 years of age, and to adjust prescribing practice accordingly until blood test results are available. A summary of considerations when prescribing antidepressants, antipsychotics, mood stabilisers, anxiolytics/hypnotics, and anti‐dementia drugs in the context of CKD is provided in Table 34.2; the reader is directed to the latest edition of the Maudsley Prescribing Guidelines in Psychiatry for further information on individual drugs [31]. General principles when prescribing psychiatric medications in CKD are as follows.

. 1 Psychotropic and other medications should be rationalised to minimise the risk of direct nephrotoxicity. Decisions to continue lithium treatment (especially when GFR drops below 60 mL/min per 1.73 m2) should be made following a risk–benefit mul- tidisciplinary discussion involving both renal and psychiatric practitioners, alongside the patient. Drugs with anticholinergic effects should be used cautiously, given the risk of urinary retention. As a rule, advice from renal physicians/specialist pharma- cists should be sought where psychiatric prescription is being considered in a patient with moderate/severe CKD or end‐stage renal failure (ESRF).

. 2 There is a risk of drug accumulation (including accumulation of active metabolites) [28] in patients with CKD. As such, drugs that are substantially renally excreted (e.g. lithium, amisulpride, sulpiride) should be used with caution (see Table 34.2), and as a rule all medications should be started at a low dose and up‐titrated slowly, ideally with plasma level monitoring. Furthermore, long‐acting preparations such as antip- sychotic depots, which are hard to titrate safely in the context of changing renal function, should be avoided.

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Chronic Kidney Disease 293

Table 34.2 Special considerations when prescribing antidepressants, antipsychotics, mood stabilisers, anxiolytics and hypnotics, and anti‐dementia drugs in the context of chronic kidney disease (CKD) [31].

Drug class Special considerations

Antidepressants Specific evidence for use in CKD with bupropion, citalopram, escitalopram, fluoxetine, paroxetine, and sertraline

[34–39]; however, note recent evidence suggesting that sertraline’s efficacy in CKD may be limited [40]. There is risk of urinary retention, sedation, and confusion with tricyclic antidepressants. Desvenlafaxine has also been associated with urinary retention

Antipsychotics Monitor anticholinergic, hypotensive, and sedative effects of antipsychotics.

Avoid highly anticholinergic agents where possible
Consider metabolic side effects of some antipsychotics (in particular clozapine, olanzapine, quetiapine, risperidone, and paliperidone) which may indirectly increase risk of progressive CKD [30]

Where possible avoid using long‐ acting injectable formulations

Dose adjustment required in moderate/severe CKD?

For many antidepressants no specific dose adjustments are recommended by manufacturers; however, a principle of starting at a low dose and increasing slowly is widely suggested. Some antidepressants have specific dosing advice by manufacturers or are contraindicated when GFR drops below a threshold. The reader is encouraged to review the summary of product characteristics for a given antidepressant prior to prescribing in patients with CKD, and is directed to the latest edition of the Maudsley Prescribing Guidelines in Psychiatry for further information on individual drugs [31]

Most antipsychotics can be used in severe CKD, although with all antipsychotics caution is advised (start with low dose and titrate). The reader is encouraged to review the summary of product characteristics for a given antipsychotic prior to prescribing in patients with CKD, and is directed to the latest edition of the Maudsley Prescribing Guidelines in Psychiatry for further information on individual drugs [31]

For paliperidone (where renal clearance is reduced by 71% in severe kidney disease), manufacturer recommendations are as follows: oral treatment contraindicated if GFR <10 mL/min, depot contraindicated if GFR <50 mL/min. Although not contraindicated in severe kidney disease, similar caution is recommended with risperidone

Amisulpride and sulpiride are principally excreted renally so should be avoided in ESRF. For less severe CKD, manufacturer recommendations are as follows:

▪ Amisulpride: if GFR 30–60 mL/min, give 50% of dose; if GFR
10–30 mL/min, give 33% of dose

▪ Sulpiride: if GFR 30–60 mL/min, give 70% normal dose; if GFR
10–30 mL/min, give 50% of dose

Reasonable choices in CKD

Citalopram (although monitor for QTc prolongation)

Low‐dose olanzapine (although beware metabolic side effects) or haloperidol

(continued )

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294 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 34.2 (Continued)

Drug class

Mood stabilisers

Special considerations

Long‐term treatment with lithium may cause progressive irreversible impaired renal function, altered renal histology, nephrogenic diabetes insipidus (see Chapter 31), and nephrotic syndrome. Lithium causes CKD via chronic interstitial nephritis, glomerulonephritis, and formation of renal cysts Carbamazepine is associated with increased rates of CKD [5]
Consider metabolic side effects of lithium and sodium valproate which may indirectly increase risk of progressive CKD

Monitor for excessive sedation

N/A

Dose adjustment required in moderate/severe CKD?

Apart from lithium, no specific dose adjustments are advised, although with all mood stabilisers caution is advised (start with small dose and titrate) Lithium is not only nephrotoxic but is also almost entirely renally excreted.
As such, it is contraindicated in severe renal impairment (consider if continued prescription is appropriate when GFR <60 mL/min). Where a decision is made to continue lithium despite renal impairment, the following dose adjustments are recommended:
■ If GFR 10–50 mL/min, give 50–75%

normal dose and monitor levels
■ If GFR <10 mL/min, give 25–50% normal dose and monitor levels

Caution advised with all agents: start with small dose and titrate

No dose adjustment required with donepezil
Start galantamine, memantine, and rivastigmine at low dose and titrate

Reasonable choices in CKD

Low‐dose lamotrigine with up‐titration as required (if possible, with plasma concentration monitoring)

Lorazepam (as short‐acting) and zopiclone

No specific agent deemed to be superior in CKD

CHAPTER 34

Anxiolytics and hypnotics

Anti‐dementia drugs

ESRF, end‐stage renal failure; GFR, glomerular filtration rate.

3 Diminished drug clearance in CKD increases the risk of side effects with certain medications (e.g. sedation and confusion with benzodiazepines). Thus, as described, low doses of medication with cautious titration should be employed. Avoid drugs associated with QTc interval prolongation given the prevalence of electrolyte distur- bance in CKD, and polypharmacy to minimise the risk of drug interactions and asso- ciated adverse effects.

End‐stage renal failure

Management of ESRF can be particularly challenging in the context of SMI. Many ESRF patients require regular (usually three times weekly) haemodialysis at a dedicated unit or will receive self‐administered home dialysis; fluctuations in mental state may impact ability to adhere to dialysis timetables with inevitable risk to physical health. Furthermore, these patients will be maintained on a ‘renal’ diet, which has considerable restrictions in water and potassium content; adhering to this regimen in the setting of poor mental health may be difficult. In such circumstances, a multidisciplinary decision

Chronic Kidney Disease 295

will need to be made regarding what level of social care that individual requires. Where a patient has received a renal transplant, consideration must be given to potential inter- actions between immunosuppressant and psychiatric medication. For example, CYP3A4 inducers (e.g. carbamazepine and St John’s Wort) can reduce concentrations of the immunosuppressant tacrolimus leading to transplant rejection [32,33]. Again, multidisci- plinary working between psychiatry and renal colleagues is required to avoid poten- tially fatal complications.

References

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3(1):1–150.

2. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease: a systematic review and meta‐analysis. PLoS One 2016;11(7):e0158765.

3. Tzeng NS, Hsu YH, Ho SY, et al. Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched‐cohort study. BMJ Open 2015;5(1):e006777.

4. Smith DJ, Martin D, McLean G, et al. Multimorbidity in bipolar disorder and undertreatment of cardiovascular disease: a cross sectional study. BMC Med 2013;11:263.

5. Kessing LV, Gerds TA, Feldt‐Rasmussen B, et al. Use of lithium and anticonvulsants and the rate of chronic kidney disease: a nationwide population‐based study. JAMA Psychiatry 2015;72(12):1182–1191.

6. Iwagami M, Mansfield KE, Hayes JF, et al. Severe mental illness and chronic kidney disease: a cross‐sectional study in the United Kingdom. Clin Epidemiol 2018;10:421–429.

7. Osborn DPJ, Wright CA, Levy G, et al. Relative risk of diabetes, dyslipidaemia, hypertension and the metabolic syndrome in people with severe mental illnesses: Systematic review and metaanalysis. BMC Psychiatry 2008;8(1):84.

8. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta‐analysis. Diabetes Care 2008;31(12):2383–2390.

9. Perez‐Pinar M, Mathur R, Foguet Q, et al. Cardiovascular risk factors among patients with schizophrenia, bipolar, depressive, anxiety, and personality disorders. Eur Psychiatry 2016;35:8–15.

10. Ayerbe L, Forgnone I, Addo J, et al. Hypertension risk and clinical care in patients with bipolar disorder or schizophrenia; a systematic review and meta‐analysis. J Affect Disord 2018;225:665–670.

11. Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000;11(8):1439–1448.

12. Kanofsky JD, Woesner ME, Harris AZ, et al. A case of acute renal failure in a patient recently treated with clozapine and a review of previ- ously reported cases. Prim Care Companion CNS Disord 2011;13(3):PCC.10br01091.

13. An NY, Lee J, Noh JS. A case of clozapine induced acute renal failure. Psychiatry Investig 2013;10(1):92–94.

14. Knights MJ, Finlay E. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol
2014;29(7):1131–1138.

15. Eguchi E, Shimazu K, Nishiguchi K, et al. Granulomatous interstitial nephritis associated with atypical drug‐induced hypersensitivity syn-
drome induced by carbamazepine. Clin Exp Nephrol 2012;16(1):168–172.

16. He LY, Peng YM, Fu X, et al. Dibenzodiazepine derivative quetiapine‐ and olanzapine‐induced chronic interstitial nephritis. Renal Failure
2013;35(5):657–659.

17. Onishi A, Yamamoto H, Akimoto T, et al. Reversible acute renal failure associated with clomipramine‐induced interstitial nephritis. Clin Exp
Nephrol 2007;11(3):241–243.

18. Semaan WE, Doyon J, Jolicoeur F, Duchesneau J. Dose‐dependent urinary retention following olanzapine administration. Ann Pharmacother
2006;40(9):1693.

19. Novicki DE, Willscher MK. Case profile: anticholinergic‐induced hydronephrosis. Urology 1979;13(3):324–325.

20. Hedayati SS, Finkelstein FO. Epidemiology, diagnosis, and management of depression in patients with CKD. Am J Kidney Dis
2009;54(4):741–752.

21. Pereira BDS, Fernandes NDS, de Melo NP, et al. Beyond quality of life: a cross sectional study on the mental health of patients with chronic
kidney disease undergoing dialysis and their caregivers. Health Qual Life Outcomes 2017;15(1):74.

22. Perazella MA, Khan S. Increased mortality in chronic kidney disease: a call to action. Am J Med Sci 2006;331(3):150–153.

23. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the
American Heart Association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology
and prevention. Circulation 2003;108(17):2154–2169.

24. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol
2006;17(7):2034–2047.

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25. Bello AK, Alrukhaimi M, Ashuntantang GE, et al. Complications of chronic kidney disease: current state, knowledge gaps, and strategy for action. Kidney Int Suppl 2017;7(2):122–129.

26. Hsu CY, Ordonez JD, Chertow GM, et al. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 2008;74(1):101–107.

27. Thomas R, Kanso A, Sedor JR. Chronic kidney disease and its complications. Prim Care 2008;35(2):329–344, vii.

28. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3–5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant
2012;27(10):3736–3745.

29. Crowe AV, Howse M, Bell GM, Henry JA. Substance abuse and the kidney. Q J Med 2000;93(3):147–152.

30. Pillinger T, McCutcheon R, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia,
predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta‐analysis. Lancet
Psychiatry 2020;7(1):64–77.

31. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry, 13th edn. Chichester: Wiley Blackwell, 2018.

32. Mai I, Stormer E, Bauer S, et al. Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal
transplant patients. Nephrol Dial Transplant 2003;18(4):819–822.

33. Wada K, Takada M, Sakai M, et al. Drug interaction between tacrolimus and carbamazepine in a Japanese heart transplant recipient: a case
report. J Heart Lung Transpl 2009;28(4):409–411.

34. Worrall SP, Almond MK, Dhillon S. Pharmacokinetics of bupropion and its metabolites in haemodialysis patients who smoke. A single dose
study. Nephron Clin Pract 2004;97(3):c83–c89.

35. Joffe P, Larsen FS, Pedersen V, et al. Single‐dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cir-
rhosis compared with healthy subjects. Eur J Clin Pharmacol 1998;54(3):237–242.

36. Yazici AE, Erdem P, Erdem A, et al. Efficacy and tolerability of escitalopram in depressed patients with end stage renal disease: an open
placebo‐controlled study. Klin Psikofarmakol B 2012;22(1):23–30.

37. Blumenfield M, Levy NB, Spinowitz B, et al. Fluoxetine in depressed patients on dialysis. Int J Psychiat Med 1997;27(1):71–80.

38. Doyle GD, Laher M, Kelly JG, et al. The pharmacokinetics of paroxetine in renal impairment. Acta Psychiatr Scand 1989;80:89–90.

39. Friedli K, Guirguis A, Almond M, et al. Sertraline versus placebo in patients with major depressive disorder undergoing hemodialysis: a
randomized, controlled feasibility trial. Clin J Am Soc Nephrol 2017;12(2):280–286.

40. Hedayati SS, Gregg LP, Carmody T, et al. Effect of sertraline on depressive symptoms in patients with chronic kidney disease without dialysis
dependence: the CAST randomized clinical trial. JAMA 2017;318(19):1876–1890.

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Part 6

Sexual and Reproductive Health

Chapter 35

Sexual Dysfunction

Rudiger Pittrof

Sexual dysfunction (SD) describes difficulty experienced at any stage of sexual activity, including pleasure, desire, arousal, or orgasm. In the US general population, the preva- lence of SD is estimated at 43% for women, and 31% for men [1]. Prevalence estimates are even higher in people with serious mental illness (SMI), with SD reported in 60–80% of individuals with anxiety, mood, or psychotic disorders [2–6]. The aetiology of SD is multifactorial, including psychological, physiological, and pharmacological precipi- tants [7], and a number of these precipitants are more prevalent in people with SMI. For example, rates of type 2 diabetes mellitus (T2DM), a major risk factor for SD (up to 75% of men with T2DM experience erectile dysfunction [8]), are increased in psy- chiatric patients [9,10]. Furthermore, SD is associated with use of serotonergic antide- pressants, prolactin‐inducing antipsychotics, mood stabilisers that lower testosterone, and anxiolytics [11]. SD is recognised to have a significant impact on the quality of life and ongoing mental distress of people with SMI [12], and contributes to poor psycho- tropic medication concordance [13,14]. Thus, identifying and addressing SD is a key part of holistic care provision.

ASSESSMENT OF A PATIENT WITH SEXUAL DYSFUNCTION History

▪ Embarrassment and stigma associated with SD is a significant barrier to its discussion with healthcare professionals and thus identification [15]. Box 35.1 provides exam- ple phrases that a clinician may use to broach the subject.

▪ Consider using a questionnaire or rating scale, for example the Arizona Sexual Experiences Scale (ASEX) [16]. The ASEX assesses each of the following: strength of
The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry, First Edition. David M. Taylor, Fiona Gaughran, and Toby Pillinger.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Box 35.1 Normalising discussion about sexual dysfunction: example phrases and approaches Example phrases

▪ ‘Many men have problems with their sex life. Some stop wanting sex, some cannot get an erec- tion, or sometimes their sperm comes too early or not at all. Many of my patients have these problems, so I ask everyone about this. Is this something that concerns you too?’

▪ ‘Many women have problems with their sex life. Some stop wanting sex, some cannot get in the mood for sex, and many cannot achieve an orgasm. Many of my patients have these problems, so I ask everyone about this. Is this something that concerns you too?’
Notes

▪ Some psychiatric clinics employ pre‐assessment psychotropic side‐effect rating assessments. This can provide a convenient entry point to discussion about sexual dysfunction, for example ‘On the side‐effect assessment you ticked experiencing problems with sex. May men/women have prob- lems with their sex life… [continue with example phrases above]’.

▪ As the clinician you may need to endure a few seconds of awkward silence after asking questions about sexual dysfunction. However, allowing a patient to talk about his or her sexual dysfunction is destigmatising, can improve self‐esteem, and will facilitate future discussion. Framing any con- versation in the context that most men and women report sexual dysfunction at some point in their lives helps to normalise experiences.

300 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

sex drive, ease of sexual arousal, for men the ability to get and maintain an erection, for women the ease with which the vagina becomes moist/wet during sex, the ability to reach orgasm, the satisfaction of orgasm.

▪ Assess the time frame over which sexual dysfunction has occurred. Erectile dys- function that occurs gradually often points to problems with the blood supply or nerves supplying the penis, while a sudden loss of sexual desire or the ability to get erections is more causally suggestive of medication or psychological difficulties.

▪ As part of a discussion about SD, establish the extent to which SD is impacting qual- ity of life, the patient’s view on the aetiology of SD, treatments they have previously sought (e.g. from primary care or over the counter), and if they are considering stop- ping (or have stopped) their psychiatric medication.

▪ Take a past medical history for comorbid physical health complaints associated with SD. These include obesity, hypertension, hypercholesterolaemia, diabetes mellitus, Parkinson’s disease, previous surgical treatments for prostate cancer/prostatic hyper- trophy, and surgery/injury to pelvic area/spinal cord.

▪ Take a drug history assessing for medical and psychiatric drugs associated with SD (Figure 35.1 and Box 35.2). Polypharmacy increases the risk of SD [17].

▪ Take a social history assessing smoking status, alcohol use, and recreational drug use, all of which are associated with SD.

▪ Screen for stress, anxiety, or depressive symptoms that may be contributing to SD.

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Venlafaxine Paliperidone

Clozapine Benzodiazepines

Lithium Psychostimulants

Non-lithium mood stabilisers

SSRIs

‘First generation’ antipsychotics

Risperidone

Tricyclic antidepressants Quetiapine

Olanzapine

Lurasidone Cariprazine Brexpiprazole Aripiprazole
Buspirone Bupropion Vortioxetine

Strength of Evidence

Figure 35.1 Approximate rates of sexual dysfunction with psychiatric drugs and associated strength of evidence. Source: adapted from Clayton et al. [11].

Examination and investigations

▪ Ask if the patient has noticed anything abnormal about their genitals. If the answer is yes, either offer to examine the patient or arrange an examination via primary care, a local sexual health clinic, gynaecology, or urology as appropriate.

▪ Perform a set of basic observations, noting for evidence of hypertension (see Chapter 5).

▪ Check prolactin levels and HbA1c (see Chapters 11 and 13). MANAGEMENT
Management of SD will of course depend on the underlying cause; non‐pharmacologi- cal and pharmacological approaches are detailed in the following sections. Where SD improves there may be an increased risk of pregnancy and sexually transmitted infec- tion (see Chapters 36 and 38).

Duloxetine Mirtazapine

Sexual Dysfunction 301

Rates of sexual dysfunction

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Box 35.2 Medications and recreational drugs implicated in sexual dysfunction General medical drugs

▪ Antihypertensives

▪ Diuretics

▪ Hormone treatments (e.g. 5α‐reductase inhibitors versus benign prostatic hypertrophy)

▪ Contraceptive hormones

▪ Metformin

▪ Antihistamines
Psychiatric drugs (see Figure 35.1)

▪ Antipsychotics (although note large variation between different agents)

▪ Antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin/
noradrenaline reuptake inhibitors (SNRIs), monoamine oxidase inhibitors

▪ Mood stabilisers: lithium, sodium valproate, lamotrigine, carbamazepine
Recreational drugs

■ Practically all recreational drugs, including alcohol and nicotine

302 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Non‐pharmacological management

Where poor physical health is implicated in SD, there is evidence that weight loss [18], smoking cessation [19], a Mediterranean diet [20], and exercise [21] can improve sexual function (see Chapters 10, 14, and 46). Bearing in mind the cardiometabolic burden in people with SMI, we recommend that these lifestyle interventions are considered for all patients. The efficacy of such interventions in treating SD may have a psychological com- ponent; there is evidence that the placebo effect accounts for up to 70% of treatment response for SD in females and up to 50% of treatment response for erectile dysfunction [22]. Thus, any lifestyle interventions should be accompanied by motivational interview- ing reinforcing their potential efficacy. Psychosexual therapy may be appropriate where physiological/pharmacological causes of SD are ruled out and where there is a clear psy- chological precipitant (e.g. previous sexual violence or childhood sexual abuse).

Pharmacological management

▪ The first step in pharmacological management is considering rationalisation of medi- cation. Any changes to physical healthcare medication should be made in dialogue with either primary or secondary medical services. Pharmacological management of physiological causes of SD may also be indicated, for example diabetes mellitus and hypertension (see Chapters 5 and 11).

▪ Where psychiatric medication is implicated, the following should be considered.

■ For antidepressants, if patients have achieved full remission of depressive symp- toms then dose reduction may be considered. Where switching antidepressants is considered, lower‐risk antidepressants for SD include agomelatine, bupropion, mir-

tazapine, vilazodone, vortioxetine, and moclobemide [11].

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▪ For antipsychotics, SD is often associated with hyperprolactinaemia, and the reader is directed to Chapter 13 on this topic. Essentially, either adjunctive aripiprazole [23] (except for with amisulpride treatment, where such an intervention tends to be ineffective) [24] or a switch to aripiprazole should be considered in patients with symptomatic antipsychotic‐induced hyperprolactinaemia. Adjunctive aripiprazole in females with antipsychotic‐induced hyperprolactinaemia has been shown to improve SD in 50% of cases [25], and aripiprazole in long‐acting injectable formu- lation is associated with improved sexual functioning compared with paliperidone in both men and women [26]. However, antipsychotic‐related SD may also be related to histamine receptor antagonism (increasing sedation), α1‐receptor antago- nism (resulting in erectile dysfunction), and dopamine receptor antagonism (reduc- ing motivation and reward). Thus, trialling an agent with less of a sedative profile and/or one with a lower preponderance to cause secondary negative symptoms may be considered (e.g. aripiprazole) [27].

▪ Where benzodiazepines are implicated, attempt slow reduction and cessation. Where mood stabilisers are implicated, a risk–benefit decision should be made regarding their continuation. Rates of SD with lithium may be reduced compared with other mood stabilisers, and thus a cross‐titration to lithium may be considered [11].

▪ Phosphodiesterase inhibitors (e.g. sildenafil and tadalafil, among others) are effective treatments for erectile dysfunction [28] and considered so safe that, in the UK, sildenafil (Viagra Connect) can be bought over the counter without a prescription. Phosphodiesterase inhibitors have also been shown to be effective and well tolerated in patients with schizophrenia [29]. Side effects of phosphodiesterase inhibitors include headache, flushing, dyspepsia, blurred vision, and nasal congestion. Furthermore, pre- scribers should be aware that sildenafil can prolong the QTc and increases the risk of hypotension (see Chapter 3). Guidance on use of sildenafil is provided in Box 35.3.

▪ Bupropion is a noradrenaline/dopamine reuptake inhibitor. In the UK it is licensed for smoking cessation. At doses of 150–400 mg/day it has been used off‐label for the treatment of hypoactive sexual desire disorder, with a Cochrane review concluding that ‘for women with antidepressant‐induced sexual dysfunction the addition of

Sexual Dysfunction 303

Box 35.3 Guidance on use of sildenafila

▪ Reassure that sildenafil is safe and commonly used, pointing to its availability over the counter as evidence of this.

▪ Sildenafil does not influence arousal, but will help the man, if aroused, to get and maintain an erection.

▪ Counsel the man to take half (25 mg) of a 50‐mg tablet one hour before planned sexual activity. Absorption is delayed and reduced if taken with or after food. It works for about four hours. Counsel the patient not to take more than 50 mg/day. Most men only need 25 mg but, if neces- sary, the dose may be increased to 50 mg.

▪ In terms of common side effects, one in five men will get a headache, and one in five men will experience flushes.a
a Longer‐acting phosphodiesterase inhibitors are available (e.g. tadalafil)

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304 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

bupropion at higher doses (300 mg/day) appears to be the most promising approach

studied so far’ [28].

▪ In 2015, the US Food and Drug Administration (FDA) approved flibanserin as a
treatment for hypoactive sexual desire disorder in premenopausal women, despite concern about suboptimal risk–benefit trade‐offs [30]. A subsequent meta‐analysis of five trials including 5914 women showed that use of flibanserin leads to only a small improvement in sexual functioning, and a more recent review found that flibanserin was as effective as cognitive behavioural therapy and mindfulness meditation train- ing [30,31]. It is clearly not a ‘female Viagra’ even if its marketing tries to suggest this.

▪ Low testosterone is associated with poor sexual function. If hyperprolactinaemia is responsible for low testosterone, then hyperprolactinaemia should be addressed (see Chapter 13). There is evidence that transdermal testosterone is effective in women with SSRI/SNRI‐emergent loss of libido (see also Chapter 63) and in men who continue to take serotonergic antidepressants with low or low‐normal testosterone levels [32,33].
References

1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281(6):537–544.

2. Peuskens J, Sienaert P, De Hert M. Sexual dysfunction: the unspoken side effect of antipsychotics. Eur Psychiatry 1998;13(1 Suppl
1):23s–30s.

3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999;19(1):67–85.

4. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry
2002;63(4):357–366.

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8. Hackett GI. Erectile dysfunction, diabetes and cardiovascular risk. Br J Diabetes 2016;16(2):52–57.

9. Ward M, Druss B. The epidemiology of diabetes in psychotic disorders. Lancet Psychiatry 2015;2(5):431–451.

10. Moulton CD, Pickup JC, Ismail K. The link between depression and diabetes: the search for shared mechanisms. Lancet Diabetes Endocrinol 2015;3(6):461–471.

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13. Rosenberg KP, Bleiberg KL, Koscis J, Gross C. A survey of sexual side effects among severely mentally ill patients taking psychotropic medica-
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2001;18(2):161–166.

16. McGahuey CA, Delgado PL, Gelenberg AJ. Assessment of sexual dysfunction using the Arizona Sexual Experiences Scale (ASEX) and impli-
cations for the treatment of depression. Psychiatr Ann 1999;29(1):39‐45.

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outpatients. Psychiatry Clin Neurosci 2012;66(5):405–410.

18. Theleritis C, Bonaccorso S, Habib N, et al. Sexual dysfunction and central obesity in patients with first episode psychosis. Eur Psychiatry
2017;42:1–7.

19. Biebel MG, Burnett AL, Sadeghi‐Nejad H. Male sexual function and smoking. Sex Med Rev 2016;4(4):366–375.

20. Maiorino MI, Bellastella G, Caputo M, et al. Effects of Mediterranean diet on sexual function in people with newly diagnosed type 2 diabetes:
The MEDITA trial. J Diabetes Complications 2016;30(8):1519–1524.

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25. Kelly DL, Powell MM, Wehring HJ, et al. Adjunct aripiprazole reduces prolactin and prolactin‐related adverse effects in premenopausal women with psychosis: results from the DAAMSEL clinical trial. J Clin Psychopharmacol 2018;38(4):317–326.

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31. Pyke RE, Clayton AH. Effect size in efficacy trials of women with decreased sexual desire. Sex Med Rev 2018;6(3):358–366.

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antidepressants: a randomized, placebo‐controlled clinical trial. J Sex Marital Ther 2011;37(4):243–254.

CHAPTER 35

Chapter 36

Contraception

Neha Pathak, Usha Kumar

Mental illness contributes to several adverse reproductive health outcomes including increased risk of unintended pregnancy [1]. Thus, pregnancy planning and contracep- tion counselling for people with serious mental illness (SMI) should form a key part of holistic care provision. However, contraception screening in mental health settings is often suboptimal [2,3]. This is despite the additional reproductive vulnerabilities asso- ciated with mental illness, including teratogenicity of certain psychotropic medications (see Chapter 62); higher rates of risky sexual behaviour, coercive sex, and sexually transmitted infections (see Chapter 38) [4]; and higher prevalence of contraceptive non‐ use, misuse, and discontinuation [1]. The association between poor mental health and unintended pregnancy is bidirectional, with unintended pregnancy a risk factor for perinatal depression [5]. The mental health implications of unintended pregnancy go beyond that of the mother’s; unplanned pregnancy where the child is not wanted increases risk of schizophrenia in that child [6].

In the UK, the National Institute for Health and Care Excellence (NICE) advises that clinicians engage in conversations about contraception and pregnancy with all women of present or future childbearing potential who have a new, existing, or past mental health diagnosis [7]. This conversation should cover contraception and pregnancy plan- ning; the effects of pregnancy and childbirth on mental health; and how mental health and associated treatment may affect the woman, fetus, or baby. This chapter should equip mental healthcare providers with the core knowledge to discuss contraception and pregnancy planning with people with SMI. The reader is also directed to the complementary Chapter 62 on pregnancy.

308 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

CLINICAL APPROACH

Contraceptive counselling should be performed opportunistically at primary care con- sultations, antenatal/postnatal appointments, mental health appointments, and during psychiatric inpatient admissions. As part of an assessment, aim to cover the following.

▪ Establish current need for contraception including emergency contraception on day of assessment. As part of this discussion, define current risk of pregnancy (including date of last sexual intercourse), any pregnancy plans, partner history, and contracep- tion currently used.

▪ Determine contraceptive preferences: types currently and previously used, reasons for stopping previous types, any preferred choice, any concerns about specific types.

▪ Take a past medical and surgical history, drug history (with allergy status), obstetric history, gynaecological history (in women record last menstrual period and any men- strual problems), family history of venous thromboembolism, and social history (smoking status, alcohol and substance misuse, domestic violence).

▪ If the patient might be pregnant, perform a pregnancy test. Note that pregnancy can- not be excluded using a urinary test until 21 days or more after last unprotected sexual intercourse. Check blood pressure and calculate body mass index (BMI), the results of which may contribute to contraceptive decision‐making.
CONTRACEPTIVE OPTIONS
Table 36.1 provides a description of the different contraceptive options available. The Faculty of Sexual and Reproductive Healthcare (FSRH) provides more detailed guid- ance and regularly publishes statements based on new evidence [8]. Broadly, there are three group of contraceptives.
1 Methods not dependent on the user: the patient does not need to remember taking or using the contraceptive. These drugs include long‐acting reversible contraceptives (LARCs) and sterilisation. LARCs are the most effective types of contraception and are defined as methods administered less than once per menstrual cycle or month.
2 User‐dependent methods: the patient must remember to use the contraceptive regu- larly or during sex, resulting in greater variation in efficacy. These are less suited to chaotic lifestyles.
3 Emergency contraception: contraception is used after unprotected sex or if the con- traception used has failed. The most effective method is the copper intrauterine device (IUD), which can be inserted up to five days after first unprotected sexual intercourse (UPSI) in a menstrual cycle or up to five days after the earliest likely date of ovulation (whichever is later). Oral methods include ulipristal acetate or levonorg- estrel pills which can be used, respectively, up to 120 hours and 72 hours post UPSI; ulipristal acetate is the more effective of the two.

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Table 36.1 Contraception options. Methods not dependent on the user Long‐acting reversible contraceptives (LARCs)

Subdermal implants

Injectables

Intrauterine systems

Copper intrauterine device

Pregnancy rate: <1 in 1000 users in 1 year
What: small flexible rod releasing progestogen under the skin of the upper arm inserted in a

simple procedure under local anaesthetic
How: inhibits ovulation, thickens cervical mucus, thins the endometrium

Advantages: not user‐dependent, lasts for 3 years but can be removed sooner, no impact on fertility

Disadvantages: can cause irregular bleeding or amenorrhoea, involves procedure, effectiveness reduced by liver enzyme inducers

Pregnancy rate: <1 in 100 users in 1 year with perfect use (6 in 100 users in 1 year with typical use)

What: progestogen injection 13 weekly (intramuscular Depo Provera/subcutaneous Sayana Press) or eight weekly (Noristerat); Sayana Press injection can be self‐administered

How: inhibits ovulation, thickens cervical mucus, thins the endometrium Advantages: no need to do anything for the duration, can stop heavy painful periods

Disadvantages: periods may stop/be irregular/last longer, delayed return of fertility, weight gain, need to remember to repeat injections at regular intervals

Pregnancy rate: <1 in 100 users in 1 year
What: small T‐shaped plastic device inserted into the uterus (a short procedure when awake)

that releases progestogen
How: thins the endometrium, thickens cervical mucus

Advantages: not user‐dependent, lasts for 3–5 years depending on the type; periods usually become lighter, shorter and less painful; no impact on fertility

Disadvantages: periods may stop/be irregular/light spotting may occur, insertion may be uncomfortable and carries a small risk of infection/uterine perforation, small increased risk of ectopic pregnancy in the unlikely event of a pregnancy

Pregnancy rate: <1 in 100 users in 1 year
What: small T‐shaped plastic and copper device inserted into the uterus (a short procedure

when awake)

How: prevents egg and sperm meeting (fertilisation), makes endometrium unfavourable for implantation

Advantages: works immediately, can be used as emergency contraception, works for 5–10 years depending on type but can be removed sooner, not user‐dependent, no impact on fertility, hormone‐free

Disadvantages: periods may become heavier, longer, or more painful; insertion may be uncomfortable and carries a small risk of bleeding, infection, and uterine perforation; small increased risk of ectopic pregnancy in the unlikely event of a pregnancy

(continued )

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Table 36.1 (Continued)

Methods not dependent on the user

Sterilisation

Male Pregnancy rate: 1 in 2000 users in 1 year
What: vas deferens are cut, sealed, or tied (irreversible)

How: stops fertilisation
Advantages: permanent, under local anaesthetic

Disadvantages: can take at least 8 weeks to become effective, may experience testicular pain post procedure

Female Pregnancy rate: 1 in 200 users in 1 year
What: fallopian tubes are cut, sealed or blocked in an operation

How: stops fertilisation
Advantages: permanent, not easily reversed, periods unaffected
Disadvantages: operative and anaesthetic risk, small increased risk of ectopic pregnancy

User‐dependent methods

Combined hormonal contraception

Progestogen‐only pill

Male condoms

Female condoms

Pregnancy rate: <1 in 100 users in 1 year if used perfectly (9 in 100 users in 1 year with typical use)

What: pill, transdermal patch, or vaginal ring releasing oestrogen and progestogen

How: inhibits ovulation, thickens cervical mucus, thins the endometrium

Advantages: periods can become lighter and less painful, reduced risk of certain cancers (ovarian/endometrial/colon), can improve acne, no impact on fertility

Disadvantages: user must remember to take pill (daily) or change patch (weekly)/ring (3‐ weekly); small risk of thromboembolism, breast cancer, cervical cancer; can have side effects, e.g. headache, nausea, mood change (especially in adolescents), breast tenderness; effectiveness reduced by liver enzyme inducers

Pregnancy rate: <1 in 100 users in 1 year if used perfectly (9 in 100 users in 1 year with typical use) What: pill containing progestogen to be taken daily with no break
How: thickens cervical mucus, can inhibit ovulation
Advantages: useful alternative if contraindication to oestrogen, can improve painful periods

Disadvantages: periods may stop/become lighter, irregular or more frequent/last longer; may get premenstrual syndrome (PMS)‐type side effects; ineffective if taken >3 hours or >12 hours late depending on which type; effectiveness reduced by liver enzyme inducers

Pregnancy rate: 2 in 100 users in 1 year if used perfectly (18 in 100 users with typical use)

What: thin barrier placed over erect penis

How: stops sperm entering the vagina

Advantages: widely available, protects from sexually transmitted infections, no serious side effects, hormone‐free

Disadvantages: can fall off, split or easily spill semen if removed incorrectly, interrupts sex

Pregnancy rate: 5 in 100 users in 1 year if used perfectly (21 in 100 users with typical use)

What: thin silicone barrier that loosely lines the vagina

How: stops sperm entering the vagina

Advantages: can be inserted before sex, can help protect from sexually transmitted infections, no serious side effects

Disadvantages: not as widely available as male condoms, may get pushed into vagina during sexual intercourse

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Contraception 311

Table 36.1 (Continued)
Methods not dependent on the user

Diaphragm/cap with spermicide

Fertility awareness methods

Pregnancy rate: 6 in 100 users in 1 year if used perfectly (12 in 100 users with typical use) What: flexible latex or silicone device inserted into the vagina
How: covers the cervix to prevent sperm entering the uterus
Advantages: can be inserted before sex, no serious side effects

Disadvantages: need extra spermicide if having sex more than once, can take time to learn to use effectively

Pregnancy rate: 1 in 100 users in 1 year with perfect use (24 in 100 users with typical use) What: combines fertility indicators such as basal body temperature and cervical secretions to

determine when safe to have sex

How: avoiding sex at fertile times of the menstrual cycle

Advantages: no serious side effects

Disadvantages: need high motivation to keep daily records, takes time to learn to use effectively, sex must be planned

Emergency contraception

Copper intrauterine device

Ulipristal acetate

Levonorgestrel

Pregnancy rate: <1 in 1000 users; most effective emergency method

What: small T‐shaped plastic and copper device inserted into the uterus (a short procedure when awake) to be inserted up to 5 days post first unprotected sexual intercourse (UPSI) in a menstrual cycle or up to 5 days after the earliest likely date of ovulation (whichever is later)

How: prevents fertilisation and/or implantation
Advantages: most effective method, provides ongoing contraception, not affected by body

mass index (BMI) or other drugs

Disadvantages: periods may become heavier, longer, or more painful; insertion may be uncomfortable and carries a small risk of infection, bleeding, and uterine perforation; small increased risk of ectopic pregnancy if it fails

Pregnancy rate: second most effective emergency method, 1–2 in 100 users

What: tablet containing ulipristal acetate to be taken within 120 hours of first UPSI

How: delays/inhibits ovulation

Advantages: no procedure, more effective than levonorgestrel, no serious side effects, can use more than once per cycle

Disadvantages: ineffective after ovulation has occurred; effectiveness may be reduced by liver enzyme inducers; must wait 5 days before using other hormonal contraception; may experience nausea, vomiting, headaches, or painful/altered next period

Pregnancy rate: up to 3 in 100 users

What: tablet containing a type of progestogen to be taken within 72 hours of UPSI

How: delays/inhibits ovulation

Advantages: no procedure, can start other contraceptives immediately, no serious side effects, can use more than once per cycle

Disadvantages: ineffective after ovulation has occurred; effectiveness may be reduced by liver enzyme inducers or weight >70 kg/BMI >26 kg/m2; may experience nausea, vomiting, headaches, or painful/altered next period

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312 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

The UK Medical Eligibility Criteria (UKMEC) is a freely available and easy‐to‐use tool designed to help clinicians determine which contraceptives are safe for patients based on their comorbid medical conditions [9]. Medical conditions considered by the UKMEC include ischaemic heart disease and cardiovascular risk factors; venous thromboembolism and risk factors; neurological conditions (e.g. migraine, epilepsy); breast and reproductive tract conditions; endocrine conditions (e.g. type 2 diabetes mellitus, thyroid disease); infectious disease status (e.g. human immuno- deficiency or tuberculosis infection), gastrointestinal disease; rheumatological dis- ease; and reproductive history. History of depression is also included in the UKMEC assessment. Comorbid conditions are ranked on a scale of 1–4 based on their suitability in association with individual contraceptive methods; 1 indicates that the condition has no restriction for use of that contraceptive method, and 4 indicates that the condition represents an unacceptable health risk if that contra- ceptive method is used. It is recommended that the UKMEC is consulted before making contraceptive decisions.

Patient information leaflets for different contraceptive methods are available online through the Family Planning Association [10]. Patients should be advised how long they need to use additional contraception such as condoms before their chosen contra- ception becomes effective and be given a plan for follow‐up.

ETHICAL AND LEGAL CONSIDERATIONS

Contraceptive decisions should be non‐coercive and autonomous. In people with SMI, loss of capacity may be temporary and/or improve with treatment. Ulysses contracts can apply to contraceptive decisions, where a woman gives informed consent when she is most stable and indicates that she wants her consent to remain valid if she later becomes unwell [11].

Under English law, ‘Gillick competence’ means that children under the age of 16 are able to consent to his or her own medical treatment without parental involvement or consent [12]. Fraser guidelines are specific to contraception, abortion, and sexual health interventions [13]. In this case, advice and treatment can be given to under 16‐year‐ olds, provided:

▪ he or she has sufficient maturity and intelligence to understand the nature and impli- cations of the proposed treatment

▪ he or she cannot be persuaded to tell his or her parents or to allow the doctor to tell them

▪ he or she is very likely to begin or continue having sexual intercourse with or without contraceptive treatment

▪ his or her physical or mental health is likely to suffer unless he or she receives the advice or treatment

▪ the advice or treatment is in his or her best interests.

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Contraception 313

WHEN TO REFER

Referral to sexual/reproductive health specialists may be indicated for complex contra- ceptive decisions (e.g. in the context of multiple comorbidities) or for complex LARC procedures (e.g. failed IUD insertions in primary care). It is beneficial to patients for psychiatric services to work closely with sexual and reproductive health services to provide timely and effective contraception.

SPECIAL CONSIDERATIONS IN PATIENTS WITH SERIOUS MENTAL ILLNESS

Contraception and mood

Table 36.2 details factors specific to mental health disorders that may influence contra- ceptive decisions. Although there are anecdotal reports of hormonal contraception’s association with emotional lability, most studies have failed to show evidence that this method of contraception negatively impacts mood (including in women with depressive or bipolar affective disorders), although there is evidence that adolescents may be vulnerable to contraception‐related mood disturbance [14–16].

Table 36.2 Specific considerations regarding contraception in people with serious mental illness.

Mental illness

Bipolar affective disorder Psychotic disorders

Anxiety and depression

Eating disorders

Substance misuse disorders

Issues to consider

Impulsivity and risky sexual behaviour associated with mania Mood stabilisers resulting in drug interactions and teratogenicity

Paranoia associated with indwelling contraception

Antipsychotic‐induced hyperprolactinaemia and resultant amenorrhoea or oligomenorrhoea associated with perception of infertility

Cardiovascular disease, obesity, and smoking are contraindications to combined hormonal contraception

Mood stabilisers as adjuncts resulting in drug interactions and teratogenicity

Heightened negative perceptions of contraception and its impact on mood

Impact of fluctuating or low motivation on user‐dependent contraceptive methods (condoms, pills, patches, rings)

Weight gain concerns
Amenorrhoea and a perception of infertility

High risk of unplanned pregnancy, risk of fetal exposure to alcohol, drugs, tobacco

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314 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Contraception and cardiometabolic disease

Increased rates of cardiovascular disease, obesity, and smoking in patients with SMI are an important consideration in contraceptive decision‐making and are a contraindica- tion to use of combined hormonal contraception. Of note, injectable contraceptives are the contraceptive type most associated with weight gain, typically in younger patients who are already overweight.

Contraception and fertility

Progestogen‐only injectable contraception can delay fertility by up to one year. There is no evidence of an association between infertility and other types of contraception. For amenorrhoeic patients (e.g. people with eating disorders), return of ovulation and therefore fertility precedes return of a first period; thus being on effective contraception before this is essential to avoid unwanted pregnancy.

Contraception and psychiatric medication

Sexually active women of reproductive age who are taking known teratogenic drugs or drugs with potential teratogenic effects must use highly effective contraception, such as a copper IUD, levonorgestrel intrauterine system (LNG‐IUS), or progestogen‐only implant. A pregnancy prevention plan should be in place to ensure there is no risk of conception. The reader is directed to Chapter 62 for further information on the terato- genic potential of different psychiatric drugs.

Clinicians should be aware of potential interactions between contraceptives and psy- chiatric drugs. For example, psychiatric drugs that are CYP3A4 inducers (e.g. carba- mazepine and St John’s Wort) reduce the bioavailability and hence contraceptive efficacy of combined hormonal contraceptives, the progestogen‐only pill, and the subdermal implant both during use and for up to 28 days after stopping enzyme‐inducer treatment. Thus, patients on enzyme inducers should be encouraged to use intrauterine contraception or injectables. Conversely, combined hormonal contraceptives increase plasma clozapine concentrations; where co‐prescribed, monitor for clozapine‐related side effects and monitor plasma levels [17]. Where there are concerns regarding poten- tial drug interactions between contraceptives and other prescribed medication, discus- sion with pharmacy colleagues is recommended.

References

1. Seeman MV, Ross R. Prescribing contraceptives for women with schizophrenia. J Psychiatr Pract 2011;17(4):258–269.

2. Coverdale JH, Aruffo JF. Aids and family‐planning counseling of psychiatrically ill women in community mental‐health clinics. Community
Ment Health J 1992;28(1):13–20.

3. Zacher J, Peterson J, Lempicki K, Zaror P. Comparing current practices of screening for pregnancy and contraceptive use in female veterans
of child‐bearing age prescribed psychotropic medications in a mental health versus a women’s health clinic. Ment Health Clin
2013;3(2):71–77.

4. Field N, Prah P, Mercer CH, et al. Are depression and poor sexual health neglected comorbidities? Evidence from a population sample. BMJ
Open 2016;6(3):e010521.

5. Yanikkerem E, Ay S, Piro N. Planned and unplanned pregnancy: effects on health practice and depression during pregnancy. J Obstet
Gynaecol Res 2013;39(1):180–187.

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6. Myhrman A, Rantakallio P, Isohanni M, et al. Unwantedness of a pregnancy and schizophrenia in the child. Br J Psychiatry 1996;169(5):637–640.

7. National Institute for Health and Care Excellence. Antenatal and Postnatal Mental Health: Clinical Management and Service Guidance. Clinical Guideline CG192. London: NICE, 2014. https://www.nice.org.uk/guidance/cg192

8. Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists. Standards and Guidance, 2020. https://www.fsrh.org/standards‐and‐guidance/

9. Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists. UK Medical Eligibility Criteria For Contraceptive Use, 2016. https://www.fsrh.org/standards‐and‐guidance/documents/ukmec‐2016/

10. Family Planning Association (FPA). Leaflet and booklet downloads: contraceptive methods. https://www.fpa.org.uk/professionals/resources/ leaflet‐and‐booklet‐downloads

11. Miller LJ. Sexuality, reproduction, and family planning in women with schizophrenia. Schizophr Bull 1997;23(4):623–635.

12. Great Britain. England. Court of Appeal, Civil Division. Gillick v. West Norfolk and Wisbech Area Health Authority. Engl Law Rep. 1984
Dec 19;1985(1):533–559.

13. Wheeler R. Gillick or Fraser? A plea for consistency over competence in children. BMJ 2006;332(7545):807.

14. Pagano HP, Zapata LB, Berry‐Bibee EN, et al. Safety of hormonal contraception and intrauterine devices among women with depressive and
bipolar disorders: a systematic review. Contraception 2016;94(6):641–649.

15. Worly BL, Gur TL, Schaffir J. The relationship between progestin hormonal contraception and depression: a systematic review. Contraception
2018;97(6):478–489.

16. de Wit AE, Booij SH, Giltay EJ, et al. Association of use of oral contraceptives with depressive symptoms among adolescents and young
women. JAMA Psychiatry 2020;77(1):52–59.

17. Bookholt DE, Bogers JP. Oral contraceptives raise plasma clozapine concentrations. J Clin Psychopharmacol 2014;34(3):389–390.

CHAPTER 36

Chapter 37

Infertility

Rudiger Pittrof

In the UK, one in eight women and one in ten men aged 16–74 years experience infertil- ity, defined as unsuccessfully attempting to conceive for a year or longer [1]. Infertility data in people with serious mental illness (SMI) are scarce. However, a prospective cohort study drawing on the entire Danish population born after 1950 showed that people with SMI have significantly lower first‐child fertility rates compared with the general population [2]. Furthermore, compared with the general population, women with psychotic illness are less likely to receive fertility treatment, and fertility treatment in this group is less successful [3].

ADDRESSING INFERTILITY IN PSYCHIATRIC PRACTICE

Psychiatric practitioners are well positioned to help their patients address fertility con- cerns, facilitate onward referral, and provide support during a time associated with significant psychological distress [4]. In the UK, if a heterosexual couple has regular (every two to three days) unprotected sex for one year without conception, then clinical assessment and investigation for infertility are indicated [5]. Fertility declines with age and if the woman is aged 36 years or older, referral should not be delayed.

As part of a conversation, assess the importance of having children for the patient, and discuss any concerns that patient may have about their ability to cope in pregnancy or as a parent. Confirm that the couple are engaging in sufficient sex; anything less than once a week dramatically reduces the risk of conception. Simple pre‐conception advice can also be provided (Box 37.1). Undertake a medication review, assessing for any drugs that may pose a risk to an unborn child (see Chapter 62) and for any drugs that may be contributing to sexual dysfunction (see Chapter 35). Check prolactin levels if sexual dysfunction is suspected. Based on these assessments, rationalisation of

Box 37.1 Pre‐conception advice [5]

▪ Sexual intercourse every two to three days optimises the chance of pregnancy.

▪ Women who are trying to become pregnant should not drink more than 1–2 units of alcohol per
week and avoid episodes of intoxication.

▪ Women who smoke should be informed that this is likely to reduce their fertility. Passive smoking
is also likely to reduce likelihood of conception. Where appropriate refer to smoking cessation
services (see Chapter 46).

▪ Women who have a body mass index (BMI) over 30 kg/m2 should be informed that they are likely
to take longer to conceive. Similarly, men with a BMI over 30 kg/m2 are likely to have reduced
fertility. Thus, where appropriate, advise weight loss (see Chapter 14).

▪ Women with a BMI under 19 kg/m2 and who have irregular menstruation or are not menstruating
should be advised that increasing body weight is likely to improve their chances of conception.

318 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

psychiatric medication may be indicated. This information should be included in any onward referrals to primary/secondary care.

ONWARD REFERRAL AND FURTHER TESTS FOR INFERTILITY

Initial tests for infertility can be performed in primary care. For the man, this involves semen analysis, and for the woman a mid‐luteal phase progesterone level to confirm ovulation (blood test taken seven days before expected period). In the UK, onward referral for people presenting with infertility vary between health authorities and should be directed by primary care [5].

INFERTILITY TREATMENTS

There are three main types of fertility treatment: medical, surgical, and assisted concep- tion. Medical treatment involves the use of drugs to induce ovulation (e.g. clomifene) and surgical treatment may be indicated for women with fallopian tube obstruction/ endometriosis or for men with epididymal obstruction. Assisted conception describes means of conception other than via normal coitus. This includes intrauterine insemina- tion (where sperm is placed in the woman’s uterus using a fine plastic tube) and in vitro fertilisation (where one or more eggs are retrieved from the woman and mixed with the man’s sperm; the resultant embryo is then injected into the uterus via the cervix).

References

1. Datta J, Palmer MJ, Tanton C, et al. Prevalence of infertility and help seeking among 15 000 women and men. Hum Reprod 2016;31(9):2108–2118.

2. Laursen TM, Munk‐Olsen T. Reproductive patterns in psychotic patients. Schizophr Res 2010;121(1–3):234–240.

3. Ebdrup NH, Assens M, Hougaard CO, et al. Assisted reproductive technology (ART) treatment in women with schizophrenia or related psy-
chotic disorder: a national cohort study. Eur J Obstet Gynecol Reprod Biol 2014;177:115–120.

4. Nachtigall RD, Becker G, Wozny M. The effects of gender‐specific diagnosis on men’s and women’s response to infertility. Fertil Steril
1992;57(1):113–121.

5. National Institute for Health and Care Excellence. Fertility Problems: Assessment and Treatment. Clinical Guideline CG156. London: NICE,
2013. Available at https://www.nice.org.uk/guidance/cg156

CHAPTER 37

Chapter 38

Sexually Transmitted Infection

Harriet Le Voir, Rudiger Pittrof

There are several shared risk factors for sexually transmitted infection (STI) and serious mental illness (SMI), including low socioeconomic status, abuse (e.g. childhood and/or sexual abuse), and recreational drug use [1–5]. Risk of STI is further increased in people who at times lack capacity to make decisions about sexual activity (e.g. negotiation of condom use). This chapter outlines an approach to history taking, diagnosis, and man- agement of STIs in the SMI population. The reader is also directed to complementary chapters on contraception (Chapter 36), sexual dysfunction (Chapter 35), pregnancy (Chapter 62), and human immunodeficiency virus (HIV; Chapter 45).

HISTORY

When taking an STI history, the clinician should be sensitive to the patient’s previous sexual experiences that may be contributing to poor mental health (e.g. in the context of same‐sex relationships that are not culturally approved or a history of sexual abuse). Furthermore, capacity to consent to STI testing will need to be considered in some patients. Patients may be surprised to be asked about their sex life; clear explanations about the rationale for such a discussion will provide reassurance. Assessment of STI risk should take place in the context of broader discussions about sexual dysfunction and contraception.

Typical symptoms of common STIs are presented in Table 38.1. To enquire about such symptoms, use a phrase such as ‘Do you have any genital symptoms you are con- cerned about, for example discharge, abnormal bleeding, pain when passing urine, or ulcers?’ To enquire whether a male patient has had sex with another man, use a phrase such as ‘About one in ten men have had sex with another man in the past. Have you ever had sex with a man?’ Box 38.1 provides a series of questions that assess risk of a

Box 38.1 Identifying risk of blood‐borne virus sexual transmission
Answering yes to any of the following questions should indicate testing for HIV and hepatitis B/C.

▪ Have you had sex with someone who has HIV or hepatitis?

▪ Have you had sex with someone who injects drugs, or do you inject drugs?

▪ Have you had sex with someone who is born outside Europe/Australasia/North America?

▪ Have you paid for sex or been paid for sex?

▪ Have you had sex with men (if male) or bisexual men (if female)?

320 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 38.1 Symptoms of sexually transmitted infections.

Symptoms

Discharge, dysuria, testicular/ pelvic pain

Wart‐like lesions

Blisters and ulcers

Rectal symptoms

Rash

Aetiology

Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium

Human papillomavirus

Herpes simplex virus, Treponema pallidum (syphilis)

Chlamydia trachomatis (and lymphogranuloma venereum subtype), Neisseria gonorrhoeae, herpes simplex virus

Treponema pallidum (syphilis), HIV

sexually transmitted blood‐borne virus infection (HIV and hepatis B and C). Forensic examination may be indicated where non‐consensual sex has taken place in the last seven days. In this scenario, discussion with a local sexual assault centre is indicated.

STI TESTING IN PSYCHIATRY

In certain areas, home testing kits for STI (including HIV) can be ordered online (e.g. in London, via http://www.shl.uk). Such kits may be appropriate for patients reluctant to attend sexual health clinics. However, home testing kits may not be practical or appropriate for all patients owing to logistical barriers such as the need for online registration and relaying test results back via text message. HIV and syphilis testing should already be routinely performed in psychiatric practice. For patients with systemic symptoms con- sider repeating syphilis, HIV (rash and/or flu‐like symptoms), and hepatitis B/C testing (fatigue, jaundice, itching, nausea/vomiting). If testing for STIs other than HIV and syphilis is required in a patient who is unable to attend a sexual health clinic, then dis- cussion with local sexual health services is recommended. For an inpatient with symp- toms suggestive of an STI who may lack capacity to consent to STI testing, a risk–benefit decision regarding investigation/treatment will need to be made. This will weigh up the immediate benefits of treatment (symptomatic relief and reduction in long‐term poor physical health) against the potential distress to the patient in terms of attending a

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Sexually Transmitted Infection 321

Box 38.2 Screening tests recommended for STI based on presenting complaint Symptomatic male

▪ First‐void urine sample for Chlamydia trachomatis and Neisseria gonorrhoeae gonorrhoea (com- bined test), Mycoplasma genitalium, and Trichomonas vaginalis: total of three samples required for nucleic acid amplification tests (NAATs)

▪ Microscopy, culture, and sensitivity of urethral discharge

▪ Syphilis and HIV blood tests
Symptomatic female

▪ Vaginal swab for C. trachomatis, N. gonorrhoeae, and T. vaginalis NAATs

▪ Microscopy, culture, and sensitivity for N. gonorrhoeae culture

▪ Syphilis and HIV blood tests
Genital ulcers

▪ Herpes simplex virus and syphilis swab for polymerase chain reaction (PCR)

▪ C. trachomatis and N. gonorrhoeae swab for NAATs

▪ Syphilis and HIV blood tests
Rectal symptoms

▪ C. trachomatis and N. gonorrhoeae swab for NAATs

▪ Herpes simplex virus swab for PCR

▪ Syphilis and HIV blood tests
HIV screening test (fourth‐generation antibody and antigen), syphilis antibody, hepatitis B core antibody, and HCV antibody are recommended for all patients who have had unprotected sex. Discussion with the local laboratory to identify which serology blood bottles are required is advised to avoid rejected samples.

sexual health clinic and/or the necessary associated investigations. Box 38.2 describes the investigations indicated depending on presenting complaint, and Box 38.3 the appropriate time frame for STI testing based on date of last sexual contact.

DETERMINING URGENCY OF CLINICAL ACTION/REFERRAL

1 Symptoms/results/presentations that require urgent action (same day):

. a Any genital injury or anything causing severe pain, particularly acute scrotal or pelvic pain; erections that are painful or persist for longer than two hours; and genital ulcers in the presence of neurological symptoms/acute psychiatric symp-
toms (which could indicate herpes encephalitis; see Chapter 81).

. b Where HIV post‐exposure prophylaxis is indicated (if a man who is presumed to be HIV negative has had unprotected receptive anal sex in the last 72 hours).
Please see Chapter 45.

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Box 38.3 When to perform STI testing based on date of last sexual contact Chlamydia and gonorrhoea

■ Two weeks after unprotected sex HIV

▪ Four weeks after unprotected sex if blood test, or

▪ Three months after unprotected sex with saliva/finger‐prick test
Syphilis

▪ Three months after unprotected sex

▪ Two weeks after genital ulcer symptoms if initial test negative
Hepatitis

■ Three months after unprotected sex
Sexual health screening is advised every three months if regular changes of partner

322 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

c A new positive HIV or syphilis test should always be discussed with local sexual health services within 24 hours to assess urgency of need for assessment and treatment.

. 2 Symptoms that need to be discussed with local sexual health services within three days: genital or anal ulcers or blisters, penile discharge, or anything that is distressing the patient.

. 3 Symptoms that can await discussion with a local sexual health clinic for up to two weeks if immediate discussion is impractical (e.g. if acutely unwell on a psychiatric ward): genital skin problems that are not ulcers, rectal or vaginal discharge that is not distressing, blood in semen, scrotal masses, long‐term pelvic or scrotal pain, rec- tal pain that is not distressing, and mild rectal bleeding.
REFERRAL TO SEXUAL HEALTH SERVICES

Discussion with local sexual health services is recommended if a patient requires an STI test or treatment. Men who have sex with men, those who are involved in transactional sex (e.g. sex for money, drugs, food, or shelter), and those who have been a victim of sexual violence should also be seen by sexual health services. Ask a health adviser from the sexual health service to speak directly to the patient on the phone to arrange/offer a meeting. If possible and appropriate, offer to go with the patient to the meeting, as attending sexual health services can be daunting.

There are many services available within a sexual health clinic: human papillomavi- rus (HPV) vaccination for men who have sex with men, hepatitis A and B vaccination,

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information about HIV pre‐ and post‐exposure prophylaxis (see Chapter 45), counselling and training relating to risk reduction, condom use, safer recreational drug use in the context of sex, safer dating, and sexuality.

Treatment of STI

In the case of a positive STI test, best practice is for the patient to be reviewed by sexual health services who will guide appropriate management. Current first‐line treatment options are outlined in Table 38.2, although treatment regimens are regularly updated (see http://www.bashh.org) and should be guided by local protocols.

Contact tracing is important to prevent both complications in the partner and re‐infection. Where available, health advisors in a sexual health clinic are best placed to provide this service. Anonymous contact tracing for partner notification of infection can also be carried out by sexual health services, with consent from the patient.

Sexually Transmitted Infection 323

Table 38.2 Typical treatment regimens for sexually transmitted infections.

Infection

Chlamydia trachomatis

Symptomatic rectal

Chlamydia
Neisseria gonorrhoeae

Trichomonas vaginalis Mycoplasma genitalium

Genital herpes simplex virus

Genital warts (human papillomavirus)

Syphilis

HIV

Typical first‐line treatment

Oral doxycyclinea 100 mg b.d. for 7 days

Oral doxycycline 100 mg b.d. for 21 days until LGV status known

Ceftriaxone 1 g i.m. stat
Oral metronidazole 400 mg b.d. for 5 days

Discuss with local sexual health clinic

Alternative treatment

Oral azithromycin 1 g stat, then 500 mg o.d. for 2 days (3 days total)

Oral options possible with guidance from culture results

Oral metronidazole 2 g stat (not in pregnancy)

Oral aciclovir 400 mg t.d.s. for 5 days, salt water bathing, simple analgesia, urgent medical assessment if unable to pass urine or neurological symptoms

Cryotherapy/topical podophyllotoxin/topical imiquimod: discuss with sexual health services. Delay of less than four weeks does not impact treatment efficacy

Dependent on stage of infection relating to serology (RPR), symptoms, and history of previous syphilis treatment. Usually either penicillin‐based intramuscular injection or oral doxycycline

See Chapter 45. Discussion with HIV service required. CD4 count required to help guide urgency of clinical state for HIV team

a Doxycycline should not be used in pregnant women (see Chapter 62). LGV, lymphogranuloma venereum; RPR, rapid plasma reagin.

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324 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

References

1. Huang SY, Hung JH, Hu LY, et al. Risk of sexually transmitted infections following depressive disorder: a nationwide population‐based cohort study. Medicine (Baltimore) 2018;97(43):e12539.

2. World Health Organization Executive Board, 124th Session. HIV/AIDS and mental health: report by the Secretariat. EB124/6, 20 November 2008. https://apps.who.int/iris/handle/10665/2107

3. Magidson JF, Blashill AJ, Wall MM, et al. Relationship between psychiatric disorders and sexually transmitted diseases in a nationally repre- sentative sample. J Psychosom Res 2014;76(4):322–328.

4. Petrak J, Byrne A, Baker M. The association between abuse in childhood and STD/HIV risk behaviours in female genitourinary (GU) clinic attendees. Sex Transm Infect 2000;76(6):457–461.

5. Whooley MA, Simon GE. Primary care: managing depression in medical outpatients. N Engl J Med 2000;343(26):1942–1950.

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Part 7

Infectious Diseases

Chapter 39

Pneumonia

Emma McGuire, Loren Bailey, Peter Saunders, Meera Chand

Pneumonia is an infection of the lungs that results in acute lower respiratory symptoms, including cough and difficulty in breathing, which may be accompanied by fever. There may be new focal chest signs on examination and if chest X‐ray is performed there is new shadowing which cannot be ascribed to any other cause (e.g. pulmonary oedema or infarction) [1].

Pneumonia can be broadly categorised as community‐acquired pneumonia (CAP) or hospital‐acquired pneumonia (HAP), the latter occurring after 48 hours of hospitalisa- tion or within two weeks of discharge from hospital [1]. Pneumonia acquired in long‐ term care facilities may be caused by either community or healthcare‐associated respiratory pathogens. Psychiatric hospital‐acquired pneumonia (PHAP) is defined as pneumonia that occurs during psychiatric hospitalisation. PHAP is associated with sig- nificant mortality, estimated at 21.3%, and is reported to account for 9.5–18% of deaths in psychiatric hospitals [2–4].

CAP can be caused by bacteria or viruses (Box 39.1). Whilst a small number of patho- gens account for most pneumonia, causes vary significantly with age, with pneumococcal pneumonia, influenza, and aspiration pneumonia predominating in the elderly [5]. There is also seasonal variation, particularly evident in viral causes, either alone or in association with bacterial co‐infection. In the context of immunosuppression (HIV infection, steroids, post transplantation) the range of organisms causing pneumonia is broader. Consideration should also be given to non‐infective mimics of pneumonia, including pulmonary oedema, pulmonary embolism, lung cancer, and vasculitic or connective tissue disease.

At the time of writing this book, coronavirus disease 2019 (COVID‐19), an infec- tious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐ CoV‐2), has resulted in an ongoing pandemic [6], with the elderly and individuals with comorbidities such as respiratory and cardiovascular disease at increased risk of severe disease and death [7].

Box 39.1 Common causative organisms of pneumonia

Community‐acquired pneumonia

Bacteria (common)

Streptococcus pneumoniae Haemophilus influenzae
Staphylococcus aureus (including MRSA) Streptococcus pyogenes

Moraxella catarrhalis Klebsiella pneumoniae Mycoplasma pneumoniae Legionella spp. Chlamydophila pneumoniae Mycobacterium tuberculosis

Bacteria (less common; consider depending on setting and exposures)

Chlamydia psittaci

Q fever
Endemic mycoses

Viruses

Influenza A and B Parainfluenza
Respiratory syncytial virus Human metapneumovirus Adenoviruses

Seasonal coronaviruses (e.g. MERS Co‐V)
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)

Hospital‐acquired pneumonia

Staphylococcus aureus (including MRSA)
Gram‐negative organisms such as Pseudomonas spp., Enterobacteriaceae and Acinetobacter spp.

Aspiration pneumonia

Multifactorial: chemical injury ± mixed upper respiratory tract bacteria, commonly including anaerobes

Immunocompromise

In addition to conventional causes of CAP: Atypical mycobacteria
Nocardia spp.
Cytomegalovirus

Pneumocystis jirovecii
Aspergillus spp. and other moulds Cryptococcus spp.

MRSA, methicillin‐resistant Staphylococcus aureus; MERS Co‐V, Middle Eastern respiratory syndrome‐related coronavirus.

328 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

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Pneumonia 329

PNEUMONIA AND SERIOUS MENTAL ILLNESS

Patients with serious mental illness (SMI) and pneumonia are more likely to present late and have higher rates of admission to the intensive care unit (ICU) and mortality [8–11]. Indeed, in schizophrenia, patients are seven times more likely to die as a con- sequence of pneumonia or influenza compared with the general population [12]. There is a higher prevalence of smoking, substance abuse, and obesity among patients with SMI, all of which are independently associated with worse outcomes in pneumo- nia (see Chapters 24 and 46) [7]. There may also be reduced respiratory reserve due to nutritional deficiency and poorer control of pulmonary comorbidities such as asthma and chronic obstructive pulmonary disease (COPD) (see Chapters 47 and 48) [13]. There is a higher prevalence of HIV among patients with SMI which is associ- ated with increased severity and frequency of CAP, as well as opportunistic infections (see Chapter 45) [14,15]. Rates of homelessness, incarceration, and vitamin D defi- ciency are disproportionately high among patients with SMI, all of which are risk factors for tuberculosis (TB; see Chapter 44) [16–19]. In the general population, indi- viduals at highest risk for severe disease and death from COVID‐19 infection include people aged over 60 years, those who smoke, and those with underlying conditions such as obesity, hypertension, diabetes, cardiovascular disease, chronic respiratory disease, and cancer [7,20]. Owing to increased multimorbidity and rates of smoking, patients with serious mental illness represent a vulnerable population for developing severe COVID‐19 infection.

Psychotropic medications may also elevate the risk of respiratory complications including aspiration pneumonia (see Chapter 27) [9,11,21,22]. In particular, clozapine is associated with increased risk of pneumonia, which may be related not only to increased risk of salivary aspiration, but also its immunosuppressive effects [23,24].

DIAGNOSTIC PRINCIPLES History

. 1 Typical symptoms include fever, cough, difficulty in breathing, and pleuritic chest pain.

. 2 Atypical presentations include confusion, gastrointestinal symptoms (e.g. diarrhoea,
abdominal pain), headache, myalgia, or rash.

. 3 Elderly or immunosuppressed patients may be afebrile and may present with atypical
features.

. 4 Coryzal symptoms suggestive of viral infection include sore throat, runny nose, and
myalgia.

. 5 Take note of any TB risk factors and symptoms: homelessness, incarceration, migra-
tion, personal history of TB, contact with a known case of TB, or prolonged fever,
weight loss, or night sweats.

. 6 Symptoms of COVID‐19 include fever, cough, fatigue, myalgia, shortness of breath,
loss of smell and taste, and diarrhoea.

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330 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

. 7 Take a travel history (discuss with an infection specialist or microbiologist if there is a history of recent foreign travel).

. 8 Medication history, including psychiatric treatments associated with hypersaliva- tion and therefore potential aspiration, e.g. clozapine (see Chapter 27); note any allergies to antibiotics.

. 9 Past medical history, including:

. a respiratory disease such as asthma, COPD, interstitial lung disease

. b immunosuppression such as HIV, steroid use, bone marrow or solid organ
transplantation

. c chronic cardiac, renal or hepatic failure or diabetes mellitus.

. 10 Social history, including: a smoking
b alcohol intake
c recreational drug use d homelessness
e incarceration.

Examination

. 1 Check observations, including temperature, respiratory rate, blood pressure, and pulse oximetry. Consider scoring these with a clinical warning system such as the National Early Warning Score (NEWS) 2 [25].

. 2 Assess for the presence of septic shock and manage accordingly (see Chapter 72).

. 3 Assess fluid status: indicators of volume deficit include thirst, hypotension, dry skin
or mucous membranes, reduced skin turgor, sunken eyes.

. 4 Assess nutritional status: indicators include weight, thin skin or hair, muscle wasting,
nail changes, bruising, oedema.

. 5 Palpate the chest for tactile fremitus (may be increased in pneumonia or decreased if
there is a pleural effusion), and for chest expansion (may be unilaterally reduced in
pneumonia).

. 6 Percuss the chest for dullness (pneumonia or effusion) or hyper‐resonance (pneumo-
thorax or emphysema).

. 7 Auscultate the chest for signs of pneumonia (bronchial breathing, crackles, increased
vocal resonance) or pleural effusion (reduced breath sounds, friction rub). Note that pneumonia may be complicated by parapneumonic effusion or empyema.

Investigations

Recommended investigations for pneumonia in community‐based patients and general medical hospital‐based patients are documented in Table 39.1. Additional investiga- tions may be indicated in immunocompromise or following recent travel; liaise with an infectious disease specialist or microbiologist. Causative organisms of pneumonia in psychiatric inpatients may differ from those in general medical inpatients. At present, there is no specific guidance for management of PHAP and we would recommend tailoring investigations to the severity of the presentation, and if necessary following discussion with general medical services.

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Investigation

Chest X‐ray

Blood tests:
Full blood count (FBC) Urea and electrolytes Liver function tests

C‐reactive protein Pulse oximetry

Sputum culture

Blood culture

Urine pneumococcal antigen

Urine Legionella antigena

Sputum AFBa
Viral PCR on nose or

throat swab

HIV test Clozapine levels

Community setting

Not necessary unless diagnosis is in doubt or underlying pathology such as lung cancer is suspected

Consider
FBC is recommended in patients taking clozapine, mianserin, mirtazapine, or carbamazepine to assess for neutropenia

Consider

Recommended for moderate or severe pneumonia
Consider in mild pneumonia not responding to empirical antibiotics

Not routinely recommended

Consider if risk factors or suspicion of tuberculosis

Not routinely recommended; however refer to local policy if COVID‐19 is suspected

Consider for all patients

Hospital setting

Recommended

Recommended
FBC is recommended in patients taking clozapine, mianserin, mirtazapine, or carbamazepine to assess for neutropenia

Recommended at diagnosis and regularly if clinically indicated (consider medical admission if not available)

Recommended, ideally prior to antibiotic therapy

Recommended if available, ideally prior to antibiotic therapy

Recommended in moderate to severe CAP

Recommended in severe CAP Consider in moderate CAP

Consider if risk factors or suspicion of tuberculosisb

Recommended in influenza season or on clinical suspicion such as coryzal symptomsb
Refer to local policy if COVID‐19 is suspected

Consider for all patients

Pneumonia 331

Table 39.1 Recommended investigations for pneumonia in patients being managed in the community or in hospital.

Consider for all patients taking clozapine (see section Pharmacological considerations in SMI patients)

a Consider discussion with an infection specialist if atypical clinical features are present or if tuberculosis is suspected (see section History). b If tuberculosis, influenza or COVID‐19 are suspected in hospitalised patients, remember to isolate according to local policy and use personal protective equipment (PPE) whilst awaiting investigation results.
AFB, acid‐fast bacilli; HIV, human immunodeficiency virus; PCR, polymerase chain reaction.

Source: adapted from National Institute for Health and Care Excellence [1] and Lim et al. [26].

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332 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

MANAGEMENT

▪ For CAP, assess the severity using clinical judgement, supported by the CURB‐65 score (Table 39.2) [27]. Alternative clinical risk scoring systems include the Pneumonia Severity Index (PSI) [28].

▪ Severity of pneumonia will guide clinical management (Table 39.3) [1,26].

▪ In PHAP, predictors of mortality include age over 65, body mass index less than
18.5 kg/m2, and bilateral pneumonic infiltration [2].

▪ Individuals at highest risk for severe disease and death from COVID‐19 infection
include people aged over 60 years, those who smoke, and those with underlying con- ditions such as obesity, hypertension, diabetes, cardiovascular disease, chronic res- piratory disease, and cancer.
Non‐pharmacological

▪ Advise patients to rest and drink plenty of fluids, and encourage smoking cessation (see Chapter 46).

▪ Repeat chest X‐ray after about six weeks to assess for resolution of radiological changes and rule out underlying malignancy [26].

▪ Arrange vaccination in accordance with national guidance. In the UK, pneumococcal and influenza vaccination is advised after recovery from pneumonia if the patient is over 65 years old, a smoker, a long‐term facility resident, or has a chronic medical condition (cardiac disease, respiratory disease, liver disease, renal failure, diabetes, alcoholism, or immunosuppression) [29]. Patients with SMI are at higher risk than others of pneumococcal disease, but in the UK are not yet recognised as a high‐risk group in current immunisation policies [30]. We recommend that where key risk fac- tors for pneumococcal disease are identified in patients with SMI (e.g. smoking, dia- betes) that vaccination is offered.

▪ For inpatients with pneumonia:
Table 39.2 CURB‐65 scoring for severity of community‐acquired pneumonia [27].

Clinical feature

Confusion

Uraemiaa

Respiratory rate

Blood pressure

Age ≥65 years

a For hospitalised patients.
AMTS, abbreviated mental test score.

Details Points

AMTS ≤ 8/10 or new disorientation in person, place or time 1

Urea >7 mmol/L 1

≥30 breaths/minute 1

Systolic <90 mmHg or diastolic ≤60 mmHg 1

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Pneumonia 333

Table 39.3 Guidelines on management of CAP by severity, in the UK general population.a

Severity Mortality

Low (CURB‐65: <3% 0–1)

Moderate 3–15% (CURB‐65: 2)

High >15% (CURB‐65: 3–5)

Treatment site

Home‐based care

Consider hospital‐ based care

Hospital‐based care Consider critical care review

Preferred treatment

Amoxicillin

Amoxicillin and clarithromycin, or Benzylpenicillin and clarithromycin

Co‐amoxiclav and clarithromycin

Alternative treatment

Doxycycline, or Clarithromycin

Doxycycline, or Levofloxacin, or Moxifloxacin

Benzylpenicillin and either Levofloxacin or Ciprofloxacin
or

Clarithromycin and either Cefuroxime or Cefotaxime or Ceftriaxone

a Antibiotic prescribing guidelines are for reference only and will differ between different geographic areas. Clinicians should consult local and national guidance.
Source: adapted from National Institute for Health and Care Excellence [1] and Lim et al. [26].

▪ If COVID‐19, influenza, TB, or travel‐related infections are suspected, isolate according to local policy and use personal protective equipment (PPE) whilst await- ing investigation results (refer to local policy).

▪ Patients requiring oxygen therapy to maintain their target saturations should be considered for transfer to a medical ward (target saturations are generally 94–98%, or 88–92% in those at risk of hypercapnic respiratory failure) [26].

■ For outpatients with suspected COVID‐19, follow local/national policy regarding self‐isolation and further management.

Pharmacological

▪ Review allergy status before prescribing antibiotics.

▪ Empiric antibiotic choice will depend on the clinical diagnosis (CAP, HAP, or aspira-
tion pneumonia).

▪ Refer to local antimicrobial prescribing guidelines which take into account the geo-
graphically variable prevalence and antimicrobial resistance of respiratory patho- gens. National UK recommendations for the treatment of CAP are provided in Table 39.3 [31]. North American readers are directed to the Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the manage- ment of CAP [32].

▪ Use oral antibiotics when possible for mild to moderate pneumonia. If intravenous antibiotics are required, consider transfer to a general medical ward.

▪ Duration for CAP: five days for low severity, seven to ten days for moderate to severe [1].

▪ Duration for HAP: five days [1].

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334 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ Consider venous thromboembolism prophylaxis in all inpatients with pneumonia who are not fully mobile [26].

▪ Steroids are not indicated in CAP [1].

▪ Consider oseltamivir during influenza season for patients with evidence of
lower respiratory tract infection and/or underlying medical conditions (see Chapter 40) [33].
Pharmacological considerations in SMI patients

▪ Abrupt smoking cessation can affect psychiatric medication levels (such as clozap- ine), so consider therapeutic drug monitoring (see Chapter 46) [34].

▪ Clozapine levels can rise during acute infection, and therefore close monitoring of plasma levels and dose reduction may be required [35].

▪ Ciprofloxacin and erythromycin may cause a rise in clozapine levels and increased risk of toxicity, so monitoring of plasma levels is recommended [36,37].

▪ Macrolides and quinolones may cause QTc prolongation: consider ECG monitoring if prescribed alongside other medications that prolong QTc (see Chapter 3) [38].

▪ Neuropsychiatric side effects of quinolones include insomnia (common), and anxiety, depression, hallucinations, and confusion (rare) [38].

▪ Neuropsychiatric side effects of macrolides include insomnia (common) and anxiety (uncommon) [38].

▪ Prescription of psychotropic medication (including clozapine) can generally continue in patients with pneumonia (including patients with COVID‐19); however, as previ- ously described doses may need to be reviewed. There are of course caveats to this advice, for example considering stopping predominantly renally excreted drugs such as lithium in the context of acute kidney injury (see Chapter 73). Where prescribing decisions are unclear, seek multidisciplinary input from general medical colleagues and pharmacy.

▪ Signs and symptoms of pneumonia (including influenza and COVID‐19) can mimic those seen in severe clozapine‐associated complications such as neutropenic sepsis and myocarditis; thus, screening for these presentations in patients receiving clozap- ine is recommended (see Chapters 8, 16, and 72).
When to refer to a medical subspecialty

▪ Advise patients that symptoms should steadily improve, although the rate of improve- ment will vary, and some symptoms are quicker to resolve than others [1]:

▪ in general, symptoms should start to improve within three days

▪ after one week, fever should have resolved

▪ after four weeks, sputum production should have substantially reduced

▪ after three months, most symptoms should have resolved, although fatigue may
persist

▪ most patients will feel back to normal after six months.

▪ When to seek local microbiology advice:

■ in suspected TB (see Chapter 44)

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Pneumonia 335

▪ in suspected COVID‐19

▪ in patients who are immunosuppressed

▪ in patients who have recently travelled abroad

▪ in patients who are failing to improve on empiric treatment

▪ discuss positive test results to appropriately narrow antimicrobial therapy.

▪ When to seek medical advice (e.g. respiratory input):

▪ if pneumonia is severe or complicated by respiratory failure (such as failure to meet
target saturations without oxygen)

▪ if there is evidence of more severe disease, such as an elevated NEWS 2 score or
features of septic shock

▪ in those with multiple medical comorbidities

▪ if there is suspicion of malignancy or other underlying lung disease.

▪ Seek HIV specialist advice when managing infections in HIV‐positive patients (see Chapter 45).
References
1. National Institute for Health and Care Excellence. Pneumonia in Adults: Diagnosis and Management. Clinical Guideline CG191. London: NICE, 2014. Av ailable at https://www.nice.org.uk/guidance/cg191
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11. Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol 2014;10:425–448.

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2015;72(12):1172–1181.

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14. Rosenberg SD, Goodman LA, Osher FC, et al. Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public
Health 2001;91:31–37.

15. Singh D, Berkman A, Bresnahan M. Seroprevalence and HIV‐associated factors among adults with severe mental illness: a vulnerable popula-
tion. S Afr Med J 2009;99(7):523–527.

16. Birmingham L. The mental health of prisoners. Adv Psychiatr Treat 2003;9:191–201.

17. Rees S. Mental ill health in the adult single homeless population: a review of the literature. London: Crisis, Public Health Resource Unit, 2009.
Available at https://www.crisis.org.uk/media/20611/crisis_mental_ill_health_2009.pdf

18. Public Health England. Tuberculosis in England: 2019 report. London: PHE, 2019. Available at https://assets.publishing.service.gov.uk/
government/uploads/system/uploads/attachment_data/file/821334/Tuberculosis_in_England‐annual_report_2019.pdf

19. Lally J, Gardner‐Sood P, Firdosi M, et al. Clinical correlates of vitamin D deficiency in established psychosis. BMC Psychiatry 2016;16:76.

20. World Health Organization.WHO Statement: tobacco use and COVID‐19.https://www.who.int/news‐room/detail/11‐05‐2020‐who‐statement‐
tobacco‐use‐and‐covid‐19

21. Herzig SJ, LaSalvia MT, Naidus E, et al. Antipsychotics and the risk of aspiration pneumonia in individuals hospitalised for non‐psychiatric
conditions: a cohort study. J Am Geriatr Soc 2007;65(12):2580–2586.

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336 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

22. Gurrera RJ, Parlee AC, Perry NL. Aspiration pneumonia: an underappreciated risk of clozapine treatment. J Clin Psychopharmacol 2016;36(2):174–176.

23. Stoecker ZR, George WT, O’Brien JB, et al. Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months. Int Clin Psychopharmacol 2017;32(3):155–160.

24. Hung GC, Liu HC, Yang SY, et al. Antipsychotic re‐exposure and recurrent pneumonia in schizophrenia: a nested case‐control study. J Clin Psychiatry 2016;77(1):60–66.

25. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of acute‐illness severity in the NHS. Updated report of a working party. London: RCP, 2017.

26. Lim WS, Baudouin SV, George RC et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009;64(Suppl 3): iii1–iii55.

27. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58(5):377–382.

28. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low‐risk patients with community‐acquired pneumonia. N Engl J Med 1997;336(4):243–250.

29. Department of Health. Immunisation Against Infectious Disease: The Green Book. Chapter 25: Pneumococcal. https://www.gov.uk/govern- ment/publications/pneumococcal‐the‐green‐book‐chapter‐25

30. Seminog OO, Goldacre MJ. Risk of pneumonia and pneumococcal disease in people with severe mental illness: English record linkage studies. Thorax 2013;68(2):171–176.

31. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections: summary. Clin Microbiol Infect 2011;17(Suppl 6):1–24.

32. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community‐acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27–S72.

33. Public Health England. Guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza. Version 10.0. London: PHE, September 2019. Available at https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/ file/833572/PHE_guidance_antivirals_influenza_201920.pdf

34. Cormac I, Brown A, Creasy S, et al. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clo- zapine. Acta Psychiatr Scand 2010;121:393–397.

35. Clark SR, Warren NS, Kim G, et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res 2018;192:50–56.

36. Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and N‐desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol 2000;56(8):585–589.

37. Cohen LG, Chesley S, Eugenio L, et al. Erythromycin‐induced clozapine toxic reaction. Arch Intern Med 1996;156(6):675–677.

38. Joint Formulary Committee. British National Formulary, 76th edn. London: BMJ Group and Pharmaceutical Press, 2018.

CHAPTER 39

Chapter 40

Influenza

Anna Riddell, Eithne MacMahon

Influenza viruses cause both upper and lower respiratory tract infections. There are three types of influenza virus responsible: A, B, and C. Influenza A and B cause seasonal epidemics and are responsible for the morbidity and mortality associated with influ- enza. Influenza A also causes pandemics: when a new influenza A virus pandemic strain emerges, fewer people in the population have pre‐existing immunity, leading to many more cases of influenza and a greater number of severe cases. Influenza C generally causes milder disease.

Influenza tends to pass from person to person via coughing and sneezing; this expels infectious particles which are then inhaled by another person [1]. Contact with surfaces contaminated with infectious particles is another important mode of transmission [1]. The median time taken between exposure to influenza virus and onset of symptoms (the incubation period) is 1.4 days but can be up to 4 days [2].

In temperate climates, influenza tends to occur seasonally during the colder winter months [3]. In tropical climates, the seasonality of influenza is less predictable but may be associated with months of higher rainfall [3]. Influenza is unusual out of ‘flu season’ but should be considered in travellers recently returned from an area with circulating influenza.

The severity of illness from influenza infection ranges from mild to severe. In the UK, it is estimated that an average of 600 people a year die from complications of flu, although during severe seasons this can increase dramatically, with 13,000 influenza‐ attributable deaths recorded in the UK in 2008–2009 [4].

Various patient groups are vulnerable to severe influenza infection, summarised in Box 40.1. Owing to increased multimorbidity and institutionalisation, patients with serious mental illness represent a vulnerable population.

Box 40.1 Risk factors for severe influenza infection

▪ Pregnancy (including two weeks postpartum)

▪ Children under six months

▪ Elderly over 65 years

▪ Chronic disease: diabetes mellitus; cardiovascular, respiratory, renal, liver, or neurological disease;
asplenia or splenic dysfunction

▪ Immunocompromised state (due to either underlying disease or immunosuppressive therapy)

▪ Morbid obesity (BMI >40 kg/m2)

338 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

DIAGNOSTIC PRINCIPLES History

. 1 Symptoms are variable and inconsistent, but the classic infection often includes sudden‐onset illness with fever, cough, headache, myalgia, extreme fatigue, sore throat, and runny nose.

. 2 Record any work that may increase exposure to influenza, e.g. healthcare or travel to an area with circulating influenza.

. 3 Past medical history:

. a malignancy

. b immunocompromised state (including immunosuppressive therapy, transplanta-
tion, chemotherapy, recent treatment for leukaemia or lymphoma, HIV, hypo-
splenism, asplenia)

. c chronic respiratory, heart, renal, liver, or neurological disease

. d diabetes mellitus

. e pregnancy.

. 4 Travel history (including contact with a healthcare facility abroad).

. 5 Social history, with attention to smoking status and residence with people who may
be vulnerable to influenza infection.

Examination

. 1 Check for signs of sepsis and systemic shock: assess temperature, heart rate, blood pressure, and Glasgow Coma Scale (GCS) score (see Chapter 72).

. 2 Respiratory examination: check oxygen saturations; look for evidence of respiratory distress and signs of lower respiratory tract infection suggestive of influenza pneu- monia or super‐added bacterial infection.

. 3 Cardiovascular examination to assess for exacerbation of heart disease or pulmo- nary oedema.

. 4 Calculate body mass index (BMI): obesity is a risk factor for increased disease sever- ity and mortality in infected individuals [5].

CHAPTER 40

Investigations

No investigations may be required for a community‐based patient where there are no risk factors for complicated influenza. However, in more severe cases and/or in at‐risk individuals, the following tests may be requested.

. 1 Bloods:

. a full blood count with differential white cell count

. b renal function

. c liver function

. d clotting

. e C‐reactive protein

. f blood glucose measurement

. g throat and nose swab for respiratory viral polymerase chain reaction (PCR)

. h throat swab for microscopy, bacterial culture, and sensitivity.

. 2 Consider chest X‐ray to assess for consolidation or pulmonary oedema, if appropri- ate (although where these are suspected, referral to general medical colleagues is recommended).

. 3 Although unlikely to be immediately available in a psychiatric setting, ‘point‐of‐care’ testing for influenza A/B virus from a nasal swab is now available in some general medical hospitals [6]. The new molecular point‐of‐care tests have high sensitivity and specificity, with results in less than half an hour, thereby facilitating appropriate treatment of infected individuals and avoiding inappropriate treatment of non‐ infected individuals.
MANAGEMENT

▪ In patients where no risk factors for complicated influenza are identified, rest and antipyretics (e.g. paracetamol) are recommended.

▪ Time off work may be advisable depending on symptoms and to prevent onward spread of infection.

▪ The patient should be warned that the duration of symptoms is approximately one week, and that full recovery with return to normal activities may take even longer.

▪ Patients should be informed about simple measures to prevent onward transmission
(Box 40.2).

Influenza 339

Box 40.2 Techniques to avoid influenza and prevent onward transmission

▪ Catch it: Cover mouth and nose when coughing or sneezing

▪ Bin it: Dispose of used tissues

▪ Kill it: Wash hands

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340 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Pharmacological treatment

▪ Patients with risk factors for severe infection (see Box 40.1) should be given pharma- cological treatment. This should be started immediately if influenza is circulating or there is a high index of suspicion while waiting for test results.

▪ The neuraminidase inhibitors oseltamivir (oral 75 mg twice daily for five days) and zanamivir (inhalation 10 mg twice daily for five days) are the only effective available pharmacological therapies for influenza virus infection in the UK (Table 40.1) [7].

▪ Inhaled zanamivir is contraindicated in patients with underlying airways disease. Newer neuraminidase inhibitors are being developed. Therapy with neuraminidase inhibitors should be initiated as soon as possible after the start of symptoms as the greatest benefits of therapy have been observed if taken within the first 48 hours after development of symptoms [8].

▪ The main benefits of neuraminidase inhibitor therapy are to reduce the duration of symptoms and to reduce severity of illness [8].
Interactions with psychiatric medications

▪ The neuraminidase inhibitors are well tolerated with few drug interactions.

▪ There are no reported interactions of neuraminidase inhibitors with psychiatric
medications.

▪ As the neuraminidase inhibitors are renally excreted, elevated plasma concentrations
of oseltamivir in patients with renal dysfunction have been observed. Dose reduction is therefore recommended in those patients with a creatinine clearance of less than 30 mL/min [9].
When to refer to a specialist

▪ If severely unwell (e.g. hypotension, tachycardia, respiratory distress), the patient should be admitted to general medial hospital for monitoring and further investiga- tions. Oseltamivir should be commenced, and additional broad‐spectrum antibiotics considered. Discussion with an infectious diseases specialist is recommended.

▪ If the patient has already been taking oseltamivir or zanamivir as post‐exposure prophylaxis (see following section) and they develop symptoms suggestive of influ- enza, change delivered dose to reflect treatment rather than prophylaxis (i.e. treat- ment is given twice rather than once daily). In the community consider a review in

Table 40.1 Pharmacological treatment and prophylaxis of influenza in adults.

Neuraminidase inhibitor

Oseltamivir Zanamivir

Mode of administration

Oral (tablet)

Inhalera

Dose for treatment

75 mg twice daily for 5 days

10 mg twice daily for 5 days

Dose for prophylaxis

75 mg once daily for 10 days

10 mg once daily for 10 days

CHAPTER 40

a Intravenous preparation is available but only after discussion with an infectious diseases specialist.

primary care, or in severe cases a review in the emergency department, followed by discussion with an infectious diseases specialist. In severe cases, admission to the intensive care department may be required.

PREVENTING SPREAD OF INFLUENZA

▪ Strict infection control is key to preventing the spread of influenza in healthcare set- tings. Staff with influenza should not be at work. Patients and staff should adopt good hand hygiene practice: ‘catch it, bin it, kill it’ (see Box 40.2). Either alcohol sani- tisers or soap and water are appropriate for washing hands.

▪ Patients should avoid vulnerable individuals if unwell (see Box 40.1).

▪ On inpatient wards, infection control measures should include isolation rooms to prevent nosocomial transmission, and ideally nursing should involve use of gloves,
masks, and aprons/gowns.
Post‐exposure prophylaxis

▪ Prompt pharmacological prophylaxis is advised for patients with risk factors for severe infection (see Box 40.1) who have been exposed to a confirmed case of influ- enza, or when influenza infection is circulating locally.

▪ In the UK, oseltamivir (oral 75 mg once daily for 10 days post exposure) or zanamivir (inhalation 10 mg once daily for up to 28 days) may be offered (see Table 40.1).

▪ In a hospital/residential setting, consider offering all inpatient contacts prophylaxis, regardless of vaccination history.
Pre‐exposure prophylaxis: vaccination

▪ Influenza vaccines contains both influenza A virus subtypes (H1N1 and H3N2) and B virus strain(s).

▪ Vaccination offers significant additional individual protection and benefit in long‐ stay facilities and should be offered to all at‐risk individuals over six months of age (see Box 40.1), and to individuals who are in frequent contact with those who are at risk (e.g. household contacts and healthcare providers).

▪ Vaccination is the most important intervention available to reduce the risk of acquir- ing influenza, providing protection against the anticipated seasonal circulating strains.

▪ In the UK, the reader is directed to the influenza chapter in The Green Book, which
provides the latest information on vaccines and vaccine procedures [10].

▪ The World Health Organization (WHO) manages a twice‐yearly meeting where the content of the influenza vaccine for the forthcoming season is decided based on global surveillance data of the viruses circulating the season before [11]. The vaccine content is based on prediction of the strains likely to be circulating the following season and for this reason can sometimes be mismatched, leading to lower efficacy. However, vaccination reduces the severity of influenza illness, hospitalisations, and deaths from
influenza [12].

Influenza 341

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342 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ Annual re‐vaccination is required.

▪ All staff should receive annual vaccination for personal protection and to minimise
nosocomial transmission.
References

1. Killingley B, Nguyen‐Van‐Tam J. Routes of influenza transmission. Influenza Other Respir Viruses 2013;7(Suppl 2):42–51.

2. Lessler J, Reich NG, Brookmeyer R, et al. Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis
2009;9(5):291–300.

3. Tamerius JD, Shaman J, Alonso WJ, et al. Environmental predictors of seasonal influenza epidemics across temperate and tropical climates.
PLoS Pathog 2013;9(3):e1003194.

4. Green HK, Andrews N, Fleming D, et al. Mortality attributable to influenza in England and Wales prior to, during and after the 2009 pan-
demic. PLoS One 2013;8(12):e79360.

5. Sun Y, Wang Q, Yang G, et al. Weight and prognosis for influenza A(H1N1)pdm09 infection during the pandemic period between 2009 and
2011: a systematic review of observational studies with meta‐analysis. Infect Dis (Lond) 2016;48(11–12):813–822.

6. World Health Organization. WHO recommendations on the use of rapid testing for influenza diagnosis. https://www.who.int/influenza/
resources/documents/RapidTestInfluenza_WebVersion.pdf (accessed 11 November 2019).

7. National Institute for Health and Care Excellence. Amantadine, Oseltamavir and Zanamivir for the Treatment of Influenza. Technology
Apraisal Guidance TA168. London: NICE, 2009. https://www.nice.org.uk/Guidance/TA168

8. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363–1373.

9. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64‐0802. Clin Pharmacokinet
1999;37(6):471–484.

10. Public Health England. Influenza: The Green Book, chapter 19. Influenza immunisation information including updates for public health
professionals. https://www.gov.uk/government/publications/influenza‐the‐green‐book‐chapter‐19 (accessed 1 August 2019).

11. Ziegler T, Mamahit A, Cox NJ. 65 years of influenza surveillance by a World Health Organization‐coordinated global network. Influenza
Other Respir Viruses 2018;12(5):558–565.

12. Arriola C, Garg S, Anderson EJ, et al. Influenza vaccination modifies disease severity among community‐dwelling adults hospitalized with
influenza. Clin Infect Dis 2017;65(8):1289–1297.

CHAPTER 40

Chapter 41

Urinary Tract Infection

Sian Cooper, Conor Maguire

Urinary tract infection (UTI) is caused by microorganism growth in the urine. It can be classified as uncomplicated or complicated. Uncomplicated UTI describes an infection of the lower urinary tract, i.e. urethra and/or bladder (‘cystitis’), while complicated UTI describes infection of the urinary tract that may ascend to the kidney (pyelonephritis) or prostate, accompanied by systemic features of infection (e.g. fever and rigors), pelvic/ renal‐angle pain, and potentially sepsis (see Chapter 72). Recurrent UTI is defined as a UTI that reoccurs with a new causative organism, whereas relapsed UTI is defined by re‐infection with the same organism. UTI is most commonly caused by bacteria (Box 41.1). While a small number of pathogens account for most infections, in immu- nosuppression the range of organisms causing UTI is broader.

Box 41.1 Common causative organisms of urinary tract infections in the UK Community acquired

Escherichia coli
Enterobacteriaceae (including Klesbsiella spp. and Proteus spp.) Enterococci
Staphylococcus saprophyticus

Healthcare associated

Pseudomonas
Methicillin‐resistant Staphylococcus aureus (MRSA)
Extended‐spectrum beta‐lactamase (ESBL)‐producing Enterobacteriaceae Carbapenem‐resistant Enterobacteriaceae (CRE)

344 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Asymptomatic pyuria (elevated number of white blood cells in the urine in the absence of urinary symptoms) and asymptomatic bacteriuria (isolation of bacteria con- sistent with UTI in the absence of urinary symptoms) is commonly observed. Indeed, on urine testing, pyuria has been recorded in up to 45% of chronically disabled or incon- tinent adults, and up to 90% of individuals living in nursing homes [1]. Prevalence of asymptomatic bacteriuria is highly variable, and increases with age, in postmenopausal women, and in those with type 2 diabetes mellitus [2]. In people living in healthcare facilities, asymptomatic bacteriuria has been observed in 25–50% of women and 5–21% of men, with no associated increase in mortality or morbidity if left untreated [3]. Bacteriuria is seen in up to 100% of patients with chronic indwelling catheters [2]. In many patient groups, asymptomatic pyuria/bacteriuria in the absence of symptoms or signs of sepsis does not require antibiotic treatment (e.g. premenopausal non‐preg- nant women; diabetic women; elderly institutionalised men and women; and patients with indwelling urethral catheters) [4]. However, treatment of asymptomatic pyruria/ bacteriuria is indicated in pregnant women and patients who have recently undergone a traumatic urological procedure (e.g. transurethral resection of the prostate). Asymptomatic pyuria/bacteriuria in patients with neutropenia (see Chapter 16) or in those who are otherwise immunosuppressed should be discussed with microbiology.

URINARY TRACT INFECTION AND SERIOUS MENTAL ILLNESS

Positive urinalysis for leucocytes/nitrites has been observed in up to 21% of psychiatric inpatients with psychosis, over ten times the prevalence seen in the general population [5]. Patients with serious mental illness are at increased risk of infection compared with the general population [6], and are more likely to present with comorbidities such as diabetes mellitus that increase risk of UTI. For example, young men with type 2 diabe- tes are four times more likely to have a UTI compared with non‐diabetic individuals [7].

DIAGNOSTIC PRINCIPLES

History

Presenting complaint

Typical symptoms of UTI are increased urinary frequency, dysuria, urgency, haematu- ria, and suprapubic pain. Complicated infections may be heralded by fever, rigors, and flank pain. Patients with poor verbal communication may present with non‐specific symptoms such as lethargy or confusion. Older adults or immunosuppressed patients may be afebrile and can present with atypical features (e.g. acute confusion; see Chapter 50) [8].

History and examination are vital in screening for differential diagnoses, which include acute appendicitis, diverticulitis, cholecystitis (see Chapter 88), salpingitis, rup- tured ovarian cyst, or ectopic pregnancy (see Chapter 87).

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Urinary Tract Infection 345

Past medical history

Consider the following:

▪ pregnancy or menopause

▪ known structural abnormalities of the urological tract such as urinary stones, chronic
urinary retention, long‐term urinary catheterisation

▪ recent instrumentation of the urinary tract

▪ conditions that predispose to neurological dysregulation of bladder function (e.g.
multiple sclerosis, Parkinson’s disease, diabetic neuropathy)

▪ recent inpatient admission (increased risk of drug‐resistant infection)

▪ immunosuppression such as HIV, steroid use, bone marrow or solid organ transplan-
tation, poorly controlled diabetes

▪ chronic cardiac, renal, or hepatic failure (risk of decompensation in context of inter-
current UTI)

▪ sexual/gynaecological history including sexually transmitted infections (see
Chapter 38).
Drug history
Review all medications including treatments associated with urinary stasis/retention (such as psychiatric drugs with anticholinergic activity) or those that may cause neutro- penia (see Chapter 16). Record any antibiotic allergies.
Social history
Ascertain smoking status, alcohol intake, the use of recreational drugs, and housing circumstance (i.e. if homeless).
Examination

▪ Check observations, including temperature, respiratory rate, blood pressure, and pulse oximetry. Consider scoring these with a clinical warning system such as NEWS 2 [9].

▪ Assess for the presence of sepsis and manage accordingly (see Chapter 72).

▪ Assess fluid status (indicators of volume deficit: thirst, hypotension, dry skin or mucous membranes, reduced skin turgor, sunken eyes); dehydration may be an indi-
cator for admission for intravenous fluids.

▪ Palpate the abdomen for suprapubic and flank tenderness/dullness.

▪ Consider a chaperoned pelvic examination for cervical motion tenderness in sexually
active women to investigate possible pelvic inflammatory disease. Amongst male patients, a chaperoned digital rectal examination may be indicated to aid a diagnosis of prostatitis.
Investigations
Recommended investigations for UTI in community‐based patients and general medi- cal hospital‐based patients are documented in Table 41.1. Additional investigations may be indicated in the immunocompromised (e.g. requiring broader infection screen

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346 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Table 41.1 Recommended investigations for UTI in patients being managed in the community or in hospital.

Investigation

Urinalysis

Mid‐stream urine (MSU) for cultures

Blood tests:
Full blood count (FBC)
Urea and electrolytes C‐reactive protein

Pulse oximetry

Blood culture

Urine pregnancy test

Ultrasound urinary tract

HIV test

Clozapine levels

Community setting

Recommended

Recommended if leucocytes/nitrites positive on urinalysis or resistant organism suspected

Consider
FBC is recommended in patients taking clozapine, mianserin, mirtazapine, or carbamazepine to assess for neutropenia

Consider

Not routinely recommended

To exclude ectopic pregnancy and guide antibiotic choice

Not routinely recommended

Consider

Hospital setting

Recommended

Recommended if leucocytes/nitrites positive on urinalysis or resistant organism suspected

Recommended
FBC is recommended in patients taking clozapine, mianserin, mirtazapine, or carbamazepine to assess for neutropenia

Recommended at diagnosis and regularly if clinically indicated

Recommended if signs of sepsis, ideally prior to antibiotic therapy

To exclude ectopic pregnancy and guide antibiotic choice

Recommended if adverse features

Consider

CHAPTER 41

Consider for all patients taking clozapine (see section Pharmacological considerations in serious mental illness)

Source: adapted from National Institute for Health and Care Excellence [10].

such as tuberculosis cultures), patients with recurrent UTIs (may require imaging of the urinary tract), or in patients where resistant organisms have previously been cultured (discussion with an infectious disease specialist or microbiologist is recommended). At present, there is no specific guidance for management of psychiatric hospital‐associated UTI, and we would recommend tailoring investigations to the severity of the presenta- tion, and if necessary following discussion with general medical services.

Urinalysis should be performed on a mid‐stream clean‐catch urine (MSU) sample to assess for the presence of nitrites and leucocyte esterase. Although a positive urinalysis is not diagnostic of a UTI, treat empirically with antibiotics if the patient is sympto- matic and nitrites or leucocytes (pyuria) are present on urinalysis. It should be noted that some microorganisms do not produce nitrites. Absence of pyuria likely indicates an alternative diagnosis (Table 41.2).

Growth of greater than 105 organisms per millilitre in a fresh MSU sample is diagnos- tic of UTI in a symptomatic patient [11]. If fewer organisms grow but significant pyuria is observed (>20 white blood cells per mm3), this still may be regarded as an indication to treat. When in doubt, discuss with a microbiologist [12]. Send the sample for micros-

Urinary Tract Infection 347

Table 41.2 Determining likelihood of urinary tract infection based on urinalysis [12].

Leucocyte esterase

Negative

Positive

Negative or positive

Nitrite

Negative

Positive

Interpretation

UTI unlikely

UTI moderately likely

UTI highly likely

copy, culture and sensitivity to document the organism and antimicrobial therapy options, especially in patients who are male, pregnant, immunosuppressed, or presenting with recurrent infections. If the patient has a catheter, urinalysis is not helpful. However, microscopy, culture and sensitivity may still be performed, labelling the sample clearly as a catheter specimen. Similarly, the elderly may have ‘symptomless bacteriuria’ due to ageing changes, including incomplete bladder emptying, prostatic hypertrophy in men, and postmenopausal oestrogen loss in women, which may not require treatment.

Blood tests are generally not necessary in the outpatient setting unless the patient has specific signs or symptoms (sepsis, urinary retention, dehydration). For women of child- bearing age, consider a pregnancy test as this is relevant for management and antibiotic choice.

Imaging of the abdomen (e.g. ultrasound) is not indicated unless the patient requires hospitalisation, persistence of symptoms beyond 48–72 hours, recurrence within a short period of time, or if urine outflow obstruction is suspected. The role of imaging is to establish a potential structural cause of UTI, or complication such as abscess forma- tion secondary to infection.

MANAGEMENT Non‐pharmacological

▪ Advise patients to drink plenty of fluids.

▪ Give paracetamol to reduce fever if no contraindications.

▪ There is insufficient evidence to recommend cranberry juice [3].

▪ For inpatients with carbapenem‐resistant Enterobacteriaceae, isolate according to
local policy.
Pharmacological

▪ Review allergy status before prescribing antibiotics.

▪ Empiric antibiotic choice will depend on the clinical diagnosis (community‐acquired
or hospital‐associated disease).

▪ Refer to local antimicrobial prescribing guidelines that consider the geographically
variable prevalence and antimicrobial resistance of urinary pathogens. National

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348 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Institute for Health and Care Excellence (NICE) guidance on common antibiotics for

the treatment of UTI is provided in Table 41.3.

▪ Long‐term catheterisation is often associated with colonisation by antibiotic‐resistant
organisms such as Pseudomonas [13]. Where treatment is required, discussion with
microbiology is advised.

▪ Use oral antibiotics where possible for uncomplicated UTI. If intravenous antibiotics
are required, consider transfer to a general medical ward.

▪ For non‐pregnant women with no adverse features (i.e. no evidence of complicated
UTI), consider a ‘watchful waiting’ approach whereby a back‐up antibiotic prescription
is provided that can be started if there is no improvement in symptoms after 48 hours.

▪ Duration of treatment should be three days for uncomplicated UTIs in women and
seven days in men or pregnant women [10].

▪ Consider venous thromboembolism prophylaxis in all inpatients with UTI who are
not fully mobile (see Chapter 18).
Table 41.3 Common antibiotic regimens for uncomplicated urinary tract infection in the UK.a

CHAPTER 41

Antibiotic class

Antimetabolite

Quinolone

β‐Lactam

Antibiotic example

Trimethoprim
200 mg b.d. (p.o.)

Nitrofurantoin
50 mg q.d.s. (p.o.)

Ciprofloxacin 250–500 mg (p.o.) b.d.

Co‐amoxiclav 625 mg t.d.s.

Amoxicillin 250–500 mg (p.o.) t.d.s.

Cephalosporins, e.g. cefalexin 250 mg q.d.s./500 mg b.d.

Considerations

Contraindicated in pregnancy, reduce dose in renal impairment

Contraindicated if eGFR <45 mL/min; caution if anaemia, diabetes mellitus, electrolyte imbalance, vitamin B (particularly folate) deficiency. Considered safe in pregnancy, excreted in breast milk

Avoid in pregnancy and breastfeeding, risk of articular damage, renal failure

Avoid in pregnancy and breastfeeding unless essential, caution in renal and hepatic impairment

Use for asymptomatic bacteriuria in pregnancy, reduce dose in renal failure

No evidence of teratogenicity, excreted in breast milk

Interactions with psychotropics

May increase risk of bone marrow aplasia if given with bone marrow suppressants

None documented

Lowers seizure threshold, risk of ‘psychiatric complications’, CYP1A2 inhibitor

None documented

a Non‐pregnant women should be treated for three days, men and pregnant women for seven days. Consult local antimicrobial guide- lines as resistance patterns can vary.
eGFR, estimated glomerular filtration rate.

Urinary Tract Infection 349

Pharmacological considerations in serious mental illness

▪ Abrupt smoking cessation can alter psychiatric medication levels (such as clozapine), so consider therapeutic drug monitoring (see Chapter 46).

▪ Clozapine levels can rise during acute infection, and therefore close monitoring of plasma levels and dose reduction may be required [14].

▪ Ciprofloxacin and erythromycin may cause a rise in clozapine levels and increased risk of toxicity, so monitoring of plasma levels is recommended [15].

▪ Macrolides and quinolones may cause QTc prolongation, so consider ECG monitor- ing if prescribed alongside other medications that prolong QTc (see Chapter 3).

▪ Neuropsychiatric side effects of quinolones include insomnia (common), and anxiety, depression, hallucinations, and confusion (rare).

▪ Neuropsychiatric side effects of macrolides include insomnia (common) and anxiety (uncommon).
Pregnant women (see also Chapter 62)
Prompt treatment of UTI is mandatory in pregnancy due to greater risk of complica- tions, such as pyelonephritis or premature labour [16]. Send an MSU sample to micro- biology before commencing antimicrobials; if a group B Streptococcus is isolated, inform antenatal services. Refer to local antimicrobial prescribing guidelines, although a reasonable first‐line prescription would be nitrofurantoin 100 mg modified release twice daily for seven days.
When to refer to a medical subspecialty

▪ Advise patients that symptoms should steadily improve, although the rate of improve- ment will vary, and some symptoms are quicker to resolve than others. In general, symptoms should start to improve within 48 hours.

▪ When to seek local microbiology advice:

▪ with suspected resistant organisms

▪ in patients who are immunosuppressed

▪ in patients who are failing to improve on empiric treatment.

▪ When to seek acute medical advice:

▪ If there is evidence of more severe disease, such as an elevated NEWS 2 score or
features of septic shock

▪ if oral treatment is not possible and/or the patient is dehydrated

▪ in those with multiple medical comorbidities

▪ if there is suspicion of structural urological disease or obstruction.

▪ Seek HIV specialist advice when managing infections in HIV‐positive patients (see Chapter 45).
Routine referral to urology for recurrent UTIs is indicated in:

▪ recurrent UTIs in men [17]

▪ suspected urinary tract structural abnormality (e.g. previous surgery or trauma, cal-
culi, symptoms of fistula)

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350 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

▪ obstructive symptoms, such as those attributable to prostatic hypertrophy

▪ previous abdominal or pelvic malignancy

▪ unusual pathogens cultured such as Proteus or Yersinia

▪ persistent bacteriuria despite antimicrobials

▪ immunocompromise, diabetes mellitus

▪ persistent microscopic haematuria in men, proteinuria.
Urgent referral (two‐week wait) to urology services is indicated:

▪ if urological cancer is suspected (persistent haematuria, recurrent unexplained UTI)

▪ age over 45 years with unexplained visible haematuria without UTI or persistent
haematuria after successful treatment of UTI

▪ age over 60 years with unexplained microscopic haematuria and lower urinary tract
symptoms or elevated white cell count on blood test [18].
References

1. Detweiler K, Mayers D, Fletcher SG. Bacteruria and urinary tract infections in the elderly. Urol Clin North Am 2015;42(4):561–568.

2. Nicolle LE. The paradigm shift to non‐treatment of asymptomatic bacteriuria. Pathogens. 2016;5(2):38.

3. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2012;(10):CD001321.

4. Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic
bacteriuria in adults. Clin Infect Dis 2005;40(5):643–654.

5. Graham KL, Carson CM, Ezeoke A, et al. Urinary tract infections in acute psychosis. J Clin Psychiatry 2014;75(4):379–385.

6. Pankiewicz‐Dulacz M, Stenager E, Chen M, Stenager E. Incidence rates and risk of hospital registered infections among schizophrenia
patients before and after onset of illness: a population‐based nationwide register study. J Clin Med. 2018;7(12):485.

7. Hirji I, Guo ZC, Andersson SW, et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice
Research Database (GPRD). J Diabetes Complications 2012;26(6):513–516.

8. Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis 2002;2(11):659–666.

9. Royal College of Physicians. National Early Warning Score (NEWS) 2. https://www.rcplondon.ac.uk/projects/outputs/national‐early‐
warning‐score‐news‐2 (accessed 22 April 2019).

10. National Institute for Health and Care Excellence. Urinary Tract Infections in Adults. Quality Standard QS90. London: NICE, 2015. https://
http://www.nice.org.uk/guidance/qs90/chapter/Quality‐statement‐5‐Antibiotic‐treatment‐for‐asymptomatic‐adults‐with‐catheters‐and‐
nonpregnant‐women

11. Public Health England. Investigation of urine. https://www.gov.uk/government/publications/smi‐b‐41‐investigation‐of‐urine

12. Public Health England. Diagnosis of urinary tract infections:quick reference guide. https://www.gov.uk/government/consultations/
diagnosis‐of‐urinary‐tract‐infections‐quick‐reference‐guide

13. Sabir N, Ikram A, Zaman G, et al. Bacterial biofilm‐based catheter‐associated urinary tract infections: causative pathogens and antibiotic
resistance. Am J Infect Control 2017;45(10):1101–1105.

14. Clark SR, Warren NS, Kim G, et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res
2018;192:50–56.

15. Cohen LG, Chesley S, Eugenio L, et al. Erythromycin‐induced clozapine toxic reaction. Arch Intern Med 1996;156(6):675–677.

16. Juthani‐Mehta M, Drickamer MA, Towle V, et al. Nursing home practitioner survey of diagnostic criteria for urinary tract infections. J Am
Geriatr Soc 2005;53(11):1986–1990.

17. National Institute for Health and Care Excellence. Lower urinary tract infection in men. Clinical Knowledge Summary. https://cks.nice.org.
uk/urinary‐tract‐infection‐lower‐men#!topicSummary

18. National Institute for Health and Care Excellence. Urological cancers: recognition and referral. Clinical Knowledge Summary. https://cks.
nice.org.uk/urological‐cancers‐recognition‐and‐referral#!scenario

CHAPTER 41

Chapter 42

Gastroenteritis

Maria Krutikov, Luke Snell

Gastroenteritis is a transient infection of the bowel with a virus, bacterium, or parasite. It is characterised by sudden‐onset diarrhoea, with or without vomiting [1]. Some forms are highly contagious (e.g. norovirus). Food poisoning is a form of gastroenteritis caused by ingestion of contaminated food, often with acute and severe symptoms. Gastroenteritis is associated with significant mortality rates, especially in low‐ and middle‐income countries, with children particularly vulnerable. Indeed, according to the Centers for Disease Control, viral gastroenteritis accounts for approximately 200,000 childhood deaths per year worldwide [2].

The main causes and associated presentations of gastroenteritis in high/middle income countries are outlined in Table 42.1. Rotavirus and adenovirus are the most common causes in children, while norovirus is a frequent cause in adults. In general medical hospitals, gastroenteritis is most commonly caused by norovirus, Clostridium difficile (if recent antibiotics), and Escherichia coli. Data in psychiatric units are not yet available. In sexually active individuals who have anal sexual intercourse, especially men who have sex with men, Shigella flexneri and giardiasis are common causes of infection (see Chapter 38). Parasitic infections are usually related to travel but can be associated with unclean water supply [1,3–5].

DIAGNOSTIC PRINCIPLES History
Presenting complaint
Ask about the following:

▪ frequency of bowel motions, duration of symptoms

▪ stool consistency and colour including presence of blood or mucus
The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry, First Edition. David M. Taylor, Fiona Gaughran, and Toby Pillinger.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Table 42.1 Common causes of gastroenteritis.

Organism Viruses

Norovirus

Rotavirus

Adenovirus

Bacteria

Campylobacter spp.

Enterohaemorrhagic

Escherichia coli

Non‐typhoidal

Salmonella

Shigella spp.

Clostridium difficile

Listeria monocytogenes

Staphylococcus aureus

Bacillus cereus

Parasites

Giardia lamblia

Cryptosporidium parvum

Entamoeba histolytica (amoebiasis)

Presentation

Vomiting, watery diarrhoea, fever, muscle aches

Fever, vomiting and diarrhoea

Diarrhoea, conjunctival and respiratory infection

Fever, crampy abdominal pain, vomiting, diarrhoea, muscle aches

Bloody diarrhoea, abdominal cramps

Watery bloody diarrhoea, abdominal cramps, fever, headache, rarely septic joint

Bloody diarrhoea, cramps, fever

Cramping abdominal pain and distension, fever, foul‐smelling diarrhoea

Fever, watery diarrhoea, nausea, vomiting, headache, joint pains

Nausea, vomiting and abdominal

Nausea and profuse vomiting

Acute and chronic diarrhoea with abdominal cramps, bloating and flatulence

Abdominal cramping and bloating, weight loss, watery diarrhoea, fever, weight loss

Usually mild but can cause blood and mucus in stool with fevers. Rarely, extra‐ intestinal amoebic abscesses (e.g. liver)

Incubation period

24–48 hours

10–72 hours

1–3 days

1–8 days

1–3 days

N/A

1–10 days

1–6 hours

7–14 days

2–28 days

1–3 weeks

Common sources

Shellfish, prepared foods, vegetables, fruits, close contacts

Faecally contaminated water or food

Faecally contaminated water/food

Undercooked meat (especially poultry), unpasteurised milk

Contaminated food, especially undercooked meat

Poultry, eggs, meat, fish, unpasteurised milk

Contaminated water, raw vegetables

Antibiotic use

Soft cheeses, processed meats, pates, unwashed fruit

Prepared food

Rice, meat

Faecally contaminated food or water

Vegetables, fruit, unpasteurised milk

Faecally contaminated food or water

Highest risk group/ setting

Healthcare settings, schools, cruise ships

Infants under age 5, winter seasonal pattern

Children

Contact with young animals, travel to resource‐ limited settings

Contact with infected animals, healthcare settings and nursing homes

Travel to resource‐limited settings, contact with animals, immunosuppressed

Sexual transmission, daycare centres, travel to resource‐limited settings

Recent antibiotics, hospitalisation, gastric acid suppression

Pregnancy, immunocompromise, children, adults >65 years

Eating from buffet/ prepared food

Travellers, sexual transmission, swimming pools, daycare centres

Immunosuppression, swimming pool use, animal exposure

Travel to resource‐limited settings, sexual transmission

▪ vomiting, haematemesis (see gastrointestinal bleeding Chapter 20)

▪ fever

▪ abdominal pain (location, quality, duration, exacerbating and relieving factors)

▪ any associated symptoms (e.g. weight loss, muscle aches, conjunctivitis, joint
swelling)

▪ food consumed over 24 hours preceding symptoms, with focus especially on unpas-
teurised dairy products or uncooked meat or fish, unwashed vegetables, eating at a
buffet

▪ any affected contacts

▪ exposure to animals and contact with fresh water.
Past medical history
History of inflammatory bowel disease, immunosuppression, other bowel pathology, and HIV and hepatitis status.
Medication history
Enquire about use of opiates (constipation and overflow diarrhoea), laxatives, and proton pump inhibitors (increased risk of Clostridium difficile). Metformin can cause gastrointestinal side effects, and in acute kidney injury (secondary to dehydra- tion) is associated with lactic acidosis; therefore, consider withholding metformin during severe episodes of gastroenteritis [6]. Gastric hypomotility may be seen with clozapine [7], for which overflow diarrhoea may be a presenting complaint (see Chapter 28).
Social history
Sexual history, travel within the last six months, recreational drug use, and alcohol intake.
Examination

▪ Observations: temperature, blood pressure, heart rate, and respiratory rate.

▪ Fluid status: check mucous membranes and skin turgor, capillary refill time, and

hypotension (Table 42.2).

Table 42.2 Clinical features of dehydration.

Gastroenteritis 353

Symptoms

Signs

Mild dehydration

Light‐headedness, anorexia, nausea, fatigue

Postural hypotension

Moderate dehydration

Nausea, headache, dizziness, fatigue, muscle cramps

Dry tongue, sunken eyes, reduced skin elasticity (turgor), postural hypotension, tachycardia, oliguria

Severe dehydration

Apathy, weakness, confusion leading to loss of consciousness

Tachycardia, hypotension (systolic blood pressure <90 mmHg), capillary refill time >3 s, oliguria or anuria

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354 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

■ Examine abdomen: look for evidence of peritonism with rebound tenderness or guard- ing (see Chapter 88), palpate for areas of tenderness, and auscultate for presence of bowel sounds or borborygmic or high‐pitched sounds suggestive of bowel obstruction.

Investigations

Investigations may not be required, especially if the infection is mild and risk of com- plications is low. Most causes of gastroenteritis are self‐limiting and do not require antimicrobial therapy.

If symptoms are persistent or there are signs of dehydration, consider performing blood tests to quantify degree of inflammatory response (C‐reactive protein and white cell count) and to check electrolytes and renal function (sodium, potassium, urea, and creatinine). These results may guide whether a patient requires a general medical review.

It is recommended that stool samples are sent if there is [1]:

▪ presence of blood or pus in stool

▪ immunosuppression

▪ history of recent hospitalisation or antibiotic use

▪ persistent diarrhoea

▪ recent travel to resource‐poor setting

▪ as part of outbreak or cluster of cases.
What to send

▪ Send stool in specimen pot. Advise patient to pass the stool into a clean empty plastic food container and ensure urine has not mixed with stool.

▪ In all cases send two samples, one to virology for viral nucleic acid detection and one to microbiology for faecal microscopy, culture, and sensitivity.

▪ If recent antibiotic use, then also send a separate sample to microbiology for Clostridium difficile testing.

▪ If recent travel, sexual anal intercourse, or symptoms lasting more than 10 days, send a separate sample to microbiology for microscopy (ova, cysts, and parasites).
MANAGEMENT
In most patients, gastroenteritis is a self‐limiting illness that does not require specific therapy, and management is usually supportive.
Non‐pharmacological
Hospital inpatients with suspected gastroenteritis should be isolated as soon as symp- toms are reported. This should ideally be in a separate room with access to their own toilet facilities until symptoms have resolved. All staff and visitors should wear gloves

CHAPTER 42

and plastic aprons when entering the room. Ensure hand‐washing with soap and water on removal of protective equipment when leaving the room and hands should subse- quently be cleaned with alcohol hand rub (at least 60–95% ethanol or isopropanol).

The patient should be given strict instructions on hand hygiene and the importance of washing hands with soap and water after using the toilet. If more than one case is suspected within one healthcare facility, this should be discussed with the responsible infection control practitioner [1,8].

Pharmacological

Anti‐diarrhoeal drugs (e.g. loperamide)

Not usually advised but may be used if symptoms are persistent and mild. Do not pre- scribe if the patient has fevers or blood or mucus in stools, or if the patient has con- firmed shigellosis or verotoxin‐producing E. coli 0157 [1,8,9].

Anti‐emetics

Not usually advised, but can be used for symptomatic relief (see Chapter 21).

Antibiotics

Not usually advised as most cases of gastroenteritis are viral, and even when bacterial in aetiology, infections are usually self‐limiting. Discussion with microbiology is always recommended if antibiotic treatment is being considered, and decisions may be guided by culture results. Table 42.3 provides examples of aetiologies where treatment may be considered, and antibiotics that may be prescribed.

Table 42.3 Examples of antibiotic treatments for bacterial gastroenteritis according to pathogen [1,9].

Gastroenteritis 355

Pathogen

Campylobacter

Non‐typhoidal Salmonella

Shigella

Entamoeba histolytica

Giardia lamblia

Indication to treat

Severe symptoms, non‐resolving (>1 week), immunocompromise

Age >50, history of valvular or endovascular abnormality

Severe disease, immunocompromise, bloody diarrhoea

Treatment recommended in all cases

Antibiotics

Erythromycin Ciprofloxacina

Ciprofloxacin

Ciprofloxacin Azithromycin

Discuss with microbiologist

Metronidazoleb

a Ciprofloxacin lowers seizure threshold, is associated with ‘psychiatric complications’, and is a CYP1A2 inhibitor. b Metronidazole can be associated with depression, and (rarely) psychosis.

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356 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

When to refer

Patients with evidence of evolving sepsis (see Chapter 72), severe dehydration/hypovol- aemia, or an acute abdomen (see Chapter 88) should be discussed with medical/surgical colleagues as appropriate and transferred to the accident and emergency department.

Absolute indications for emergency admission to hospital

▪ Signs or symptoms of shock/sepsis or severe dehydration (see Table 42.2).

▪ Severe vomiting so unable to retain oral fluids.
Consider assessment in a general medical hospital if:

▪ age over 65 (higher risk of complications)

▪ severe abdominal pain and tenderness

▪ bloody diarrhoea

▪ faecal incontinence

▪ diarrhoea lasting more than 10 days

▪ recent foreign travel

▪ comorbid medical conditions/treatments that increase risk of severe disease (e.g.
immunodeficiency or immunosuppression, diabetes mellitus, chronic renal, liver, res- piratory, or cardiac disease).
When to report to local Health Protection Unit (UK guidance)
Urgent notification (same day by telephone) is indicated in cases of infectious bloody diarrhoea, haemolytic uraemic syndrome, and cholera. Routine notification (written within three days) is indicated in cases of food poisoning. The UK reader is directed to local contact details found on the Public Health England website [10].
References

1. National Institute for Health and Care Excellence. Gastroenteritis. Clinical Knowledge Summary. https://cks.nice.org.uk/gastroenteriti s#!topicSummary

2. Monroe SS. Control and prevention of viral gastroenteritis. Emerg Infect Dis 2011;17(8):1347–1348.

3. Tam CC, O’Brien SJ, Tompkins DS, et al. Changes in causes of acute gastroenteritis in the United Kingdom over 15 years: microbiologic
findings from 2 prospective, population‐based studies of infectious intestinal disease. Clin Infect Dis 2012;54(9):1275–1286.

4. Bresee JS, Marcus R, Venezia RA, et al. The etiology of severe acute gastroenteritis among adults visiting emergency departments in the United
States. J Infect Dis 2012;205(9):1374–1381.

5. Marder EP, Cieslak PR, Cronquist AB, et al. Incidence and trends of infections with pathogens transmitted commonly through food and the
effect of increasing use of culture‐independent diagnostic tests on surveillance: foodborne diseases active surveillance network, 10 US sites,
2013–2016. MMWR Morbid Mortal Wkly Rep 2017;66(15):397–403.

6. El‐Hennawy AS, Jacob S, Mahmood AK. Metformin‐associated lactic acidosis precipitated by diarrhea. Am J Ther 2007;14(4):403–405.

7. Palmer SE, McLean RM, Ellis PM, Harrison‐Woolrych M. Life‐threatening clozapine‐induced gastrointestinal hypomotility: an analysis of
102 cases. J Clin Psychiatry 2008;69(5):759–768.

8. Riddle MS, DuPont HL, Connor BA. ACG Clinical Guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am
J Gastroenterol 2016;111(5):602–622.

9. Public Health England. Summary of antimicrobial prescribing guidance: managing common infections. https://www.gov.uk/government/
publications/managing‐common‐infections‐guidance‐for‐primary‐care

10. Public Health England. Notifiable diseases and causative organisms: how to report. May 2010. https://www.gov.uk/guidance/
notifiable‐diseases‐and‐causative‐organisms‐how‐to‐report#laboratories‐report‐notifiable‐organisms‐causative‐agents

CHAPTER 42

Chapter 43

Viral Hepatitis

Klara Doherty, Aisling Considine, Kosh Agarwal

There are several viruses that cause hepatitis, the most common being hepatitis A, B, and C. Most people recover from hepatitis A with no lasting liver damage, but hepatitis B and C can cause long‐term liver disease and even liver cancer. As such, they form the focus of this chapter.

HEPATITIS B

Hepatitis B virus (HBV) is a highly infectious blood‐borne virus that may be spontane- ously cleared after acute infection or instead may develop into a chronic (carrier) state. Globally, mother‐to‐child transmission in the perinatal period is the most common route of acquisition and leads to a chronic carrier state in 90% of infants infected, making chronic HBV endemic in many parts of sub‐Saharan Africa and Central and Southeast Asia [1,2]. In the UK, sex and intravenous drug use are the most significant routes of transmission [3]. In immunocompetent adults, 90–95% spontaneously clear acute HBV [4], although acute fulminant hepatitis can occur. Rates of HBV carriage amongst people with severe mental illness (SMI) is poorly studied but likely to be higher than in the gen- eral population [5].

Chronic HBV can progress to cirrhosis and hepatocellular carcinoma and current man- agement is focused on halting progression towards liver damage (and preventing onward transmission) through lifelong pharmacological viral suppression. For those at risk of HBV, there is a highly effective vaccine. Thus, management in primary care and psychiat- ric care should focus on identifying those at risk of HBV and chronic HBV carriers.

Box 43.1 Screening for hepatitis B [1]

▪ Birth, living, and/or healthcare work in an endemic country

▪ Sexual partner from endemic country

▪ Family members, children, sexual partners, and household contacts of HBV case

▪ Intravenous drug use or partner of intravenous drug user

▪ Sex workers

▪ Ten or more new sexual partners per year, especially if unprotected

▪ Medical or dental procedures abroad

▪ Tattooing, traditional circumcision or scarification, acupuncture

▪ Sharing razors and/or toothbrushes with known HBV case

▪ Clinical evidence of liver disease

▪ Deranged liver function tests

▪ If immunosuppressive therapy is due to commence

▪ Previous incarceration

358 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Diagnostic principles

History

Acute HBV may present with jaundice, nausea, vomiting, abdominal pain, fever, malaise, arthralgia, maculopapular or urticarial skin rash, or (rarely) fulminant hepatitis with confusion and systemic inflammatory response. Chronic HBV may present with stigmata of chronic liver disease (CLD) or may also present with acute symptoms. However, both acute and chronic HBV are most commonly asymptomatic, so establishing risk factors for HBV infection to guide screening is key (Box 43.1) [1]. Obtaining a family history of viral hepatitis, liver cirrhosis, or hepatocellular carcinoma is also important to provide insight into risk for HBV and to guide further management [6].

Examination

Most patients will have a normal examination. There may however be evidence of CLD including finger clubbing, palmar erythema, asterixis, spider naevi, jaundice, and ascites. There may be evidence of routes of transmission such as tattoos or needle marks.

Investigations

Serology

HBV infection usually only becomes clinically apparent once complications develop, so proactive screening of all patients with risk factors for exposure is key (see Box 43.1). Screening uses serological markers summarised in Table 43.1.

Other investigations

While awaiting secondary care referral, consider requesting:

▪ liver function tests

▪ clotting screen
■ alpha‐fetoprotein

CHAPTER 43

Viral Hepatitis 359

Table 43.1 Interpretation of hepatitis B serology.

HBsAg (surface antigen)

−

Anti‐HBs (surface antibody)

−

+/−

−

Anti‐HBc (core antibody)

−

IgM anti‐HBc (core IgM antibody)

−

+/−

−

Interpretation

Past immunisationa

Past infection with clearance of virusb

Early infectionc

Acute infectiond

Acute resolving infectione

Chronic carrier statef

a Titre must be >10 mIU/mL.
b Patient immune.
c 4–6 weeks from exposure.
d HBsAg disappears 24 weeks from exposure, anti‐HBc IgM disappears 32 weeks from exposure. e Anti‐HBs appears from 32 weeks from exposure.

f Defined as HBsAg positive six months or more from exposure.

▪ blood‐borne virus screen (hepatitis C antibody, hepatitis A IgG, hepatitis D antibody, HIV antibody)

▪ urea and electrolytes

▪ full blood count

▪ liver ultrasound if clinical evidence of liver disease.
Management
Acute
Patients with symptoms and exposure history consistent with acute HBV should be dis- cussed with an on‐call medical team and/or referred for acute medical assessment, espe- cially if associated with deranged liver function tests and/or clotting. Signs of acute hepatic failure, such as acute confusion and systemic inflammatory response, requires urgent referral to secondary care. Acute HBV is a notifiable disease and Public Health England should be informed.
Chronic
Patients with confirmed chronic HBV should be referred to a specialist multidisciplinary team for monitoring and consideration of treatment. A referral letter should include doc- umentation of evidence of CLD on history or examination, record of any family history of hepatocellular carcinoma, and results of serological tests and any other investigations that have been carried out including imaging.

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360 The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Pharmacological therapy will normally be lifelong and is aimed at viral suppression to prevent hepatic complications and onward transmission. Commonly used antivirals in the UK include tenofovir and entecavir, which will be prescribed by the patient’s specialist team.

Advice to patients

To limit hepatotoxicity

▪ Abstain from alcohol (accelerates hepatic complications in HBV).

▪ Use paracetamol within recommended limits.

▪ Maintain a healthy weight.

▪ Importance of full adherence to antiviral treatment.
To avoid transmission

▪ Do not donate blood or blood products.

▪ Avoid sharing razors or toothbrushes.

▪ Avoid sharing needles or drug‐snorting paraphernalia.

▪ Use barrier protection for sexual encounters.
Patients can also be directed to information provided by the British Liver Trust (www. britishlivertrust.org.uk) and the Hepatitis B Positive Trust (www.hepbpositive.org.uk).
Prescribing in HBV and serious mental illness
Carbamazepine reduces levels of tenofovir, and therefore concurrent use is contraindi- cated. Otherwise, there are no expected drug–drug interactions between tenofovir and entecavir and co

deemagclinic

Physical Health Conditions in Psychiatry