guidelines

 

THE AMERICAN PSYCHIATRIC ASSOCIATION

PRACTICE GUIDELINE

FOR THE

Treatment of Patients With Schizophrenia

THIRD EDITION

  

                             

THE AMERICAN PSYCHIATRIC ASSOCIATION PRACTICE GUIDELINE FOR THE Treatment of Patients With Schizophrenia

THIRD EDITION

Guideline Writing Group

George A. Keepers, M.D., Chair
Laura J. Fochtmann, M.D., M.B.I., Vice-Chair; Methodologist Joan M. Anzia, M.D.
Sheldon Benjamin, M.D.
Jeffrey M. Lyness, M.D.
Ramin Mojtabai, M.D.
Mark Servis, M.D.
Art Walaszek, M.D.
Peter Buckley, M.D.
Mark F. Lenzenweger, Ph.D.
Alexander S. Young, M.D., M.S.H.S.
Amanda Degenhardt, M.D.

Systematic Review Group

Laura J. Fochtmann, M.D., M.B.I., Methodologist

Seung-Hee Hong

Committee on Practice Guidelines

Daniel J. Anzia, M.D., Chair
R. Scott Benson, M.D.
Thomas J. Craig, M.D.
Catherine Crone, M.D.
Annette L. Hanson, M.D.
John M. Oldham, M.D.
Carlos N. Pato, M.D., Ph.D.
Michael J. Vergare, M.D.
Joel Yager, M.D., Consultant
Laura J. Fochtmann, M.D., M.B.I., Consultant

APA Assembly Liaisons

Daniel Dahl, M.D.
Bhasker Dave, M.D.
Evan Eyler, M.D.
Annette L. Hanson, M.D. Jason W. Hunziker, M.D. Marvin Koss, M.D.
Robert M. McCarron, D.O. John P.D. Shemo, M.D.

APA wishes to acknowledge the contributions of APA staff and former staff (Jennifer Medicus, Seung-Hee Hong, Samantha Shugarman, Michelle Dirst, Kristin Kroeger Ptakowski). APA also wishes to acknowledge the contribution of Amanda S. Eloma, Pharm.D., BCPP, in reviewing information related to medications in the guideline and associated tables. In addition, APA and the Guideline Writing Group especially thank Laura J. Fochtmann, M.D., M.B.I.; Seung-Hee Hong; and Jennifer Medicus for their outstanding work and effort in developing this guideline. APA also thanks the APA Committee on Practice Guidelines (Daniel J. Anzia, M.D., Chair), liaisons from the APA Assembly for their input and assistance, and APA Councils and others for providing feedback during the comment period.

The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards. As medical research and practice continue to ad- vance, however, therapeutic standards may change. Moreover, specific situations may require a specific ther- apeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family.

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Copyright © 2021 American Psychiatric Association

ALL RIGHTS RESERVED

Third Edition

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Library of Congress Cataloging-in-Publication Data

Names: American Psychiatric Association, author, issuing body.
Title: The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia / Guideline Writing Group, Systematic Review Group, Committee on Practice Guidelines.
Other titles: Treatment of patients with schizophrenia
Description: Third edition. | Washington, DC : American Psychiatric Association, [2021] | Preceded by: Practice guideline for the treatment of patients with schizophrenia. 2nd ed. c2004. | Includes bibliographical references. Identifiers: LCCN 2020016573 (print) | LCCN 2020016574 (ebook) | ISBN 9780890424698 (paperback ; alk. paper) | ISBN 9780890424742 (ebook)
Subjects: MESH: Schizophrenia—therapy | Practice Guideline
Classification: LCC RC514 (print) | LCC RC514 (ebook) | NLM WM 203 | DDC 616.89/8—dc23
LC record available at https://lccn.loc.gov/2020016573
LC ebook record available at https://lccn.loc.gov/2020016574

British Library Cataloguing in Publication Data

A CIP record is available from the British Library.

Contents

Acronyms/Abbreviations……………………………… xi

Introduction………………………………………. 1

Rationale ………………………………………….1

Scope of Document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

OverviewoftheDevelopmentProcess …………………….. 2

Rating the Strengths of Guideline Statements and SupportingResearchEvidence …………………….. 3

ProperUseofGuidelines………………………………. 4

GuidelineStatementSummary…………………………. 5

Guideline Statements and Implementation . . . . . . . . . . . . . . . . . . . . . . 7

AssessmentandDeterminationofTreatmentPlan…………….. 7 Statement 1: Assessment of Possible Schizophrenia . . . . . . . . . . . . . 7 Implementation ………………………………………7

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . . .16

Review of Available Guidelines From Other Organizations . . . . . . . . . . .17

QualityMeasurementConsiderations ………………………17 Statement2:UseofQuantitativeMeasures……………….. 18 Implementation ……………………………………..18

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . . .20

Review of Available Guidelines From Other Organizations . . . . . . . . . . .22

QualityMeasurementConsiderations ………………………22 Statement 3: Evidence-Based Treatment Planning . . . . . . . . . . . . . . 23 Implementation ……………………………………..23

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . . .32

Review of Available Guidelines From Other Organizations . . . . . . . . . . 33 QualityMeasurementConsiderations …………………….. 33

Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Statement4:AntipsychoticMedications ………………….33 Implementation…………………………………….. 34

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement …………………. 80

Review of Available Guidelines From Other Organizations . . . . . . . . . . 81

QualityMeasurementConsiderations …………………….. 82 Statement 5: Continuing Medications. . . . . . . . . . . . . . . . . . . . . . . . . 83 Implementation…………………………………….. 83

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement …………………. 84

Review of Available Guidelines From Other Organizations . . . . . . . . . . 85

QualityMeasurementConsiderations …………………….. 85 Statement 6: Continuing the Same Medications. . . . . . . . . . . . . . . . . 85 Implementation…………………………………….. 85

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement …………………. 87

Review of Available Guidelines From Other Organizations . . . . . . . . . . 87

QualityMeasurementConsiderations …………………….. 87 Statement 7: Clozapine in Treatment-Resistant Schizophrenia . . . . . 88 Implementation…………………………………….. 88

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement …………………. 95

Review of Available Guidelines From Other Organizations . . . . . . . . . . 96

QualityMeasurementConsiderations …………………….. 96 Statement8:ClozapineinSuicideRisk …………………..97 Implementation…………………………………….. 97

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement …………………. 97

Review of Available Guidelines From Other Organizations . . . . . . . . . . 98 QualityMeasurementConsiderations …………………….. 98

Statement9:ClozapineinAggressiveBehavior…………….. 99

Implementation ……………………………………..99

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . . .99

Review of Available Guidelines From Other Organizations . . . . . . . . . .100 QualityMeasurementConsiderations ……………………..101

Statement 10: Long-Acting Injectable Antipsychotic Medications. . 101

Implementation …………………………………….101

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .103

Review of Available Guidelines From Other Organizations . . . . . . . . . .104

QualityMeasurementConsiderations ……………………..104 Statement 11: Anticholinergic Medications for Acute Dystonia . . . . 104 Implementation …………………………………….104

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .106

Review of Available Guidelines From Other Organizations . . . . . . . . . .106

QualityMeasurementConsiderations ……………………..107 Statement12:TreatmentsforParkinsonism………………. 107 Implementation …………………………………….107

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .108

Review of Available Guidelines From Other Organizations . . . . . . . . . .111

QualityMeasurementConsiderations ……………………..111 Statement13:TreatmentsforAkathisia…………………. 111 Implementation …………………………………….111

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .112

Review of Available Guidelines From Other Organizations . . . . . . . . . .113

QualityMeasurementConsiderations ……………………..113 Statement 14: VMAT2 Medications for Tardive Dyskinesia . . . . . . . 113 Implementation …………………………………….113

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 117

Review of Available Guidelines From Other Organizations . . . . . . . . . 118

QualityMeasurementConsiderations ……………………. 118 Psychosocial Interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Statement 15: Coordinated Specialty Care Programs . . . . . . . . . . . 119 Implementation……………………………………. 119

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 119

Review of Available Guidelines From Other Organizations . . . . . . . . . 120

QualityMeasurementConsiderations ……………………. 120 Statement 16: Cognitive-Behavioral Therapy . . . . . . . . . . . . . . . . . . 120 Implementation……………………………………. 121

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 122

Review of Available Guidelines From Other Organizations . . . . . . . . . 122

QualityMeasurementConsiderations ……………………. 123 Statement 17: Psychoeducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Implementation……………………………………. 123

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 124

Review of Available Guidelines From Other Organizations . . . . . . . . . 124

QualityMeasurementConsiderations ……………………. 124 Statement18:SupportedEmploymentServices ……………125 Implementation……………………………………. 125

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 126

Review of Available Guidelines From Other Organizations . . . . . . . . . 127

QualityMeasurementConsiderations ……………………. 127 Statement 19: Assertive Community Treatment . . . . . . . . . . . . . . . . 127 Implementation……………………………………. 127

Balancing of Potential Benefits and Harms in Rating theStrengthoftheGuidelineStatement ………………… 128

Review of Available Guidelines From Other Organizations . . . . . . . . . .129

QualityMeasurementConsiderations ……………………..129 Statement20:FamilyInterventions…………………….. 129 Implementation …………………………………….129

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .131

Review of Available Guidelines From Other Organizations . . . . . . . . . .131

QualityMeasurementConsiderations ……………………..132

Statement 21: Self-Management Skills and Recovery-Focused Interventions………………………………… 132

Implementation …………………………………….132

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .133

Review of Available Guidelines From Other Organizations . . . . . . . . . .133

QualityMeasurementConsiderations ……………………..133 Statement22:CognitiveRemediation ………………….. 134 Implementation …………………………………….134

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .134

Review of Available Guidelines From Other Organizations . . . . . . . . . .135

QualityMeasurementConsiderations ……………………..135 Statement23:SocialSkillsTraining……………………. 135 Implementation …………………………………….135

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .136

Review of Available Guidelines From Other Organizations . . . . . . . . . .137

QualityMeasurementConsiderations ……………………..137 Statement24:SupportivePsychotherapy ……………….. 137 Implementation …………………………………….137

Balancing of Potential Benefits and Harms in Rating
the Strength of the Guideline Statement . . . . . . . . . . . . . . . . . . . . . .138

Review of Available Guidelines From Other Organizations . . . . . . . . . .138 QualityMeasurementConsiderations ……………………..138

Areas for Further Research in Individuals With Schizophrenia . . . . . 139

GuidelineDevelopmentProcess………………………. 143

Management of Potential Conflicts of Interest. . . . . . . . . . . . . . . . . . . 143 Guideline Writing Group Composition . . . . . . . . . . . . . . . . . . . . . . . . . 143 Systematic Review Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 Rating the Strength of Supporting Research Evidence . . . . . . . . . . . . 144 Rating the Strength of Guideline Statements. . . . . . . . . . . . . . . . . . . . 144 Use of Guidelines to Enhance Quality of Care . . . . . . . . . . . . . . . . . . . 145 ExternalReview ……………………………………147 FundingandApproval ……………………………….147

GlossaryofTerms………………………………… 149 References……………………………………… 153 Disclosures …………………………………….. 197 Individuals and Organizations That Submitted Comments . . . . . . . . 199 Appendix A.

ClinicalQuestions ………………………………… 201

Appendix B.
Search Strategies, Study Selection, and Search Results . . . . . . . . . 203

AHRQ Review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Treatment of Neurological Side Effects of
Antipsychotic Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Appendix C.
Review of Research Evidence Supporting Guideline Statements. . . 209

AssessmentandDeterminationofTreatmentPlan ……………209 Statement 1: Assessment of Possible Schizophrenia. . . . . . . . . . . . 209 Statement 2: Use of Quantitative Measures . . . . . . . . . . . . . . . . . . . 209 Statement 3: Evidence-Based Treatment Planning . . . . . . . . . . . . . 210

Pharmacotherapy………………………………….. 210 Statement4:AntipsychoticMedications ………………… 210 Statement5:ContinuingMedications…………………… 218 Statement6:ContinuingtheSameMedications …………… 220 Statement 7: Clozapine in Treatment-Resistant Schizophrenia . . . . 222 Statement8:ClozapineinSuicideRisk …………………. 227 Statement9:ClozapineinAggressiveBehavior……………. 229 Statement 10: Long-Acting Injectable Antipsychotic Medications. . 230 Statement 11: Anticholinergic Medications for Acute Dystonia . . . . 235 Statement12:TreatmentsforParkinsonism………………. 236 Statement13:TreatmentsforAkathisia…………………. 237 Statement 14: VMAT2 Medications for Tardive Dyskinesia . . . . . . . 237

PsychosocialInterventions …………………………… 241

Statement 15: Coordinated Specialty Care Programs . . . . . . . . . . . 241

Statement16:Cognitive-BehavioralTherapy……………… 243

Statement17:Psychoeducation………………………. 244

Statement18:SupportedEmploymentServices …………… 246

Statement19:AssertiveCommunityTreatment……………. 247

Statement20:FamilyInterventions…………………….. 249

Statement 21: Self-Management Skills and Recovery-Focused Interventions………………………………… 250

Statement22:CognitiveRemediation ………………….. 252 Statement23:SocialSkillsTraining……………………. 254 Statement24:SupportivePsychotherapy ……………….. 255

Appendix D. StrengthofEvidence………………………………. 257

TableD–1.Pharmacologicaltreatment …………………… 258 TableD–2.Assertivecommunitytreatment(ACT)……………. 278 TableD–3.Cognitive-behavioraltherapy(CBT)……………… 280 TableD–4.Cognitiveremediation ………………………. 282

Table D–5. Family interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Table D–6. Intensive case management. . . . . . . . . . . . . . . . . . . . . . . . 287 Table D–7. Illness management and recovery . . . . . . . . . . . . . . . . . . . 288 Table D–8. Psychoeducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 TableD–9.Socialskillstraining …………………………291 Table D–10. Supported employment . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Table D–11. Supportive therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Table D–12. Early interventions for patients

with first-episode psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Table D–13. Co-occurring substance use and schizophrenia . . . . . . . 297

Acronyms/Abbreviations

Assertive community treatment
Agency for Healthcare Research and Quality

Number needed to harm Number needed to treat National Quality Forum

ACT
AHRQ
AIMS
ANC
APA
BAP
BMI
BPRS
CATIE
Clinical Antipsychotic Trials of Interven- tion Effectiveness

NNH
NNT
NQF
OR
PANSS-6
Positive and Negative Syndrome Scale, 6-item version

PANSS-30 Positive and Negative Syndrome Scale, 30-item version
PORT Schizophrenia Patient Outcomes Research Team

PROMIS Patient-Reported Outcomes Measurement Information System
RAISE Recovery After an Initial Schizophrenia Ep- isode

RANZCP Royal Australian and New Zealand Col- lege of Psychiatry
RCT Randomized controlled trial
REMS Risk Evaluation and Mitigation Strategy RR Relative risk

SANS Scale for the Assessment of Negative Symp- toms
SAPS Scale for the Assessment of Positive Symptoms

Abnormal Involuntary Movement Scale Absolute neutrophil count

Odds ratio

American Psychiatric Association
British Association for Psychopharmacology Body mass index

Brief Psychiatric Rating Scale

Cognitive-behavioral therapy Cognitive-behavioral therapy for psychosis

CBT
CBTp
CDC
CGI
CI
CrI
CSC
CSG
CYP
DISCUS
Dyskinesia Identification System: Con- densed User Scale

DSM Diagnostic and Statistical Manual of Mental Disorders
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition

ECG Electrocardiography

Centers for Disease Control and Prevention Clinical Global Impression

Confidence interval Credible interval

Coordinated specialty care Canadian Schizophrenia Guidelines

Cytochrome P450

Electroconvulsive therapy
U.S. Food and Drug Administration First-generation antipsychotic Global Assessment of Functioning

Standardized mean difference Strength of evidence

ECT
FDA
FGA
GAF
GRADE
Grading of Recommendations Assessment, Development and Evaluation

Transcranial magnetic stimulation
Treatment Response and Resistance in Psy-

HIPAA Health Insurance Portability and Account- ability Act

TMS
TRRIP
chosis
UKU
VMAT2
Vesicular monoamine transporter 2 WFSBP World Federation of Societies of Biological Psychiatry

WHODAS 2.0 World Health Organization Disabil- ity Schedule 2.0
WHOQOL-BREF World Health Organization Qual- ity of Life scale

WMD Weighted mean difference XR Extended release

Human immunodeficiency virus Hazard ratio

Udvalg for Kliniske Undersogelser

HIV
HR
ICD
IPS
LAI
MD
NICE
lence
NMDA N-methyl-D-aspartate
NMS Neuroleptic malignant syndrome

International Classification of Diseases Individual placement and support

Long-acting injectable Mean difference

National Institute for Health and Care Excel-

xi

Standard deviation Social Functioning Scale

SD
SFS
SGA
SIGN
SMD
SOE
SOFAS
Social and Occupational Functioning Assess- ment Scale

TdP Torsades de pointes

Second-generation antipsychotic
Scottish Intercollegiate Guidelines Network

Introduction

Rationale

The goal of this guideline is to improve the quality of care and treatment outcomes for patients with schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association 2013a). Since publication of the last American Psychiatric Association (APA) practice guideline (American Psychiatric Association 2004) and guideline watch on schizophrenia (American Psychiatric Association 2009a), there have been many studies on new pharmacological and nonpharmacological treatments for schizophrenia. Additional research has expanded our knowledge of previously available treatments. This practice guideline aims to help clinicians optimize care for their patients by providing evidence-based statements that are intended to enhance knowledge and increase the appropriate use of treatments for schizophrenia.

Schizophrenia is associated with significant health, social, occupational, and economic burdens as a result of its early onset and its severe and often persistent symptoms (American Psychiatric As- sociation 2013a). Worldwide, schizophrenia is one of the top 20 causes of disability (GBD 2017 Dis- ease and Injury Incidence and Prevalence Collaborators 2018). Economic burdens associated with schizophrenia are high (Chapel et al. 2017; Jin and Mosweu 2017), with an estimated cost of more than $150 billion annually in the United States based on 2013 data (Cloutier et al. 2016). Lost pro- ductivity due to unemployment and caregiving each account for approximately one-third of total costs, and direct health care costs account for approximately one-quarter of total costs. The lifetime prevalence of schizophrenia is estimated to be approximately 0.7% (McGrath et al. 2008; Moreno- KÐstner et al. 2018; van der Werf et al. 2014), although findings vary depending on the study loca- tion, demographic characteristics of the sample, the approach used for case finding, the method used for diagnostic confirmation, and the diagnostic criteria used.

Schizophrenia is also associated with increased mortality, with a shortened life span and standard- ized mortality ratios that are reported to be twofold to fourfold those in the general population (Hayes et al. 2017; Heilä et al. 2005; Hjorth j et al. 2017; Laursen et al. 2014; Lee et al. 2018; Oakley et al. 2018; Olfson et al. 2015; Tanskanen et al. 2018; Walker et al. 2015). The common co-occurrence of other psychiatric disorders (Plana-Ripoll et al. 2019), including substance use disorders (Hunt et al. 2018), contributes to morbidity and mortality among individuals with schizophrenia. About 4%– 10% of persons with schizophrenia die by suicide, with rates that are highest among males in the early course of the disorder (Drake et al. 1985; Heilä et al. 2005; Hor and Taylor 2010; Inskip et al. 1998; Laursen et al. 2014; Nordentoft et al. 2011; Palmer et al. 2005; Popovic et al. 2014; Saha et al. 2007; Tanskanen et al. 2018). Additional causes of death include other unnatural causes, such as accidents and traumatic injuries, and physical conditions, such as cardiovascular, respiratory, and infectious diseases and malignancies, particularly lung cancer (American Psychiatric Association 2013a; Hayes et al. 2017; Heilä et al. 2005; Hjorth j et al. 2017; Laursen et al. 2014; Lee et al. 2018; Oakley et al. 2018; Olfson et al. 2015; Tanskanen et al. 2018; Walker et al. 2015). Increases in morbidity and mor- tality related to physical health in individuals with schizophrenia are likely associated with such fac- tors as obesity, diabetes, hyperlipidemia, greater use of cigarettes, reduced engagement in health maintenance (e.g., diet, exercise), and disparities in access to preventive health care and treatment for physical conditions (Bergamo et al. 2014; De Hert et al. 2011; Druss et al. 2000; Janssen et al. 2015; Kisely et al. 2007, 2013; Kugathasan et al. 2018; Lawrence et al. 2010; Moore et al. 2015). Lack of ac- cess to adequate psychiatric treatment may also influence mortality (Schoenbaum et al. 2017).

1

This practice guideline focuses on evidence-based pharmacological and nonpharmacological treatments for schizophrenia. In addition, it includes statements related to assessment and treat- ment planning, which are an integral part of patient-centered care. Thus, the overall goal of this guideline is to enhance the treatment of schizophrenia for affected individuals, thereby reducing the mortality, morbidity, and significant psychosocial and health consequences of this important psychiatric condition.

Scope of Document

The scope of this document is shaped by Treatments for Schizophrenia in Adults (McDonagh et al. 2017), a systematic review commissioned by the Agency for Healthcare Research and Quality (AHRQ) that serves as a principal source of information for this guideline on the basis of its methodological rigor and adherence to accepted standards for systematic reviews. This guideline is focused on the treat- ment of patients with schizophrenia, and, as such, the statements in this guideline will be relevant to individuals with a diagnosis of schizophrenia. The AHRQ review uses the DSM-5 definition of schizophrenia; however, many of the systematic reviews included studies that used earlier DSM or International Classification of Diseases (ICD) criteria for schizophrenia. Several studies, particularly those assessing harms and psychosocial interventions, also included patients with a schizophrenia spectrum disorder diagnosis. Consequently, discussion of treatment, particularly treatment of first- episode psychosis, may also be relevant to individuals with schizophreniform disorder.

Although many of the studies included in the systematic review also included individuals with a diagnosis of schizoaffective disorder, these data were rarely analyzed separately in a way that would permit unique recommendations to be crafted for this group of patients. In addition, this guideline does not address issues related to identification or treatment of attenuated psychosis syn- drome or related syndromes of high psychosis risk, which were not part of the AHRQ systematic review.

Data are also limited on individuals with schizophrenia and significant physical health condi- tions or co-occurring psychiatric conditions, including substance use disorders. Many of the avail- able studies excluded these individuals from the clinical trial or did not analyze data separately for these patient subgroups. Nevertheless, in the absence of more robust evidence, the statements in this guideline should generally be applicable to individuals with co-occurring conditions, includ- ing individuals who receive treatment using integrated collaborative care or inpatient or outpatient medical settings. Although treatment-related costs are often barriers to receiving treatment, and cost-effectiveness considerations are relevant to health care policy, few high-quality studies exist on the cost-effectiveness of treatments for schizophrenia. In addition, costs of treatment typically differ by country and geographic region and vary widely with the health system and payment model. Consequently, cost-effectiveness considerations are outside the scope of this guideline and its rec- ommendations.

Overview of the Development Process

Since the publication of the Institute of Medicine (now known as the National Academy of Medi- cine) report Clinical Practice Guidelines We Can Trust (Institute of Medicine 2011), there has been an increasing focus on using clearly defined, transparent processes for rating the quality of evidence and the strength of the overall body of evidence in systematic reviews of the scientific literature. This guideline was developed using a process intended to be consistent with the recommendations of the Institute of Medicine (2011) and the Principles for the Development of Specialty Society Clinical Guidelines of the Council of Medical Specialty Societies (2012). Parameters used for the guideline’s systematic review are included with the full text of the guideline; the development process is fully de-

2

APA Practice Guidelines

scribed in the following document available at the APA website: http://www.psychiatry.org/psychiatrists/ practice/clinical-practice-guidelines/guideline-development-process.

Rating the Strengths of Guideline Statements and Supporting Research Evidence

Development of guideline statements entails weighing the potential benefits and harms of each statement and then identifying the level of confidence in that determination. This concept of bal- ancing benefits and harms to determine guideline recommendations and strength of recommenda- tions is a hallmark of Grading of Recommendations Assessment, Development and Evaluation (GRADE), which is used by multiple professional organizations around the world to develop prac- tice guideline recommendations (Guyatt et al. 2013). With the GRADE approach, recommendations are rated by assessing the confidence that the benefits of the statement outweigh the harms and bur- dens of the statement, determining the confidence in estimates of effect as reflected by the quality of evidence, estimating patient values and preferences (including whether they are similar across the patient population), and identifying whether resource expenditures are worth the expected net benefit of following the recommendation (Andrews et al. 2013).

In weighing the balance of benefits and harms for each statement in this guideline, our level of con- fidence is informed by available evidence, which includes evidence from clinical trials as well as ex- pert opinion and patient values and preferences. Evidence for the benefit of a particular intervention within a specific clinical context is identified through systematic review and is then balanced against the evidence for harms. In this regard, harms are broadly defined and may include serious adverse events, less serious adverse events that affect tolerability, minor adverse events, negative effects of the intervention on quality of life, barriers and inconveniences associated with treatment, direct and in- direct costs of the intervention (including opportunity costs), and other negative aspects of the treat- ment that may influence decision-making by the patient, the clinician, or both.

Many topics covered in this guideline have relied on forms of evidence such as consensus opin- ions of experienced clinicians or indirect findings from observational studies rather than research from randomized trials. It is well recognized that there are guideline topics and clinical circum- stances for which high-quality evidence from clinical trials is not possible or is unethical to obtain (Council of Medical Specialty Societies 2012). For example, many questions need to be asked as part of an assessment, and inquiring about a particular symptom or element of the history cannot be separated out for study as a discrete intervention. It would also be impossible to separate changes in outcomes due to assessment from changes in outcomes due to ensuing treatment. Research on psychiatric assessments and some psychiatric interventions can also be complicated by multiple confounding factors such as the interaction between the clinician and the patient or the patient’s unique circumstances and experiences. The GRADE working group and guidelines developed by other professional organizations have noted that a strong recommendation or good practice statement may be appropriate even in the absence of research evidence when sensible alternatives do not exist (Andrews et al. 2013; Brito et al. 2013; Djulbegovic et al. 2009; Hazlehurst et al. 2013). For each guideline statement, we have described the type and strength of the available evidence as well as the factors, including patient preferences, that were used in determining the balance of benefits and harms.

The authors of the guideline determined each final rating, as described in the section “Guideline Development Process,” that is endorsed by the APA Board of Trustees. A recommendation (denoted by the numeral 1 after the guideline statement) indicates confidence that the benefits of the inter- vention clearly outweigh harms. A suggestion (denoted by the numeral 2 after the guideline state- ment) indicates greater uncertainty: although the benefits of the statement are still viewed as outweighing the harms, the balance of benefits and harms is more difficult to judge, or the benefits

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 3

or the harms may be less clear. With a suggestion, patient values and preferences may be more vari- able, and this can influence the clinical decision that is ultimately made.

Each guideline statement also has an associated rating for the strength of supporting research evi- dence. Three ratings are used: high, moderate, and low (denoted by the letters A, B, and C, respec- tively). These ratings reflect the level of confidence that the evidence for a guideline statement reflects a true effect based on consistency of findings across studies, directness of the effect on a spe- cific health outcome, precision of the estimate of effect, and risk of bias in available studies (Agency for Healthcare Research and Quality 2014; Balshem et al. 2011; Guyatt et al. 2006).

Proper Use of Guidelines

The APA Practice Guidelines are assessments of current (as of the date of authorship) scientific and clinical information provided as an educational service. The guidelines 1) should not be considered as a statement of the standard of care or inclusive of all proper treatments or methods of care, 2) are not continually updated and may not reflect the most recent evidence because new evidence may emerge between the time information is developed and when the guidelines are published or read, 3) address only the question(s) or issue(s) specifically identified, 4) do not mandate any particular course of medical care, 5) are not intended to substitute for the independent professional judgment of the treating clinician, and 6) do not account for individual variation among patients. As such, it is not possible to draw conclusions about the effects of omitting a particular recommendation, either in general or for a specific patient. Furthermore, adherence to these guidelines will not ensure a suc- cessful outcome for every individual, nor should these guidelines be interpreted as including all proper methods of evaluation and care or excluding other acceptable methods of evaluation and care aimed at the same results. The ultimate recommendation regarding a particular assessment, clinical procedure, or treatment plan must be made by the clinician directly involved in the patient’s care in light of the psychiatric evaluation, other clinical data, and the diagnostic and treatment options avail- able. Such recommendations should be made in collaboration with the patient, whenever possible, and should incorporate the patient’s personal and sociocultural preferences and values in order to en- hance the therapeutic alliance, adherence to treatment, and treatment outcomes.

For all of these reasons, APA cautions against the use of guidelines in litigation. Use of these guide- lines is voluntary. APA provides the guidelines on an “as is” basis and makes no warranty, expressed or implied, regarding them. APA assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the guidelines or for any errors or omissions.

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APA Practice Guidelines

Guideline Statement Summary

Assessment and Determination of Treatment Plan

1. APA recommends (1C) that the initial assessment of a patient with a possible psychotic disorder include the reason the individual is presenting for evaluation; the patient’s goals and prefer- ences for treatment; a review of psychiatric symptoms and trauma history; an assessment of tobacco use and other substance use; a psychiatric treatment history; an assessment of physical health; an assessment of psychosocial and cultural factors; a mental status examination, in- cluding cognitive assessment; and an assessment of risk of suicide and aggressive behaviors, as outlined in APA’s Practice Guidelines for the Psychiatric Evaluation of Adults (3rd edition).

2. APA recommends (1C) that the initial psychiatric evaluation of a patient with a possible psy- chotic disorder include a quantitative measure to identify and determine the severity of symp- toms and impairments of functioning that may be a focus of treatment.

3. APA recommends (1C) that patients with schizophrenia have a documented, comprehensive, and person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments.

Pharmacotherapy

4. APA recommends (1A) that patients with schizophrenia be treated with an antipsychotic medi- cation and monitored for effectiveness and side effects.*

5. APA recommends (1A) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with an antipsychotic medication.*

6. APA suggests (2B) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with the same antipsychotic medication.*

7. APA recommends (1B) that patients with treatment-resistant schizophrenia be treated with
clozapine.*

8. APA recommends (1B) that patients with schizophrenia be treated with clozapine if the risk for
suicide attempts or suicide remains substantial despite other treatments.*

9. APA suggests (2C) that patients with schizophrenia be treated with clozapine if the risk for ag-
gressive behavior remains substantial despite other treatments.*

10. APA suggests (2B) that patients receive treatment with a long-acting injectable antipsychotic
medication if they prefer such treatment or if they have a history of poor or uncertain adher-
ence.*

11. APA recommends (1C) that patients who have acute dystonia associated with antipsychotic
therapy be treated with an anticholinergic medication.

12. APA suggests (2C) the following options for patients who have parkinsonism associated with
antipsychotic therapy: lowering the dosage of the antipsychotic medication, switching to an- other antipsychotic medication, or treating with an anticholinergic medication.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

5

13. APA suggests (2C) the following options for patients who have akathisia associated with anti- psychotic therapy: lowering the dosage of the antipsychotic medication, switching to another antipsychotic medication, adding a benzodiazepine medication, or adding a beta-adrenergic blocking agent.

14. APA recommends (1B) that patients who have moderate to severe or disabling tardive dyskine- sia associated with antipsychotic therapy be treated with a reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2).

Psychosocial Interventions

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APA Practice Guidelines

15. 16.

17. 18.

19.

20. 21.

22. 23.

24.

APA recommends (1B) that patients with schizophrenia who are experiencing a first episode of psychosis be treated in a coordinated specialty care program.*
APA recommends (1B) that patients with schizophrenia be treated with cognitive-behavioral therapy for psychosis (CBTp).*

APA recommends (1B) that patients with schizophrenia receive psychoeducation.*
APA recommends (1B) that patients with schizophrenia receive supported employment ser- vices.*
APA recommends (1B) that patients with schizophrenia receive assertive community treatment if there is a history of poor engagement with services leading to frequent relapse or social dis- ruption (e.g., homelessness; legal difficulties, including imprisonment).*
APA suggests (2B) that patients with schizophrenia who have ongoing contact with family re- ceive family interventions.*
APA suggests (2C) that patients with schizophrenia receive interventions aimed at developing self-management skills and enhancing person-oriented recovery.*
APA suggests (2C) that patients with schizophrenia receive cognitive remediation.*
APA suggests (2C) that patients with schizophrenia who have a therapeutic goal of enhanced social functioning receive social skills training.*
APA suggests (2C) that patients with schizophrenia be treated with supportive psychotherapy.*

Guideline Statements and Implementation

Assessment and Determination of Treatment Plan

STATEMENT 1: Assessment of Possible Schizophrenia

APA recommends (1C) that the initial assessment of a patient with a possible psychotic disorder in- clude the reason the individual is presenting for evaluation; the patient’s goals and preferences for treatment; a review of psychiatric symptoms and trauma history; an assessment of tobacco use and other substance use; a psychiatric treatment history; an assessment of physical health; an assess- ment of psychosocial and cultural factors; a mental status examination, including cognitive assess- ment; and an assessment of risk of suicide and aggressive behaviors, as outlined in APA’s Practice Guidelines for the Psychiatric Evaluation of Adults (3rd edition).

Implementation

The importance of the psychiatric evaluation cannot be underestimated because it serves as the initial basis for a therapeutic relationship with the patient and provides information that is crucial to differ- ential diagnosis, shared decision-making about treatment, and educating patients and family mem- bers about such factors as illness course and prognosis. APA’s Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a) describe recommended and suggested elements of assessment for any individual who presents with psychiatric symptoms (Table 1). These elements are by no means comprehensive, and additional areas of inquiry will be- come apparent as the evaluation unfolds, depending on the responses to initial questions, the present- ing concerns, the observations of the clinician during the assessment, the complexity and urgency of clinical decision-making, and other aspects of the clinical context. In many circumstances, aspects of the evaluation will extend across multiple visits (American Psychiatric Association 2016a).

The specific approach to the interview will depend on many factors, including the patient’s abil- ity to communicate, degree of cooperation, level of insight, illness severity, and ability to recall his- torical details (American Psychiatric Association 2016a). Such factors as the patient’s health literacy (Clausen et al. 2016) and cultural background (Lewis-Fernández et al. 2016) can also influence the patient’s understanding or interpretation of questions. Typically, a psychiatric evaluation involves a direct interview between the patient and the clinician (American Psychiatric Association 2016a). The use of open-ended empathic questions about the patient’s current life circumstances and rea- sons for evaluation can provide an initial picture of the individual and serve as a way of establish- ing rapport. Such questions can be followed up with additional structured inquiry about history, symptoms, or observations made during the assessment.

Throughout the assessment process, it is important to gain an understanding of the patient’s goals, their view of the illness, and preferences for treatment. This information will serve as a start- ing point for person-centered care and shared decision-making with the patient, family, and other persons of support (Dixon et al. 2016; Hamann and Heres 2019). It will also provide a framework for recovery, which has been defined as “a process of change through which individuals improve their health and wellness, live self-directed lives, and strive to reach their full potential” (Substance Abuse

7

TABLE 1. Recommended aspects of the initial psychiatric evaluation

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APA Practice Guidelines

History of present illness

• Reason that the patient is presenting for evaluation, including current symptoms, behaviors, and precipitating factors

• Current psychiatric diagnoses and psychiatric review of systems
Psychiatric history

• Hospitalization and emergency department visits for psychiatric issues, including substance use disorders

• Psychiatric treatments (type, duration, and, where applicable, doses)

• Response and adherence to psychiatric treatments, including psychosocial treatments, pharmacotherapy, and other interventions such as electroconvulsive therapy or transcranial magnetic stimulation

• Prior psychiatric diagnoses and symptoms, including

• Hallucinations (including command hallucinations), delusions, and negative symptoms

• Aggressive ideas or behaviors (e.g., homicide, domestic or workplace violence, other physically or sexually aggressive threats or acts)

• Suicidal ideas, suicide plans, and suicide attempts, including details of each attempt (e.g., context, method, damage, potential lethality, intent) and attempts that were aborted or interrupted

• Intentional self-injury in which there was no suicide intent

• Impulsivity Substance use history

• Use of tobacco, alcohol, and other substances (e.g., vaping, marijuana, cocaine, heroin, hallucinogens) and any misuse of prescribed or over-the-counter medications or supplements

• Current or recent substance use disorder or change in use of alcohol or other substances Medical history

• Whether or not the patient has an ongoing relationship with a primary care health professional

• Allergies or drug sensitivities

• All medications the patient is currently taking or has recently taken and the side effects of these medications (i.e., both prescribed and nonprescribed medications, herbal and nutritional supplements, and vitamins)

• Past or current medical illnesses and related hospitalizations

• Relevant past or current treatments, including surgeries, other procedures, or complementary and alternative medical treatments

• Sexual and reproductive history

• Cardiopulmonary status

• Past or current neurological or neurocognitive disorders or symptoms

• Past physical trauma, including head injuries

• Past or current endocrinological disease

• Past or current infectious disease, including sexually transmitted diseases, HIV, tuberculosis, hepatitis C, and locally endemic infectious diseases such as Lyme disease

• Past or current sleep abnormalities, including sleep apnea

• Past or current symptoms or conditions associated with significant pain and discomfort

• Additional review of systems, as indicated
Family history

• Including history of suicidal behaviors or aggressive behaviors in biological relatives

Personal and social history

• • •

• • •

Preferred language and need for an interpreter
Personal/cultural beliefs, sociocultural environment, and cultural explanations of psychiatric illness

Presence of psychosocial stressors (e.g., financial, housing, legal, school/occupational, or interpersonal/relationship problems; lack of social support; painful, disfiguring, or terminal medical illness)

Exposure to physical, sexual, or emotional trauma
Exposure to violence or aggressive behavior, including combat exposure or childhood abuse Legal or disciplinary consequences of past aggressive behaviors

TABLE 1. Recommended aspects of the initial psychiatric evaluation (continued)

Examination, including mental status examination

• General appearance and nutritional status

• Height, weight, and body mass index (BMI)

• Vital signs

• Skin, including any stigmata of trauma, self-injury, or drug use

• Coordination and gait

• Involuntary movements or abnormalities of motor tone

• Sight and hearing

• Speech, including fluency and articulation

• Mood, degree of hopelessness, and level of anxiety

• Thought content, process, and perceptions, including current hallucinations, delusions, negative symptoms, and insight

• Cognition

• Current suicidal ideas, suicide plans, and suicide intent, including active or passive thoughts of suicide or death

• If current suicidal ideas are present, assess patient’s intended course of action if current symptoms worsen; access to suicide methods, including firearms; possible motivations for suicide (e.g., attention or reaction from others, revenge, shame, humiliation, delusional guilt, command hallucinations); reasons for living (e.g., sense of responsibility to children or others, religious beliefs); and quality and strength of the therapeutic alliance

• Current aggressive ideas, including thoughts of physical or sexual aggression or homicide

• If current aggressive ideas are present, assess specific individuals or groups toward whom homicidal or aggressive ideas or behaviors have been directed in the past or at present, access to firearms, and impulsivity, including anger management issues

Source. Adapted from APA’s Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd Edition. Arlington VA, American Psychiatric Association, 2016. Copyright © 2016 American Psychiatric Association. Used with permission.

and Mental Health Services Administration 2012a, p. 3). Consequently, discussions of goals should be focused beyond symptom relief and may include goals related to schooling, employment, living situation, relationships, leisure activities, and other aspects of functioning and quality of life. Ques- tions about the patient’s views may help determine whether the patient is aware of having an illness and whether the patient has other explanations for symptoms that are helpful to them (Saks 2009). Patients may have specific views about such topics as medications, other treatment approaches, mechanical restraints, or involuntary treatment based on prior treatment experiences. They may also be able to delineate strategies that have been helpful for them in coping with or managing their symptoms in the past (Cohen et al. 2017). Some patients will have completed a psychiatric advance directive (Murray and Wortzel 2019), which is important to review with the patient if it exists.

In addition to direct interview, patients may be asked to complete electronic or paper-based forms that ask about psychiatric symptoms or key aspects of the history (American Psychiatric As- sociation 2016a). When available, prior medical records, electronic prescription databases, and in- put from other treating clinicians can add further details to the history or corroborate information obtained in the interview (American Psychiatric Association 2016a).

Family members, friends, and other individuals involved in the patient’s support network can be an important part of the patient’s care team and valuable sources of collateral information about the reason for evaluation, the patient’s past history, and current symptoms and behavior (American Psychiatric Association 2016a). Outreach to family, friends, and others in the support network will typically occur with the patient’s permission. In situations in which the patient is given the opportu- nity and does not object, necessary information can be shared with family members or other persons involved in the patient’s care or payment for care (Office for Civil Rights 2017b). For example, if a relative or person of support is present with the patient at an appointment, the clinician may discuss information about medications or give education about warning signs of a developing emergency.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 9

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APA Practice Guidelines

In some instances, however, patients may ask that family or others not be contacted. When this is the case, patients can usually identify someone whom they trust to provide additional information, and they are often willing to reconsider contact as treatment proceeds. It is also useful to discuss the reasons that the patient has concerns about contacts with family members or other important people in the patient’s life. For example, a patient may wish to avoid burdening a loved one, may have felt unsupported by a particular family member in the past, or may be experiencing delusional beliefs that involve a family member or friend. The patient may also want to limit the information that clini- cians receive about past or recent treatment, symptoms, or behaviors. Even when a patient does not want a specific person to be contacted, the clinician may listen to information provided by that indi- vidual, as long as confidential information is not provided to the informant (American Psychiatric Association 2016a). Also, to prevent or lessen a serious and imminent threat to the health or safety of the patient or others, The Principles of Medical Ethics (American Psychiatric Association 2013f) and the Health Insurance Portability and Accountability Act of 1996 (HIPAA; Office for Civil Rights 2017b) permit clinicians to disclose necessary information about a patient to family members, care- givers, law enforcement, or other persons involved with the patient as well as to jails, prisons, and law enforcement officials having lawful custody of the patient. HIPAA also permits health care pro- viders to disclose necessary information to the patient’s family, friends, or other persons involved in the patient’s care or payment for care when such disclosure is judged to be in the best interests of the patient and the patient either is not present or is unable to agree or object to a disclosure be- cause of incapacity or emergency circumstances. Examples of such circumstances are not limited to unconsciousness and may also include such circumstances as temporary psychosis or intoxication with alcohol or other substances (Office for Civil Rights 2017b).

Although it is beyond the scope of this guideline to discuss the differential diagnosis and evalua- tion of psychotic disorders, many features and aspects of clinical course will enter into such a deter- mination in addition to psychotic symptoms per se. Clinicians should also be mindful that biases can influence assessment and diagnosis, with disparities in diagnosis based on race being particularly common (Olbert et al. 2018; Schwartz and Blankenship 2014). The clinician should be alert to fea- tures of the history, including family, developmental, and academic history, that may suggest spe- cific conditions or a need for additional physical or laboratory evaluation. Examples of conditions that can mimic schizophrenia in their initial presentation include neurosyphilis, Huntington’s dis- ease, Wilson’s disease, and anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (Lieberman and First 2018). Individuals with 22q11.2 deletion syndrome have a substantially increased risk of developing schizophrenia (Bassett et al. 2017; McDonald-McGinn et al. 2015; Van et al. 2017). In ad- dition, the presence of a 22q11.2 deletion is associated with an increased likelihood of neurocogni- tive and physical health impairments (McDonald-McGinn et al. 2015; Moberg et al. 2018; Swillen and McDonald-McGinn 2015), which has implications for treatment (Fung et al. 2015; Mosheva et al. 2019). Psychotic symptoms can also occur in the context of other neurological and systemic ill- nesses, with or without delirium, and such acute states can at times be mistaken for an acute exac- erbation of schizophrenia. Furthermore, because a significant fraction of individuals with psychosis will have a shift in diagnosis over time, the diagnosis may need to be reevaluated as new informa- tion about the patient’s illness course and symptoms becomes available (Bromet et al. 2011). Spe- cialty consultation can be helpful in establishing and clarifying diagnosis (Coulter et al. 2019), particularly if the illness symptoms or course appear to be atypical or if the patient is not respond- ing to treatment.

A thorough history is also important for identifying the presence of co-occurring psychiatric con- ditions or physical disorders that need to be addressed in treatment planning (American Psychiat- ric Association 2016a; Firth et al. 2019). For example, individuals with serious mental illness have higher rates of smoking, higher rates of heavy smoking, and lower rates of smoking cessation than do community samples (Cook et al. 2014; de Leon and Diaz 2005; Myles et al. 2012; Wium-Andersen et al. 2015). Furthermore, the use of cannabis may be more frequent in individuals with schizophre- nia (Koskinen et al. 2010) and associated with greater symptom severity or earlier onset of psycho-

sis (Carney et al. 2017; Large et al. 2011). Other substance use disorders, if present, can also produce or exacerbate symptoms of psychosis (American Psychiatric Association 2016a; Large et al. 2014). Thus, as part of the initial evaluation, it is important to determine whether the patient uses tobacco, cannabis, or other substances such as alcohol, caffeine, cocaine, opioids, sedative-hypnotic agents, stimulants, 3,4-methylenedioxymethamphetamine (MDMA), solvents, androgenic steroids, hallu- cinogens, or synthetic substances (e.g., “bath salts,” K2, Spice). The route by which substances are used (e.g., ingestion, smoking, vaping, intranasal, intravenous) is similarly important to document.

Mortality is increased in individuals with schizophrenia (Brown et al. 2000; Fazel et al. 2014; Olfson et al. 2015), and the average life span is shortened by a decade or more, with much of this de- crease related to increased rates of co-occurring physical conditions (Laursen et al. 2013; Saha et al. 2007; Walker et al. 2015). Adverse health effects of smoking also contribute to an increased risk of mortality among individuals with schizophrenia (Lariscy et al. 2018; Reynolds et al. 2018; Tam et al. 2016). Many other conditions are more frequent in individuals with serious mental illness in general (Janssen et al. 2015; McGinty et al. 2016) and schizophrenia in particular (Henderson et al. 2015), including, but not limited to, poor oral health (Kisely et al. 2015), hepatitis C infection (Chasser et al. 2017; Hauser and Kern 2015; Hughes et al. 2016), HIV infection (Hobkirk et al. 2015; Hughes et al. 2016), cancer (Olfson et al. 2015), sleep apnea (Myles et al. 2016; Stubbs et al. 2016b), obesity (Janssen et al. 2015), diabetes mellitus (Vancampfort et al. 2016a), metabolic syndrome (Vancampfort et al. 2015), and cardiovascular disease (Correll et al. 2017c). These disorders, if present, can contribute to mortality or reduced quality of life, and some may be induced or exacerbated by psychiatric medications. Laboratory tests and physical examination as part of the initial evaluation can help to identify common co-occurring conditions and can serve as a baseline for subsequent monitoring during treatment (Table 2).

As part of the initial evaluation, it is also useful to inquire about the course and duration of symptoms prior to treatment (i.e., duration of untreated psychosis) (Penttilä et al. 2014; Register- Brown and Hong 2014; Santesteban-Echarri et al. 2017) and whether the patient has received any mental health treatment. If the patient has received treatment previously, it is important to ask about a broad range of treatments and other approaches to addressing the patient’s symptoms and functioning and to specifically ask about the full range of treatment settings (e.g., outpatient, partial hospitalization, inpatient) and approaches that the patient has found helpful or problematic (Amer- ican Psychiatric Association 2016a). Although most patients will comment on prior medications, psychotherapy, or psychiatric hospitalizations if asked about treatment history, specific questions may be needed to gather details of such treatments. Prompting may be needed to learn information about the patient’s experiences with other interventions such as psychosocial rehabilitation, sup- ported employment, assertive community treatment (ACT), court-ordered treatment, treatment while incarcerated, substance use treatments, neuromodulatory therapies (e.g., electroconvulsive therapy [ECT], transcranial magnetic stimulation [TMS]), 12-step programs, self-help groups, spir- itual healers, and complementary or alternative treatment approaches. Pharmacy databases and patients’ lists of active medications are not likely to include long-acting injectable (LAI) medica- tions (e.g., antipsychotics, naltrexone, buprenorphine) or implants (e.g., buprenorphine, contracep- tive agents), over-the-counter medications, herbal products, or nutritional supplements. For each specific type of intervention that the patient has received, it is helpful to learn more about the du- ration, mode of delivery (e.g., formulation, route, and dose for medications; format, type, and fre- quency of treatment for psychotherapy), response (including tolerability, changes in quality of life, level of functioning, and symptom response/remission), and degree of adherence.

The psychosocial history reviews the stages of the patient’s life and may include attention to perinatal events, delays in developmental milestones, academic history and performance (includ- ing learning difficulties, special education interventions, or disciplinary actions), relationship and sexual history, interpersonal functioning (including in social and family roles, such as parenting), occupational history (including military history), legal history, and identification of major life events (e.g., parental loss, divorce, traumatic experiences, migration history) and psychosocial

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 11

TABLE 2. Suggested physical and laboratory assessments for patients with schizophrenia Initial or baseline assessmentsa Follow-up assessmentsb

Assessments to monitor physical status and detect concomitant physical conditions

 

Vital signs

Body weight and height

Hematology

Blood chemistries

Pregnancy

Toxicology

Electrophysiological studies

Imaging Genetic testing

Pulse, blood pressure

Body weight, height, BMIc

CBC, including ANC

Electrolytes, renal function tests, liver function tests, TSH

Pregnancy test for women of childbearing potential

Drug toxicology screen, if clinically indicated

EEG, if indicated on the basis of neurological examination or history

Brain imaging (CT or MRI, with MRI being preferred), if indicated on the basis of neurological examination or historyd

Chromosomal testing, if indicated on the basis of physical examination or history, including developmental historye

Pulse, blood pressure, temperature as clinically indicated

BMIc every visit for 6 months and at least quarterly thereafter

CBC, including ANC if clinically indicated (e.g., patients treated with clozapine)

As clinically indicated

Drug toxicology screen, if clinically indicated

Assessments related to other specific side effects of treatment

Diabetesf Hyperlipidemia Metabolic syndrome

QTc prolongation

Hyperprolactinemia

Screening for diabetes risk factors,g fasting blood glucoseh

Lipid paneli

Determine whether metabolic syndrome criteria are metj

ECG before treatment with chlorpromazine, droperidol, iloperidone, pimozide, thioridazine, or ziprasidonek or in the presence of cardiac risk factorsl

Screening for symptoms of hyperprolactinemiam Prolactin level, if indicated on the basis of

clinical history

Fasting blood glucose or hemoglobin A1C at
4 months after initiating a new treatment and at least annually thereafterh

Lipid paneli at 4 months after initiating a new antipsychotic medication and at least annually thereafter

Determine whether metabolic syndrome criteria are metj at 4 months after initiating a new antipsychotic medication and at least annually thereafter

ECG with significant change in dose of chlorpromazine, droperidol, iloperidone, pimozide, thioridazine, or ziprasidonek or with the addition of other medications that can affect QTc interval in patients with cardiac risk factorsl or elevated baseline QTc intervals

Screening for symptoms of hyperprolactinemia at each visit until stable, then yearly if treated with an antipsychotic known to increase prolactinm

Prolactin level, if indicated on the basis of clinical history

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APA Practice Guidelines

TABLE 2. Suggested physical and laboratory assessments for patients with schizophrenia (continued) Initial or baseline assessmentsa Follow-up assessmentsb

Assessments related to other specific side effects of treatment (continued)

 

Antipsychotic- induced movement disorders

Clinical assessment of akathisia, dystonia, parkinsonism, and other abnormal involuntary movements, including tardive dyskinesian

Assessment with a structured instrument (e.g., AIMS, DISCUS) if such movements are present

Clinical assessment of akathisia, dystonia, parkinsonism, and other abnormal involuntary movements, including tardive dyskinesia, at each visitn

Assessment with a structured instrument (e.g., AIMS, DISCUS) at a minimum of every 6 months in patients at high risk of tardive dyskinesiao and at least every 12 months in other patientsp as well as if a new onset or exacerbation of preexisting movements is detected at any visit

aAPA’s Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a) recommends that the initial psychiatric evaluation of a patient include assessment of whether or not the patient has an ongoing relationship with a primary care health professional. Preventive care and other tests, such as screening for hepatitis C or HIV, are expected to occur as a part of routine primary care. Nevertheless, determining whether a patient is receiving primary care and inquiring about the patient’s relationship with their primary care practitioner can be a starting point for improved access to quality health care and preventive services.

bAlthough this practice guideline recommends that patients treated with antipsychotic medications be monitored for physical conditions and side effects on a regular basis, there are no absolute criteria for frequency of monitoring. Occurrence of conditions and side effects may be influenced by the patient’s history, preexisting conditions, and use of other medications in addition to antipsychotic agents. Thus, decisions about monitoring patients for physical conditions, specific side effects, or abnormalities in laboratory test results will neces- sarily depend on the clinical circumstances. In general, assessments related to physical conditions and specific medication-related side effects will be done at the time of initiating or changing antipsychotic medications or when adding other medications that contribute to these side effects.

cBMI may be calculated by using the formula weight in kg/(height in m)2 or the formula 703 × weight in lb/(height in inches)2 or by using a BMI calculator available from the National Heart, Lung, and Blood Institute (www.nhlbi.nih.gov/health/educational/lose_wt/ BMI/bmicalc.htm). A person with a BMI of 25–29.9 is considered overweight, and one with a BMI of 30 or higher is considered obese. In addition to BMI, waist circumference can be used as an indicator of risk (>35 inches for women and >40 inches for men). Except for patients with a BMI of <18.5, an increase in BMI of 1 unit would suggest a need for intervention by monitoring weight more closely, engaging the patient in a weight management program, using an adjunctive treatment to reduce weight, or changing the antipsychotic medication.

dFactors that suggest a possible need for imaging include focal neurological signs, new onset of seizures, later age at symptom onset, symptoms suggestive of intracranial pathology (e.g., chronic or severe headaches, nausea, vomiting), and symptoms suggestive of au- toimmune encephalitis (e.g., rapid progression of working memory deficits over less than 3 months; decreased or altered level of con- sciousness, lethargy, or personality change; Graus et al. 2016). In the absence of such indications, decisions about imaging should consider that the yield of routine brain imaging is low, with <1% of studies showing potentially serious incidental findings or abnormal- ities that would influence treatment (Cunqueiro et al. 2019; Falkenberg et al. 2017; Forbes et al. 2019; Gibson et al. 2018). On the other hand, routine imaging is a low-risk procedure, and a negative finding can be reassuring to patients and to families. If imaging is ordered, it is rarely necessary to delay other treatment or hospitalization while awaiting imaging results.

eFactors that may suggest a possible need for chromosomal testing (e.g., to identify abnormalities such as 22q11.2 deletion syndrome) include mild dysmorphic features, hypernasal speech, developmental delays, intellectual impairments, learning difficulties, and con- genital heart defects (Bassett and Chow 1999; Miller et al. 2010).

fThe U.S. Food and Drug Administration has requested that all manufacturers of second-generation antipsychotic medications (SGAs) in- clude a warning in their product labeling regarding hyperglycemia and diabetes mellitus. Although precise risk estimates for hyperglyce- mia-related adverse events are not available for each agent, epidemiological studies suggested an increased risk of treatment-emergent adverse events with SGAs, including extreme hyperglycemia. In some patients, this hyperglycemia was associated with ketoacidosis, hyperosmolar coma, or death.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 13

TABLE 2. Suggested physical and laboratory assessments for patients with schizophrenia (continued)

gFactors that indicate an increased risk for undiagnosed diabetes include a BMI >25, a first-degree relative with diabetes, habitual phys- ical inactivity, being a member of a high-risk ethnic population (African American, Hispanic, American Indian, Asian American, Pacific Islander), history of cardiovascular disease, hypertension (≥140/90 mmHg or on therapy for hypertension), high-density lipoprotein cholesterol (HDL-C) <35 mg/dL (0.90 mmol/L) and/or triglyceride level >250 mg/dL (2.82 mmol/L), polycystic ovary syndrome (in women), having had gestational diabetes, and other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) (American Diabetes Association 2018). Symptoms of possible diabetes include frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased fatigue, irritability, and blurry vision.

hWhen screening for the presence of diabetes, criteria for diagnosis include a fasting blood glucose higher than 125 mg/dL, where fasting is defined as no caloric intake for at least 8 hours (American Diabetes Association 2018). Alternatively, a hemoglobin A1C of 6.5% or greater can be used. Other acceptable approaches for diagnosis of diabetes include an oral glucose tolerance test or a random blood glu- cose of at least 200 mg/dL in conjunction with a hyperglycemic crisis or classic symptoms of hyperglycemia. With all of these approach- es, results should be confirmed by repeat testing unless unequivocal hyperglycemia is present. In patients with hemoglobinopathies or conditions associated with increased red blood cell turnover (e.g., second- or third-trimester pregnancy, hemodialysis, recent blood loss, transfusion, erythropoietin therapy), fasting blood glucose should be used rather than hemoglobin A1C. An abnormal value of fasting blood glucose or hemoglobin A1C suggests a need for medical consultation. More frequent monitoring may be indicated in the presence of weight change, symptoms of diabetes, or a random measure of blood glucose >200 mg/dL.

iAdditional information on screening and management of patients with lipid disorders can be found in the AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA Guideline on the Management of Blood Cholesterol (Grundy et al. 2018).

jMetabolic syndrome is currently defined by the presence of at least three of the following five risk factors: elevated waist circumference (defined for the United States and Canada as >102 cm [40.2 inches] for men and >88 cm [34.6 inches] for women); elevated triglycerides of ≥150 mg/dL (or drug treatment for elevated triglycerides, such as fibrates, nicotinic acid, or high-dose omega-3 fatty acids); reduced HDL-C of <40 mg/dL in men or <50 mg/dL in women (or drug treatment for reduced HDL-C, such as fibrates or nicotinic acid); ele- vated blood pressure (BP) with systolic BP ≥130 mmHg and/or diastolic BP ≥85 mmHg (or antihypertensive treatment in a patient with a history of hypertension); and elevated fasting glucose ≥100 mg/dL (or drug treatment for elevated glucose) (Alberti et al. 2009).

kUsing an adverse drug event causality analysis intended to evaluate the risk of sudden death when taking a specific medication (Woosley et al. 2017), the listed drugs have been categorized as prolonging the QT interval and being clearly associated with a known risk of torsades de pointes, even when taken as recommended (Woosley et al. 2009).

lIn this context, risk factors include non-modifiable (e.g., congenital long QT syndrome, age, sex, family history of sudden cardiac death, personal or family history of structural or functional heart disease, personal history of drug-induced QT prolongation, metabolizer sta- tus) and modifiable risk factors (e.g., starvation; bradycardia; risk or presence of hypokalemia, hypomagnesemia, or hypocalcemia; ex- cess dose or rapid intravenous infusion of QTc interval–prolonging drugs; simultaneous use of multiple drugs that prolong QTc intervals; or factors affecting drug metabolism such as drug-drug interactions, acute or chronic kidney disease, or hepatic impairment) (Funk et al. 2018).

mScreening should assess changes in libido, menstrual changes, or galactorrhea in women, and changes in libido or in erectile or ejacu- latory function in men.

nAssessment can occur through clinical examination or through the use of a structured evaluative tool such as the Abnormal Involuntary Movement Scale (AIMS; Guy 1976; Munetz and Benjamin 1988) or the Dyskinesia Identification System: Condensed User Scale (DISCUS; Kalachnik and Sprague 1993). For a copy of the AIMS, see http://www.aacap.org/App_Themes/AACAP/docs/member_resources/ toolbox_for_clinical_practice_and_outcomes/monitoring/AIMS.pdf, and for a copy of the DISCUS, see https://portal.ct.gov/-/ media/DDS/Health/hcsma20002b.pdf.

oPatients at increased risk for developing abnormal involuntary movements include individuals older than 55 years; women; individuals with a mood disorder, substance use disorder, intellectual disability, or central nervous system injury; individuals with high cumulative exposure to antipsychotic medications, particularly high-potency dopamine D2 receptor antagonists; and patients who experience acute dystonic reactions, clinically significant parkinsonism, or akathisia (Carbon et al. 2017, 2018; Miller et al. 2005; Solmi et al. 2018a). Ab- normal involuntary movements can also emerge or worsen with antipsychotic cessation.

pFrequency of monitoring for involuntary movements in individuals receiving treatment with an antipsychotic medication is also subject to local regulations in some jurisdictions.

Abbreviations. AIMS=Abnormal Involuntary Movement Scale; ANC=absolute neutrophil count; BMI=body mass index; CBC=complete blood count; CT=computed tomography; DISCUS=Dyskinesia Identification System: Condensed User Scale; ECG=electrocardiography; EEG=electroencephalogram; MRI=magnetic resonance imaging; QTc=corrected QT interval; TSH=thyroid-stimulating hormone.

14 APA Practice Guidelines

stressors (e.g., financial, housing, legal, school/occupational, or interpersonal/relationship prob- lems; lack of social support; painful, disfiguring, or terminal medical illness) (American Psychiatric Association 2016a; Barnhill 2014; MacKinnon et al. 2016; Smith et al. 2019). Information about the patient’s family constellation and persons who provide support will serve as a foundation for working collaboratively with the patient and their support network. The cultural history also em- phasizes relationships, both familial and nonfamilial, and the role of important cultural and reli- gious influences on the patient’s life (Aggarwal and Lewis-Fernández 2015; American Psychiatric Association 2013a; Lewis-Fernández et al. 2016).

The mental status examination is an integral part of the initial assessment. A full delineation of the mental status examination is beyond the scope of this document, and detailed information on con- ducting the examination is available elsewhere (American Psychiatric Association 2016a; Barnhill 2014; MacKinnon et al. 2016; Smith et al. 2019; Strub and Black 2000). However, for individuals with possible schizophrenia, a detailed inquiry into hallucinations and delusions will often identify psy- chotic experiences in addition to the presenting concerns. Negative symptoms and cognitive im- pairment are common and influence outcomes (Bowie et al. 2006; Green 2016; Jordan et al. 2014; Rabinowitz et al. 2012; Santesteban-Echarri et al. 2017) but may go undetected without specific at- tention during the evaluation. Negative symptoms also can be difficult to differentiate from lack of interest or reduced motivation due to depression, medication side effects, substance use, or neuro- logical conditions.

Insight is also impaired in a significant proportion of individuals with schizophrenia (Mohamed et al. 2009) and can manifest as a decreased awareness of having a disorder, symptoms, conse- quences of illness, or a need for treatment (Mintz et al. 2003). Consequently, inquiring about the pa- tient’s degree of insight and judgment will provide information relevant to risk assessment, treatment outcomes, and adherence (Mintz et al. 2003; Mohamed et al. 2009).

Risk assessment is another essential part of the initial psychiatric evaluation (American Psychi- atric Association 2004). It requires synthesizing information gathered in the history and mental sta- tus examination and identifying modifiable risk factors for suicidal or aggressive behaviors that can serve as targets of intervention in constructing a plan of treatment. Suicidal ideas are common in individuals who have had a psychotic experience (Bromet et al. 2017). Death due to suicide has been estimated to occur in about 4%–10% of individuals with schizophrenia (Drake et al. 1985; Heilä et al. 2005; Hor and Taylor 2010; Inskip et al. 1998; Laursen et al. 2014; Nordentoft et al. 2011; Palmer et al. 2005; Popovic et al. 2014; Tanskanen et al. 2018; Yates et al. 2019), yielding a greater than tenfold increase in standardized mortality ratios (Saha et al. 2007). Among individuals with schizophrenia, suicide attempts and suicide may be more common early in the course of the illness (Popovic et al. 2014) and can occur even before initial treatment for psychosis (Challis et al. 2013).

In individuals with schizophrenia, many of the risk factors that contribute to the risks of suicidal or aggressive behaviors are the same as factors increasing risk in other disorders. For example, in in- dividuals with schizophrenia, an increased risk of suicidal or aggressive behaviors has been associ- ated with male sex, expressed suicidal ideation, a history of attempted suicide or other suicide-related behaviors, and the presence of alcohol use disorder or other substance use disorder (Cassidy et al. 2018; Challis et al. 2013; Fazel et al. 2009a, 2014; Fleischhacker et al. 2014; Hawton et al. 2005; Hor and Taylor 2010; Østergaard et al. 2017; Pompili et al. 2007; Popovic et al. 2014; Roché et al. 2018; Sariaslan et al. 2016; Singh et al. 2012; Swanson et al. 2006; Witt et al. 2013, 2014). Firearm access is an additional contributor to suicide risk (Alban et al. 2018; Anestis and Houtsma 2018; Siegel and Rothman 2016). Additional factors that have been identified as increasing risk for suicide among individuals with schizophrenia include depressive symptoms, hopelessness, agitation or motor restlessness, fear of mental disintegration, recent loss, recency of diagnosis or hospitalization, re- peated hospitalizations, high intelligence, young age, and poor adherence to treatment (Cassidy et al. 2018; Fleischhacker et al. 2014; Hawton et al. 2005; Lopez-Morinigo et al. 2014; Pompili et al. 2007; Popovic et al. 2014; Randall et al. 2014). It is not clear whether preserved insight is associated with an increase in suicide risk among individuals with schizophrenia (Hor and Taylor 2010) or

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 15

whether this is an apparent increase that is mediated by other factors such as hopelessness (L¬pez- Morí igo et al. 2012).

Although reduced risk of suicide was associated with hallucinations in one meta-analysis (Hawton et al. 2005), the presence of auditory command hallucinations may confer increased risk (Harkavy- Friedman et al. 2003; Wong et al. 2013). Command hallucinations can also be relevant when assessing individuals for a risk of aggressive behaviors (McNiel et al. 2000; Swanson et al. 2006), although the relationship between experiencing commands and acting on them is complex (Braham et al. 2004). Persecutory delusions may also contribute to risk of aggression, particularly in the absence of treat- ment or in association with significant anger (Coid et al. 2013; Keers et al. 2014; Swanson et al. 2006).

Among individuals with psychotic illnesses, prior suicidal threats, angry affect, impulsivity, hostil- ity, recent violent victimization, childhood sexual abuse, medication nonadherence, and a history of in- voluntary treatment were also associated with an increased risk of aggressive behavior (Buchanan et al. 2019; Large and Nielssen 2011; Reagu et al. 2013; Swanson et al. 2006; Witt et al. 2013, 2014). Other factors associated with a risk of aggression are similar to findings in individuals without psy- chosis and include male sex, young age, access to firearms, the presence of substance use, traumatic brain injury, a history of attempted suicide or other suicide-related behaviors, and prior aggressive behavior, including that associated with legal consequences (Buchanan et al. 2019; Cassidy et al. 2018; Fazel et al. 2009a, 2009b, 2014; Fleischhacker et al. 2014; Large and Nielssen 2011; Monuteaux et al. 2015; Østergaard et al. 2017; Popovic et al. 2014; Roché et al. 2018; Sariaslan et al. 2016; Short et al. 2013; Singh et al. 2012; Swanson et al. 2006; Witt et al. 2013, 2015).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In an individual with a possible psychotic disorder, a detailed assessment is important in establish- ing a diagnosis, recognizing co-occurring conditions (including substance use disorders, other psy- chiatric disorders, and other physical health disorders), identifying psychosocial issues, and developing a plan of treatment that can reduce associated symptoms, morbidity, and mortality.

Harms*

Some individuals may become anxious, suspicious, or annoyed if asked multiple questions during the evaluation. This could interfere with the therapeutic relationship between the patient and the clinician. Another potential consequence is that time used to focus on a detailed assessment (as out- lined in the Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition; American Psychi- atric Association 2016a) could reduce time available to address other issues of importance to the pa- tient or of relevance to diagnosis and treatment planning.

Patient Preferences

Although there is no specific evidence on patient preferences related to assessment in individuals with a possible psychotic disorder, clinical experience suggests that the majority of patients are co- operative with and accepting of these types of questions as part of an initial assessment.

*Harms may include serious adverse events; less serious adverse events that affect tolerability; minor adverse events; negative effects of the intervention on quality of life; barriers and inconveniences associated with treatment; and other negative aspects of the treatment that may influence decision-making by the patient, the clinician, or both.

16 APA Practice Guidelines

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. This recommendation is also consistent with the APA Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a). The level of research ev- idence is rated as low because there is minimal research on the benefits and harms of assessing these aspects of history and examination as part of an initial assessment. Nevertheless, expert opin- ion suggests that conducting such assessments as part of the initial psychiatric evaluation improves the diagnosis and treatment planning in individuals with a psychiatric disorder. For additional de- tails, see the Practice Guidelines for the Psychiatric Evaluation of Adults. For additional discussion of the research evidence, see Appendix C, Statement 1.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Relevant guidelines from the following organizations were reviewed: British Association for Psy- chopharmacology (BAP), Canadian Psychiatric Association and Schizophrenia Society of Canada, National Institute for Health and Care Excellence (NICE), Royal Australian and New Zealand Col- lege of Psychiatry (RANZCP), Scottish Intercollegiate Guidelines Network (SIGN), World Federa- tion of Societies of Biological Psychiatry (WFSBP), and Schizophrenia Patient Outcomes Research Team (PORT). Information from them is generally consistent with this guideline statement. Other guidelines on the treatment of schizophrenia incorporate recommendations related to the need for a comprehensive initial assessment (Addington et al. 2017a; National Institute for Health and Care Excellence 2014), including identification of prior and current psychiatric symptoms and diagnoses (Addington et al. 2017a; Hasan et al. 2015; National Institute for Health and Care Excellence 2014), assessment of tobacco use (Addington et al. 2017a; National Institute for Health and Care Excel- lence 2014), assessment of substance use (Addington et al. 2017a; Barnes et al. 2011; Crockford and Addington 2017; Galletly et al. 2016; National Institute for Health and Care Excellence 2014), phys- ical health history and examination (Addington et al. 2017a; National Institute for Health and Care Excellence 2014), assessment of psychosocial factors (Addington et al. 2017a; Galletly et al. 2016; National Institute for Health and Care Excellence 2014), and mental status examination (Addington et al. 2017a), including assessment of the risk of harm to self or others (Addington et al. 2017a; Hasan et al. 2015; National Institute for Health and Care Excellence 2014). Several other guidelines also provide information on the circumstances in which an electrocardiogram is suggested (Barnes et al. 2011; National Institute for Health and Care Excellence 2014; Pringsheim et al. 2017).

Quality Measurement Considerations

For patients with psychotic disorders, including schizophrenia, several components of the initial psychiatric evaluation have potential relevance for quality measure development, although such quality measures do not exist at present. A first step toward development of scientifically sound quality measures is identification of discrete indicators that signal the delivery of high-quality care. This step may be challenging to accomplish given the breadth of content within the initial psychi- atric assessment and the difficulty in ascertaining evaluation details from chart or administrative data. However, it may still be possible to use available evidence and expert-recommended consen- sus to develop and specify electronic and clinical data registry quality measures. Additionally, as discussed in the APA Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a), quality improvement efforts at the local level could assess whether specific aspects of the evaluation such as a risk assessment were completed while still allowing flex- ibility in the documentation of findings.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 17

STATEMENT 2: Use of Quantitative Measures

APA recommends (1C) that the initial psychiatric evaluation of a patient with a possible psychotic disorder include a quantitative measure to identify and determine the severity of symptoms and impairments of functioning that may be a focus of treatment.

Implementation

APA’s Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a) provides a general description of the use of quantitative measures as part of the initial psychiatric evaluation. In the assessment of a patient with a possible psychotic disorder, quantitative measures can also be used to help detect and determine the severity of psychosis and associated symptoms. The intent of using a quantitative measure is not to establish a diagnosis but rather to complement other aspects of the screening and assessment process. Depending on the measure, it can aid in treatment planning by providing a structured replicable way to document the patient’s baseline symptoms. It can also help to determine which symptoms should be the target of intervention on the basis of such factors as frequency of occurrence, magnitude, potential for asso- ciated harm to the patient or others, and associated distress to the patient.

As treatment proceeds, use of quantitative measures allows more precise tracking of whether nonpharmacological and pharmacological treatments are having their intended effect or whether a shift in the treatment plan is needed. This record of a patient’s response to treatment is of particular value when the treatment is nonstandard (e.g., combination of antipsychotics) or expensive. It can also provide helpful information about the actual effects of prior treatments. In addition, patients’ ratings can be compared with family members’ impressions of treatment effects to clarify the lon- gitudinal course of the patient’s illness.

Much of the treatment-related research in psychiatry has used clinician-rated scales to determine patient outcomes; however, patient-rated scales are typically less time-consuming to administer than clinician-rated scales. In addition, they provide important insights into the patient’s experience that support person-centered care. The use of anchored, self-rated scales with criteria to assess the severity and frequency of symptoms can also help patients become more informed self-observers. However, correlations between patient- and clinician-rated scales are often modest (Harvey 2011; Spitz et al. 2017), suggesting that both types of quantitative measures provide useful information. If a mis- match is noted in the self-assessment of patients as compared with assessments of other observers, this may provide information relevant to outcomes. The accuracy of self-assessments of ability, skills, performance, or decisions (also termed introspective accuracy) is a better predictor of every- day functional deficits than objective measures of neurocognitive or social cognitive performance (Silberstein and Harvey 2019).

The exact frequency at which measures are warranted will depend on clinical circumstances. Use of quantitative measures over time will help assure that key elements of information are collected to guide treatment (Lewis et al. 2019). Consequently, it is preferable to use a consistent approach to quantitative measurement for a given patient because each rating scale defines and measures psy- chosis and other symptoms differently.

Although recommending a particular scale, patient- or clinician-rated, is outside the scope of this practice guideline, a number of objective, quantitative rating scales to monitor clinical status in schizophrenia are available (American Psychiatric Association 2013a; Rush et al. 2008). The Clini- cian-Rated Dimensions of Psychosis Symptom Severity (American Psychiatric Association 2013b), which is included in DSM-5 for further research and clinical evaluation, contains eight domains that are rated on a scale from 0 (not present) to 4 (present and severe) on the basis of symptoms in the prior 7 days. A 6-item version of the Positive and Negative Syndrome Scale (PANSS-6; Bech et al. 2018; Østergaard et al. 2018b) consists of the PANSS items for delusions, conceptual disorgani- zation, hallucinations, blunted affect, social withdrawal, and lack of spontaneity and flow of con-

18

APA Practice Guidelines

versation (Kay et al. 1987). Data on the PANSS-6 suggest that it correlates highly with scores on the 30-item version of the Positive and Negative Syndrome Scale (PANSS-30; Østergaard et al. 2018a, 2018b). Furthermore, the PANSS-6 is sensitive to changes with treatment and able to identify symp- tom remission with a high degree of accuracy (Østergaard et al. 2018a, 2018b) if individuals who are performing ratings are appropriately trained (Opler et al. 2017). Clinician-rated scales may also be selected to assess specific clinical presentations, such as using the Bush-Francis Catatonia Rating Scale for individuals with catatonic features (Bush et al. 1996a). Other clinician-rated scales are commonly used for monitoring psychopathology in research but are likely to be too lengthy for routine clinical use. These include the PANSS-30 (Kay et al. 1987), the Scale for the Assessment of Negative Symptoms (SANS; Andreasen 1984a), the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen 1984b), and the Brief Psychiatric Rating Scale (BPRS; https://mha.ohio.gov/ Portals/0/assets/HealthProfessionals/About MH and Addiction Treatment/First Episode Psy- chosis/Brief-Psychiatric-Rating-Scale.pdf) (Leucht et al. 2005; Overall and Gorham 1962; Ventura et al. 1993).

In terms of patient-rated scales, the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure— Adult (American Psychiatric Association 2013c) includes a total of 23 items in 13 domains, with only 2 items related to psychosis. Nevertheless, it may be useful for identifying and tracking symptoms other than psychosis, including those related to co-occurring disorders. DSM-5 also includes 36-item self- and proxy-administered versions of the World Health Organization Disability Schedule 2.0 (WHODAS 2.0) for assessing functioning difficulties due to health and mental health conditions (American Psychiatric Association 2013d; ÜstÐn et al. 2010). Other options for assessing function- ing include the Social and Occupational Functioning Assessment Scale (SOFAS; American Psychi- atric Association 2000) and the Personal and Social Performance scale (Morosini et al. 2000). Several versions of Patient-Reported Outcomes Measurement Information System (PROMIS) scales, which ad- dress social roles and functioning, are also available (www.healthmeasures.net/explore-measurement- systems/promis). The use of ratings from other informants is particularly helpful in assessing the patient’s level of functioning because individuals with schizophrenia often have a different view of their functioning than do family members or others involved in their lives (Harvey 2011).

For a nonspecific measure of quality of life, patients can be asked to rate their overall (physical and mental) quality of life in the past month on a scale from 0 (“about as bad as dying”) to 10 (“life is per- fect”) (UnÐtzer et al. 2002). In individuals with chronic mental illness, the Satisfaction With Life Scale (Diener et al. 1985) has been developed and used to assess life satisfaction and quality of life. Quality of life can also be measured using a scale developed by the World Health Organization, the WHOQOL- BREF (Skevington et al. 2004; WHOQOL Group 1998) (http://depts.washington.edu/seaqol/ WHOQOL-BREF). The Centers for Disease Control and Prevention Healthy Days Measure (HRQOL- 14) and Healthy Days Core Module (HRQOL-4) (www.cdc.gov/hrqol/hrqol14_measure.htm) have also been used in general population samples to assess physical and emotional symptoms as re- lated to an individual’s perceived sense of well-being (Moriarty et al. 2003).

Rating scales should always be implemented in a way that supports developing and maintaining the therapeutic relationship with the patient. Reviewing scale results with the patient can help fos- ter a collaborative dialogue about progress toward symptom improvement, functioning gains, and recovery goals. Such review may help clinicians, patients, families, and other support persons rec- ognize that improvement is taking place or, conversely, identify issues that need further attention.

If more than one quantitative measure is being used, it is important to minimize duplication of questions and avoid overwhelming the patient with an excessive number of scales to complete. In ad- dition, when choosing among available quantitative measures, objectives of scale use (e.g., screening, documenting baseline symptoms, ongoing monitoring) should be considered. Optimal scale proper- ties (e.g., sensitivity, specificity) will differ depending on the desired purpose, but assessments of scale validity and reliability are typically conducted cross-sectionally in research contexts.

Because many scales ask the patient to rate symptoms over several weeks, they may not be sen- sitive to change. This can be problematic in acute care settings, where treatment adjustments and

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 19

20

APA Practice Guidelines

symptom improvement can occur fairly quickly. Some symptom-based quantitative measures fo- cus either on symptom frequency over the observation period or on symptom severity. Although these features often increase or decrease in parallel, that is not invariably the case. Other quantita- tive measures ask the patient to consider both symptom frequency and severity, which can also make the findings difficult to interpret.

Other factors that can affect the statistical reliability and validity of rating scale measures include comorbid illnesses and patient age, language, race, ethnicity, cultural background, literacy, and health literacy. These factors and others can lead patients to misinterpret questions or bias the rat- ings that they record, either unintentionally (e.g., to please the clinician with their progress) or in- tentionally (e.g., to obtain controlled substances, to support claims of disability). Thus, the answers to questions and the summative scores on quantitative measures need to be interpreted in the con- text of the clinical presentation.

The type and extent of quantitative measures used will also be mediated by the clinical setting, the time available for evaluation, and the urgency of the situation. In some clinical contexts, such as a planned outpatient assessment, patients may be asked to complete electronic- or paper-based quantitative measures, either prior to the visit or on arrival at the office (Allen et al. 2009; Harding et al. 2011). Between or prior to visits, electronic approaches (e.g., mobile phone applications, clin- ical registries, patient portal sites in electronic health records) may also facilitate obtaining quanti- tative measurements (Lewis et al. 2019; Palmier-Claus et al. 2012; K. Wang et al. 2018). In other clin- ical contexts, such as acute inpatient settings, electronic modes of data capture may be more cumbersome, and patients may need more assistance in completion of scales. As an alternative, printed versions of scales may be completed by the patient or a proxy or administered by the clini- cian. In other clinical circumstances, however, printed or electronic versions of quantitative scales may not be readily available or information may not be available to complete all scale items. In emergency settings, use of a quantitative rating scale may need to be postponed until the acute cri- sis has subsided or until the patient’s clinical status permits a detailed examination.

Although available information suggests that ambulatory patients are generally cooperative, some individuals may be unwilling to complete quantitative measures (Narrow et al. 2013). Severe symptoms, co-occurring psychiatric conditions, low health literacy, reading difficulties, or cogni- tive impairment may limit some patients’ ability to complete self-report instruments (Harding et al. 2011; Valenstein et al. 2009; Zimmerman et al. 2011). In these circumstances, it may be necessary to place greater reliance on collateral sources of information such as family members, other treating health professionals, or staff members of community residence programs, if applicable. If collateral sources of information are not immediately available, treatment may also need to proceed, with ad- justments in the plan, if indicated, as additional knowledge is gained. If time constraints are pres- ent, the clinician may wish to focus on rating of relevant target symptoms (e.g., on a Likert scale). In emergent circumstances, safety of the patient and others must take precedence; the initial assess- ment may need to be brief, with a more detailed assessment and incorporation of quantitative mea- sures once the acute clinical situation has been stabilized.

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Clinical decision-making, including but not limited to diagnosis and treatment planning, requires a careful and systematic assessment of the type, frequency, and magnitude of psychiatric symptoms as well as an assessment of the impact of those symptoms on the patient’s day-to-day functioning and quality of life. Intuitively, and by analogy with other medical specialties in which treatment is guided by standardized measurement (e.g., of physiological signs or laboratory tests), the use of a systematic and quantifiable approach to assessment would seemingly produce better patient out-

comes and greater standardization of care across patients. As electronic health records become more commonly used, electronic capture of quantitative measures can facilitate use of computer- ized decision-support systems in guiding evidence-based treatment, catalyzing additional im- provements in outcomes and quality of care.

Use of a quantitative measure as part of the initial evaluation can establish baseline information on the patient’s symptoms and level of functioning and can help determine specific targets of treat- ment in the context of shared decision-making. When administered through paper-based or elec- tronic self-report and as compared with a clinical interview, a quantitative measure may help the clinician to conduct a more consistent and comprehensive review of the multiplicity of symptoms that the patient may be experiencing. Using systematic measures may also increase the efficiency of asking routine questions and allow more time for clinicians to focus on symptoms of greatest se- verity or issues of most concern to the patient. Such measures may also facilitate collection of infor- mation from the patient’s family or other collateral informants on factors such as symptoms or functioning. When used on a longitudinal basis, quantitative measures can help determine whether nonpharmacological and pharmacological treatments are having their intended effect or whether a shift in the treatment plan is needed to address symptoms, treatment-related side effects, level of distress, functioning impairments, or potential for harm to the patient or others.

Without the use of a consistent quantitative measure, recall biases may confound the ability of patients and clinicians to compare past and current levels or patterns of symptoms and functioning. When patients have had substantial improvements in symptoms and functioning, it can be easy to focus on the improvements and overlook residual symptoms or side effects of treatment that are contributing to ongoing impairment or reduced quality of life. Thus, ongoing use of quantitative assessments may foster identification of residual symptoms or impairments and early detection of illness recurrence. Systematic use of quantitative measures can also facilitate communication among treating clinicians and can serve as a basis for enhanced management of populations of pa- tients as well as individual patients. Although mobile apps may be capable of assisting with quan- titative measurement, there is no current evidence on which to base recommendations about use of mobile apps in the treatment of schizophrenia.

Harms

The harms of using a quantitative measure include the time required for administration and review. The amount of time available for an initial psychiatric evaluation is typically constrained by clini- cian availability, cost, and other factors. Under such circumstances, time that is used to obtain quan- titative measures could introduce harms by reducing time available to address other issues of importance to the patient or of relevance to clinical decision-making. Overreliance on quantitative measures may also cause other aspects of the patient’s symptoms and clinical presentation to be overlooked.

Some patients may view quantitative measures as impersonal or may feel annoyed by having to complete detailed scales, particularly if done frequently. If a patient feels negatively about quanti- tative measures, this could alter the therapeutic alliance. In addition, some patients may have dif- ficulty completing self-report scales or may interpret questions incorrectly. Patients may also provide inaccurate information about their symptoms, and relying on inaccurate information can have a negative impact on clinical decision-making, including recommendations for treatment.

Systematic use of measures may require changes in workflow or staffing to distribute scales, in- crease time needed to review results with the patient, or lead to unreimbursed costs (e.g., to inte- grate measures into electronic health record systems, to pay to use copyrighted versions of scales).

Patient Preferences

Clinical experience suggests that the majority of patients are cooperative with and accepting of quantitative measures as part of an initial or subsequent assessment. Most patients will be able to

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appreciate the ways in which the use of quantitative measures will be of benefit to them. For exam- ple, in the testing of the DSM-5 Cross-Cutting Symptom Measure as part of the DSM-5 field trials, quantitative measures were found to be acceptable to patients (Clarke et al. 2014; Mościcki et al. 2013), and only a small fraction of individuals felt that measurement of symptoms would not be helpful to their treating clinician (Mościcki et al. 2013).

The fact that the clinician is using a systematic approach to address the patients’ symptoms and functioning sends a positive message that could improve the therapeutic relationship. Especially in developed countries, patients are used to and expect digital, computerized information exchange, including for health-related monitoring and communication. For these patients, the use of quanti- tative measures within the context of an electronic health record, mobile app, or other computer- ized technology may be more convenient.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. This recommendation is also consistent with Guideline VII, “Quantitative Assessment,” in the APA’s Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiat- ric Association 2016a). Although quantitative measures have been used for reporting purposes as well as research, the level of research evidence for this recommendation is rated as low because it remains unclear whether routine use of these scales in clinical practice improves overall outcomes. Nonetheless, expert opinion suggests that use of quantitative measures will enhance clinical deci- sion-making and improve treatment outcomes. For additional discussion of the research evidence, see Appendix C, Statement 2.

There is minimal research on the harms of using quantitative measures as part of the psychiatric evaluation as compared with assessment as usual. However, expert opinion suggests that harms of assessment are minimal compared with the benefits of such assessments in improving identifica- tion and assessment of psychiatric symptoms. For additional details, see the APA’s Practice Guide- lines for the Psychiatric Evaluation of Adults, 3rd edition (American Psychiatric Association 2016a).

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Multiple guidelines from other organizations were reviewed (Addington et al. 2017a, 2017b; Barnes et al. 2011; Buchanan et al. 2010; Crockford and Addington 2017; Galletly et al. 2016; Hasan et al. 2012, 2013, 2015; National Institute for Health and Care Excellence 2014; Norman et al. 2017; Pringsheim et al. 2017; Scottish Intercollegiate Guidelines Network 2013). None of these guidelines specifically recommend using quantitative measures as part of the initial assessment in individuals with schizophrenia, but several guidelines (Barnes et al. 2011; Galletly et al. 2016) do recommend use of rating scales under some circumstances at baseline or as part of ongoing monitoring.

Quality Measurement Considerations

There is insufficient consensus on the most appropriate quantitative measures (i.e., rating scales) to use in assessing individuals with psychotic disorders, including schizophrenia. Nevertheless, data do support the use of clinician-reported, symptom-based ratings to guide treatment. Patient-rated scales may be clinically useful in identifying patient concerns or subjective experiences (e.g., med- ication side effects). On the basis of these potential benefits, a process-focused internal or health sys- tem–based quality improvement measure could determine rates of quantitative measure use, and

quality improvement initiatives could be implemented to increase the frequency with which such measures are used in individuals with schizophrenia.

STATEMENT 3: Evidence-Based Treatment Planning

APA recommends (1C) that patients with schizophrenia have a documented, comprehensive, and person-centered treatment plan that includes evidence-based nonpharmacological and pharmaco- logical treatments.

Implementation

When treating individuals with schizophrenia, a person-centered treatment plan should be devel- oped, documented in the medical record, and updated with the patient at appropriate intervals. A person-centered treatment plan can be recorded as part of an evaluation note or progress note and does not need to adhere to a defined development process (e.g., face-to-face multidisciplinary team meeting) or format (e.g., time-specified goals and objectives). Depending on the urgency of the ini- tial clinical presentation, the availability of laboratory results, and other sources of information, the initial treatment plan may need to be augmented over several visits as more details of history and treatment response are obtained.

As treatment proceeds, the treatment plan will require iterative reevaluation and adjustment prompted by such factors as inadequate treatment response, difficulties with tolerability or adher- ence, impairments in insight, changes in presenting issues or symptoms, or revisions in diagnosis. In adapting treatment to the needs of the individual patient, tailoring of the treatment plan may also be needed on the basis of sociocultural or demographic factors, with an aim of enhancing qual- ity of life or aspects of functioning (e.g., social, academic, occupational). Factors that influence med- ication metabolism (e.g., age, sex, body weight, renal or hepatic function, smoking status, use of multiple concurrent medications) may also require adjustments to the treatment plan in terms of either typical medication doses or frequency of monitoring. For most individuals with schizophre- nia, it is challenging to piece together a coherent picture of the patient’s longitudinal course from medical records. Thus, it is important to note the rationale for any changes in the treatment plan as well as the specific changes that are being made because an accurate history of past and current treatments and responses to them is a key part of future treatment planning.

Aims of Treatment Planning

The overarching aims of treatment planning are 1) to promote and maintain recovery, 2) to maximize quality of life and adaptive functioning, and 3) to reduce or eliminate symptoms. To achieve these aims, it is crucial to identify the patient’s aspirations, goals for treatment, and treatment-related pref- erences. Depending on prevailing state laws, psychiatric advance directives are one approach to en- couraging patients to contemplate and state their preferences about treatment choices (Easter et al. 2017; Kemp et al. 2015; Shields et al. 2014; Wilder et al. 2010). For patients who have completed a psychiatric advance directive, wellness recovery action plan (Copeland 2000), or individualized cri- sis prevention or safety plan (Stanley and Brown 2012, 2019; Stanley et al. 2018), these documents will be important to review with the patient when crafting a person-centered approach to care. Dis- cussions with the patient, other treating health professionals, family members, and others involved in the patient’s life can each be vital in developing a full picture of the patient and formulating a person-centered treatment plan, using shared decision-making whenever possible. The patient and others may express opinions about specific treatment approaches or identify practical barriers to the patient’s ability to participate in treatment, such as lack of insight, cognitive impairments, dis- organization, or inadequate social resources.

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Elements of the Treatment Plan

Depending on the clinical circumstances and input from the patient and others, a comprehensive and person-centered treatment plan will typically delineate treatments aimed at improving func- tioning, reducing positive and negative symptoms, and addressing co-occurring psychiatric symp- toms or disorders. In each of these respects, it is essential to consider both nonpharmacological and pharmacological treatment approaches and recognize that a combination of nonpharmacological and pharmacological treatments will likely be needed to optimize outcomes. Other elements of the treatment plan may include the following:

• determining the most appropriate treatment setting

• delineating plans for addressing risks of harm to self or others (if present)

• addressing barriers to adherence

• engaging family members and others involved in the patient’s life

• providing information to patients, family members, and others involved in the patient’s life
about treatment options, early symptoms of relapse, need for ongoing monitoring, coping strat-
egies, case management services, and community resources, including peer-support programs

• incorporating goals of treatment related to

• social support networks

• interpersonal, family, or intimate relationships

• parenting status

• living situation

• past trauma or victimization

• school or employment

• financial considerations, including disability income support, when indicated

• insurance status

• legal system involvement

• identifying additional needs for

• history or mental status examination

• physical examination (either by the evaluating clinician or by another health professional)

• laboratory testing, imaging, electrocardiography (ECG), or other clinical studies (if indicated
on the basis of the history, examination, and planned treatments)

• collaborating with other treating clinicians (including provision of integrated care) to avoid fragmentation of treatment efforts and assure that co-occurring substance use disorders and physical health conditions are managed
Engagement of Family Members and Other Persons of Support
Discussions with the patient, family members, and others will typically occur as part of the initial assessment (see Statement 1), and additional input will be needed as treatment proceeds and the treatment plan is updated. Family members and others involved in the patient’s life may also ex- press specific concerns about the individual’s symptoms or behaviors, which, if present, should be documented and addressed. Most individuals welcome involvement of family members and other persons of support (Cohen et al. 2013; Drapalski et al. 2018; Mueser et al. 2015), and family members can be an important part of the care team. Family members can also be provided with educational materials or directed to organizations that offer education to family members and other persons of support (Mental Health America 2019; National Alliance on Mental Illness 2019a).
Strategies to Promote Adherence
Strategies to promote adherence are always important to consider when developing a patient-centered treatment plan (Ferrando et al. 2014). Maintaining adherence to treatment is often challenging

(Acosta et al. 2012; Shafrin et al. 2016; Valenstein et al. 2006), and poor adherence is associated with poor outcomes, including increased risks of relapse, rehospitalization, suicidal and aggressive behav- iors, and mortality (Bowtell et al. 2018; Cassidy et al. 2018; Goff et al. 2017; Hawton et al. 2005; Hui et al. 2018; Kishi et al. 2019; Leucht et al. 2012; Thompson et al. 2018; Tiihonen et al. 2018; Vermeulen et al. 2017; Witt et al. 2013). Treatment planning to address adherence will depend on the specific contributing factors and whether reduced adherence is related to medication use, missed appoint- ments, or other aspects of treatment. Issues that may influence adherence include, but are not limited to, lack of awareness of illness, forgetting to take doses, difficulties managing complex regimens (e.g., due to cognitive impairment, frequency of doses, or number of medications), side effects that are of particular importance to the patient (e.g., weight gain, akathisia, sexual dysfunction, effects on cogni- tion), financial barriers (e.g., cost, insurance coverage), perceived risks and benefits of treatment, in- sufficient understanding of medication benefits for symptoms that are important to the patient, ambivalence or suspiciousness of medications or treatment in general, lack of a perceived need for treatment (e.g., due to feeling good or not viewing self as ill; due to personal, religious, or cultural be- liefs), co-occurring conditions (e.g., depression; alcohol, cannabis, or other substance use disorder), high levels of hostility, persecutory delusions, prior difficulties with adherence, prior experiences with treatment (e.g., effectiveness, side effects), limited geographic availability or accessibility of ser- vices, financial or insurance constraints on medications or visits, difficulties in the therapeutic rela- tionship, lack of support from significant others for treatment, cultural or family beliefs about illness or treatment, and perceptions of stigma about having an illness and taking medication (Acosta et al. 2012; Ascher-Svanum et al. 2006; Czobor et al. 2015; Foglia et al. 2017; García et al. 2016; Haddad et al. 2014; Hartung et al. 2017; Hatch et al. 2017; Higashi et al. 2013; Kane et al. 2013; MacEwan et al. 2016a; Mueser et al. 2015; Pyne et al. 2014; Shafrin et al. 2016; Velligan et al. 2017; Volavka et al. 2016; Wade et al. 2017). Adherence with appointments can also be influenced by financial barriers, diffi- culties scheduling visits around work or school schedules, or issues with transportation or with childcare. Addressing these barriers as part of the treatment plan will require active collaboration and problem-solving between the clinician and patient, often with input from the patient’s family and others involved in the patient’s’ life (Mueser et al. 2015).

When assessing adherence, it is important to take a patient-centered approach in inquiring in a nonjudgmental way whether the individual has experienced difficulties with taking medication (Haddad et al. 2014). Obtaining information from patient diaries, patient-completed rating scales, pharmacy records, family members, or other collateral sources of information can be useful supple- ments to subjective patient reporting (Acosta et al. 2012; Haddad et al. 2014; Hatch et al. 2017; Kane et al. 2013). Tablet counts, monitoring using electronic pill bottle caps, and drug formulations with implanted sensors have also been used to assess adherence with antipsychotic medications (Acosta et al. 2012; Haddad et al. 2014). It can also be useful to obtain medication blood levels. Levels of clozapine have been best studied, but blood levels of other antipsychotic medications are also avail- able. Although the utility of routine therapeutic monitoring is unclear for antipsychotic medica- tions other than clozapine, blood levels may help in establishing whether a patient is taking the medication (Hiemke et al. 2018; Horvitz-Lennon et al. 2017; Lopez and Kane 2013; Lopez et al. 2017; McCutcheon et al. 2018; Predmore et al. 2018). Urine levels of antipsychotic medications can also be used to assess for adherence (Velligan et al. 2006).

In terms of enhancing adherence, a wide range of approaches have been tried. However, evi- dence on the most effective techniques remains limited (Hartung et al. 2017), and different ap- proaches will likely be needed for different patients. A checklist that includes barriers, facilitators, and motivators for adherence has been developed and may be helpful in promoting discussion and identifying adherence-related factors in individual patients (Pyne et al. 2014). In addition to con- ducting ongoing monitoring of adherence as treatment proceeds, it can be helpful to focus on opti- mizing treatment efficacy, addressing side effects and concerns about treatment, adjusting dosing to minimize side effects while maintaining efficacy, providing information about the illness and its treatments, engaging in shared decision-making, fostering a strong therapeutic alliance, and engag-

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ing family members and other community and social supports, as appropriate (Acosta et al. 2012; Haddad et al. 2014; Hamann and Heres 2019; Kane et al. 2013; Rezansoff et al. 2017).

For some patients, the formulation of the antipsychotic medication may influence adherence (see Statement 4, Table 3). For example, rapidly dissolving tablets, oral concentrates, or LAI formulations may be preferable for patients who have difficulty swallowing pills or who are ambivalent about medications and inconsistent in swallowing them. For individuals who have difficulty remembering to take medication, LAI formulations of medications can be used, oral medication regimens can be simplified to reduce the number of pills or daily doses, watches or cell phone alarms can be used as reminders to take medications, pillboxes may be filled with the week’s medication, and family or sig- nificant others may be enlisted to assist with medication if cognitive impairments are present. An- other approach that can be used to improve adherence is behavioral tailoring, which involves cuing oneself to take medications by incorporating adherence into one’s daily routine (Kreyenbuhl et al. 2016; Mueser et al. 2002). If financial issues with medications are affecting adherence, reassessment of the treatment regimen may be needed, or patients’ assistance programs may be pursued (e.g., through pharmaceutical company programs or a discount program such as GoodRx, http://www.goodrx.com). When a patient does not appear for appointments or is nonadherent in other ways, assertive outreach such as telephone calls or secure messages may be helpful in reengaging the patient in treatment.

Addressing Risks for Suicidal and Aggressive Behavior

Identifying risk factors and estimating risks for suicidal and aggressive behaviors are essential parts of psychiatric evaluation (American Psychiatric Association 2016a and as described in detail in Statement 1, subsection “Implementation”). Despite identification of these risk factors, it is not possible to predict whether an individual patient will engage in aggressive behaviors or attempt or die by suicide. However, when an increased risk for such behaviors is present, it is important that the treatment plan reevaluates the setting of care and implements approaches to target and reduce modifiable risk factors. Although demographic and historical risk factors are static, potentially modifiable risk factors may include poor adherence, core symptoms of schizophrenia (e.g., halluci- nations, delusions), co-occurring symptoms (e.g., depression, hopelessness, hostility, impulsivity), and co-occurring diagnoses (e.g., depression, alcohol use disorder, other substance use disorders). Additional elements of the treatment plan can address periods of increased risk (e.g., shortly after diagnosis, during incarceration, subsequent to hospital discharge).

Addressing Tobacco Use and Other Substance Use Disorders

Individuals with schizophrenia have high rates of nicotine dependence (Centers for Disease Control and Prevention 2020; Cook et al. 2014; de Leon and Diaz 2005; Dickerson et al. 2018; Hartz et al. 2014; Myles et al. 2012; Smith et al. 2014; Wium-Andersen et al. 2015), cannabis use (Brunette et al. 2018; Hartz et al. 2014; Hunt et al. 2018; Koskinen et al. 2010; Nesvåg et al. 2015; Toftdahl et al. 2016), and use of alcohol and other substances (Brunette et al. 2018; Hartz et al. 2014; Hunt et al. 2018; Nesvåg et al. 2015; Toftdahl et al. 2016). Smoking is a major contributor to increased mortality in individuals with serious mental illness (Reynolds et al. 2018; Tam et al. 2016), and the adverse health consequences of smoking are well documented (Lariscy et al. 2018; U.S. Department of Health and Human Services 2014; Van Schayck et al. 2017). Thus, smoking cessation is recom- mended for any individual who smokes. Some studies have assessed smoking cessation ap- proaches targeted to individuals with mental illnesses, but specific evidence in patients with schizophrenia is still limited (Sharma et al. 2017). Thus, smoking cessation approaches will typi- cally follow guidelines for the general population (National Cancer Institute 2019; SAMHSA-HRSA Center of Excellence for Integrated Health Solutions 2018; Siu et al. 2015; Van Schayck et al. 2017; Verbiest et al. 2017). Although quit rates may be lower in individuals with schizophrenia than in the general population (Lum et al. 2018; Streck et al. 2020), health education and motivational in-

terviewing approaches can be helpful in those who are ambivalent about stopping cigarette use (Levounis et al. 2017) or who have had prior unsuccessful attempts at smoking cessation.

Rates of cannabis use and other substance use are also increased among individuals with schizophre- nia (Hartz et al. 2014; Hunt et al. 2018; Swartz et al. 2006). Cannabis use has been associated with an increased incidence (Nielsen et al. 2017; Vaucher et al. 2018) and earlier onset (Donoghue et al. 2014; Helle et al. 2016; Kelley et al. 2016; Large et al. 2011) of schizophrenia, and it may also contrib- ute to a higher burden of symptoms (Carney et al. 2017; Oluwoye et al. 2018). Other substance use disorders are associated with a poorer prognosis in individuals with schizophrenia (Brunette et al. 2018; Conus et al. 2017; Weibell et al. 2017) and, as noted previously, can contribute to risk of suicide or aggressive behavior. Thus, it is important for the treatment plan to address substance use disor- ders when they are present. Screening, Brief Intervention, and Referral to Treatment (SBIRT) can be integrated into a range of clinical settings (Agerwala and McCance-Katz 2012; SAMHSA-HRSA Center of Excellence for Integrated Health Solutions 2019). Often, a comprehensive integrated treat- ment model is suggested in which the same clinicians or team of clinicians provide treatment for schizophrenia as well as treatment of substance use disorders. However, if an integrated treatment is unavailable, the treatment plan should address both disorders with communication and collab- oration among treating clinicians. For patients who do not recognize the need for treatment of a substance use disorder, a stagewise motivational approach can be pursued (Catley et al. 2016; Levounis et al. 2017).

Addressing Other Concomitant Psychiatric Symptoms and Diagnoses

Depressive symptoms are common in individuals with schizophrenia and should be addressed as part of treatment planning. The approach to treating depression will be grounded in a careful differ- ential diagnosis that considers the possible contributions of demoralization, negative symptoms of schizophrenia, side effects of antipsychotic medications, substance intoxication or withdrawal, phys- ical health condition, or a co-occurring major depressive episode. Depressive symptoms that occur during an acute episode of psychosis often improve as psychotic symptoms respond to treatment.

Evidence on the use of antidepressants to treat depression in individuals with schizophrenia comes from multiple trials, many of which have small sample sizes or factors that increase the risk of bias in the findings (Dondé et al. 2018; Gregory et al. 2017; Helfer et al. 2016). Nevertheless, a meta-analysis suggests that the addition of antidepressant medications results in small beneficial effects on symptoms of depression, quality of life, and response rates as well as on positive symp- toms, negative symptoms, and overall symptoms (Helfer et al. 2016). These effects were more prominent in patients with more severe depressive symptoms. Furthermore, antidepressant treat- ment did not appear to be associated with exacerbation of psychosis or significant differences in ad- verse effects (Helfer et al. 2016). Nonpharmacological treatments for depression in schizophrenia have been less well studied but could also be incorporated into treatment planning (Dondé et al. 2018; Opoka and Lincoln 2017).

Treatments for posttraumatic stress disorder (Brand et al. 2018; Sin et al. 2017b) and anxiety (Howells et al. 2017) in individuals with schizophrenia have been less well studied. Nevertheless, many individuals with schizophrenia will have experienced violent victimization (de Vries et al. 2019; Morgan et al. 2016; Roy et al. 2014) or childhood adversity (Bonoldi et al. 2013; Schalinski et al. 2019; Trotta et al. 2015; Varese et al. 2012), and the impact of these experiences needs to be con- sidered as part of a patient-centered treatment plan (Center for Substance Abuse Treatment 2014). When anxiety symptoms are present in individuals with schizophrenia, the possible contributions of psychotic symptoms, medication side effects, substance intoxication or withdrawal, or co-occurring anxiety disorders may suggest an approach to treatment. Given the relative safety of adjunctive an- tidepressant medications in individuals with schizophrenia and depression, these medications may be considered if otherwise indicated to treat posttraumatic stress disorder or an anxiety disorder. On the other hand, studies on the use of benzodiazepines in schizophrenia are limited (Dold et al.

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2012), and long-term use of benzodiazepines may be associated with increased risk of poorer out- comes, including side effects (Dold et al. 2013; Fond et al. 2018; Fontanella et al. 2016; Tiihonen et al. 2016) or misuse (Maust et al. 2019). Nonpharmacological treatments for posttraumatic stress dis- order in individuals with schizophrenia have been less well studied but may have modest benefits and do not appear to have significant adverse effects as compared with usual care (Brand et al. 2018; Sin et al. 2017b).

In terms of the use of stimulants to treat preexisting attention-deficit/hyperactivity disorder in individuals with schizophrenia, available evidence is also very limited but suggests a potential for worsening of psychotic symptoms as well as potential for development of a stimulant use disorder (Sara et al. 2014; Solmi et al. 2019). Thus, if stimulant medications are used, monitoring for these possible adverse effects is warranted as part of the treatment plan.

Addressing Other Concomitant Health Conditions

As described in Statement 1, other health conditions are more frequent in individuals with serious mental illness in general (Firth et al. 2019; Janssen et al. 2015; McGinty et al. 2016) and schizophrenia in particular (Henderson et al. 2015). Such disorders include but are not limited to poor oral health (Kisely et al. 2015), hepatitis C infection (Chasser et al. 2017; Hauser and Kern 2015; Hughes et al. 2016), HIV infection (Hobkirk et al. 2015; Hughes et al. 2016), cancer (Olfson et al. 2015), sleep apnea (Myles et al. 2016; Stubbs et al. 2016b), obesity (Janssen et al. 2015), diabetes mellitus (Vancampfort et al. 2016a), metabolic syndrome (Vancampfort et al. 2015), and cardiovascular disease (Correll et al. 2017c). These disorders, if present, can contribute to mortality or reduced quality of life, and some may be induced or exacerbated by psychiatric medications. Impairments in renal and hepatic function, if present, can influence treatment recommendations.

Table 2 (see Statement 1) provides a discussion of suggested physical and laboratory assessments for patients with schizophrenia as part of initial evaluation and follow-up assessments. Such assess- ments are important for prevention, early recognition, and treatment of abnormalities such as glu- cose dysregulation, hyperlipidemia, and metabolic syndrome. It is important that patients have access to primary care clinicians who can work with the psychiatrist to diagnose and treat concur- rent physical health conditions (American Psychiatric Association 2016a), but the psychiatrist may also provide ongoing monitoring and treatment of common medical conditions in conjunction with primary care clinicians (Druss et al. 2018).

Pregnancy and Postpartum Period

Women with childbearing potential and at risk for pregnancy should be assisted in obtaining effec- tive contraception if pregnancy is not desired. For women who are planning to become pregnant or who are pregnant or in the postpartum period, it is essential to collaborate with the patient, her ob- stetrician-gynecologist or other obstetric practitioner, and, if involved, her partner or other persons of support. For women who are breastfeeding, collaboration with the infant’s pediatrician is simi- larly important. The overall goal is to develop a plan of care aimed at optimizing outcomes for both the patient and her infant. In addition, during pregnancy and postpartum, frequent reassessment will be needed to determine whether any modifications to the treatment plan are indicated.

As with any decisions related to the use of psychiatric medications prior to conception, during pregnancy, or while breastfeeding, it is essential to consider the potential benefits of treatment as well as the potential harms of untreated illness and the potential for negative fetal or neonatal ef- fects. Untreated or inadequately treated maternal psychiatric illness can result in poor adherence to prenatal care, inadequate nutrition, increased alcohol or tobacco use, and disruptions to the family environment and mother-infant bonding (ACOG Committee on Practice Bulletins—Obstetrics 2008; American Academy of Pediatrics and the American College of Obstetricians and Gynecolo- gists 2017; Tosato et al. 2017). For women with childbearing potential, decisions about medications and advice about contraceptive practices should consider the potential effects if pregnancy were to

occur. Some medications are best avoided in women with childbearing potential; for example, val- proic acid should be avoided because of its teratogenic effects (Briggs et al. 2017) and association with maternal metabolic syndrome.

All psychotropic medications studied to date cross the placenta, are present in amniotic fluid, and enter human breast milk (American Academy of Pediatrics and the American College of Ob- stetricians and Gynecologists 2017). In addition, the period from the third through the eighth week of gestation is associated with greatest risk for teratogenesis (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists 2017). If a woman becomes pregnant while taking an antipsychotic medication, consideration should be given to consulting an obstetri- cian-gynecologist or maternal/fetal medicine subspecialist in addition to discussion with the pre- scribing clinician before indicated psychotropic medications are stopped to determine whether the risks of stopping the medication outweigh any possible fetal risks (American Academy of Pediat- rics and the American College of Obstetricians and Gynecologists 2017; U.S. Food and Drug Ad- ministration 2011a). For many women, the eighth week of gestation will already have passed before obstetric care begins, and stopping medication will not avoid or reduce teratogenic risk. Thus, for a woman with schizophrenia, the benefits of continued treatment with antipsychotic medications in minimizing relapse will generally outweigh the potential for fetal risk (Briggs et al. 2017).

Knowledge of the effects of antipsychotic medications is limited to observational and registry- based studies. Although limited information is known about newer second-generation antipsy- chotic medications (SGAs), first-generation antipsychotic medications (FGAs) have been in wide use for more than 40 years, and older SGAs have been available for several decades. The available data suggest that these medications have minimal risk in terms of teratogenic or toxic effects on the fetus (ACOG Committee on Practice Bulletins—Obstetrics 2008; Briggs et al. 2017; Chisolm and Payne 2016). There does appear to be a risk of withdrawal symptoms or neurological effects of an- tipsychotic medications in the newborn if an antipsychotic medication is used in the third trimester (Briggs et al. 2017; U.S. Food and Drug Administration 2011a). Symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding (Briggs et al. 2017; U.S. Food and Drug Administration 2011a). Nevertheless, tapering of antipsychotic medication late in pregnancy is not advisable because of the associated risk of relapse. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays (U.S. Food and Drug Admin- istration 2011a). The possibility of these effects signals the importance of close monitoring of the newborn in conjunction with the infant’s pediatrician. As noted above, however, the benefits of treatment for the mother and the longer-term benefits of treatment for the infant (e.g., enhanced mother-infant bonding, better adherence to prenatal care and nutrition, lesser rates of prenatal al- cohol or tobacco use) will generally favor continuing and not tapering antipsychotic treatment.

A number of other considerations are relevant when treating women with an antipsychotic med- ication during pregnancy. In general, symptoms should be managed with the lowest effective dose, although it is preferable to maintain efficacy using a single medication at a higher dose rather than using multiple medications at lower doses (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists 2017). If a patient’s symptoms are well controlled on a specific medication, it is usually not advisable to switch to a different antipsychotic medication, even if more safety information is available for a different drug (Chisolm and Payne 2016). Chang- ing medications exposes the fetus to two different medications and also increases possibilities for symptom relapse in the patient.

As with all women who are pregnant, regular prenatal care is essential to ensuring optimal ma- ternal-fetal outcomes (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists 2017; American College of Obstetricians and Gynecologists 2018). Close moni- toring for symptom recurrence and for side effects is important during pregnancy and in the post- partum period because the physiological alterations of pregnancy may affect the absorption, distribution, metabolism, and elimination of medications and may necessitate adjustments in med-

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ication doses (ACOG Committee on Practice Bulletins—Obstetrics 2008; Chisolm and Payne 2016). Women who are taking antipsychotic medications are also at increased risk of obesity and hyper- glycemia, and folate supplementation to reduce risks of neural tube defects and assessment for di- abetes during pregnancy are important elements of prenatal care (Briggs et al. 2017).

In terms of breastfeeding, limited information is available, but infants may be exposed to clini- cally significant levels of medication in breast milk, and the long-term effects of such exposure are not known (Sachs et al. 2013). Accordingly, mothers who wish to breastfeed their infants should re- view the potential benefits of breastfeeding as well as potential risks in the context of shared deci- sion-making (American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice and the Breastfeeding Expert Work Group 2016; Sachs et al. 2013), with associated moni- toring of growth and development by the infant’s pediatrician (Sachs et al. 2013).

Additional information related to the use of antipsychotic medications during pregnancy and while breastfeeding can be found at the websites of the U.S. Food and Drug Administration (FDA; http://www.fda.gov), REPROTOX (www.reprotox.org), the Teratogen Information System (TERIS; http://www.depts.washington.edu/terisweb/teris), and the U.S. National Library of Medicine’s LactMed (www.ncbi.nlm.nih.gov/books/NBK501922). For women who have been treated with an SGA during pregnancy, enrolling in the National Pregnancy Registry for Atypical Antipsychotics is sug- gested (MGH Center for Women’s Mental Health 2019).

Determining a Treatment Setting

In determining a treatment setting, considerations for individuals with schizophrenia are similar to those for individuals with other diagnoses. Thus, in general, patients should be cared for in the least restrictive setting that is likely to be safe and to allow for effective treatment. If inpatient care is deemed essential, efforts should be made to hospitalize patients voluntarily. However, if hospital- ization is deemed essential but is not accepted voluntarily by the patient, state or jurisdictional re- quirements for involuntary hospitalization should be followed. Indications for hospitalization usually include the patient posing a serious threat of harm to self or others or being unable to care for himself or herself and needing constant supervision or support as a result. Other possible indi- cations for hospitalization include psychiatric or other medical problems that make outpatient treatment unsafe or ineffective or new onset of psychosis that warrants initial inpatient stabilization to promote reduction of acute symptoms and permit engagement in treatment.

For individuals with schizophrenia and other significant health issues, determination of a treat- ment setting will require weighing the pluses and minuses of possible settings to identify the opti- mal location for care. For example, individuals who require significant medical or surgical interventions or monitoring that are not typically available on a psychiatric inpatient service will likely be better served on a general hospital unit or in an intensive care setting with input from con- sultation-liaison psychiatrists. Considerable efforts may be needed to help staff who are unfamiliar with psychotic disorders engage with the patient (Freudenreich et al. 2019). In other circumstances, management of the patient on an inpatient psychiatric service in collaboration with consultants of other medical specialties will be optimal.

Less restrictive settings may be indicated when a patient does not meet criteria for inpatient treatment but requires more monitoring or assistance than is available in routine outpatient care. Such settings and programs may include ACT (Substance Abuse and Mental Health Services Ad- ministration 2008), assisted outpatient treatment, intensive outpatient treatment, partial hospital- ization, and day hospitalization.

Involuntary Treatment Considerations

Under some circumstances, individuals may not wish to participate in treatment or take medica- tions, even if they have severe symptoms. In states where psychiatric advance directives are avail- able, patients may be able to state their preferences about treatment choices while they have

capacity in the event of future decompensation and an inability to participate in decision-making. Even in the absence of a psychiatric advance directive, patients can often be helped to accept phar- macological treatment over time and with psychotherapeutic interactions that are aimed toward identifying subjectively distressing symptoms that have previously responded to treatment. Fam- ily members and other persons of support can also be helpful in encouraging the patient to engage in treatment.

Prevailing state laws will determine other steps to take if an individual lacks capacity but re- quires treatment. Some states have processes by which pharmacological treatment may be admin- istered involuntarily, whereas in other states a judicial hearing may be needed to obtain permission to treat a patient who lacks capacity.

For a small subgroup of patients with repeated relapses, rehospitalizations, or even reincarcera- tions associated with nonadherence or impairments in insight, involuntary outpatient commitment may warrant inclusion in the treatment plan to improve adherence, prevent psychiatric deteriora- tion, enhance outcomes, and promote recovery (American Psychiatric Association 2015; Gaynes et al. 2015; Harris et al. 2019; Segal et al. 2017a, 2017b; Swartz et al. 2017). Involuntary outpatient com- mitment (which also may be referred to as assisted outpatient treatment, mandated community treatment, outpatient court-ordered treatment, or a community treatment order) is increasingly available but varies among countries (Burns et al. 2013; Harris et al. 2019) and jurisdictions within the United States (Meldrum et al. 2016) in its criteria and implementation. Effective implementation requires adequate resources and individualized treatment planning (American Psychiatric Associ- ation 2015) if psychiatric (Gaynes et al. 2015; Harris et al. 2019; Segal et al. 2017a; Swartz et al. 2017) and physical health (Segal et al. 2017b) benefits are to be realized. As with any form of involuntary treatment, decisions about involuntary outpatient commitment require balancing ethical consider- ations related to patient autonomy and self-determination with considerations about the individ- ual’s best interest (American Psychiatric Association 2015).

Addressing Needs of Patients With Schizophrenia in Correctional Settings

Rates of serious mental illness, including schizophrenia, are higher in correctional settings (e.g., prisons, jails, police lockups, detention facilities) than in the general population (Al-Rousan et al. 2017; Bebbington et al. 2017; Bradley-Engen et al. 2010; Hall et al. 2019; Steadman et al. 2009). Care- ful assessment and treatment planning are essential when individuals with schizophrenia are in correctional settings. Although some aspects of treatment may need to be adjusted to conform with unique aspects of correctional settings (Tamburello et al. 2018), many individuals experience gaps in care during incarceration (Fries et al. 2013; Reingle Gonzalez and Connell 2014; Wilper et al. 2009), and access should be preserved to essential elements of treatment, including antipsychotic medications (American Psychiatric Association 2009b) and treatment for concomitant substance use disorders (American Psychiatric Association 2007).

While in the correctional system, individuals with schizophrenia may be withdrawn or disorga- nized or behave in a disruptive manner. These behaviors may result in disciplinary infractions, which may lead the individual with schizophrenia to be placed in a locked-down setting. Such units are often called administrative segregation, disciplinary segregation, or restricted housing units (Krelstein 2002; Semenza and Grosholz 2019) and have been conceptualized as having three main characteristics: social isolation, sensory deprivation, and confinement (Zubek et al. 1969). Each of these elements can vary significantly, but inmates typically spend an average of 23 hours per day in a cell, have limited human interaction and minimal or no access to programs, and are maintained in an environment that is designed to exert maximum control over the person, which has raised broader ethical considerations about the long-term use of such settings (Ahalt and Williams 2016; Ahalt et al. 2017; American Psychiatric Association 2017, 2018; American Public Health Association 2013; Cloud et al. 2015; National Commission on Correctional Health Care 2016).

Inmates’ responses to the segregation experience differ, and relevant scientific literature is sparse (Kapoor and Trestman 2016; O’Keefe et al. 2013). In addition, mental health clinicians working in

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 31

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such facilities frequently report that inmates without preexisting serious mental disorders develop irritability, anxiety, and other dysphoric symptoms when housed in these units for long periods of time (Metzner 2002). Difficulties in providing appropriate and adequate access to mental health care and treatment are especially problematic in any segregation environment and are related to lo- gistical issues that frequently include inadequate office space and limited access to inmates because of security issues (Metzner 2003; Metzner and Fellner 2010). In addition, because of their inherently punitive structure, such units typically provide very little support or access to relevant treatment modalities or a therapeutic milieu. Furthermore, rates of self-injury and suicide appear to be higher in such settings than elsewhere in the correctional system (Baillargeon et al. 2009b; Glowa-Kollisch et al. 2016; Kaba et al. 2014; Way et al. 2005). Consequently, persons with schizophrenia should gen- erally not be placed in a 23-hour/day lockdown for behaviors that are directly related to schizo- phrenia because such an intervention is likely to exacerbate rather than reduce psychotic symptoms, as well as increase rather than reduce disruptive behaviors (American College of Cor- rectional Physicians 2013; American Psychiatric Association 2016b, 2017; American Public Health Association 2013; National Commission on Correctional Health Care 2016).

Individuals with schizophrenia, like other individuals with serious mental illness, are at increased risk for symptom relapse and gaps in treatment on release from a correctional setting. Services are of- ten needed to reduce the likelihood of recidivism and maintain continuity of care for treatment of schizophrenia and concomitant disorders (e.g., substance use disorders, other medical conditions). Thus, discharge planning is a crucial aspect of care for inmates with schizophrenia, particularly for those who have been incarcerated for significant periods of time. Often, inmates with schizophrenia have been alienated from systems of care and psychosocial supports prior to arrest, and this estrange- ment is compounded by incarceration. As a result, inmates will likely need assistance around the time of discharge, which can encompass various domains, including housing, treatment needs, financial support, and obtaining supplemental security income/social security disability and related Medicaid benefits (American Psychiatric Association 2009c; Angell et al. 2014; Baillargeon et al. 2009a, 2010; Draine et al. 2010; Gertner et al. 2019; Morrissey et al. 2016; Wenzlow et al. 2011).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Development and documentation of a comprehensive, person-centered treatment plan assures that the clinician has considered the available nonpharmacological and pharmacological options for treat- ment and has identified those treatments that are best suited to the needs of the individual patient, with a goal of improving overall outcome. It may also assist in forming a therapeutic relationship, eliciting patient preferences, permitting education about possible treatments, setting expectations for treatment, and establishing a framework for shared decision-making. Documentation of a treatment plan promotes accurate communication among all those caring for the patient and can serve as a re- minder of prior discussions about treatment.

Harms

The only identifiable harm from this recommendation relates to the time spent in discussion and documentation that may reduce the opportunity to focus on other aspects of the evaluation.

Patient Preferences

Clinical experience suggests that patients are cooperative with and accepting of efforts to establish treatment plans.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. The level of research evidence is rated as low because no information is available on the harms of such an approach. There is also minimal research on whether developing and document- ing a specific treatment plan improves outcomes as compared with assessment and documentation as usual. However, indirect evidence, including expert opinion, supports the benefits of compre- hensive treatment planning. For additional discussion of the research evidence, see Appendix C, Statement 3.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Information from other guidelines (Addington et al. 2017a, 2017b; Barnes et al. 2011; Buchanan et al. 2010; Crockford and Addington 2017; Galletly et al. 2016; Hasan et al. 2012, 2013, 2015; National Institute for Health and Care Excellence 2014; Norman et al. 2017; Pringsheim et al. 2017; Scottish Intercollegiate Guidelines Network 2013) is generally consistent with this guideline statement in ei- ther explicitly or implicitly recommending development of a person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments.

Quality Measurement Considerations

It is not known whether psychiatrists and other mental health professionals typically document a com- prehensive and person-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments, and there is likely to be variability. Although a well-defined and scientifi- cally sound quality measure could be developed to assess for the implementation of an evidence-based treatment plan that meets consensus-based features of person-centered care, clinical judgment would still be needed to determine whether a documented treatment plan is comprehensive and adapted to individual needs and preferences. Manual review of charts to evaluate for the presence of such a person- centered treatment plan would be burdensome and time-consuming to implement.

A quality measure could assess the presence or absence of text in the medical record that would reflect treatment planning. When considering the development of such quality measures, there should be a thorough examination of the potential for unintended negative consequences, such as increased documentation burden or overuse of standardized language that meets the quality mea- sure criteria but would inaccurately reflect what occurred in practice.

Pharmacotherapy

STATEMENT 4: Antipsychotic Medications

APA recommends (1A) that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects.*

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Implementation

Selection of an Antipsychotic Medication

General Principles

In the treatment of schizophrenia, antipsychotic medication is one important component. The choice of an antipsychotic agent depends on many factors that are specific to an individual patient. Thus, before initiating treatment with antipsychotic medication, it is recommended that as part of selecting a medication, the treating clinician gather information on the patient’s treatment-related preferences and prior treatment responses and then discuss with the patient the potential benefits and risks of medication as compared with other management options. Many patients will wish family members or other persons of support to be involved in this discussion. The depth of this dis- cussion will, of course, be determined by the patient’s condition. Even with agitated patients and patients with thought disorder, however, the therapeutic alliance will be enhanced if the patient and physician can identify target symptoms (e.g., anxiety, poor sleep, and, for patients with insight, hallucinations and delusions) that are subjectively distressing and that antipsychotics can amelio- rate. Mentioning the possibility of acute side effects (e.g., dizziness, sedation, restlessness) helps pa- tients identify and report side-effect occurrence and also may help maintain a therapeutic alliance. Patients with schizophrenia often have attentional and other cognitive impairments that may be more severe during an acute illness exacerbation, so it is helpful to return to the topic of identifica- tion of target symptoms and discussion of acute and longer-term side effects on multiple occasions as treatment proceeds.

An evidence-based ranking of FGAs and SGAs or an algorithmic approach to antipsychotic se- lection is not possible because of the significant heterogeneity in clinical trial designs, the limited numbers of head-to-head comparisons of antipsychotic medications, and the limited clinical trial data for a number of the antipsychotic medications. By the same token, it is not possible to note a preference for either SGAs or FGAs. Although there may be clinically meaningful distinctions in response to and tolerability of different antipsychotic medications in an individual patient, there is no definitive evidence that one antipsychotic will have consistently superior efficacy compared with another, with the possible exception of clozapine. Although data in first-episode schizophre- nia are more limited, there appears to be no difference in response among the SGAs that have been studied (McDonagh et al. 2017; Zhu et al. 2017). Furthermore, there is no reliable strategy to predict response or risk of side effects with one agent compared with another. Consequently, the choice of a particular antipsychotic agent will typically occur in the context of discussion with the patient about the likely benefits and possible side effects of medication options and will incorporate patient preferences; the patient’s past responses to treatment (including symptom response and tolerabil- ity); the medication’s side-effect profile (see Table 6); the presence of physical health conditions that may be affected by medication side effects; and other medication-related factors such as available formulations, potential for drug-drug interactions, receptor binding profiles, and pharmacokinetic considerations (Tables 3–9).

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 35

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b

First-generation antipsychotics

Chlorpromazine

Thorazine

Tablet: 10, 25, 50, 100, 200 Short-acting injection (HCl):

25–100

200–800

Oral: 1,000–2,000

IM dosing is typically 25–50 mg per upper outer quadrant of gluteal with 200 mg/day maximum. Do not inject subcutaneously. Use much lower IM doses than oral doses because oral first-pass metabolism is significant.

Fluphenazine

Prolixin

Tablet: 1, 2.5, 5, 10
Oral concentrate: 5/mL (120 mL) Elixir: 2.5/5 mL (60 mL) Short-acting injection (HCl):

2.5–10

6–20

Oral: 40 IM: 10

Short-acting IM dose is 33%–50% of oral dose. Dilute oral concentrate immediately before use to ensure palatability and stability.

Haloperidol

Haldol

Tablet: 0.5, 1, 2, 5, 10, 20
Oral concentrate: 2/mL (5 mL,

1–15

5–20

Oral:100 IM: 20

2–5 mg IM can be given every 4–8 hours.

Loxapine

Loxitane

Capsule: 5, 10, 25, 50 Aerosol powder breath-

20

60–100h

Oral: 250 Aerosol: 10

Oral inhalation formulation (Adasuve) to treat agitation requires REMS program because of potential for bronchospasm.

Molindone Perphenazine

Moban Trilafon

activated inhalation: 10 Tablet: 5, 10, 25
Tablet: 2, 4, 8, 16

50–75 8–16

30–100h 8–32

225 64

CYP2D6 poor metabolizers will have higher blood concentrations.

Pimozide

Orap

Tablet: 1, 2

0.5–2

2–4

10

Pimozide does not have an FDA indication for schizophrenia but is sometimes used off-label or to treat delusional disorders such as delusional parasitosis. Avoid concomitant use of CYP1A2 or CYP3A4 inducers or inhibitors. Perform CYP2D6 genotyping if doses greater than 4 mg/ day are used. In poor CYP2D6 metabolizers, do not give more than 4 mg/day and do not increase dose earlier than 14 days.

Trade Available U.S. formulations namec (mg, unless otherwise noted)

Initial dose (mg/day)

Typical dose range (mg/day)

Maximum daily dose (mg/day)

Commentsd,e,f,g

25/mL (1 mL, 2 mL)

2.5/mL (10 mL)

15 mL, 120 mL)
Short-acting injection (lactate):

5/mL (1 mL, 10 mL)

  

36 APA Practice Guidelines

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b (continued)

Trade Available U.S. formulations namec (mg, unless otherwise noted)

Initial dose (mg/day)

Typical dose range (mg/day)

Maximum daily dose (mg/day)

Commentsd,e,f,g

First-generation antipsychotics (continued)

Thioridazine

Mellaril

Tablet: 10, 25, 50, 100

150–300

300–800h

800

Use is associated with dose-related QTc prolongation. Baseline ECG and serum potassium level are recommended. Avoid use if QTc interval is >450 msec or with concomitant use of drugs that prolong the QTc interval or inhibit CYP2D6. Reserve use for patients who do not show an acceptable response to adequate courses of treatment with other antipsychotic drugs.

Thiothixene Trifluoperazine

Navane Stelazine

Capsule: 1, 2, 5, 10 Tablet: 1, 2, 5, 10

6–10 4–10

15–30 15–20

60 50

Smoking may reduce levels via CYP1A2 induction.

Second-generation antipsychotics

Aripiprazole

Abilify

Tablet: 2, 5, 10, 15, 20, 30 Tablet, disintegrating: 10, 15 Tablet with ingestible event

10–15

10–15

30

Adjust dose if a poor CYP2D6 metabolizer or with concomitant use of a CYP3A4 inhibitor, CYP3A4 inducer, or CYP2D6 inhibitor. Tablet and oral solution may be interchanged on a mg-per-mg basis, up to 25 mg. Doses using 30 mg tablets should be exchanged for 25 mg oral solution. Orally disintegrating tablets (Abilify Discmelt) are bioequivalent to the immediate-release tablets (Abilify). Mycite tablet cannot be split or crushed.

Asenapine

Saphris

Tablet, sublingual: 2.5, 5, 10

10

20

20

Consider dose adjustment in smokers and with concomitant use of CYP1A2 inhibitors. Do not split, crush, or swallow. Place under tongue and allow to dissolve completely. Do not eat or drink for 10 minutes after administration to ensure absorption.

marker (Mycite): 2, 5, 10, 15, 20,

30
Solution: 1/mL (150 mL)

Smoking may reduce levels via CYP1A2 induction.

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 37

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b (continued)

Cariprazine Clozapine

Vraylar

Capsule: 1.5, 3, 4.5, 6

1.5 12.5–25

1.5–6 300–450e

6i 900

Adjust dose with concomitant use of a strong CYP3A4 inhibitor or inducer.

Trade Available U.S. formulations namec (mg, unless otherwise noted)

Initial dose (mg/day)

Typical dose range (mg/day)

Maximum daily dose (mg/day)

Commentsd,e,f,g

Second-generation antipsychotics (continued)

Asenapine

Secuado

Transdermal system: 3.8 mg/ 24 hours, 5.7 mg/24 hours, 7.6 mg/24 hours

3.8

3.8–7.6

7.6

Consider dose adjustment in smokers and with concomitant use of CYP1A2 inhibitors. A dose of 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine; 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine. Apply to clean, dry, and intact skin on the upper arm, upper back, abdomen, or hip; rotate sites when applying a new transdermal system. Do not cut. Do not apply external heat sources to the transdermal system.

Brexpiprazole

Rexulti

Tablet: 0.25, 0.5, 1, 2, 3, 4

1

2–4

4

Adjust dose if a poor CYP2D6 metabolizer or with concomitant use of moderate/strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, or strong CYP3A4 inducers.

Clozaril, FazaClo, Versacloz

Tablet: 25, 50, 100, 200
Tablet, disintegrating: 12.5, 25,

Prescribers must complete clozapine REMS education (www.clozapinerems.com) and follow requirements for a baseline CBC and ANC and for ANC monitoring before and during treatment. When initiating clozapine, increase in 25–50 mg/day increments for

100, 150, 200
Oral suspension: 50/mL

(100 mL)

2 weeks, then further increments not exceeding 100 mg up to twice weekly. For treatment interruptions of 2 or more days, restart at
12.5 mg once or twice daily. Retitration can occur more rapidly than with initial treatment. With treatment interruptions of more than 30 days, recommendations for initial titration and monitoring frequency should be followed. Adjust dose with concomitant use of strong CYP1A2 inhibitors and with strong CYP3A4 inducers. Smoking reduces clozapine levels via CYP1A2 induction. Clozapine levels can be informative in making dose adjustments.j

  

38 APA Practice Guidelines

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b (continued)

Lurasidone Olanzapine

Latuda Zyprexa

Tablet: 20, 40, 60, 80, 120

40 5–10

40–120 10–20

160 20k

Administer with food (≥ 350 calories). Adjust dose for concomitant use of moderate to strong CYP3A4 inhibitors or inducers.

Paliperidone

Invega

Tablet, extended release: 1.5, 3, 6, 9

6

3–12

12

If exceeding 6 mg daily, increases of 3 mg/day are recommended at intervals of more than 5 days, up to a maximum of 12 mg/day. Uses OROS; do not split or crush tablet. Use of extended-release tablet is not recommended with preexisting severe gastrointestinal narrowing disorders. Tablet shell is expelled in the stool.

Trade Available U.S. formulations namec (mg, unless otherwise noted)

Initial dose (mg/day)

Typical dose range (mg/day)

Maximum daily dose (mg/day)

Commentsd,e,f,g

Second-generation antipsychotics (continued)

Iloperidone

Fanapt

Tablet: 1, 2, 4, 6, 8, 10, 12

2

12–24

24

Titrate slowly (no more than 4 mg/day increase in dose). Follow initial titration approach if more than 3-day gap in treatment. Adjust dose with concomitant use of strong CYP2D6 or CYP3A4 inhibitors and reduce dose by 50% in CYP2D6 poor metabolizers.

Tablet: 2.5, 5, 7.5, 10, 15, 20 Tablet, disintegrating: 5, 10, 15, 20 Short-acting IM powder for

Short-acting IM formulation is used primarily for agitation, with usual dose of 2.5–10 mg IM and maximum dosage of 30 mg/day. Administer IM slowly, deep into muscle. Do not use subcutaneously. Concomitant use of IM olanzapine with parenteral benzodiazepines is not recommended because of potential for excessive sedation and cardiorespiratory depression. Smokers may require a 30% greater daily dose than nonsmokers because of CYP1A2 induction. Women may need lower daily doses. Approximately 40% of an oral dose is removed by first-pass metabolism as compared with IM dose. IM elimination half-life is ~1.5 times greater in the elderly. Oral dissolving tablet dissolves rapidly in saliva and may be swallowed with or without liquid. Olanzapine may be administered with or without food/ meals.

solution: 10/2 mL

   

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 39

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b (continued)

Risperidone

Risperdal

Tablet: 0.25, 0.5, 1, 2, 3, 4 Tablet, disintegrating: 0.25, 0.5,

2

2–8

8l

Use lower initial doses and slower titration rates with CrCl <30 mL/min or severe hepatic impairment (Child-Pugh class C). Fraction of free risperidone is increased with hepatic impairment, and the initial starting dose is

Ziprasidone

Geodon

Capsule: 20, 40, 60, 80 Solution reconstituted, IM: 20

40

80–160

320

Give capsules with >500 calories of food. No data suggest improved efficacy at higher doses. See labeling for reconstitution and storage of IM formulation. Short-acting IM formulation is used primarily for agitation, with usual dosage of 20 mg/day and maximum dosage of 40 mg/day.

Trade Available U.S. formulations namec (mg, unless otherwise noted)

Initial dose (mg/day)

Typical dose range (mg/day)

Maximum daily dose (mg/day)

Commentsd,e,f,g

Second-generation antipsychotics (continued)

Quetiapine

Seroquel

Tablet, immediate release: 25, 50, 100, 200, 300, 400

Immediate release: 50

400–800

800

Dosage is once daily for extended release and divided dosing for immediate release. Do not split or crush extended-release tablets. Immediate- release tablets are marginally affected by food, whereas extended-release tablets are significantly affected by a high-fat meal. Give extended-release tablets without food or with <300 calories. Retitrate for gap in treatment of more than 1 week. Adjust dose for concomitant use of strong CYP3A4 inhibitors or inducers.

Tablet, extended release: 50, 150, 200, 300, 400

Extended release: 300

1, 2, 3, 4
Oral solution: 1/mL (30 mL)

aThis table and subsequent medication-related tables include information compiled from multiple sources. Detailed information on such issues as dose regimen, dose adjustments, medi- cation administration procedures, handling precautions, and storage can be found in product labeling. It is recommended that readers consult product labeling information for authoritative information on these medications.

0.5 mg twice daily, which may be increased in increments of 0.5 mg or less, administered twice daily. With renal or hepatic impairment, increase in intervals of 1 week or more for doses > 1.5 mg twice daily. Adjust dose with concomitant use of inducers or inhibitors of CYP2D6. Check labeling for compatible liquids with oral solution. Do not split or crush oral disintegrating tablets. Inform patients with phenylketonuria that oral disintegrating tablets contain phenylalanine.

 

40 APA Practice Guidelines

TABLE 3. Antipsychotic medications: available oral and short-acting intramuscular formulations and dosing considerationsa,b (continued)

bLong-acting injectable formulations of antipsychotic medications are described separately in Tables 7, 8, and 9. Droperidol is a first-generation antipsychotic medication but is not included because it is available only in a parenteral formulation for short-term use, primarily for treatment of agitation or postoperative nausea and vomiting. Pimavanserin is a second-generation antipsychotic but is not included because it is FDA indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (Nuplazid [10 and 34 mg pimavanserin] 2018; Nuplazid [17 mg pimavanserin] 2018). Mesoridazine and triflupromazine were previously marketed in the United States but are no longer available. Other antipsy- chotic medications and other formulations of the listed medications may be available in Canada.

cThe most common U.S. trade names are included for reference only. At the time of publication, some of these products may be manufactured only as generic products.

dElderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared with placebo, and an FDA black box warning applies to all anti- psychotic medications. Antipsychotic agents with an indication for augmentation treatment in major depressive disorder (e.g., aripiprazole, brexpiprazole) have an additional black box warning related to increased risk of suicidal thinking/behaviors.

eMay be taken without regard to food or other medications unless specifically noted. fTablets can be crushed or split unless specifically noted.

gAs described by Pugh et al. (1973), Child-Pugh class A corresponds to a Child-Pugh score of 5–6, class B corresponds to a Child-Pugh score of 7–9, and class C corresponds to a Child-Pugh score of 10–15.

hUsually given in divided doses.
iUp to 9 mg/day has been studied in clinical trials.

jClozapine levels should be drawn after at least 3 days on a stable dose and about 12 hours after the last dose. Levels associated with efficacy show individual variation, but efficacy typically begins at a level above 250 ng/mL, with the most efficacy seen at levels higher than 350 ng/mL.

kOlanzapine has been used at higher dosages, typically up to 30 mg/day, although some case series describe use of up to 60 mg/day.

lDosages of risperidone up to 16 mg/day have been studied in clinical trials; however, doses >6 mg for twice-daily dosing do not appear to confer additional benefit and have a higher incidence of extrapyramidal symptoms than do lower doses.

Abbreviations. ANC=absolute neutrophil count; CBC=complete blood count; CrCl=creatinine clearance; CYP=cytochrome P450; ECG=electrocardiography; HCl=hydrochloride; OROS=osmotic-controlled release oral delivery system; QTc=corrected QT interval; REMS=risk evaluation and mitigation strategy.

Source. Hiemke et al. 2018; Koytchev et al. 1996; Lexicomp 2019; Micromedex 2019; Mountjoy et al. 1999; Procyshyn et al. 2019.

Package insert references. Abilify 2017, 2019; Abilify Maintena 2018; Abilify Mycite 2017; Aripiprazole orally disintegrating tablets 2018; Aripiprazole solution 2016; Aristada 2019; Aristada Initio 2019; Chlorpromazine hydrochloride injection 2010, 2016; Chlorpromazine hydrochloride tablets 2018; Clozapine 2017; Clozaril 2017, 2019; Fanapt 2017; FazaClo 2017; Fluphenazine decanoate injection 2018; Fluphenazine hydrochloride elixir 2016; Fluphenazine hydrochloride injection 2010; Fluphenazine hydrochloride solution, concentrate 2010; Fluphenazine hy- drochloride tablets 2016; Geodon 2018; Haldol decanoate injection 2019; Haldol lactate injection 2019; Haloperidol 2008; Haloperidol lactate 2008; Haloperidol lactate injection 2011; Halo- peridol lactate oral solution 2016; Haloperidol tablets 2015; Invega 2018, 2019; Invega Sustenna 2018a, 2018b; Invega Trinza 2018a, 2018b; Latuda 2018; Loxapac 2014; Loxitane 2017; Moban 2017; Molindone hydrochloride tablets 2014, 2018; Navane 2010; Orap 2014, 2018, 2019; Perphenazine 2016, 2017; Perseris 2018; Rexulti 2019; Risperdal 2019; Risperdal Consta 2019; Risper- idone orally disintegrating tablets 2019; Saphris 2017; Seroquel 2019; Seroquel XR 2019; Thioridazine hydrochloride 2016; Trifluoperazine 2017; Vraylar 2019; Zyprexa 2018a, 2018b; Zyprexa Relprevv 2018.

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 41

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations

First-generation antipsychotics

Chlorpromazine

Thorazine 32%

CYP2D6 (major),

Fluphenazine

Prolixin 2.7%

Oral: 2 hours 99% IM: 1.5–2 hours

CYP2D6 (major) substrate

7-hydroxy- fluphenazine, fluphenazine sulfoxide

4.4–16.4 hours

Renal and fecal; exact proportion unclear

Contraindi- cated by manufac- turer

Use with caution

Haloperidol

Haldol 60%–70%

Oral: 2–6 hours 89%– IM: 20 minutes 93%

CYP2D6 (major), CYP3A4 (major), CYP1A2 (minor) substrate; 50%– 60% glucuronida- tion

Hydroxymetab- olite-reduced haloperidol

14–37 hours

15%fecal,30% renal (1% as unchanged drug)

No dose adjustments noted

No dose adjustments noted

Loxapine

Loxitane 99%

1.5–3 hours 97%

CYP1A2 (minor), CYP2D6 (minor), CYP3A4 (minor) substrate; P- glycoprotein inhibitor

N-desmethyl loxapine (amoxapine), 8-hydroxyloxa- pine

Biphasic: initial 5 hours, terminal 19 hours

Renal and fecal

No dose adjustments noted

No dose adjustments noted

Molindone Perphenazine

Moban Unclear Trilafon 20%–40%

1.5 hours 76%

CYP2D6 substrate

Multiple

1.5 hours

Renal and fecal

Use with caution

No dose adjustments noted

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

Perphenazine: 91%– 1–3 hours 99%

CYP2D6 (major), CYP1A2 (minor), CYP2C19(minor), CYP2C9 (minor), CYP3A4 (minor) substrate

7-hydroxyper- phenazine (responsiblefor 70% of the activity)

Perphenazine: 9–12 hours 7-hydroxyper- phenazine:

5% fecal, 70% renal

Contraindi- catedinliver damage

Use with caution

7-hydroxyper- phenazine: 2–4 hours

10–19 hours

binding transporters

Metabolites

Excretion

2.8 hours 90%–
99% CYP1A2 (minor),

NOR2CPZ, NOR2CPZ SULF, and 3-OH CPZ

Biphasic: initial 2 hours, terminal 30 hours

Primarily renal(<1%as unchanged drug)

Use with caution

Use with caution; not dialyzable

CYP3A4 (minor) substrate

  

42 APA Practice Guidelines

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Thiothixene

Navane

~ 50%; erratic absorption

1–2 hours 90%

CYP1A2 (major) substrate

None noted

34 hours

Feces (unchanged drug and metabolites)

No dose adjustments noted

No dose adjustments noted

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

First-generation antipsychotics (continued)

Pimozide

Orap

≥ 50%

6–8 hours 99%

CYP1A2 (major), CYP2D6 (major), CYP3A4 (major) substrate

Unknown activ- ity: 4-bis-(4- fluorophenyl) butyric acid, 1-(4-piperidyl)- 2-benzimidaz- olinone

55 hours

Primarily renal

Use with caution

Use with caution

Thioridazine

Mellaril

25%–33%

1–4 hours 96%– 99%

CYP2D6 (major) substrate and moderate inhibitor, CYP2C19 (minor) substrate

Mesoridazine (twice as potent as thioridazine), sulforidazine

21–24 hours

Minimal renal

Use with caution

No dose adjustments noted

Trifluoperazine Stelazine Erratic absorption

1.5–6 hours 90%– 99%

CYP1A2 (major) substrate

N-desmethyltri- fluoperazine, 7- hydroxytriflu- operazine, and other metabo- lites

3–12 hours

Renal

Contraindi- cated in hepatic disease

No dose adjustments noted

Second-generation antipsychotics

Aripiprazole

Abilify 87%

3–5 hours >99%

CYP2D6 (major), CYP3A4 (major) substrate

Dehydro- aripiprazole

75 hours,
94 hours dehy-

55%fecal,25% renal

No dose adjustments noted

No dose adjustments noted

binding transporters

Metabolites

Excretion

droaripipra-

zole
146 hours in

poor CYP2D6 metabolizers

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 43

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Asenapine

Saphris

35% 0.5–1.5 hours 95%

CYP1A2 (major), CYP2D6 (minor), CYP3A4 (minor) substrate; glucuronidation by UGT1A4; CYP2D6 weak inhibitor

Inactive: N(+)- glucuronide, N-desmethyl- asenapine, and N-desmethyl- asenapine N– carbamoyl glucuronide

24

hours

40% fecal, 50% renal

Contraindi- cated in se- vere hepatic impairment (Child-Pugh class C)

No dose adjustments noted

Asenapine

Secuado

Not Not 95% applicable available

CYP1A2 (major), CYP2D6 (minor), CYP3A4 (minor) substrate; glucuronidation by UGT1A4; CYP2D6 weak inhibitor

Inactive: N(+)- glucuronide, N-desmethyl- asenapine, and N-desmethyl- asenapine N– carbamoyl glucuronide

24 hours

40%fecal,50% renal

Contraindi- cated in se- vere hepatic impairment (Child-Pugh class C)

No dose adjustments noted

Brexpiprazole

Rexulti

95% 4 hours >99%

CYP3A4 (major), CYP2D6 (major) substrate

Inactive: DM- 3411

91 hours

46%fecal,25% renal

Moderate to severe im- pairment (Child-Pugh class B or C): use maxi- mum dos- age of 2 mg/ day in MDD and 3 mg/ day in schizophre- nia

CrCl <60 mL/min- ute: use maximum dosage of 2 mg/day in MDD and

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination
half-life in
adults Excretion

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

binding transporters

Metabolites

3 mg/day in schizo- phrenia

  

44 APA Practice Guidelines

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Clozapine

Clozaril, 27%–60% 2.2–2.5 hours 97% FazaClo, (range: 1–6
Versa- hours)
cloz

CYP1A2 (major), CYP2A6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor) substrate

N-desmethyl- clozapine (active), hydroxylated and N-oxide derivatives (inactive)

4–66 hours (steady state 12 hours)

30%fecal,50% renal

Significant impair- ment: dose reduction may be nec- essary

Significant impair- ment: dose reduction may be nec- essary

Iloperidone

Fanapt 96% 2–4 hours 92%–
97% CYP3A4 (minor)

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

Cariprazine

Vraylar High 3–6 hours 91%–

Desmethyl cariprazine (DCAR), didesmethyl cariprazine (DDCAR)

binding transporters

Metabolites

Excretion

CYP3A4 (major), 97% CYP2D6 (minor)

Cariprazine: 2–4 days DCAR: 1–2

21% renal

Severe im- pairment (Child-Pugh class C): not recom- mended

CrCl <30 mL/min- ute: not rec- ommended

substrate

CYP2D6 (major),

P88 P95

Extensive metabolizers: iloperidone 18 hours, P88 26 hours, P95 23 hours

~20% fecal, ~50% renal

Moderate im- No dose

substrate, CYP3A4 weak inhibitor

pairment: use with caution

adjustments noted

days DDCAR: 1–3

weeks

Poor metabo- lizers:

Severe im- pairment: not recom- mended

iloperidone 33 hours, P88 37 hours, P95 31 hours

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 45

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Lurasidone

Latuda 9–19%

1–3 hours

99%

CYP3A4 (major) substrate, CYP3A4 weak inhibitor

Lurasidone 18– ~80% fecal,

Moderate to severe he- paticimpair- ment(Child- Pugh class B and class C): use 20 mg/ day initially, with maxi- mum dose of 80 mg/ day and 40 mg/day, re- spectively

Olanzapine

Zyprexa >57%

Oral: 6 hours IM: 15–45 min-

93%

CYP1A2 (major), CYP2D6 (minor) substrate; metab- olized via direct glucuronidation

10-N– glucuronide, 4-N-desmethyl olanzapine (inactive)

30 hours

30%fecal,57% Use with renal caution

Notremoved by dialysis

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination
half-life in
adults Excretion

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

utes

binding transporters

Metabolites

ID-14283, ID-
14326 (active);
ID-20219, ID- 20220(inactive) 10hours

~9% renal

For CrCl <50 mL/min- ute:initial20 mg/day, maximum dose 80 mg/ day

40 hours ID-14283: 7.5–

  

46 APA Practice Guidelines

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Quetiapine

Seroquel 100%

Immediate release: 1.5 hours

83%

CYP3A4 (major), CYP2D6 (minor) substrate

Active: norqueti- apine, 7-hydroxyque- tiapine

Quetiapine: 6–7 hours

20%fecal,73% renal

Immediate release: ini- tial 25 mg/ day dose, increase by 25–50 mg/ day to effec- tive dose

No dose adjustments noted

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

Paliperidone

Invega 28%

24 hours

74%

P-glycoprotein/ ABCB1, CYP2D6 (minor), CYP3A4 (minor) substrate

Activity unclear: M1, M9, M10, M11, M12, M16

23 hours; 24–51 hours with renal impairment (CrCl <80 mL/minute)

11% fecal, 80% renal

Mild to mod- erate: no ad- justment necessary

Not recom- mended for CrCl < 10 mL/min- ute; for CrCl 10–49 mL/min- ute and CrCl 50–79 mL/min- ute, use maximum dosage of

Extended release: 6 hours

Norquetiapine: 12 hours

binding transporters

Metabolites

Excretion

Inactive: queti- apine sulfoxide (major), parent acid metabolite

Severe: not studied

Extended re- lease: initial 50 mg/day, increase by 50 mg/day to effective dose

3 mg/day and 6 mg/ day, respec- tively

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 47

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

Risperidone

Risperdal

Absolute: 70%

1 hour

90%

CYP2D6 (major), CYP3A4 (minor), P-glycoprotein/ ABCB1 substrate, N-dealkylation (minor), CYP2D6 weak inhibitor

Active: 9- hydroxy- risperidone

Risperidone: 3–20 hours

14%fecal,70% renal

Mild or mod- erate im- pairment (Child-Pugh class A or B): reduce dose

Mild or mod- erate im- pairment (CrCl ≥ 30 mL/min- ute): reduce dose

Tablet relative to oral solution: 94%

9-hydroxy- risperidone: 21–30 hours

binding transporters

Metabolites

Excretion

Severe im- pairment (Child-Pugh class C): ini- tial 0.5 mg twice a day, increase by no more than 0.5 mg twice a day; may in- crease to to- tal dosage >1.5mg twice a day at1weekor greater

Severe im- pairment (CrCl < 30 mL/min- ute): initial 0.5 mg twice a day, increase by no more than 0.5 mg twice a day; may in- crease to dosage > 1.5 mg twice a dayat1 week or greater

   

48 APA Practice Guidelines

TABLE 4. Antipsychotic medications: pharmacokinetics/pharmacodynamics of oral and short-acting intramuscular formulations (continued)

Ziprasidone

Geodon

Oral with food: 60%

Oral: 6–8 hours IM: 60 minutes

> 99%

CYP1A2 (minor), CYP3A4 (minor) substrate, glutathione, aldehyde oxidase

Active: benziso- thiazole sulfox- ide (major), benzisothi- azole sulfone (major), ziprasidone sulfoxide, S-methyl- dihydro- ziprasidone

Oral: 7 hours IM: 2–5 hours

66% fecal, 20% renal

Use with caution

No oral dose adjustments noted

Trade Oral bio- Time to peak name availability level

Metabolic Protein enzymes/

Elimination half-life in adults

Hepatic Renal impairmenta impairment

Second-generation antipsychotics (continued)

IM:100%

binding transporters

Metabolites

Excretion

aAs described by Pugh et al. (1973), Child-Pugh class A corresponds to a Child-Pugh score of 5–6, class B corresponds to a Child-Pugh score of 7–9, and class C corresponds to a Child-Pugh score of 10–15.

Abbreviations. CrCl=creatinine clearance; CYP=cytochrome P450; MDD=major depressive disorder; UGT=uridine 5’-diphospho-glucuronosyltransferase. Source. Hiemke et al. 2018; Koytchev et al. 1996; Lexicomp 2019; Micromedex 2019; Mountjoy et al. 1999; Procyshyn et al. 2019; Vermeir et al. 2008.

IM formula- tion con- tains a renally cleared ex- cipient, cy- clodextrin; use with caution

   

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 49

TABLE 5. Antipsychotic receptor binding properties

Trade name D1 First-generation antipsychotics

D2 D3 D4 D5

5-HT1A 5-HT2A

Musc 5-HT2C 5-HT7 H1 M1

α1 α2 Comments +++ +

Chlorpromazine Fluphenazine Haloperidol Loxapine Molindone Perphenazine Pimozide

Thorazine + Prolixin ++ Haldol + Loxitane ++ Moban 0 Trilafon ++ Orap 0

+++ +++ ++ + ++++ ++++ ++ ++ +++ +++ +++ + ++ ++ +++ ++ ++ ++ 0

0 +++ + ++ 0 ++ 0 +++ 0 0

++ ++ +++ ++ + +++ ++ 0 0 + 0 0 ++ ++ +++ + 0 0 0 0 + ++ +++ 0 0 ++++ + +

+++ 0 ++ 0 ++ 0 0 + ++ + + +

Thioridazine Thiothixene Trifluoperazine

Mellaril ++ Navane + Stelazine +

++ +++ ++ + ++++ ++++ + + +++ ++++ ++

+ ++ + ++ + ++

++ ++ ++ +++ 0 ++ +++ 0
+ + ++ +

+++ + ++ 0 ++ 0

Second-generation antipsychotics

Aripiprazole Asenapine Brexpiprazole Cariprazine Clozapine

Abilify +

//// +++ + 0 +++ ++++ +++ /// +++ ++++ /// ++++

/// +++ +++ ++++ //// ++++ /// ++

++ ++ ++ 0
++++ ++++ +++ 0
++ +++ ++ 0
+ + ++ 0 +

Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

Fanapt + Latuda + Zyprexa ++ Invega + Seroquel 0 Risperdal + Geodon +

++ ++ ++ + +++ ++ ++
++ ++ ++ ++ +++ +++ ++ ++ + + 0 0 +++ +++ +++ + +++ +++ ++ +

// ++++ / ++++ 0 +++ + ++++ / +

++ ++ + 0
+ ++++ 0 0 ++ + +++ +++ ++ +++ +++ 0
0 + +++ + ++ +++ ++ 0 ++++ +++ ++ 0

+++ +++ ++ ++ ++ + +++ ++ ++ 0 +++ +++ +++ +

Saphris, Secuado +++

Rexulti +

Vraylar

Clozaril,FazaClo, + Versacloz

+ + ++ +

/ +++

++ ++ +++ ///

+++ +

++++ ++++ ++ ++++ +++ ++

0 +++ + ++

Moderate activity at dopamine transporter

+ ++++ /// ++++

Weak activity at norepinephrine and serotonin transporter

Note. ++++=very strong binding (Ki <1 nM); +++=strong binding (1 nM ≤Ki<10 nM); ++=moderate binding (10 nM ≤Ki <100 nM); +=weak binding (100 nM ≤Ki <1,000 nM); 0=very weak or negligible binding (Ki ≥1,000 nM). For partial agonists, / is used instead of + to denote relative binding values.

Source. Latuda 2018; Lexicomp 2019; Maeda et al. 2014; Micromedex 2019; Olten and Bloch 2018; PDSP 2019; Procyshyn et al. 2019; Rexulti 2019; Roth et al. 2000; Saphris 2017; Vraylar 2019.

++ + +++ +++ +++ ++++

  

50 APA Practice Guidelines

TABLE 6. Antipsychotic medications: relative side effects of oral formulations

First-generation antipsychotics

Chlorpromazine Fluphenazine Haloperidol Loxapine Molindone Perphenazine Pimozide Thioridazine Thiothixene Trifluoperazine

Thorazine Prolixin Haldol Loxitane Moban Trilafon Orap Mellaril Navane Stelazine

++ ++ +++ +++ +++ +++ ++ ++ ++ ++ ++ ++ +++ +++ + + +++ +++ ++ ++

++

+++

+++

++

++

++

++

+

+++

++

+++  +

+++  +++

+++  +++

++  ++

++  ++

++  ++

+++ +++ + ++ +++ +++ ++ ++

+++ +++ + +
+ + ++ ++ + ++ ++ ++ + + +++ +++ + + ++ +

Aripiprazole Asenapine Brexpiprazole Cariprazine Clozapine

Abilify ++ +

+ ++ + + +

+ + ++ ++

+  +

+  +

+  +

+ +
+ ++ + ++ ++ ++ +++ +++

Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

Fanapt + + Latuda ++ ++ Zyprexa ++ ++ Invega ++ ++ Seroquel + + Risperdal ++ ++ Geodon ++ +

+ ++ + ++ + ++ +

+ ++ ++ +
+ ++ ++ +++ + + ++ +++ + ++

+ ++ + ++ ++ +++ + + ++ +++ + ++ + ++

Trade
name Akathisia Parkinsonism Dystonia

Tardive
dyskinesia Hyperprolactinemiaa Anticholinergic Sedation

Second-generation antipsychotics

Saphris ++ +

Rexulti ++ +

Vraylar ++ +

Clozaril, + + FazaClo,
Versacloz

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 51

TABLE 6. Antipsychotic medications: relative side effects of oral formulations (continued)

First-generation antipsychotics

Perphenazine Pimozide Thioridazine

Trilafon Orap Mellaril

+ ++ +++ + ++ +++

++ ++ + + +++ + + +

Thiothixene Trifluoperazine

Navane Stelazine

+++ + + +

++  + + +

++  ++ + +

Trade
name Seizures

QT Orthostasis prolongation

Weight gain Hyperlipidemia

Glucose
abnormalities Comments

Second-generation antipsychotics

Aripiprazole Abilify + +

+ + +

+ FDA safety alert for impulse control disorders (e.g.,

Asenapine Saphris + ++ Brexpiprazole Rexulti + + Cariprazine Vraylar + +

++ Oral hypoesthesia ++ + ++ +

+++ +++ + ++ + ++ ++ ++

++  + ++

++  + +

++  + +

+ + +

Chlorpromazine Thorazine ++
Fluphenazine Prolixin +
Haloperidol Haldol +
Loxapine Loxitane + MolindoneMoban++++++ +

+++ ++ +

+ Pigmentary retinopathy; high rates of sexual dysfunction;

++ ++ ++
++ ++ + +

avoid use if QTc interval is
> 450 msec or with concomitant use of drugs that prolong the QTc interval or inhibit CYP2D6

gambling, binge eating); may reduce hyperprolactinemia with other antipsychotics

   

52 APA Practice Guidelines

TABLE 6. Antipsychotic medications: relative side effects of oral formulations (continued)

Iloperidone Lurasidone

Fanapt + Latuda +

+++ +++ + +

++ + ++

Olanzapine Paliperidone Quetiapine Risperidone

Zyprexa ++ Invega + Seroquel ++ Risperdal +

++  ++

++  ++

++  ++

++  ++

+++ +++ +++

++  ++ +

++  +++ ++

Ziprasidone

Geodon +

++ +++

+ + +

Trade
name Seizures Orthostasis

QT Glucose

Second-generation antipsychotics (continued)

Clozapine

Clozaril, +++ FazaClo, Versacloz

+++ ++

+++ +++

+++ Increased salivation common; high rate of sexual

prolongation Weight gain Hyperlipidemia

abnormalities Comments

aIn general, rates of sexual dysfunction parallel rates of hyperprolactinemia except where noted in comments.
Note. +=seldom; ++=sometimes; +++=often. CYP=cytochrome P450.
Source. Credible Meds 2019; Hirsch et al. 2017; La Torre et al. 2013; Lexicomp 2019; Micromedex 2019; Pisani et al. 2002; Procyshyn et al. 2019; van Dijk et al. 2018.

+ ++

++ Dose-related creatinine increase in some patients

++ +

++ Intraoperative floppy iris syndrome reported

dysfunction; severe constipation and paralytic ileus possible; fever can occur with initiation; myocarditis is infrequent; cardiomyopathy and severe neutropenia are rare

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 53

TABLE 7. Long-acting injectable antipsychotic medications: availability and injection-related considerationsa

First-generation antipsychotics

Fluphenazine

Prolixin Decanoate

25/mL (5 mL)

Vial, sesame oil vehicle with 1.2% benzyl alcohol

Deep IM gluteal or del- toid injection; use of Z- track technique rec- ommendede

Skin reactions reported

Monitor for hypotension. In sesame oil, be alert for allergy. For detailed instructions on needle size and product handling, refer to labeling.

Haloperidol

Haldol Decanoate

50/mL (1 mL, 5 mL), 100/mL (1 mL, 5 mL)

Vial, sesame oil vehicle with 1.2% benzyl alcohol

Deep IM gluteal or deltoid injection; use of Z-track technique recommendede

Inflammation and nodules reported, especially with dose >100 mg/mL

Do not administer more than 3 mL per injection site. In sesame oil, be alert for allergy. For detailed instructions on needle size, refer to labeling.

Second-generation antipsychotics

Aripiprazole monohydrate

Abilify Maintena

300, 400

Kit with either prefilled syringe or single-use vial

Slow IM injection into gluteal or deltoid muscle

Occasional redness, swelling, induration (mild to moderate)

Rotate injection sites. Do not massage muscle after injection. For detailed instructions on needle size and product reconstitution, refer to labeling.

Aripiprazole lauroxil

Aristada Initio

675/2.4 mL

Kit with prefilled syringe

IM deltoid or gluteal muscle

Common: pain Infrequent: induration,

Only to be used as a single dose to initiate Aristada treatment or to reinitiate treatment following a missed dose of Aristada. Not for repeat dosing. Not interchangeable with Aristada. Avoid concomitant injection of Aristada Initio and Aristada into the same deltoid or gluteal muscle. Refer to labeling for detailed instructions on injection site, needle length, and instructions to ensure a uniform suspension.

Aripiprazole lauroxil

Aristada

441/1.6 mL, 662/2.4 mL, 882 /3.2 mL, 1,064/3.9 mL

Kit with prefilled syringe

IM deltoid or gluteal muscle for 441 mg IM gluteal muscle for

Common: pain Infrequent: induration,

Not interchangeable with Aristada Initio. Avoid concomitant injection of Aristada Initio and Aristada into the same deltoid or gluteal muscle. Refer to labeling for detailed instructions on injection site, needle length, and instructions to ensure a uniform suspension.

Available strengthsb

(mg, unless Trade name otherwise noted)

How supplied

Injection site and techniquec

Reactions at injection sited

Comments

662 mg, 882 mg, or 1,064 mg

swelling, redness

swelling, redness

  

54 APA Practice Guidelines

TABLE 7. Long-acting injectable antipsychotic medications: availability and injection-related considerationsa (continued) Available strengthsb

Olanzapine

Zyprexa Relprevv

210, 300, 405

Kit with vial containing diluent and vial with powder for reconstituting suspension

Deep IM gluteal injection only; do not administer subcutaneously

Infrequent induration or mass at injection site

Because of risk of postinjection delirium/ sedation syndrome, must be given in a registered health care facility with ready access to emergency response services, and patient must be observed for at least 3 hours postinjection and accompanied on discharge. Requires use of FDA REMS program (www.zyprexarelprevv program.com/public/Default.aspx). Do not massage muscle after injection. The combined effects of age, smoking, and biological sex may lead to significant pharmacokinetic differences. For de- tailed instructions on product handling and reconstitution, refer to labeling.

Paliperidone palmitate

Invega Sustenna

39/0.25 mL, 78/0.5 mL, 117/0.75 mL, 156/1 mL, 234/1.5 mL

Kit with prefilled syringe

IM only; slow, deep IM deltoid injection for first 2 doses, then deep deltoid or gluteal injection (upper outer quadrant) thereafter

Occasional redness, swelling, induration

The two initial deltoid IM injections help attain therapeutic concentrations rapidly. Alternate deltoid injections (right and left deltoid muscle). For detailed instructions on needle size and product reconstitution, refer to labeling.

Paliperidone palmitate

Invega Trinza

273/0.875 mL, 410/ 1.315 mL, 546/1.75 mL, 819/2.625 mL

Kit with prefilled syringe

IM only; slow, deep IM deltoid or gluteal injection

Infrequent redness or swelling

Shake prefilled syringe for 15 seconds within 5 minutes prior to administration. For detailed instructions on needle size, product handling, and reconstitution, refer to labeling.

(mg, unless Trade name otherwise noted)

How supplied

Injection site and techniquec

Reactions at injection sited

Comments

Second-generation antipsychotics (continued)

   

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 55

TABLE 7. Long-acting injectable antipsychotic medications: availability and injection-related considerationsa (continued) Available strengthsb

(mg, unless Trade name otherwise noted)

How supplied

Injection site and techniquec

Reactions at injection sited

Comments

Second-generation antipsychotics (continued)

Risperidone

Risperdal Consta

12.5, 25, 37.5, 50

Kit with prefilled syringe and vial for reconstitution

Deep IM injection into the deltoid or gluteal (upper outer quadrant)

Occasional redness, swelling, induration

Alternate injection sites. Refrigerate and store at 2°C–8°C and protect from light. Vial should come to room temperature for at least 30 minutes before reconstituting. May be stored at 25°C for up to 7 days prior to administration. For detailed instructions on product handling and reconstitution, refer to labeling.

Risperidone

Perseris

90/0.6 mL, 120/0.8 mL

Kit with prefilled syringes containing powder and diluent

Abdominal subcutane- ous injection only

Lump at injection site may persist for several weeks

Alternate injection sites. Inject only in area without skin conditions, irritation, reddening, bruising, infection, or scarring; do not rub or massage injection sites. Store at 2°C–8°C and protect from light. Allow package to come to room temperature for at least 15 minutes before injection. For detailed instructions on product handling and reconstitution, refer to labeling.

aThis table and the subsequent table on long-acting injectable antipsychotic medications include information compiled from multiple sources. It is recommended that readers consult prod- uct labeling information for authoritative information on these medications. Detailed information on issues such as dose regimen, dose adjustments, medication administration procedures, appropriate needle size based on injection site and patient weight, product reconstitution, handling precautions, and storage can also be found in product labeling.

bAvailable strengths are based on U.S. products; strengths and products available in other countries may differ.
cEach injection must be administered only by a health care professional. Long-acting injectable antipsychotic medications should never be administered intravenously. dPain at injection site noted for all products.

eSource. Government of South Australia Health: Injection Sites. Available at: http://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/clinical+resources/ clinical+programs+and+practice+guidelines/medicines+and+drugs/injection+techniques#Z%20track. Accessed July 21, 2020. Northumberland, Tyne and Wear NHS Foundation Trust: Standard for the Assessment and Management of Physical Health. Appendix 2: Injection Sites. Available at: http://www.ntw.nhs.uk/content/uploads/2015/06/AMPH-PGN-10-IMI-App2- Injection-Sites-V01-iss-Sep7.pdf. Accessed January 20, 2019.

Abbreviations. REMS=risk evaluation and mitigation strategy.

Source. Abilify Maintena 2018; Andorn et al. 2019; Aristada 2019; Aristada Initio 2019; Invega Sustenna 2018a, 2018b; Invega Trinza 2018a, 2018b; Lexicomp 2019; Micromedex 2019; Perseris 2018; Procyshyn et al. 2019; Risperdal Consta 2019; Zyprexa Relprevv 2018.

  

56 APA Practice Guidelines

TABLE 8. Long-acting injectable antipsychotic medications: dosing

Haloperidol

Haldol Decanoate

For each 5 mg/day oral, give 50–75 mg decanoate every
4 weeks

Determined by oral dose and/ or risk of relapse up to a maximum of 100 mg

50–200 (10–15 times

450/month

4 weeks

Taper and discontinue after two to three injections

If initial dose is > 100 mg, split into two injections separated by 3–7 days.

Trade
name Dose conversions

Initial dose (mg)

Typical dose (mg)

Maximum dose (mg)

Dosing frequency

Need for initial oral supplementation

Comments

First-generation antipsychotics

Fluphenazine

Prolixin Decanoate

For each 10 mg/day oral, give 12.5 mg decanoate every 3 weeks

6.25–25 every 2 weeks

6.25–25 every 2–4 weeks

100

2–4 weeks

Decrease oral dose by half after first injection, then discontinue with second injection

Increase in 12.5 mg incre- ments if doses
>50 mg are needed.

Second-generation antipsychotics

Aripiprazole monohy- drate

Abilify Maintena

Not applicable

400

400

400/month

Monthly

Continue oral for 14 days after initial injection

Follow labeling if scheduled injections are missed. Dose adjust for poor CYP2D6 metabolizers, for those taking CYP2D6 and/or CYP3A4 inhibitors, or because of adverse effects. Avoid use with CYP3A4 inducers.

Aripiprazole lauroxil

Aristada Initio

Not applicable

675

675

675

Single dose to initiate Aristada treatment or reinitiate treatment after a missed Aristada dose. Not for repeated dosing.

Must be adminis- tered in conjunc- tion with one
30 mg dose of oral aripiprazole

For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole before use. Aristada Initio and Aristada are not interchangeable. See labeling for dose adjustments.

previous oral dose)

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 57

TABLE 8. Long-acting injectable antipsychotic medications: dosing (continued)

Aripiprazole lauroxil

Aristada

10mg/dayorally,give 441 mg IM/month 15mg/dayorally,give

Monthly: 441, 662, 882

Monthly: 441, 662, 882

882/month

Monthly: 441, 662, 882

There are two ways to initiate treatment:

Aristada Initio and Aristada are not interchangeable. The first Aristada injection may be given on the same day as Aristada Initio or up to 10 days thereafter.

Olanzapine

Zyprexa Relprevv

10 mg/day orally, 210 mg every
2 weeks for four doses or 405 mg ery

Determined by oral dose

150mg,210mg, or 300 mg every 2 weeks or 300 mg or 405 mg every 4 weeks

300 mg every 2 weeks or 405 mg every 4 weeks

2–4 weeks

Not required

Give 150 mg every
4 weeks in patients who may have sensitivity to side effects or slower metabolism. Smokers may require a greater daily dose than non- smokers, and women may need lower daily doses than expected.

Trade
name Dose conversions

Initial dose (mg)

Typical dose (mg)

Maximum dose (mg)

Dosing frequency

Need for initial
oral
supplementation Comments

Second-generation antipsychotics (continued)

662 mg/month IM, 882 mg IM every
6 weeks, or 1,064 mg IM every 2 months

Every 6 weeks: 882

Every 6 weeks: 882

Every 6 weeks: 882

1. Give one IM in- jection of Aris- tada Initio 675 mg and one dose of oral aripipra- zole

20 mg/day or greater orally, give 882 mg/ month IM

30 mg or

4 weeks
15 mg/day orally,

300 mg every
2 weeks for four doses

20 mg/day orally, 300 mg every
2 weeks

ev-

Every 2 months: 1,064

Every2months: 1,064

Every2months: 1,064

2. Give 21 days of oral aripiprazole in conjunction with the first Aristada injection

  

58 APA Practice Guidelines

TABLE 8. Long-acting injectable antipsychotic medications: dosing (continued)

Paliperidone palmitate

Invega Trinza

Conversion from monthly Invega Sustenna to every 3- month injections of Invega Trinza:

Dependent on last dose of monthly paliperidone

273–819

819/3 months

Every 3 months

Not applicable

Change to Trinza after at least four Invega Sustenna doses (with two doses at same strength). For changes from IM Trinza to oral or to IM Sustenna, see labeling. Doses are expressed as amount of paliperidone palmitate rather than as paliperidone. Avoid using with a strong inducer of CYP3A4 and/ or P-glycoprotein.

Trade
name Dose conversions

Initial dose (mg)

Typical dose (mg)

Maximum dose (mg)

Dosing frequency

Need for initial
oral
supplementation Comments

Second-generation antipsychotics (continued)

Paliperidone Invega

3 mg oral paliperidone, give 39–78 mg IM
6 mg oral, give 117 mg

234 mg IM on day 1 and
156 mg IM
1 week later, both adminis- tered in the deltoid muscle

78–234 mg monthly beginning at week 5

234mg/month

Monthly

Not required

Contains range of particle sizes for rapid and delayed absorption. For changes to oral or other LAI to Sustenna, see labeling. Doses are expressed as amount of paliperidone palmitate rather than as paliperidone. Avoid using with a strong inducer of CYP3A4 and/or P-glycoprotein.

palmitate

Sustenna

IM
9 mg oral, give 156 mg

IM
12 mg oral, give 234 mg

IM

78 mg, give 273 mg 117 mg, give 410 mg 156 mg, give 546 mg 234 mg, give 819 mg

   

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 59

TABLE 8. Long-acting injectable antipsychotic medications: dosing (continued)

Risperidone

Perseris

Oral risperidone to subcutaneous risperidone ex- tended release:

Determined by oral dose

90–120 monthly

120/month

Monthly

Neither a loading dose nor oral overlap is needed

May not be appropriate for patients taking less than 3 mg or more than 4 mg of oral risperidone daily. Adjust dose with concomitant CYP2D6 inhibitors or CYP3A4 inducers.

Abbreviations.

120 mg/month CYP=cytochrome P450; LAI=long-acting injectable.

Trade
name Dose conversions

Initial dose (mg)

Typical dose (mg)

Maximum dose (mg)

Dosing frequency

Need for initial
oral
supplementation Comments

Second-generation antipsychotics (continued)

Risperidone

Risperdal Consta

Oral risperidone to Risperdal Consta IM:
≤3 mg/day, give

25 every 2 weeks

25–50 every 2 weeks

50 every 2 weeks

2 weeks

Continue oral for 3 weeks (21 days)

Upward dose adjustment should not be made more frequently than every 4 weeks.

25 mg/2 weeks >3 to ≤5 mg/day, give 37.5 mg/

2 weeks
>5 mg/day, give

50 mg/2 weeks

3 mg/day, give 90 mg/month 4 mg/day, give

Source. Abilify Maintena 2018; Aristada 2019; Aristada Initio 2019; Bai et al. 2007; Hamann et al. 1990; Invega Sustenna 2018a, 2018b; Invega Trinza 2018a, 2018b; Kreyenbuhl et al. 2010; Lexicomp 2019; Micromedex 2019; Nasser et al. 2016; Perseris 2018; Procyshyn et al. 2019; Risperdal Consta 2019; Zyprexa Relprevv 2018.

  

60 APA Practice Guidelines

TABLE 9. Long-acting injectable antipsychotic medications: pharmacological characteristics

First-generation antipsychotics

Fluphenazine Haloperidol

Prolixin Decanoate

8–10 hours 6 days

2 months 3–4 months

6–9 days for single injection and 14–26 days for multiple doses

Major CYP2D6 substrate
Major CYP2D6 and CYP3A4 substrate

Second-generation antipsychotics

Aripiprazole monohydrate Aripiprazole lauroxil Aripiprazole lauroxil Olanzapine

Abilify Maintena

4 days (deltoid); 5–7 days (gluteal)

By fourth dose

300 mg: 29.9 days
400 mg: 46.5 days (400 mg) with

Give no sooner than 26 days between injections.

Paliperidone palmitate

Invega Sustenna

25–49 days; increased in renal disease

CrCl 50–79 mL/minute: initiate at 156 mg on day 1, followed by 117 mg 1 week later, both administered in the deltoid muscle. Main- tenance dose of 78 mg. Use not recom- mended in patients with CrCl

Paliperidone palmitate

Invega Trinza

30–33 days

Not applicable

84–95 days with deltoid injection; 118–139 days with gluteal injection; increased in renal disease

Do not use in patients with CrCl <50 mL/ minute.

Trade name

Time to peak plasma level

Time to steady state

Elimination half-life

Commentsa

Haldol Decanoate

21 days

Aristada Initio

16–35 days (median 27 days)

Not applicable

Not interchangeable with Aristada because of differing pharmacokinetic profiles

Aristada

Not available

4 months

53.9–57.2 days

Not interchangeable with Aristada Initio because of differing pharmacokinetic profiles

Zyprexa Relprevv

7 days 13 days

~3 months 2–3 months

30 days

CYP2D6 and CYP3A4 substrate Major CYP1A2 substrate

gluteal injection 15–18 days

Major CYP2D6 and CYP3A4 substrate

CYP2D6 and CYP3A4 substrate

<50 mL/minute.
Substrate of P-glycoprotein/ABCB1

Substrate of P-glycoprotein/ABCB1

   

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 61

TABLE 9. Long-acting injectable antipsychotic medications: pharmacological characteristics (continued)

Trade name Second-generation antipsychotics (continued)

Time to peak plasma level

Time to steady state

Elimination half-life

Commentsa

Risperidone

Risperdal Consta

29–31 days

2 months

3–6 days; increased in renal or hepatic disease

For renal/hepatic impairment: initiate with oral dosing (0.5 mg twice a day for 1 week, then 1 mg twice a day or 2 mg daily for
1 week); if tolerated, begin 25 mg IM every 2 weeks and continue oral dosing for

Risperidone

Perseris

Two peaks:
4–6 hours and 10–14 days

2 months

9–11 days

For renal/hepatic impairment: use with cau- tion with renal impairment; has not been studied. If oral risperidone is tolerated and effective at doses up to 3 mg/day,

substrate; weak CYP2D6 inhibitor aIf a dose of a long-acting injectable antipsychotic medication is missed, refer to product labeling for information on adjustments to medication dose or administration frequency.

Abbreviations. CrCl=creatinine clearance; CYP=cytochrome P450.

Source. Abilify Maintena 2018; Aristada 2019; Aristada Initio 2019; Invega Sustenna 2018a, 2018b; Invega Trinza 2018a, 2018b; Jann et al. 1985; Lexicomp 2019; Lindenmayer 2010; Micromedex 2019; Perseris 2018; Procyshyn et al. 2019; Risperdal Consta 2019; Saklad 2018; Zyprexa Relprevv 2018.

21 days. An initial IM dose of 12.5 mg may

also be considered.
Major substrate of CYP2D6 and minor

substrate of CYP3A4 (minor) substrate; weak CYP2D6 inhibitor

90 mg/month can be considered.
Major CYP2D6 substrate and minor CYP3A4

62

APA Practice Guidelines

Factors Influencing Choice of an Antipsychotic Medication

Available Drug Formulations

Medication choice may be influenced by available formulations of specific medications, such as oral concentrates or rapidly dissolving tablets for patients who have difficulty swallowing pills or who are ambivalent about medications and inconsistent in swallowing them. Use of ingestible sen- sors with associated monitoring technology may assist in evaluating ingestion, although the FDA notes that improvements in adherence have not yet been shown (U.S. Food and Drug Administra- tion 2017). LAI formulations may be preferred by some patients (Heres et al. 2007; Patel et al. 2009; Walburn et al. 2001) and may be particularly useful for patients with a history of poor or uncertain adherence (see Statement 10). Short-acting parenteral formulations of antipsychotic agents are available for short-term use in individuals who are unable to take oral medications or for emer- gency administration in acutely agitated patients.

Drug-Drug Interactions and Metabolism

Careful attention must be paid to the potential for interactions of antipsychotic agents with other pre- scribed medications. For example, when multiple medications are prescribed, side effects (e.g., seda- tion, anticholinergic effects) can be additive. In addition, drug interactions can influence the amount of free drug in the blood that is available to act at receptors. Because most antipsychotic medications are highly bound to plasma proteins, the addition of other protein-bound medications will displace drug molecules from proteins, resulting in a greater proportion of unbound drug in the blood. An- other common cause of drug-drug interactions relates to interactions at metabolic enzymes such as cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferases, and flavin-containing monooxy- genases (Ouzzine et al. 2014; Phillips and Shephard 2017; Rowland et al. 2013; Zanger and Schwab 2013). In particular, hepatic metabolism of antipsychotic medications via CYP enzymes has been widely studied (see Lexicomp 2019; Micromedex 2019). Medications may compete with each other for the same CYP enzyme, or they may induce or inhibit the activity of CYP enzymes, altering levels of drugs that are metabolized through that route. For antipsychotic medications that have active metabolites, shifts in CYP enzyme activity can influence the relative amounts of the active metab- olite. Consequently, when a patient is taking multiple medications, it is useful to check for possible drug-drug interactions using electronic drug interaction software (e.g., Web-based software, drug interaction checking embedded in electronic health record software).

In addition to drug-drug interactions, a number of other factors can influence CYP enzymes and thereby affect antipsychotic medication levels in blood. For example, smoking tobacco or marijuana induces CYP1A2, resulting in a corresponding reduction of levels of drugs that are metabolized through that enzyme, including clozapine and olanzapine (Anderson and Chan 2016; Kroon 2007; Scherf-Clavel et al. 2019). Conversely, with cessation of smoking (either intentionally or with ad- mission to a smoke-free facility), there will be corresponding increases in the levels of drugs metab- olized via CYP1A2. These shifts in blood levels can be quite significant and contribute to shifts in medication effectiveness or toxicity. Several of the main phytocannabinoids in marijuana (e.g., Δ9- tetrahydrocannabinol, cannabidiol) are metabolized via CYP3A4, and cannabidiol may also inhibit CYP2C19 (Anderson and Chan 2016).

Furthermore, levels of antipsychotic medications, the relative proportions of active metabolites, and other pharmacokinetic properties such as medication or active metabolite half-life can be influ- enced by genetic differences in metabolic enzyme activity. Polymorphisms of CYP2D6 have been subjected to the most study (Eum et al. 2016; Zhou 2009), show substantial variation in their occur- rence in the population by ethnicity (Bertilsson 2007; Gaedigk et al. 2017), and are likely to have the greatest potential for impact on antipsychotic medication metabolism. Polymorphisms of the ATP- binding cassette subfamily B member 1 (ABCB1) gene, which affects P-glycoprotein membrane trans- port, may influence brain concentrations of drugs, including antipsychotic agents (Moons et al. 2011). Although the applicability of gene polymorphism testing to the clinical choice of an antipsychotic

medication is still being explored (Bousman and Dunlop 2018; Koopmans et al. 2018; Lagishetty et al. 2016), the FDA has incorporated testing for CYP2D6 polymorphisms into its labeling recommen- dations for dosing of pimozide on the basis of the increased risk of electrocardiographic changes in poor metabolizers at doses higher than 4 mg/day (0.05 mg/kg/day in children) (Rogers et al. 2012; U.S. Food and Drug Administration 2011b). In addition, product labeling for a number of other an- tipsychotic medications refers to a need for dose adjustments based on metabolizer status (U.S. Food and Drug Administration 2019). Additional information on the clinical pharmacogenomics of antipsychotic medications is available through the Clinical Pharmacogenetics Implementation Consortium (https://cpicpgx.org; Relling and Klein 2011), the Pharmacogene Variation Consor- tium (www.pharmvar.org; Gaedigk et al. 2018), and the Pharmacogenomics Knowledgebase (www.pharmgkb.org; Whirl-Carrillo et al. 2012).

Pharmacokinetic Properties

The absorption of some antipsychotic medications is affected by the presence of food in the stomach (see Statement 4, Tables 3 and 4). Some individuals may have difficulty in adhering to appropriate meal size or content, which could influence choice of these medications.

The half-life of an antipsychotic medication is another pharmacokinetic property that may be useful to consider in choosing among antipsychotic agents. Antipsychotic agents with a short half- life (see Statement 4, Tables 3 and 4) are more likely to require divided dosing in contrast to anti- psychotic medications with a half-life that is closer to 24 hours. An oral antipsychotic medication with a longer half-life or an LAI may be preferable for patients who are prone to forget doses or who are intermittently nonadherent to treatment. Nevertheless, if an antipsychotic medication (or active metabolite) half-life is significantly longer than 24 hours, it is important to be aware that steady state may not be reached for some time. This can complicate interpreting the patient’s re- sponse to adjustments in doses in terms of therapeutic benefits and side effects. Additional caution may be needed when an antipsychotic medication with a long half-life is chosen for older individ- uals, for an individual who is taking other medications that may affect drug metabolism, or for in- dividuals with renal or hepatic impairment.

Older individuals often exhibit additional physiological changes relative to younger persons, in- cluding a reduced cardiac output (and concomitant reduction in renal and hepatic blood flow), re- duced glomerular filtration rate, possible reduction in hepatic metabolism, and increased fat content. These changes may alter the absorption, distribution, metabolism, and excretion of medi- cations and may also result in prolonged drug effects and greater sensitivity to medications, in terms of both therapeutic response and side effects (Kaiser 2015).

Side-Effect Profile

The side-effect profile of an antipsychotic agent is a significant factor in the choice of a specific med- ication (see Statement 4, Table 6). Often, a patient will express concerns about a particular side effect of medication (e.g., weight gain). A specific side effect (e.g., akathisia, weight gain, sedation, ortho- static hypotension, sexual dysfunction) may also have limited a patient’s treatment adherence or ability to function in the past. If a patient has a concomitant physical condition (e.g., diabetes, car- diac conduction abnormalities, a seizure disorder), choice of medication will need to consider the likelihood of exacerbating an existing health condition. Older individuals may be more sensitive to some medication side effects, such as tardive dyskinesia, orthostatic hypotension, or anticholiner- gic effects of medications. Thus, a medication that has a lower likelihood of these side effects might be preferred. In contrast, there may be circumstances in which a medication side effect may be help- ful. For example, in a patient who is not sleeping well, a more sedating antipsychotic might be cho- sen and administered at bedtime. Regardless of the initial side effect–related considerations in the choice of an antipsychotic medication, it is important to continue to monitor for side effects as treat- ment proceeds and to have additional discussions with the patient about side effects as they relate to treatment preferences.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 63

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APA Practice Guidelines

Initiation of Treatment With an Antipsychotic Medication

The initial goal of acute treatment with an antipsychotic medication is to reduce acute symptoms, with the aim of returning the individual to his or her baseline level of functioning. Later, maintenance treatment will aim to prevent recurrence of symptoms and maximize functioning and quality of life.

The initial dose of medication will depend on such factors as the medication formulation, the characteristics of the patient, and whether a prior trial of antipsychotic medication has occurred. With the exception of clozapine, the dose of most antipsychotic medications can be increased rela- tively quickly to a typical therapeutic dose once an initial dose has been tolerated. For patients who have previously been treated with an oral or LAI antipsychotic medication, more rapid resumption of an effective medication dose is often appropriate. Although as-needed or emergency administra- tion of antipsychotic medication may, at times, be useful in individuals with acute agitation, it can also reduce tolerability and contribute to a perception that premature dose increases are needed.

Younger individuals who are experiencing a first episode of psychosis may be more likely to gain weight or develop adverse metabolic effects of antipsychotic medications (Correll et al. 2014; Jensen et al. 2019). This can influence selection of an initial medication. In such individuals, a lower initial medication dose may help in minimizing acute side effects of antipsychotic medication and may improve a patient’s willingness to continue with treatment (Czobor et al. 2015; Gaebel et al. 2010). Because a first episode of psychosis may respond more rapidly and may require a lower medication dose than later episodes do, use of a lower initial medication dose is also reasonable (Takeuchi et al. 2019). In older individuals, particularly those with concomitant physical health issues who are receiv- ing multiple medications, recommended starting doses of medication are one-quarter to one-half of the usual adult starting dose on the basis of pharmacokinetic considerations (Howard et al. 2000).

Determining the optimal dose of antipsychotic medication during acute treatment is compli- cated by the fact that there is usually a delay between initiation of treatment and full therapeutic response. Patients may take between 2 and 4 weeks to show an initial response and longer periods of time to show full or optimal response. Once a therapeutic dose of the antipsychotic medication is reached, overly rapid or premature escalation of medication doses can affect tolerability. Prema- ture dose increases can also create the false impression of enhanced efficacy due to a higher dose when the observed response is actually related to elapsed time at a steady state level of medication. Available evidence suggests that patients who have not exhibited at least a 20% reduction in symp- toms (or minimal improvement) by about 2 weeks on a therapeutic dose are unlikely to be much improved at 4–6 weeks as reflected by at least a 50% reduction in symptoms (Samara et al. 2015). Consequently, monitoring of the patient’s clinical status for 2–4 weeks is warranted on a therapeu- tic dose unless the patient is having uncomfortable side effects.

Initiation of treatment with clozapine is a notable exception to this general approach because it re- quires a slow dose titration to minimize the risks of seizure, orthostatic hypotension, and excessive sedation (Clozaril 2019). Large, rapid increases in clozapine dosage have led to cardiovascular col- lapse and death, particularly in patients taking respiratory depressant medications such as benzodi- azepines. From a starting dose of 12.5 mg once or twice daily, the daily clozapine dosage can be in- creased by, at most, 25–50 mg/day to a target dose of 300–450 mg/day (Clozaril 2019). Subsequent dose increases, if needed, should be of 100 mg or less, once or twice weekly. A slower rate of titration may be needed for patients with an initial episode of schizophrenia and in those who are older, se- verely debilitated, or sensitive to side effects. Those with a preexisting central nervous system condi- tion, including individuals with 22q11.2 deletion syndrome, also warrant a slower rate of titration and may have an increased risk of seizures at usual doses. Use of divided doses can be helpful in reducing side effects during initial dose titration, although many patients are ultimately treated with a single dose at bedtime to minimize daytime sedation and facilitate adherence (Takeuchi et al. 2016). Al- though efficacy is often seen at a dosage of 300–450 mg/day, some individuals may need higher dos- ages of clozapine, to a maximum daily dose of 900 mg, for full response. Blood levels of clozapine can be helpful to obtain if making adjustments to clozapine doses (see Statement 7).

With clozapine, safety monitoring during treatment is important in order to minimize the risk of adverse events. The U.S. Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program (www.clozapinerems.com)1 includes required training that must be completed by prescribers (Clozapine REMS Program 2019a), resource materials (Clozapine REMS Program 2019b), and a shared patient registry for all clozapine manufacturers’ products that permits tracking of absolute neu- trophil counts (ANCs) and documentation of decisions about continued treatment. The Clozapine REMS site provides instructions about threshold values for ANCs in hematologically normal individ- uals and in those with benign ethnic neutropenia, which is most common in individuals of African de- scent and is associated with normal ANCs that are lower than standard reference ranges (Clozapine REMS Program 2014). The site also describes the required frequencies for ANC monitoring, which vary with ANC values. Because the highest risk of severe neutropenia (ANC<500/μL) occurs within the initial 6 months of clozapine treatment (Alvir et al. 1993; Clozapine REMS Program 2019c; Myles et al. 2018), the frequency of ANC monitoring is also reduced with longer treatment duration. In pa- tients who have stopped or interrupted treatment with clozapine for 30 days or more, the initial dose titration for clozapine and the monitoring frequency for treatment initiation should be followed.

With clozapine as well as with other antipsychotic medications, some common early side effects such as sedation, postural hypotension, or nausea may improve or resolve after the first several days or weeks of treatment, and patients can be encouraged to tolerate or temporarily manage these short- term effects. Other side effects, notably parkinsonism and akathisia, are likely to persist with long-term treatment, and additional approaches to management may be needed (see Statements 12 and 13).

If treatment with an LAI antipsychotic medication is planned, a trial of the oral formulation of the same medication is usually given to assure tolerability. The conversion from an oral dose of medication to a corresponding dose of an LAI antipsychotic depends on the specific medication (Meyer 2017), and product labeling for each medication describes approximate conversion ratios and whether a period of concomitant oral and LAI medication is needed.

Strategies to Address Initial Nonresponse or Partial Response to Antipsychotic Treatment

If a patient is showing response within several weeks of treatment initiation, continuing with the same medication and monitoring for continued improvement is appropriate. However, if there is no significant improvement after several weeks of treatment (e.g., <20% improvement in symptoms) or if improvement plateaus before substantial improvement is achieved (e.g., >50% improvement in symptoms, minimal impairment in functioning), it is important to consider whether factors are pres- ent that are influencing treatment response. Such factors may include concomitant substance use, rapid medication metabolism, poor medication absorption, interactions with other medications, and other effects on drug metabolism (e.g., smoking) that could affect blood levels of medication.

Difficulties with adherence are a common contributor to reduced response. (For a detailed dis- cussion of adherence, see Statement 3.) When adherence is poor or uncertain, use of an LAI formu- lation of an antipsychotic may improve adherence as well as response. Determination of the blood concentration of the drug may also be helpful if the patient is being treated with a medication (e.g., clozapine) for which blood level has some correlation with clinical response. For other antipsy- chotic medications, a blood level can help to determine if poor adherence or subtherapeutic levels may be contributing to poor response (Bishara et al. 2013; de Oliveira et al. 1996; Hiemke et al. 2004; Lopez and Kane 2013; McCutcheon et al. 2018; Melkote et al. 2018; Sparshatt et al. 2010; Uchida et al. 2011b; Van Putten et al. 1991). Depending on the patient’s symptoms, the possibility of another concomitant disorder should be considered. For example, in a patient with negative symptoms, an untreated major depressive disorder may also be present.

1For Canadian prescribers, use the appropriate Canadian clozapine registry, not the U.S. Clozapine REMS Program.

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If no factors that would affect treatment response have been identified, raising the dose for a fi- nite period, such as 2–4 weeks, can be tried. Although the incremental efficacy of higher doses has not been established (Samara et al. 2018), some patients may show benefit if they are able to tolerate a higher dose of antipsychotic medication without significant side effects. If dose adjustment does not result in an adequate response, a different antipsychotic medication should be considered. Tables 5 and 6 in Statement 4 can be consulted to identify antipsychotic medications with other receptor binding profiles or different side effects. Because each patient responds differently to antipsychotic medications in terms of therapeutic effects and side effects, adequate trials of multiple antipsy- chotic medications may be needed before antipsychotic treatment is optimized, and it can be help- ful to advise patients of this possibility.

If a patient has had minimal or no response to two trials of antipsychotic medication of 2–4 weeks’ duration at an adequate dose (Howes et al. 2017; Samara et al. 2015), a trial of clozapine is recom- mended (see Statement 7). A trial of clozapine is also recommended for a patient with a persistent risk of suicide that has not responded to other treatments and is suggested for a patient with a per- sistent risk of aggressive behavior that has not responded to other treatments (see Statements 8 and 9). A trial of clozapine may also be appropriate in individuals who show a response to treatment (i.e., have more than a 20% reduction in symptoms) yet still have significant symptoms or impair- ments in functioning (Howes et al. 2017). In fact, clozapine is often underused (Carruthers et al. 2016; Latimer et al. 2013; Olfson et al. 2016; Stroup et al. 2014; Tang et al. 2017), and many patients would benefit from earlier consideration of clozapine initiation.

For individuals with treatment-resistant schizophrenia who are unable to tolerate clozapine or are not interested in pursuing a trial of clozapine, the limited available evidence suggests no benefit from high doses of antipsychotic medication, and treatment-related side effects are likely to be in- creased (Dold et al. 2015). However, a trial of a different antipsychotic medication may be helpful, particularly if there is no response or only a partial response to the most recently used medication.

Augmentation treatment can also be considered, although a trial of clozapine should not be de- layed by multiple attempts at augmentation therapy. Particularly for patients with negative symp- toms or depression, augmentation of antipsychotic therapy with an antidepressant medication may also be helpful (Helfer et al. 2016; Stroup et al. 2019). Use of a benzodiazepine, such as lorazepam, is also suggested in patients who exhibit catatonia (Bush et al. 1996b; Fink 2013; Pelzer et al. 2018; Unal et al. 2017). Other augmentation approaches (e.g., antipsychotics, anticonvulsants, benzodiaze- pines, lithium) have also been studied, although evidence is mixed and primarily from small, short- term open-label studies (Correll et al. 2017b; Galling et al. 2017; Ortiz-Orendain et al. 2017). For com- bination therapy with two antipsychotic medications, data from a large nationwide cohort study suggest that emergency visits and rehospitalization rates may be reduced in individuals receiving polypharmacy as compared with monotherapy (Tiihonen et al. 2019). In addition, there is no evi- dence that combining drugs is any more harmful than using a single medication, beyond the common side effects from each drug. Nevertheless, if multiple drugs are used, monitoring for benefits and side effects is important, and it is preferable to limit changes in dose to one drug at a time. In addition, if a patient experiences an exacerbation of symptoms while on a stable dose of medication, a reconsider- ation of the treatment plan is warranted rather than simply adding medications to the existing regimen.

Monitoring During Treatment With an Antipsychotic Medication

During treatment with an antipsychotic medication, it is important to monitor medication adherence, therapeutic benefits of treatment, and treatment-related side effects. The patient’s clinical status can also be affected by changes in physical health, adjustments to other psychotropic and nonpsycho- tropic medications, and other factors, such as cessation or resumption of smoking.

Adherence to antipsychotic treatment is a common problem that affects treatment outcomes. There are many barriers to treatment adherence as well as facilitators and motivators of adherence, each of which will differ for an individual patient (Hatch et al. 2017; Kane et al. 2013; Pyne et al. 2014). Thus, it is important to take a patient-centered approach in inquiring in a nonjudgmental

way whether the individual has experienced difficulties with taking medication since the last visit. (For a detailed discussion of factors related to adherence, see Statement 3.)

Monitoring of treatment response is also essential for identifying whether there are reductions in the severity of functional impairments or target symptoms, including positive symptoms, nega- tive symptoms, and other symptoms that are a focus of treatment. Use of a quantitative measure (see Statement 2) can assist in determining whether the antipsychotic medication is producing ther- apeutic benefits, including reductions in symptom severity and improvements in functioning. If a lack of response or a partial response is noted, additional assessment will be needed to identify and address possible contributors as described in the subsection “Strategies to Address Initial Nonre- sponse or Partial Response to Antipsychotic Treatment.” If an antipsychotic medication dose is be- ing decreased, monitoring can help detect a return of symptoms prior to a more serious relapse.

Monitoring for the presence of side effects is also important throughout the course of antipsychotic treatment. Some side effects (e.g., sedation, nausea) are prominent with treatment initiation but dissi- pate, at least to some extent, with continued treatment. Other side effects (e.g., hypotension, akathisia) may be present initially and increase in severity with titration of the medication dose. Still other side effects emerge only after longer periods of treatment (e.g., tardive dyskinesia) or become more notice- able to patients as their acute symptoms are better controlled (e.g., sexual dysfunction). Table 2 in Statement 1 gives suggestions for baseline assessments and monitoring frequencies for some side ef- fects, clinical measurements, and laboratory studies. Specific attention may need to be given to clini- cal workflow to assure that indicated monitoring is conducted because rates of follow-up testing and screening for metabolic side effects of treatment appear to be low (Morrato et al. 2009). Patients should also be asked about other common side effects of antipsychotic medications, which may vary with the specific medication that is prescribed (see Statement 4, Table 6).

Use of rating scales can help assure that patients are asked about side effects in a systematic fash- ion. Although the clinician-rated Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale (Lingjaerde et al. 1987) is often used to assess side effects of antipsychotic medications in clinical trials (van Strien et al. 2015), it can be time-consuming to administer. However, a self-rated ver- sion of the UKU Side Effect Rating Scale (LindstrÐm et al. 2001) is also available (http://scnp.org/ fileadmin/SCNP/SCNP/UKU/UKU-Pat-%20English%20.pdf). Another self-rating scale, the Glasgow Antipsychotic Side-effect Scale, has two versions: one for use in patients treated with clozapine (www.sussexpartnership.nhs.uk/sites/default/files/documents/gass_for_clozapine .pdf) (Hynes et al. 2015) and one for patients treated with other antipsychotic medications (www.southernhealth.nhs.uk/_resources/assets/inline/full/0/38222.pdf) (Waddell and Taylor 2008). Other rating scales are aimed at identifying and assessing the severity of a specific type of side effect. For example, the clinician-administered Abnormal Involuntary Movement Scale (AIMS; http://www.aacap.org/App_Themes/AACAP/docs/member_resources/toolbox_for_clinical_practice_ and_outcomes/monitoring/AIMS.pdf) (Guy 1976) or the Dyskinesia Identification System: Condensed User Scale (DISCUS; https://portal.ct.gov/-/media/DDS/Health/hcsma20002b.pdf) (Kalachnik and Sprague 1993) can complement clinical assessment in identifying and monitoring tardive dyskinesia and other abnormal movements. Another example, the self-rated Changes in Sexual Functioning Questionnaire (www.dbsalliance.org/wp-content/uploads/2019/02/Restoring_Intimacy_CSFQ_ Handout.pdf) (Clayton et al. 1997a, 1997b; Depression and Bipolar Support Alliance 2019; Keller et al. 2006), can help to identify sexual side effects of antipsychotic treatment, which is an issue that pa- tients may find difficult to discuss yet can lead them to discontinue treatment.

Treatment-Emergent Side Effects of Antipsychotic Medications

As with most medications, antipsychotic medications have been associated with a number of side effects that can develop as treatment proceeds. Table 6 in Statement 4 shows the relative tendencies for antipsychotic medications to be associated with specific side effects. In addition, each of these side effects is described in further detail below.

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Early in the course of treatment, common side effects include sedation; orthostatic changes in blood pressure; and anticholinergic side effects such as dry mouth, constipation, and difficulty with urination.

Of the side effects related to dopamine D2 receptor antagonist effects of antipsychotics, acute dystonia also appears early in treatment. It is particularly common with high-potency antipsy- chotic medications (e.g., haloperidol, fluphenazine) and can be life-threatening if associated with laryngospasm. Neuroleptic malignant syndrome (NMS) can also be life-threatening because of as- sociated hyperthermia and autonomic instability. It typically occurs within the first month of anti- psychotic treatment, with resumption of treatment, or with an increase in the dose of antipsychotic medication. Akathisia and medication-induced parkinsonism can also occur in the initial weeks of treatment or after increases in medication doses. Hyperprolactinemia, related to D2 receptor antag- onism in the hypothalamic-pituitary axis, can lead to breast enlargement, galactorrhea, sexual dys- function, and, in women, menstrual disturbances. These elevations in prolactin also occur in the initial weeks to months of treatment. On the other hand, tardive syndromes, including tardive dys- kinesia, develop later, often months or even years after treatment initiation.

Side effects related to metabolic syndrome are common. Generally, they are observed in the initial months of treatment, but they can also occur later in treatment. These side effects include weight gain; hyperlipidemia; and glucose dysregulation, including development of diabetes mellitus.

Clozapine treatment is associated with a number of side effects that are less commonly seen with other antipsychotic medications. Severe neutropenia is most often seen early in treatment and is po- tentially life-threatening; however, with current regulatory requirements for monitoring ANC levels during treatment, it is rare. When seizures occur with clozapine, it is typically with very high doses or blood levels of clozapine, rapid increases in clozapine dose, or shifts in medication levels (related to drug-drug interactions or effects of smoking on drug metabolism). Myocarditis is infrequent and generally occurs early in treatment. Cardiomyopathy is rare and generally occurs later in the treat- ment course. Gastrointestinal effects of clozapine can also be significant, and in some patients it is as- sociated with fecal impaction or paralytic ileus. Sialorrhea and tachycardia are each commonly observed during treatment with clozapine but can generally be managed conservatively.

Allergic and Dermatological Side Effects

Cutaneous allergic reactions occur infrequently with antipsychotic medications, but hypersensitiv- ity can manifest as maculopapular erythematous rashes, typically of the trunk, face, neck, and ex- tremities. Medication discontinuation or administration of an antihistamine is usually effective in reversing these symptoms.

In terms of other dermatological side effects, on rare occasions, thioridazine treatment is noted to be associated with hyperpigmentation of the skin. Dermatological reactions, including hyperpigmen- tation and cutaneous reactions, have also been reported with risperidone, clozapine, olanzapine, que- tiapine, and haloperidol (Bliss and Warnock 2013). Photosensitivity reactions, resulting in severe sunburn, are also most commonly observed with low-potency phenothiazine medications. A blue- gray discoloration of the skin in body areas exposed to sunlight has been reported in patients receiv- ing long-term chlorpromazine treatment. Consequently, patients who are taking these medications should be instructed to avoid excessive sunlight and use sunscreen.

Cardiovascular Effects

Hyperlipidemia

There is some evidence that certain antipsychotic medications, particularly clozapine and olanzapine, may increase the risk for hyperlipidemias (Buhagiar and Jabbar 2019; Bushe and Paton 2005; Meyer and Koro 2004; Mitchell et al. 2013a). However, there is also a suggestion that some patients may have a dyslipidemia prior to starting on antipsychotic treatment (Misiak et al. 2017; Pillinger et al. 2017b; Yan et al. 2013). Some patients develop an elevation of triglyceride levels in association with

antipsychotic treatment that rarely is sufficiently high as to be associated with development of pan- creatitis (Alastal et al. 2016). It is unclear whether triglyceridemia with antipsychotic treatment is a direct result of the medication or an indirect result of increased triglycerides in the blood with con- comitant diabetes (Yan et al. 2013). In any patient with hyperlipidemia, it is also important to assess for other contributors to metabolic syndrome (Mitchell et al. 2012, 2013b) and ensure that the pa- tient is receiving treatment with a lipid-lowering agent, as clinically indicated.

Myocarditis and Cardiomyopathy

Myocarditis and cardiomyopathy have been reported in some patients treated with clozapine and have resulted in death in some individuals. The etiology of these cardiac effects is unclear, although an immune-mediated mechanism has been suggested (R ge et al. 2012). For myocarditis, the re- ported incidence has varied from 0.015% to 8.5% (Bellissima et al. 2018). For reasons that are un- clear, the highest rates have been reported in Australia (Ronaldson et al. 2015); rates elsewhere appear to be much lower. For example, an early study using the U.S. Clozaril National Registry found 17 confirmed cases of myocarditis in a total of 189,405 individuals who had received clozap- ine (La Grenade et al. 2001). A recent national registry study of outpatients in Denmark found 1 of 3,262 (0.03%) clozapine-treated patients developed myocarditis in the initial 2 months of treatment (Rohde et al. 2018). These authors estimated that a maximum of 0.28% of patients treated with clozapine would experience fatality due to clozapine-associated myocarditis, which is comparable to rates of cardiac adverse effects with other antipsychotic medications. For cardiomyopathy, the reported incidence is even less clear but appears to be considerably lower than rates of clozapine- associated myocarditis (Higgins et al. 2019; Khan et al. 2017; Rohde et al. 2018; Ronaldson et al. 2015).

Although cardiomyopathy has been reported throughout the course of clozapine treatment, the onset of myocarditis typically occurs during the first month of treatment and is heralded by short- ness of breath, tachycardia, and fever (Bellissima et al. 2018; Ronaldson et al. 2015). Other features can include fatigue, chest pain, palpitations, and peripheral edema. Diagnosis can be challenging because of the nonspecific nature of these symptoms. For example, primary tachycardia is common with clozapine treatment without signifying underlying cardiac disease. Fever can also occur with clozapine initiation yet often resolves quickly and without evidence of myocarditis (Bruno et al. 2015; Lowe et al. 2007; Pui-yin Chung et al. 2008).

Recommendations for monitoring have varied, but there is no evidence or consensus that pre- emptive screening is necessary or helpful. However, if myocarditis or cardiomyopathy is sus- pected, a recent systematic review suggests seeking cardiology consultation as well as monitoring C-reactive protein and troponin (I and T subtypes) and obtaining an electrocardiogram as indicated (Knoph et al. 2018). Cardiac magnetic resonance imaging may also be indicated in some individuals.

In patients who do develop myocarditis or cardiomyopathy in conjunction with clozapine treat- ment, clozapine is typically discontinued. Subsequent decisions about resuming clozapine are in- dividualized and should be based on the benefits and risks of treatment as compared with other therapeutic alternatives.

Orthostatic Hypotension

Orthostatic hypotension, a drop in blood pressure when changing from lying down or sitting to standing, is dose-related and due to the α-receptor-blocking effects of antipsychotic medications. When severe, orthostatic hypotension can cause syncope, dizziness, or falls. Older or severely debil- itated patients, patients in the dose-titration phase of clozapine therapy, and patients with peripheral vascular disease or a compromised cardiovascular status may be at particular risk. Patients who ex- perience orthostatic hypotension must be cautioned to sit on the edge of the bed for a minute before standing up, to move slowly when going from lying down or sitting to standing, and to seek assis- tance when needed. Management strategies for orthostatic hypotension include using supportive measures (e.g., use of support stockings, increased dietary salt and fluid intake); reducing the speed

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of antipsychotic dose titration; decreasing or dividing doses of antipsychotic medication; switching to an antipsychotic medication without antiadrenergic effects; and, as a last resort, administration of the salt/fluid-retaining corticosteroid fludrocortisone to increase intravascular volume (Mar and Raj 2018; Shen et al. 2017). For patients who are receiving concomitant antihypertensive treatment, ad- justments to the dose of these medications may be needed.

QTc Prolongation

The QT interval on the electrocardiogram reflects the length of time required for ventricular repo- larization and varies with heart rate (Funk et al. 2018). Several approaches exist for calculating a QT interval corrected for heart rate (QTc). Although the Bazett formula remains the one most widely used for drug monitoring and research, alternative correction formulas, such as the Fridericia and Framingham formulas, have been shown to most accurately correct for rate and improve prediction of mortality. In order to accurately predict risk, clinicians should be familiar with an alternative cor- rection formula (Aytemir et al. 1999; Rautaharju et al. 2009; Vandenberk et al. 2016). Significant pro- longation of the QTc interval is associated with increased risk for a ventricular tachyarrhythmia, torsades de pointes (TdP), which can lead to life-threatening consequences (e.g., ventricular fibrilla- tion, sudden death). When the QTc interval is prolonged, a decision about the antipsychotic medica- tion choice or changes requires a comprehensive risk-benefit assessment. A QTc interval > 500 msec is sometimes viewed as a threshold for concern; however, “there is no absolute QTc interval at which a psychotropic should not be used” (Funk et al. 2018, p. 2).

Studies that have examined the risks of QTc prolongation with antipsychotic treatment have varied in study quality, sample sizes, and the physical health of study subjects. Sources are available that cat- egorize medications on the basis of their level of risk for QTc prolongation and TdP (Woosley et al. 2009), but the quality of data that informs such categorizations is also variable (Funk et al. 2018). Nevertheless, among the FGAs, chlorpromazine, droperidol, thioridazine, and pimozide appear to be associated with the greatest risk of QTc prolongation. The FDA recommends that thioridazine be used only when patients have not had a clinically acceptable response to other available antipsy- chotics (U.S. National Library of Medicine 2018b). Pimozide labeling also includes specific instruc- tions related to medication dosing and QTc interval prolongation (U.S. National Library of Medicine 2018a). Orally administered haloperidol has been associated with only a mild increase in QTc interval length in healthy individuals; however, the risk of QTc interval prolongation and TdP appears to be greater with intravenous administration in medically ill individuals (Funk et al. 2018). Most SGAs have also been associated with some QTc interval prolongation, with ziprasidone and iloperidone appearing to have the greatest likelihood of QTc prolongation. The FDA has re- quired that a warning about QTc prolongation be included with product labeling for ziprasidone (Geodon 2018), quetiapine (Quetiapine 2011; Seroquel XR 2019), iloperidone (Fanapt 2017), and paliperidone (Invega 2018, 2019; Invega Sustenna 2018a, 2018b; Invega Trinza 2018a, 2018b).

Factors to consider when making a determination about selecting or changing antipsychotic medications include whether the patient is taking other medications that are known to prolong QTc intervals; whether the patient has factors that would influence drug metabolism, leading to higher blood levels of a drug (e.g., poor metabolizer status, pharmacokinetic drug-drug interactions, he- patic or renal disease, drug toxicity); whether the patient is known to have a significant cardiac risk factor (e.g., congenital long QT syndrome, structural or functional cardiac disease, bradycardia, family history of sudden cardiac death); and other factors associated with an increased risk of TdP (e.g., female sex; advanced age; personal history of drug-induced QTc prolongation; severe acute illness; starvation; risk or presence of hypokalemia, hypomagnesemia, or hypocalcemia) (Funk et al. 2018). For individuals with these risk factors, antipsychotic medications with a regulatory warn- ing or those with a known risk of QTc prolongation are not recommended for use if safer medica- tion alternatives are available. Input from cardiology consultants should be considered when significant cardiac disease or other risk factors for QTc prolongation are present, although routine cardiology consultation is not indicated for patients without cardiac risk factors (Funk et al. 2018).

Tachycardia

Tachycardia can be primary (e.g., with clozapine), a reflex response to orthostatic hypotension, or a result of anticholinergic effects. It appears to be particularly common in individuals who are treated with clozapine (Lally et al. 2016a), but it may also be seen in individuals treated with other antipsychotic medications, particularly low-potency phenothiazines. Although healthy patients may be able to tolerate some increase in resting pulse rate, this may not be the case for patients with preexisting heart disease. In patients with significant tachycardia (heart rates above 110–120 bpm), ECG is warranted, as is an assessment for other potential causes of tachycardia (e.g., fever, anemia, smoking, hyperthyroidism, respiratory disease, cardiovascular disorders, caffeine and other stim- ulants, side effects of other medications). Early in treatment with clozapine, the possibility of myo- carditis should be considered. Management strategies for tachycardia with antipsychotic medications include reducing the dose of medication, discontinuing medications with anticholiner- gic or stimulant properties, and using the strategies described above to reduce any contributing or- thostatic hypotension. Case reports have discussed the use of medications such as β-blocking agents for persistent and significant tachycardia with clozapine. Nevertheless, treatment is not indicated unless the patient is symptomatic or the patient’s heart rate is substantially greater than 120 bpm because data from more rigorous studies are not available and these medications can contribute to other side effects, such as orthostatic hypotension (Lally et al. 2016a). If tachycardia is accompanied by pain, shortness of breath, fever, or signs of a myocardial infarction or heart rhythm problem, emergency assessment is essential.

Endocrine Side Effects

Glucose Dysregulation and Diabetes Mellitus

Evidence from meta-analyses of RCTs, population-based studies, and case-control studies suggests that some antipsychotic medications, clozapine and olanzapine in particular, are associated with an increased risk of hyperglycemia and diabetes (Hirsch et al. 2017; Ward and Druss 2015; Whicher et al. 2018; Zhang et al. 2017). Complicating the evaluation of antipsychotic-related risk of diabetes is that some patients with first-episode psychosis seem to have abnormal glucose regulation that pre- cedes antipsychotic treatment (Greenhalgh et al. 2017; Perry et al. 2016; Pillinger et al. 2017a). In ad- dition, obesity and treatment-related weight gain may contribute to diabetes risk. Nevertheless, there are some patients without other known risk factors who develop insulin resistance early in the course of antipsychotic treatment. In some individuals, diabetic ketoacidosis and nonketotic hy- perosmolar coma have been reported in the absence of a known diagnosis of diabetes (Guenette et al. 2013; Kato et al. 2015; Liao and Phan 2014; Polcwiartek et al. 2016; Vuk et al. 2017). Given the rare occurrence of extreme hyperglycemia, ketoacidosis, hyperosmolar coma, or death and the sugges- tion from epidemiological studies of an increased risk of treatment-emergent adverse events with SGAs, the FDA has requested that all manufacturers of SGA medications include a warning in their product labeling regarding hyperglycemia and diabetes mellitus (Rostack 2003). When individuals with schizophrenia do develop diabetes, management principles should follow current guidelines for any patient with diabetes (Holt and Mitchell 2015; Scott et al. 2012). Given the existence of fre- quent health disparities for individuals with serious mental illness (Mangurian et al. 2016; Scott et al. 2012), clinicians can also help in ensuring that patients are obtaining appropriate diabetes care and encourage patients to engage in lifestyle interventions to improve diabetes self-management (Cimo et al. 2012). In any patient with diabetes, it is also important to assess for other contributors to metabolic syndrome (Mitchell et al. 2012, 2013b).

Hyperprolactinemia

Prolactin elevation is frequent in patients treated with antipsychotics (Ajmal et al. 2014; Cookson et al. 2012; Kinon et al. 2003; Lally et al. 2017a; Leucht et al. 2013; Rubio-Abadal et al. 2016), which in- crease prolactin secretion by blocking the inhibitory actions of dopamine on lactotrophic cells in the

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anterior pituitary. Consequently, hyperprolactinemia is observed more frequently with the use of antipsychotics that are more potent at blocking dopamine receptors (Tsuboi et al. 2013).

In both men and women, prolactin-related disruption of the hypothalamic-pituitary-gonadal axis can lead to decreased sexual interest and impaired sexual function (Kirino 2017; Rubio-Abadal et al. 2016). Other effects of hyperprolactinemia may include breast tenderness, breast enlargement, and lactation (Ajmal et al. 2014; Cookson et al. 2012). Because prolactin also regulates gonadal func- tion, hyperprolactinemia can lead to decreased production of gonadal hormones, including estro- gen and testosterone, resulting in disruption or elimination of menstrual cycles in women. In addition, in lactating mothers, suppression of prolactin may be detrimental, and the potential for this effect should be considered.

The long-term clinical consequences of chronic elevation of prolactin are poorly understood. Chronic hypogonadal states may increase the risk of osteopenia/osteoporosis and fractures may be increased in individuals with schizophrenia, but a direct link to antipsychotic-induced hyperpro- lactinemia has not been established (Bolton et al. 2017; Stubbs et al. 2014, 2015; Tseng et al. 2015; Weaver et al. 2019). In addition, some concern has been expressed about potential effects of hyper- prolactinemia on the risk of breast or endometrial cancer; however, the available evidence suggests that such risks, if they exist, are likely to be small (De Hert et al. 2016; Froes Brandao et al. 2016; Klil- Drori et al. 2017; Pottegård et al. 2018; Wang et al. 2002).

If a patient is experiencing clinical symptoms of prolactin elevation, the dose of antipsychotic med- ication may be reduced, or the medication regimen may be switched to an antipsychotic with less ef- fect on prolactin such as one with partial agonist activity at dopamine receptors (Ajmal et al. 2014; Grigg et al. 2017; Yoon et al. 2016). Administration of a dopamine agonist such as bromocriptine may also be considered.

Sexual Function Disturbances

A majority of patients with schizophrenia report some difficulties with sexual function. Although multiple factors are likely to contribute and rates vary widely depending on the study, it is clear that antipsychotic treatment contributes to sexual dysfunction (de Boer et al. 2015; La Torre et al. 2013; Marques et al. 2012; Serretti and Chiesa 2011; van Dijk et al. 2018). Effects of antipsychotic agents on sexual function may be mediated directly via drug actions on adrenergic and serotonergic recep- tors or indirectly through effects on prolactin and gonadal hormones (Kirino 2017; Knegtering et al. 2008; Rubio-Abadal et al. 2016). Loss of libido and anorgasmia can occur in men and in women; erectile dysfunction and ejaculatory disturbances also occur in men (La Torre et al. 2013; Marques et al. 2012; Serretti and Chiesa 2011; van Dijk et al. 2018). Retrograde ejaculation has also been re- ported with specific antipsychotic medications (e.g., thioridazine, risperidone) (Chouinard et al. 1993; de Boer et al. 2015; Kotin et al. 1976). In addition, it is important to note that priapism can also occur in association with antipsychotic treatment, particularly in individuals with other underlying risk factors such as sickle cell disease (Burnett and Bivalacqua 2011; Sood et al. 2008).

Despite the high rates of occurrence of sexual dysfunction with antipsychotic medication, many patients will not spontaneously report such difficulties. Thus, it is important to ask patients specif- ically about these side effects. Structured rating scales also exist to assess sexual side effects during antipsychotic treatment, and these can be used to supplement information obtained via interview (Clayton et al. 1997a, 1997b; de Boer et al. 2014; Depression and Bipolar Support Alliance 2019; Keller et al. 2006). Education about sexual side effects of medication can also be provided to the pa- tient to communicate that these symptoms may occur but can be addressed (de Boer et al. 2015).

When sexual side effects of antipsychotic therapy are of significant concern to the patient, a reduc- tion in medication dose or change in medication may be considered in addition to an assessment of other potential contributing factors (e.g., hyperprolactinemia, other medications, psychological fac- tors) (de Boer et al. 2015; La Torre et al. 2013). Priapism, if it occurs, requires urgent urological con- sultation.

Gastrointestinal Side Effects

The most common gastrointestinal side effects of antipsychotic medications are related to anti- cholinergic side effects and include dry mouth and constipation, as noted in the subsection “Treatment-Emergent Side Effects of Antipsychotic Medications.” Patients and families should be educated about monitoring for constipation, and, if present, constipation should be reported promptly to clinicians. With clozapine in particular, gastrointestinal hypomotility can be severe and can result in fecal impaction or paralytic ileus (Every-Palmer and Ellis 2017; Leung et al. 2017; Palmer et al. 2008). Thus, if constipation is severe or does not resolve, the patient should obtain urgent medical care.

To prevent development of constipation in patients at increased risk (e.g., older patients, patients treated with clozapine), it is useful to minimize the doses and number of contributory medications such as other anticholinergic medications and opioids. A stool softener (e.g., docusate [Colace]) can be started. Activity and exercise should be encouraged to stimulate motility.

If constipation does develop, initial treatment can include stool softeners (e.g., docusate [Colace]) or osmotic laxatives (e.g., lactulose [Enulose], polyethylene glycol [Miralax], bisacodyl [Dulcolax]). Second-line treatments include stimulant laxatives (e.g., senna [Senokot], senna tea, cascara, sodium picosulfate). If constipation persists, an enema (e.g., Fleet) should be considered. A combination of treatments may be needed to treat constipation and then to prevent its recurrence.

Hepatic effects have also been reported with antipsychotic medications, including elevation of liver enzyme levels and cholestatic jaundice (U.S. Department of Health and Human Services and U.S. National Library of Medicine 2017b). Cholestatic jaundice is rare and has been reported primar- ily with chlorpromazine (U.S. Department of Health and Human Services and U.S. National Library of Medicine 2017a). It usually occurs within the first month after the initiation of treatment and gen- erally requires discontinuation of treatment. However, given the relative infrequency of antipsy- chotic-induced jaundice, other etiologies for jaundice should be evaluated before the cause is judged to be antipsychotic medication.

Hematological Effects

Hematological effects are of greatest concern with clozapine; however, they have also been reported with other antipsychotic agents and may include inhibition of leukopoiesis, purpura, hemolytic anemia, and pancytopenia (Balon and Berchou 1986; Myles et al. 2019; Pisciotta 1969). For example, with chlorpromazine, transient benign leukopenia (white blood cell count <3,500/mm3) is com- mon, and severe neutropenia has been reported in 0.08% of patients, typically within the first few months of treatment (Pisciotta 1969).

There is no clear etiology of severe neutropenia or agranulocytosis with antipsychotic medica- tions. With clozapine, a complex polygenic trait appears likely, perhaps involving the human leu- kocyte antigen locus or a group of hepatic transporter genes (de With et al. 2017; Legge et al. 2017). Initial estimates suggested that severe neutropenia would develop in 1%–2% of patients treated with clozapine, with fatal agranulocytosis in approximately 15% of those individuals (Alvir et al. 1993; Honigfeld et al. 1998). However, data from the initial 5 years of monitoring through clozapine registries showed a rate of severe neutropenia of 0.38%, with death occurring in only 3.1% of those cases (Honigfeld et al. 1998). A recent meta-analysis suggested an incidence of severe neutropenia in 0.9% of clozapine-treated patients, with a case fatality rate for individuals with severe neutrope- nia of 2.1% (Myles et al. 2018). For clozapine-treated patients as a group, the incidence of death due to severe neutropenia was 0.013% (Myles et al. 2018), suggesting that clozapine is quite safe with appropriate monitoring. Nevertheless, patients who are receiving clozapine should be advised to report any sign of infection (e.g., sore throat, fever, weakness, lethargy) immediately so that a deci- sion can be made about obtaining additional evaluation.

If severe neutropenia does develop, it is usually reversible if clozapine is discontinued immedi- ately and secondary complications (e.g., sepsis) are given intensive treatment. Granulocyte colony–

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stimulating factor has been used to accelerate granulopoietic function and shorten recovery time (Lally et al. 2017c; Myles et al. 2017).

Although there have been reports of successful resumption of clozapine after severe neutropenia, the risk of recurrence remains high (Lally et al. 2017b; Manu et al. 2018). For patients with a good clinical response to clozapine after multiple unsuccessful trials of other antipsychotic medications, the benefits and risks of rechallenge require thorough consideration and discussion with the patient and in- volved family members. Under such circumstances, case reports have suggested using granulocyte col- ony–stimulating factor to reduce the risk of recurrence, although evidence is limited (Lally et al. 2017b).

Neurological Side Effects

Acute Dystonia

Medication-induced acute dystonia is defined in DSM-5 as

[a]bnormal and prolonged contraction of the muscles of the eyes (oculogyric crisis), head, neck (torticol- lis or retrocollis), limbs, or trunk developing within a few days of starting or raising the dosage of a medication (such as a neuroleptic) or after reducing the dosage of a medication used to treat extrapyra- midal symptoms. (American Psychiatric Association 2013a, p. 711)

A dystonic spasm of the axial muscles along the spinal cord can result in opisthotonos, in which the head, neck, and spinal column are hyperextended in an arched position. Rarely, acute dystonia can also present as life-threatening laryngospasm, which results in an inability to breathe (Ganesh et al. 2015; Koek and Pi 1989). Acute dystonia is sudden in onset and painful and can cause patients great distress. Because of the dramatic appearance of acute dystonia, health professionals who are unfa- miliar with the condition may incorrectly attribute these reactions to catatonic signs or unusual be- havior on the part of patients, and oculogyric crises can sometimes be misinterpreted as indicative of seizure activity.

In individuals treated with FGAs, it is estimated that up to 10% of patients may experience an acute dystonic episode, and with SGAs, rates of acute dystonia may be less than 2% (Martino et al. 2018; Miller et al. 2008; Satterthwaite et al. 2008). Additional factors that increase the risk of acute dystonia with antipsychotic medication include young age, male sex, ethnicity, recent cocaine use, high medication dose, and intramuscular route of medication administration (Gray and Pi 1998; Spina et al. 1993; van Harten et al. 1999). For further discussion of acute dystonia, including its treat- ment, see Statement 11.

Akathisia

Medication-induced acute akathisia is defined in DSM-5 as

[s]ubjective complaints of restlessness, often accompanied by observed excessive movements (e.g., fid- gety movements of the legs, rocking from foot to foot, pacing, inability to sit or stand still), developing within a few weeks of starting or raising the dosage of a medication (such as a neuroleptic) or after re- ducing the dosage of a medication used to treat extrapyramidal symptoms. (American Psychiatric As- sociation 2013a, p. 711)

Akathisia is sometimes difficult to distinguish from psychomotor agitation associated with psycho- sis, leading to a cycle of increasing doses of antipsychotic medication that lead to further increases in akathisia. Even in mild forms in which the patient is able to control most movements, akathisia is often extremely distressing to patients and is a frequent cause of nonadherence with antipsy- chotic treatment. If allowed to persist, akathisia can contribute to feelings of dysphoria and, in some instances, suicidal behaviors. The reported rates of akathisia vary from 10%–15% to as many as one- third of patients treated with antipsychotic medication, even when SGAs are used (Juncal-Ruiz et al. 2017; Martino et al. 2018; Mentzel et al. 2017; Miller et al. 2008). For further discussion of akathi- sia, including its treatment, see Statement 13.

Parkinsonism

Medication-induced parkinsonism, which is termed neuroleptic-induced parkinsonism and other medication-induced parkinsonism in DSM-5, is defined as

[p]arkinsonian tremor, muscular rigidity, akinesia (i.e., loss of movement or difficulty initiating move- ment), or bradykinesia (i.e., slowing movement) developing within a few weeks of starting or raising the dosage of a medication (e.g., a neuroleptic) or after reducing the dosage of a medication used to treat extrapyramidal symptoms. (American Psychiatric Association 2013a, p. 709)

These symptoms of medication-induced parkinsonism are dose-dependent and generally resolve with discontinuation of antipsychotic medication. It is important to appreciate that medication- induced parkinsonism can affect emotional and cognitive function, at times in the absence of de- tectable motor symptoms. As a result, it can be difficult to distinguish the negative symptoms of schizophrenia or concomitant depression from medication-induced parkinsonism. In addition, emotional and cognitive features of medication-induced parkinsonism can be subjectively un- pleasant and can contribute to poor medication adherence (Acosta et al. 2012; Ascher-Svanum et al. 2006). For further discussion of medication-induced parkinsonism, including its treatment, see Statement 12.

Neuroleptic Malignant Syndrome

NMS is characterized by a classic triad of rigidity, hyperthermia (>100.4°F/38.0°C on at least two occasions, measured orally), and sympathetic nervous system lability, including hypertension and tachycardia, in the context of exposure to a dopamine antagonist (or withdrawal of a dopamine ag- onist), typically within 72 hours of symptom development (American Psychiatric Association 2013a; Gurrera et al. 2011, 2017). In addition, NMS is associated with an elevated level of serum cre- atine kinase (typically, at least four times the upper limit of normal), tachypnea, change in mental status (e.g., delirium, stupor), and lack of another identified etiology for the symptoms. Notably, however, the onset and clinical features of NMS can vary and may make recognition more difficult. If misdiagnosed and mistreated, NMS can be fatal (Berman 2011; Rosebush and Stewart 1989; Strawn et al. 2007).

Other diagnostic considerations in patients presenting with possible NMS include malignant catatonia, malignant hyperthermia (in association with anesthetic administration), heat stroke (for which patients treated with antipsychotics have a heightened susceptibility), serotonin syndrome (in patients also taking serotonergic drugs such as selective serotonin reuptake inhibitors), benign elevations in the level of serum creatine kinase, fever in association with clozapine treatment, alco- hol or sedative withdrawal, anticholinergic syndrome, hyperthermia associated with use of stimu- lants and hallucinogens, central nervous system infections, limbic encephalitis, and inflammatory or autoimmune conditions (American Psychiatric Association 2013a; Berman 2011; Rosebush and Stewart 1989; Strawn et al. 2007).

NMS has been reported with almost all medications that block dopamine receptors, but a greater risk of occurrence appears to be associated with high-potency FGAs (Schneider et al. 2018; StÐbner et al. 2004). Risk also may be increased by use of short-acting intramuscular formulations of anti- psychotic medications, use of higher total drug dosages, or rapid increases in the dosage of the an- tipsychotic medication (Keck et al. 1989; Sachdev et al. 1997; Viejo et al. 2003). Additional risk factors for NMS include acute agitation, dehydration, exhaustion, iron deficiency, physical illness, preexisting neurological disability, and a prior episode of NMS (American Psychiatric Association 2013a; Keck et al. 1989; Sachdev et al. 1997; Strawn et al. 2007).

Because NMS is rare, with an estimated incidence of 0.01%–0.02% among individuals treated with antipsychotics (Schneider et al. 2018; StÐbner et al. 2004), most evidence regarding NMS treatment comes from single case reports or case series. Antipsychotic medications should always be discontin- ued, and supportive treatment to maintain hydration and to treat the fever and cardiovascular, renal,

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or other symptoms should be provided (American Psychiatric Association 2013a; Berman 2011; Strawn et al. 2007). NMS is usually self-limited, with resolution within a week of medication discon- tinuation in the majority of patients; however, prolonged symptoms of NMS do occur and may be as- sociated with use of LAI antipsychotic medications (Caroff and Mann 1988; Caroff et al. 2000).

In addition to antipsychotic discontinuation and supportive care, a number of approaches have been used to treat NMS, although evidence is limited to case reports and case series (Pileggi and Cook 2016; Strawn et al. 2007). Benzodiazepines, such as lorazepam, have been used because of their benefits in treating catatonia and the parallels between malignant catatonia and NMS. As a postsynaptic D2 receptor agonist, bromocriptine has been used to counteract the dopamine antag- onist effects of the antipsychotic medication. Dantrolene, a direct-acting skeletal muscle relaxant, has also been used, particularly in severe cases of NMS, because of its benefits in treating malignant hyperthermia. When NMS has not responded to these interventions or when catatonic symptoms persist after the resolution of NMS, case reports suggest that ECT can be beneficial (Caroff et al. 2000; Pileggi and Cook 2016; Strawn et al. 2007; Wittenauer Welsh et al. 2016). Assistance with emergency management of NMS is recommended and can be obtained through NMSContact (www.mhaus.org/nmsis/nmscontact).

Once NMS has resolved, caution is needed when resuming an antipsychotic medication because re- currence has been reported (Rosebush and Stewart 1989; Strawn et al. 2007; Susman and Addonizio 1988). Generally, when treatment is resumed, doses are increased gradually, and a medication other than the precipitating agent is used, typically one with a lower potency at blocking dopamine D2 receptors.

Seizures

Among the antipsychotic medications, clozapine is associated with the greatest likelihood of a sei- zure, and patients with a history of an idiopathic or medication-induced seizure may have a higher risk (Alldredge 1999; Devinsky and Pacia 1994; Wong and Delva 2007). Although generalized tonic- clonic seizures are most frequent, other types of seizures may occur. Seizures may also be preceded by myoclonus or drop attacks.

The seizure risk with clozapine is increased by rapid increases in dose as well as at high blood levels or doses of the drug. The overall seizure rate is 2.8%; with low-dose treatment (<300 mg/day) the risk is 1%, with medium doses (300–599 mg/day) the risk is 2.7%, and with high doses (>599 mg/day) the risk is 4.4% (Devinsky et al. 1991). Therefore, a slow initial titration of clozapine dose is essential, and patients should be cautioned not to drive or engage in other potentially hazardous activities while clozapine is being titrated. In individuals at high risk of seizure, prophylactic treatment with an anticonvulsant medication can be considered. FGAs can also lower the seizure threshold in a dose-related manner and result in the development of generalized tonic-clonic seizures (Alldredge 1999). Nevertheless, at usual dose ranges, seizure rates are below 1% for all FGAs.

In patients who do experience a seizure while taking clozapine or another antipsychotic medication, neurological consultation will be important for delineating the risks of a further seizure, determining whether anticonvulsant therapy (e.g., valproate) is indicated, and collaborating with the clinician in de- termining whether changes to the patient’s antipsychotic regimen are indicated (Alldredge 1999; Wong and Delva 2007).

Tardive Syndromes, Including Tardive Dyskinesia

Tardive syndromes are persistent abnormal involuntary movement disorders caused by sustained ex- posure to antipsychotic medication, the most common of which are tardive dyskinesia, tardive dys- tonia, and tardive akathisia (Frei et al. 2018). They begin later in treatment than acute dystonia, akathisia, or medication-induced parkinsonism, and they persist and may even increase, despite re- duction in dose or discontinuation of the antipsychotic medication. Typically, tardive dyskinesia pres- ents as “[i]nvoluntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphrag-

matic, or trunk muscles)” (American Psychiatric Association 2013a, p. 712), whereas tardive dysto- nia and tardive akathisia resemble their acute counterparts in phenomenology.

Tardive dyskinesia has been reported after exposure to any of the available antipsychotic medi- cations (Carbon et al. 2017, 2018). It occurs at a rate of approximately 4%–8% per year in adult pa- tients treated with FGAs (Carbon et al. 2018; Woods et al. 2010), a risk that appears to be at least three times that observed with SGAs (Carbon et al. 2018; O’Brien 2016; Woods et al. 2010). Various factors are associated with greater vulnerability to tardive dyskinesia, including age greater than 55 years; female sex; white or African race/ethnicity; presence of a mood disorder, intellectual dis- ability, or central nervous system injury; and past or current akathisia, clinically significant parkin- sonism, or acute dystonic reactions (Patterson-Lomba et al. 2019; Solmi et al. 2018a).

Although the majority of patients who develop tardive dyskinesia have mild symptoms, a small proportion will develop symptoms of moderate or severe degree. Tardive dyskinesia can have sig- nificant effects on quality of life and can be associated with social withdrawal (McEvoy et al. 2019). Although the impact appears to be influenced by the severity of tardive dyskinesia, individuals with mild symptoms can also experience negative effects on quality of life.

Evaluation of the risk of tardive dyskinesia is complicated by the fact that dyskinetic movements may be observed with a reduction in antipsychotic medication dose, which is termed a withdrawal-emergent dyskinesia (American Psychiatric Association 2013a). Fluctuations in symptoms are also common and may be influenced by such factors as psychosocial stressors. Furthermore, spontaneous dyskinesias, which are clinically indistinguishable from tardive dyskinesia, have been described in elderly patients before the advent of antipsychotic medications and in up to 20% of never-medicated patients with chronic schizophrenia (Blanchet et al. 2004; Crow et al. 1982; Fenton et al. 1997; Saltz et al. 1991). In longer-term studies, findings are often confounded by the sequential or concomitant use of more than one antipsychotic medication and the lack of systematic prospective assessments for the presence of a movement disorder (Tarsy and Baldessarini 2006). Nevertheless, evaluation for the presence of tardive syndromes is important in order to identify them, minimize worsening, and institute clinically indicated treatment. For further discussion of tardive syndromes, including their treatment, see Statement 14.

Ophthalmological Effects

The most common ophthalmological effects of antipsychotic medications are related to the anticholin- ergic effects of these agents and include blurred vision and exacerbation of open-angle glaucoma. Pig- mentary retinopathies and corneal opacities can occur with chronic administration of the low-potency medications thioridazine and chlorpromazine, particularly at high doses (e.g., more than 800 mg/day of thioridazine) (Matsuo et al. 2016). With SGAs, including quetiapine, evidence does not suggest any increase in the likelihood of cataract development (Laties et al. 2015; Pakzad-Vaezi et al. 2013). If pa- tients do undergo cataract surgery, however, there have been case reports of intraoperative floppy-iris syndrome in individuals treated with antipsychotic medications, a complication that has been asso- ciated with use of medications that block α1-adrenergic receptors (Chatziralli and Sergentanis 2011). Although adverse ophthalmological effects of antipsychotic medications are infrequent, encouraging regular eye care is important to maintaining good vision for individuals with schizophrenia (ViertiÐ et al. 2007), particularly because of high rates of diabetes and other health conditions that can affect sight.

Other Side Effects

Anticholinergic Effects

The anticholinergic effects of some antipsychotic medications (along with the anticholinergic effects of antiparkinsonian medications, if concurrently administered) can produce a variety of peripheral side effects, including dry mouth, blurred vision, constipation, tachycardia, urinary retention, and ef- fects on thermoregulation (e.g., hyperthermia in hot weather) (Nasrallah and Tandon 2017; Ozbilen and Adams 2009). Central anticholinergic effects can include impaired learning and memory and slowed cognition (Ang et al. 2017; Vinogradov et al. 2009).

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Because most anticholinergic side effects are mild and tolerable, they are often overlooked. Never- theless, they can have multiple implications for patients, including impaired quality of life and signif- icant health complications (Salahudeen et al. 2015). For example, dry mouth is associated with an in- creased risk for multiple dental complications (Singh and Papas 2014), and drinking high-calorie fluids in response to dry mouth can contribute to weight gain. The muscarinic receptor antagonist properties of antipsychotic drugs can be particularly problematic in older individuals and can con- tribute to problems such as urinary retention, confusion, fecal impaction, and anticholinergic toxicity (with delirium, somnolence, and hallucinations) (Nasrallah and Tandon 2017). Anticholinergic properties of antipsychotic or antiparkinsonian medications can also precipitate acute angle-closure glaucoma (Lachkar and Bouassida 2007), although patients with treated glaucoma seem to be able to tolerate these medications with careful monitoring (Bower et al. 2018).

The propensity of an antipsychotic medication to cause anticholinergic effects should be consid- ered when choosing an antipsychotic agent initially, particularly in older individuals or those with physical conditions that may confer a greater risk of anticholinergic complications. In selecting a medication, it is also important to keep in mind the total anticholinergic burden from antipsychotic medications, antiparkinsonian medications, urological medications (e.g., oxybutynin), nonselec- tive antihistamines (e.g., hydroxyzine, diphenhydramine), and other medications with anticholin- ergic side effects. For this reason, antiparkinsonian medications with anticholinergic properties are not typically administered on a prophylactic basis. When anticholinergic side effects do occur, they are often dose-related and thus may improve with lowering of the dose or administering the med- ications that have anticholinergic properties in divided doses. For additional discussion of anticho- linergic properties of antiparkisonian medications, see Statement 12.

Fever

Fever (>38°C) should prompt assessment for possible etiologies, including NMS or infection. In hot weather, the possibility of heat stroke should be considered in patients who do not have access to air-conditioned environments due to the increased risk of heat-related events in individuals with psychiatric illness (Bouchama et al. 2007) and the effects of some antipsychotics and anticholinergic agents on thermoregulation (Martin-Latry et al. 2007). In patients who are treated with clozapine, a brief self-limiting fever may occur during the first few weeks of treatment and responds to sup- portive measures (Bruno et al. 2015; Lowe et al. 2007; Pui-yin Chung et al. 2008). However, it is also essential to assess for the presence of potentially life-threatening complications, including NMS, se- vere neutropenia, and myocarditis.

Sedation

Sedation is a very common side effect of antipsychotic medications (Citrome 2017a; Leucht et al. 2013). This effect may be related to antagonist effects of those drugs on histamine, adrenergic, and dopamine receptors (Michl et al. 2014). Sedation is most pronounced in the initial phases of treat- ment, and many patients develop some tolerance to the sedating effects with continued administra- tion. For agitated patients, the sedating effects of these medications in the initial phase of treatment can have therapeutic benefits. Bedtime sedation can also be desirable for patients who are having dif- ficulty sleeping. However, persistent sedation, including daytime drowsiness, increased sleep time, and reduced cognitive acuity, can interfere with social, recreational, and vocational function.

Lowering of the daily dose, consolidation of divided doses into one evening dose, or changing to a less sedating antipsychotic medication may be effective in reducing the severity of sedation. Coffee or other caffeine can be helpful in the morning but can also interact with medications (e.g., contribute to tachycardia; raise blood levels of medications, including clozapine). Adding a stimu- lant medication is not typically helpful and can lead to additional side effects. If sedation or the risk of sedation is significant (e.g., during initial clozapine titration), patients should be cautioned not to drive or engage in potentially hazardous activities.

Sialorrhea

Sialorrhea (or hypersalivation) is a frequent side effect of clozapine (Maher et al. 2016) but can also be observed with other antipsychotic medications (Essali et al. 2013). The etiology of sialorrhea is un- clear but may relate to decreased saliva clearance, although actions on muscarinic or α-adrenergic receptors have also been postulated (EkstrÐm et al. 2010). Sialorrhea can contribute to reductions in quality of life and can also be associated with complications such as aspiration pneumonia (Dzahini et al. 2018; Kaplan et al. 2018; Stoecker et al. 2017).

During the day, patients can be encouraged to chew sugarless gum, which stimulates the swal- lowing reflex. Because sialorrhea may be more bothersome at night, patients may be advised to place a towel on their pillow and change to a clean towel in the middle of the night to minimize discomfort. Pharmacological approaches to address sialorrhea come from small studies and case re- ports and include use of low-dose or topical anticholinergic medications, such as glycopyrrolate or sublingual ophthalmic atropine 1% drops (Bird et al. 2011; Liang et al. 2010; Man et al. 2017). Di- phenhydramine has also been studied (Chen et al. 2019); however, because clozapine and other an- tipsychotics can have significant anticholinergic properties themselves and anticholinergics have small effects on sialorrhea, the use of agents with added anticholinergic effects should be ap- proached cautiously. Terazosin and, in severe refractory cases, botulinum toxin have also been used (Bird et al. 2011; Liang et al. 2010; Man et al. 2017).

Weight Gain

Weight gain occurs with most antipsychotic agents and appears to relate to actions of these medi- cations as histamine H1 receptor antagonists, although actions on serotonin and muscarinic recep- tors may also play a role (He et al. 2013; Kroeze et al. 2003; Michl et al. 2014; Olten and Bloch 2018). Reviews and meta-analyses have compared average weight gains with antipsychotic treatment and the proportion of patients who gain 7% or more of body weight (Bak et al. 2014; Leucht et al. 2013; Zhang et al. 2013). Nevertheless, there is substantial variability in the amount of weight gain that will occur in an individual patient who is treated with a specific antipsychotic medication. Typi- cally, weight gain is progressive over the first 6 months of treatment, although some patients con- tinue to gain weight indefinitely (Alvarez-Jimenez et al. 2008). In addition, younger individuals who are experiencing a first episode of psychosis may be more likely than older individuals to gain weight with antipsychotic medication (Correll et al. 2014; Jensen et al. 2019). In identifying individ- uals with schizophrenia who experience weight gain with antipsychotic treatment, self-reported awareness may be less effective than objective measurement (Gao et al. 2016).

Obesity, in general, can contribute to an increase in risk for mortality and morbidity, including increased rates of cardiovascular disease, hypertension, cancers, diabetes, osteoarthritis, and sleep apnea (Aune et al. 2016; Bellou et al. 2018; Jehan et al. 2018; Lauby-Secretan et al. 2016; Stringhini et al. 2017). Consequently, weight gain with antipsychotic medications is also likely to contribute to an increase in physical health conditions and mortality. Prevention of weight gain should, thus, be a high priority because weight loss is difficult for most patients. Efforts should be made to intervene proactively with weight gain of 5–10 pounds because people who are obese rarely lose more than 10% of body weight with weight loss regimens.

A number of studies have evaluated the effectiveness of specific interventions to prevent or treat antipsychotic-induced weight gain (Caemmerer et al. 2012; Das et al. 2012; de Silva et al. 2016; Gierisch et al. 2014; Mahmood et al. 2013; Manu et al. 2015; Mizuno et al. 2014; Mukundan et al. 2010; Vancampfort et al. 2019; Zheng et al. 2015). Nutritional interventions have shown small but consistent benefits (Bonfioli et al. 2012), although patients who are willing to enroll in and are able to adhere to such studies may not be representative. Nevertheless, nutritional approaches may be suggested for their benefits for overall health as well as for weight. Such approaches include specialized behavioral health interventions, in-person community interventions (e.g., Weight Watchers), services that include meal delivery (e.g., Jenny Craig), and Internet-based interventions (e.g., Omada Health). In

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addition, some programs have begun to integrate dietitians into the treatment team, given the nutritional challenges that exist for many individuals with serious mental illness (Teasdale et al. 2017). Other nonpharmacological approaches that have been studied include exercise and cognitive- behavioral therapy approaches (Bonfioli et al. 2012; Caemmerer et al. 2012; Das et al. 2012).

In collaboration with the patient’s primary care clinician, medication strategies for weight loss can be considered. Of the pharmacological treatments that have been assessed, metformin has been studied most often. It has been shown to be safe in individuals without hyperglycemia, shows mod- est benefits on weight (with average weight loss of 3–4 kg), and can reverse metabolic abnormalities in patients with obesity or other metabolic problems (Das et al. 2012; de Silva et al. 2016; McGinty et al. 2016; Mizuno et al. 2014; Siskind et al. 2016a; Vancampfort et al. 2019; Zheng et al. 2015; Zhuo et al. 2018). However, most studies have been small, and follow-up periods have not been longer than 6 months. Modest benefit has also been seen in several studies of glucagon-like peptide-1 re- ceptor agonists (Siskind et al. 2019) and small studies of topiramate (Mahmood et al. 2013; Mizuno et al. 2014; Vancampfort et al. 2019; Zhuo et al. 2018). Other medications have been examined in small trials or case series, with less consistent findings (Mizuno et al. 2014). This limited evidence and the modest benefit of these pharmacological treatments need to be considered in light of po- tential adverse effects.

Another consideration for a patient who has experienced significant weight gain with antipsy- chotic treatment is to change or augment treatment with a medication with lower weight-gain lia- bility (Vancampfort et al. 2019). When possible, other medications that can cause weight gain (e.g., valproate) should be tapered and discontinued. Such decisions need to consider the extent of the patient’s response to the current medication regimen, the risks to the patient if relapse occurs with a medication change, and the likelihood that a medication change will be beneficial in terms of weight loss or other side effects (Manu et al. 2015; Mukundan et al. 2010; Newcomer et al. 2013; Vancampfort et al. 2019). In any patient with weight gain, it is also important to assess for other con- tributors to metabolic syndrome (Mitchell et al. 2012, 2013b).

The benefits of exercise appear to be small in terms of weight loss in individuals with schizophrenia (Firth et al. 2015; Pearsall et al. 2014; Vancampfort et al. 2017, 2019). Nevertheless, many individuals with schizophrenia do not engage in physical activity (Stubbs et al. 2016a; Vancampfort et al. 2016b), and exercise can be suggested for its benefits to overall health, improved cardiorespiratory fitness, and other aspects of functioning (Dauwan et al. 2016; Firth et al. 2015, 2017; Vancampfort et al. 2017, 2019). Health promotion coaching interventions focused on individuals with mental illness, such as the In SHAPE program, can also be pursued and may be associated with weight loss and reduced cardio- vascular risk (Bartels et al. 2015; Naslund et al. 2016; Van Citters et al. 2010; Verhaeghe et al. 2013).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of an antipsychotic medication in the treatment of schizophrenia can improve positive and neg- ative symptoms of psychosis (high strength of research evidence) and can also lead to reductions in depression and improvements in quality of life and functioning (moderate strength of research evidence). A meta-analysis of double-blind, randomized, placebo-controlled trials showed a me- dium effect size for overall efficacy (Leucht et al. 2017), with the greatest effect on positive symp- toms. The rates of achieving any response or a good response were also significantly greater in pa- tients who received an antipsychotic medication. In addition, the proportion of individuals who dropped out of treatment for any reason and for lack of efficacy was significantly less in those who were treated with an antipsychotic medication. Research evidence from head-to-head comparison studies and network meta-analysis (McDonagh et al. 2017) showed no consistent evidence that fa- vored a specific antipsychotic medication, with the possible exception of clozapine.

Harms

The harms of using an antipsychotic medication in the treatment of schizophrenia include sedation, side effects mediated through dopamine receptor blockade (e.g., acute dystonia, akathisia, parkin- sonism, tardive syndromes, NMS, hyperprolactinemia), disturbances in sexual function, anticho- linergic effects, weight gain, glucose abnormalities, hyperlipidemia, orthostatic hypotension, tachycardia, and QTc prolongation. Clozapine has additional harms associated with its use, includ- ing sialorrhea, seizures, neutropenia (which can be severe and life-threatening), myocarditis, and cardiomyopathy. Among the antipsychotic medications, there is variability in the rates at which each of these effects occurs, and no specific medication appears to be devoid of possible side effects.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of antipsychotic medications as part of a treatment plan. A survey of patient preferences reported that patients viewed an ability to think more clearly and an ability to stop hallucinations or paranoia as important efficacy- related reasons to take an antipsychotic medication (Achtyes et al. 2018). However, patients also re- ported concerns about side effects, particularly weight gain, sedation, and restlessness, as reasons that they might not wish to take antipsychotic medications. Some patients might also choose not to take an antipsychotic medication when they are feeling well or if they do not view themselves as having a condition that requires treatment. Some patients may also prefer one medication over another med- ication on the basis of prior treatment experiences or other factors.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. Although harms of antipsychotic medications can be significant, the impact of schizophre- nia on patients’ lives is also substantial, and consistent benefits of antipsychotic treatment were found. Harms of treatment can be mitigated by selecting medications on the basis of individual characteristics and preferences of patients as well as by choosing a medication on the basis of its side-effect profile, pharmacological characteristics, and other factors. For clozapine, the additional benefits of treatment were viewed as outweighing the additional rare but serious harms and the need for ANC monitoring to reduce the likelihood of severe neutropenia. For additional discussion of the research evidence, see Appendix C, Statement 4.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Information from other guidelines is consistent with this guideline statement. Other guidelines on the treatment of schizophrenia (BAP, Canadian Schizophrenia Guidelines [CSG], NICE, PORT, RANZCP, SIGN, WFSBP) all recommend use of an antipsychotic medication in the treatment of schizophrenia, with the selection of a specific medication on an individualized basis with consid- eration of medication characteristics, patient characteristics, and patient preferences (Addington et al. 2017a, 2017b; Barnes et al. 2011; Buchanan et al. 2010; Crockford and Addington 2017; Galletly et al. 2016; Hasan et al. 2012; National Institute for Health and Care Excellence 2014; Pringsheim et al. 2017; Remington et al. 2017; Scottish Intercollegiate Guidelines Network 2013). Each guideline also recommends monitoring during the course of treatment to assess therapeutic response and treatment-related side effects.

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Quality Measurement Considerations

In clinical practice, almost all individuals with schizophrenia are offered an antipsychotic medica- tion. Thus, a quality measure is unlikely to enhance outcomes if it examines only whether an indi- vidual with schizophrenia is offered or receives an initial prescription for antipsychotic treatment. An existing National Quality Forum–endorsed measure, “Adherence to Antipsychotic Medications for Individuals with Schizophrenia” (NQF #1879, http://www.qualityforum.org/QPS/1879), is aimed at assessing whether an antipsychotic medication is continued once it is begun. For individuals who are at least 18 years old and who have a diagnosis of schizophrenia or schizoaffective disorder, this measure assesses the percentage who have been dispensed an antipsychotic medication (as re- flected by at least two such prescriptions being filled) and who had a proportion of covered days of at least 0.8 during a 12 consecutive month measurement period. By requiring ongoing prescrib- ing of antipsychotic medication, this measure is more likely to be associated with improvements in outcomes for patients. Nevertheless, this measure does have several limitations. It uses pharmacy claims data or electronic prescription orders to examine whether a medication has been prescribed, but such measures do not guarantee treatment adherence. For instance, a prescriber could submit an antipsychotic medication prescription and the patient could fill the prescription at the pharmacy, but the patient might not actually take the medication. This measure also does not determine the adequacy of the medication or the medication dose and could be met through continuous prescrip- tions of a subtherapeutic dose or clinically ineffective antipsychotic. Another limitation is the diffi- culty in determining the proportion of covered days in a 12 consecutive month period, particularly when patients have transitions in care between settings or treating clinicians.

Quality measures, quality improvement initiatives, or electronic decision supports may be ap- propriate for monitoring side effects of antipsychotic treatment. Evidence suggests that rates of guideline concordant monitoring are low for metabolic risk factors, including lipids, diabetes, and weight (Mitchell et al. 2012; Morrato et al. 2009). Several measures endorsed by NQF address such monitoring. NQF #1932, “Diabetes Screening for People With Schizophrenia or Bipolar Disorder Who Are Using Antipsychotic Medications” (www.qualityforum.org/QPS/1932) measures the percentage of patients ages 18–64 years with schizophrenia or bipolar disorder “who were dis- pensed an antipsychotic medication and had a diabetes screening test during the measurement year.” Because this measure is focused on screening, it excludes monitoring of individuals who had diabetes in the measurement year or in the preceding year.

NQF #1927, “Cardiovascular Health Screening for People With Schizophrenia or Bipolar Disorder Who Are Prescribed Antipsychotic Medications” (www.qualityforum.org/QPS/1927) measures the percentage of individuals ages 25–64 years with schizophrenia or bipolar disorder “who were pre- scribed any antipsychotic medication and who received a cardiovascular health screening during the measurement year,” where cardiovascular health screening consists of “one or more LDL-C screenings performed during the measurement year.” Individuals are excluded from this screening measure for having evidence of preexisting cardiovascular disease as defined by precise criteria in the measure text. Presently, the specific elements of these criteria can often be challenging to deter- mine from unstructured electronic health records.

Two additional NQF-approved measures, NQF #1933 (www.qualityforum.org/QPS/1933) and NQF #1934 (www.qualityforum.org/QPS/1934) address cardiovascular and diabetes monitoring, respectively, for individuals with preexisting cardiovascular disease or diabetes. Each of these mea- sures is limited to individuals who are ages 18–64 years. The cardiovascular monitoring measure requires that individuals receive “an LDL-C test performed during the measurement year,” whereas the diabetes monitoring measure requires “[o]ne or more HbA1c tests and one or more LDL-C tests performed during the measurement year.” These measures have been tested for feasi- bility, usability, reliability, and validity at the health plan, integrated delivery system, and popula- tion levels; however, before holding individual clinicians or facilities accountable for the delivered quality of care, the measures would need additional testing at these levels.

STATEMENT 5: Continuing Medications

APA recommends (1A) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with an antipsychotic medication.*

Implementation

For individuals with a diagnosis of schizophrenia whose symptoms have improved with an anti- psychotic medication, there are a number of benefits to maintenance treatment, including reduced risks of relapse (Bowtell et al. 2018; Goff et al. 2017; Hui et al. 2018; Kishi et al. 2019; Leucht et al. 2012; Thompson et al. 2018), rehospitalization (Tiihonen et al. 2018), and death (Tiihonen et al. 2018; Vermeulen et al. 2017). When administered on a long-term basis, however, antipsychotic medications are also associated with a greater incidence of weight gain, sedation, and movement disorders (Leucht et al. 2012). In addition, some studies have raised questions about whether long-term antipsychotic treatment might be associated with other adverse effects on functioning or health, including loss of brain volume (Davidson 2018; Goff et al. 2017). These data are heterogeneous, and when compared with withholding treatment, there was minimal evidence to suggest negative effects of maintenance treatments on outcomes (Goff et al. 2017; Huhtaniska et al. 2017). In addition, it may be possible to mit- igate these risks by preventive interventions (e.g., early intervention for weight gain, screening for lipid and glucose abnormalities) and careful monitoring for side effects of medication. Nevertheless, as treat- ment proceeds, the pluses and minuses of continuing treatment with an antipsychotic medication should be reviewed with the patient in the context of shared decision-making. It will typically be beneficial to include family members or other persons of support in such discussions (Hamann and Heres 2019).

Despite the benefits of continued antipsychotic treatment for the majority of patients, maintain- ing adherence to an antipsychotic medication can be difficult (Acosta et al. 2012; Shafrin et al. 2016; Valenstein et al. 2006). Barriers to, facilitators of, and motivators of treatment adherence will differ for each patient. Engaging family members or other persons of support can be helpful in fostering adherence (Mueser et al. 2015). Other approaches to assessing and enhancing adherence are de- scribed in detail in Statement 3.

For some patients, the formulation of the antipsychotic medication may influence adherence (see Statement 4, Table 3). For example, rapidly dissolving tablets or oral concentrates may be preferable for patients who have difficulty swallowing pills or who are ambivalent about medications and in- consistent in swallowing them. LAI formulations may be preferred by some patients (Heres et al. 2007; Patel et al. 2009; Walburn et al. 2001) and may be particularly useful for patients with a history of poor or uncertain adherence (see Statement 10).

It is also important to assess the ongoing benefits and side effects of treatment that may indicate a need for adjustments to medication doses or changes in medications. The use of quantitative mea- sures can be helpful in systematically assessing each of these realms (see Statement 2). The optimal dose of medication is one that provides the best medication benefits yet is tolerable in terms of med- ication side effects. For some patients, adjustments in dose will be required during the course of treatment to maintain this balance (Essock et al. 2006). Such factors as addition or discontinuation of interacting medications, changes in smoking status, changes in patient body mass, changes in re- nal or hepatic status, or changes in drug absorption (e.g., with bariatric surgery) may influence medication pharmacokinetics and require increases or decreases in medication dose. In order to minimize the risk of extended side effects, when medications with a long half-life are used and par- ticularly when LAI antipsychotic medications are used, considerations about changes in dose need to consider the extended actions of these medications.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Evidence on the rationale and approach to planned reductions of medication doses is limited. Unless a medication requires emergent discontinuation, gradual reductions in doses are preferable, with close monitoring for recurrent symptoms.

Shared decision-making discussions with the patient should consider the patient’s recovery goals, the potential benefits of medication changes or dose reductions in terms of changes or dim- inution of side effects, and the potential harms of medication changes or dose reductions (Davidson 2018). The longitudinal course of the patient’s episode and the certainty of the diagnosis should also be considered. There may be some individuals with a brief episode of psychosis or uncertain psy- chotic diagnosis (e.g., possible substance-induced psychosis or mood-related psychosis) who may not require continuing antipsychotic treatment. On the other hand, individuals with chronic symp- toms, repeated relapses, and clear diagnostic features of schizophrenia will likely have poorer out- comes if medications are stopped. In addition to symptom recurrence and relapse, medication ces- sation may be associated with hospitalization, legal difficulties, reduced likelihood of response with reinstatement of treatment, or poorer psychosocial outcomes (Correll et al. 2018; Hui et al. 2018; Takeuchi et al. 2019; Wilper et al. 2009). It will typically be beneficial to include family mem- bers or other persons of support in discussions of medication changes or dose reductions.

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of an antipsychotic medication that has already been associated with symptom response can maintain improvements in symptoms as well as promote enhanced functioning and quality of life (high strength of research evidence). Long-term treatment with an antipsychotic medication has also been associated with a reduction in mortality as compared with no antipsychotic treatment in individuals with schizophrenia. In contrast, discontinuation of antipsychotic treatment can be as- sociated with increases in symptoms and risk of hospitalization and poorer long-term outcomes, including greater mortality in the long term (low strength of research evidence).

Harms

The harms of continuing use of an antipsychotic medication can vary depending on whether the patient is experiencing any significant side effects from the medication that would have long-term untoward effects. For patients whose medications are well tolerated, long-term risks include tar- dive syndromes from antipsychotic medications. For other patients, long-term risks will vary ac- cording to the specific side effect, with metabolic effects of antipsychotic medication serving as a possible contributor to long-term health risks. Some studies have raised concerns about changes in brain region volumes with antipsychotic treatment, but these findings are heterogeneous and in- consistent.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of antipsy- chotic medications as part of a treatment plan. This is particularly true when the medication has been associated with a response in symptoms. Indeed, a survey of patient preferences reported that patients viewed an ability to think more clearly and an ability to stop hallucinations or paranoia as important efficacy-related reasons to take an antipsychotic medication (Achtyes et al. 2018). Pa- tients are also likely to value the long-term benefits that have been shown with continued antipsy- chotic treatment, including reductions in relapses, hospitalizations, and mortality. However, patients also report concerns about side effects, particularly weight gain, sedation, and restlessness, that can make them reluctant to take antipsychotic medications on a long-term basis. In addition,

some patients may choose not to take an antipsychotic medication when they are feeling well or if they do not view themselves as having a condition that requires treatment.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. Although harms of antipsychotic medications can be significant and the long-term effects of antipsychotic medications are not well studied, the impact of schizophrenia on patients’ lives is also substantial, and consistent benefits of continued antipsychotic treatment were found. Overall, rates of mortality appear to be reduced by ongoing treatment with an antipsychotic medication as compared with no treatment. In addition, harms of treatment can be mitigated by using the lowest effective dose; by selecting medications on the basis of individual characteristics and preferences of patients; and by choosing a medication on the basis of its side-effect profile, pharmacological char- acteristics, and other factors. For additional discussion of the research evidence, see Appendix C, Statement 5.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Information from other guidelines is consistent with this guideline statement. Other guidelines on the treatment of schizophrenia (BAP, NICE, PORT, SIGN, WFSBP) recommend continued use of an antipsychotic medication in the treatment of schizophrenia once symptom response has been achieved (Barnes et al. 2011; Buchanan et al. 2010; Hasan et al. 2013; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013). Other guidelines (RANZCP, BAP, SIGN, NICE) also suggest the use of LAI antipsychotic medications on the basis of patient preference or when adherence has been poor or uncertain (Barnes et al. 2011; Galletly et al. 2016; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013). Use of a gradual reduction in dose, including a gradual cross-taper when changing medications, is noted by several guidelines (BAP, NICE, SIGN) along with an emphasis on close monitoring for signs of relapse (Barnes et al. 2011; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

See Statement 4 for a discussion of quality measures related to initiation and ongoing use of an an- tipsychotic medication.

STATEMENT 6: Continuing the Same Medications

APA suggests (2B) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with the same antipsychotic medication.*

Implementation

As noted in Statement 5, it is important for treatment with an antipsychotic medication to be main- tained once symptoms have improved. Specifically, for individuals with a diagnosis of schizophrenia,

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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there are a number of benefits to continued treatment with an antipsychotic medication, including re- duced risks of relapse (Bowtell et al. 2018; Goff et al. 2017; Hui et al. 2018; Kishi et al. 2019; Leucht et al. 2012; Thompson et al. 2018), rehospitalization (Tiihonen et al. 2018), and death (Tiihonen et al. 2018; Vermeulen et al. 2017). Implicitly, continued treatment with an effective and tolerable medi- cation would be preferable to potential destabilization or treatment discontinuation. This inference is also consistent with clinical observations that individualizing choice of an antipsychotic medica- tion is important. In clinical trials, a change to a different medication has been associated with ear- lier discontinuation of treatment as compared with continuation of the same antipsychotic medication (Essock et al. 2006; Stroup et al. 2011).

For these reasons, it will be optimal to continue on the same medication for most patients. Nev- ertheless, under some circumstances, it may be necessary to consider a change from one antipsy- chotic medication to another one. For example, a patient may have experienced some degree of response to initial treatment but may still have significant symptoms or difficulties in functioning that would warrant a trial of a different medication. Another reason to change medications would be to initiate treatment with an LAI antipsychotic if the current oral medication is unavailable in an LAI formulation (see Statement 10). A medication change may also be considered because of pa- tient preferences, medication availability, or side effects. Given the long-term health risks of meta- bolic syndrome and obesity, weight gain and development of diabetes or metabolic syndrome are common reasons that a change to a different medication may be discussed.

In a randomized study that examined the effects of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk, a change to aripiprazole was associated with improvements in non-HDL cholesterol, serum triglycerides, and weight as well as a small reduc- tion in 10-year risk of coronary heart disease but no difference in the odds of having metabolic syn- drome (Stroup et al. 2011, 2013). Individuals who switched to aripiprazole, as compared with those who remained on their initial medication, had a higher rate of discontinuing treatment but showed no significant increases in symptoms or hospitalizations. In addition, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that individuals who experienced issues with med- ication efficacy or tolerability in an early phase of the trial could still go on to do well with a differ- ent medication in a subsequent phase of the trial (McEvoy et al. 2006; Rosenheck et al. 2009; Stroup et al. 2007, 2009).

These findings suggest that a change in medication can be of benefit to patients under some cir- cumstances but also suggest that the possible benefits and risks of a medication change should be reviewed with the patient in the context of shared decision-making. Such discussions with the pa- tient should consider the patient’s recovery goals, the potential benefits of medication changes or dose reductions in terms of changes in or diminution of side effects, and the potential harms of medication changes or dose reductions (Davidson 2018). It will typically be beneficial to include family members or other persons of support in such discussions.

Only a limited amount of research has explored the optimal approach for changing antipsychotic medications when warranted. The typical approach is a gradual cross-taper in which the second an- tipsychotic medication is begun and gradually increased in dose as the initial antipsychotic medi- cation is gradually tapered. However, the few studies that are available do not suggest differences between gradual discontinuation as compared with immediate discontinuation of the first medica- tion (Takeuchi et al. 2017a). In addition, no differences have been seen between starting the second antipsychotic and discontinuing the first antipsychotic at the same time as compared with starting the second antipsychotic and waiting before discontinuing the first antipsychotic agent (Takeuchi et al. 2017b). Regardless of the approach that is taken, careful monitoring is essential to avoid the risks of reduced adherence and clinical destabilization if a change in medications is undertaken. Depending on the pharmacological properties of the medications, including pharmacokinetic and receptor binding profiles (see Statement 4, Tables 4 and 5), side effects of medications may also emerge (e.g., insomnia with a shift to a less sedating medication, withdrawal dyskinesia with a shift to a medication with less prominent dopamine D2 receptor blockade) (Cerovecki et al. 2013).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of an antipsychotic medication that has already been associated with symptom response can maintain improvements in symptoms as well as promote enhanced functioning and quality of life. In contrast, changes in antipsychotic treatment can be associated with early treatment discontinu- ation, increases in symptoms, clinical destabilization, and worsening of treatment tolerability.

Harms

The harms of continuing use of the same antipsychotic medication can vary depending on whether the patient is experiencing any significant side effects from the medication that would have long- term untoward effects. Continuing the same medication could lead to greater long-term risks such as metabolic effects or tardive syndromes from antipsychotic medications, but this would depend on the side-effect profile of the medication. In some instances, changing to a different medication could worsen long-term side-effect risk rather than reduce such risks.

Patient Preferences

Clinical experience suggests that most patients prefer to continue to take an antipsychotic medica- tion that has led to a response in symptoms. Once they have found a medication that is effective and well tolerated, many individuals experience anxiety if they are unable to continue with that medication because of realistic concerns about a possible return of symptoms, reductions in func- tioning, risk of hospitalization, and other potential consequences of medication changes. However, other patients may not wish to remain on a given antipsychotic medication because of concerns about side effects or other factors that make continued treatment difficult.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. Although most patients prefer to continue taking the same medication once their symptoms have responded, there are reasons that a change in medication may be indicated, and factors such as medication side-effect profiles, medication availability, and patient preferences for specific med- ications also may play a role in decisions to continue with the same medication. For additional dis- cussion of the research evidence, see Appendix C, Statement 6.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this suggestion.

Review of Available Guidelines From Other Organizations

Information from other guidelines is consistent with this guideline statement. Other guidelines on the treatment of schizophrenia (SIGN, WFSBP) note that treatment should usually continue with the same antipsychotic medication that led to the best response and had the best individual side- effect profile, given the risk of destabilization with switching an antipsychotic regimen (Hasan et al. 2013; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a quality measure or for elec- tronic decision support. However, health plans may wish to implement internal process measures

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to assess and reduce rates at which changes to stable medication regimens are made on the basis of nonclinical factors such as pre-authorization requirements or formulary changes.

STATEMENT 7: Clozapine in Treatment-Resistant Schizophrenia

APA recommends (1B) that patients with treatment-resistant schizophrenia be treated with clozapine.*

Implementation

Identification of Treatment-Resistant Schizophrenia

Clozapine is recommended for individuals with treatment-resistant schizophrenia, but there is consid- erable variation in definitions of treatment-resistant schizophrenia in clinical trials and in practice (Howes et al. 2017). For the purpose of future research trials, the Treatment Response and Resistance in Psychosis (TRRIP) Working Group conducted a detailed systematic review of clinical trials in treatment- resistant schizophrenia and used a consensus-based approach to establish minimum and optimum cri- teria for identifying treatment-resistant schizophrenia (Howes et al. 2017). In addition to a diagnosis of schizophrenia, the identification of treatment-resistant schizophrenia rests on the persistence of signifi- cant symptoms despite adequate pharmacological treatment (Howes et al. 2017). More specifically, the TRRIP Working Group recommended that symptoms be of at least 12 weeks’ duration in total, be of at least moderate severity, and be associated with at least moderate functional impairment as determined by validated rating scales (e.g., PANSS, BPRS, or SANS and SAPS for symptoms and a score <60 on the SOFAS as a measure of functioning). If a prospective medication trial of at least 6 weeks at adequate dose has not led to symptom reduction of more than 20%, this provides additional evidence of treatment re- sistance. It is helpful to note whether the persistent symptoms include positive, negative, or cognitive symptoms because responses to these symptom domains may differ.

In terms of treatment adequacy, the TRRIP Working Group recommended that at least two anti- psychotic trials should be conducted with different antipsychotic medications with at least 6 weeks at a therapeutic dosage of medication for each and with adherence of at least 80% of prescribed dos- ages (Howes et al. 2017). A therapeutic dosage of medication was defined as the midpoint of the target range for acute treatment of schizophrenia according to the manufacturer’s product labeling or the equivalent of at least 600 mg of chlorpromazine per day (Howes et al. 2017). (For tables of dose equivalents, see College of Psychiatric and Neurologic Pharmacists 2019; Leucht et al. 2014, 2015; Rothe et al. 2018.) The consensus criteria include at least one antipsychotic blood level to as- sess adherence, obtaining information on adherence from at least two sources (e.g., pill counts, dis- pensing chart reviews, patient/carer reports), and obtaining information on past treatment response from patient/carer reports and other sources.

For clinical purposes, a common definition is that a patient’s symptoms have shown no response or partial and suboptimal response to two antipsychotic medication trials of at least 6 weeks each at an adequate dosage of medication, and some definitions specify using medications from differ- ent classes (e.g., SGA vs. FGA). However, if there is no significant improvement after several weeks of treatment (e.g., <20% improvement in symptoms), the likelihood of substantial improvement (e.g., > 50% improvement in symptoms) is small (Howes et al. 2017; Samara et al. 2015), and a longer trial of the medication may not be warranted. It should also be noted that a medication trial cannot be viewed as adequate if truncated in terms of duration or dosage because of poor tolerability or if limited by poor adherence. Accordingly, some experts suggest a trial of an LAI antipsychotic med- ication before deciding that a patient’s symptoms are treatment-resistant.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Initiation of Treatment With Clozapine

After a patient is identified as having treatment-resistant schizophrenia, the clinician should en- gage the patient in discussion about clozapine treatment. A trial of clozapine may also be appropri- ate in individuals who show a response to treatment (i.e., have at least a 20% reduction in symptoms) yet still have significant symptoms or impairments in functioning (Howes et al. 2017). In fact, clozapine is often underused (Carruthers et al. 2016; Latimer et al. 2013; Olfson et al. 2016; Stroup et al. 2014; Tang et al. 2017), and many patients would benefit from earlier consideration of clozapine initiation.

Discussion of clozapine should emphasize principles of shared decision-making; including fam- ily members or other persons of support in such discussions is often beneficial. In terms of a pa- tient’s recovery goals, most individuals value an ability to think more clearly and stop hallucinations or delusions when deciding about medication changes (Achtyes et al. 2018). In ad- dition, most patients who receive clozapine view it positively. For example, one large survey of in- dividuals with schizophrenia or schizoaffective disorder who were taking an antipsychotic medication found that the vast majority of those taking clozapine adhered to treatment and found it helpful, whereas only approximately 5% found it not helpful (Siskind et al. 2017a). In contrast, most other antipsychotic medications were viewed less positively (Siskind et al. 2017a). Neverthe- less, it is important to identify patient concerns about clozapine and address them insofar as is pos- sible. For example, patients may express concerns about the burdens of required blood work and may encounter logistical barriers such as access to transportation (Farooq et al. 2019; Gee et al. 2017; Verdoux et al. 2018). However, they may be willing to consider clozapine if logistical barriers can be overcome or if given the information that blood monitoring requirements become less frequent over time. Concerns about other side effects, such as weight gain or somnolence, may also contrib- ute to a reluctance to switch to clozapine (Achtyes et al. 2018). It can be helpful to have an open dis- cussion of these side effects and a well-defined plan for monitoring as treatment proceeds. Peer-run support groups that directly address living with side effects can help patients develop strategies for coping with side effects.

Clinicians may also have concerns about clozapine that can serve as a barrier to treatment. For example, many clinicians have limited experience in using clozapine and sometimes express con- cerns about paperwork burdens, patient adherence with monitoring, and side effects (Daod et al. 2019; Farooq et al. 2019; Gee et al. 2017; Kelly and Love 2019; Kelly et al. 2018; Leung et al. 2019; Verdoux et al. 2018; Warnez and Alessi-Severini 2014). Many clinicians overestimate the likelihood of severe neutropenia and are reluctant to begin clozapine on an outpatient basis (Farooq et al. 2019). Education about the use of clozapine and its side effects can be useful in addressing clinician- related prescribing barriers.

When initiating treatment with clozapine, a slow dose titration is essential to minimize the risks of seizure, orthostatic hypotension, and excessive sedation (Clozaril 2019). Large, rapid increases in clozapine dosage have led to cardiovascular collapse and death, particularly in patients taking respi- ratory depressant medications such as benzodiazepines. From a starting dosage of 12.5 mg once or twice daily, the dosage of clozapine can be increased by, at most, 25–50 mg/day to a target dosage of 300–450 mg/day (Clozaril 2019). Subsequent dose increases, if needed, should be of 100 mg or less, once or twice weekly. Although efficacy is often seen at a dosage of 300–450 mg/day, some individ- uals may need higher dosages of clozapine, to a maximum daily dose of 900 mg, for full response. A slower rate of titration may be needed for patients with an initial episode of schizophrenia and in those who are older, severely debilitated, or sensitive to side effects. Those with a preexisting cen- tral nervous system condition, including individuals with 22q11.2 deletion syndrome, also warrant a slower rate of titration and may have an increased risk of seizures at usual doses. Use of divided doses can be helpful in reducing side effects during initial dose titration, although many patients are ultimately treated with a single dose at bedtime to minimize daytime sedation and facilitate ad- herence (Takeuchi et al. 2016).

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Monitoring for therapeutic benefits and side effects of clozapine should occur throughout the dose titration phase (see Statement 4). Because titration of clozapine proceeds slowly, the therapeu- tic benefits may not be noticed immediately, and side effects may be more prominent than benefits. Thus, it can be helpful to provide patients with education and reassurance about the expected time- table of therapeutic effects of clozapine.

If clozapine is being resumed after a gap in treatment of 48 hours or more, it should be restarted at 12.5 mg once or twice daily. If that dosage is well tolerated, the dose may be increased to a ther- apeutic range more quickly than recommended for initial treatment. If a decision is made to stop clozapine, it is best to taper the dose unless the medication is being stopped for medically urgent reasons (e.g., severe neutropenia, myocarditis, NMS).

Use of Clozapine Levels During Treatment With Clozapine

While the dose of clozapine is being titrated, it is useful to obtain blood levels of clozapine and its major active metabolite, norclozapine (N-desmethylclozapine) (Couchman et al. 2010). Blood levels can also be helpful if there are questions about medication adherence, less efficacy or more side ef- fects than expected, potential medication interactions, or other factors that may be influencing clozapine levels. Although there is substantial variation between individuals, clozapine levels on a specific dosage will generally be greater in nonsmokers than in smokers, in heavy caffeine users than in nonusers, in women than in men, and in older individuals than in younger individuals (Carrillo et al. 1998; Ismail et al. 2012). In addition, changing between different generic forms of clozapine can lead to a 5%–10% difference in blood levels. Levels of clozapine should be drawn at steady state (3 days or more after a dose change) and at a trough in medication levels (about 12 hours after the last dose). Typically, patients will receive a bedtime dose of clozapine and then have a level drawn the following morning before receiving an additional dose. There is not an absolute level of clozapine that is associated with either efficacy or toxicity (Remington et al. 2013; Spina et al. 2000; Stark and Scott 2012; Suzuki et al. 2011; VanderZwaag et al. 1996). In most patients, efficacy will be highest at levels greater than 350 ng/mL of clozapine, but some patients will show response or pre- vention of relapse at levels as low as 200 ng/mL. The risk of developing seizures increases with the blood level of clozapine.

As with the results of any laboratory test, interpretation of clozapine levels should consider the clinical context. For example, if a clozapine level is much higher than expected, assess for dose-related side effects and clinical evidence of toxicity. If the patient’s clinical status does not suggest signs of clozapine toxicity, then determine the timing of the level (e.g., peak vs. trough) and identify any po- tential for drug interactions, changes in smoking status, or incorrect specimen labeling. If levels are much lower than expected, such factors as poor adherence, rapid metabolism, drug interactions, or changes in smoking status may also be relevant.

Typically, the level of norclozapine will be reported along with the blood level of clozapine. Nor- clozapine is the major active metabolite of clozapine and appears to differ from clozapine in efficacy and side effects. Nevertheless, the value of norclozapine levels in guiding clinical decisions is unclear. Because the half-life of norclozapine is greater than the half-life of clozapine, a clozapine:norclozapine ratio less than 0.5 can suggest poor adherence over the previous day or rapid metabolism of clozapine (e.g., via CYP1A2 induction). A clozapine:norclozapine ratio greater than 3.0 could suggest that metabolic pathways are saturated or inhibited by a concomitant medication. Shifts in the ratio of clozapine to norclozapine can also result from other drug-drug interactions or if nontrough levels are obtained (Couchman et al. 2010; Ellison and Dufresne 2015).

Monitoring for Side Effects During Treatment With Clozapine

With clozapine, safety monitoring during treatment is important to minimize the risk of adverse events. The Clozapine REMS Program (www.clozapinerems.com)1 is required for prescribing of

clozapine in the United States. The REMS program includes required training that must be completed by prescribers (Clozapine REMS Program 2019a), resource materials (Clozapine REMS Program 2019b), and a shared patient registry for all clozapine manufacturers’ products that permits tracking of ANCs and documentation of decisions about continued treatment. The Clozapine REMS site pro- vides instructions about threshold values for ANCs in hematologically normal individuals and in those with benign ethnic neutropenia, which is most common in individuals of African descent and is associated with ANCs that are lower than standard reference ranges (Clozapine REMS Program 2014). It also describes the required frequencies for ANC monitoring, which vary with ANC values. In patients who have stopped or interrupted treatment with clozapine for 30 days or more, the initial dose titration for clozapine and the monitoring frequency for treatment initiation should be followed.

Because the highest risk of severe neutropenia (ANC <500/μL) occurs within the initial 6 months of clozapine treatment (Alvir et al. 1993; Clozapine REMS Program 2019c; Myles et al. 2018), ANC mon- itoring is more frequent early in treatment and is required less often with longer treatment duration. The need for ANC monitoring can be a common practical issue for patients because of the time and trans- portation needed to obtain blood tests at a laboratory. The availability of point-of-care testing for white blood cell counts may mitigate these barriers for patients and facilitate treatment with clozapine.

In addition to neutropenia, clozapine treatment can be associated with several other important side effects. Potentially serious cardiac complications of clozapine treatment include myocarditis and car- diomyopathy. Myocarditis is infrequent and generally occurs during the first month of treatment, whereas cardiomyopathy is rare and generally occurs later in the treatment course (Bellissima et al. 2018; Ronaldson et al. 2015). Myocarditis usually is heralded by shortness of breath, tachycardia, and fever, but diagnosis can be challenging because of the nonspecific nature of other symptoms, which can include fatigue, chest pain, palpitations, peripheral edema, and hypereosinophilia. In patients who do develop myocarditis or cardiomyopathy in conjunction with clozapine treatment, clozapine is typically discontinued. Subsequent decisions about resuming clozapine are individualized and are based on the benefits and risks of treatment as compared with other therapeutic alternatives.

In patients who are treated with clozapine, a brief self-limiting fever (>38°C) may also occur during the first few weeks of clozapine treatment; this fever responds to supportive measures (Bruno et al. 2015; Lowe et al. 2007; Pui-yin Chung et al. 2008). However, in a febrile patient, it is essential to assess for the presence of potentially life-threatening complications, including NMS, se- vere neutropenia, infection, and myocarditis.

Other potentially serious side effects of clozapine treatment include seizures, orthostatic hypo- tension, and gastrointestinal effects. When seizures occur with clozapine, they typically occur with very high doses of clozapine, rapid increases in clozapine dose, or shifts in medication levels (re- lated to drug-drug interactions or effects of smoking on drug metabolism) (Devinsky et al. 1991). Therefore, a slow initial titration of clozapine dose is essential, and patients should be cautioned not to drive or engage in other potentially hazardous activities while clozapine is being titrated. If a sei- zure does occur with clozapine, dose adjustment may be needed, or adjunctive anticonvulsant med- ication (e.g., valproate) may be considered in conjunction with neurological consultation (Alldredge 1999; Wong and Delva 2007).

Orthostatic hypotension can also occur with clozapine and is most common with treatment initi- ation. Older patients and patients with peripheral vascular disease or a compromised cardiovascular status may be at particular risk. When severe, orthostatic hypotension can cause syncope, dizziness, or falls. Patients who experience orthostatic hypotension must be cautioned to sit on the edge of the bed for a minute before standing up, move slowly when going from lying down or sitting to stand- ing, and seek assistance when needed. Management strategies for orthostatic hypotension include supportive measures (e.g., use of support stockings, increased dietary salt and fluid intake), reduc- ing the speed of clozapine dose titration, and decreasing or dividing doses of clozapine. As a last re-

1For Canadian prescribers, use the appropriate Canadian clozapine registry, not the U.S. Clozapine REMS Program.

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sort, administration of the salt/fluid-retaining corticosteroid fludrocortisone can be considered to increase intravascular volume, but it is important to be mindful of the potential for immunosup- pressive effects and development of diabetes with this medication (Mar and Raj 2018; Shen et al. 2017). For patients who are receiving concomitant antihypertensive treatment, adjustments to the dose of these medications may be needed.

Gastrointestinal effects of clozapine can also be significant and in some patients are associated with fecal impaction or paralytic ileus (Every-Palmer and Ellis 2017; Leung et al. 2017). Thus, the patient should obtain urgent medical care if experiencing constipation that is severe or does not re- solve. To prevent development of constipation, it is useful to minimize the doses and number of con- tributory medications such as other anticholinergic medications and opioids. Activity and exercise should be encouraged to stimulate motility. A stool softener (e.g., docusate [Colace]) can be started for patients at increased risk (e.g., older patients). If constipation does develop, initial treatment can include stool softeners (e.g., docusate [Colace]) or osmotic laxatives (e.g., lactulose [Enulose], poly- ethylene glycol [Miralax], bisacody, [Dulcolax]). Second-line treatments include stimulant laxatives (e.g., senna [Senokot], senna tea, cascara, sodium picosulfate). If constipation persists, an enema (e.g., Fleet) should be considered. A combination of treatments may be needed to treat constipation and then to prevent its recurrence.

Side effects related to metabolic syndrome are common and generally are observed in the initial months of treatment but can also occur later in treatment. These side effects include weight gain (Alvarez-Jimenez et al. 2008; Leucht et al. 2013; Zhang et al. 2013); hyperlipidemia (Buhagiar and Jabbar 2019; Bushe and Paton 2005; Meyer and Koro 2004; Mitchell et al. 2013a); and glucose dys- regulation, including development of diabetes mellitus (Hirsch et al. 2017; Ward and Druss 2015; Whicher et al. 2018; Zhang et al. 2017). Monitoring of body mass index, hemoglobin A1c, and lipid levels is important during clozapine treatment, as outlined in Statement 1, Table 2. If diabetes or hyperlipidemia is identified, it should be treated, typically by the patient’s primary care clinician. When weight gain occurs, it is usually progressive over the first 6 months of treatment, although some patients continue to gain weight indefinitely (Alvarez-Jimenez et al. 2008). Prevention of weight gain should, thus, be a high priority because weight loss is difficult for most patients. Efforts should be made to intervene proactively with weight gain of 5–10 pounds, and other medications that can cause weight gain (e.g., valproate) should be tapered and discontinued when possible. Dietary interventions, such as specialized behavioral health interventions, in-person community interven- tions (e.g., Weight Watchers), services that include meal delivery (e.g., Jenny Craig), or Internet-based interventions (e.g., Omada Health), should be suggested (Bonfioli et al. 2012).

In collaboration with the patient’s primary care clinician, metformin or nonstimulant medica- tions for weight loss can be considered. Metformin has been shown to be safe in individuals with- out hyperglycemia and can reduce body weight and reverse metabolic abnormalities in patients with obesity or other metabolic problems (Das et al. 2012; de Silva et al. 2016; McGinty et al. 2016; Mizuno et al. 2014; Siskind et al. 2016a; Vancampfort et al. 2019; Zheng et al. 2015; Zhuo et al. 2018). Fewer studies have been done with glucagon-like peptide-1 agonist medications, but the available data suggest that body weight and metabolic risk factors are reduced by these medications as com- pared with placebo (Siskind et al. 2019). The benefits of exercise appear to be small in terms of weight loss in individuals with schizophrenia (Firth et al. 2015; Pearsall et al. 2014; Vancampfort et al. 2017, 2019). Nevertheless, many individuals with schizophrenia do not engage in physical activ- ity (Stubbs et al. 2016a; Vancampfort et al. 2016b), and exercise can be suggested for its benefits for overall health, improved cardiorespiratory fitness, and other aspects of functioning (Dauwan et al. 2016; Firth et al. 2015, 2017; Vancampfort et al. 2017, 2019).

Sedation, sialorrhea, and tachycardia are each commonly observed during treatment with clozapine but can generally be managed conservatively. Sedation is most pronounced in the initial phases of treatment with clozapine, and many patients develop some tolerance to the sedating ef- fects with continued administration. However, persistent sedation, including daytime drowsiness and increased sleep time, can interfere with social, recreational, and vocational function. Lowering

of the daily dose, consolidating divided doses into one evening dose, or changing to a less sedating antipsychotic medication may be effective in reducing the severity of sedation. Coffee or other forms of caffeine can be helpful in the morning but can also interact with medications (e.g., contrib- ute to tachycardia; raise blood levels of medications, including clozapine). Adding a stimulant medication is not typically helpful and can lead to additional side effects. If sedation or the risk of sedation is significant (e.g., during initial clozapine titration), patients should be cautioned not to drive or engage in potentially hazardous activities.

Sialorrhea (or hypersalivation) is also a frequent side effect of clozapine that can contribute to reductions in quality of life and complications such as aspiration pneumonia (Dzahini et al. 2018; Kaplan et al. 2018; Stoecker et al. 2017). Because sialorrhea may be more bothersome at night, pa- tients may be advised to place a towel on their pillow and change to a clean towel in the middle of the night to minimize discomfort. During the day, patients can be encouraged to chew sugarless gum, which stimulates the swallowing reflex. Pharmacological approaches to address sialorrhea come from small studies and case reports and include use of low-dose or topical anticholinergic medications, such as glycopyrrolate or sublingual ophthalmic atropine 1% drops (Bird et al. 2011; Liang et al. 2010; Man et al. 2017). Diphenhydramine has also been studied (Chen et al. 2019); how- ever, because clozapine and other antipsychotics can have significant anticholinergic properties themselves and anticholinergics have small effects on sialorrhea, the use of agents with added an- ticholinergic effects should be approached cautiously. Terazosin and, in severe refractory cases, bot- ulinum toxin have also been used (Bird et al. 2011; Liang et al. 2010; Man et al. 2017).

Healthy patients can usually tolerate some increase in resting pulse rate, although this may not be the case for patients with preexisting heart disease. In patients with significant tachycardia (heart rates above 110–120 bpm), an ECG is warranted, as is assessment for other potential causes of tachycardia (e.g., fever, anemia, smoking, hyperthyroidism, respiratory disease, cardiovascular disorders, caffeine, other stimulants, and side effects of other medications). Early in treatment with clozapine, the possibility of myocarditis should be considered. If tachycardia is accompanied by pain, shortness of breath, fever, or signs of a myocardial infarction or heart rhythm problem, emer- gency assessment is essential. Management strategies for tachycardia with any antipsychotic med- ication include reducing the dose of medication; discontinuing medications with anticholinergic or stimulant properties; and addressing orthostatic hypotension, if present. Case reports have dis- cussed the use of medications such as β-blocking agents for persistent and significant tachycardia with clozapine. Nevertheless, treatment is not indicated unless the patient is symptomatic or the patient’s heart rate is substantially greater than 120 bpm because data from more rigorous studies are not available and these medications can contribute to other side effects such as orthostatic hy- potension (Lally et al. 2016a).

Side effects related to dopamine D2 receptor antagonism (e.g., acute dystonia, akathisia, medication- induced parkinsonism, NMS, tardive syndromes, hyperprolactinemia) can occur but are less frequent with clozapine than with many other antipsychotic medications. For additional information on the rec- ognition and management of these side effects, see Statement 4, subsection “Treatment-Emergent Side Effects of Antipsychotic Medications.”

Other Approaches to Treatment-Resistant Schizophrenia

For all patients with treatment-resistant schizophrenia, it is important to conduct a review of the treatment plan at periodic intervals (see Statement 3). In addition to a review of prior medication trials, it is essential to review the psychosocial treatments that a patient has received and whether addition of one or more psychosocial interventions would be of benefit. For example, some patients may not have received cognitive-behavioral therapy for psychosis (CBTp) as recommended in Statement 16 or initial benefits of CBTp may have faded if CBTp was stopped. Under such circum- stances, treatment with CBTp may be warranted (Burns et al. 2014; Morrison et al. 2018). Engaging families or persons of support in CBTp can also be helpful (Turkington and Spencer 2019). A similar review of potential additions to the treatment plan can occur with other psychosocial treatments.

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Optimizing Treatment With Clozapine

Although studies suggest that at least one-third of individuals with treatment-resistant schizophrenia will respond to clozapine (Kahn et al. 2018; McEvoy et al. 2006), some patients will not have a com- plete response. Before concluding that a patient has not responded to clozapine, it is important to as- sure that an adequate target dose has been reached (typically 300–450 mg/day) and that steady state levels of clozapine and norclozapine appear sufficient to produce therapeutic benefit. Although no absolute level of clozapine is associated with efficacy (Remington et al. 2013; Spina et al. 2000; Suzuki et al. 2011; VanderZwaag et al. 1996), if no response is evident and clozapine is well tolerated, the clozapine dose should be increased to achieve a clozapine level of greater than 350 ng/mL. In gen- eral, this dose of medication should be continued for at least 8 weeks to determine response, al- though further increases in dose can also be made, as tolerated. If there continues to be no evidence of benefit, as for any patient treated with clozapine, the value of the medication should be assessed periodically in terms of the patient’s response, the medication side effects, and the availability of any newer treatment options. Longitudinal use of a quantitative measure (see Statement 2) can be helpful in assessing functioning and overall response and identifying specific symptoms that have or have not responded to treatment.

Continuing Clozapine and Augmenting With Another Medication

For individuals who do not respond to clozapine alone, the evidence base for other treatments is lim- ited, although a number of options have been tried. Augmentation of clozapine with another medi- cation has shown no significant benefit in double-blind trials, although some benefit was noted in open-label trials and meta-analyses of trials that were generally of low quality (Barber et al. 2017; Correll et al. 2017b; Galling et al. 2017; Sinclair and Adams 2014; Siskind et al. 2018; Veerman et al. 2014; Wagner et al. 2019a). Studies have included augmentation with other antipsychotic medica- tions (FGAs and SGAs), anticonvulsants, and other medications. If a trial of augmentation therapy is undertaken, it is important to consider the potential additive effects of the medications on side effects and the potential for drug-drug interactions. Periodic review of the patient’s medication reg- imen is also important in order to identify and reduce or discontinue medications that are not ef- fective, that are no longer necessary, or that are contributing to an inordinate burden of side effects. As noted in the previous subsection, longitudinal use of a quantitative measure can assist in mak- ing such determinations.

Augmenting Clozapine or Another Antipsychotic Medication With Electroconvulsive Therapy

There is also evidence for benefits of ECT in combination with clozapine as compared with clozapine alone in most (Ahmed et al. 2017; Grover et al. 2015; Lally et al. 2016b; Petrides et al. 2015; Pompili et al. 2013; G. Wang et al. 2018), but not all (Melzer-Ribeiro et al. 2017), studies. Rates of headache and reports of memory impairment were more frequent with clozapine plus ECT than with clozapine alone; however, symptomatic improvement and rates of remission at the end of treatment were sig- nificantly greater in the group that received adjunctive ECT. For this reason, ECT could be consid- ered for clozapine-resistant schizophrenia, particularly in patients who also have catatonia or sig- nificant suicide risk or who require a rapid response because of the severity of their psychiatric or medical condition. For individuals who show a response to ECT, treatment with ECT on a mainte- nance basis could be considered as an adjunct to clozapine.

Some studies have shown evidence for benefits of ECT in combination with antipsychotic med- ications other than clozapine (Ahmed et al. 2017; Ali et al. 2019; Pompili et al. 2013; Sinclair et al. 2019; Zheng et al. 2016). Particularly in patients who also have catatonia or significant suicide risk or who require a rapid response due to the severity of their psychiatric or medical condition, ECT could be considered. For individuals who show a response to ECT, treatment with ECT on a main- tenance basis could be considered.

Although studies have also been done with TMS for treatment of hallucinations and for treat- ment of negative symptoms, at present there is insufficient evidence of benefit to suggest use of TMS in individuals with schizophrenia (Dollfus et al. 2016; Dougall et al. 2015; He et al. 2017).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of clozapine in individuals with treatment-resistant schizophrenia can be associated with re- ductions in psychotic symptoms, higher rates of treatment response, and lower rates of treatment discontinuation due to lack of efficacy (low to moderate strength of research evidence) as well as lower rates of self-harm, suicide attempts, or hospitalizations to prevent suicide (moderate strength of research evidence). Overall rates of hospitalization are also reduced during treatment with clozapine as compared with other oral antipsychotic medications (low strength of research evi- dence). All-cause mortality is also reduced in individuals treated with clozapine as compared with other individuals with treatment-resistant schizophrenia (moderate strength of research evidence).

Harms

Although overall rates of adverse events do not differ with clozapine as compared with risperidone (low strength of research evidence), clozapine does have a higher risk of study withdrawal due to ad- verse events than some other SGAs (low strength of research evidence). Specific harms of using clozapine include rare but serious effects, including severe neutropenia, myocarditis, cardiomyopa- thy, and NMS. These harms cannot be eliminated, but risks of severe neutropenia are lessened by required ANC monitoring. Early attention to and recognition of NMS and cardiac complications of clozapine use may also reduce risk. Seizures are also more frequent with clozapine than other an- tipsychotics but can be minimized by slow titration of the clozapine dose, avoidance of very high clozapine doses, and attention to pharmacokinetic factors that may lead to rapid shifts in clozapine levels. Constipation can also be significant with clozapine and in some patients is associated with fecal impaction or paralytic ileus. Other side effects that are more common with clozapine than other antipsychotic medications include sialorrhea, tachycardia, fever, dizziness, sedation, and weight gain. Rates of hyperglycemia and diabetes may also be increased.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of clozapine as part of a treatment plan; however, other patients may express concerns about the burdens of re- quired blood work, including logistical barriers such as access to transportation (Farooq et al. 2019; Gee et al. 2017; Verdoux et al. 2018). Concerns about other side effects, such as weight gain or som- nolence, may also contribute to a reluctance to switch to clozapine (Achtyes et al. 2018). On the other hand, when deciding about medication changes, most patients value an ability to think more clearly and stop hallucinations or delusions (Achtyes et al. 2018; Kuhnigk et al. 2012; Levitan et al. 2015), and most patients who receive clozapine view it positively. For example, one large survey of individuals with schizophrenia or schizoaffective disorder who were taking an antipsychotic med- ication found that the vast majority of those taking clozapine adhered to treatment and found it helpful, whereas only approximately 5% found it not helpful (Siskind et al. 2017a). In contrast, most other antipsychotic medications were viewed less positively (Siskind et al. 2017a). In addition, in the CATIE study, clozapine and combination antipsychotic treatment regimens were frequently se- lected by patients who stopped a previous medication because of inadequate therapeutic effect and by those with relatively severe symptoms (Stroup et al. 2009).

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Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. For individuals with treatment-resistant schizophrenia, the risks of inadequately treated ill- ness are substantial in terms of reduced quality of life (Kennedy et al. 2014) and increased mortality (Cho et al. 2019; Vermeulen et al. 2019; Wimberley et al. 2017) as well as negative effects for informal caregivers (Brain et al. 2018). Even in individuals who have had an inadequate response to other antipsychotic medications, a substantial fraction shows a clinically relevant response to clozapine. With careful monitoring to minimize the risk of harms from clozapine, the benefits of clozapine in pa- tients with treatment-resistant schizophrenia were viewed as significantly outweighing the harms of treatment. For additional discussion of the research evidence, see Appendix C, Statement 7.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Practice guidelines (BAP, CSG, NICE, RANZCP, SIGN, WFSBP, PORT) are consistent in recommend- ing clozapine for individuals with treatment-resistant schizophrenia (Barnes et al. 2011; Buchanan et al. 2010; Galletly et al. 2016; Hasan et al. 2012; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013). In terms of other therapies for treatment- resistant schizophrenia, several guidelines (SIGN, WFSBP, BAP) recommend augmentation treat- ment with an antidepressant for treatment-resistant illness associated with negative symptoms (Barnes et al. 2011; Hasan et al. 2012; Scottish Intercollegiate Guidelines Network 2013). For indi- viduals with catatonia, the WFSBP recommends benzodiazepines and ECT (Hasan et al. 2012). In ad- dition, ECT is mentioned in several guidelines (e.g., SIGN, RANZCP, WFSBP) as being appropriate in individuals with treatment-resistant schizophrenia.

Quality Measurement Considerations

Studies suggest that clozapine is underused and that a significant proportion of individuals with treat- ment-resistant schizophrenia do not receive treatment with clozapine, although there is significant vari- ation between and within countries (Addington et al. 2012; Bachmann et al. 2017; Carruthers et al. 2016; Keller et al. 2014; Olfson et al. 2016; Stroup et al. 2014; Tang et al. 2017). Thus, internal quality improvement programs may wish to focus on ways to increase use of clozapine in individuals with treatment-resistant schizophrenia and track rates of clozapine use in this patient population. Inter- nal quality improvement programs could also focus on increasing use of quantitative measures (i.e., rating scales) to improve identification of individuals with treatment-resistant schizophrenia and facilitate systematic longitudinal tracking of functioning, symptoms, and side-effect burdens. If quality measures are considered for development at the provider, facility, health plan, integrated delivery system, or population level, testing of feasibility, usability, reliability, and validity would be essential prior to use for purposes of accountability.

Electronic decision support would be challenging to implement and would depend on accurate and consistent entry of structured information. Nevertheless, in combination with rating scale data and prior prescribing histories, electronic decision support could help identify individuals with treatment-resistant illness who would benefit from a trial of clozapine.

STATEMENT 8: Clozapine in Suicide Risk

APA recommends (1B) that patients with schizophrenia be treated with clozapine if the risk for suicide attempts or suicide remains substantial despite other treatments.*

Implementation

Treatment with clozapine can be effective in reducing suicidal behavior if risk remains substantial despite other treatments. In addition, treatment with clozapine can be effective in reducing rates of suicide attempts and suicide in individuals with schizophrenia, regardless of whether formal crite- ria for treatment resistance have been met. Risk factors for suicidal behavior in individuals with schizophrenia are described in Statement 1, subsection “Implementation.” Although demographic and historical risk factors are static, a number of other risk factors are potentially modifiable and can serve as targets of intervention in constructing a plan of treatment (for additional details, see Statement 3). As in other circumstances in which patients do not appear to be responding fully to treatment, attention to adherence is crucial (for additional details, see Statement 3). For details of initiating and monitoring clozapine treatment, see Statement 7, subsections “Initiation of Treatment With Clozapine,” “Use of Clozapine Levels During Treatment With Clozapine,” and “Monitoring for Side Effects During Treatment With Clozapine.”

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals with schizophrenia who are at significant risk for suicide attempts or suicide, use of clozapine can be associated with lower rates of self-harm, suicide attempts, or hospitalization to prevent suicide (moderate strength of research evidence). Additional benefits of clozapine treat- ment include higher rates of treatment response (low to moderate strength of research evidence) and reductions in psychotic symptoms, all-cause mortality, overall hospitalization rates, and treat- ment discontinuation due to lack of efficacy (low to moderate strength of research evidence).

Harms

Although overall rates of adverse events do not differ with clozapine as compared with risperidone (low strength of research evidence), clozapine does have a higher risk of study withdrawal due to adverse events than some other SGAs (low strength of research evidence). Specific harms of using clozapine include rare but serious effects, including severe neutropenia, myocarditis, cardiomyopa- thy, and NMS. These harms cannot be eliminated, but risks of severe neutropenia are lessened by required ANC monitoring. Early attention to and recognition of NMS and cardiac complications of clozapine use may also reduce risk. Seizures are also more frequent with clozapine than other an- tipsychotics but can be minimized by slow titration of the clozapine dose, avoidance of very high clozapine doses, and attention to pharmacokinetic factors that may lead to rapid shifts in clozapine levels. Constipation can also be significant with clozapine and in some patients is associated with fecal impaction or paralytic ileus. Other side effects that are more common with clozapine than other antipsychotic medications include sialorrhea, tachycardia, fever, dizziness, sedation, and weight gain. Rates of hyperglycemia and diabetes may also be increased.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of clozapine as part of a treatment plan; however, other patients may express concerns about the burdens of re- quired blood work, including logistical barriers such as access to transportation (Farooq et al. 2019; Gee et al. 2017; Verdoux et al. 2018). Concerns about other side effects, such as weight gain or som- nolence, may also contribute to a reluctance to switch to clozapine (Achtyes et al. 2018). On the other hand, when deciding about medication changes, most patients value an ability to think more clearly and stop hallucinations or delusions (Achtyes et al. 2018; Kuhnigk et al. 2012; Levitan et al. 2015), and most patients who receive clozapine view it positively. For example, one large survey of individuals with schizophrenia or schizoaffective disorder who were taking an antipsychotic med- ication found that the vast majority of those taking clozapine adhered to treatment and found it helpful, whereas only approximately 5% found it not helpful (Siskind et al. 2017a). In contrast, most other antipsychotic medications were viewed less positively (Siskind et al. 2017a).

Balancing of Benefits and Harms

The potential benefits of this recommendation were viewed as far outweighing the potential harms. For individuals at significant risk for suicide attempts or suicide despite other treatments, the ben- efit of clozapine in reducing suicide-related risk is significant. With careful monitoring to minimize the risk of harms from clozapine, the benefit of clozapine in such patients was viewed as signifi- cantly outweighing the harms of treatment. For additional discussion of the research evidence, see Appendix C, Statement 8.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Other guidelines do not specifically mention the use of clozapine for individuals with schizophre- nia who are at substantial risk for suicide attempts or suicide despite other treatment. Guidelines (BAP, CSG, NICE, RANZCP, SIGN, WFSBP, PORT) are consistent, however, in recommending clozapine for individuals with treatment-resistant schizophrenia (Barnes et al. 2011; Buchanan et al. 2010; Galletly et al. 2016; Hasan et al. 2012; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

Studies suggest that clozapine is underused and that a significant proportion of individuals with treat- ment-resistant schizophrenia do not receive treatment with clozapine, although there is significant vari- ation between and within countries (Addington et al. 2012; Bachmann et al. 2017; Carruthers et al. 2016; Keller et al. 2014; Olfson et al. 2016; Stroup et al. 2014; Tang et al. 2017). Given low utilization of clozapine in general (Addington et al. 2012; Bachmann et al. 2017; Carruthers et al. 2016; Keller et al. 2014; Olfson et al. 2016; Stroup et al. 2014; Tang et al. 2017) and the high rates of suicidal ideas among individuals with treatment-resistant schizophrenia (Kennedy et al. 2014), it is likely that many individuals at significant suicide risk are not receiving treatment with clozapine. Thus, internal quality improvement programs may wish to focus on ways to increase and track use of clozapine in individuals with schizophrenia who have significant suicide risk that persists despite other treat- ments. Internal quality improvement programs could also focus on increasing the use of quantitative measures to improve identification and monitoring of individuals with risk factors for suicide.

If quality measures are considered for development at the provider, facility, health plan, inte- grated delivery system, or population level, testing of feasibility, usability, reliability, and validity would be essential prior to use for purposes of accountability. In particular, it is currently not pos- sible to identify from most administrative data people at increased risk for suicide. Clinical assess- ment or patient self-report data are likely to be required.

Electronic decision support using passive alerts may be able to prompt clinicians to consider clozapine; however, such prompts would be challenging to implement because they would depend on accurate and consistent entry of structured information about diagnosis, suicidal ideation, and suicide attempts. Nevertheless, in combination with rating scale data, electronic decision support could help identify individuals with schizophrenia and significant suicide risk who would benefit from a trial of clozapine.

STATEMENT 9: Clozapine in Aggressive Behavior

APA suggests (2C) that patients with schizophrenia be treated with clozapine if the risk for aggressive behavior remains substantial despite other treatments.*

Implementation

Treatment with clozapine can be effective in reducing aggressive behavior if risk remains substantial despite other treatments. As in other circumstances in which patients do not appear to be responding fully to treatment, attention to adherence is crucial (for additional details, see Statement 3). Risk fac- tors for aggressive behavior in individuals with schizophrenia are described in Statement 1, subsec- tion “Implementation.” Although demographic and historical risk factors are static, a number of other risk factors are potentially modifiable and can serve as targets of intervention in constructing a plan of treatment (for additional details, see Statement 3). For details of initiating and monitoring clozapine treatment, see Statement 7, subsections “Initiation of Treatment With Clozapine,” “Use of Clozapine Levels During Treatment With Clozapine,” and “Monitoring for Side Effects During Treat- ment With Clozapine.”

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals with schizophrenia who are at significant risk for aggressive behavior, use of clozapine may reduce the likelihood of aggressive behaviors (low strength of research evidence). Additional benefits of clozapine treatment include higher rates of treatment response (low to moderate strength of research evidence); reductions in psychotic symptoms, all-cause mortality, overall hospitalization rates, and treatment discontinuation due to lack of efficacy (low to moderate strength of research ev- idence); and lower rates of self-harm, suicide attempts, or hospitalizations to prevent suicide (moder- ate strength of research evidence).

Harms

Although overall rates of adverse events do not differ with clozapine as compared with risperidone (low strength of research evidence), clozapine does have a higher risk of study withdrawal due to ad- verse events than some other SGAs (low strength of research evidence). Specific harms of using clozapine include rare but serious effects, including severe neutropenia, myocarditis, cardiomyopa-

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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thy, and NMS. These harms cannot be eliminated, but risks of severe neutropenia are lessened by required ANC monitoring. Early attention to and recognition of NMS and cardiac complications of clozapine use may also reduce risk. Seizures are also more frequent with clozapine than other an- tipsychotics but can be minimized by slow titration of the clozapine dose, avoidance of very high clozapine doses, and attention to pharmacokinetic factors that may lead to rapid shifts in clozapine levels. Constipation can also be significant with clozapine and in some patients is associated with fecal impaction or paralytic ileus. Other side effects that are more common with clozapine than other antipsychotic medications include sialorrhea, tachycardia, fever, dizziness, sedation, and weight gain. Rates of hyperglycemia and diabetes may also be increased.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of clozapine as part of a treatment plan; however, other patients may express concerns about the burdens of re- quired blood work, including logistical barriers such as access to transportation (Farooq et al. 2019; Gee et al. 2017; Verdoux et al. 2018). Concerns about other side effects, such as weight gain or som- nolence, may also contribute to a reluctance to switch to clozapine (Achtyes et al. 2018). On the other hand, when deciding about medication changes, most patients value an ability to think more clearly and stop hallucinations or delusions (Achtyes et al. 2018; Kuhnigk et al. 2012; Levitan et al. 2015), and most patients who receive clozapine view it positively. For example, one large survey of individuals with schizophrenia or schizoaffective disorder who were taking an antipsychotic med- ication found that the vast majority of those taking clozapine adhered to treatment and found it helpful, whereas only approximately 5% found it not helpful (Siskind et al. 2017a). In contrast, most other antipsychotic medications were viewed less positively (Siskind et al. 2017a).

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. For individuals at significant risk for aggressive behavior despite other treatments, there ap- pears to be some benefit of clozapine in reducing aggression risk. In addition, clozapine may lead to indirect reductions in the risk of aggressive behavior by reducing other contributory risk factors for aggression such as hallucinations and delusions. Thus, with consideration of patient prefer- ences and careful monitoring to minimize the risk of harms from clozapine, the benefit of clozapine in such patients was viewed as likely to outweigh the harms of treatment. For additional discussion of the research evidence, see Appendix C, Statement 9.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this sug- gestion.

Review of Available Guidelines From Other Organizations

Information from other guidelines is consistent with this guideline statement. The SIGN, RANZCP, BAP, and PORT guidelines all suggest consideration of clozapine for individuals with hostility or aggressive behaviors that do not respond to other interventions (Barnes et al. 2011; Buchanan et al. 2010; Galletly et al. 2016; Hasan et al. 2012; Scottish Intercollegiate Guidelines Network 2013). In ad- dition, guidelines (BAP, CSG, NICE, RANZCP, SIGN, WFSBP, PORT) are consistent in recommend- ing clozapine for individuals with treatment-resistant schizophrenia (Barnes et al. 2011; Buchanan et al. 2010; Galletly et al. 2016; Hasan et al. 2012; National Institute for Health and Care Excellence 2014; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a quality measure for pur- poses of accountability. Electronic decision support using passive alerts may be able to prompt cli- nicians to consider clozapine; however, such prompts would be challenging to implement because they would depend on accurate and consistent entry of structured information about diagnosis and risk factors for aggression. Nevertheless, in combination with rating scale data, electronic decision support could help identify individuals with schizophrenia and significant aggression risk who may benefit from a trial of clozapine.

STATEMENT 10: Long-Acting Injectable Antipsychotic Medications

APA suggests (2B) that patients receive treatment with a long-acting injectable antipsy- chotic medication if they prefer such treatment or if they have a history of poor or uncer- tain adherence.*

Implementation

LAI formulations of antipsychotic medications can provide a number of benefits for patients, fam- ilies, and clinicians, yet they are often underutilized (Brown et al. 2014; Correll et al. 2016; Lawson et al. 2015; Sultana et al. 2019). Racial differences also exist in the proportion of individuals who are treated with LAI antipsychotic medications, with greater use of these formulations in Black patients than in white patients (Brown et al. 2014; Lawson et al. 2015).

With LAI antipsychotic medications, there is greater assurance that a patient will receive medi- cation continuously because there are fewer opportunities to miss a medication dose and clinicians will be immediately aware of a missed visit or injection, yielding greater time for intervention be- fore symptoms recur (Correll et al. 2016; Velligan et al. 2010; West et al. 2008). Presumably due to improved adherence, advantages of LAI antipsychotics include the potential for a decreased risk of mortality; reduced risk of hospitalization; and decreased rates of treatment discontinuation, includ- ing discontinuation due to inefficacy (see Appendix C, Statement 10). Other benefits for patients in- clude a subjective sense of better symptom control, greater convenience as a result of needing to take fewer medications daily, and reduced conflict with family members or other persons of sup- port related to medication-related reminders (Caroli et al. 2011; Correll et al. 2016; Iyer et al. 2013; Yeo et al. 2019). Although some patients may not wish to experience the discomfort associated with receiving injections of medications, this is not a major barrier for most patients. In addition, discom- fort can often be minimized by using SGA LAIs rather than FGA LAIs, which have sesame oil– based vehicles, or by using an LAI with a small injection volume or lower administration frequency (Correll et al. 2016).

Consistent with principles of patient-centered care, it may be preferable to educate patients about the availability of LAI antipsychotic medications when discussing other aspects of antipsy- chotic treatment. Indeed, many patients will accept and may prefer LAIs if provided with informa- tion about the pluses and minuses of LAIs in the context of shared decision-making (Caroli et al. 2011; Heres et al. 2007; Kane et al. 2019; Waddell and Taylor 2009; Weiden et al. 2015; Yeo et al. 2019). Preference rates for LAIs are even higher among individuals who have personal experience in receiving an LAI formulation of an antipsychotic medication (Heres et al. 2007; Patel et al. 2009; Waddell and Taylor 2009).

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Discussions about LAI antipsychotic medications often occur with patients who have had diffi- culty in adhering to oral medications. However, such discussions can also take place at other junc- tures. For example, if an individual has not responded to treatment with an oral antipsychotic medication, a trial of an LAI may be warranted (Howes et al. 2017; see Statement 4, subsection “Strategies to Address Initial Nonresponse or Partial Response to Antipsychotic Treatment”) be- cause breaks in the continuity of oral medication therapy can be unrecognized (Lopez et al. 2017). An LAI formulation of an antipsychotic may also be considered when patients are transitioning be- tween settings (e.g., at inpatient discharge, on release from a correctional facility), when future ad- herence is uncertain and the risk of reduced adherence may be increased. Although LAI antipsychotic medications have typically been used in individuals with multiple episodes of schizophrenia, some studies have used an LAI antipsychotic formulation earlier in the course of ill- ness (Kane et al. 2019; Subotnik et al. 2015), when rates of poor adherence may be greater. Earlier discussion of an LAI may also be considered in individuals who are at increased risk of poor adher- ence due to a limited awareness of needing treatment or a co-occurring substance use disorder (García et al. 2016; Velligan et al. 2009).

If a decision is made to initiate treatment with an LAI, aspects of medication selection are similar to those for selection of an oral medication in terms of considering prior response, prior tolerability, pharmacological considerations, and side-effect profiles (see Statement 4). Patients may also have specific preferences and values related to the frequency of injection and the type and location of the injection (e.g., IM deltoid or gluteal sites, subcutaneous abdominal site; Heres et al. 2012). Because the oral and LAI formulations of a specific antipsychotic medication are comparable, a trial of the same oral antipsychotic will typically occur first to assure efficacy and tolerability (SMI Adviser 2019). Pa- tients will experience medication side effects for a longer period of time after drug discontinuation with LAIs than with oral medications because of pharmacokinetic differences in the formulations, but this is not usually a problem if the oral formulation has first been well tolerated. Nevertheless, caution is warranted in a patient who has experienced NMS previously (Correll et al. 2016).

The conversion from an oral dose of medication to a corresponding dose of an LAI antipsychotic depends on the specific medication (see Statement 4, Tables 7, 8, and 9; Meyer 2013, 2017); product labeling for each medication describes approximate conversion ratios and whether a period of con- comitant oral and LAI medication is needed. If the patient is taking an oral medication that lacks a corresponding LAI formulation, a change in antipsychotic medication may be needed if an LAI for- mulation is clinically indicated or preferred (see Statement 6).

When administering LAI antipsychotic injections, it is important to follow recommendations for safe injection practices (Centers for Disease Control and Prevention 2019a, 2019b) and infection control precautions (Centers for Disease Control and Prevention 2016, 2019b) as well as instructions from product labeling. Product labeling also contains important information on storage and recon- stitution of LAI antipsychotic formulations as well as information on how to handle missed or late doses of medications (see Statement 4, Tables 7–9).

There are several barriers related to the use of LAI formulations of antipsychotic medications. For patients, there may be logistical barriers (e.g., access to transportation, childcare, school or work schedules) that depend on the frequency of appointments needed to receive an LAI antipsychotic medication. Other logistical barriers for patients may relate to such factors as cost or insurance au- thorizations for LAI antipsychotic agents. For clinicians, lack of knowledge and limited experience in using LAI antipsychotic medications contribute to underuse (Correll et al. 2016). Skill and expe- rience in administering injections may be lacking, and nursing staff may not be available to give injections.

Additional barriers relate to the decision to suggest an LAI antipsychotic medication. Clinicians often do not consider LAI antipsychotic medications as a treatment option (Hamann et al. 2014; Heres et al. 2006; Kirschner et al. 2013; Weiden et al. 2015), even when such use is appropriate. Fur- thermore, clinicians may overestimate patients’ adherence with oral medications when considering relative benefits of LAIs (Correll et al. 2016; Lopez et al. 2017) or underestimate the acceptability of

LAIs to patients (Hamann et al. 2010; Iyer et al. 2013; Patel et al. 2010a, 2010b; Weiden et al. 2015). At an organizational level, there may be a lack of resources, space, or trained personnel to admin- ister injections (Correll et al. 2016; Velligan et al. 2011). Thus, workflows may need to be adjusted, partnerships may need to be developed with primary care clinicians to administer LAI antipsy- chotic injections, or other concerted efforts may be needed to address logistical and clinical barriers to LAI antipsychotic use.

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of an LAI antipsychotic medication in the treatment of schizophrenia may be associated with improved outcomes. Although meta-analyses of head-to-head RCTs comparing LAI with oral an- tipsychotics (McDonagh et al. 2017) and other meta-analyses of RCTs (Kishi et al. 2016a, 2016b; Kishimoto et al. 2014; Ostuzzi et al. 2017) do not show evidence of benefit from LAIs relative to oral antipsychotic medications, observational data from nationwide registry databases (Taipale et al. 2018a, 2018b; Tiihonen et al. 2011, 2017), cohort studies (Kishimoto et al. 2018), and “mirror image” studies (Kishimoto et al. 2013) suggest that use of LAI antipsychotic agents as compared with oral antipsychotic medications is associated with a decreased risk of mortality, reduced risk of hospital- ization, and decreased rates of study discontinuation (including discontinuation due to inefficacy).

Harms

The harms of using an LAI antipsychotic medication in the treatment of schizophrenia are generally comparable to the harms of using an oral formulation of the same medication. For some patients, side effects with LAIs may be less problematic because peaks and troughs of medication levels will be less prominent than with oral medications because of the pharmacokinetic differences in the medication formulations. On the other hand, patients may experience medication side effects for a longer period of time with LAIs than with oral medications, again because of pharmacokinetic dif- ferences. In addition, patients may experience injection-related side effects, including pain, swell- ing, redness, or induration at the injection site, with LAI antipsychotic agents.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of an LAI anti- psychotic medication as part of a treatment plan, particularly when the option of an LAI and the pluses and minuses of an LAI antipsychotic are reviewed in the context of shared decision-making (Caroli et al. 2011; Heres et al. 2007; Kane et al. 2019; Waddell and Taylor 2009; Weiden et al. 2015; Yeo et al. 2019). Attitudes about LAIs are typically more positive among patients who have previ- ously received or currently receive an LAI antipsychotic medication than in those who have never been treated with an LAI medication (Patel et al. 2009). Many patients prefer the convenience of re- ceiving an infrequent injection rather than needing to remember to take oral medications. They also value the potential benefits of an LAI antipsychotic medication in terms of better subjective symp- tom reduction or improved long-term outcomes. On the other hand, some patients may not wish to experience the discomfort associated with receiving injections of medications.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. The outcomes associated with use of an LAI formulation of an antipsychotic medication are at least as good as using an oral formulation of the medication and may be better, particularly in terms of treatment discontinuation, rehospitalization, and mortality risk. Many experts infer that

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the relative benefits of LAI antipsychotic medications as compared with equivalent oral formula- tions are related to improved adherence (Velligan et al. 2010; West et al. 2008), although specific data to test this supposition are not available. Nevertheless, use of an LAI antipsychotic may have additional advantages in patients who have difficulty with adherence or in whom adherence is un- certain. The side effects of treatment with an LAI antipsychotic medication are also comparable to side effects with the corresponding oral medication. For additional discussion of the research evi- dence, see Appendix C, Statement 10.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this sug- gestion.

Review of Available Guidelines From Other Organizations

Information from other guidelines is consistent with this guideline statement (Barnes et al. 2011; Buchanan et al. 2010; Galletly et al. 2016; Hasan et al. 2012; National Institute for Health and Care Excellence 2014; Remington et al. 2017; Scottish Intercollegiate Guidelines Network 2013). Other guidelines on the treatment of schizophrenia suggest use of LAIs based on patient preference (BAP, CSG, NICE, PORT, RANZCP, SIGN) or in the context of poor or uncertain adherence (BAP, NICE, RANZCP, SIGN). The RANZCP and WFSBP guidelines also note that LAIs should be considered if there has been a poor response to oral medication, and the RANZCP guideline notes that LAIs should be offered to patients early in the clinical course of schizophrenia.

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a quality measure. However, only a small proportion of individuals with schizophrenia receive an LAI antipsychotic medication in clinical practice (Brown et al. 2014; Correll et al. 2016; Lawson et al. 2015; Sultana et al. 2019). Be- cause adherence is poor or uncertain in many individuals with schizophrenia, patients may benefit from or prefer to receive an LAI antipsychotic medication if one is offered. Consequently, electronic decision support could suggest that clinicians consider an LAI antipsychotic medication if poor ad- herence is documented or with repeated hospitalizations or emergency visits. In addition, health care organizations may wish to ensure that they will provide treatment with an LAI antipsychotic medication to patients when appropriate. Health care organizations and health plans may also wish to implement internal process measures to assess and increase rates at which LAI antipsychot- ics are used.

STATEMENT 11: Anticholinergic Medications for Acute Dystonia

APA recommends (1C) that patients who have acute dystonia associated with antipsychotic therapy be treated with an anticholinergic medication.

Implementation

Medication-induced acute dystonia is defined in DSM-5 as

[a]bnormal and prolonged contraction of the muscles of the eyes (oculogyric crisis), head, neck (torticollis or retrocollis), limbs, or trunk developing within a few days of starting or raising the dosage of a med- ication (such as a neuroleptic) or after reducing the dosage of a medication used to treat extrapyramidal symptoms. (American Psychiatric Association 2013a, p. 711)

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A dystonic spasm of the axial muscles along the spinal cord can result in opisthotonos, in which the head, neck, and spinal column are hyperextended in an arched position. Rarely, acute dystonia can also present as life-threatening laryngospasm, which results in an inability to breathe (Ganesh et al. 2015; Koek and Pi 1989). Acute dystonia is sudden in onset and painful and can cause patients great distress. Because of the dramatic appearance of acute dystonia, health professionals who are unfa- miliar with the condition may incorrectly attribute these reactions to catatonic signs or unusual be- havior on the part of patients, and oculogyric crises can sometimes be misinterpreted as indicative of seizure activity. In individuals treated with FGAs, it is estimated that up to 10% of patients may experience an acute dystonic episode, and with SGAs, rates of acute dystonia may be less than 2% (Martino et al. 2018; Miller et al. 2008; Satterthwaite et al. 2008). Additional factors that increase the risk of acute dystonia with antipsychotic medication include young age, male sex, ethnicity, recent cocaine use, high medication dose, and intramuscular route of medication administration (Gray and Pi 1998; Spina et al. 1993; van Harten et al. 1999).

There are a limited number of clinical studies of anticholinergic medications in acute dystonia associated with antipsychotic therapy. Nevertheless, a large amount of clinical experience suggests that acute dystonia can be reversed by administration of diphenhydramine, a histamine receptor antagonist with anticholinergic properties. Typically, it is administered intramuscularly to treat acute dystonia, but it can also be administered intravenously in emergent situations, as with acute dystonia associated with laryngospasm. Alternatively, benztropine can also be administered intra- muscularly. Once the acute dystonia has resolved, it may be necessary to continue an oral anticho- linergic medication to prevent recurrence, at least until other changes in medications can take place such as reducing the dose of medication or changing to an antipsychotic medication that is less likely to be associated with acute dystonia. Typically, a medication such as benztropine or trihexy- phenidyl is used for this purpose because of the shorter half-life of oral diphenhydramine and a need for more frequent dosing. For additional details of dosing and use of these medications, see Statement 12, Table 10. Regardless of the anticholinergic medication that is chosen, it is important to use the lowest dose that is able to treat acute dystonia and continue the anticholinergic medica- tion for the shortest time needed to prevent dystonia from recurring. After several weeks to months, anticholinergic medications can sometimes be reduced or withdrawn without recurrence of dystonia or worsening of other antipsychotic-induced neurological symptoms (Desmarais et al. 2012). Medications with anticholinergic effects can result in multiple difficulties for patients, includ- ing impaired quality of life, impaired cognition, and significant health complications (Salahudeen et al. 2015). Dry mouth due to anticholinergic effects is associated with an increased risk for multiple dental complications (Singh and Papas 2014), and drinking high-calorie fluids in response to dry mouth can contribute to weight gain. Medications with anticholinergic effects can also precipitate acute angle-closure glaucoma (Lachkar and Bouassida 2007), although patients with treated glau- coma seem to be able to tolerate these medications with careful monitoring (Bower et al. 2018). Other peripheral side effects of anticholinergic medications can include blurred vision, constipation, tachycardia, urinary retention, and effects on thermoregulation (e.g., hyperthermia in hot weather) (Nasrallah and Tandon 2017; Ozbilen and Adams 2009), and central anticholinergic effects can in- clude impaired learning and memory and slowed cognition (Ang et al. 2017; Vinogradov et al. 2009). Older individuals can be particularly sensitive to these anticholinergic effects and can de- velop problems such as urinary retention, confusion, fecal impaction, and anticholinergic toxicity (with delirium, somnolence, and hallucinations) (Nasrallah and Tandon 2017). In addition, it is im- portant to consider the anticholinergic side effects associated with other medications that a patient is taking, such as antipsychotic medications, some antidepressant medications, urological medica- tions (e.g., oxybutynin), and nonselective antihistamines (e.g., hydroxyzine, diphenhydramine).

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Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals who have acute dystonia associated with antipsychotic therapy, the use of medications with anticholinergic properties (including diphenhydramine, benztropine, and trihexyphenidyl) can be associated with rapid symptom relief. In addition, continuing treatment with an anticholinergic medication can prevent the return of dystonia until other adjustments to the treatment regimen can be made to minimize the risk of recurrence.

Harms

The harms of using a medication with anticholinergic properties to treat acute dystonia include side ef- fects such as dry mouth, blurred vision, precipitation of acute angle-closure glaucoma, constipation (and in some cases fecal impaction), tachycardia, urinary retention, effects on thermoregulation (e.g., hyper- thermia in hot weather), impaired learning and memory, slowed cognition, and anticholinergic toxicity (with delirium, somnolence, and hallucinations). These harms are likely to be greater in older individu- als and may be augmented in individuals taking other medications with anticholinergic properties.

Patient Preferences

Clinical experience suggests that acute dystonia associated with antipsychotic therapy is very un- comfortable for patients, and most of them are frightened by it. As a result, patients are typically cooperative with and accepting of acute treatment with an anticholinergic agent. They may also be willing to take one of these medications to prevent the return of dystonia. However, some patients may be troubled by side effects such as blurred vision, dry mouth, and constipation and may wish to avoid more significant side effects associated with anticholinergic medications.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. For the majority of patients who are experiencing acute dystonia associated with antipsy- chotic therapy, the rapid relief of symptoms with anticholinergic treatment outweighs the side ef- fects associated with these medications, at least on a short-term basis. In patients who experience acute laryngeal dystonia, rapid administration of a medication with anticholinergic properties, such as diphenhydramine, can be lifesaving. Nevertheless, the long-term benefits and harms of an- ticholinergic medications are less clear, and, in this context, harms may outweigh benefits. For ad- ditional discussion of the research evidence, see Appendix C, Statement 11.

Differences of Opinion Among Writing Group Members

Eight writing group members voted to recommend this statement. One writing group member dis- agreed with this statement out of concern that a reduction in antipsychotic medication dose or a change in medication may be preferable to immediate use of an anticholinergic medication in some situations. In addition, one writing group member expressed concern that the use of the phrase “anticholinergic medication” in the statement may be misleading because diphenhydramine is typically viewed as an antihistamine but may be preferable to other anticholinergic medications to treat acute dystonia.

Review of Available Guidelines From Other Organizations

The guidelines of the WFSBP are in agreement with this recommendation, noting that acute dysto- nia responds dramatically to administration of anticholinergic or antihistaminic medication (Hasan et al. 2013). The guideline of the BAP notes that use for acute dystonia “should be determined on

an individual basis, taking account of factors such as the patient’s history of extrapyramidal side effects and the risk of anticholinergic side effects” (Barnes et al. 2011, p. 7).

Quality Measurement Considerations

This guideline statement is not appropriate for use as a quality measure or as part of electronic clin- ical decision support. Even with short-term treatment, some patients could have the potential to de- velop significant anticholinergic side effects, which would need to be incorporated into exclusion and exemption criteria. With reductions in the use of high doses of high-potency FGAs, the fre- quency of acute dystonia is significantly reduced. Any measure would apply only to a small num- ber of individuals, which would complicate testing for feasibility, usability, reliability, and validity.

STATEMENT 12: Treatments for Parkinsonism

APA suggests (2C) the following options for patients who have parkinsonism associated with anti- psychotic therapy: lowering the dosage of the antipsychotic medication, switching to another anti- psychotic medication, or treating with an anticholinergic medication.

Implementation

Medication-induced parkinsonism, which is termed neuroleptic-induced parkinsonism and other medication-induced parkinsonism in DSM-5, is defined as

[p]arkinsonian tremor, muscular rigidity, akinesia (i.e., loss of movement or difficulty initiating move- ment), or bradykinesia (i.e., slowing movement) developing within a few weeks of starting or raising the dosage of a medication (e.g., a neuroleptic) or after reducing the dosage of a medication used to treat extrapyramidal symptoms. (American Psychiatric Association 2013a, p. 709)

These symptoms of medication-induced parkinsonism are dose-dependent and generally resolve with discontinuation of antipsychotic medication. It is important to appreciate that medication-induced parkinsonism can affect emotional and cognitive function, at times in the absence of detectable motor symptoms. As a result, it can be difficult to distinguish the negative symptoms of schizophrenia or con- comitant depression from medication-induced parkinsonism. In addition, emotional and cognitive features of medication-induced parkinsonism can be subjectively unpleasant and can contribute to poor medication adherence (Acosta et al. 2012; Ascher-Svanum et al. 2006).

A number of approaches can be taken when a patient is experiencing medication-induced par- kinsonism. A reduction in the dose of the antipsychotic medication, if feasible, is often helpful in reducing parkinsonism. In some individuals, it may be appropriate to change the antipsychotic medication to one with a lower likelihood of parkinsonism (see Statement 4, Table 6). For individ- uals who are highly sensitive to medication-induced parkinsonism, clozapine may be considered. However, before reducing the dose of medication or changing to another antipsychotic medication, the benefits of reduced parkinsonism should be weighed against the potential for an increase in psychotic symptoms. Careful monitoring for symptom recurrence is always important when mak- ing changes or reducing doses of antipsychotic medications, and use of quantitative measures can be helpful in this regard, as described in Statement 2.

The use of an anticholinergic medication is another option, either on a short-term basis, until a change in dose or a change in medication can occur, or on a longer-term basis, if a change in dose or change in medication is not feasible. In most circumstances, an anticholinergic medication will be started only after parkinsonian symptoms are apparent. However, some individuals may be at increased risk of developing parkinsonism (e.g., those with significant parkinsonism with prior treatment), and prophylactic use of an anticholinergic medication may occasionally be warranted.

Typically, a medication such as benztropine or trihexyphenidyl is used to treat medication-induced parkinsonism because diphenhydramine has a shorter half-life and greater likelihood of sedation.

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However, oral or intramuscular diphenhydramine can also be used on an acute basis. Additional details on these medications are provided in Table 10. It should also be noted that different symp- toms of parkinsonism (e.g., rigidity, tremors, akinesia) may have a differential response to anticho- linergic medications, and different treatment approaches may be needed to address each of these symptoms. Parkinsonism should also be distinguished from tardive dyskinesia, which can be wors- ened by use of anticholinergic medications (Bergman and Soares-Weiser 2018; Cogentin 2013).

If an anticholinergic medication is used, it is important to adjust the medication to the lowest dose that is able to treat the parkinsonian symptoms. In addition, it is also important to use the medication for the shortest time necessary. After several weeks to months, anticholinergic medica- tions can sometimes be reduced or withdrawn without recurrence of parkinsonism or worsening of other antipsychotic-induced neurological symptoms (Desmarais et al. 2012). Medications with anticholinergic effects can result in multiple difficulties for patients, including impaired quality of life, impaired cognition, and significant health complications (Salahudeen et al. 2015). Dry mouth due to anticholinergic effects is associated with an increased risk for multiple dental complications (Singh and Papas 2014), and drinking high-calorie fluids in response to dry mouth can contribute to weight gain. Medications with anticholinergic effects can also precipitate acute angle-closure glaucoma (Lachkar and Bouassida 2007), although patients with treated glaucoma seem to be able to tolerate these medications with careful monitoring (Bower et al. 2018).

Other peripheral side effects of anticholinergic medications can include blurred vision, constipa- tion, tachycardia, urinary retention, and effects on thermoregulation (e.g., hyperthermia in hot weather) (Nasrallah and Tandon 2017; Ozbilen and Adams 2009), and central anticholinergic effects can include impaired learning and memory and slowed cognition (Ang et al. 2017; Vinogradov et al. 2009). Older individuals can be particularly sensitive to these anticholinergic effects and can de- velop problems such as urinary retention, confusion, fecal impaction, and anticholinergic toxicity (with delirium, somnolence, and hallucinations) (Nasrallah and Tandon 2017). In addition, it is im- portant to consider the anticholinergic side effects associated with other medications that a patient is taking, such as antipsychotic medications, some antidepressant medications, urological medica- tions (e.g., oxybutynin), and nonselective antihistamines (e.g., hydroxyzine, diphenhydramine).

Amantadine is an alternative to using an anticholinergic medication to treat medication-induced parkinsonism. Studies of amantadine have had small samples, but the available evidence and clin- ical experience suggest that amantadine may have comparable or somewhat less benefit than anti- cholinergic agents in treating medication-induced parkinsonism (Ananth et al. 1975; Borison 1983; DiMascio et al. 1976; Fann and Lake 1976; Greenblatt et al. 1977; Kelly et al. 1974; KÐnig et al. 1996; McEvoy 1987; McEvoy et al. 1987; Mindham et al. 1972; Silver et al. 1995). With the absence of an- ticholinergic properties, side effects, including cognitive impairment, are less prominent with amantadine than with anticholinergic agents. Common adverse effects with amantadine include nausea, dizziness, insomnia, nervousness, impaired concentration, fatigue, and livedo reticularis. Hallucinations and suicidal thoughts have also been reported, as has an increased seizure fre- quency in individuals with preexisting seizure disorder (Micromedex 2019).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals who have medication-induced parkinsonism, a reduction in signs and symptoms such as rigidity, tremor, and bradykinesia can be of significant benefit, whether such a reduction is achieved by reducing the dose of antipsychotic medication, changing to another antipsychotic medication that has less propensity to cause parkinsonism, or using medications with anticholin- ergic properties to treat the parkinsonism.

TABLE 10. Medications for treatment of medication-induced parkinsonisma Benztropine

Trihexyphenidyl hydrochloride

Artane

Acute dystonia, parkinsonism

Muscarinic antagonist

Oral elixir: 0.4/mL (473 mL)

Tablet: 2, 5

Oral: 5–15

100% 1.3

Not known Not known None known

Not known
4
Urine and bile

No dose adjustments noted in labeling

 

Trade nameb Typical use

Mechanism of action

Available formulations (mg,unlessotherwise noted)

Typical dose range (mg/day)

Bioavailability

Time to peak level (hours)

Protein binding

Metabolism

Metabolic enzymes/ transporters

Metabolites

Elimination half-life (hours)

Excretion
Hepatic impairment

Amantadine

Symmetrel Parkinsonism

Uncompetitive NMDA receptor antagonist (weak)

Tablet: 100 Tablet, extended

release: 129, 193, 258 Capsule: 100 Capsule, liquid filled:

100
Capsule, extended

release: 68.5, 137 Oral syrup: 50/5 mL

Immediate-release tablet or capsule: 100–300

Extended-release tablet: 129–322

86%–94%

Immediate release: 2–4 Extended release: 7.5–

12 67%

Primarily renal

Substrate of organic cation transporter 2

Multiple; unknown activity

16–17

Urine 85% unchanged; 0.6% fecal

No dose adjustments noted in labeling

mesylate

Cogentin

Acute dystonia, parkinsonism

Muscarinic antagonist

Tablet: 0.5, 1, 2 Solution, injection:

1/mL (2 mL)

Tablet: 0.5–6.0 Solution, injection:

1–2

29%

Oral: 7
IM: minutes

95%

Hepatic

Substrate of CYP2D6 (minor)

Not known 7
Urine

No dose adjustments noted in labeling

Diphenhydramine

Benadryl

Acute dystonia, parkinsonism

Histamine H1 antago- nist

Capsule: 25, 50
Oral elixir: 12.5/5 mL Oral solution: 12.5/

5 mL, 6.25/1 mL Tablet: 25, 50 Solution, injection:

50/1 mL
Other brand-name

formulations are available for allergy relief

Oral: 75–200 Solution, injection:

10–50

40%–70% 1–4

76%–85%

Hepatic

Extensively hepatic N- demethylation via CYP2D6; minor de- methylation via CYP1A2, CYP2C9, and CYP2C19; inhib- its CYP2D6 (weak)

Inactive

4–8

Urine (as metabolites and unchanged drug)

No dose adjustments noted in labeling

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109

TABLE 10. Medications for treatment of medication-induced parkinsonisma (continued)

 

Renal impairment

Comments

Amantadine

Elimination half-life increases with renal impairment

Negligible removal by dialysis; do not crush or divide extended- release products

Benztropine mesylate

No dose adjustments noted in labeling

Onset of action with IV dose is comparable to IM

Diphenhydramine

No dose adjustments noted in labeling; however, dosing interval may need to be increased or dosage reduced in older individuals and those with renal impairments

Total daily dose typically divided into 3–4 doses per day

Maximum daily dose 300 mg for oral and 400 mg for IM/IV, with 100 mg maximum dose for IV/IM

IV dose at a rate of
25 mg/minute; IM dose by deep IM injection because subcutaneous or intradermal injection can cause local necrosis

Trihexyphenidyl hydrochloride

No dose adjustments noted in labeling

aThis table includes information compiled from multiple sources. Detailed information on such issues as dose regimen, dose adjust- ments, medication administration procedures, handling precautions, and storage can be found in product labeling. It is recommended that readers consult product labeling information for authoritative information on these medications.

bThe most common U.S. trade names are included for reference only. At the time of publication, some of these products may be manu- factured only as generic products. Other medications or other formulations of the listed medications may be available in Canada.

Abbreviations. CYP=cytochrome P450; NMDA=N-methyl-D-aspartate.

Source. Amantadine hydrochloride capsules 2015; Amantadine hydrochloride oral solution 2015; Amantadine hydrochloride tablets 2019; Benadryl 2018; Benztropine injection 2017; Benztropine tablets 2017; Cogentin 2013; Diphenhydramine hydrochloride injection 2019; Lexicomp 2019; Micromedex 2019; Pendopharm 2015; Procyshyn et al. 2019; Trihexyphenidyl hydrochloride oral solution 2010; Trihexyphenidyl hydrochloride tablets 2015.

Harms

Reducing the dose of an antipsychotic medication or changing to a different antipsychotic medication can be associated with an increase in psychotic symptoms. The harms of using a medication with an- ticholinergic properties to treat medication-induced parkinsonism include side effects such as dry mouth, blurred vision, precipitation of acute angle-closure glaucoma, constipation (and in some cases fecal impaction), tachycardia, urinary retention, effects on thermoregulation (e.g., hyperthermia in hot weather), impaired learning and memory, slowed cognition, and anticholinergic toxicity (with de- lirium, somnolence, and hallucinations). These harms are likely to be greater in older individuals and may be augmented in individuals taking other medications with anticholinergic properties.

Patient Preferences

Clinical experience suggests that most patients are bothered by medication-induced parkinsonism and would like to minimize or eliminate this side effect of antipsychotic medication. However,

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most patients will also want to minimize the chance that psychotic symptoms will increase. Many patients are also troubled by side effects such as blurred vision, dry mouth, and constipation and may wish to avoid more significant side effects associated with anticholinergic medications. Con- sequently, the balance of these possible risks and benefits of different approaches to addressing medication-induced parkinsonism is likely to vary for each individual and his or her risk factors and personal preferences.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms because medication-induced parkinsonism can affect the patient’s quality of life, and pa- tients would prefer to address it, if feasible. However, each of the available options for decreasing or eliminating medication-induced parkinsonism has associated risks and characteristics, and pref- erences of each patient need to be taken into consideration. In addition, the long-term benefits and harms of anticholinergic medications are less clear, and harms of long-term use may outweigh ben- efits. For additional discussion of the research evidence, see Appendix C, Statement 12.

Differences of Opinion Among Writing Group Members

Eight writing group members voted to suggest this statement. One writing group member dis- agreed with this statement, believing that a reduction in antipsychotic medication dose or a change in medication would be preferable to use of an anticholinergic medication.

Review of Available Guidelines From Other Organizations

Statements from other guidelines vary in their approach to medication-induced parkinsonism. The WFSBP guideline notes that use of SGAs or reductions in medication doses should be the primary treatment for medication-induced parkinsonism (Hasan et al. 2013). The BAP guideline notes that decisions about the use of anticholinergic medications for medication-induced parkinsonism should be made on an individual basis, but these medications should not be given prophylactically (Barnes et al. 2011). The PORT guideline notes that prophylactic use of antiparkinsonian agents is not warranted in patients treated with SGAs but may be indicated on an individual basis in patients treated with FGAs (Buchanan et al. 2010).

Quality Measurement Considerations

As a suggestion, this statement is not appropriate for use as a quality measure. It is also not appro- priate for incorporation into electronic decision support.

STATEMENT 13: Treatments for Akathisia

APA suggests (2C) the following options for patients who have akathisia associated with antipsy- chotic therapy: lowering the dosage of the antipsychotic medication, switching to another antipsy- chotic medication, adding a benzodiazepine medication, or adding a beta-adrenergic blocking agent.

Implementation

Medication-induced acute akathisia is defined in DSM-5 as

[s]ubjective complaints of restlessness, often accompanied by observed excessive movements (e.g., fid- gety movements of the legs, rocking from foot to foot, pacing, inability to sit or stand still), developing within a few weeks of starting or raising the dosage of a medication (such as a neuroleptic) or after re- ducing the dosage of a medication used to treat extrapyramidal symptoms. (American Psychiatric As- sociation 2013a, p. 711)

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Akathisia is sometimes difficult to distinguish from psychomotor agitation associated with psycho- sis, leading to a cycle of increasing doses of antipsychotic medication that lead to further increases in akathisia. Even in mild forms in which the patient is able to control most movements, akathisia is often extremely distressing to patients and is a frequent cause of nonadherence with antipsy- chotic treatment. If allowed to persist, akathisia can contribute to feelings of dysphoria and, in some instances, suicidal behaviors. The reported rates of akathisia vary from 10%–15% to as many as one- third of patients treated with antipsychotic medication, even when SGAs are used (Juncal-Ruiz et al. 2017; Martino et al. 2018; Mentzel et al. 2017; Miller et al. 2008).

A number of approaches can be taken when a patient is experiencing antipsychotic-induced akathi- sia. A reduction in the dose of the antipsychotic medication, if feasible, is often helpful in reducing akathisia. In some individuals, it may be appropriate to change the antipsychotic medication to one with a lower likelihood of akathisia (see Statement 4, Table 6). However, before reducing the dose of medication or changing to another antipsychotic medication, the benefits of reduced akathisia should be weighed against the potential for an increase in psychotic symptoms. Careful monitoring for symp- tom recurrence is always important when making changes or reducing doses of antipsychotic medica- tions, and use of quantitative measures can be helpful in this regard, as described in Statement 2.

Benzodiazepine medications, including lorazepam and clonazepam, can also be helpful in the treatment of akathisia. Among other side effects, somnolence and cognitive difficulties can be asso- ciated with benzodiazepine use (Lexicomp 2019; Micromedex 2019). In addition, problems with co- ordination as a result of benzodiazepines can contribute to falls, particularly in older individuals (Donnelly et al. 2017). Although benzodiazepines are much safer than older sedative agents, respi- ratory depression can be seen with high doses of a benzodiazepine, particularly in combination with alcohol, other sedating medications, or opioids (Hirschtritt et al. 2017). Caution may also be indicated in prescribing benzodiazepines to individuals with sleep apnea, although few studies are available (Mason et al. 2015). Individuals who are treated with a benzodiazepine may also take them in higher amounts or more frequently than intended. In some patients, a sedative, hypnotic, or anxiolytic use disorder may develop, particularly in individuals with a past or current diagnosis of alcohol use disorder or another substance use disorder.

Another option for treatment of akathisia is the β-adrenergic blocking agent propranolol (Pringsheim et al. 2018), which is typically administered in divided doses, with a total daily dose of 30–120 mg. When using propranolol, it is important to monitor blood pressure with increases in dose and recog- nize that taking propranolol with protein-rich foods can increase bioavailability by 50%. In addition, propranolol is metabolized by CYP1A2, CYP2D6, CYP2C19, and CYP3A4, which can contribute to drug-drug interactions. Some literature also suggests that mirtazapine may reduce akathisia in some patients (Perry et al. 2018; Poyurovsky and Weizman 2018; Praharaj et al. 2015). In contrast, akathi- sia tends not to respond to anticholinergic agents (Pringsheim et al. 2018; Rathbone and Soares- Weiser 2006).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals who have akathisia associated with antipsychotic medication, a reduction in symp- toms can be of significant benefit, whether such a reduction is achieved by reducing the dose of an- tipsychotic medication, changing to another antipsychotic medication that has less propensity to cause akathisia, or using a benzodiazepine or a β-adrenergic blocking agent to treat akathisia.

Harms

Reducing the dose of an antipsychotic medication or changing to a different antipsychotic medication can be associated with an increase in psychotic symptoms. The harms of using a benzodiazepine can

include somnolence, cognitive difficulties, problems with coordination, and risk of misuse or develop- ment of a sedative use disorder. In high doses and particularly in combination with alcohol, other se- dating medications, or opioids, respiratory depression may occur. With use of a β-adrenergic blocking agent, such as propranolol, the primary harm relates to lowering of blood pressure.

Patient Preferences

Clinical experience suggests that most patients are bothered by akathisia and, in some instances, very distressed by it. Thus, almost all patients would like to minimize or eliminate this side effect of antipsychotic medication. However, most patients will also want to minimize the chance that psychotic symptoms will increase. They may also be concerned about the possible side effects of medications such as benzodiazepines and β-adrenergic blocking agents. Consequently, the balance of these possible risks and benefits of different approaches to addressing akathisia are likely to vary for each individual and his or her risk factors and personal preferences.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms because akathisia can affect the patient’s quality of life, and patients would prefer to address it, if feasible. However, each of the available options for decreasing or eliminating akathisia has as- sociated risks and characteristics, and the preferences of each patient need to be taken into consid- eration. For additional discussion of the research evidence, see Appendix C, Statement 13.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this suggestion.

Review of Available Guidelines From Other Organizations

The WFSBP guideline notes that there is some evidence that benzodiazepines are effective in the treatment of akathisia and that there is very limited evidence to support the use of centrally active β-adrenergic blocking agents in the treatment of akathisia (Hasan et al. 2013).

Quality Measurement Considerations

As a suggestion, this statement is not appropriate for use as a quality measure. It is also not appro- priate for incorporation into electronic decision support.

STATEMENT 14: VMAT2 Medications for Tardive Dyskinesia

APA recommends (1B) that patients who have moderate to severe or disabling tardive dyskinesia as- sociated with antipsychotic therapy be treated with a reversible inhibitor of the vesicular mono- amine transporter 2 (VMAT2).

Implementation

Tardive syndromes are persistent abnormal involuntary movement disorders caused by sustained exposure to antipsychotic medication, the most common of which are tardive dyskinesia, tardive dystonia, and tardive akathisia (Frei et al. 2018). They begin later in treatment than acute dystonia, akathisia, or medication-induced parkinsonism, and they persist and may even increase, despite re- duction in dose or discontinuation of the antipsychotic medication. Typically, tardive dyskinesia presents as “[i]nvoluntary athetoid or choreiform movements (lasting at least a few weeks) gener- ally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal,

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diaphragmatic, or trunk muscles)” (American Psychiatric Association 2013a, p. 712), whereas tar- dive dystonia and tardive akathisia resemble their acute counterparts in phenomenology.

Tardive dyskinesia has been reported after exposure to any of the available antipsychotic medi- cations (Carbon et al. 2017, 2018). It occurs at a rate of approximately 4%–8% per year in adult pa- tients treated with FGAs (Carbon et al. 2018; Woods et al. 2010), a risk that appears to be at least three times that observed with SGAs (Carbon et al. 2018; O’Brien 2016; Woods et al. 2010). Various factors are associated with greater vulnerability to tardive dyskinesia, including age greater than 55 years; female sex; white or African race/ethnicity; presence of a mood disorder, intellectual dis- ability, or central nervous system injury; and past or current akathisia, clinically significant parkin- sonism, or acute dystonic reactions (Patterson-Lomba et al. 2019; Solmi et al. 2018a).

Evaluation for the presence of tardive syndromes is important in order to identify them, mini- mize worsening, and institute clinically indicated treatment. However, evaluation of the risk of tar- dive dyskinesia is complicated by the fact that dyskinetic movements may be observed with a reduction in antipsychotic medication dose, which is termed a withdrawal-emergent dyskinesia (American Psychiatric Association 2013a). Fluctuations in symptoms are also common and may be influenced by such factors as psychosocial stressors. Furthermore, spontaneous dyskinesias, which are clinically indistinguishable from tardive dyskinesia, have been described in elderly patients be- fore the advent of antipsychotic medications and in up to 20% of never-medicated patients with chronic schizophrenia (Blanchet et al. 2004; Crow et al. 1982; Fenton et al. 1997; Saltz et al. 1991).

Regular assessment of patients for tardive syndromes through clinical examination or through the use of a structured evaluative tool can aid in identifying tardive syndromes, clarifying their likely etiology, monitoring their longitudinal course, and determining the effects of medication changes or treatments for tardive dyskinesia (see Statement 1, Table 2). The AIMS and the DISCUS are examples of such tools (Guy 1976; Kalachnik and Sprague 1993; Munetz and Benjamin 1988). When using scales such as the AIMS or the DISCUS, it should be noted that there is no specific score threshold that suggests a need for intervention, although ranges of scores are noted to correspond with mild, moderate, and severe symptoms. In addition, the same total score can be associated with significantly different clinical manifestations and varying impacts on the patient. Patients, family members, and other persons of support may be able to provide information about the onset of movements; their longitudinal course in relation to treatment or other precipitants; and their im- pact on functioning, health status (including dentition), and quality of life.

Although the majority of patients who develop tardive dyskinesia have mild symptoms, a small proportion will develop symptoms of moderate or severe degree. In such circumstances, assessment for other contributors to a movement disorder is also warranted (Jinnah and Factor 2015; Mehta et al. 2015; Poewe and Djamshidian-Tehrani 2015; Preskorn et al. 2015; Waln and Jankovic 2015). In addition to a neurological examination and complete history of motor symptoms and past and current medications, history and laboratory testing may include liver function tests, thyroid function tests, se- rum calcium, complete blood count, and antiphospholipid antibodies. Depending on the results of the history and evaluation, additional studies may be indicated (e.g., ceruloplasmin for Wilson’s dis- ease; brain MRI for basal ganglia changes with Huntington’s disease, stroke, or other lesions; lumbar puncture for anti-NMDA receptor encephalitis). If dyskinetic movements have begun or have in- creased in the context of antipsychotic dose reduction, it is important to assess the longitudinal course of symptoms for up to several months because spontaneous reductions or resolution of the dyskinesia may occur.

If no contributing etiology is identified and moderate to severe or disabling tardive dyskinesia per- sists, treatment is recommended with a reversible inhibitor of the VMAT2. Treatment with a VMAT2 inhibitor can also be considered for patients with mild tardive dyskinesia on the basis of such factors as patient preference, associated impairment, or effect on psychosocial functioning. Table 11 shows the characteristics of VMAT2 inhibitors that are currently available in the United States.

TABLE 11. Reversible inhibitors of human vesicular monoamine transporter type 2a

 

Trade nameb
Available formulations (mg) Typical dose range (mg/day) Bioavailability
Time to peak level (hours) Protein binding

Metabolism

Metabolic enzymes/ transporters

Metabolites
Elimination half-life (hours) Excretion
Hepatic impairment

Renal impairment Common adverse effects

Effect of food on bioavailability

Deutetrabenazine

Austedo

Tablet: 6, 9, 12

12–48

80%

3–4

60%–68% (α-HTBZ) 59%–63% (β-HTBZ)

Hepatic

Major substrate of CYP2D6, minor substrate of CYP1A2 and CYP3A4

Deuterated α-HTBZ and β-HTBZ: active

Deuterated α-HTBZ and β-HTBZ: 9–10

Urine: ~75%–85% changed Feces: ~8%–11%

Contraindicated

No information available Sedation

Food affects maximal concentration. Administer with food. Swallow tablets whole and do not chew, crush, or break.

Tetrabenazine

Xenazine Tablet: 12.5, 25 25–75
75%
1–2

82%–85%
60%–68% (α-HTBZ) 59%–63% (β-HTBZ)

Hepatic
Major substrate of CYP2D6

α-HTBZ, β-HTBZ, and O– dealkylated HTBZ: active

α-HTBZ: 4–8 β-HTBZ: 2–4

Urine: ~75% changed Feces: ~7%–16%

Contraindicated

No information available

Sedation, depression, extrapyramidal effects, insomnia, akathisia, anxiety, nausea, falls

Unaffected by food

Valbenazine

Ingrezza

Capsule: 40, 80

40–80

49%

0.5–1

> 99%
64% α-HTBZ

Hepatic

Major substrate of CYP3A4, minor substrate of CYP2D6

α-HTBZ: active

15–22

Urine: 60% Feces: 30%

Maximum dose of 40 mg daily with moderate to severe impairment (Child- Pugh score 7–15)

Use not recommended in severe renal impairment (CrCl<30 mL/minute)

Sedation

Can be taken with or without food. High-fat meals decrease the Cmax and AUC for valbenazine, but values for the active metabolite (α-HTBZ) are unchanged.

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TABLE 11.

Reversible inhibitors of human vesicular monoamine transporter type 2a (continued)

Deutetrabenazine

Give in divided doses; increase from initial dose of 12 mg/day by 6 mg/week to maximum dose of 48 mg/ day. Retitrate dose for treatment interruptions of more than 1 week.

Follow product labeling if switching from tetrabenazine to deutetrabenazine. Do not exceed total daily dosage of 36 mg/day (18 mg/dose) in poor CYP2D6 metabolizers or patients taking a strong CYP2D6 inhibitor.

Assess ECG before and after increasing the daily dose above 24 mg in patients at risk for QTc prolongation.

Avoid use in patients with congenital long QT syndrome, with arrhythmias associated with a prolonged QT interval, or with other risks for QTc prolongation (e.g., drugs known to prolong QTc intervals, reduced metabolism via CYP2D6).

Tetrabenazine Valbenazine

Commentsc

Give in divided doses; increase from initial dose of 25–50 mg/day by 12.5 mg/ week to maximum of 150– 200 mg/day. Retitrate dose for treatment interruptions of more than 5 days.

Test for CYP2D6 metabolizer status before giving doses >50 mg/day.

Do not exceed 50 mg/day in poor metabolizers or in patients treated with a strong inhibitor of CYP2D6.

Avoid use in patients with congenital long QT syndrome, with arrhythmias associated with a prolonged QT interval, or with other risks for QTc prolongation (e.g., drugs known to prolong QTc intervals, reduced metabolism via CYP2D6).

Initiate at 40 mg/day and increase to 80 mg/day after 1 week. Continuation of 40 mg/day may be considered for some patients.

Use is not recommended with strong CYP3A4 inducer. A reduced dose is recommended with concomitant use of strong CYP3A4 or CYP2D6 inhibitors or in poor CYP2D6 metabolizers.

Avoid use in patients with congenital long QT syndrome, with arrhythmias associated with a prolonged QT interval, or with other risks for QTc prolongation (e.g., drugs known to prolong QTc intervals, reduced metabolism via CYP2D6 or CYP3A4).

aThis table includes information compiled from multiple sources. Detailed information on such issues as dose regimen, dose adjust- ments, medication administration procedures, handling precautions, and storage can be found in product labeling. It is recommended that readers consult product labeling information for authoritative information on these medications.

bThe most common U.S. trade names are included for reference only. At the time of publication, some of these products may be manu- factured only as generic products.

cAll VMAT2 inhibitors are contraindicated within 2 weeks of a monoamine oxidase inhibitor, within 20 days of reserpine, or in patients with active suicidal ideas or untreated depression. Tetrabenazine and deutetrabenazine carry a boxed warning related to depression and suicidal ideation in patients with Huntington’s disease.

Abbreviations. AUC=area under the curve; Cmax=maximum plasma concentration; CrCl=creatinine clearance; CYP=cytochrome P450; ECG=electrocardiogram; HTBZ=dihydrotetrabenazine.

Source. Austedo 2019; Ingrezza 2019; Lexicomp 2019; Micromedex 2019; Xenazine 2018.

In general, deutetrabenazine or valbenazine is preferred over tetrabenazine because of the greater evidence base supporting their use. In addition, tetrabenazine has a shorter half-life and greater rates of associated depression when used in the treatment of patients with Huntington’s disease. Other factors that may influence choice of a VMAT2 inhibitor relate to hepatic or renal function; tetrabenazine and deutetrabenazine are contraindicated in individuals with hepatic im- pairment, whereas valbenazine is not recommended for use in individuals with severe renal im- pairment. The metabolism of these medications is also somewhat different. Although all of these medications are substrates for CYP2D6 and CYP3A4, tetrabenazine and deutetrabenazine are ma- jor substrates for CYP2D6, whereas valbenazine is a major substrate for CYP3A4. Consequently, the

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patient’s CYP2D6 metabolizer status or use of concomitant medications that influence these meta- bolic enzymes may affect the choice of a VMAT2 inhibitor. In terms of side effects, these medica- tions are generally well tolerated, with sedation being most common. In initial studies of tetrabenazine in patients with Huntington’s disease, significant rates of depression were noted as well as concerns about suicidal ideas and behaviors (Shen et al. 2013). However, in studies of deu- tetrabenazine and valbenazine in patients with tardive dyskinesia, there were no apparent increases in depression or suicidal ideas either in the randomized portions of the clinical trials or in longer open-label extension periods (Solmi et al. 2018b). Nevertheless, depression or suicidal ideas could oc- cur during treatment for tardive dyskinesia, and clinicians will want to be alert to this possibility.

Small clinical trials and case series have examined other treatments for tardive dyskinesia. A lower dose of antipsychotic medication can be considered, although evidence for this approach is minimal (Bergman et al. 2017), and the potential for benefit needs to be weighed against the possibil- ity of recurrent symptoms or relapse. Some benefits have been noted with benzodiazepines (Bergman et al. 2018a), although the potential for benefits must be weighed against the potential side effects of these medications, including somnolence, cognitive difficulties, problems with coordination, and risk of misuse or development of a sedative use disorder. In high doses and particularly in com- bination with alcohol, other sedating medications, or opioids, respiratory depression may occur. A change in antipsychotic therapy to a lower-potency medication (particularly clozapine) may also be associated with a reduction in tardive dyskinesia, particularly for individuals with moderate to severe symptoms (Mentzel et al. 2018). Again, however, the potential benefits of changing medica- tion should be considered in light of the possibility of symptom recurrence.

In general, giving a higher dose of an antipsychotic may suppress movements of tardive dyski- nesia in the short term but would be expected to escalate further development of tardive dyskinesia in the long term. Nevertheless, there may be life-threatening circumstances (e.g., patients with con- stant movement, gagging, or choking) in which rapid suppression of dyskinesia is needed, and ju- dicious use of an antipsychotic may be appropriate. Anticholinergic medications do not improve and may even worsen tardive dyskinesia (Bergman and Soares-Weiser 2018; Cogentin 2013) in ad- dition to producing significant side effects.

For individuals with other tardive syndromes, other approaches may be helpful on an individual basis. For example, depending on the muscle group that is affected, injections of botulinum toxin have been used to treat tardive dystonia (Brashear et al. 1998; Jinnah and Factor 2015; Kiriakakis et al. 1998). In addition, tardive dystonia may respond to β-adrenergic blocking agents (Hatcher-Martin et al. 2016), and in rare cases of severe intractable tardive dystonia, deep brain stimulation might be considered (Paschen and Deuschl 2018). High doses of anticholinergic agents have also been used to treat severe tardive dystonia (Burke et al. 1982; Kang et al. 1986; Wojcik et al. 1991), although these medications are not useful in treating tardive dyskinesia (Bergman and Soares-Weiser 2018; Cogentin 2013). Reserpine, which also depletes monoamines, should not be used to treat tardive syndromes because it has high rates of associated depression and suicidal ideas and lowers blood pressure (Micromedex 2019). Other treatments, such as vitamin B6 or vitamin E, are less likely to be associated with harms but do not appear to be associated with benefits in treating tardive dyskine- sia (Adelufosi et al. 2015; Soares-Weiser et al. 2018a).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

In individuals with moderate to severe or disabling tardive dyskinesia associated with antipsy- chotic therapy, VMAT2 inhibitors can be associated with significant reductions in motor signs and symptoms of tardive dyskinesia. These medications may also be effective in other tardive syn- dromes.

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Harms

The harms of treatment with VMAT2 inhibitors include sedation and, with tetrabenazine, extrapy- ramidal effects, akathisia, insomnia, anxiety, nausea, and falls. Depression and suicidal ideas have been reported in individuals who were administered VMAT2 inhibitors for treatment of Hunting- ton’s disease. Such effects are possible in individuals treated for tardive dyskinesia, although they were not reported in clinical trials.

Patient Preferences

Clinical experience suggests that most patients with moderate to severe or disabling tardive dyski- nesia wish to have a diminution of their motor signs and symptoms. Most patients would be will- ing to take medication to achieve a reduction in motor signs and symptoms, particularly if it is well tolerated.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. The majority of individuals with moderate to severe or disabling tardive dyskinesia would have a greater likelihood of experiencing benefits of a VMAT2 inhibitor than experiencing harms. Patient preferences to reduce motor signs and symptoms are also likely to favor treatment. For ad- ditional discussion of the research evidence, see Appendix C, Statement 14.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

The WFSBP guideline notes that tetrabenazine might have positive effects on tardive dyskinesia (Hasan et al. 2013). It also notes that the risk of tardive dyskinesia is less with SGAs than with FGAs and that there is limited evidence of benefit with clozapine for tardive dyskinesia. Information on a range of other treatments is noted to be even less conclusive. The practice guideline of the Amer- ican Academy of Neurology, which was published before the availability of deutetrabenazine and valbenazine, notes that tetrabenazine might be considered as a treatment for tardive syndromes (Bhidayasiri et al. 2013).

Quality Measurement Considerations

If a quality measure on VMAT2 inhibitor treatment of tardive syndromes is considered at the pro- vider, facility, health plan, integrated delivery system, or population level, testing of feasibility, usabil- ity, reliability, and validity would be essential prior to use for purposes of accountability. However, it may be possible and preferable to incorporate this recommendation into internal facility or health plan initiatives focused on enhanced identification and treatment of tardive syndromes.

Electronic decision support using passive alerts may be able to prompt clinicians to consider a VMAT2 inhibitor, although such prompts would depend on accurate and consistent entry of struc- tured information about the presence of a tardive syndrome, its severity, and its associated degree of disability. Nevertheless, in combination with rating scale data (e.g., AIMS), electronic decision support could help identify individuals with a tardive syndrome who may benefit from a trial of a VMAT2 inhibitor. Information from laboratory data, diagnoses, or problem lists would also be helpful to incorporate in terms of potential contraindications to VMAT2 inhibitor treatment (e.g., tetrabenazine and deutetrabenazine are contraindicated in the presence of hepatic impairment; val- benazine is not recommended for use in individuals with severe renal impairment).

Psychosocial Interventions

STATEMENT 15: Coordinated Specialty Care Programs

APA recommends (1B) that patients with schizophrenia who are experiencing a first epi- sode of psychosis be treated in a coordinated specialty care program.*

Implementation

For individuals with a first episode of psychosis, coordinated specialty care (CSC) programs have been developed that integrate a number of evidence-based interventions into a comprehensive treat- ment package. For example, the NAVIGATE program, which was developed for the Recovery After an Initial Schizophrenia Episode (RAISE) Early Treatment research initiative, uses a collaborative, shared decision-making approach that incorporates family involvement and education, individual resiliency training, supported employment and education, and individualized medication treatment (Mueser et al. 2015; National Institute of Mental Health 2019a). Similar CSC programs, which are sometimes referred to as team-based, multicomponent interventions, have also been used in other countries for treatment of early psychosis (Anderson et al. 2018; Craig et al. 2004; Secher et al. 2015). These treatment programs often include individuals with diagnoses other than schizophrenia but have been associated with a number of benefits, including lower mortality (Anderson et al. 2018), lower rates of relapse, better quality of life, better global function, and greater likelihood of working or being in school after receiving up to 2 years of treatment (McDonagh et al. 2017). Patients in such programs may also experience a greater sense of empowerment and support for their autonomy (Browne et al. 2017). Programs are also available that are aimed at early identification and treatment of attenuated psychosis syndrome or related syndromes of high psychosis risk (J. Addington et al. 2017; Cotton et al. 2016); however, these programs are not within the scope of this guideline recom- mendation because they include individuals who do not have a psychiatric diagnosis or who have diagnoses other than schizophrenia at later follow-up times (Fusar-Poli et al. 2016; Iorfino et al. 2019).

The main barriers to implementing this recommendation in practice relate to the limited avail- ability of first-episode, multicomponent treatment programs. For state health agencies, health sys- tems, or organizations that are implementing these programs, barriers include such issues as funding, training, and implementation support. However, consultation and implementation mate- rials are available to help guide the establishment of new programs with evidence-based ap- proaches (National Institute of Mental Health 2019b; NAVIGATE 2019; OnTrackNY 2019). Tools are also available to assess fidelity of CSC programs to intended implementation principles (Add- ington et al. 2016, 2018; Durbin et al. 2019; Essock and Addington 2018).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of a CSC program for individuals with a first episode of psychosis can be associated with lower mortality, lower rates of relapse, better quality of life, better global function, and greater likelihood of working or being in school after receiving up to 2 years of treatment (low to moderate strength of research evidence).

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Harms

The harms of a CSC program for individuals with a first episode of psychosis are not well delin- eated but are likely to be small.

Patient Preferences

Clinical experience suggests that many patients with a first episode of psychosis are cooperative with and accepting of a CSC program; however, other patients may not wish to take part in such a program out of a belief that they do not have a condition that requires treatment or because of lo- gistical barriers that influence their ability to access the more intensive treatment provided by such a program.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. CSC treatment programs are generally viewed positively by patients, and they improve a number of patient-oriented outcomes with minimal risk of harms. For additional discussion of the research evidence, see Appendix C, Statement 15.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Other guidelines did not specifically address the use of CSC programs, but they do endorse many of the individual elements of such programs (e.g., family engagement, psychoeducation, supported employment, medication treatment).

Quality Measurement Considerations

More patients may benefit from CSC programs in the United States than currently receive it. Conse- quently, state mental health agencies, health plans, and health organizations may wish to implement initiatives to increase the use of a CSC program among individuals with a first episode of psychosis.

This guideline statement would not be appropriate for a performance-based quality measure unless it were tested for feasibility, usability, reliability, and validity. Factors such as geographic variations in treatment availability would need to be considered in testing any quality measures related to CSC pro- gram use. It may also be difficult to determine whether a patient is receiving appropriate CSC services.

Electronic decision support using passive alerts may be able to prompt clinicians to consider re- ferral to a CSC program if the presence of a first episode of schizophrenia and the patient’s history of prior treatment were accurately and consistently entered into the electronic record as structured data. The electronic record could also incorporate reference information on the location and referral processes for CSC treatment programs in the local area.

STATEMENT 16: Cognitive-Behavioral Therapy

APA recommends (1B) that patients with schizophrenia be treated with cognitive-behavioral therapy for psychosis (CBTp).*

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Implementation

The use of cognitive-behavioral therapy (CBT) for individuals with schizophrenia has a number of potential benefits, including improvements in quality of life and global, social, and occupational func- tion and reductions in core symptoms of illness, such as positive symptoms. However, it is important to appreciate that these benefits have been found in studies of CBT that is adapted to use for individ- uals with psychosis (CBTp), which has some differences from CBT that is focused on other indica- tions. More specifically, CBTp focuses on guiding patients to develop their own alternative explanations for maladaptive cognitive assumptions that are healthier and realistic and do not per- petuate the patient’s convictions regarding the veracity of delusional beliefs or hallucinatory experi- ences. Thus, the overall approach with CBTp includes developing a collaborative and nonjudgmental therapeutic relationship in which patients can learn to monitor relationships between thoughts, feel- ings, behaviors, and symptoms and to evaluate the perceptions, beliefs, and thought processes that contribute to symptoms (Beck and Rector 2005; Beck et al. 2009; Beck Institute 2019; Hardy 2019; Kingdon and Turkington 2019; Landa 2019; Lecomte et al. 2016; Morrison 2017; Turkington et al. 2006; Wright et al. 2009). (Videos that demonstrate some of the approaches to CBTp are available at I Can Feel Better, http://www.icanfeelbetter.org/cbtpskills.) Through this dual focus on monitoring and evaluation, patients can develop beneficial coping strategies and improve functioning, with behav- ioral self-monitoring serving as a basis for graded task assignments or activity scheduling. In addi- tion, symptoms can be discussed as being within a range of normal experiences (e.g., hearing a loved one’s voice in the context of grief), and alternative explanations for symptoms can be devel- oped that help reduce associated stress (Turkington et al. 2006).

CBTp can be started in any treatment setting, including inpatient settings, and during any phase of illness (Turkington et al. 2006), although some initial reduction in symptoms may be needed for optimal participation (Burns et al. 2014; Valmaggia et al. 2008). It can also be conducted in group as well as in individual formats, either in person or via Web-based delivery platforms. CBTp can also be made available to family members or other persons of support (Turkington and Spencer 2019). Although patient preferences and treatment availability may influence choice of a delivery method, there do not appear to be clear-cut differences in the treatment benefits of group as compared with individual CBTp (McDonagh et al. 2017; Wykes et al. 2008).

The duration of treatment with CBTp has varied in research and clinical practice, with a range from 8 weeks to 5 years of treatment reported in the literature (McDonagh et al. 2017). However, guidelines from other countries recommend a minimum treatment duration of 16 sessions of CBTp (National Institute for Health and Care Excellence 2014; Norman et al. 2017; Scottish Intercollegiate Guidelines Network 2013). Although the available research suggests that treatment benefits are no longer significant when assessed more than 6 months after the end of a CBTp course (McDonagh et al. 2017), it is unclear whether longer durations of treatment with CBTp will result in greater ben- efits or will help in maintaining treatment-related improvements.

Issues with implementation of CBTp have also been examined. Although the methodological rigor of most studies has been low (Ince et al. 2016), common barriers to CBTp have been identified. For example, some individuals with schizophrenia may be too symptomatic or are experiencing too many side effects (e.g., sedation) to allow effective participation, particularly in inpatient settings. From a patient-centered perspective, CBTp was sometimes viewed as more emotionally challenging and requiring more effort (e.g., homework) than other psychological therapies (Wood et al. 2015). However, engagement strategies, such as motivational interviewing, can be useful in helping patients explore whether CBTp might have potential benefits for them that would offset such concerns.

Attitudinal barriers of staff and organizational management were also found to be common and included a lack of understanding of CBTp and negative expectancies about its value. In addition to inadequate availability of trained staff, staff reported difficulty in identifying patients who were most likely to benefit from CBTp as well as a lack of dedicated time to provide CBTp. Insufficient initial training and insufficient reinforcement of training were also common. Thus, for CBTp to be

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effective, individuals who are providing CBTp should have appropriate training using established approaches, supervision in CBTp techniques, and experience in treating individuals with schizo- phrenia. In addition, concerted efforts may be needed to foster positive attitudes and assure ade- quate time to deliver CBTp. At organizational or health system levels, attention to enhancing the availability of CBTp is also important given the limited availability of CBTp in the United States. Stepped-care approaches, learning collaborative models, and other approaches to best-practice consultations show promise as ways to enhance delivery of CBTp in community settings (Creed et al. 2014; Kopelovich et al. 2019a, 2019b; Stirman et al. 2010).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of CBTp in the treatment of schizophrenia can be associated with overall reductions in core ill- ness symptoms, such as positive symptoms (moderate strength of research evidence). CBTp can also be associated with short-term improvements (e.g., for up to 6 months) in quality of life (low strength of research evidence) and global, social, and occupational function (moderate strength of research evidence).

Harms

The harms of CBTp in the treatment of schizophrenia are not well delineated or systematically stud- ied but are likely to be small based on the small number of reported harms in clinical trials.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of CBTp as part of a treatment plan; however, other patients may not wish to participate in CBTp, may be reluctant to adhere to assignments between sessions, or may experience logistical barriers (e.g., time, access to transportation, childcare, cost) to attending CBTp sessions.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. Specifically, the potential for modest benefits in important patient-centered outcomes during and for periods of up to 6 months after CBTp treatment seemed to outweigh the minimal harms of CBTp treatment. For additional discussion of the research evidence, see Appendix C, Statement 16.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Statements from other practice guidelines are consistent with this recommendation. The RANZCP and NICE guidelines recommend the use of CBTp for all individuals with schizophrenia (Galletly et al. 2016; National Institute for Health and Care Excellence 2014), whereas the SIGN, CSG, and PORT guidelines recommend CBTp for individuals who have persistent symptoms despite treat- ment with an antipsychotic medication (Dixon et al. 2010; Norman et al. 2017; Scottish Intercolle- giate Guidelines Network 2013). The NICE, SIGN, and CSG guidelines note that CBTp should include at least 16 planned sessions (National Institute for Health and Care Excellence 2014; Norman et al. 2017; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

This guideline statement may not be appropriate for a performance-based quality measure because of the impact of logistical barriers to CBTp, including geographic variations in availability of CBTp, and the difficulty in identifying whether delivered psychotherapy is CBTp. Reminders about CBTp are also not well suited to incorporation into electronic health record clinical decision support. An- ecdotal observations suggest that use of CBTp is infrequent in the United States (Kopelovich et al. 2019b). Consequently, health organizations and health plans may wish to implement programs to increase the use of CBTp among individuals with schizophrenia.

STATEMENT 17: Psychoeducation

APA recommends (1B) that patients with schizophrenia receive psychoeducation.*

Implementation

Elements of psychoeducation are an integral part of good clinical practice. For example, APA’s Prac- tice Guidelines for the Psychiatric Evaluation of Adults emphasizes the importance of involving patients in treatment-related decision-making and recommends providing the patient with education about the differential diagnosis, risks of untreated illness, treatment options, and benefits and risks of treat- ment (American Psychiatric Association 2016a). In addition, these informal approaches to psycho- education have been expanded into formal, systematically delivered programs of psychoeducation that have been evaluated through clinical trials (Pekkala and Merinder 2002; Xia et al. 2011).

The psychoeducational programs that have been studied have varied in their format, duration, and scope. Some psychoeducational programs are delivered on an individual basis, whereas others are delivered in a group format, often in conjunction with family members or other individuals who are involved in the patient’s life. In clinical trials, a 12-session program of psychoeducation is the norm; however, briefer psychoeducation programs of 10 sessions or fewer have also been stud- ied (Pekkala and Merinder 2002; Xia et al. 2011). Typically, psychoeducation is conducted on an out- patient basis, but elements of formal psychoeducation programs can also be incorporated into care in inpatient settings.

Information that is commonly conveyed in a psychoeducation program includes key informa- tion about diagnosis, symptoms, psychosocial interventions, medications, and side effects as well as information about stress and coping, crisis plans, early warning signs, and suicide and relapse prevention (Bäuml et al. 2006). Teaching of illness management or self-management strategies (Substance Abuse and Mental Health Services Administration 2010a), as discussed in Statement 21, is often incorporated into psychoeducation. In addition to conveying empathy and respect for the in- dividual, psychoeducation is delivered in a manner that aims to stimulate hope, reassurance, resil- ience, and empowerment. Typically, psychoeducation incorporates multiple educational modalities, such as workbooks (McCrary et al. 2019), pamphlets, videos, and individual or group discussions in achieving the goals of psychoeducation. Information that may be useful to patients and families as a part of psychoeducation is available through SMI Adviser (https://smiadviser.org). Barriers to providing psychoeducation as a part of the treatment plan relate primarily to program availability. Online delivery of psychoeducation may be one approach to enhancing availability.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of psychoeducation in the treatment of schizophrenia can be associated with a number of po- tential benefits, including improvements in global function (low strength of research evidence) and reductions in relapse rates (moderate strength of research evidence). Enhancements in treatment adherence and improved satisfaction with mental health services have also been noted in some studies.

Harms

The harms of psychoeducation are likely to be minimal on the basis of results from clinical trials that show no differences in the rate of harms experienced by individuals treated with psychoedu- cation as compared with usual care (low strength of research evidence).

Patient Preferences

Clinical experience suggests that most patients are interested in receiving information about their diagnosis and potential treatments as part of their care. In addition, most patients are accepting of more formal and systematic approaches to psychoeducation. However, some patients may not wish to participate in psychoeducation or may experience logistical barriers (e.g., time, access to transportation, childcare, costs) in attending psychoeducation sessions.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. Specifically, any minimal harms of psychoeducation seem to be outweighed by the potential for modest benefits in important patient-centered outcomes such as improvements in global func- tion and reductions in relapse rates. For additional discussion of the research evidence, see Appen- dix C, Statement 17.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Guidelines from other organizations, including CSG, RANZCP, and SIGN, note the value of psy- choeducation for individuals with schizophrenia, including information about diagnosis (Galletly et al. 2016; Norman et al. 2017; Scottish Intercollegiate Guidelines Network 2013).

Quality Measurement Considerations

This guideline statement may not be appropriate for a performance-based quality measure because of the diversity of psychoeducational approaches and services and uncertainty regarding linking specific patient needs for psychoeducation with markers of delivery of psychoeducation. Remind- ers about psychoeducation are also not well suited to incorporation into electronic health record clinical decision support. However, health organizations and health plans may wish to implement quality improvement efforts to increase the use of formal psychoeducational programs among in- dividuals with schizophrenia.

STATEMENT 18: Supported Employment Services

APA recommends (1B) that patients with schizophrenia receive supported employment ser- vices.*

Implementation

Supported employment differs from other vocational rehabilitation services in providing assistance in searching for and maintaining competitive employment concurrently with job training, embed- ded job support, and mental health treatment (Becker and Drake 2003; Frederick and VanderWeele 2019; Substance Abuse and Mental Health Services Administration 2010b). In contrast, other voca- tional rehabilitation approaches focus on training before placement and put greater emphasis on placement in sheltered and transitional employment rather than in a competitive employment set- ting (Marino and Dixon 2014). For individuals whose goals are related to educational advancement prior to pursuit of employment, supported educational services may also be pursued (Substance Abuse and Mental Health Services Administration 2012b).

Of approaches to supported employment, the bulk of studies involve individual placement and support (IPS; Becker and Drake 2003; Frederick and VanderWeele 2019; McDonagh et al. 2017; Sub- stance Abuse and Mental Health Services Administration 2010b). In addition to a focus on rapid attainment of competitive employment, IPS emphasizes patient preferences in the types of jobs sought, the nature of the services that are delivered, and the outreach that occurs with potential em- ployers (Marino and Dixon 2014). Patient preferences also guide whether to disclose the presence of a psychiatric illness to the employer, with more than half of individuals choosing to disclose this information (DeTore et al. 2019). Services are offered to anyone who is interested, with no exclusion criteria for participation. Additional principles of IPS include individualized long-term job support and integration of employment specialists with the clinical team. Employment specialists also de- velop relationships with community employers and provide personalized benefits counseling to participants.

Evidence consistently shows that supported employment is associated with greater rates of com- petitive employment than transitional employment or prevocational training, although prevoca- tional training is superior to no vocational intervention at all (Marshall et al. 2014; McDonagh et al. 2017; Metcalfe et al. 2018; Modini et al. 2016; Richter and Hoffmann 2019; Suijkerbuijk et al. 2017). Augmenting supported employment with symptom-related skills training, training in workplace fundamentals, or cognitive training may assist in gaining and maintaining competitive employ- ment (Dewa et al. 2018; Suijkerbuijk et al. 2017). Other benefits of supported employment include greater number of hours worked per week, a longer duration of each job, a longer duration of total employment, and an increase in earnings (McDonagh et al. 2017). Individuals receiving supported employment are also more likely to obtain job-related accommodations than individuals with men- tal illness who are not receiving supported employment (McDowell and Fossey 2015). Such accom- modations typically relate to assistance from the supported employment coach but may also include flexible scheduling, reduced hours, modified job duties, and modified training and super- vision. In addition to job-related benefits of supported employment, there is some evidence of mod- est reductions in symptoms and a reduced risk of hospitalization associated with obtaining a job (Bouwmans et al. 2015; Burns et al. 2007; Charzyńska et al. 2015; Hoffmann et al. 2014; Luciano et al. 2014).

Among individuals who receive supported employment, factors that may be associated with a greater likelihood of success include lower levels of symptoms, higher levels of cognitive function-

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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ing (e.g., attention, memory, executive functioning, psychomotor speed), greater work success in the past, higher levels of educational attainment, and greater interest in obtaining employment (Kirsh 2016). Peer support and support from families and others in the patient’s social network may also be associated with better outcomes, although these factors have been less well studied (Kirsh 2016). Even when individuals do not experience initial success with supported employment, addi- tion of cognitive remediation may improve vocational outcomes (McGurk et al. 2015, 2016).

There are a number of barriers to supported employment, including economic and regulatory fac- tors (Kirsh 2016; Metcalfe et al. 2018; Modini et al. 2016) and the limited number of available programs (Marshall et al. 2014; Sherman et al. 2017). Although data are limited, employers may be reluctant to participate in supported employment out of concern about the impact of providing work-related ac- commodations and because of discrimination and bias toward individuals with serious mental illness (Kirsh 2016). Treating clinicians may also serve as a barrier by having inappropriately limited ex- pectations (Kirsh 2016) and being unaware that some individuals with schizophrenia are able to function at high levels of occupational achievement (Cohen et al. 2017). In addition, concerns about losing disability benefits or health insurance may lead some individuals to forgo supported em- ployment opportunities (Kirsh 2016). Such concerns are not entirely unrealistic because many of the competitive jobs that individuals do obtain are entry-level and/or part-time positions without health insurance benefits (Kirsh 2016). Within supported employment programs, organizational barriers to success have included poor fidelity to supported employment principles (Marshall et al. 2014); insufficient time devoted to leading and management of the programs; and insufficient train- ing, skills, and business and public relations knowledge of program staff (Kirsh 2016; Swanson et al. 2013). Each of these barriers is important to address at individual, systems, and policy levels so that more patients can benefit from supported employment interventions.

For clinicians and organizations wishing to learn more about supported employment or develop supported employment programs, additional information is available through SMI Adviser (https://smiadviser.org), NAVIGATE (https://navigateconsultants.org/manuals), and the Boston University Center for Psychiatric Rehabilitation (https://cpr.bu.edu).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of supported employment as part of the treatment of schizophrenia can be associated with sig- nificantly better employment outcomes, including a significantly greater likelihood of obtaining competitive employment, a significantly greater likelihood of working more than 20 hours per week, more weeks of employment, and greater earnings relative to vocational training or no voca- tional interventions (moderate strength of research evidence).

Harms

The harms of supported employment in the treatment of schizophrenia are not well delineated or systematically reported but are likely to be small.

Patient Preferences

Clinical experience suggests that few patients are currently receiving supported employment, but a significant number of individuals may be interested in supported employment if it were readily avail- able and offered to them. However, some individuals may be in school, have responsibilities at home, or already be employed. Others would rather not seek employment or may have concerns about losses of benefits or health insurance if they did pursue competitive employment. Logistical barriers (e.g., ac- cess to transportation, childcare) may also affect patient preferences related to supported employment.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. Specifically, the potential for benefits in important patient-centered outcomes related to em- ployment seemed to outweigh the minimal harms of supported employment programs. For addi- tional discussion of the research evidence, see Appendix C, Statement 18.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

Guidelines from other organizations are generally consistent with this recommendation. NICE and PORT recommend that supported employment be offered to individuals with schizophrenia who wish to find or return to work (Dixon et al. 2010; National Institute for Health and Care Excellence 2014), and RANZCP recommends IPS services for individuals with first-episode psychosis (Galletly et al. 2016). RANZCP, NICE, and CSG also emphasize the appropriateness of other occupational or educational activities for individuals with schizophrenia (Galletly et al. 2016; National Institute for Health and Care Excellence 2014; Norman et al. 2017).

Quality Measurement Considerations

This guideline statement may not be appropriate for a performance-based quality measure because of the barriers to supported employment, including variations in availability, and difficulty identi- fying when patients desire competitive employment. Reminders about supported employment are also not well suited to incorporation into electronic health record clinical decision support. How- ever, given the infrequent availability of supported employment in the United States, health orga- nizations and health plans may wish to implement programs to increase the use of supported employment among individuals with schizophrenia.

STATEMENT 19: Assertive Community Treatment

APA recommends (1B) that patients with schizophrenia receive assertive community treat- ment if there is a history of poor engagement with services leading to frequent relapse or social disruption (e.g., homelessness; legal difficulties, including imprisonment).*

Implementation

ACT, sometimes referred to as programs of assertive community treatment, is a multidisci- plinary, team-based approach in which patients receive individualized care outside a formal clin- ical setting. Thus, individuals may be engaged in their homes, workplaces, or other community locations. Continuity of care is enhanced because individuals work with an assigned team, which has 24/7 availability, rather than being assigned to a designated clinician for care. Team members typically include a psychiatrist, nurse, and social worker or case manager. Peer specialists, voca- tional specialists, and clinicians with expertise in substance use treatment are often part of the team as well.

Other features of ACT include its provision of personalized and flexible care that addresses the pa- tient’s needs and preferences without time limits or other constraints on services. Particularly in rural

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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areas, some ACT teams are augmenting face-to-face visits with telepsychiatry visits, although re- search will be needed to determine whether such an approach alters the benefits of ACT (Swanson and Trestman 2018). ACT teams also work with a smaller number of individuals than traditional outpatient clinicians or case managers do, which contributes to the ability to provide frequent visits and a more personalized and comprehensive approach to care. For these reasons, ACT is often used in individuals who have a history of poor engagement with services that leads to frequent relapse or social disruption (e.g., homelessness; legal difficulties, including imprisonment), although it can also be used for individuals who are better engaged but still have high rates of service utilization. Many individuals who are referred for ACT are also at risk for poor adherence and may benefit from consideration of an LAI antipsychotic medication (see Statement 10).

Studies of ACT suggest that it is associated with symptom improvement comparable to other treatment delivery approaches and that individuals who receive ACT are more likely to be domi- ciled, living independently, and working and less likely to be hospitalized as compared with indi- viduals who receive treatment as usual (McDonagh et al. 2017). Although ACT has multiple strengths that would make it an attractive approach in individuals with co-occurring disorders and schizophrenia, the impact of ACT on physical health has not been well studied (Vanderlip et al. 2017). Also, in individuals with a concomitant substance use disorder, research to date has not shown associated improvements in functioning, mortality, or substance use as compared with usual care (McDonagh et al. 2017).

In terms of implementation barriers, there is often limited availability of ACT programs. Fund- ing these programs can be challenging because the comprehensive and multidisciplinary nature of ACT services is not well aligned with payment models in the U.S. health care delivery system (Monroe-DeVita et al. 2012). Effective delivery of ACT services is also dependent on having a high level of fidelity to ACT program standards (Monroe-DeVita et al. 2012; Thorning et al. 2016), and this requires considerable training as well as ongoing mentoring, collaboration, and consultation with individuals who are skilled in ACT implementation. Attention to outcomes and organiza- tional culture is also important in providing a team-based approach that is warm, flexible, prag- matic, collaborative, and supportive of patients’ recovery (Monroe-DeVita et al. 2012). For organi- zations or state mental health systems that are implementing ACT programs, a number of resources are available (Center for Evidence-Based Practices 2019; Substance Abuse and Mental Health Ser- vices Administration 2008; Thorning et al. 2016).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of ACT in the treatment of schizophrenia can be associated with a number of benefits as com- pared with treatment as usual, including a greater likelihood of being domiciled, living inde- pendently, or working and a lower likelihood of being hospitalized (low to moderate strength of research evidence).

Harms

The harms of ACT in the treatment of schizophrenia are not well delineated but are likely to be small.

Patient Preferences

Clinical experience suggests that most patients are cooperative with and accepting of ACT, partic- ularly once they have engaged with treatment. In some circumstances, patients may be reluctant to accept ACT services because of impaired awareness of a need for treatment. In this context, ACT may be used as one component of court-mandated care (e.g., assisted outpatient treatment, com-

munity treatment order, outpatient commitment). However, in the few studies that have examined patient perceptions, ACT is generally viewed as supporting patients and building relationships in a recovery-oriented fashion (Appelbaum and Le Melle 2008; Morse et al. 2016).

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as far outweighing the potential harms. ACT is generally viewed positively by patients, and it improves a number of patient-oriented outcomes with minimal risk of harms. For additional discussion of the research evidence, see Appendix C, Statement 19.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this recom- mendation.

Review of Available Guidelines From Other Organizations

This guideline recommendation is consistent with the SIGN recommendation to offer assertive out- reach to individuals with schizophrenia who “make high use of inpatient services, who show re- sidual psychotic symptoms and who have a history of poor engagement with services leading to frequent relapse and/or social breakdown (for example homelessness)” (Scottish Intercollegiate Guidelines Network 2013, p. 8). The PORT guideline also notes that ACT should be included in sys- tems of care that serve individuals with schizophrenia and that it “should be provided to individ- uals who are at risk for repeated hospitalizations or have recent homelessness” (Dixon et al. 2010, p. 49). In addition, RANZCP recommends the use of ACT “after initial contact, during crises and after discharge from hospital” in individuals with schizophrenia (Galletly et al. 2016, p. 29).

Quality Measurement Considerations

This guideline statement may not be appropriate for a performance-based quality measure because of the impact of logistical barriers to ACT, including geographic variations in availability. Remind- ers about ACT are also not well suited to incorporation into electronic health record clinical deci- sion support because of the multiple patient-specific factors that may contribute to a decision to recommend ACT. However, anecdotal observations suggest that more patients may benefit from ACT in the United States than currently receive it. Consequently, state mental health agencies, health plans, and health organizations may wish to implement programs to increase the use of ACT among individuals with schizophrenia who have had a history of poor engagement with services, leading to frequent relapse or social disruption (e.g., homelessness; legal difficulties, including im- prisonment).

STATEMENT 20: Family Interventions

APA suggests (2B) that patients with schizophrenia who have ongoing contact with family receive family interventions.*

Implementation

An important aspect of good psychiatric treatment is involvement of family members, person(s) of support, and other individuals who play a key role in the patient’s life. In addition to spouses, par-

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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ents, children, or other biological or nonbiological relatives, such individuals may include people who reside with the patient, intimate partners, and close friends who are an integral part of the pa- tient’s support network. Such individuals benefit from discussion of such topics as diagnosis and management of schizophrenia, types of support that are available, and ways to plan for and access help in a crisis. Other goals include helping individuals repair or strengthen their connections with family members and other members of their support system.

Family interventions are systematically delivered, extend beyond conveying of information, and focus on the future rather than on past events (Mueser et al. 2013). The family interventions that are suggested in this guideline statement go beyond the basics of family involvement and illness edu- cation that are important for good clinical care. They may include structured approaches to prob- lem-solving, training in how to cope with illness symptoms, assistance with improving family communication, provision of emotional support, and strategies for reducing stress and enhancing social support networks (McDonagh et al. 2017; McFarlane 2016; Mueser et al. 2013). Family inter- ventions can be particularly important early in the course of schizophrenia (McFarlane 2016) but can also be helpful during any phase of treatment.

Most patients want family to be involved in their treatment (Cohen et al. 2013). Nevertheless, even when a patient does not wish for a specific person to be involved in his or her care, the clinician may listen to information provided by that individual, as long as confidential information is not pro- vided to the informant (American Psychiatric Association 2016a). Although some health profession- als may be unsure about legal or regulatory aspects of sharing information, general information that is not specific to the patient can be provided (e.g., common approaches to treatment, general information about medications and their side effects, available support and emergency assistance). Also, to prevent or lessen a serious and imminent threat to the health or safety of the patient or oth- ers, the “Principles of Medical Ethics” (American Psychiatric Association 2013f) and HIPAA (Office for Civil Rights 2017a, 2017b) permit clinicians to disclose necessary information about a patient to family members, caregivers, law enforcement, or other persons involved with the patient. HIPAA also permits health care providers to disclose necessary information to the patient’s family, friends, or other persons involved in the patient’s care or payment for care when such disclosure is judged to be in the best interests of the patient and the patient is not present or is unable to agree or object to a disclosure because of incapacity or emergency circumstances (Office for Civil Rights 2017b).

The family interventions that have been studied include a variety of formats and approaches (McDonagh et al. 2017; McFarlane 2016). Interventions may or may not include the patient and can be conducted with a single family or a multifamily group. In many early studies, family interven- tions included the patient and were led by a member of the patient’s clinical care team. This ap- proach allowed a liaison to develop among the care team, the patient, members of the family, and other person(s) of support. Other studies have been conducted independent of the patient’s care team. In terms of approach, some family interventions focus on psychoeducation, whereas other in- terventions incorporate other treatment elements (e.g., motivational interviewing, goal setting, cog- nitive-behavioral intervention, behavioral family therapy, support groups, social network development, communication training, role-playing, stress management, relaxation training). Given the diversity of options for family interventions, the selection of a specific approach should consider the preferences of the patient and family in collaboration with the clinician.

Benefits of family interventions include reductions in core symptoms of illness and reductions in relapses, including rehospitalization (McDonagh et al. 2017). Some studies have also shown ben- efits for family members such as reductions in levels of burden and distress or improvements in re- lationships among family members (McFarlane 2016; Sin et al. 2017a). Evidence suggests that benefits of family interventions are greatest when more than 10 treatment sessions are delivered over a period of at least 7 months (McDonagh et al. 2017). However, the Family-to-Family interven- tion available through the National Alliance on Mental Illness has shown significant benefits using a 12-week program consisting of weekly sessions of 2–3 hours each (Dixon et al. 2011; Lucksted et al. 2013; Marcus et al. 2013; Toohey et al. 2016).

A common barrier to implementing family interventions relates to program availability. How- ever, guidance is available on developing family intervention programs focused on psychoeduca- tion (Glynn et al. 2014; Substance Abuse and Mental Health Services Administration 2009). In addition, the National Alliance on Mental Illness has reduced this barrier through its Family-to- Family program, which has led to a significant expansion in the availability of family interventions (National Alliance on Mental Illness 2019b). Additional barriers include constraints of family mem- bers (e.g., work schedules, access to transportation, childcare, health issues) that may limit their ability to be involved in frequent family sessions. Similar logistical barriers can exist for patients when family interventions incorporate patient participation. Other implementation barriers in- clude organizational and clinician-focused barriers such as time and cost constraints and insuffi- cient understanding of the potential benefits of family intervention (Ince et al. 2016).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of family interventions in the treatment of schizophrenia can reduce the likelihood of relapse (low to moderate strength of research evidence) and reduce core illness symptoms (low strength of research evidence).

Harms

The harms of family interventions in the treatment of schizophrenia are not well documented but appear to be minimal.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of family inter- ventions as part of a treatment plan; however, other patients may have had difficulties in relation- ships with family members in the past and may not want family members to be involved in their treatment.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. For patients who have ongoing contact with their families, including relatives and signifi- cant others, there are distinct benefits to family interventions. However, some patients may not be in favor of family involvement even when they do have some ongoing contact with family mem- bers, and, for this reason, the statement was suggested rather than being recommended for all in- dividuals. For additional discussion of the research evidence, see Appendix C, Statement 20.

Differences of Opinion Among Writing Group Members

Eight writing group members voted in favor of this suggestion. One writing group member dis- agreed with this statement as worded and felt that it would be preferable for the guideline state- ment to make specific mention of other persons of support who may be involved with the patient and are commonly included in such interventions in addition to family members.

Review of Available Guidelines From Other Organizations

This guideline statement is consistent with guidelines from other organizations. CSG, NICE, RANZCP, SIGN, and PORT guidelines all recommend offering family interventions when an individ- ual with schizophrenia reside with or are in close contact with family (Dixon et al. 2010; Galletly et

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 131

al. 2016; National Institute for Health and Care Excellence 2014; Norman et al. 2017; Scottish Inter- collegiate Guidelines Network 2013). These guidelines also emphasize the importance of providing information to family and others involved in the patient’s care on such topics as diagnosis and man- agement of schizophrenia, types of support that are available, and ways to access help in a crisis.

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a performance-based quality measure or for incorporation into electronic decision support. Nevertheless, given the potential benefits of this approach, health care organizations and health plans may wish to track the avail- ability and utilization of family interventions.

STATEMENT 21: Self-Management Skills and Recovery-Focused Interventions

APA suggests (2C) that patients with schizophrenia receive interventions aimed at devel- oping self-management skills and enhancing person-oriented recovery.*

Implementation

Illness self-management training programs have been applied to help address many chronic con- ditions and are designed to improve knowledge about one’s illness and management of symptoms (Grady and Gough 2014). Goals include reducing the risk of relapse, recognizing signs of relapse, developing a relapse prevention plan, and enhancing coping skills to address persistent symptoms, with the aim of improving quality of life and social and occupational functioning. In the studies in- cluded in the AHRQ review (McDonagh et al. 2017), self-management training was generally deliv- ered in a group setting with sessions of 45–90 minutes each, and the number of intervention sessions ranged from 7 to 48 sessions. However, the evidence suggested better outcomes in patients who par- ticipated in at least 10 self-management intervention sessions. Self-management sessions were typi- cally facilitated by clinicians, although peer-facilitated sessions have also been used. In addition, some studies have used individually targeted interventions, either face-to-face or via computer-based formats (Lean et al. 2019). Self-management approaches have also been used to address co-occurring medical conditions in individuals with serious mental illness, including schizophrenia, with benefits that included increased patient activation and improved health-related quality of life (Druss et al. 2010; Goldberg et al. 2013; Muralidharan et al. 2019).

Recovery-focused interventions have also been developed that focus on fostering self-determination in relation to a patient’s personal goals, needs, and strengths. Such approaches may include ele- ments of self-management skill development, psychoeducation, and peer-based interventions but also include components and activities that allow participants to share experiences and receive sup- port, learn and practice strategies for success, and identify and take steps toward reaching personal goals. Studies of peer-based interventions are limited (Castelein et al. 2015; Chien et al. 2019), and studies of recovery-focused interventions have also been small in number. Nevertheless, the avail- able information suggests that these interventions may promote increased recovery, hope, and em- powerment among individuals with serious mental illnesses (Le Boutillier et al. 2011; Mueser et al. 2013; Thomas et al. 2018).

The most common barrier to implementing this guideline statement is the availability of programs for developing self-management skills and enhancing person-oriented recovery. However, a toolkit for developing illness management and recovery-based programs in mental health is available through the

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

132 APA Practice Guidelines

Substance Abuse and Mental Health Services Administration (https://store.samhsa.gov/product/ Illness-Management-and-Recovery-Evidence-Based-Practices-EBP-KIT/sma09-4463). Other resources are available through the Boston University Center for Psychiatric Rehabilitation (https://cpr.bu.edu), the Center on Integrated Health Care and Self-Directed Recovery (www.center4healthandsdc.org), Digital Opportunities for Outcomes in Recovery Services (https://skills.digitalpsych.org), Mental Health America (www.mhanational.org/self-help-tools), the National Alliance on Mental Illness (www.nami.org), NAVIGATE (https://navigateconsultants.org/manuals), SMI Adviser (https:// smiadviser.org/individuals-families), and the Temple University Collaborative on Community In- clusion (www.tucollaborative.org).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of interventions aimed at developing self-management skills and enhancing person-oriented recovery in individuals with schizophrenia can be associated with reductions in symptom severity and risk of relapse and an increased sense of hope and empowerment (low to moderate strength of research evidence). Self-management approaches that are aimed at addressing co-occurring medi- cal conditions in individuals with serious mental illness also have benefits that include increased patient activation and improved health-related quality of life.

Harms

The harms of interventions aimed at developing self-management skills and enhancing person-oriented recovery in the treatment of schizophrenia are not well studied but are likely to be minimal.

Patient Preferences

Clinical experience suggests that most patients are cooperative with and accepting of interventions aimed at developing self-management skills and enhancing person-oriented recovery. However, some patients may not wish to take part in such interventions because of personal preferences or logistical barriers to attending group sessions (e.g., access to transportation, childcare).

Balancing of Benefits and Harms

The potential benefits of this guideline statement in terms of patient engagement, empowerment, and beneficial outcomes were viewed as likely to outweigh the potential harms, which were viewed as minimal. For additional discussion of the research evidence, see Appendix C, Statement 21.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this sug- gestion.

Review of Available Guidelines From Other Organizations

This guideline statement is consistent with recommendations of other guidelines (RANZCP, NICE) that support the use of self-management and peer-support programs in the treatment of individu- als with schizophrenia (Galletly et al. 2016; National Institute for Health and Care Excellence 2014).

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a performance-based quality measure or for incorporation into electronic decision support. Nevertheless, given the potential ben-

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 133

efits of such interventions, health care organizations and health plans may wish to track the availabil- ity and utilization of programs to develop self-management skills and enhance person-oriented recovery.

STATEMENT 22: Cognitive Remediation

APA suggests (2C) that patients with schizophrenia receive cognitive remediation.*

Implementation

Cognitive remediation approaches are intended to address cognitive difficulties that can accom- pany schizophrenia, with the aim of enhancing function and quality of life. A number of different cognitive remediation approaches have been used, typically in group or computer-based formats, in an effort to enhance cognitive processes such as attention, memory, executive function, social cognition, or meta-cognition (Delahunty and Morice 1996; Medalia et al. 2018; Reeder et al. 2016; Wykes et al. 2011). Some programs have focused on improving cognitive flexibility (e.g., shifting cognitive sets), working memory (e.g., sequencing, multitasking, delayed recall), and planning (e.g., sequencing and chunking, active coding), whereas meta-cognitive approaches have at- tempted to teach patients how and when particular strategies that bypass specific cognitive limita- tions can be used. Some programs add aspects of social and communication skills to neurocognitive elements of remediation (Pentaraki et al. 2017).

Although this variability in program format and content confounds interpretation of the evidence, cognitive remediation does seem to result in improvements in cognition, symptoms, and function in individuals with schizophrenia, at least on a short-term basis (Harvey et al. 2018; McDonagh et al. 2017; Revell et al. 2015). Although long-term follow-up studies of cognitive remediation are not available in individuals with schizophrenia, data from healthy older individuals show long-term improvements as a result of cognitive training (Rebok et al. 2014). Beneficial effects on psychosocial outcomes seem particularly robust when cognitive remediation is used as a component of or ad- junct to other forms of psychiatric rehabilitation rather than being delivered as a stand-alone inter- vention (McGurk et al. 2007; Revell et al. 2015; van Duin et al. 2019; Wykes et al. 2011). However, some apparent improvements in cognitive performance may result from practicing specific tasks and may not produce generalizable changes in other contexts. Furthermore, the specific elements of a particular cognitive remediation program may influence the benefits that are observed (Cella and Wykes 2019).

The primary barriers to use of cognitive remediation are related to program availability. Online delivery of cognitive remediation may be one way to overcome these barriers. Information and training on developing cognitive remediation programs are available (Medalia 2019; Medalia et al. 2018). In addition, Web-based programs have been used in clinical trials and may provide options for patients without access to in-person cognitive remediation programs (Jahshan et al. 2019; Kukla et al. 2018).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of cognitive remediation is associated with moderate improvements in specific aspects of cog- nition (Harvey et al. 2018; Wykes et al. 2011) as well as small positive effects on social, occupational,

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

134 APA Practice Guidelines

and global function (low strength of research evidence); core illness symptoms (low strength of re- search evidence); and negative symptoms (moderate strength of research evidence) compared with usual care over approximately 16 weeks of treatment (McDonagh et al. 2017).

Harms

The harms of cognitive remediation in the treatment of schizophrenia are not well studied but are likely to be small.

Patient Preferences

Evidence from research trials suggests that patients are likely to be cooperative with and accepting of cognitive remediation as part of a treatment plan (Reeder et al. 2016); however, other patients may not wish to participate because of logistical barriers (e.g., time, cost, access to transportation, childcare).

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms, which were viewed as minimal. Differences in patient preferences, variability in the appro- priateness of cognitive remediation for individuals with schizophrenia, and the unclear durability of benefits led to suggesting cognitive remediation rather than recommending it. For additional discussion of the research evidence, see Appendix C, Statement 22.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this suggestion.

Review of Available Guidelines From Other Organizations

The RANZCP guideline recommends that cognitive remediation be available to individuals with schizophrenia if cognitive impairment is present and should be specifically “offered when cogni- tive deficits are affecting recovery and function” (Galletly et al. 2016, p. 20). The SIGN and CSG guidelines note that cognitive remediation “may be considered for individuals diagnosed with schizophrenia who have persisting problems associated with cognitive difficulties” (Norman et al. 2017, p. 621; Scottish Intercollegiate Guidelines Network 2013, p. 28).

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a performance-based quality measure or for incorporation into electronic decision support.

STATEMENT 23: Social Skills Training

APA suggests (2C) that patients with schizophrenia who have a therapeutic goal of en- hanced social functioning receive social skills training.*

Implementation

Social skills training in the treatment of schizophrenia can improve social function, core illness symp- toms, and negative symptoms more than usual care can (McDonagh et al. 2017). Reductions in relapse rates, including rehospitalization rates, have also been noted in some studies (McDonagh et al. 2017).

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 135

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Social skills training has an overarching goal of improving interpersonal and social skills but can be delivered using a number of approaches (Almerie et al. 2015; Kopelowicz et al. 2006; Turner et al. 2018). These include cognitive-behavioral, social-cognitive, interpersonal, and functional adap- tive skills training. Social skills training is delivered in a group format and includes homework as- signments to facilitate skill acquisition. Other specific elements of the intervention will vary with the theoretical emphasis of the training. However, examples of techniques that can be used in social skills training include role-playing, modeling, and feedback approaches to enhance interpersonal interactions; behaviorally oriented exercises in assertiveness, appropriate contextual responses, and verbal and nonverbal communication; and instruction and practice with social and emotional perceptions (Almerie et al. 2015; Kopelowicz et al. 2006; Turner et al. 2018). These techniques are aimed at generating improvements in typical social behaviors such as making eye contact, smiling at appropriate times, actively listening to others, and sustaining conversations. In some social skills training programs, group sessions are augmented with video or technologically based interven- tions, in vivo community trips to practice social skills (Glynn et al. 2002; Mueser et al. 2010), and involvement of support people who are accessible, pleasant, and knowledgeable about the local en- vironments’ resources and limitations (Mueser et al. 2010; Tauber et al. 2000).

As with other psychosocial interventions, availability of social skills training is a common barrier to its incorporation into treatment. However, information about social skills training is available for organizations that wish to develop such programs (Bellack and Goldberg 2019; Bellack et al. 2004; Granholm et al. 2016).

Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Social skills training in the treatment of schizophrenia can improve social function, core illness symptoms, and negative symptoms more than usual care can (low strength of research evidence).

Harms

The harms of social skills training in the treatment of schizophrenia have not been well documented but appear to be minimal.

Patient Preferences

Clinical experience suggests that many patients are cooperative with and accepting of social skills training as part of a treatment plan; however, other patients may not wish to take part in social skills training because of logistical barriers (e.g., time, cost, access to transportation, childcare) or having goals for treatment that are unrelated to social skills.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. Although the harms appear to be minimal, there is a low strength of research evidence for benefits, and patient preferences may differ in terms of desiring to focus on social skills as a part of treatment. Consequently, this guideline statement was rated as a suggestion. For additional discus- sion of the research evidence, see Appendix C, Statement 23.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this sug- gestion.

Review of Available Guidelines From Other Organizations

Other guidelines are generally consistent with this guideline statement. The PORT, RANZCP, CSG, and SIGN guidelines suggest offering social skills training to individuals with schizophrenia who have deficits in social skills (Buchanan et al. 2010; Galletly et al. 2016; Norman et al. 2017; Scottish Intercollegiate Guidelines Network 2013). However, the NICE guideline notes that social skills training should not be routinely offered to individuals with schizophrenia (National Institute for Health and Care Excellence 2014).

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a performance-based quality measure or for incorporation into electronic decision support. Nevertheless, given the potential ben- efits of such an approach for some patients, health care organizations and health plans may wish to track the availability and utilization of social skills training for individuals with schizophrenia.

STATEMENT 24: Supportive Psychotherapy

APA suggests (2C) that patients with schizophrenia be treated with supportive psychotherapy.*

Implementation

Supportive psychotherapy is commonly a part of the treatment plan in individuals with schizo- phrenia who are not receiving other modes of psychotherapy (e.g., CBTp). Because the evidence re- lated to its benefits is limited, supportive psychotherapy should not take precedence over other evidence-based psychosocial treatments (e.g., CSC, CBTp, psychoeducation). When compared with treatment as usual, no advantage was seen for supportive psychotherapy in terms of global or so- cial function (L. A. Buckley et al. 2015; McDonagh et al. 2017); however, these findings are difficult to interpret given the frequent use of supportive psychotherapy techniques as part of usual care. When compared with insight-oriented psychotherapies, a small number of early studies suggested that supportive psychotherapy might be associated with better outcomes in coping skills, adher- ence, and relapse (Fenton 2000; Hogarty et al. 1997; Stanton et al. 1984).

The focus of supportive psychotherapy is reality based and present centered (Kates and Rockland 1994; Novalis et al. 1993; Winston 2014; Winston et al. 2012). It commonly aims to help patients cope with symptoms, improve adaptive skills, and enhance self-esteem, although descriptions of the goals of supportive psychotherapy have varied. Examples of techniques used to foster these goals include reassurance; praise; encouragement; explanation; clarification; reframing; guidance; sug- gestion; and use of a conversational, nonconfrontational style of communication. Many of the com- mon elements that have been identified in effective psychotherapies, including a positive therapeutic alliance, are also integral to supportive psychotherapy (Frank and Frank 1991; Wampold 2015). Typically, supportive psychotherapy is conducted in conjunction with medication management at a frequency that can vary from weekly to every few months depending on the needs of the individual patient. Other psychosocial treatments can also be used as part of the treat- ment plan in conjunction with these modalities.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 137

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Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement

Benefits

Use of supportive psychotherapy in the treatment of schizophrenia was not associated with relative benefits in global or social function as compared with treatment as usual (low strength of research evidence). However, treatment as usual already incorporates supportive psychotherapy under most circumstances. In addition, clinical experience suggests that supportive psychotherapy may be associated with such benefits as strengthening the therapeutic alliance, reducing demoraliza- tion, and developing practical coping strategies in the treatment of individuals with schizophrenia.

Harms

The harms of using supportive psychotherapy in the treatment of schizophrenia appear to be small, although evidence is limited. However, if supportive psychotherapy is used preferentially instead of a treatment that is associated with more robust evidence of benefit, there may be indirect nega- tive effects.

Patient Preferences

Clinical experience suggests that most patients are cooperative with and accepting of supportive psychotherapy as part of a treatment plan, even when they are reluctant to engage in other psycho- social interventions. However, some patients may not wish to engage in psychotherapy or may have logistical barriers (e.g., time, access to transportation, financial considerations) that make it difficult to attend psychotherapy sessions.

Balancing of Benefits and Harms

The potential benefits of this guideline statement were viewed as likely to outweigh the potential harms. In clinical practice, the use of supportive psychotherapy is commonplace as part of the treat- ment of schizophrenia, which makes it challenging to interpret the research comparisons of sup- portive psychotherapy versus treatment as usual. Given the limited evidence of any harms of supportive psychotherapy, the potential benefits of supportive psychotherapy appear to be greater than the harms. For additional discussion of the research evidence, see Appendix C, Statement 24.

Differences of Opinion Among Writing Group Members

There were no differences of opinion. The writing group voted unanimously in favor of this sug- gestion.

Review of Available Guidelines From Other Organizations

The NICE guideline notes that supportive psychotherapy should not be offered routinely to indi- viduals with schizophrenia if other psychosocial treatments that have greater efficacy are available (National Institute for Health and Care Excellence 2014). However, the NICE guideline also notes that patient preferences should be taken into account, particularly if other psychosocial interven- tions are not available locally.

Quality Measurement Considerations

As a suggestion, this guideline statement is not appropriate for use as a performance-based quality measure or for incorporation into electronic decision support.

Areas for Further Research
in Individuals With Schizophrenia

Overall

• Improve the generalizability of study populations

• Enhance study recruitment approaches and use a priori specification of subgroup analyses to
obtain data on treatment effects in inpatients, minority groups, women, older individuals, indi- viduals with multiple psychiatric or physical health conditions, and individuals with severe and/or treatment-resistant illness

• Assure that sample sizes are adequate to achieve statistical power

• Assure that studies report data in a consistent fashion and prespecify outcomes of interest

• Assure that studies identify the magnitude of change in scale scores that constitutes a clinically
meaningful difference

• Increase collection of data on patient-centered outcomes (e.g., quality of life, social functioning,
physical health, recovery)

• Improve systematic collection of information on harms, including in studies of psychosocial in-
terventions

• Identify approaches (e.g., pharmacogenomics, biomarkers, symptom clusters, and other predic-
tive variables) for optimizing treatment selection

• Determine efficient, valid, and reliable approaches to quantitative measurement of positive
symptoms, negative symptoms, functioning, quality of life, and treatment-related side effects

• Determine ways in which demographic or sociocultural factors influence treatment outcomes

• Determine the durability of treatment effects and potential for long-term harms through long-
term studies (e.g., at least 1 year of treatment with follow-up assessments at 3–5 years)

• Determine the benefits, harms, and appropriate use of treatments in individuals with co-occurring disorders (e.g., stimulants in co-occurring ADHD; benzodiazepines with co-occurring anxiety; smoking cessation interventions, including medication and nonmedication approaches with co-
occurring nicotine dependence)

• Identify methods that will allow information from mobile technologies, wearable technology,
and large-scale data analytics to inform assessment, treatment, and future research

• Determine optimal monitoring frequencies and approaches to detect treatment-related benefits
and side effects

• Identify optimal approaches to improving physical health in individuals with schizophrenia

• Identify optimal approaches to treatment of co-occurring substance use disorders in individuals
with schizophrenia

• Identify approaches to redesigning workflows and models of care delivery to improve the use
of best practices in the treatment of schizophrenia

• Identify approaches to determining the optimal setting of care (e.g., inpatient, partial hospital,
intensive outpatient, psychosocial rehabilitation, Clubhouse models)

• Identify optimal approaches to integrate recovery-based and peer-based programs into other
models of care delivery

• Identify optimal approaches to care coordination and case management, including intensive
case management

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Medications and Other Somatic Interventions

• Determine the comparative effectiveness of newer SGAs (including LAI formulations) versus comparable doses of other SGAs and some FGAs

• Determine the comparative harms of antipsychotic medications, including long-term harms and rare but serious harms

• Determine optimal antipsychotic treatment approaches for individuals with suicidal or aggres- sive behaviors, including additional studies of clozapine for aggressive behavior

• Identify risks and benefits of using other medications (e.g., lithium, anticonvulsants, antidepres- sants, stimulants, benzodiazepines, other sedative-hypnotics) in combination with antipsy- chotic medications to address specific target symptoms or treatment nonresponse

• Identify risks and benefits of concomitant use of more than one antipsychotic medication

• Identify risks and benefits of strategies to minimize or treat side effects of antipsychotic medi- cations, including use of concomitant medications, reductions in antipsychotic dose, or chang-
ing to a different antipsychotic medication

• Determine optimal approaches to making medication changes (i.e., switching from one antipsy-
chotic to another) to minimize risk of relapse and reduce potential for treatment-related side effects

• Identify optimal clinical approaches for determining when a treatment trial is adequate and
when treatment resistance is present

• Determine relationships between blood levels of antipsychotic medications (including active
metabolites) and therapeutic response that can be used to guide dose titration and determina-
tion of treatment adequacy

• Identify whether there are subgroups of patients for whom medication discontinuation may be
possible

• Determine whether intermittent treatment or early relapse is associated with increased long-
term harms (e.g., greater treatment resistance, neurobiological changes)

• Determine optimal approaches to prevention and treatment of specific side effects of antipsy- chotic medications, including neurological side effects, weight gain, diabetes, metabolic syn-
drome, and cardiovascular disease

• Determine the optimal duration of treatments for neurological side effects (e.g., VMAT2 inhibi-
tors for tardive dyskinesia, anticholinergic agents for parkinsonism)

• Determine the efficacy and comparative effectiveness of neurostimulation approaches (e.g.,
ECT, TMS) in conjunction with other treatments for schizophrenia
Psychosocial Interventions

• •

• •

Assure that psychosocial interventions are clearly defined and described and that measure- ments of fidelity to the intervention model are incorporated into the study design
Conduct research on optimizing long-term outcomes with psychosocial interventions (e.g., use of booster treatment sessions or continued treatment at a lower frequency for maintenance of therapeutic benefits in those with a good initial response)

Develop approaches to reduce the heterogeneity in usual care groups, which makes it difficult to interpret and compare studies of psychosocial interventions that use usual care as a control comparison
Assure that studies of psychosocial interventions determine the intensity, frequency, and dura- tion of treatment that is needed to optimize outcomes

• Develop methods to study psychosocial interventions to identify key contributors to benefit (e.g., clinician experience, treatment fidelity, use of shared decision-making, clinician-patient al- liance, family engagement, setting of care)

• Investigate the benefits and harms of other psychosocial interventions (e.g., mindfulness, accep- tance and commitment therapy, metacognitive reflection and insight therapy, Open Dialogue, exercise, music and dance therapies)

• Determine benefits, harms, and optimal approaches for implementation of peer-based services, recovery-oriented programs, and self-management strategies

• Determine the components of multicomponent interventions (e.g., CSC) that are crucial to pos- itive outcomes

• Determine the effectiveness and sustainability of CSC with longer-term program participation

• Determine the elements of supported employment programs that are most likely to foster long-
term competitive employment

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 141

Guideline Development Process

This guideline was developed using a process intended to meet standards of the Institute of Medicine (2011) (now known as the National Academy of Medicine). The process is fully described in a document available on the American Psychiatric Association (APA) website at http://www.psychiatry.org/psychiatrists/practice/clinical- practice-guidelines/guideline-development-process.

Management of Potential Conflicts of Interest

Members of the Guideline Writing Group (GWG) are required to disclose all potential conflicts of interest before appointment, before and during guideline development, and on publication. If any potential conflicts are found or disclosed during the guideline development process, the member must recuse himself or herself from any related discussion and voting on a related recommenda- tion. The members of both the GWG and the Systematic Review Group (SRG) reported no conflicts of interest. The “Disclosures” section includes more detailed disclosure information for each GWG and SRG member involved in the guideline’s development.

Guideline Writing Group Composition

The GWG was initially composed of eight psychiatrists with general research and clinical expertise and a psychiatric resident (A.D.). This non-topic-specific group was intended to provide diverse and balanced views on the guideline topic in order to minimize potential bias. One psychiatrist (P.B.) and one psychologist (M.F.L.) were added to provide subject matter expertise in schizophrenia. An addi- tional member (A.S.Y.) provided input on quality measure considerations. The vice-chair of the GWG (L.J.F.) provided methodological expertise on such topics as appraising the strength of research evi- dence. The GWG was also diverse and balanced with respect to other characteristics, such as geo- graphic location and demographic background. The National Alliance on Mental Illness, Mental Health America, and the Schizophrenia and Related Disorders Alliance of America reviewed the draft and provided perspective from patients, families, and other care partners.

Systematic Review Methodology

The Agency for Healthcare Research and Quality’s (AHRQ) systematic review, Treatments for Schizophrenia in Adults (McDonagh et al. 2017), served as the predominant source of information for this guideline. APA also conducted a search of additional systematic reviews and meta-analyses to include consideration of placebo-controlled trials that were not part of the AHRQ review. An addi- tional search was conducted in MEDLINE (PubMed) and PsycINFO on treatments for neurological side effects of antipsychotic medications, including acute dystonia, parkinsonism, akathisia, and tardive syndromes. The search terms, limits used, and dates of these searches are available in Ap- pendix B. Results were limited to English-language, adult (18 and older), and human-only studies. These titles and abstracts were reviewed for relevance by one individual (L.J.F.). Available guide- lines from other organizations were also reviewed (Addington et al. 2017a, 2017b; Barnes et al. 2011; Buchanan et al. 2010; Crockford and Addington 2017; Galletly et al. 2016; Hasan et al. 2012; Na-

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tional Institute for Health and Care Excellence 2014; Pringsheim et al. 2017; Scottish Intercollegiate Guidelines Network 2013).

Rating the Strength of Supporting Research Evidence

Strength of supporting research evidence describes the level of confidence that findings from scientific observation and testing of an effect of an intervention reflect the true effect. Confidence is enhanced by such factors as rigorous study design and minimal potential for study bias.

Ratings were determined, in accordance with the AHRQ’s “Methods Guide for Effectiveness and Comparative Effectiveness Reviews” (Agency for Healthcare Research and Quality 2014), by the methodologist (L.J.F.) and reviewed by members of the SRG and GWG. Available clinical trials were assessed across four primary domains: risk of bias, consistency of findings across studies, di- rectness of the effect on a specific health outcome, and precision of the estimate of effect.

The ratings are defined as follows:

• High (denoted by the letter A) = high confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

• Moderate (denoted by the letter B)=moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

• Low (denoted by the letter C)=low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the
estimate.
The AHRQ has an additional category of insufficient for evidence that is unavailable or does not permit estimation of an effect. APA uses the low rating when evidence is insufficient because there is low confidence in the conclusion and further research, if conducted, would likely change the es- timated effect or confidence in the estimated effect.
Rating the Strength of Guideline Statements
Each guideline statement is separately rated to indicate strength of recommendation and strength of supporting research evidence. Strength of recommendation describes the level of confidence that potential benefits of an intervention outweigh potential harms. This level of confidence is a consen- sus judgment of the authors of the guideline and is informed by available evidence, which includes evidence from clinical trials as well as expert opinion and patient values and preferences.
There are two possible ratings: recommendation or suggestion. A recommendation (denoted by the numeral 1 after the guideline statement) indicates confidence that the benefits of the intervention clearly outweigh harms. A suggestion (denoted by the numeral 2 after the guideline statement) indi- cates greater uncertainty. Although the benefits of the statement are still viewed as outweighing the harms, the balance of benefits and harms is more difficult to judge, or the benefits or the harms may be less clear. With a suggestion, patient values and preferences may be more variable, and this can in- fluence the clinical decision that is ultimately made. These strengths of recommendation correspond to ratings of strong or weak (also termed conditional) as defined under the Grading of Recommenda- tions Assessment, Development and Evaluation (GRADE) method for rating recommendations in clinical practice guidelines (described in publications such as Guyatt et al. 2008 and others available on the website of the GRADE working group at http://www.gradeworkinggroup.org).
When a negative statement is made, ratings of strength of recommendation should be under- stood as meaning the inverse of the above (e.g., recommendation indicates confidence that harms clearly outweigh benefits).

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The GWG determined ratings of strength of recommendation by a modified Delphi method us- ing blind, iterative voting and discussion. In order for the GWG members to be able to ask for clar- ifications about the evidence, the wording of statements, or the process, the vice-chair of the GWG served as a resource and did not vote on statements. All other formally appointed GWG members, including the chair, voted.

In weighing potential benefits and harms, GWG members considered the strength of supporting research evidence, their own clinical experiences and opinions, and patient preferences. For recom- mendations, at least 10 out of 11 members must have voted to recommend the intervention or as- sessment after three rounds of voting, and at most 1 member was allowed to vote other than “recommend” the intervention or assessment. On the basis of the discussion among the GWG members, adjustments to the wording of recommendations could be made between the voting rounds. If this level of consensus was not achieved, the GWG could have agreed to make a sugges- tion rather than a recommendation. No suggestion or statement could have been made if 3 or more members voted “no statement.” Differences of opinion within the GWG about ratings of strength of recommendation, if any, are described in the subsection “Balancing of Potential Benefits and Harms in Rating the Strength of the Guideline Statement” for each statement.

Use of Guidelines to Enhance Quality of Care

Clinical practice guidelines can help enhance quality by synthesizing available research evidence and delineating recommendations for care on the basis of the available evidence. In some circumstances, practice guideline recommendations will be appropriate to use in developing quality measures. Guideline statements can also be used in other ways, such as educational activities or electronic clin- ical decision support, to enhance the quality of care that patients receive. Furthermore, when avail- ability of services is a major barrier to implementing guideline recommendations, improved tracking of service availability and program development initiatives may need to be implemented by health organizations, health insurance plans, federal or state agencies, or other regulatory programs.

Typically, guideline recommendations that are chosen for development into quality measures will advance one or more aims of the Institute of Medicine’s report on Crossing the Quality Chasm (Institute of Medicine Committee on Quality of Health Care in America 2001) and the ongoing work guided by the multistakeholder-integrated, AHRQ-led National Quality Strategy by facilitating care that is safe, effective, patient centered, timely, efficient, and equitable. To achieve these aims, a broad range of quality measures (Watkins et al. 2015) is needed that spans the entire continuum of care (e.g., prevention, screening, assessment, treatment, continuing care), addresses the different levels of the health system hierarchy (e.g., system-wide, organization, program/department, individual clini- cians), and includes measures of different types (e.g., process, outcome, patient-centered experience). Emphasis is also needed on factors that influence the dissemination and adoption of evidence- based practices (Drake et al. 2008; Greenhalgh et al. 2004; Horvitz-Lennon et al. 2009).

Measure development is complex and requires detailed development of specification and pilot testing (Center for Health Policy/Center for Primary Care and Outcomes Research and Battelle Me- morial Institute 2011; Fernandes-Taylor and Harris 2012; Iyer et al. 2016; Pincus et al. 2016; Watkins et al. 2011). Generally, however, measure development should be guided by the available evidence and focused on measures that are broadly relevant and meaningful to patients, clinicians, and pol- icy makers. Measure feasibility is another crucial aspect of measure development but is often de- cided on the basis of current data availability, which limits opportunities for development of novel measurement concepts. Furthermore, innovation in workflow and data collection systems can ben- efit from looking beyond practical limitations in the early development stages in order to foster de- velopment of meaningful measures.

Often, quality measures will focus on gaps in care or on care processes and outcomes that have significant variability across specialties, health care settings, geographic areas, or patients’ demo-

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 145

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APA Practice Guidelines

graphic characteristics. Administrative databases, registries, and data from electronic health re- cords can help to identify gaps in care and key domains that would benefit from performance im- provements (Acevedo et al. 2015; Patel et al. 2015; Watkins et al. 2016). Nevertheless, for some guideline statements, evidence of practice gaps or variability will be based on anecdotal observa- tions if the typical practices of psychiatrists and other health professionals are unknown. Variability in the use of guideline-recommended approaches may reflect appropriate differences that are tai- lored to the patient’s preferences, treatment of co-occurring illnesses, or other clinical circumstances that may not have been studied in the available research. On the other hand, variability may indi- cate a need to strengthen clinician knowledge or address other barriers to adoption of best practices (Drake et al. 2008; Greenhalgh et al. 2004; Horvitz-Lennon et al. 2009). When performance is com- pared among organizations, variability may reflect a need for quality improvement initiatives to improve overall outcomes but could also reflect case-mix differences such as socioeconomic factors or the prevalence of co-occurring illnesses.

When a guideline recommendation is considered for development into a quality measure, it must be possible to define the applicable patient group (i.e., the denominator) and the clinical ac- tion or outcome of interest that is measured (i.e., the numerator) in validated, clear, and quantifiable terms. Furthermore, the health system’s or clinician’s performance on the measure must be readily ascertained from chart review, patient-reported outcome measures, registries, or administrative data. Documentation of quality measures can be challenging and, depending on the practice set- ting, can pose practical barriers to meaningful interpretation of quality measures based on guide- line recommendations. For example, when recommendations relate to patient assessment or treatment selection, clinical judgment may need to be used to determine whether the clinician has addressed the factors that merit emphasis for an individual patient. In other circumstances, stan- dardized instruments can facilitate quality measurement reporting, but it is difficult to assess the appropriateness of clinical judgment in a validated, standardized manner. Furthermore, utilization of standardized assessments remains low (Fortney et al. 2017), and clinical findings are not rou- tinely documented in a standardized format. Many clinicians appropriately use free text prose to describe symptoms, response to treatment, discussions with family, plans of treatment, and other aspects of care and clinical decision-making. Reviewing these free text records for measurement purposes would be impractical, and it would be difficult to hold clinicians accountable to such mea- sures without significant increases in electronic medical record use and advances in natural lan- guage processing technology.

Conceptually, quality measures can be developed for purposes of accountability, for internal or health system–based quality improvement, or both. Accountability measures require clinicians to report their rate of performance of a specified process, intermediate outcome, or outcome in a spec- ified group of patients. Because these data are used to determine financial incentives or penalties based on performance, accountability measures must be scientifically validated, have a strong evi- dence base, and fill gaps in care. In contrast, internal or health system–based quality improvement measures are typically designed by and for individual providers, health systems, or payers. They typically focus on measurements that can suggest ways for clinicians or administrators to improve efficiency and delivery of services within a particular setting. Internal or health system–based qual- ity improvement programs may or may not link performance with payment, and, in general, these measures are not subject to strict testing and validation requirements.

Quality improvement activities, including performance measures derived from these guidelines, should yield improvements in quality of care to justify any clinician burden (e.g., documentation burden) or related administrative costs (e.g., for manual extraction of data from charts, for modifi- cations of electronic medical record systems to capture required data elements). Possible unin- tended consequences of any derived measures also need to be addressed in testing of a fully specified measure in a variety of practice settings. For example, highly specified measures may lead to overuse of standardized language that does not accurately reflect what has occurred in practice. If multiple discrete fields are used to capture information on a paper or electronic record form, data

will be easily retrievable and reportable, but oversimplification is a possible unintended conse- quence of measurement. Just as guideline developers must balance the benefits and harms of a par- ticular guideline recommendation, developers of performance measures must weigh the potential benefits, burdens, and unintended consequences in optimizing quality measure design and testing.

External Review

This guideline was made available for review in May–June 2019 by stakeholders, including the APA membership, scientific and clinical experts, allied organizations, and the public. In addition, a number of patient advocacy organizations were invited for input. A total of 98 individuals and 20 organiza- tions submitted comments on the guideline (for a list of the names, see the section “Individuals and Organizations That Submitted Comments”). The chair and co-chair of the GWG reviewed and ad- dressed all comments received; substantive issues were reviewed by the GWG.

Funding and Approval

This guideline development project was funded and supported by the APA without any involve- ment of industry or external funding. The guideline was submitted to the APA Assembly and APA Board of Trustees and approved on November 17, 2019 and December 15, 2019, respectively.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 147

Glossary of Terms

Adequate dose The dose of a medication at which therapeutic effects occurred when tested in clinical trials in a comparable population of subjects. This dose will differ for each medication and may need to be adjusted in an individual patient to address factors that would influence drug absorption, metabolism, elimination, or other pharmacokinetic properties.

Adequate response A reduction in symptoms as a result of treatment that is associated with clinically sig- nificant benefit in functioning and/or quality of life. A reduction in symptoms of 50% or more is sometimes used as a threshold for adequacy of response.

Antipsychotic medication One of a group of medications used in the treatment of psychosis. Some of the antipsychotic medications are also approved for use in other conditions such as mood disorders or Tourette’s syndrome. The first-generation antipsychotic (FGA) medications, sometimes referred to as typical antipsy- chotic medications, were the initial medications to be discovered. The FGAs include, but are not limited to, chlorpromazine, droperidol, fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, thi- oridazine, thiothixene, and trifluoperazine. The second-generation antipsychotic (SGA) medications, some- times referred to as atypical antipsychotic medications, include, but are not limited, to aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risper- idone, and ziprasidone. In terms of the Neuroscience-based Nomenclature (www.nbn2.org), antipsychotic medications are categorized as follows:

• Dopamine D2 receptor antagonists: fluphenazine, haloperidol, perphenazine, pimozide

• D2 and serotonin type 2 (5-HT2) receptor antagonists: chlorpromazine, iloperidone, loxapine,
lurasidone, olanzapine, thioridazine, trifluoperazine, ziprasidone

• D2 and 5-HT1A receptor partial agonist and 5-HT2A receptor antagonist: aripiprazole, brexpiprazole

• 5-HT2, D2, and norepinephrine (NE) α2 receptor antagonist: asenapine

• D2, 5-HT2, and NE α2 receptor antagonists: clozapine, paliperidone, risperidone

• D2 and 5-HT2 receptor antagonist and NE transporter reuptake inhibitor: quetiapine
Within each group of antipsychotic medications, there is significant variability in the pharmacological prop- erties and side-effect profiles of specific drugs.
Assessment The process of obtaining information about a patient through any of a variety of methods, including face-to-face interview, review of medical records, physical examination (by the psychiatrist, an- other physician, or a medically trained clinician), diagnostic testing, or history taking from collateral sources (American Psychiatric Association 2016a).
Capacity for decision making The ability of an individual, when faced with a specific clinical or treatment- related decision, “to communicate a choice, to understand the relevant information, to appreciate the medical consequences of the situation, and to reason about treatment choices” (Appelbaum 2007, p. 1835).
Comprehensive and person-centered treatment plan A plan of treatment that is developed as an outgrowth of the psychiatric evaluation and is modified as clinically indicated. A comprehensive treatment plan can include nonpharmacological treatments, pharmacological treatments, or both. It is individualized to the patient’s clinical presentation, safety-related needs, concomitant medical conditions, personal background,

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relationships, life circumstances, and strengths and vulnerabilities. There is no prescribed format that a comprehensive treatment plan must follow. The breadth and depth of the initial treatment plan will depend on the amount of time and extent of information that are available, as well as the needs of the patients and the care setting. Additions and modifications to the treatment plan are made as additional information accrues (e.g., from family, staff, medical records, and other collateral sources) and the patient’s responses to clinical interventions are observed.

Contraindication A situation in which a drug or procedure should not be used because it may be harmful to the patient.

Delusion A false belief based on incorrect inference about external reality that is firmly held despite what almost everyone else believes and despite what constitutes incontrovertible and obvious proof or evidence to the contrary. The belief is not ordinarily accepted by other members of the person’s culture or subculture (i.e., it is not an article of religious faith) (American Psychiatric Association 2013e). The content of a delusion may include a variety of themes (e.g., persecutory, referential, somatic, religious, grandiose) (American Psychiatric Association 2013a).

Disorganized thinking Disorganized thinking (also referred to as formal thought disorder) is typically in- ferred from the individual’s speech and must be severe enough to substantially impair effective communi- cation. The individual may switch from one topic to another (derailment or loose associations), provide answers to questions in an obliquely related or completely unrelated fashion (tangentiality), or exhibit se- verely disorganized and nearly incomprehensible speech that resembles receptive aphasia in its linguistic disorganization (incoherence or “word salad”) (adapted from American Psychiatric Association 2013a).

Grossly disorganized or abnormal motor behavior Grossly disorganized or abnormal motor behavior may manifest itself in a variety of ways, ranging from childlike “silliness” to unpredictable agitation. Problems may be noted in any form of goal-directed behavior, leading to difficulties in performing activities of daily living. Catatonic behavior is another manifestation of abnormal motor behavior and can range from resis- tance to instructions (negativism); to maintaining a rigid, inappropriate, or bizarre posture; to a complete lack of verbal and motor responses (mutism and stupor). It can also include purposeless and excessive motor activity without obvious cause (catatonic excitement). Other features are repeated stereotyped movements, staring, grimacing, mutism, and the echoing of speech (adapted from American Psychiatric Association 2013a).

Hallucination Perception-like experiences that occur without an external stimulus. Hallucinations are vivid and clear, with the full force and impact of normal perceptions, and not under voluntary control. They may occur in any sensory modality (American Psychiatric Association 2013a).

Hepatic failure Deterioration of liver function that results in coagulation abnormality (usually an interna- tional normalized ratio greater than or equal to 1.5) and any degree of mental alteration (encephalopathy). Although there is no identifiable cause in approximately 15% of cases of acute hepatic failure, typical etiol- ogies include drug-induced liver injury, viral hepatitis, autoimmune liver disease, and shock or hypoperfu- sion (Lee et al. 2011).

Hepatic impairment Inability of the liver to function normally; typically defined in severity according to laboratory values and clinical characteristics as reflected by the Child-Pugh score or the Model for End-Stage Liver Disease (MELD) score (Ghany and Hoofnagle 2018; U.S. Food and Drug Administration 2003).

Hopelessness Feeling of despair about the future out of the belief that there is no possibility of a solution to current problems or a positive outcome.

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I2 A statistical estimate of the proportion of the variance that is due to heterogeneity.

Impulsivity Acting on the spur of the moment in response to immediate stimuli, acting on a momentary basis without a plan or consideration of outcomes, difficulty establishing and following plans, or having a sense of urgency and exhibiting self-harming behavior under emotional distress (American Psychiatric As- sociation 2013f).

Initial psychiatric evaluation A comprehensive assessment of a patient that has the following aims: identify the reason that the patient is presenting for evaluation; establish rapport with the patient; understand the patient’s background, relationships, current life circumstances, and strengths and vulnerabilities; establish whether the patient has a psychiatric condition; collect information needed to develop a differential diagnosis and clinical formulation; identify immediate concerns for patient safety; and develop an initial treatment plan or revise an existing plan in collaboration with the patient. Relevant information may be obtained by interviewing the patient; reviewing prior records; or obtaining collateral information from treating clinicians, family members, or others involved in the patient’s life. Physical examination, laboratory studies, imaging, psychological or neuropsychological testing, or other assessments may also be included. The psychiatric evaluation may occur in a variety of settings, including inpatient or outpatient psychiatric settings and other medical settings. The evaluation is usually time intensive. The amount of time spent depends on the com- plexity of the problem, the clinical setting, and the patient’s ability and willingness to cooperate with the assessment.Severalmeetingswiththepatient(andfamilyorothers)overtimemaybenecessary.Psychiatrists may conduct other types of evaluations that have other goals (e.g., forensic evaluations) or that may be more focused and circumscribed than a psychiatric evaluation as defined here. Guidelines are not intended to address such evaluations (American Psychiatric Association 2016a).

Negative symptoms Negative symptoms can be prominent in schizophrenia and can include diminution of emotional expression (eye contact; intonation of speech; and movements of the hand, head, and face), de- crease in motivated self-initiated purposeful activities (avolition), diminution of speech output (alogia), decrease in the ability to experience pleasure from positive stimuli (anhedonia), or apparent lack of interest in social interactions (asociality) (adapted from American Psychiatric Association 2013a).

Over-the-counter medications or supplements Drugs or supplements that can be bought without a prescription.

Person-centered care Care that is respectful of and responsive to individual preferences, needs, and values and ensures that an individual’s values guide all clinical decisions; sometimes referred to as patient-centered care (Institute of Medicine Committee on Quality of Health Care in America 2001). In person-centered care, patients, families, and other persons of support are provided with information that allows them to make informed decisions (Institute of Medicine 2006). Evidence-based interventions should be adapted to meet individual needs and preferences where possible (van Dulmen et al. 2015), and shared decision-making and self-management approaches are encouraged (Institute of Medicine 2006). Person-centered care is achieved through a dynamic and collaborative relationship among individuals, families, other persons of support, and treating clinicians that supports the individual’s realistic health and life goals and informs decision-making to the extent that the individual desires (American Geriatrics Society Expert Panel on Person-Centered Care 2016).

Renal impairment Inability of the kidney(s) to function normally, typically described in terms of reductions in creatinine clearance or estimated glomerular filtration rate (eGFR). An eGFR of 60–89 mL/min/1.73 m2 indicates mildly reduced kidney function; an eGFR of 30–59 mL/min/1.73 m2 indicates moderately reduced kidney function; an eGFR of 15–29 mL/min/1.73 m2 indicates severely reduced kidney function; and an eGFR of less than 15 mL/min/1.73 m2 indicates a very severe reduction in kidney function or end-stage renal disease (Kidney Disease: Improving Global Outcomes [KDIGO] CKD Work Group 2013).

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Suicidal ideas Thoughts of serving as the agent of one’s own death.
Suicide Death caused by self-directed injurious behavior with any intent to die as a result of the behavior

(Crosby et al. 2011).

Suicide attempt A nonfatal, self-directed, potentially injurious behavior with any intent to die as a result of the behavior. A suicide attempt may or may not result in injury (Crosby et al. 2011). It may be aborted by the individual or interrupted by another individual.

Suicide intent Subjective expectation and desire for a self-injurious act to end in death.
Suicide means The instrument or object used to engage in self-inflicted injurious behavior with any intent

to die as a result of the behavior.

Suicide method The mechanism used to engage in self-inflicted injurious behavior with any intent to die as a result of the behavior.

Suicide plan Delineation of the method, means, time, place, or other details for engaging in self-inflicted injurious behavior with any intent to die as a result of the behavior.

Therapeutic alliance A characteristic of the relationship between the patient and clinician that describes the sense of collaboration in pursuing therapeutic goals as well as the patient’s sense of attachment to the clinician and perception of whether the clinician is helpful (Gabbard 2009).

Trauma history A history of events in the patient’s life with the potential to have been emotionally traumatic, including but not limited to exposure to actual or threatened death, serious injury, illness, or sexual violence. Exposure may occur through direct experience or by observing an event in person or through technology (e.g., television, audio or video recording) or by learning of an event that occurred to a close family member or close friend. Trauma could also include early adversity, neglect, maltreatment, emotional abuse, physical abuse, or sexual abuse occurring in childhood; exposure to natural or man-made disasters; exposure to combat situations; being a victim of a violent crime; involvement in a serious motor vehicle accident; or having serious or painful or prolonged medical experiences (e.g., intensive care unit stay).

Treatment as usual Treatment that is consistent with care received for a specific condition in a real-world nonresearch context. Treatment as usual, sometimes referred to as usual care or standard care, is often used as an active comparison condition for studies of new interventions. Elements of treatment as usual are heterogeneous and differ with each study but can include medication treatment, medication management, case management, rehabilitation services, and psychotherapy (McDonagh et al. 2017).

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Disclosures

The Guideline Writing Group and Systematic Review Group reported the following disclosures during devel- opment and approval of this guideline:

Dr. Keepers is employed as Professor and Chair of the Department of Psychiatry by Oregon Health & Science University. He receives travel funds from the American Board of Psychiatry and Neurology, the American College of Psychiatry, and the Accreditation Council for Graduate Medi- cal Education related to his activities as a member or chair of various committees. He reports no conflicts of interest with his work on this guideline.

Dr. Fochtmann is employed by Stony Brook University, where she is a Distinguished Service Pro- fessor of Psychiatry, Pharmacological Sciences, and Biomedical Informatics. She also serves as a Dep- uty Chief Medical Information Officer for Stony Brook Medicine. Dr. Fochtmann has received payment for grant reviews for the National Institute of Mental Health (NIMH) and is a co-investigator on a grant funded by NIMH. She consults for the American Psychiatric Association on the develop- ment of practice guidelines and has received travel funds to attend meetings related to these duties. She reports no conflicts of interest with her work on this guideline.

Dr. Anzia is employed as Professor of Psychiatry and Behavioral Sciences and Residency Pro- gram Director/Vice Chair for Education at Northwestern University/Feinberg School of Medicine. She receives part of her salary from the Medical Staff Office of Northwestern Medicine for her role as Physician Health Liaison. Dr. Anzia receives travel funds from the American Board of Psychiatry and Neurology, the American College of Psychiatry, and the Accreditation Council for Graduate Medical Education for her activities as Board Director, committee chair, and various other commit- tees. She has no conflicts of interest with her work on this guideline.

Dr. Benjamin is employed as the Interim Chair of Psychiatry at University of Massachusetts Medical School and UMass Memorial Health Care, where he is also Director of Residency Training, Director of Neuropsychiatry, and Professor of Psychiatry and Neurology. He periodically receives honoraria for lectures, provides consultation to the Massachusetts Department of Mental Health, and serves as an expert witness on neuropsychiatric issues. He is a partner in and author for Brain Educators, LLC, a publisher of educational materials designed to improve neuropsychiatric assess- ment skills. Any income received is used to offset production and development costs of the mate- rials. He reports no conflicts of interest with his work on this guideline.

Dr. Lyness is employed as Senior Associate Dean for Academic Affairs and Professor of Psychi- atry and Neurology in the School of Medicine & Dentistry at the University of Rochester Medical Center. He receives compensation for his work as a Psychiatry Director of the American Board of Psychiatry and Neurology. At times he provides independent medical examinations for various at- torneys. He has no other relevant financial or fiduciary interests and reports no conflicts of interest with his work on this guideline.

Dr. Mojtabai is employed as Professor of Public Health at Johns Hopkins Bloomberg School of Pub- lic Health in Baltimore, Maryland, and as a psychiatrist at Johns Hopkins Hospital. During the period of preparation of this guideline, he received royalties from UpToDate, Inc., and consulting fees from the RAND Corporation. He reports no conflicts of interest with his work on this guideline.

Dr. Servis is employed as Professor of Psychiatry and Behavioral Sciences and the Vice Dean for Medical Education at the University of California Davis School of Medicine. He consults to the Medical Board of California and serves on the Psychiatry Residency in Training Examination Edi-

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torial Board for the American College of Psychiatrists and the Interdisciplinary Review Committee for the USMLE Step 2 Examination for the National Board of Medical Examiners. He reports no conflicts of interest with his work on this guideline.

Dr. Walaszek is employed as Professor of Psychiatry at the University of Wisconsin School of Medicine and Public Health, where he is Residency Training Director and Vice Chair for Education and Faculty Development. He is past President of the American Association of Directors of Psychi- atric Residency Training. He reports no conflict of interest with his work on this guideline.

Dr. Buckley is Dean of the Virginia Commonwealth University School of Medicine. He receives payment for grant reviews for the National Institute of Mental Health (NIMH) and conducts col- laborative research funded by NIMH, the Stanley Foundation, and the Brain and Behavior Research Foundation. He reports no conflicts of interest with his work on this guideline.

Dr. Lenzenweger is employed as Distinguished Professor of Psychology at the State University of New York at Binghamton. He is also appointed as Adjunct Professor of Psychology in Psychiatry, Department of Psychiatry, Weill Cornell Medical College. He has received consulting fees for re- search consultations to the Personality Disorders Institute at Weill Cornell Medical College. He also maintains an independent clinical practice in Ithaca, New York. He reports no conflicts of interest with his work on this guideline.

Dr. Young is employed as Professor of Psychiatry at the University of California Los Angeles and as Physician at the Department of Veterans Affairs in Los Angeles, California. He served on the American Psychiatric Association’s Council on Quality Care and received travel funds to attend meetings related to those duties. He reports no conflicts of interest with his work on this guideline.

Dr. Degenhardt is employed as a fifth-year resident in psychiatry by Vancouver Coastal Health at the University of British Columbia in Vancouver, British Columbia, Canada. She is a member of the APA Council of Research and APA Leadership fellowship. She is also on the board of directors of the Canadian Psychiatric Association (CPA), is Chair of the CPA Members-in-Training Executive Committee, and various other committees. She has received travel funds to attend meetings related to these duties. She reports no conflicts of interest with her work on this guideline.

Individuals and Organizations That Submitted Comments

Donald Addington, M.B.B.S. Jonathan E. Alpert, M.D., Ph.D. Gustavo Alva, M.D., DFAPA Anne S. Bassett, M.D., FRCPC Scott R. Beach, M.D.

Lora Beebe, Ph.D., PMHNP-BC, FAAN Jeffrey Bennett, M.D., A.B.
Jolene Bostwick, Pharm.D. Vasileios-Panteleimon Bozikas, M.D., Ph.D. Nancy Burke, Ph.D.

Stanley N. Caroff, M.D.
Nicola Cascella, M.D.
Christopher Celano, M.D.
Michael Champion, M.D.
Hemlata Charitar, M.D., Ph.D., FAPA Leslie Citrome, M.D., M.P.H. Michael Davidson, M.D.

Erica Davis, Pharm.D., BCPS, BCPP Sonia Dollfus, M.D., Ph.D.
Gail A. Edelsohn, M.D., M.S.P.H. Michael Enenbach, M.D.

Peter Falkai, Dr. med.
Marlene Freeman, M.D.
Oliver Freudenreich, M.D., FACLP
Kenneth Fung, M.D.
Margo C. Funk, M.D., M.A.
Wolfgang Gaebel, Dr. med.
Carles Garcia-Ribera, M.D., Ph.D.
Paul Gionfriddo
Christina Girgis, M.D.
Robert M. Goisman, M.D.
Lisa W. Goldstone, M.S., Pharm.D., BCPS, BCPP Philip D. Harvey, Ph.D.
Steven Hoge, M.D.
William G. Honer, M.D., FRCPC, FCAHS
Liwei L. Hua, M.D., Ph.D.
Nikola Ilankovic, M.D., Ph.D., DFAPA
Kelly Irwin, M.D., M.P.H.
John M. Kane, M.D.
Reena Kapoor, M.D.
Michael B. Knable, D.O.
Maju Koola, M.D.
Sarah L. Kopelovich, Ph.D.
Robert S. Laitman, M.D.
Susan N Legacy, M.D., M.S.

Raquel L¬pez-Carrilero
Paul H. Lysaker, Ph.D.
Stephen Marder, M.D.
Russell L. Margolis, M.D.
Ashley M. Schnakenberg Martin, Ph.D. Patrick McGorry

John McGrath, M.D., Ph.D.
Alice Medalia, Ph.D.
Gaurav Mehta, CPA Lead for Obesity, M.B.B.S., DCP,

M.Sc. (Psych), M.Sc. (Diabetes), FAcadMEd,

FRCPC, FAPA, CISAM, CCSAM, DAM, CBE Jeffrey L. Metzner, M.D.
Jonathan Meyer, M.D.
Linda Michaels, Psy.D.

Kim T. Mueser, Ph.D.
Janice Muhr, Ph.D.
Sachin Nagendrappa, M.D. Anna-Greta Nylander, Ph.D., M.B.A. Susana Ochoa

Carol A. Ott, Pharm.D., BCPP Raymond Patterson, M.D. Edmond Pi, M.D.
Debra Pinals, M.D.

Rajiv Radhakrishnan, M.B.B.S., M.D. Gary Remington, M.D., Ph.D. Arnold Robbins, M.D.
Alvin Rosenfeld, M.D.

Ada Ruiz-Ripoll, M.D., Ph.D.
Stephen R. Saklad, Pharm.D., BCPP
Elyn R. Saks, B.A., M.Litt., J.D., Ph.D., LL.D. (hon) John P.D. Shemo, M.D.
Dan Siskind, M.B.B.S., M.P.H., Ph.D., FRANZCP John Snook, J.D.
Amro Soliman, M.Sc., ARCPsych, M.D.
Melina Spyridaki-Dodd, M.D.
Linda Whitten Stalters, M.S.N., APRN (ret)
David M. Tobolowsky, M.D.
John Torous, M.D., M.B.I.
Robert Trestman, Ph.D., M.D.
Margaret Tuttle, M.D.
Nina Vadiei, Pharm.D., BCPP
John Waddington, Ph.D., D.Sc.
Scott Weigold, M.D.
Kazunari Yoshida, M.D., Ph.D.

199

Academy of Consultation-Liaison Psychiatry
Alkermes, Inc.
American Academy of Child and Adolescent Psychiatry
American Psychological Association
American Society of Clinical Psychopharmacology
APA Council on Consultation-Liaison Psychiatry Workgroup on QTc Prolongation and Psychotropic Medications APA Council on Psychiatry and the Law, Subcommittee on Correctional Psychiatry
ATP Clinical Research
Cairo Neuropsychiatric Clinic
Canadian Psychiatric Association
College of Psychiatric & Neurologic Pharmacists
International Society for Psychological and Social Approaches to Psychosis, United States Chapter International Society of Psychiatric Nurses
Mental Health America
National Alliance on Mental Illness
Psychotherapy Action Network
Schizophrenia and Related Disorders Alliance of America
Schizophrenia International Research Society
Treatment Advocacy Center Psychiatric Advisory Board
World Psychiatric Association Section on Schizophrenia

200 APA Practice Guidelines

Appendix A.

Clinical Questions

The following key questions formed the basis of the Agency for Healthcare Research and Quality review:

. 1a.  Whatarethecomparativebenefitsandharmsofpharmacologicaltreatmentsforadultswithschizophrenia?

. 1b.  Howdothebenefitsandharmsofpharmacologicaltreatmentsforadultswithschizophreniavarybypatient
characteristics?

. 2a.  Whatarethebenefitsandharmsofpsychosocialandothernonpharmacologicaltreatmentsforadultswith
schizophrenia?

. 2b.  Howdothebenefitsandharmsofpsychosocialandothernonpharmacologicaltreatmentsforadultswith
schizophrenia vary by patient characteristics (e.g., age, sex, race, ethnicity, socioeconomic status, time since illness onset, prior treatment history, co-occurring psychiatric disorders, pregnancy)?

The following key questions formed the basis of searches related to neurological side effects of antipsychotic medications:

1. What are the comparative benefits and harms of pharmacological treatments for acute dystonia associated with antipsychotic therapy?

2. What are the comparative benefits and harms of pharmacological treatments for parkinsonism associated with antipsychotic therapy?

3. What are the comparative benefits and harms of pharmacological treatments for akathisia associated with antipsychotic therapy?

4. What are the comparative benefits and harms of pharmacological treatments for tardive syndromes asso- ciated with antipsychotic therapy?

201

Appendix B.
Search Strategies, Study Selection, and Search Results

AHRQ Review

The Agency for Healthcare Research and Quality’s (AHRQ) systematic review Treatments for Schizo- phrenia in Adults (McDonagh et al. 2017) served as the predominant source of information for this guideline. Databases that were searched are Ovid MEDLINE® (PubMed®), the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO®. Re- sults were limited to English-language, adult (18 and older), and human-only studies. The search varied by key question because high-quality systematic reviews were used as a starting point for the review. For key question 1, search dates for first-generation antipsychotic medications (FGAs) versus second-generation antipsychotic medications (SGAs) began in 2011 and for SGAs versus SGAs began in 2013. Key question 2 did not restrict the start date. All searches were conducted through February 1, 2017. The search strategies used can be found in Appendix A of the AHRQ re- view (McDonagh et al. 2017).

The AHRQ review (McDonagh et al. 2017) adhered to the procedures outlined in the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews (Agency for Healthcare Research and Quality 2014). Recent, comprehensive, good- or fair-quality systematic reviews served as a primary source of evidence, supplemented by information from randomized controlled trials (RCTs) published since the systematic reviews or when no systematic reviews were available. For assessment of harms of treatment, systematic reviews of observational trials were also in- cluded. Eligibility for inclusion and exclusion of articles adhered to preestablished criteria. Specif- ically, the AHRQ review included articles that had at least 12 weeks of follow-up and were conducted in outpatient settings in countries that were relevant to the United States’ health care system. Articles that addressed benefits of treatment were included if at least 90% of the sample had a diagnosis of schizophrenia (or schizophreniform disorder), with a schizophrenia spectrum disor- der in at least 50% of the sample (minimum sample size >50) for studies of harms of treatment. For key questions that related to antipsychotic treatment, all of the SGAs were included; for FGAs, studies on fluphenazine, haloperidol, and perphenazine were included. Only head-to-head com- parison studies were included. For studies of psychosocial and other nonpharmacological interven- tions, studies were included if they compared usual care, standard care, treatment as usual, or a waitlist control group to active treatment with assertive community treatment, cognitive adaptive training, cognitive-behavioral therapy, cognitive remediation, early interventions for first-episode psychosis, family interventions, intensive case management, illness self-management training, in- terventions for co-occurring schizophrenia and substance use, psychoeducation, social skills train- ing, supported employment, or supportive psychotherapy.

Using these criteria, titles and abstracts were reviewed by two individuals (McDonagh et al. 2017). Full-text articles were retrieved if either reviewer felt inclusion was warranted. Full-text ar- ticles were also evaluated by two reviewers, and disagreements about inclusion were resolved by consensus. Included studies are listed in Appendix B of the AHRQ review, and excluded studies

203

(with the reason for exclusion) are listed in Appendix C of the AHRQ review (McDonagh et al. 2017). For key question 1 on antipsychotic treatment, 698 citations were identified, 519 of which were excluded on the basis of title and abstract review, yielding 179 full-text articles that were re- viewed, of which 38 were included in the final AHRQ review. For key question 2 on psychosocial and other nonpharmacological interventions, 2,766 citations were identified, 1,871 of which were excluded on the basis of title and abstract review, yielding 895 full-text articles that were reviewed, of which 53 were included in the final AHRQ review. Additional summary information about the included studies is shown in Table B-1, and additional details can be found in the AHRQ review (McDonagh et al. 2017).

For included studies, abstracted information was verified for accuracy and completeness by a second individual and included citation, year, study design, setting, funding source, country, sam- ple size, eligibility criteria, clinical characteristics, and other characteristics of the study design, population, intervention, and outcomes (McDonagh et al. 2017). In addition, individual controlled trials and systematic reviews were assessed by two team members with predefined criteria for study quality, yielding ratings of “good,” “fair,” or “poor,” with disagreements resolved by consen- sus (McDonagh et al. 2017). Included systematic reviews were generally of good quality, whereas additional included studies were generally of fair quality.

Treatment of Neurological Side Effects of Antipsychotic Medications

Additional searches were undertaken to supplement the AHRQ review and to identify studies that addressed approaches to treatment of neurological side effects of antipsychotic medications. Search strategies for MEDLINE (PubMed) and Cochrane Library are shown in Tables B–2 and B–3, respec- tively. For each search, all available citations were identified from the inception of the database to July 29, 2018, the date when the searches were conducted. A search of MEDLINE yielded 2,980 ci- tations, and a search of the Cochrane Library yielded 2,450. After duplicate citations were removed, titles and abstracts for 4,196 articles were screened by one reviewer (L.J.F.) to identify articles in hu- mans, 18 years of age or older, published in English, that investigated the treatment of antipsy- chotic-associated dystonia, parkinsonism, akathisia, tardive syndromes, or neuroleptic malignant syndrome. Systematic reviews and meta-analyses were used as a primary source of evidence, and if multiple Cochrane reviews on a topic had been done, only the most recent review was included. For topics on which no systematic review was available, RCTs with a sample size of at least 20 sub- jects and observational studies with a sample of at least 50 individuals were included. Included studies had a follow-up period of at least 1 week for acute dystonia or neuroleptic malignant syn- drome and 8 weeks for other side effects.

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The APA Practice Guideline for the Treatment of Patients With Schizophrenia 205

TABLE B–1.

Studies used in the Agency for Healthcare Research Quality review

FGA vs. SGA

1 2 1 1 1 1

111 138 14

118,503 47,189 2,281

5 24 1

7 28 1

1,055 6,672 118

119,558 53,861 2,399

SGA vs. SGA

Assertive community treatment

Cognitive adaptive training

0 0 3 3 2 2 0 0

0 89 57 0

0 7,154 2,885 0

3 5 4 4

4 6 5 9

290 823 341

290 7,977 3,226 2,363

Cognitive- behavioral therapy

Cognitive remediation

Early intervention for first-episode psychosis

2,363

Family interventions

1 1 1 1 1 1

27 10 32

2,297 1,652 3,165

6 1 0

8 1 0

562 77 0

2,859 1,729 3,165

Intensive case management

Interventions for schizophrenia and co-occurring SUD

Illness self- management

1 1

13

1,404

1

1

210

1,614

Psychoeducation

1 1 0 0 1 1

10 0 14

1,125 0 2,265

0 3 2

0 4 3

0 433 1,477

1,125 433 3,742

Social skills training

Supported employment

Supportive psychotherapy

1 1

5

822

0

0

0

822

Systematic Number of reviews publications

Number of additional trials

Number of publications

subjects in additional trials

Total number of subjects

Abbreviations. FGA=first-generation antipsychotic; SGA=second-generation antipsychotic; SUD=substance use disorder. Source. Adapted from McDonagh et al. 2017.

Number of trials in systematic reviews

Number of subjects in systematic reviews

Number of

TABLE B–2. Strategy for MEDLINE (PubMed) search on treatments for neurological side effects of antipsychotic medications

ID Search

. #1  Search “Akineton”[TIAB] OR “Amantadine”[MH] OR “Amantadine”[TIAB] OR “Artane”[TIAB] OR “Atropine”[MH] OR “Atropine”[TIAB] OR “Benadryl”[TIAB] OR “Benztropine”[MH] OR “Benztropine”[TIAB] OR “Biperiden”[MH] OR “Biperiden”[TIAB] OR “Bromocriptine”[MH] OR “bromocriptine”[TIAB] OR “Cogentin”[TIAB] OR “Cuvposa”[TIAB] OR “Dantrium”[TIAB] OR “Dantrolene”[MH] OR “Dantrolene”[TIAB] OR “Diphenhydramine”[MH] OR “Diphenhydramine”[TIAB] OR “Glycopyrrolate”[MH] OR “Glycopyrrolate”[TIAB] OR “Nitoman”[TIAB] OR “Procyclidine”[MH] OR “Procyclidine”[TIAB] OR “Robinul”[TIAB] OR “Symmetrel”[TIAB] OR “Tetrabenazine”[MH] OR “Tetrabenazine”[TIAB] OR “Trihexyphenidyl”[MH] OR “Trihexyphenidyl”[TIAB] OR “Xenazine”[TIAB] OR “beta blocker”[TIAB] OR “beta blockers”[TIAB] OR “beta adrenergic antagonist”[TIAB] OR “beta adrenergic antagonists”[TIAB] OR “beta adrenergic blocking”[TIAB] OR “beta adrenergic blocking agent”[TIAB] OR “beta adrenergic blocking agents”[TIAB] OR “adrenergic beta antagonists”[TIAB] OR “propranolol”[TIAB] OR “pindolol”[TIAB] OR “atenolol”[TIAB] OR “inderal”[TIAB] OR “muscarinic antagonists”[MeSH Terms] OR “adrenergic beta antagonists”[MeSH Terms] OR “amantadine”[MeSH Terms] OR “benztropine”[MeSH Terms] OR “diphenhydramine”[MeSH Terms] OR “trihexyphenidyl”[MeSH Terms] OR “propranolol”[MeSH Terms] OR “pindolol”[MeSH Terms] OR “atenolol”[MeSH Terms]

. #2  Search “9-hydroxy-risperidone”[TIAB] OR “abilify”[TIAB] OR “antipsychotic agents”[MeSH Major Topic] OR “antipsychotic agents”[MeSH Terms] OR “antipsychotic”[TIAB] OR “antipsychotics”[TIAB] OR “aripiprazole”[NM] OR “aripiprazole”[TIAB] OR “Asenapine”[NM] OR “Asenapine”[TIAB] OR “Chlorpromazine”[MH] OR “Chlorpromazine”[NM] OR “Chlorpromazine”[TIAB] OR “Chlorprothixene”[MH] OR “Chlorprothixene”[NM] OR “Chlorprothixene”[TIAB] OR “Clopixol”[TIAB] OR “Clozapine”[MH] OR “clozapine”[NM] OR “clozapine”[TIAB] OR “clozaril”[TIAB] OR “Consta”[TIAB] OR “Droperidol”[MH] OR “droperidol”[NM] OR “droperidol”[TIAB] OR “Fanapt”[TIAB] OR “Fazaclo”[TIAB] OR “Fluanxol”[TIAB] OR “flupenthixol”[NM] OR “flupenthixol”[TIAB] OR “flupenthixol”[TIAB] OR “fluphenazine depot”[NM] OR “fluphenazine depot”[TIAB] OR “fluphenazine enanthate”[NM] OR “fluphenazine enanthate”[TIAB] OR “Fluphenazine”[MH] OR “Fluphenazine”[TIAB] OR “Geodon”[TIAB] OR “Haldol”[TIAB] OR “haloperidol decanoate”[NM] OR “haloperidol decanoate”[TIAB] OR “Haloperidol”[MH] OR “haloperidol”[NM] OR “haloperidol”[TIAB] OR “Iloperidone”[TIAB] OR “Inapsine”[TIAB] OR “Invega”[TIAB] OR “Largactil”[TIAB] OR “Loxapac”[TIAB] OR “Loxapine”[MH] OR “Loxapine”[NM] OR “Loxapine”[TIAB] OR “Loxitane”[TIAB] OR “Lurasidone”[TIAB] OR “Mellaril”[TIAB] OR “Mesoridazine”[MH] OR “Mesoridazine”[NM] OR “Mesoridazine”[TIAB] OR “Moban”[TIAB] OR “Modecate”[TIAB] OR “Molindone”[MH] OR “Molindone”[NM] OR “Molindone”[TIAB] OR “Navane”[TIAB] OR “olanzapine”[NM] OR “olanzapine”[TIAB] OR “Orap”[TIAB] OR “paliperidone palmitate”[NM] OR “Perphenazine”[MH] OR “Paliperidone”[TIAB] OR “Perphenazine”[NM] OR “Perphenazine”[TIAB] OR “Pimozide”[MH] OR “Pimozide”[NM] OR “Pimozide”[TIAB] OR “Prolixin”[TIAB] OR “quetiapine”[TIAB] OR “Relprevv”[TIAB] OR “Risperdal”[TIAB] OR “Risperidone”[MH] OR “Risperidone”[NM] OR “Risperidone”[TIAB] OR “Saphris”[TIAB] OR “Serentil”[TIAB] OR “Seroquel”[TIAB] OR “Stelazine”[TIAB] OR “Sustenna”[TIAB] OR “Symbyax”[TIAB] OR “Taractan”[TIAB] OR “Thioridazine”[MH] OR “Thioridazine”[NM] OR “Thioridazine”[TIAB] OR “Thiothixene”[MH] OR “Thiothixene”[NM] OR “Thiothixene”[TIAB] OR “Thorazine”[TIAB] OR “Trifluoperazine”[MH] OR “Trifluoperazine”[NM] OR “Trifluoperazine”[TIAB] OR “Trilafon”[TIAB] OR “Zeldox”[TIAB] OR “ziprasidone”[NM] OR “ziprasidone”[TIAB] OR “zuclopenthixol”[TIAB] OR “Zydis”[TIAB] OR “Zyprexa”[TIAB]

. #3  Search “akathisia”[TIAB] OR “Akathisia, Drug-Induced”[MH] OR “drug induced parkinsonism”[TIAB] OR “Dyskinesia, Drug-Induced”[MH] OR “dystonic reaction”[TIAB] OR “dystonic reactions”[TIAB] OR “extrapyramidal reactions”[TIAB] OR “extrapyramidal side effect”[TIAB] OR “extrapyramidal side effects”[TIAB] OR “extrapyramidal signs”[TIAB] OR “extrapyramidal syndrome”[TIAB] OR “extrapyramidal syndromes”[TIAB] OR “Neuroleptic Malignant Syndrome”[MH] OR “neuroleptic malignant”[TIAB] OR “tardive dyskinesia”[TIAB] OR “tardive dystonia”[TIAB] OR “neuroleptic induced parkinsonism”[TIAB] OR “medication induced parkinsonism”[TIAB] OR “tardive akathisia”[TIAB]

Hits

163,354

 

206 APA Practice Guidelines

113,808

16,341

TABLE B–2. Strategy for MEDLINE (PubMed) search on treatments for neurological side effects of antipsychotic medications (continued)

ID Search

. #4  Search ((“animals”[MeSH Major Topic] OR “animals”[MeSH Terms] OR “animal”[TIAB] OR “animals”[TIAB] OR “rat”[TIAB] OR “mouse”[TIAB] OR “mice”[TIAB] OR “rodent”[TIAB] OR “rodents”[TIAB] OR “rats”[TIAB]) NOT (“humans”[MAJR] OR “humans”[MH] OR “human”[TIAB] OR “humans”[TIAB]))

. #5  Search “meta analysis”[TIAB] OR “meta analyses”[TIAB] OR “meta analytic”[TIAB] OR “metaanalysis”[TIAB] OR “metaanalysis”[TIAB] OR “systematic review”[TIAB] OR “systematic reviews”[TIAB] OR “meta analysis”[Publication Type] OR “randomized controlled trial”[PT] OR “randomised”[TIAB] OR “randomized”[TIAB] OR “randomisation”[TIAB] OR “randomization”[TIAB] OR “randomly”[TIAB] OR “placebo”[TIAB] OR “sham”[TIAB] OR “trial”[TIAB] OR “groups”[TIAB]

. #6  Search “controlled clinical trial”[PT] OR “blinded”[TIAB] OR “case control”[TIAB] OR “clinical trial”[TIAB] OR “clinical trials”[TIAB] OR “Cohort Analysis”[TIAB] OR “cohort research”[TIAB] OR “cohort study”[TIAB] OR “cohort trial”[TIAB] OR “comparator group”[TIAB] OR “controlled studies”[TIAB] OR “controlled study”[TIAB] OR “controlled trial”[TIAB] OR “controlled trials”[TIAB] OR “double blind”[TIAB] OR “followup study”[TIAB] OR “longitudinal research”[TIAB] OR “longitudinal study”[TIAB] OR “longitudinal trial”[TIAB] OR “multicenter trial”[TIAB] OR “multicenter trials”[TIAB] OR “naturalistic research”[TIAB] OR “naturalistic study”[TIAB] OR “naturalistic trial”[TIAB] OR “prospective cohort”[TIAB] OR “prospective research”[TIAB] OR “prospective study”[TIAB] OR “prospective trial”[TIAB] OR “retrospective cohort”[TIAB] OR “retrospective research”[TIAB] OR “retrospective study”[TIAB] OR “retrospective trial”[TIAB] OR “single blind”[TIAB]

. #7  Search (#1 AND #2) OR (#1 AND #3) OR (#2 AND #3)

. #8  Search #7 NOT #4

. #9  Search #8 AND (#5 OR #6)

. #10  Search “english”[Language] AND #9

Hits

4,437,558

2,841,422

1,513,299

15,146 11,508 3,156 2,980

  

The APA Practice Guideline for the Treatment of Patients With Schizophrenia

207

TABLE B–3. Strategy for Cochrane Library search on treatments for neurological side effects of antipsychotic medications

ID

#1

#2

#3

#4

Search

“Akineton” OR “Amantadine” OR “Artane” OR “Atropine” OR “Benadryl” OR “Benztropine” OR “Biperiden” OR “bromocriptine” OR “Cogentin” OR “Dantrium” OR “Dantrolene” OR “Diphenhydramine” OR “Glycopyrrolate” OR “Procyclidine” OR “Robinul” OR “Symmetrel” OR “Tetrabenazine” OR “Trihexyphenidyl” OR “Xenazine” OR “beta blocker” OR “beta blockers” OR “beta adrenergic antagonist” OR “beta adrenergic antagonists” OR “beta adrenergic blocking” OR “beta adrenergic blocking agent” OR “beta adrenergic blocking agents” OR “adrenergic beta antagonists” OR “propranolol” OR “pindolol” OR “atenolol” OR “inderal”:ti,ab,kw (Word variations have been searched)

“9-hydroxy-risperidone” OR “abilify” OR “antipsychotic” OR “antipsychotics” OR “aripiprazole” OR “Asenapine” OR “Chlorpromazine” OR “Chlorprothixene” OR “Clopixol” OR “clozapine” OR “clozaril” OR “Consta” OR “droperidol” OR “Fanapt” OR “Fazaclo” OR “Fluanxol” OR “flupenthixol” OR “flupenthixol” OR “fluphenazine depot” OR “fluphenazine enanthate” OR “Fluphenazine” OR “Geodon” OR “Haldol” OR “haloperidol decanoate” OR “haloperidol” OR “Iloperidone” OR “Inapsine” OR “Invega” OR “Largactil” OR “Loxapac” OR “Loxapine” OR “Loxitane” OR “Lurasidone” OR “Mellaril” OR “Mesoridazine” OR “Moban” OR “Modecate” OR “Molindone” OR “Navane” OR “olanzapine” OR “Orap” OR “Paliperidone” OR “Perphenazine” OR “Pimozide” OR “Prolixin” OR “quetiapine” OR “Relprevv” OR “Risperdal” OR “Risperidone” OR “Saphris” OR “Serentil” OR “Seroquel” OR “Stelazine” OR “Sustenna” OR “Symbyax” OR “Taractan” OR “Thioridazine” OR “Thiothixene” OR “Thorazine” OR “Trifluoperazine” OR “Trilafon” OR “Zeldox” OR “ziprasidone” OR “zuclopenthixol” OR “Zydis” OR “Zyprexa”

“akathisia” OR “drug induced parkinsonism” OR “dystonic reaction” OR “dystonic reactions” OR “extrapyramidal reactions” OR “extrapyramidal side effect” OR “extrapyramidal side effects” OR “extrapyramidal signs” OR “extrapyramidal syndrome” OR “extrapyramidal syndromes” OR “neuroleptic malignant” OR “tardive dyskinesia” OR “tardive dystonia” OR “neuroleptic induced parkinsonism” OR “medication induced parkinsonism” OR “tardive akathisia”

(#1 and #2) OR (#1 and #3) OR (#2 and #3)
Limited to Cochrane Reviews, Other Reviews and Trials

Hits

21,056

16,885

2,505

2,473 2,450

 

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APA Practice Guidelines

Full-text documents were then reviewed by one individual (L.J.F.) to determine whether they met eligibility criteria. For tardive dyskinesia, 12 systematic reviews were available, with 2 reviews of multiple treatment approaches and 1 review each related to anticholinergic medication, cholinergic medication, benzodiazepines, vitamin B6, vitamin E, calcium channel blockers, γ-aminobutyric acid agonists, non-antipsychotic catecholaminergic drugs, miscellaneous treatments, and antipsychotic reduction or cessation. For akathisia, 3 recent systematic reviews were available, with 1 review each related to β-adrenergic blocking agents, anticholinergic agents, and mirtazapine. No additional RCTs or observational studies met inclusion criteria for other treatments of akathisia (e.g., benzo- diazepines). For medication-induced parkinsonism, 1 systematic review was available, but evi- dence was insufficient to draw any definitive conclusions. For acute dystonia, 1 systematic review, 1 RCT, and 1 nonrandomized prospective study examined effects of anticholinergic medications in reducing the likelihood of acute dystonia; however, no studies meeting inclusion criteria examined use of anticholinergic agents as a treatment of acute dystonia. In addition, no studies meeting in- clusion criteria were found that addressed treatment of neuroleptic malignant syndrome.

Appendix C.
Review of Research Evidence Supporting Guideline Statements

Assessment and Determination of Treatment Plan

STATEMENT 1: Assessment of Possible Schizophrenia

APA recommends (1C) that the initial assessment of a patient with a possible psychotic dis- order include the reason the individual is presenting for evaluation; the patient’s goals and preferences for treatment; a review of psychiatric symptoms and trauma history; an assessment of tobacco use and other substance use; a psychiatric treatment history; an as- sessment of physical health; an assessment of psychosocial and cultural factors; a mental status examination, including cognitive assessment; and an assessment of risk of suicide and aggressive behaviors, as outlined in APA’s Practice Guidelines for the Psychiatric Evalu- ation of Adults (3rd edition).

Evidence for this statement comes from general principles of assessment and clinical care in psy- chiatric practice. Expert opinion suggests that conducting such assessments as part of the initial psychiatric evaluation improves diagnostic accuracy, appropriateness of treatment selection, and treatment safety. For additional details, see Guideline I, “Review of Psychiatric Symptoms, Trauma History, and Psychiatric Treatment History,” Guideline II, “Substance Use Assessment,” Guideline III, “Assessment of Suicide Risk,” Guideline IV, “Assessment of Risk for Aggressive Behaviors,” Guideline V, “Assessment of Cultural Factors,” and Guideline VI, “Assessment of Medical Health,” in the APA Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd Edition (American Psychi- atric Association 2016a). A detailed systematic review to support this statement is outside the scope of this guideline; however, less comprehensive searches of the literature did not yield any studies related to this recommendation in the context of schizophrenia treatment. Consequently, the strength of research evidence is rated as low.

Grading of the Overall Supporting Body of Research Evidence for Assessment of Possible Schizophrenia

On the basis of the limitations of the evidence for assessment of possible schizophrenia, no grading of the body of research evidence is possible.

STATEMENT 2: Use of Quantitative Measures

APA recommends (1C) that the initial psychiatric evaluation of a patient with a possible psychotic disorder include a quantitative measure to identify and determine the severity of symptoms and impairments of functioning that may be a focus of treatment.

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Evidence for this statement comes from general principles of assessment and clinical care in psy- chiatric practice. Consequently, the strength of research evidence is rated as low. Expert opinion suggests that conducting such assessments as part of the initial psychiatric evaluation improves di- agnostic accuracy, appropriateness of treatment selection, and longitudinal assessment of patient symptoms and treatment effects. This recommendation is also consistent with Guideline VII, “Quantitative Assessment,” as part of the APA Practice Guidelines for the Psychiatric Evaluation of Adults, 3rd Edition (American Psychiatric Association 2016a).

Grading of the Overall Supporting Body of Research Evidence for Use of Quantitative Measures

On the basis of the limitations of the evidence for use of quantitative measures, no grading of the body of research evidence is possible.

STATEMENT 3: Evidence-Based Treatment Planning

APA recommends (1C) that patients with schizophrenia have a documented, comprehen- sive, and person-centered treatment plan that includes evidence-based nonpharmacolog- ical and pharmacological treatments.

Evidence for this statement comes from general principles of assessment and clinical care in psy- chiatric practice. A detailed systematic review to support this statement was outside the scope of this guideline; however, less comprehensive searches of the literature did not yield any studies that directly related to this recommendation in the context of schizophrenia treatment. Consequently, the strength of research evidence is rated as low. Nevertheless, in the bulk of the literature reviewed in the Agency for Healthcare Research and Quality (AHRQ) report (McDonagh et al. 2017), phar- macotherapy was included in all treatment arms in the studies of psychosocial interventions. In- variably, in studies of pharmacotherapies, some additional form of clinical intervention is incorporated into treatment and can include elements of patient education, supportive psychother- apy, and other brief interventions.

Grading of the Overall Supporting Body of Research Evidence for Evidence-Based Treatment Planning

On the basis of the limitations of the evidence for evidence-based treatment planning, no grading of the body of research evidence is possible.

Pharmacotherapy

STATEMENT 4: Antipsychotic Medications

APA recommends (1A) that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects.*

Evidence for this statement comes from the AHRQ review (McDonagh et al. 2017) as well as from other high-quality meta-analyses that examined findings from randomized controlled trials (RCTs) of antipsychotic medications in schizophrenia (Huhn et al. 2019; Leucht et al. 2017). The data from

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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placebo-controlled trials are essential in making an initial determination of whether the benefits of antipsychotic medications outweigh the harms of antipsychotic medications. Placebo-controlled trial data as well as findings from head-to-head comparison studies and network analyses provide additional information on whether the benefits and harms of specific antipsychotic medications suggest preferential use (or nonuse) as compared with other antipsychotic medications. The strength of the research evidence is rated as high in demonstrating that the benefits of treatment with an antipsychotic medication outweigh the harms, although harms are clearly present and must be taken into consideration.

Primary evidence for placebo-controlled antipsychotic trial data came from the systematic review, Bayesian meta-analysis, and meta-regression conducted by Leucht et al. (2017), which included 167 studies (total N = 28,102) published from 1955 to 2016 that were randomized and double-blinded with placebo control groups. The authors excluded studies of acute treatment with short-acting in- tramuscular antipsychotic medications and relapse prevention (including studies of long-acting in- jectable [LAI] antipsychotic agents). Studies of clozapine were excluded because of possible superior efficacy, and studies conducted in China were excluded because of concerns about study quality. Studies were also excluded if subjects had primarily negative symptoms or significant comor- bidity in either psychiatric or physical health conditions. The median study duration was 6 weeks, with almost all studies lasting 12 weeks or less in terms of primary study outcomes. None of the stud- ies was focused on first-episode or treatment-resistant samples of subjects, and the mean illness du- ration was 13.4 years (standard deviation [SD] 4.7), with a mean subject age of 38.7 (SD 5.5). The number of studies available on each drug was highly variable, with chlorpromazine, haloperidol, olanzapine, and risperidone being most often studied, and limited information was available on some antipsychotic medications. Results are provided in Table C–1.

The authors found a moderate benefit of antipsychotic medications, with positive symptoms im- proving the most but improvements in negative symptoms, depression, quality of life, and social functioning also noted with treatment (Leucht et al. 2017). Side effects were also present but dif- fered substantially among medications. The authors also found, however, that effect sizes for anti- psychotic medications have decreased with time over the past 60 years. This seems to result from increasing placebo response rates rather than decreasing medication response, although the benefit of haloperidol as compared with placebo has decreased with time. Not surprisingly, these trends are likely to confound comparisons of newer versus older medications. Although industry spon- sorship was associated with a lower effect size as compared with studies funded by other mecha- nisms, publication bias was observed because of the tendency to avoid publishing studies with no effect of treatment.

In the AHRQ review (McDonagh et al. 2017), few head-to-head comparison studies were avail- able for most of the antipsychotic medications. In terms of functioning, the strength of evidence (SOE) was low. Older second-generation antipsychotics (SGAs; risperidone, olanzapine, queti- apine, ziprasidone) and paliperidone did not differ in terms of global functioning or employment rates, although social functioning with risperidone in an LAI formulation was better than with que- tiapine in a single study (Rouillon et al. 2013). Measures of quality of life also showed no difference among older SGAs or between older SGAs and FGAs (specifically, haloperidol and perphenazine) on the basis of a low to moderate SOE.

In terms of response rates (McDonagh et al. 2017), there was no difference between haloperidol and risperidone (16 RCTs, N=3,452; relative risk [RR] 0.94, 95% confidence interval [CI] 0.87–1.02; moderate SOE), aripiprazole (5 RCTs, N=2,185; RR 1.01, 95% CI 0.76–1.34; low SOE), quetiapine (6 RCTs, N=1,421; RR 0.99, 95% CI 0.76–1.30; low SOE), and ziprasidone (6 RCTs, N=1,283; RR 0.98, 95% CI 0.74–1.30; low SOE). However, response with olanzapine was significantly better than with halo- peridol (14 RCTs, N=4,099; RR 0.86, 95% CI 0.78–0.96; low SOE). In addition, a network meta-analysis of 46 head-to-head RCTs showed a significantly greater likelihood of response with olanzapine (odds ratio [OR] 1.71, 95% CI 1.11–2.68) and risperidone (OR 1.41, 95% CI 1.01–2.00) than quetiapine (low SOE). Olanzapine was also associated with higher remission rates as compared with haloper-

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TABLE C–1. Results of meta-analysis on placebo-controlled trials of antipsychotic treatment

All studies Drug effect size

167 105

28,102
22,741 Mean effect size = 0.47

0.42, 0.51 52%

Any response with drug vs. placebo Good response

97 30

20,690 Response ratio = 1.93 8,408 Response ratio = 1.96

1.72, 2.19 1.65, 2.44

NNT=6

At least minimal response Discontinuation for any reason Discontinuation for inefficacy

46 105 94 64

8,918 Response ratio = 1.75 22,851 Risk ratio = 1.25 23,017 Risk ratio = 2.09 18,174 SMD = 0.45

1.59, 1.07 1.20, 1.31 1.90, 2.32

NNT = 5; 51% minimal response with antipsychotic vs. 30% with placebo

Positive symptoms
Negative symptoms
Depression
Quality of life
Social functioning
Use of antiparkinsonian medications

69 33 6 10 63

18,632 SMD = 0.35 9,658 SMD = 0.27 1,900 SMD = 0.35 3,077 SMD = 0.34

0.40, 0.50 56% 0.31, 0.40 42% 0.20, 0.34 50% 0.16, 0.51 43% 0.21, 0.47 46% 1.65, 2.29

Number of studies

Number of
subjects Measure

95% CI

I2 Comments

14,942 Risk ratio=1.93

NNH = 12; 19% with antipsychotic vs. 10% with placebo

Sedation
Weight gain
Prolactin increase
QTc prolongation
Abbreviations. CI=confidence interval; NNH=number needed to harm; NNT=number needed to treat; SMD=standardized mean difference. Source. Data from Leucht et al. 2017.

86 59 51 29

18,574 Risk ratio=2.80 15,219 SMD = -0.43 15,219 SMD = -0.43

9,833 SMD = -0.19

2.30, 3.55
–0.55, –0.30 73% –0.55, –0.30 91% –0.29, –0.08 80%

NNT=8; 23% good response with antipsychotic vs. 14% with placebo

NNT = 11; 38% discontinuation with antipsychotic vs. 56% with placebo

NNT = 7; 13% discontinuation with antipsychotic vs. 26% with placebo

54% 14% with antipsychotic vs. 6% with placebo

idol (3 RCTs; pooled RR 0.65, 95% CI 0.45–0.94; I2=54%; low SOE), but there was no difference in remission rates between haloperidol and ziprasidone (3 RCTs; RR 0.89, 95% CI 0.71–1.12; low SOE). In terms of core illness symptoms (e.g., delusions, hallucinations, disorganized thinking), all SGAs that were studied were superior to placebo (standardized mean difference [SMD] –0.33 to –0.88; low SOE; McDonagh et al. 2017). Risperidone (21 RCTs, N=4,020; mean difference [MD] 3.24, 95% CI 1.62–4.86) and olanzapine (15 RCTs, N=4,209; MD 2.31, 95% CI 0.44–4.18) were associated with greater improvements in total Positive and Negative Syndrome Scale (PANSS) score as compared with haloperidol (moderate SOE), but no differences were noted in other comparisons of FGAs and SGAs (low SOE). With comparisons among SGAs, clozapine improved core illness symptoms more than other SGAs except for olanzapine (network meta-analysis of 212 RCTs; SMDs on PANSS or Brief Psychiatric Rating Scale [BPRS] –0.32 to –0.55; low SOE); olanzapine and risperidone im- proved core illness symptoms more than the other SGAs except for each other and paliperidone (SMDs –0.13 to –0.26; low SOE); and paliperidone improved core illness symptoms more than lur-

asidone and iloperidone (SMDs –0.17; low SOE).
For negative symptoms (McDonagh et al. 2017), haloperidol was less effective than olanzapine

(5 RCTs, N=535; MD based on the Scale for the Assessment of Negative Symptoms scores 2.56, 95% CI 0.94–4.18; moderate SOE), aripiprazole (3 RCTs, N=1,701; MD 0.80, 95% CI 0.14–1.46), olanzapine (14 RCTs, N=3,742; MD 1.06, 95% CI 0.46–1.67), and risperidone (22 RCTs, N=4,142; MD 0.80, 95% CI 0.14–1.46), with the latter findings based on negative symptom scores of the PANSS and having a low SOE. Other comparisons of FGAs versus SGAs showed no effects on negative symptoms (low SOE).

In an additional network meta-analysis of 32 antipsychotic medications, Huhn et al. (2019) in- cluded 402 placebo-controlled and head-to-head randomized controlled trials that included a total of 53,463 adult participants with acute symptoms and a diagnosis of schizophrenia or a related dis- order. Not included were studies that focused on individuals with a first episode of psychosis or treatment resistance and studies in which individuals had concomitant medical illnesses or a pre- dominance of negative or depressive symptoms. For the majority of antipsychotic medications, treatment was associated with a statistically significant reduction in overall symptoms as compared with placebo, and there were few significant differences between individual drugs. With antipsy- chotic medications that did not differ significantly from placebo, there were numerical differences favoring the antipsychotic medication, and the number of subjects in the network meta-analysis was small, yielding a wide credible interval (CrI). Only clozapine, amisulpride, zotepine, olanzapine, and risperidone exhibited greater efficacy than many other antipsychotic medications for overall symptoms, with the greatest benefit noted with clozapine (SMD –0.89, 95% CrI –1.08 to –0.71). Dis- continuation rates for inefficacy paralleled the findings for treatment efficacy (Huhn et al. 2019). In terms of positive symptoms, negative symptoms, and depressive symptoms, the majority of the medications showed a statistically significant difference from placebo, with the exception of several antipsychotic agents for which sample sizes were small and CrIs were wide. Few studies had as- sessed effects of antipsychotic medications on social functioning. As in the Leucht et al. (2017) meta- analysis, side-effect profiles differed considerably among the antipsychotic medications.

Few studies assessed effects of antipsychotic medications on self-harm, but among patients at high risk, the International Suicide Prevention Trial (InterSePT; Meltzer et al. 2003) found that clozapine was superior to olanzapine in preventing significant suicide attempts or hospitalization to prevent suicide (hazard ratio [HR] 0.76, 95% CI 0.58–0.97; low SOE).

In terms of dose-response effects on antipsychotic medication effectiveness, standard doses of antipsychotic medications are superior to low or very low dose treatment in reducing the risk of relapse (Uchida et al. 2011a). In addition, there is evidence of a dose-response relationship for many antipsychotic medications in short-term trials of acute efficacy (Davis and Chen 2004).

Overall discontinuation rates and time to discontinuation reflect whether a treatment is effective but also whether it is tolerable. In this regard, a network meta-analysis of 111 studies (McDonagh et al. 2017) found that rates of discontinuation were lower with the following medications:

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• Olanzapine and clozapine as compared with asenapine, cariprazine, iloperidone, lurasidone, olanzapine LAI, quetiapine, risperidone, and ziprasidone (ORs range from 0.42 for clozapine vs. iloperidone to 0.69 for clozapine vs. risperidone)

• Clozapine as compared with monthly paliperidone palmitate LAI (OR 0.56, 95% CI 0.33–0.96)

• Olanzapine as compared with paliperidone (OR 0.67, 95% CI 0.50–0.89)

• Quetiapine extended release (XR) as compared with iloperidone, olanzapine LAI, or quetiapine
(ORs 0.26–0.35)

• Risperidone and aripiprazole as compared with iloperidone or quetiapine (ORs 0.61–0.77).

• Risperidone and monthly aripiprazole LAI as compared with iloperidone (ORs 0.52 and 0.62,
respectively)
Findings on time to discontinuation are more limited and need replication (low SOE), but they sug- gest that olanzapine may have a longer time to discontinuation than quetiapine, risperidone, and ziprasidone (4 months on the basis of trial data; 1.5–2.2 months shorter on the basis of observational data); clozapine may have a longer time to discontinuation than olanzapine, risperidone, or queti- apine (7.2–7.8 months in Phase 2E of the Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE] study); and risperidone LAI may have a longer time to discontinuation than aripiprazole, clozapine, olanzapine, quetiapine, or ziprasidone (2.6–4 months).
A network meta-analysis (McDonagh et al. 2017), which used data from 90 head-to-head trials of greater than 6 weeks’ duration, found the risk of withdrawals due to adverse events was less with the following medications:

• Risperidone LAI as compared with clozapine (OR 0.27, 95% CI 0.10–0.71), lurasidone (OR 0.39, 95% CI 0.18–0.84), quetiapine XR (OR 0.43, 95% CI 0.22–0.81), risperidone (OR 0.50, 95% CI 0.25–0.99), and ziprasidone (OR 0.40, 95% CI 0.20–0.82)

• Olanzapine as compared with clozapine (OR 0.39, 95% CI 0.19–0.79), lurasidone (OR 0.57, 95% CI 0.34–0.94), quetiapine (OR 0.62, 95% CI 0.44–0.87), risperidone (OR 0.72, 95% CI 0.55–0.96), and ziprasidone (OR 0.58, 95% CI 0.41–0.82)

• Aripiprazole as compared with clozapine (OR 0.43, 95% CI 0.21–0.88) and ziprasidone (OR 0.64, 95% CI 0.44–0.94)

• Cariprazine as compared with clozapine (OR 0.40, 95% CI 0.17–0.95)

• Iloperidone as compared with clozapine (OR 0.34, 95% CI 0.13–0.91)
These findings had a low SOE, and head-to-head comparison data were not available for all available antipsychotic medications. For haloperidol, withdrawals due to adverse events were sig- nificantly higher than with SGAs (moderate SOE), specifically, aripiprazole (8 RCTs, N=3,232; RR 1.25, 95% CI 1.07–1.47; I2=0%), olanzapine (24 RCTs, N=5,708; RR 1.89, 95% CI 1.57–2.27; I2=0%), risperidone (25 RCTs, N=4,581; RR 1.32, 95% CI 1.09–1.60; I2=0%), and ziprasidone (7 RCTs, N=1,597; RR 1.68, 95% CI 1.26–2.23; I2=0%).
Overall adverse event rates also favored SGAs as compared with haloperidol (moderate SOE), specifically aripiprazole (3 RCTs, N=1,713; RR 1.11, 95% CI 1.06–1.17; I2=0%), risperidone (8 RCTs, N=1,313; RR 1.20, 95% CI 1.01–1.42; I2=84%), and ziprasidone (6 RCTs, N=1,448; RR 1.13, 95% CI 1.03–1.23; I2=31%). Among comparisons between SGAs, no differences in overall adverse events were noted (low to moderate SOE).
In terms of mortality, comparisons were difficult because of the short duration of most studies and the small number of reported events in these clinical trials (incidence rates 0%–1.17%). Never- theless, there were no significant mortality differences found between asenapine versus olanzapine (2 RCTs; RR 2.49, 95% CI 0.54–11.5; low SOE), quetiapine versus risperidone (2 RCTs; RR 3.24, 95% CI 0.72–14.6; low SOE), and paliperidone palmitate LAI (monthly) versus risperidone LAI (2 RCTs; RR 1.26, 95% CI 0.21–7.49; low SOE). Additional findings from retrospective cohort studies found

no significant difference in the risk of all-cause (1 study, N=48,595) or cardiovascular (2 studies, N=55,582) mortality between risperidone, olanzapine, and quetiapine (low SOE).

For the additional harms data described in the AHRQ report (McDonagh et al. 2017), evidence was relatively limited and did not adjust for known factors that confound risk. Data on cardiac dis- ease are mixed. A large, good-quality retrospective cohort study found no significant differences in the risk of cardiovascular death, acute coronary syndrome, or ischemic stroke between risperidone and olanzapine or quetiapine in patients ages 18–64 years within the first year of starting the drug. However, a large adverse event database study found that clozapine was significantly associated with myocarditis or cardiomyopathy, whereas olanzapine, quetiapine, and risperidone were not. In contrast, other limited evidence suggested an increased risk of cardiac arrest and arrhythmia with risperidone compared with clozapine, and data from CATIE suggested a higher estimated 10-year risk of coronary heart disease with olanzapine compared with risperidone. As compared with FGAs, the SGA aripiprazole showed a lower likelihood of cardiomyopathy or coronary heart disease.

Findings on neurological side effects such as akathisia and parkinsonism also showed significant variability among the head-to-head comparison studies, which makes it difficult to draw overall conclusions about side-effect rates or risk. For new-onset tardive dyskinesia, overall rates were low (3% of subjects treated with risperidone as compared with 1%–2% for other medications). Never- theless, findings from observational trials suggested a significant increase in risk with risperidone as compared with olanzapine (OR 1.70, 95% CI 1.35–2.14).

Metabolic effects varied with study duration, but clinically important weight gain (defined as a 7% or more increase from baseline) was greater with olanzapine than with aripiprazole (RR 2.31), asenapine (RR 2.59), clozapine (RR 1.71), quetiapine (RR 1.82), risperidone (RR 1.81), and ziprasidone (RR 5.76) across 3.7–24 months. Olanzapine had a significantly greater risk of metabolic syndrome than risperidone (pooled OR 1.60, 95% CI 1.10–2.21; I2=0%; follow-up of 6 weeks to 3 months) or ar- ipiprazole (pooled OR 2.50, 95% CI 1.32–4.76; I2 = 0%; follow-up of 3.5–12 months). In adults, obser- vational evidence indicated an increased risk of new-onset diabetes with olanzapine compared with risperidone (OR 1.16, 95% CI 1.03–1.31). A single study found diabetic ketoacidosis to be in- creased with olanzapine compared with risperidone (OR 3.5, 95% CI 1.7–7.9), but a second study found no difference in diabetic ketoacidosis, hyperglycemia, or hyperglycemic hyperosmolar state between risperidone and olanzapine, regardless of age group, but a significantly lower risk with quetiapine compared with risperidone in older patients (adjusted HR 0.69, 95% CI 0.53–0.90).

Taken together, the findings of the AHRQ review (McDonagh et al. 2017) complement the meta- analyses of Leucht et al. (2017) and Huhn et al. (2019) in showing efficacy of antipsychotic medi- cations, particularly for core illness symptoms but also for other outcomes. Furthermore, research evidence demonstrates no clear and consistent superiority of one antipsychotic medication as com- pared with other antipsychotic medications, with the exception of clozapine. In addition, the system- atic reviews suggest considerable variability in side-effect profiles among antipsychotic medications, without a clear continuum of risk for individual medications when all side effects are considered.

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Antipsychotic Medications

• Magnitude of effect: Moderate. The magnitude of effect varies among individual antipsychotic med- ications but is moderate overall on the basis of findings from meta-analyses of placebo-controlled trials.

• Risk of bias: Medium. Studies are RCTs that are summarized in multiple good-quality meta- analyses. Although the risk of bias of individual RCTs varies, most have some limitations, and, in older trials, reporting of study design features is often incomplete. Among head-to-head com- parison trials, some studies are observational trials and are associated with a higher risk of bias.

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• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The studies include subjects from countries around the world, with the exception of China. The doses of medication used are representative of usual clinical practice.

• Directness: Direct. Studies measure functioning, quality of life, core illness symptoms, negative symptoms, and response to treatment.

• Consistency: Consistent. When multiple studies that included a given comparison are available, results are generally consistent. In addition, the overall direction of effects is generally consis- tent among antipsychotic medications in placebo-controlled trials.

• Precision: Variable. For many comparisons, particularly when multiple RCTs are available, find- ings are precise. However, for other comparisons, imprecision is present because of wide confi- dence intervals that often cross the threshold for clinically significant benefit of the intervention.

• Dose-response relationship: Present. There is evidence of a dose-response relationship in acute treatment trials as well as in studies of antipsychotic medications for relapse prevention.

• Confounding factors: Present. In placebo-controlled trials, effect sizes have decreased over the past 60 years, apparently due to increases in placebo response rates; these trends are likely to confound comparisons of older and newer medications.

• Publication bias: Suspected. Among placebo-controlled trials, studies with no effect of treatment appear to have had lower rates of publication.

• Overall strength of research evidence: High. There are a large number of randomized, double- blind, placebo-controlled trials of antipsychotic medication as well as a smaller number of head- to-head comparison RCTs. Although many studies have a medium risk of bias and publication bias appears to be present, there is also consistency in overall study findings and a dose-response relationship is present, strengthening confidence in the conclusions.
Grading of the Overall Supporting Body of Research Evidence for Harms of Antipsychotic Medications

• •

• • •

Magnitude of effect: Small to moderate. The magnitude of effect for harms of antipsychotic med- ication differs by drug and by side effect but is small to moderate overall.
Risk of bias: Medium to high. Studies are RCTs that are summarized in multiple good-quality meta-analyses. Particularly in older clinical trials, side effects tend not to be assessed or reported as systematically as efficacy and effectiveness-related outcomes.

Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The studies include subjects from around the world, with the exception of China. The doses of medication used are representative of usual clinical practice.

Directness: Variable. Most studies measure overall adverse events, and some measure specific adverse effects, each of which is a direct measure. Other studies measure study withdrawal rates due to adverse effects, which is an indirect measure.
Consistency: Consistent. In studies that compare the same medication with placebo, side effect– related outcomes are generally consistent in their direction and relative degree. Head-to-head comparison data are less consistent.

Precision: Precise. Confidence intervals are narrow for comparisons in which multiple studies with good sample sizes are available. For comparisons with a small number of studies or small samples, imprecision is present because of wide confidence intervals. Head-to-head compari- sons also have imprecision due to outcomes that cross the threshold for clinically significant harms of the intervention.

Dose-response relationship: Suspected. There is less systematic information available on dose- response relationships for side effects of antipsychotic medication; however, the available evidence suggests that greater doses are associated with a greater degree of medication-related side effects.

• Confounding factors: Present. Cohort effects that are present in efficacy and effectiveness stud- ies of antipsychotic medication are also likely to be relevant when assessing harms of antipsy- chotic medication.

• Publication bias: Suspected. Among placebo-controlled trials, studies with no effect of treatment appear to have had lower rates of publication.

• Overall strength of research evidence: Moderate. Available studies are RCTs that are generally of moderate quality and have good sample sizes. Findings are consistent, with narrow confi- dence intervals for many comparisons, and are likely to exhibit a dose-response relationship.
Antipsychotic Medications in First-Episode Schizophrenia
In subgroup analyses, the AHRQ review (McDonagh et al. 2017) found that patients experiencing a first episode of schizophrenia did not show significant differences in response or remission when treated with olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, or paliperidone. An- other systematic review (Zhu et al. 2017) in individuals with a first episode of schizophrenia found that amisulpride, olanzapine, ziprasidone, and risperidone reduced overall symptoms more than haloperidol, but the evidence was noted as being of very low to moderate quality, and only 13 stud- ies were available to address this clinical question.
Treatment Approaches to Partial Response or Nonresponse
High Doses of Antipsychotic Medication
A limited amount of evidence suggests no benefit from high doses of an antipsychotic medication in individuals who have not responded to typical doses of the medication. A systematic review and meta-analysis by Dold et al. (2015) found 5 trials, which included a total of 348 patients and studied this question with FGAs or SGAs. Dose escalation was not found to confer any benefits in terms of study attrition, response rates, or symptoms (as measured by PANSS or BPRS). A subsequent system- atic review and meta-analysis by Samara et al. (2018) found 10 relevant RCTs, which included a total of 675 participants. Although no clear differences in response were noted between subjects who re- ceived the same dose of medication as compared with those who received a higher dose, many of the studies had a medium to high risk of bias. There were also no differences in other outcomes, including the proportion of individuals who left the study early because of adverse effects or for any reason.
Augmentation Pharmacotherapy
A number of pharmacotherapies have been studied as augmentation strategies in individuals with treatment-resistant schizophrenia. Evidence has been primarily from small short-term, open-label studies that have yielded mixed findings. Correll et al. (2017b) conducted a systematic search for meta-analyses that addressed the effects of combining an antipsychotic medication with another pharmacotherapy in individuals with schizophrenia. They found 29 meta-analyses that together encompassed 19,833 subjects in 381 trials and that evaluated 42 augmentation strategies. Although 14 of these augmentation therapies showed better outcomes than comparison treatment, the meta- analyses with the highest effect sizes had the lowest quality of included studies, undermining con- fidence in the benefits of augmentation.
In terms of augmentation of clozapine, Siskind et al. (2018) conducted a systematic review and meta-analysis of augmentation strategies for individuals with clozapine-refractory schizophrenia and found 46 studies of 25 interventions. They noted possible benefits of memantine for negative symptoms and aripiprazole, fluoxetine, and sodium valproate for overall psychotic symptoms but found that many of the studies had a poor study quality and short periods of follow-up, which lim- ited the ability to draw conclusions. Wagner et al. (2019a) conducted a systematic meta-review of 21 meta-analyses that examined strategies for augmenting treatment with clozapine. Although the best evidence was available for combination treatment of clozapine with FGAs or SGAs for psychotic

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symptoms and with antidepressants for persistent negative symptoms, these authors also concluded that additional high-quality clinical trials are essential before making definitive statements about clozapine augmentation. Furthermore, their findings are consistent with those of Correll et al. (2017b), who did not identify any combination medication strategies with clozapine that led to bet- ter outcomes than comparator treatments and found that available studies were of low quality.

Other meta-analyses have also examined the effects of using more than one antipsychotic medication as compared with antipsychotic monotherapy. Galling et al. (2017) found a possible benefit of aripip- razole augmentation in terms of greater improvement in negative symptoms and reductions in prolac- tin levels and body weight. However, they noted that the apparent benefits of antipsychotic augmentation in reducing total symptoms were no longer seen when the analysis was restricted to dou- ble-blind trials of higher quality. A Cochrane review of antipsychotic combination treatments for schizo- phrenia (Ortiz-Orendain et al. 2017) also found that evidence on combinations of antipsychotic medications was of very low quality. Nevertheless, data from a large nationwide cohort study in Fin- land suggested that use of two different antipsychotic medications may have some benefits as com- pared with monotherapy. Tiihonen et al. (2019) studied 62,250 patients with a diagnosis of schizophrenia and compared hospitalization rates within the same individual during periods of anti- psychotic monotherapy and periods with use of more than one antipsychotic medication. They found that rehospitalization rates with clozapine were lower than with other monotherapies and that individ- uals receiving more than one antipsychotic medication had a 7%–13% lower risk of psychiatric rehospi- talization than individuals treated with monotherapy (P<0.001). Use of multiple antipsychotic medications was also associated with a reduction in secondary outcomes (e.g., all-cause hospitalization, nonpsychiatric hospitalization, mortality). Thus, there is weak and inconsistent evidence suggesting possible benefits of combined treatment with more than one antipsychotic medication, but more re- search is needed.

On the other hand, augmentation of antipsychotic therapy with an antidepressant medication may be helpful, particularly for patients with negative symptoms or depression. Stroup et al. (2019) used U.S. Medicaid data on 81,921 adult outpatients ages 18–64 years who had a diagnosis of schizophrenia. The authors employed propensity score matching and weighted Cox proportional hazards regression models to examine the effect of adding an antidepressant, a benzodiazepine, a mood stabilizer, or an- other antipsychotic medication to existing treatment with an antipsychotic medication. These authors found that the addition of an antidepressant medication was associated with a reduced risk for psychi- atric hospitalization or emergency visits. In addition, Helfer et al. (2016) conducted a systematic review and meta-analysis of the addition of antidepressant medication to antipsychotic treatment. Data from 82 RCTs that included 3,608 subjects indicated that antidepressant augmentation was associated with improvements in quality of life (SMD –0.32, 95% CI –0.57 to –0.06) and rates of response (risk ratio 1.52, 95% CI 1.29–1.78; NNT=5, 95% CI 4–7) as well as greater reductions in depressive symptoms (SMD –0.25, 95% CI –0.38 to –0.12), positive symptoms (SMD –0.17, 95% CI –0.33 to –0.01), negative symptoms (SMD –0.30, 95% CI –0.44 to –0.16), and overall symptoms (SMD –0.24, 95% CI –0.39 to –0.09).

STATEMENT 5: Continuing Medications

APA recommends (1A) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with an antipsychotic medication.*

Evidence in support of this statement is based primarily on the evidence for antipsychotic effi- cacy in improving symptoms and quality of life as well as promoting functioning (see Statement 4 earlier in the appendix). Thus, the strength of research evidence is rated as high.

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

218 APA Practice Guidelines

Additional evidence supporting this statement comes from registry database studies and from discontinuation studies. For example, in a nationwide prospective registry study (N=6,987) with a 5-year follow-up of individuals with first-onset schizophrenia (Kiviniemi et al. 2013), there was a significant decrease in all-cause mortality in individuals taking SGAs as compared with individuals who were not taking antipsychotic medication (OR 0.69; P=0.005).

Another nationwide study (N=8,719) using prospectively collected registry data found that the lowest rates of rehospitalization or death occurred in individuals who received continuing treat- ment with an antipsychotic medication for up to 16.4 years (Tiihonen et al. 2018). Individuals who discontinued antipsychotic medication had a risk of death that was 174% higher than that in con- tinuous users of antipsychotic medications (HR 2.74, 95% CI 1.09–6.89), whereas the risk of death was 214% higher (HR 3.14, 95% CI 1.29–7.68) in nonusers of antipsychotic medications as compared with continuous users. Rates of treatment failure, which included rehospitalization as well as death, were also lower in individuals who received continuous treatment with an antipsychotic medication. More specifically, 38% of those who discontinued treatment experienced treatment fail- ure as compared with a matched group of continuous users of an antipsychotic medication, in which the rate of treatment failure was 29.3%. For nonusers of antipsychotic medication, treatment failure occurred in 56.5% as compared with 34.3% of a matched group of continuous antipsychotic medication users.

Several meta-analyses have examined mortality-related data with antipsychotic treatment. A meta-analysis of studies with follow-up periods of at least 1 year found that mortality was in- creased in individuals who did not receive antipsychotic medication as compared with those who were treated with an antipsychotic medication (pooled risk ratio 0.57, 95% CI 0.46–0.76; P<0.001 based on 22,141 deaths in 715,904 patient years in 4 cohort studies) (Vermeulen et al. 2017). With con- tinuous treatment with clozapine, mortality was found to be lower in long-term follow-up (median 5.4 years) as compared with treatment with other antipsychotic medications (mortality rate ratio 0.56, 95% CI 0.36–0.85, P=0.007 based on 1,327 deaths in 217,691 patient years in 24 studies) (Vermeulen et al. 2019).

On the basis of 10 RCTs (total N=776) with mean study duration of 18.6±5.97 months, a meta- analysis of discontinuation studies (Kishi et al. 2019) concluded that relapse rates were lower in indi- viduals with schizophrenia who continued treatment with an antipsychotic medication as compared with those who discontinued treatment (RR 0.47, 95% CI 0.35–0.62; P<0.00001; I2=31%; NNT=3). An additional meta-analysis (Thompson et al. 2018), using somewhat different inclusion and exclu- sion criteria for studies, also found that relapse rates were lower in individuals who received main- tenance treatment (N=230; 19%; 95% CI 0.05%–37%) as compared with those who stopped the an- tipsychotic medication (N=290; 53%; 95% CI 39%–68%). Although caution may be needed in interpreting these results because of methodological considerations (Moncrieff and Steingard 2019), the findings align with expert opinion on the benefits of maintenance treatment with an an- tipsychotic medication (Goff et al. 2017).

Grading of the Overall Supporting Body of Research Evidence
for the Efficacy of Continuing Treatment With an Antipsychotic Medication

• Magnitude of effect: Large. The magnitude of effect is large in terms of lower relapse rates and lower mortality for individuals who received maintenance treatment with antipsychotic medi- cations as compared with discontinuation of antipsychotic medication.

• Risk of bias: Medium. Studies include RCTs of antipsychotic discontinuation and observational studies using registry data. Although the registry studies have a greater risk of bias than RCTs, they use prospectively collected data and have good observational study designs.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The doses of medica-

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 219

tion used are representative of usual clinical practice. The observational studies include data from a nationwide registry and have broad generalizability, in contrast to RCTs with more re- strictive inclusion and exclusion criteria. However, the applicability of registry data from Nordic countries may be reduced by differences in the health care delivery system as compared with that of the United States.

• Directness: Direct. Studies measured relapse rates and mortality.

• Consistency: Consistent. Findings showing benefits of maintenance antipsychotic treatment are
consistent among the different studies and study designs.

• Precision: Variable. Most meta-analyses have narrow confidence intervals that do not cross the
threshold for clinically significant benefit of treatment; however, some studies have wider con-
fidence intervals.

• Dose-response relationship: Not assessed.

• Confounding factors: Unclear. It is possible that missing data or cohort-related effects may in-
fluence the results from multiyear registry databases. For long-term follow-up studies, which are needed to assess long-term effects of antipsychotic medication, loss of individuals to follow- up and changes in treatment over time may also confound data interpretation.

• Publication bias: Not assessed.

• Overall strength of research evidence: High. Available studies include RCTs with a medium
risk of bias. These RCTs are complemented by prospective registry studies with very large sam- ple sizes. Confidence intervals for most outcomes are relatively narrow, and findings are consis- tent in showing substantial benefit for continued antipsychotic medication treatment.
Grading of the Overall Supporting Body of Research Evidence
for the Harms of Continuing Treatment With an Antipsychotic Medication
See Statement 4, subsection “Grading of the Overall Supporting Body of Research Evidence for Harms of Antipsychotic Medications,” earlier in the appendix.
STATEMENT 6: Continuing the Same Medications
APA suggests (2B) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with the same antipsychotic medication.*
Evidence in support of this statement includes the evidence described for antipsychotic efficacy (see Statement 4 earlier in the appendix) and the evidence for continuing with antipsychotic treat- ment (see Statement 5 earlier in the appendix). Additional evidence that specifically addresses this guideline statement comes from randomized trials of a change in antipsychotic medication. On the basis of these studies, the strength of research evidence is rated as moderate.
The CATIE study provided important findings on medication changes (Essock et al. 2006). At the time of randomization, some individuals happened to be randomly assigned to a medication that they were already taking, whereas other individuals were assigned to a different antipsychotic medication. Individuals who were assigned to change to a different antipsychotic medication (N=269) had an earlier time to all-cause treatment discontinuation than those assigned to continue taking the same antipsychotic medication (N=129; Cox proportional HR 0.69; P=0.007). Although a change from olanzapine to a different antipsychotic medication was beneficial in terms of weight gain, there were no other differences in outcome measures for individuals who switched medica- tions as compared with those who continued with the same treatment (Rosenheck et al. 2009).
*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Additional evidence comes from an RCT aimed at reducing the metabolic risk of antipsychotic treatment by changing medication from olanzapine, quetiapine, or risperidone to aripiprazole (Stroup et al. 2011). Individuals were followed for 24 weeks after being assigned to continue taking their current medication (N=106) or to switch to aripiprazole (N=109). Although the two groups did not differ in the proportion of individuals with medication efficacy (as measured by the PANSS total score or change in Clinical Global Impression [CGI] severity score), individuals who switched medication were more likely to stop medication (43.9% vs. 24.5%; P = 0.0019), and treatment discon- tinuation occurred earlier in those who switched medication as compared with those who did not (HR 0.456, 95% CI 0.285–0.728; P=0.0010). However, modest but statistically significant changes did occur in weight, serum non-high-density lipoprotein cholesterol, and serum triglycerides in indi- viduals who switched to aripiprazole as compared with those who continued with olanzapine, quetiapine, or risperidone.

Together, these findings suggest that changes in antipsychotic medications may be appropriate for addressing significant side effects such as weight or metabolic considerations, but switching medications may also confer an increased risk of medication discontinuation, with associated risks of increased relapse and increased mortality.

Grading of the Overall Supporting Body of Research Evidence for the Efficacy of Continuing the Same Antipsychotic Medication

• Magnitude of effect: Moderate. Evidence from two RCTs suggests that a change in medication is associated with a moderate risk of earlier treatment discontinuation compared with continu- ing the same medication.

• Risk of bias: Medium. Studies are RCTs with a medium risk of bias based on their descriptions of randomization, blinding procedures, and study dropouts.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The studies were con- ducted in the United States. Doses of medication used are representative of usual clinical prac- tice. The available RCTs examine changes in medication aimed at reducing metabolic effects of treatment, and a change from a high metabolic risk medication to a low metabolic risk medica- tion may not be representative of other medication changes.

• Directness: Indirect. Studies measure all-cause treatment discontinuation, which combines ef- fects due to inefficacy and lack of tolerability.

• Consistency: Consistent. The two studies are consistent in showing benefits of continuing with the same antipsychotic medication.

• Precision: Precise. Confidence intervals are narrow and do not cross the threshold for clinically significant benefit of the intervention.

• Dose-response relationship: Not assessed.

• Confounding factors: Absent.

• Publication bias: Unable to be assessed.

• Overall strength of research evidence: Moderate. The two RCTs that assess changing from one
antipsychotic to another have good sample sizes and a medium risk of bias. Their findings are consistent with each other and with the results of studies discussed for Statements 4 and 5 on the benefits of antipsychotic medication treatment.
Grading of the Overall Supporting Body of Research Evidence for the Harms of Continuing the Same Antipsychotic Medication
See Statement 4, subsection “Grading of the Overall Supporting Body of Research Evidence for Harms of Antipsychotic Medications,” earlier in the appendix.

The APA Practice Guideline for the Treatment of Patients With Schizophrenia 221

STATEMENT 7: Clozapine in Treatment-Resistant Schizophrenia

APA recommends (1B) that patients with treatment-resistant schizophrenia be treated with clozapine.*

Evidence on clozapine comes from multiple RCTs, observational studies (including clinical trials and studies using administrative databases), and meta-analyses. In some instances, the studies were limited to individuals with treatment-resistant schizophrenia, whereas in other studies a for- mal determination of treatment resistance was not reported or possible. Nevertheless, most infor- mation about clozapine will be of relevance to patients with treatment-resistant schizophrenia because, in current practice, most individuals receive clozapine only after a lack of response to other treatments.

In comparisons of SGAs, the AHRQ report (McDonagh et al. 2017) found that, independent of prior treatment history, clozapine improved core illness symptoms more than other SGAs (except for olanzapine) and was associated with a lower risk of suicide or suicide attempts than olanzapine, quetiapine, and ziprasidone (low SOE). In addition, in treatment-resistant patients, clozapine treat- ment was associated with a lower rate of treatment discontinuation due to lack of efficacy than the other SGAs that were studied. It is not clear whether rates of overall treatment discontinuation with clozapine may be influenced by the increased frequency of clinical interactions related to the more intensive monitoring with clozapine as compared with other antipsychotic medications.

The AHRQ review drew on several meta-analyses related to treatment-resistant schizophrenia (Ranasinghe and Sin 2014; Samara et al. 2016; Souza et al. 2013); however, some additional studies are also relevant to this guideline statement. A meta-analysis by Siskind et al. (2016b) had consider- able overlap with the meta-analysis of Samara et al. (2016) in terms of the included studies. Despite this, the findings of the two meta-analyses were somewhat different, likely due to differences in the inclusion criteria and analytic approach (Samara and Leucht 2017). Samara et al. (2016) found few significant differences in outcomes and did not find clozapine to be significantly better than most other drugs in treatment-resistant schizophrenia. Siskind et al. (2016b) found no difference for clozapine compared with other antipsychotic medications in long-term studies but did find clozapine to be superior to other medications in short-term studies and across all studies in reducing total psychotic symptoms (24 studies, N=1,858; P<0.005). Similarly, in terms of response to treatment (as reflected by a 20%–30% reduction in symptoms), clozapine showed higher rates of response than comparators in short-term studies of treatment-resistant schizophrenia (8 studies, total N=598 for clozapine, 620 for comparators; RR 1.17, 95% CI 1.07–2.7; P=0.03; absolute risk reduction 12.48%, 95% CI 7.52–17.43; NNT=9). Again, however, studies that assessed long-term response showed no difference between clozapine and comparators. A greater benefit of clozapine than comparators was also seen when the analysis was limited to non-industry-funded trials (6 studies, N= 208; RR 1.68, 95% CI 1.20–2.35; P=0.002). In a subsequent meta-analysis using data from the same studies, Siskind et al. (2017b) found that 40.1% of treatment-resistant individuals who received clozapine had a response, with a reduction of PANSS scores of 25.8% (22 points on the PANSS) from baseline.

In an additional network meta-analysis of 32 antipsychotic medications, Huhn et al. (2019) ana- lyzed 402 placebo-controlled and head-to-head RCTs that included a total of 53,463 adult participants with acute symptoms and a diagnosis of schizophrenia or a related disorder. Studies that focused on individuals with a first episode of psychosis or treatment resistance were excluded, as were studies in which individuals had concomitant medical illnesses or a predominance of negative or depressive symptoms. Only clozapine, amisulpride, zotepine, olanzapine, and risperidone exhibited greater efficacy than many other antipsychotic medications for overall symptoms, with the greatest benefit

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

222 APA Practice Guidelines

noted with clozapine (SMD –0.89, 95% CrI –1.08 to –0.71). Clozapine also was statistically better than placebo and the majority of the other antipsychotic medications in terms of all-cause discon- tinuation (SMD 0.76, 95% CrI 0.59–0.92) and its effects on positive symptoms (SMD –0.64, 95% CrI –1.09 to –0.19), negative symptoms (SMD 0.62, 95% CrI –0.84 to –0.39), and depressive symptoms (SMD –0.52, 95% CrI –0.82 to –0.23).

Findings from studies using administrative databases also suggest benefits of treatment with clozapine. For example, a prospective nationwide study conducted over a 7.5-year period in Sweden (Tiihonen et al. 2017) found significantly reduced rates of rehospitalization with the use of clozapine as compared with no antipsychotic treatment (HR 0.53, 95% CI 0.48–0.58). In addition, the reduction in rehospitalization with clozapine was comparable to reductions in rehospitalization with LAI anti- psychotic medications, whereas other oral formulations of antipsychotic medications had higher risks of rehospitalization. In comparison with oral olanzapine, clozapine had a lower rate of treatment fail- ure (HR 0.58, 95% CI 0.53–0.63) that was comparable to the rate of treatment failure with LAI antipsy- chotic medications (range of HRs 0.65–0.80).

Similar benefits of clozapine were found in analysis of prospective registry data from Finland ob- tained for all persons with schizophrenia who received inpatient care from 1972 to 2014 (Taipale et al. 2018a). Of the 62,250 individuals in the prevalent cohort, 59% were readmitted during follow-up time of up to 20 years (median follow-up duration 14.1 years). Among oral antipsychotic medica- tions, clozapine was associated with the lowest risk for psychiatric readmission compared with no antipsychotic use (HR 0.51, 95% CI 0.49–0.53) and for all-cause readmission (HR 0.60, 95% CI 0.58– 0.61). For the 8,719 individuals with a first episode of schizophrenia, risks of psychiatric readmission and all-cause readmission were also reduced (HR 0.45, 95% CI 0.40–0.50 and HR 0.51, 95% CI 0.47– 0.56, respectively).

A meta-analysis that examined effects of clozapine on hospital use also found benefits for clozapine (Land et al. 2017). Although the vast majority of studies in the meta-analysis were obser- vational studies, use of clozapine as compared with other antipsychotic medications was associated with a significant decrease in the proportion of individuals who were hospitalized (22 studies, N=44,718; RR 0.74, 95% CI 0.69–0.80; P<0.001), although the time to rehospitalization did not differ.

In terms of suicide risk, subjects in the InterSePT study (Meltzer et al. 2003) who met criteria for treatment-resistant schizophrenia showed benefits of clozapine that were comparable to the bene- fits seen in the overall sample. For the sample as a whole, clozapine was superior to olanzapine in preventing significant suicide attempts or hospitalization to prevent suicide in high-risk patients (HR 0.76, 95% CI 0.58–0.97). Fewer clozapine-treated patients in the InterSePT study attempted sui- cide (P=0.03); required hospitalizations (P=0.05) or rescue interventions (P=0.01) to prevent suicide; or required concomitant treatment with antidepressants (P=0.01) or with anxiolytics or soporifics (P=0.03). Subjects treated with clozapine were also less likely to have CGI severity of suicidality scale ratings of “much worse” or “very much worse” (HR 0.78, 95% CI 0.61–0.99) than subjects treated with olanzapine.

In terms of mortality risk, a population-based cohort study of 2,370 patients with treatment-resistant schizophrenia found a higher rate of self-harm in individuals treated with non-clozapine antipsy- chotic medications than in those treated with clozapine (HR 1.36, 95% CI 1.04–1.78) (Wimberley et al. 2017). There was also a higher rate of all-cause mortality in patients not receiving clozapine than in those treated with clozapine (HR 1.88, 95% CI 1.16–3.05); however, the comparator group in- cluded individuals who were not taking any antipsychotic medication. When the study subjects were limited to those who were adhering to treatment, the higher mortality during treatment with other antipsychotic medications did not reach statistical significance. In the year after clozapine dis- continuation, an increase in mortality was observed (HR 2.65, 95% CI 1.47–4.78), consistent with benefits of clozapine treatment in reducing overall mortality. Another cohort study also found sig- nificant benefits of clozapine on all-cause mortality in individuals with treatment-resistant schizo- phrenia (adjusted HR 0.61, 95% CI 0.38–0.97; P=0.04) (Cho et al. 2019). These findings are also consistent with results of a meta-analysis that showed significantly lower rates of long-term crude

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mortality in patients who received continuous treatment with clozapine as compared with patients treated with other antipsychotic medications (mortality rate ratio 0.56, 95% CI 0.36–0.85; P=0.007) (Vermeulen et al. 2019).

In terms of side effects with clozapine, a network meta-analysis conducted as part of the AHRQ report (McDonagh et al. 2017) showed that clozapine had a higher risk of study withdrawal due to adverse events than some other SGAs (low SOE) but did not show differences in overall rates of adverse events as compared with risperidone (low SOE). In the meta-analysis by Siskind et al. (2016b), individuals treated with clozapine had a higher likelihood of experiencing sialorrhea (P<0.001; number needed to harm [NNH]=4), seizures (P<0.05; NNH=17), tachycardia (P<0.01; NNH=7), fever (P<0.01; NNH=19), dizziness (P<0.01; NNH=11), sedation (P<0.001; NNH=7), constipation (P<0.05; NNH=12), and nausea or vomiting (P<0.05; NNH=19) than individuals treated with comparator antipsychotic medications. In the meta-analysis by Leucht et al. (2013), all- cause treatment discontinuation was less likely with clozapine than placebo (OR 0.46, 95% CI 0.32– 0.65), as were extrapyramidal side effects (OR 0.3, 95% CI 0.17–0.62). In contrast, weight gain (SMD 0.65, 95% CI 0.31–0.99) and sedation (OR 8.82, 95% CI 4.72–15.06) were more likely with clozapine than placebo.

In an Australian national survey of 1,049 people with a diagnosis of schizophrenia or schizoaf- fective disorder who reported taking any antipsychotic medication (Siskind et al. 2017a), the pro- portion of individuals with diabetes, obesity, and metabolic syndrome was higher in individuals taking clozapine as compared with other antipsychotic medications (adjusted ORs 1.744, 1.899, and 2.300, respectively; P<0.001). In addition, clozapine was associated with a greater proportion of in- dividuals with dry or watery mouth (adjusted OR 2.721; P<0.001), difficulty swallowing (adjusted OR 1.754; P<0.01), constipation (adjusted OR 1.996; P<0.001), dizziness/vertigo (adjusted OR 1.571; P<0.01), and palpitations (adjusted OR 1.543; P<0.05). The proportion of individuals who re- ported trembling or shaking was significantly less in those treated with clozapine as compared with other antipsychotic agents (adjusted OR 0.581; P<0.01).

In the network meta-analysis by Huhn et al. (2019), individuals treated with clozapine were less likely to require use of an antiparkinsonian medication (SMD 0.46, 95% CrI 0.19–0.88) than those treated with other antipsychotic agents or placebo. However, clozapine was associated with a greater degree of weight gain (SMD 2.37, 95% CrI 1.43–3.32), sedation (SMD 3.02, 95% CrI 2.52–3.37), and ex- periencing at least one anticholinergic side effect (SMD 2.21, 95% CrI 1.26–3.47) than placebo.

Grading of the Overall Supporting Body of Research Evidence for Efficacy of Clozapine in Treatment-Resistant Schizophrenia

• Magnitude of effect: Moderate. The magnitude of clozapine’s effect varies with the study design and inclusion criteria. Some meta-analyses of RCTs show no difference for clozapine, but most studies show significant benefit, at least in the short term. Observational studies also show a magnitude of effect that is at least moderate.

• Risk of bias: Medium. Studies include RCTs and observational studies, primarily registry stud- ies. Most studies have some limitations based on their descriptions of randomization, blinding procedures, and study dropouts.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. Most individuals who receive treatment with clozapine have had at least one trial of another antipsychotic med- ication, and most would meet usual clinical criteria for treatment-resistant schizophrenia, even when this is not well specified in the study description. The doses of medication used are rep- resentative of usual clinical practice.
Directness: Variable. Studies measure psychotic symptoms, response to treatment, all-cause treatment discontinuation, psychiatric hospitalization, all-cause hospitalization, depression,

and mortality. Some of these outcomes are directly related to the review questions, and some are

indirectly related.

• Consistency: Inconsistent. Although most meta-analyses and observational studies show bene-
fits for clozapine, not all meta-analyses show superiority of clozapine to other antipsychotic
medications in individuals with treatment-resistant schizophrenia.

• Precision: Variable. Some confidence intervals are narrow without overlapping the threshold for
clinically significant benefits, whereas other confidence intervals are wide or overlapping.

• Dose-response relationship: Present. Increases in dose and corresponding increases in blood lev-
els of clozapine appear to be related to improved clinical efficacy in nontoxic ranges of dosing.

• Confounding factors: Present. Confounding factors may increase the observed effect. Addi- tional monitoring and an increased frequency of clinical contacts with clozapine may enhance the effects of the medication relative to other antipsychotic medications, at least in observational
studies.

• Publication bias: Unclear. Although publication bias for clozapine-specific studies was not
tested, publication bias is relatively common in studies of psychopharmacology because of non-
publication of negative studies.

• Overall strength of research evidence: Moderate. The available studies include RCTs of moder-
ate quality and good sample sizes. The effect sizes for clozapine vary among meta-analyses and outcomes. However, most studies, including RCTs and prospective observational studies, show benefits of clozapine as compared with other antipsychotic medications.
Grading of the Overall Supporting Body of Research Evidence for Harms of Clozapine

• Magnitude of effect: Moderate. The magnitude of effect is moderate overall but varies with the specific side effect. As compared with other antipsychotic medications, clozapine is associated with a greater risk of weight gain, sialorrhea, sedation, metabolic effects, seizures, constipation, anticholinergic side effects, tachycardia, and dizziness but a lower risk of all-cause treatment discontinuation, extrapyramidal side effects, or need for anticholinergic medication.

• Risk of bias: Medium. Studies include RCTs and a large observational study of patient-reported side effects. RCTs are of low to medium risk of bias based on their descriptions of randomiza- tion, blinding procedures, and study dropouts, whereas the observational study has a high risk of bias.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The doses of medica- tion used are representative of usual clinical practice.

• Directness: Variable. Studies measure observed and reported side effects of clozapine, as well as treatment discontinuation (all cause and due to adverse effects).

• Consistency: Consistent. Study findings are consistent in the relative magnitude and direction of effects for specific side effects and for treatment discontinuation.

• Precision: Precise. Confidence intervals are narrow and do not cross the threshold for clinically significant benefit of the intervention.

• Dose-response relationship: Not assessed. However, clinical observations suggest that many side effects do increase in occurrence or severity with the dose of clozapine.

• Confounding factors: Unclear. Not all studies assess side effects in a systematic fashion, and pa- tients may be less likely to report some side effects if they are not directly assessed.

• Publication bias: Not assessed. Nevertheless, publication bias is relatively common in studies of psychopharmacology because of nonpublication of negative studies.

• Overall strength of research evidence: Low to moderate. Available studies include RCTs and an ob- servational study. Data from several meta-analyses suggest a moderate strength of research evi-

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dence for outcomes related to clozapine harms, but the AHRQ review found a low strength of re- search evidence in a network meta-analysis, and the observational study also has a high risk of bias.

Other Interventions for Treatment-Resistant Schizophrenia

Use of Antipsychotic Medications Other Than Clozapine

The network analysis conducted as part of the AHRQ review (McDonagh et al. 2017) found that treatment-resistant patients had a small benefit with olanzapine over other older SGAs in core ill- ness symptom improvement and negative symptoms, whereas response rates and all-cause treat- ment discontinuations were not different. Negative symptoms were also significantly reduced with olanzapine as compared with haloperidol (N=2,207; MD 1.28, 95% CI 0.11–2.44), and patients treated with ziprasidone showed better response than those treated with haloperidol (N=120; RR 1.54, 95% CI 1.19–2.00).

Electroconvulsive Therapy

Some studies have shown evidence for benefits of electroconvulsive therapy (ECT) in combination with antipsychotic medications. Pompili et al. (2013) conducted a systematic review that included RCTs and observational studies, including case-control studies, and concluded that ECT in combination with antipsychotic medications may be helpful for a subgroup of individuals who have treatment re- sistance, catatonia, aggression, or suicidal behavior, particularly when rapid improvement is needed.

Zheng et al. (2016) conducted a systematic review and meta-analysis of RCTs comparing anti- psychotic medications other than clozapine with antipsychotic medication in combination with ECT in patients with treatment-resistant schizophrenia. In the 11 studies, which included 818 pa- tients, the addition of ECT was associated with greater improvements in symptoms (SMD –0.67; P<0.00001) and greater rates of study-defined response (RR 1.48; P<0.0001; NNT=6) and remission (RR 2.18; P=0.0002; NNT=8) as well as greater rates of headache (P=0.02; NNH=6) and memory impairment (P=0.001; NNH=3).

In terms of ECT augmentation of clozapine in treatment-resistant schizophrenia, Petrides et al. (2015) conducted a randomized, single-blind, 8-week trial in which patients who had not re- sponded to clozapine alone received a constant dose of clozapine or clozapine plus bilateral ECT (three times per week for 4 weeks and then twice weekly for 4 weeks for 20 total treatments). Fifty percent of the 20 patients treated with ECT plus clozapine experienced a reduction in psychotic symptoms of at least 40% and also achieved a CGI improvement rating of “much improved” and a CGI severity rating of “borderline mentally ill” or “not at all ill.” This contrasts with 19 patients who received clozapine but not ECT in the randomized phase of the trial, none of whom showed response by these criteria. When the latter group of patients received ECT in the unblinded cross- over phase of the trial, the rate of response was 47%. Global cognitive outcomes did not differ for the two randomized groups. In contrast, in another randomized trial of 23 patients who received 12 sessions of ECT as compared with sham ECT, no differences were found in PANSS score reduc- tions, although both groups showed improvement during the study (Melzer-Ribeiro et al. 2017).

Lally et al. (2016b) conducted a systematic review and found 5 trials (4 open-label studies plus the study by Petrides and colleagues, with a total of 71 subjects) in which the pooled response rate to clozapine plus ECT was 54%. When cohort studies, nonblinded randomized trials, case series, and case reports were considered, the overall response rate for clozapine plus ECT was 76% (83 of 126 patients), even though clozapine doses and serum levels were relatively high (mean serum clozapine level of 772.6 ng/mL at a mean daily dose of 506.9 mg for the 52 patients with an available clozapine level; mean daily dose 412.3 mg for the sample as a whole).

G. Wang et al. (2018) conducted a systematic review and meta-analysis of RCTs of ECT augmen- tation of clozapine for clozapine-resistant schizophrenia that included Chinese and non-Chinese studies. Findings from 18 RCTs that included 1,769 subjects showed benefits of adjunctive ECT com-

pared with clozapine alone for symptomatic improvement at post-ECT and endpoint assessments (SMD –0.88, P=0.0001 and SMD –1.44, P<0.00001, respectively). Significant benefits of adjunctive ECT were also seen in study-defined response rates and in remission rates at both assessments (P<0.00001, NNT=3 and NNT=4, respectively, for response and P≤0.0001, NNT=13 and NNT=14, respectively, for remission); however, subjective memory issues and headache were more frequent in the group that received adjunctive ECT (P<0.0001, NNH=4 and P=0.005, NNH=8, respectively).

These studies and meta-analyses suggest a beneficial effect of ECT in combination with antipsychotic medication in individuals with treatment-resistant schizophrenia and clozapine-resistant schizophrenia despite the small number of studies and low quality of observational trials. The increases in reported rates of headache and memory impairment, however, suggest a need to weigh the potential benefits and risks of ECT for the individual patient as compared with the risks of treatment-resistant schizophrenia.

Transcranial Magnetic Stimulation in Treatment-Resistant Schizophrenia

Studies have also been done with transcranial magnetic stimulation (TMS) for treatment of hallu- cinations and for treatment of negative symptoms in individuals with schizophrenia. He et al. (2017) conducted a meta-analysis of studies published in English or Chinese that studied low (1 Hz) or high (10 Hz) frequency TMS in individuals with schizophrenia. In 13 studies of 1 Hz TMS, audi- tory hallucinations showed greater improvement with active TMS as compared with sham treat- ment, but publication bias was noted, and sensitivity analysis also indicated that the meta-analytic finding was unstable and likely to change with additional research. In 7 studies of 10 Hz TMS, there was no effect of active treatment on negative symptoms as compared with sham TMS.

Aleman et al. (2018) conducted a meta-analysis of studies of TMS applied to the dorsolateral pre- frontal cortex as compared with sham TMS for treatment of negative symptoms and found a mean weighted effect size of 0.64 (0.32–0.96, total N=827); however, sham TMS showed a significant im- provement of negative symptoms from baseline to posttreatment, with a mean weighted effect size of 0.31 (0.09–0.52, total N=333). Interpretation of the findings was also complicated by the use of sev- eral different coil placements (i.e., right, left, bilateral) and variability in other stimulation parameters (e.g., frequency, intensity, number of stimuli per session, duration of treatment). A meta-analysis by Dollfus et al. (2016) of 13 parallel design trials of TMS for treatment of auditory hallucinations in schizophrenia also showed a significant placebo effect, which was greatest with the 45° position coil and was viewed as introducing substantial bias in determining TMS efficacy.

In terms of addition of TMS to clozapine, Wagner et al. (2019b) used data from the TMS for the Treatment of Negative Symptoms in Schizophrenia (RESIS) trial and examined a subgroup of patients who received treatment with clozapine with the addition of active (N=12) or sham (N=14) TMS ap- plied to the left dorsolateral prefrontal cortex for 3 weeks, with five treatment sessions per week. There was no effect of active TMS on negative symptoms, although there was significant benefit of TMS on secondary outcomes (i.e., PANSS positive symptom and general subscales; total PANSS).

These findings on benefits of TMS may change with further research using larger samples and rigorous study designs; however, at present, there is limited evidence for benefits of TMS in reduc- ing either auditory hallucinations or negative symptoms, and findings are confounded by signifi- cant placebo effects and publication biases.

STATEMENT 8: Clozapine in Suicide Risk

APA recommends (1B) that patients with schizophrenia be treated with clozapine if the risk for suicide attempts or suicide remains substantial despite other treatments.*

*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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For individuals with schizophrenia who are at substantial risk for suicide, evidence on the use of clozapine comes from retrospective cohort studies and a large pragmatic, open-label RCT (N=980). Consequently, the strength of research evidence is rated as moderate.

On the basis of findings from the InterSePT study (Meltzer et al. 2003), the AHRQ report (McDonagh et al. 2017) concluded that clozapine was superior to olanzapine in preventing significant suicide at- tempts or hospitalization to prevent suicide in high-risk patients (HR 0.76, 95% CI 0.58–0.97; moderate SOE). Fewer clozapine-treated patients in the InterSePT study attempted suicide (P=0.03); required hos- pitalizations (P=0.05) or rescue interventions (P=0.01) to prevent suicide; or required concomitant treat- ment with antidepressants (P= 0.01) or with anxiolytics or soporifics (P=0.03). Although there was not a significant difference in suicide deaths (5 for clozapine and 3 for olanzapine), Kaplan-Meier life table estimates indicated a significant reduction in the 2-year event rate in the clozapine group (P=0.02), with an NNT of 12. Data from other RCTs, in which suicide-related outcomes were reported as adverse events, showed very low event rates and no differences among antipsychotic medications.

One large retrospective study (Kiviniemi et al. 2013) used a nationwide registry to follow up with patients presenting with a first episode of schizophrenia (N=6,987). At 5 years, the risk of suicide in patients treated with clozapine was significantly reduced (OR 0.29, 95% CI 0.14–0.63), whereas suicide risk in those treated with risperidone, olanzapine, or quetiapine was comparable to the risk with no antipsychotic treatment. Another large nationwide study (N = 9,567) of patients newly start- ing treatment with SGAs found lower rates of suicide attempts in those beginning with clozapine as compared with other drugs studied (Bitter et al. 2013). Suicide attempt rates were 1.1% at 1 year in those treated with clozapine in contrast to suicide attempt rates that ranged from 2.1% to 3.7% for other SGAs at 1 year. The suicide attempt rate with clozapine treatment was also reduced as com- pared with the 6 months prior to clozapine initiation (2.2% prior to clozapine as compared with 1.1% after clozapine initiation).

For a discussion of the evidence related to the side effects of clozapine, see Statement 7 earlier in the appendix.

Grading of the Overall Supporting Body of Research Evidence
for Efficacy of Clozapine in Individuals With Substantial Risk Factors for Suicide Attempts or Suicide

• •

Magnitude of effect: Moderate to large. In the randomized controlled InterSePT study, moderate effects are present for clozapine as compared with olanzapine in reducing suicide attempts and hospitalizations to prevent suicide. As compared with other antipsychotic medications, larger effects of clozapine on suicide attempts and suicide are found in observational registry studies with longer periods of follow-up and larger sample sizes.

Risk of bias: Medium. Studies include an RCT and observational studies. There is low risk of bias in the RCT on most outcomes but a medium to high risk of bias for the observational studies because of their lack of randomization, lack of blinding, and retrospective study design. Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. Doses of clozapine used in the RCT are representative of usual clinical practice. In addition, the RCT includes individuals with an increased risk of suicide, whereas the observational studies assessed suicide-related out- comes without preselecting for high-risk individuals. Nevertheless, rates of suicide are in- creased among individuals with schizophrenia, making the observational study findings of relevance to routine clinical practice.

Directness: Variable. In the RCT, studies measured suicide attempts and deaths due to suicide, but mortality was infrequent, making statistical comparisons invalid. For the observational studies, suicide attempts and deaths from suicide were also studied. Nevertheless, observational study findings are indirect because of the lack of selection of patients at high risk of suicide.

• Consistency: Consistent. Reductions in suicide attempts are consistent in the RCT and in obser- vational studies. The reduction in suicide deaths in larger samples with longer follow-up periods is consistent with the reduction in suicide attempts.

• Precision: Precise. Confidence intervals are narrow and do not cross the threshold for clinically significant benefit of the intervention.

• Dose-response relationship: Not assessed.

• Confounding factors: Present. In the RCT, effects on suicide deaths may be reduced by the need
to intervene with increased monitoring, hospitalization, or study withdrawal if suicidal risk is sig- nificant. Additional monitoring and an increased frequency of clinical contacts with clozapine may enhance the effects of the medication relative to other antipsychotic medications, at least in observational studies.

• Publication bias: Unable to be assessed. The small number of relevant studies makes assessment of publication bias impossible.

• Overall strength of research evidence: Moderate. In terms of clozapine effects on suicidal behav- iors and suicide, available studies include an RCT and several observational studies with large samples and long periods of follow-up. Confidence intervals are relatively narrow, and the find- ings are consistent.
Grading of the Overall Supporting Body of Research Evidence
for Harms of Clozapine in Individuals With Substantial Risk Factors for Suicide Attempts or Suicide
See Statement 7, subsection “Grading of the Overall Supporting Body of Research Evidence for Harms of Clozapine,” earlier in the appendix.
STATEMENT 9: Clozapine in Aggressive Behavior
APA suggests (2C) that patients with schizophrenia be treated with clozapine if the risk for aggressive behavior remains substantial despite other treatments.*
Evidence for the use of clozapine for individuals with substantial aggressive behavior is limited, and the strength of research evidence is rated as low. A systematic review on pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders found 92 ar- ticles with sufficient methodological information to evaluate, although none were at low risk of bias (Victoroff et al. 2014). The authors found two studies (1 RCT, N=157; 1 open-label, N=44) showing that in inpatients with schizophrenia spectrum disorders, clozapine was superior to haloperidol in reducing scores on the Overt Aggression Scale (Conley et al. 2003; Ratey et al. 1993). Another RCT conducted in physically assaultive inpatients (N=100) also found clozapine to be superior to haloperidol or olan- zapine in reducing scores on the Overt Aggression Scale (Krakowski et al. 2006, 2008). In reducing hos- tility (as measured by PANSS or BPRS hostility items), 4 RCTs (3 in inpatients, 1 in outpatients) reported superiority of clozapine as compared with FGAs. Two of these studies (N=48 and N=151) compared clozapine with chlorpromazine (Claghorn et al. 1987; Niskanen et al. 1974), and the other 2 studies (N=167 and N=71) compared clozapine with haloperidol (Citrome et al. 2001; Kane et al. 2001).
These findings support the opinions of many experts in viewing clozapine as beneficial in patients at substantial risk of aggressive behaviors. Nevertheless, additional evidence from well-designed clinical trials is needed. For a discussion of the evidence related to the side effects of clozapine, see Statement 7 earlier in the appendix.
*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Grading of the Overall Supporting Body of Research Evidence
for Efficacy of Clozapine in Individuals With Substantial Risk Factors for Aggressive Behaviors

• Magnitude of effect: Unclear. Available studies report statistical superiority, but there are no good estimates of the magnitude effect either within or among studies.

• Risk of bias: High. Most of the available studies, including RCTs and open-label studies, have a significant risk of bias and a lack of reported details about randomization, blinding, and other features of study design.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. Most studies are fo- cused on inpatients, including forensic psychiatry populations, who exhibit physically assaul- tive behavior. The doses of medication used are within normal to high dose ranges for usual clinical practice.

• Directness: Variable. Studies measure multiple different outcomes, including hostility items on PANSS or BPRS, time in restraint, episodes of restraint, and episodes of assaultive behavior.

• Consistency: Consistent. Studies generally report reductions in hostility or aggressive behavior.

• Precision: Unknown. Confidence intervals are not reported in all studies or in the available meta- analysis. Nevertheless, a lack of precision is likely due to the small samples in most studies.

• Dose-response relationship: Not assessed.

• Confounding factors: Present. In observational outpatient studies, additional monitoring and
an increased frequency of clinical contacts with clozapine may enhance medication effects rela- tive to other antipsychotic medications. The high risk of bias in many of these studies suggests that confounding factors may be present but unrecognized.

• Publication bias: Unable to be assessed. The relatively small number of studies and the heteroge- neity of study designs make it difficult to assess publication bias. However, publication bias seems possible because of the tendency for negative clinical trial results to go unpublished.

• Overall strength of research evidence: Low. The available studies include RCTs and open-label studies with a high risk of bias. Although the findings are consistent, the applicability to typical clinical practice is limited. Other sources of possible bias were unable to be assessed but are likely to be present.
Grading of the Overall Supporting Body of Research Evidence
for Harms of Clozapine in Individuals With Substantial Risk Factors for Aggressive Behaviors
See Statement 7, subsection “Grading of the Overall Supporting Body of Research Evidence for Harms of Clozapine,” earlier in the appendix.
STATEMENT 10: Long-Acting Injectable Antipsychotic Medications
APA suggests (2B) that patients receive treatment with a long-acting injectable antipsy- chotic medication if they prefer such treatment or if they have a history of poor or uncer- tain adherence.*
*This guideline statement should be implemented in the context of a person-centered treatment plan that includes evi- dence-based nonpharmacological and pharmacological treatments for schizophrenia.

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Evidence for this guideline statement comes from the AHRQ review (McDonagh et al. 2017) as well as from other RCTs, registry database studies, cohort studies, “mirror image” studies, and meta-analyses of such trials. The findings from these studies are mixed because RCTs show few dif- ferences in outcomes between LAI antipsychotic medications and oral antipsychotic agents, whereas observational trials show consistent benefits of LAI formulations. There are a number of possible explanations for these apparent disparities related to the design of the studies and differ- ences in study populations (Correll et al. 2016; Fagiolini et al. 2017). Individuals who are agreeable to participating in a randomized clinical trial are more likely to be adherent to treatment than a broader population of individuals with a particular diagnosis. A greater focus on adherence-related questions and a greater frequency of visits may occur in an RCT as compared with treatment as usual, which may also influence adherence or outcomes. Consequently, the possible advantages of LAIs over oral formulations in promoting or assuring adherence may be less salient in RCTs as compared with observational trials. Although each type of study has advantages and disadvan- tages, observational trials that use registry databases are also able to examine outcomes among large numbers of individuals over many years of follow-up in contrast to the smaller numbers and shorter follow-up periods of RCTs.

In the AHRQ review (McDonagh et al. 2017), the ability to draw conclusions about the compar- ative effectiveness of LAI antipsychotic medications is limited by the relatively small number of head-to-head comparison studies among LAI antipsychotic medications or for LAI formulations as compared with oral agents. Few studies assessed differences in symptoms with treatment, but clozapine was noted to be superior to aripiprazole LAI (monthly or every 6 weeks), olanzapine LAI, paliperidone LAI (monthly and every 3 months), and risperidone LAI, whereas paliperidone LAI every 3 months was superior to oral lurasidone (low SOE). For the few comparisons where data on response were available, no differences were found (low SOE). Risperidone LAI was significantly better than quetiapine in social function over 24 months but did not differ from quetiapine on mea- sures of quality of life (low SOE). No difference in social function was found between monthly pal- iperidone palmitate LAI and biweekly risperidone LAI (low SOE). In terms of quality of life, oral aripiprazole and monthly aripiprazole LAI did not differ from one another with up to 2 years of follow-up (low SOE).

In terms of findings on harms, a network meta-analysis of 90 head-to-head RCTs showed that risperidone LAI had a significantly lower risk of withdrawal due to adverse events than clozapine (OR 0.27, 95% CI 0.10–0.71), lurasidone (OR 0.39, 95% CI 0.18–0.84), quetiapine XR (OR 0.43, 95% CI 0.22–0.81), risperidone (OR 0.50, 95% CI 0.25–0.99), or ziprasidone (OR 0.40, 95% CI 0.20–0.82). No differences in overall adverse events were found between aripiprazole as compared with monthly aripiprazole LAI or between paliperidone or monthly paliperidone palmitate LAI as compared with risperidone LAI (low SOE). In addition, no differences in extrapyramidal side effects were seen in a 28-week trial of aripiprazole and monthly paliperidone LAI or a network meta-analysis comparing monthly and 4- to 6-week aripiprazole LAI. However, monthly aripiprazole LAI had a greater incidence of extrapyramidal side effects (RR 1.88) and worse akathisia than oral aripipra- zole in the short term but not at 1 year. For mortality, no significant difference was found between monthly paliperidone palmitate LAI versus risperidone LAI (RR 1.26, 95% CI 0.21–7.49) on the ba- sis of 2 RCTs of 4–24 months’ duration (low SOE).

A number of other meta-analyses of RCTs are also available and provide complementary infor- mation to the findings in the AHRQ review. Ostuzzi et al. (2017) conducted a systematic review and meta-analysis of RCTs that compared the oral and LAI formulations of the same antipsychotic med- ication and included risperidone (6 studies), olanzapine (2 studies), aripiprazole (3 studies), zuclo- penthixol (1 study), fluphenazine (7 studies), and haloperidol (2 studies). There was a small benefit for aripiprazole LAI (2 studies, N=986; RR 0.78, 95% CI 0.64–0.95; high SOE) as compared with oral aripiprazole for all-cause discontinuation, a small benefit for oral olanzapine as compared with olanzapine LAI for discontinuation due to inefficacy (2 studies, N=1,445; RR 1.52, 95% CI 1.12–2.07; low SOE), and a small benefit for risperidone LAI as compared with oral risperidone for hyperpro-

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lactinemia (5 studies, N=891; RR 0.81, 95% CI 0.68–0.98; moderate SOE). The other comparisons showed no differences for these outcomes, and there were also no differences noted for nonre- sponse rate, relapse rate, dropouts for adverse events, extrapyramidal symptoms, or weight gain.

Kishimoto et al. (2014) examined the relative efficacy of LAI antipsychotic medications as com- pared with oral antipsychotic medications in relapse prevention and found that LAIs were similar to oral agents in outpatient studies lasting ≥1 year (12 studies; RR 0.93, 95% CI 0.71–1.07; P=0.31) and at the longest study time point across all settings (21 studies, N=4,950; RR 0.93, 95% CI 0.80– 1.08; P=0.35). When analyzed by drug, fluphenazine LAI showed greater benefit than oral antipsy- chotic agents in preventing relapse (RR 0.79, 95% CI 0.65–0.96; P=0.02); however, the authors note that this may be mediated by a cohort effect rather than a drug-specific effect because all of the fluphenazine studies predated 1992. For drug inefficacy, calculated as the sum of relapses plus dis- continuations due to inefficacy, fluphenazine LAI was again superior to oral antipsychotic agents (8 studies, N=826; RR 0.78, 95% CI 0.66–0.91; P=0.002), whereas olanzapine LAI was inferior to oral antipsychotic agents (N=1,445; RR 1.52, 95% CI 1.12–2.07; P=0.007). In preventing hospitalization, fluphenazine LAI was also superior to oral antipsychotic agents (4 studies, N=197; RR 0.82, 95% CI 0.67–0.99, P=0.04); however, pooled data for LAIs as compared with oral antipsychotic agents showed no statistically significant effects (10 studies, N=2,296; RR 0.88, 95% CI 0.75–1.03; P=0.09). No differences in all-cause discontinuation were noted in pooled analyses or for individual LAIs (fluphenazine, haloperidol, zuclopenthixol, risperidone, olanzapine).

A separate meta-analysis (Kishi et al. 2016b) examined the efficacy of paliperidone LAI or risper- idone LAI as compared with oral antipsychotic agents in patients with a recent-onset psychotic dis- order. Although there was significant heterogeneity in the study findings, LAIs and oral agents were comparable overall in relapse prevention (3 studies; N=875). The LAIs did have fewer study discontinuations because of inefficacy (RR 0.34, NNT=–50) or nonadherence (RR 0.30, NNT=–33), but LAIs also had a higher incidence of tremor (RR 2.38) or at least one adverse effect (RR 1.13). In terms of mortality with LAIs as compared with oral antipsychotic agents, another meta-analysis of 52 RCTs (Kishi et al. 2016a) found no difference between LAIs and placebo or oral antipsychotics in all-cause death or death due to suicide (total N=17,416; LAI antipsychotics=11,360, oral antipsychotics=3,910, and placebo=2,146; LAI antipsychotics vs. placebo=28.9, LAI antipsychotics vs. oral antipsychotics=64.5).

Another RCT, the Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy (PROACTIVE) study (P. F. Buckley et al. 2015), was a multisite trial conducted at 8 academic centers in the United States. The researchers randomly assigned patients with schizophrenia or schi- zoaffective disorder to risperidone LAI or the physician’s choice of an oral SGA for up to 30 months. Subjects were outpatients who were neither resistant to treatment nor experiencing a first episode of psychosis. Approximately half of the subjects (161 of 305) discontinued treatment before the end of the trial. There was no significant difference noted in the proportion with a relapse (42% for risperidone LAI vs. 32% for oral SGA; P=0.08), time to first relapse (P=0.13), or time to first hospi- talization (P=0.30). In addition, no significant differences between risperidone LAI and oral SGAs were noted for the bulk of symptom ratings (anxiety-depression, negative symptoms, excitement, affective flattening, avolition, asociality-anhedonia, CGI severity and CGI improvement). How- ever, changes in symptom scores did differ between the treatment arms, with lower Scale for the Assessment of Negative Symptoms (SANS) alogia scores with oral SGAs and greater improvement in psychotic symptoms and BRPS total scores with risperidone LAI. In patients followed after an initial relapse, 32 (11%) had two relapses, and 13 (4%) had three relapses, with no significant differ- ences in the rate or time to successive relapse between those treated with risperidone LAI and those treated with oral SGAs (Buckley et al. 2016).

In contrast to the findings from RCTs, observational studies often find benefits of LAI antipsychotic formulations as compared with oral antipsychotic formulations. Tiihonen et al. (2017) used a pro- spective national database in Sweden (with individuals as their own controls) to examine the risk of treatment failure, which was defined as psychiatric rehospitalization, admissions due to a suicide at-

tempt, discontinuation of antipsychotic medication or switch to another antipsychotic medication, or death. Of the 29,823 patients, 43.7% were rehospitalized, and 71.7% met criteria for treatment failure. The LAI formulations of antipsychotic medications were associated with a 20%–30% lower risk of re- hospitalization as compared with oral formulations of an antipsychotic (HR 0.78, 95% CI 0.72–0.84 for the total cohort; HR 0.68, 95% CI 0.53–0.86 for the incident cohort). For specific LAI antipsy- chotic medications as compared with no use of antipsychotic medication, rehospitalization risk was lowest with once-monthly paliperidone LAI (HR 0.51, 95% CI 0.41–0.64), zuclopenthixol LAI (HR 0.53, 95% CI 0.48–0.57), perphenazine LAI (HR 0.58, 95% CI 0.52–0.65), and olanzapine LAI (HR 0.58, 95% CI 0.44–0.77). Of the oral medications, rehospitalization rates were lowest with clozapine (HR 0.53, 95% CI 0.48–0.58). Rates of treatment failure were also lowest with clozapine (HR 0.58, 95% CI 0.53–0.63) and with LAI antipsychotic formulations as compared with other oral formula- tions (HR values for LAI formulations: perphenazine LAI 0.65, haloperidol LAI 0.67, zuclopen- thixol LAI 0.69, paliperidone LAI 0.72, flupentixol LAI 0.75, olanzapine LAI 0.77, and risperidone LAI 0.80).

Tiihonen et al. (2011) also compared LAI antipsychotics with their equivalent oral formulation in a nationwide cohort of 2,588 consecutive patients in Finland who had an initial admission with a diagnosis of schizophrenia. Of those individuals, only 58.2% used an antipsychotic medication af- ter discharge, and 45.7% of the cohort continued to take an antipsychotic for at least 30 days. For rehospitalization as well as for all-cause discontinuation, LAI antipsychotic had a lower adjusted hazard ratio (aHR) than the equivalent oral formulation (aHR 0.36, 95% CI 0.17–0.75; P=0.007 and aHR 0.41, 95% CI 0.27–0.61; P=<0.0001, respectively). For each LAI antipsychotic as compared with its oral equivalent, rehospitalization was lower with haloperidol LAI (aHR 0.12, 95% CI 0.01–1.13; P=0.06) but not perphenazine LAI (aHR 0.53, 95% CI 0.22–1.28; P=0.16) or risperidone LAI (aHR 0.57, 95% CI 0.30–1.08; P=0.09). Use of an LAI antipsychotic was also associated with lower rates of all-cause discontinuation for haloperidol LAI, perphenazine LAI, and risperidone LAI as compared with their oral equivalents (aHR 0.27, 95% CI 0.08–0.88; P=0.03; aHR 0.32, 95% CI 0.19–0.53; P=<0.0001; and aHR 0.44, 95% CI 0.31–0.62; P=<0.0001, respectively). Zuclopenthixol LAI showed no difference from its equivalent oral formulation in either rehospitalization or all-cause discontinuation.

Taipale et al. (2018a) used the same nationwide Finnish health care registry to assess the long- term effectiveness of antipsychotic medications on the risk of psychiatry rehospitalization over fol- low-up periods of up to 20 years (median of 14.1 years). The sample included a prevalence cohort of 62,250 individuals as well as 8,719 individuals who were followed prospectively after a first ep- isode of psychosis. The risk of psychiatric rehospitalization was lower with LAI antipsychotic med- ications than with oral antipsychotic formulations (LAI FGAs HR 0.46, 95% CI 0.40–0.54; LAI SGAs HR 0.45, 95% CI 0.39–0.52; oral FGAs HR 0.67, 95% CI 0.60–0.74; oral SGAs HR 0.57, 95% CI 0.53– 0.61) in first-episode patients, as was the risk of all-cause hospitalization (LAI FGAs HR 0.58, 95% CI 0.51–0.66; LAI SGAs HR 0.56, 95% CI 0.50–0.63; oral FGAs HR 0.80, 95% CI 0.74–0.87; oral SGAs HR 0.69, 95% CI 0.66–0.73), with similar patterns noted in the prevalence cohort.

A nationwide registry was also used by Taipale et al. (2018b) to examine all-cause mortality and its relationship to medication treatment among patients with schizophrenia in Sweden. Informa- tion was available on 29,823 individuals between 2006 and 2013, of which 4,603 patients were in the incident cohort. For LAI SGAs, the cumulative mortality rate was about one-third lower than the mortality rate for equivalent oral antipsychotics in pairwise analyses (aHRs 0.67, 95% CI 0.56–0.80). Those taking an LAI formulation of an SGA had the lowest cumulative mortality (7.5%), with me- dian follow-up of 6.9 years. Corresponding rates of cumulative mortality were 8.5% for oral SGAs, 12.2% for oral FGAs, 12.3% for LAI FGAs, and 15.2% in those who were not taking an antipsychotic medication. As compared with LAI SGAs, corresponding aHRs were 1.52 (95% CI 1.13–2.05) for oral SGAs, 1.37 (95% CI 1.01–1.86) for LAI FGAs, 1.83 (95% CI 1.33–2.50) for oral FGAs, and 3.39 (95% CI 2.53–4.56) in those who were not taking an antipsychotic medication.

MacEwan et al. (2016b) used a multistate database of U.S. Medicaid patients to examine the probability of rehospitalization after an index admission with LAI antipsychotic treatment as com-

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pared with oral antipsychotic treatment. Using multivariate logistic regression with propensity score matching for 1,450 patients with a diagnosis of schizophrenia, an LAI antipsychotic medica- tion was associated with a lower probability of readmission at 60 days postdischarge (adjusted OR 0.60, 95% CI 0.41–0.90) but not at 30 days postdischarge.

Kishimoto and colleagues conducted meta-analyses of cohort studies and mirror image studies to compare the effectiveness of LAIs versus oral antipsychotic agents in terms of hospitalization and treatment discontinuation (Kishimoto et al. 2013, 2018). On the basis of 42 prospective and ret- rospective cohort studies (total N=101,624; mean follow-up18.6±10.0 months), LAIs were found to be superior to oral antipsychotics in terms of all-cause discontinuations (10 studies, N= 37,293; risk ratio 0.78, 95% CI 0.67–0.91; P = 0.001) and hospitalization rates (15 studies, 68,009 person-years; rate ratio 0.85, 95% CI 0.78–0.93; P<0.001) but not hospitalization risk or days of hospitalization (Kishimoto et al. 2018). However, the patients treated with an LAI antipsychotic medication had longer illness durations than those treated with oral formulations of antipsychotic medication, which may have influenced the findings. In 25 mirror image studies that followed patients for at least 6 months before and after a transition between medication formulations, LAI antipsychotic med- ications were superior to oral antipsychotic medications in preventing hospitalization (16 studies, N=4,066; risk ratio 0.43, 95% CI 0.35–0.53; P<0.001) and in decreasing the number of hospitalizations (15 studies, 6,342 person-years; rate ratio 0.38, 95% CI 0.28–0.51; P<0.001) (Kishimoto et al. 2013).

Grading of the Overall Supporting Body of Research Evidence for the Efficacy of LAI Antipsychotic Medications

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Magnitude of effect: Variable. In RCTs, there are few differences in outcomes between LAI and oral formulations of antipsychotic medications. However, significant benefits with a moderate magnitude of effect are noted in observational studies, including prospective registry database studies and mirror image studies.

Risk of bias: Medium. Studies include RCTs that have some limitations in study design or re- porting of features such as randomization or blinding. Observational studies based on prospec- tive registry data are well designed but have at least a medium risk of bias because of a lack of randomization or blinding.

Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with schizoaffective disorder. The doses of medication used are not always stated but appear to be representative of usual clinical practice. The observational studies in- clude data from a nationwide registry and have broad generalizability, in contrast to RCTs with more restrictive inclusion and exclusion criteria. However, the applicability of registry data from Nordic countries may be reduced by differences in the health care delivery system as com- pared with that of the United States.

Directness: Variable. Most studies measure direct outcomes, including differences in symptoms, quality of life, functioning, relapse prevention, and rehospitalization. However, some studies as- sess indirect outcomes, including all-cause treatment discontinuation.
Consistency: Inconsistent. RCTs generally show little or no benefit of LAI as compared with oral formulations of antipsychotic medications, whereas observational studies show moderate ben- efits. However, findings are consistent for different types of observational studies, including prospective registry database studies and mirror image analyses.

Precision: Imprecise. For RCTs, confidence intervals cross the threshold for clinically significant benefit of the intervention.
Dose-response relationship: Not assessed.
Confounding factors: Unclear. Confounding factors may be present for the observational stud- ies because of the lack of randomization. Individuals with poor adherence or more severe symp- toms may be more likely to receive an LAI, which would give LAI-treated patients a greater risk of relapse or rehospitalization.

• Publication bias: Not suspected. Publication bias was not detected in the meta-analyses that spe- cifically examined this question.

• Overall strength of research evidence: Moderate. Available evidence includes data from several types of observational studies, each of which shows consistent benefits for LAI as compared with oral formulations of antipsychotic medication. The potential benefit of LAI formulations in assuring adherence may not be observable in RCTs in which patients are already selected for high adherence. Although trials are of varying quality, most have good sample sizes. When ben- eficial effects are noted, most confidence intervals are narrow. There is some variation from drug to drug, but registry data show better outcomes with LAI formulations as a group as compared with oral formulations of antipsychotic medication as a group.
Grading of the Overall Supporting Body of Research Evidence for the Harms of LAI Antipsychotic Medications

• Magnitude of effect: Variable. In general, there appear to be few differences between harms of LAI antipsychotic medications and oral formulations of antipsychotic medications, particularly when LAI and oral formulations of the same drug are compared. When differences are noted in rates of specific side effects, the magnitude of those effects is small.

• Risk of bias: Medium. In RCTs, some limitations in study design are present. In other studies, harms of treatment were not systematically assessed.

• Applicability: The included trials all involve individuals with schizophrenia. Some studies also include individuals with other diagnoses such as schizoaffective disorder. The doses of medica- tion used are not always stated but appear to be representative of usual clinical practice. The ob- servational studies include data from a nationwide registry and have broad generalizability, in contrast to RCTs with more restrictive inclusion and exclusion criteria. However, the applicabil- ity of registry data from Nordic countries may be reduced by differences in the health care de- livery system as compared with that of the United States.

• Directness: Variable. When assessments of adverse effects are conducted, studies measure spe- cific side effects. However, other studies measure study withdrawals due to adverse effects.

• Consistency: Inconsistent. Some comparisons show differences between LAI and oral formula-
tions on specific side effects, but these are not consistent among medications or meta-analyses.

• Precision: Imprecise. Confidence intervals cross the threshold for clinically significant benefit of
the intervention.

• Dose-response relationship: Not assessed. Data from studies of oral medications suggest that in-
creases in dose are likely to be associated with increases in medication side effects.

• Confounding factors: Unclear. Adverse effects are not always assessed in a systematic fashion,
and reporting biases may be present.

• Publication bias: Not suspected. Publication bias was not detected in the meta-analyses that spe-
cifically examined this question.

• Overall strength of research evidence: Low. Available studies include RCTs that assess side ef-
fects of LAI and oral formulations of antipsychotic medications. Meta-analyses and network meta-analyses are also available that include head-to-head comparison trials. In terms of ascer- tainment and reporting of information on side effects, studies have at least a medium risk of bias, and there is significant inconsistency in the findings among the available studies, making it difficult to draw conclusions with any degree of confidence.
STATEMENT 11: Anticholinergic Medications for Acute Dystonia
APA recommends (1C) that patients who have acute dystonia associated with antipsychotic therapy be treated with an anticholinergic medication.

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This recommendation is based on expert opinion and is supported by studies of the prophylactic use of anticholinergic medications to reduce the risk of acute dystonia in the initial phases of anti- psychotic therapy. The strength of research evidence for this guideline statement is rated as low. No studies were found that specifically examined the treatment of acute dystonia with anticholinergic medications in a randomized or controlled manner, although intramuscular administration of an anticholinergic agent is widely viewed as the treatment of choice for acute dystonia associated with antipsychotic therapy (Stanilla and Simpson 2017).

Information on the use of anticholinergic medications to prevent acute dystonia associated with antipsychotic therapy comes from a review of 9 studies (Arana et al. 1988), of which 4 were random- ized, blinded trials (total N=232); 2 were open trials (total N=856); and 3 were retrospective studies (total N=278). On the basis of data from all of these studies, prophylactic use of an anticholinergic medication was associated with 1.9-fold reduction in risk of acute dystonia (14.8% without prophy- laxis vs. 7.7% with prophylaxis). In patients who received a high-potency antipsychotic agent (e.g., haloperidol), the benefits of prophylactic anticholinergic medication were even more pronounced (5.4-fold reduction in risk; 46.8% without prophylaxis vs. 8.7% with prophylaxis).

A subsequent study of consecutive psychiatric admissions (N = 646) showed a lower rate of acute dystonia in patients who received anticholinergic prophylaxis (8.5% without anticholinergic pro- phylaxis vs. 2.8% with anticholinergic prophylaxis), and rates of acute dystonia were greater in in- dividuals treated with a high-potency antipsychotic agent (Spina et al. 1993). A small double-blind RCT (N=29) showed a decrease in acute dystonia associated with antipsychotic therapy in patients who received benztropine as compared with placebo, but the results did not reach statistical signif- icance (Goff et al. 1991). These studies suggest therapeutic effects of anticholinergic medications in acute dystonia associated with antipsychotic therapy, and although the studies were conducted in patients who received FGAs, they likely would also apply to acute dystonia when it occurs with use of SGAs.

Grading of the Overall Supporting Body of Research Evidence for Anticholinergic Medications for Acute Dystonia

On the basis of the limitations of the evidence for anticholinergic medications for acute dystonia, no grading of the body of research evidence is possible.

STATEMENT 12: Treatments for Parkinsonism

APA suggests (2C) the following options for patients who have parkinsonism associated with antipsychotic therapy: lowering the dosage of the antipsychotic medication, switch- ing to another antipsychotic medication, or treating with an anticholinergic medication.

This statement is based on expert opinion, and, consequently, the strength of research evidence is rated as low. Knowledge of pharmacology and pharmacokinetics suggests that side effects such as parkinsonism may be diminished by reducing the dose of a medication or changing to a medi- cation with a different side-effect profile and a lesser propensity for treatment-related parkinson- ism. Clinical experience also suggests that an anticholinergic medication can be used to treat antipsychotic-associated parkinsonism (Stanilla and Simpson 2017). A good-quality systematic re- view assessed the use of anticholinergic medication compared with placebo for parkinsonism asso- ciated with antipsychotic therapy (Dickenson et al. 2017). Although many studies of anticholinergic treatment for parkinsonism were conducted decades ago and suggested benefits of anticholiner- gics, few of these studies met the systematic review’s inclusion criteria. In addition, sample sizes in the two included studies were small, and no definitive conclusions could be drawn from the sys- tematic review.

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Grading of the Overall Supporting Body of Research Evidence for Treatments for Parkinsonism

On the basis of the limitations of the evidence for treatments for parkinsonism, no grading of the body of research evidence is possible.

STATEMENT 13: Treatments for Akathisia

APA suggests (2C) the following options for patients who have akathisia associated with antipsychotic therapy: lowering the dosage of the antipsychotic medication, switching to another antipsychotic medication, adding a benzodiazepine medication, or adding a beta- adrenergic blocking agent.

This statement is based on expert opinion, and, consequently, the strength of research evidence is rated as low. Knowledge of pharmacology and pharmacokinetics suggests that side effects such as akathisia may be diminished by reducing the dose of a medication or changing to a medication with a different side-effect profile and a lesser propensity for treatment-related akathisia. A good-quality systematic review identified some benefits of benzodiazepines for akathisia associated with anti- psychotic therapy (Lima et al. 2002), but only 2 studies (total N=27) met the inclusion criteria. An- other good-quality systematic review assessed the use of β-adrenergic blocking agents in akathisia and also found insufficient evidence to draw conclusions about therapeutic benefits (3 RCTs, total N=51; Lima et al. 2004). In addition, no reliable evidence was found to support or refute the use of anticholinergic agents as compared with placebo for akathisia associated with antipsychotic therapy (Rathbone and Soares-Weiser 2006). The literature search did not identify well-designed trials pub- lished after these systematic reviews that shed additional light on any of these treatment approaches.

Grading of the Overall Supporting Body of Research Evidence for Treatments for Akathisia

On the basis of the limitations of the evidence for treatments for akathisia, no grading of the body of research evidence is possible.

STATEMENT 14: VMAT2 Medications for Tardive Dyskinesia

APA recommends (1B) that patients who have moderate to severe or disabling tardive dys- kinesia associated with antipsychotic therapy be treated with a reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2).

This statement is based on information from a good-quality systematic review (Solmi et al. 2018b) on deutetrabenazine and valbenazine treatment; information on tetrabenazine comes from less robust clinical trials. The strength of research evidence for this guideline statement is rated as moderate.

For deutetrabenazine, data were available from 2 double-blind, placebo-controlled RCTs (Anderson et al. 2017; Fernandez et al. 2017) that enrolle