Pearls of Wisdom in Clinical Psychiatry

Different Strokes

Pearls of Wisdom in Clinical Psychiatry


Dr Arabinda Brahma Dr George V Reddy

An IPS Publication


Dr Naren P Rao

Different Strokes

Different Strokes


Different Strokes

Pearls of Wisdom in Clinical Psychiatry

An IPS Publication


Dr Arabinda Brahma Dr George V Reddy Dr Naren P Rao

Publication Committee

Indian Psychiatric Society


Different Strokes

Different Strokes: Pearls of Wisdom in Clinical Psychiatry

(A Publication by Publication Committee, Indian Psychiatric Society) Editors

Dr Arabinda Brahma Dr George V Reddy Dr Naren P Rao

First Edition: November 2021 @ Indian Psychiatric Society

Published by

Publication Committee

Indian Psychiatric Society Headquarter: Plot 43, Sector 55 Gurugram, Haryana, India, Pin – 122003

ISBN: 9798783086823


All rights reserved. No part of this publication may be reproduced, stored in a

retrieval system, stored in a database and /or published in any form or by any

means, electronic, mechanical, photocopying, recording or otherwise, without the

prior written permission of the publisher.

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It was indeed a pleasure to be selected as the Chairman of the Publication Sub Committee of Indian Psychiatric Society this year. I took the charge when the second wave of Covid pandemic was hitting our country. The task was really challenging as this pandemic was considered as the most crucial global health calamity of the century.

I would like to thank the entire executive committee of Indian Psychiatric Society, specially Dr Gautam Saha, Dr NN Raju, Dr TSS Rao, Dr KK Mishra and Dr OP Singh for their support and encouragement at each and every step.

I would also like to thank all the contributors, who have patiently cooperated out of commitment for the subject to make this book possible in such a short time.

I would also like to thank the members of Publication Sub Committee and the active and untiring support of the editorial team viz. Dr George V Reddy and Dr Naren P Rao for their support.

The book would not be here without the active support of publisher team. I acknowledge their commitment and services.

Long Live Indian Psychiatric Society! Jai Hind!

Dr. Arabinda Brahma Chairman Publication Sub Committee, IPS

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Indian Psychiatric Society Office Bearers 2021-22


Dr. Gautam Saha

Vice President

Dr. N.N. Raju

Hon. General Secretary

Dr. T.S.S. Rao

Hon. Treasurer

Dr. Kshirod K Mishra

Hon. Editor

Dr. Om Prakash Singh

Imm. Past President

Dr. P.K. Dalal

Imm. Past Hon. General Secretary

Dr. Vinay Kumar

Imm. Past Hon. Treasurer

Dr. Mukesh P. Jagiwala

Direct Council Members

Dr. Adarsh Tripathi

Dr. Alka Subramanyam

Dr. Amrit Pattojoshi

Dr. Bhaveshkumar Lakdawala

Dr. Jaisukh M. Parmar Dr. Kaushik Chatterjee Dr. Ranjan Bhattacharyya Dr. Ruma Bhattacharya Dr. Sandeep Grover

Zonal Representatives

Central Zone

Dr. Rajni Chatterji Dr. Sanjay Gupta

Eastern Zone

Dr. Samrat Kar Dr. Sujit Sarkhel

Northern Zone

Dr. Shekhawat B.S.

Dr. Garg P.D.

Southern Zone

Dr. Sureshkumar G. Dr. Vishal Indla

Western Zone

Dr. Parag S. Shah Dr. Sudhir Bhave

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As the President of the Indian Psychiatric Society, I feel really proud to announce the release of the long awaited book from Different Strokes series: Pearls of Wisdom in Clinical Psychiatry. This book covers various important clinical areas and has been enriched by contributions from academicians and clinicians from all across the country. I wish the entire Publication Committee led by Dr Arabinda Brahma, Dr George V Reddy, Dr Naren Rao and guided by Dr Vinay Kumar and Dr PK Singh all the best for the success of this endeavour.

Long live IPS!

Dr. Gautam Saha President , IPS

Dear Friends


Dr. Gautam Saha President, IPS


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It gives me immense pleasure to know that the Publication Committee of Indian Psychiatric Society is bringing out many useful books every year and it is so pertinent that an innovative edition ‘Different Stroke: Pearls of Wisdom in Clinical Psychiatry’ is thought of. This book covers various important areas which can be of help for all clinicians. The entire medical fraternity is looking forward to the details in the pages to be uncovered.

I am sure the publication subcommittee under the chairmanship of Dr. Arabinda Brahma is leaving no stone unturned with able assistance from the co-chair Dr. George V Reddy and Convener Dr. Naren P Rao under the guidance of an experienced academician Dr. P. K. Singh and resourceful EC Coordinator Dr. Vinay Kumar.

I congratulate all members of the Publication Committee and authors who must have burnt lot of midnight oil for bringing out such a wonderful publication.

Long live Indian Psychiatric Society!


— Dr. N. N. Raju

Dr. N. N. Raju, MD Professor of Psychiatry President Elect, IPS Visakhapatanm


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I am really happy to know that the Publication Committee of the Indian Psychiatric Society is bringing out the book titled, ‘Different Stroke: Pearls of Wisdom in Clinical Psychiatry’. It is indeed a timely initiative and I am sure that the readers will find this collection of articles from reputed authors quite useful. I wish the entire Publication Committee under the leadership of Dr Arabinda Brahma all the best for this and future endeavours.

Long live IPS!

Dr. TSS Rao Hony General Secretary Indian Psychiatric Society

Dear friends,


Dr. TSS Rao Hony General Secretary, IPS


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Jai hind! Jai IPS!

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Dr. Kshirod K Mishra Hon Treasurer IPS 2020-22


I am extremely happy to know that the new Avatar of ‘Different Stroke: Pearls of Wisdom in Clinical Psychiatry’ is ready for release under the able chairmanship of publication committee IPS Dr Arabinda Brahma and his team. This will be soon on the desk of IPS members and will expand the horizon of knowledge. I wish all the best to the editorial team and publication committee of IPS.

Dr. Kshirod K Mishra Hon Treasurer IPS


Dear Members


I am happy to see that the Publication Committee of the Indian Psychiatric Society is bringing out the book entitled, “Different Stroke: Pearls of Wisdom in Clinical Psychiatry” which is a collection of various articles on the important clinical issues faced by us in our day to day practice. The varied topics covered by experts from across the country are expected to enrich our knowledge and understanding of clinical psychiatry.

I congratulate the entire Publication Committee of the IPS for such a concerted effort and I wish them all the best!

Om Prakash Singh Hon. Editor, Indian Journal of Psychiatry

Dr. OP Singh Hon. Editor Indian Journal of Psychiatry

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Different Strokes is a series of books released by the Publication Committee of the Indian Psychiatric Society every year which brings forth important knowledge on various aspects of clinical psychiatry. The current issue is a collection of articles discussing various topics of clinical importance by psychiatrists from various parts of the country. The various topics have been chosen after detailed discussion with seniors in the field so that the felt need of the clinicians could be addressed. The authors are able academicians and clinicians who have taken lot of pains to ensure that the material is lucid and updated. Overall, we are sure that the readers will find the material useful in their clinical practice. For us, the editorial team, it was a nice journey preparing the write ups into a presentable compilation. I am sure this will benefit budding as well as practicing psychiatrists!

Dr Arabinda Brahma Dr George V Reddy Dr Naren P Rao

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Dr. Alka Subramanyam

Department of Psychiatry Topiwala National Medical College and BYL Nair Charitable Hospital Mumbai

Dr. Amrit Pattojoshi

Professor, Department of Psychiatry Hi-tech Medical College Hospital Bhubaneshwar, Odisha – 751001

Dr. Anil Kakunje

Professor & Head Department of Psychiatry Yenepoya Medical College University Road, Deralakatte Mangalore – 570018

Dr. Aninda Sidana

Consultant Psychiatrist

Tek Chand Sidana Memorial Hospital, Sriganganagar

Dr. Arghya Pal

Assistant Professor

Dept. of Psychiatry

All India Institute of Medical Sciences Raebareli, India

Dr. Arun B Nair

Associate Professor of Psychiatry Medical College Thiruvananthapuram

Dr. Ashish Srivastava

Consultant Psychiatrist

Institute of Psychiatry and Human Behavior, Goa

Dr. Basudeb Das

Director Professor of Psychiatry & Director

Central Institute of Psychiatry Ranchi – 834006, Jharkhand, India

Dr. Ganesh Kini K

Assistant Professor Department of Psychiatry Yenepoya Medical College University Road, Deralakatte Mangalore – 570018

Dr. Itee Shree Sidana

Consultant Psychiatrist

Tek Chand Sidana Memorial Hospital Sriganganagar

Dr. Kaustav Chakraborty

Associate Professor & Head Department of Psychiatry

College of Medicine & JNM Hospital Kalyani, Nadia, India

Dr. Lokeswara Reddy Pabbathi

Associate Professor Guntur Medical College Guntur, Andhra Pradesh

Dr. M. Aleem Siddiqui

Professor, Department of Psychiatry Era Medical College Hospital Lucknow, Uttar Pradesh

Dr. Niska Sinha

Assistant Professor, Department of Psychiatry, Indira Gandhi Institute of Medical Sciences, Patna, Bihar – 800014


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Dr. Nitu Mallik

Resident Medical Officer cum Clinical Tutor, Department of Psychiatry Medical College and Hospital Kolkata, India

Dr. PMA Nishad

Senior Resident

Department of Psychiatry Yenepoya Medical College University Road, Deralakatte Mangalore – 570018

Dr. Ranjan Bhattacharyya

Associate Professor & Head

Department of Psychiatry

Murshidabad Medical College & Hospital Director, Charak Square Diagnostic & Research Center

West Bengal, India

Dr. Rudraprasad Acharya

Resident Medical Officer cum Clinical Tutor, Department of Psychiatry Medical College and Hospital Kolkata, India

Dr. Sachin Pradeep Baliga

Assistant Professor

Department of Psychiatry

Topiwala National Medical College and BYL Nair Charitable Hospital Mumbai

Dr. Samiksha Sahu

Fellow, CAMH

Department of Psychiatry

Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai

Dr. Shobit Garg

Professor, Department of Psychiatry Shri Guru Ram Rai Institute of Medical and Health Sciences Uttarakhand – 248001, India

Dr. Sourav Khanra

Associate Professor of Psychiatry Central Institute of Psychiatry Ranchi 834006, Jharkhand, India

Dr. Udayan Majumder

Consultant Psychiatrist Modern Psychiatric Hospital & De-Addiction Centre, Agartala

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Sl. No. 1.

2. 3. 4.


6. 7.


9. 10.



Chapters Page

Prolonged antipsychotic use in growing children: Impact on 1 growth and sexuality

Itee Shree Sidana, Aninda Sidana

Hyponatremia and antidepressants: Myths and facts 6

Anil Kakunje, Ganesh Kini, PMA Nishad

Lithium and kidney: Story of a long journey 14

Arun B Nair

Hepatic adverse effects of psychotropics: How to monitor and 23 when to be alarmed?

Basudeb Das, Sourav Khanra

The varied clinical presentations of OCD: Phenomenological 33 overlaps with psychosis

Ashish Srivastava

How to pick up hypoactive delirium in ICCU? 41

Lokeswara Reddy Pabbathi

Adult High Functioning autism: How to pick up the subtle 46 shades

Samiksha Sahu, Sachin Pradeep Baliga, Alka Subramanyam

Conversion disorder: How should clinicians tackle the varied 54 presentations?

Udayan Majumder

Why is Clozapine an underutilized molecule in clinical practice? 62

Arghya Pal, Nitu Mallik, Rudraprasad Acharya

Psychiatric adverse effects of antibiotics: What clinicians need to 69 know

Ranjan Bhattacharyya, Kaustav Chakraborty

Antipsychotic use in behavioral and psychological symptoms of 76 dementia: A double edged sword ?

M. Aleem Siddiqui, Amrit Pattojoshi, Shobit Garg, Niska Sinha

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Sidana & Sidana: Prolonged antipsychotic use in growing children

1Prolonged antipsychotics use in

growing children: Impact on growth

and sexuality

Itee Shree Sidana1, Aninda Sidana1

Many of psychiatric illnesses have their onset in childhood. Presence of psychiatric illness in children is no less serious than in adults. Infact, childhood onset of psychiatric illness is a poor prognostic factor. It has adverse effects on child’s academic performance as well as social skills and can impair socio-occupational functioning of children in their adulthood. Therefore, early identification, diagnosis, and intervention is very important as it can alter the course of illness, improve prognosis, and functioning of children.

Indications of antipsychotic medications in children :

Antipsychotic medications are used for various illnesses in children. Establishing diagnosis could be difficult in children and can present with comorbidities, so, treatment in children is usually to target the key symptoms.

Antipsychotic medications are used in children for

 Psychotic illness like Schizophrenia

 Bipolar Affective disorder presenting with mania or depression when giving

antidepressants alone might be harmful

 Obsessive Compulsive disorder , when it is treatment resistant, antipsychotics

can be used as an adjuvant to SSRIs

 Autism with behavioral problems or aggression

 Intellectual disability with aggression

 Self injurious behavior

 Attention deficit hyperactivity disorder, for behavioral problems and extreme


 Conduct problems

 Disruptive mood dysregulation disorder (DMDD)

 Tic disorder

 Tourette’s syndrome

1Tek Chand Sidana Memorial Hospital, Sriganganagar


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Sidana & Sidana: Prolonged antipsychotic use in growing children

Initially, first generation antipsychotics were used like haloperidol and chlorpromazine. After introduction of second generation antipsychotics, use of second generation antipsychotics have become very common in children. Second generation antipsychotics became popular as they have lesser risk of extra pyramidal side effects.

Second generation antipsychotics block D2 dopaminergic receptors but with lower receptor occupancy as well as they block serotonergic receptors in cortico-limbic pathway.

Due to their lower receptor occupancy, they have lesser risk of extra pyramidal side effects but other side effects like weight gain, metabolic side effects, endocrinological side effects, cardiovascular risks is of concern.

Use of antipsychotic medications have dramatically increased over decades, both FDA approved as well as off-label uses like irritability, eating disorders,, attention deficit hyperactivity disorder, anxiety and dissociative disorders.1 Most commonly used antipsychotic in children is risperidone followed by olanzapine, haloperidol and quetiapine. FDA has approved use of risperidone, olanzapine, aripiprazole, haloperidol and quetiapine, and recently ziprasidone for different indications and age groups in children.

There could be many possible reasons of increased use in antipsychotic medications in children like:

 Increasing knowledge and awareness about psychiatric illness and developmental disorders in children

 Increasing acceptability of psychotropic medications use

 Decreasing tolerability towards conduct problems and aggression in family

and schools

 Limited access to non pharmacological interventions

 Limited understanding of caregivers regarding non pharmacological


 Demand for quick symptom relief

Antipsychotics induced hyperprolactinemia:

Antipsychotics have known to increase prolactin levels. Dopamine2 blockade in tuberoinfundibular pathway is associated with antipsychotics induced hyperprolactinemia.2 Children are at higher risk for adverse effects of antipsychotics including hyperprolactenemia. This could be because of age related lesser dopamine

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Sidana & Sidana: Prolonged antipsychotic use in growing children

receptors in children. Also, establishing diagnosis can be difficult in children, and is often present with comorbidities, so, polypharmacy is common in children which makes them more prone to adverse effects. Degree of prolactin elevation is dose related, however, for most of antipsychotic medications, D2 receptor occupancy for increased prolactin levels is very close to therapeutic efficacy. Genetic differences may also play a role.

Hyperprolactinemia can be asymptomatic and may not affect quality of life. But persistent elevation of prolactin levels can result in various symptoms and can be distressing. Increase in prolactin levels has inhibitory effects on male reproduction and adversely affects sexual functioning.[3]

Hyperprolactinemia can present with :

 Gynaecomastia

 Irregular menstrual cycle

 Galactorrhea

 Sexual dysfunction

 Infertility

Antipsychotics use for 4 weeks or more have shown to increase prolactin levels from baseline values of 8ng/ml to 25-28ng/ml. Out of all antipsychotics, risperidone has highest propensity of causing hyperprloctinemia.3 Haloperidol, chlorpromazine and quetiapine are also known to cause increase in prolactin levels.4,5 Clozapine and aripiprazolehave least propensity to increase prolactin levels. Whereas, Aripiprazole is known to decrease prolactin levels in dose dependent manner and is also used as a treatment to decrease psychotropic drug induced hyperprolactinemia. Aripiprazole 3mg/day is effective but 6mg/day more so. However, higher doses are unnecessary. This effect of aripiprazole is because it acts as a partial agonist at Dopamine D2 receptors and its efficacy of binding to the receptors is dependent upon the functional state of the neurotransmitter.6

Effects of antipsychotics on prolactin levels: High risk:

 Risperidone

 Amisulpiride

 First generation antipsychotics ( Haloperidol, chlorpromazine )

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Sidana & Sidana: Prolonged antipsychotic use in growing children

Low risk:

 Olanzapine  Ziprasidone

Very rare:

 Aripiprazole  Clozapine

 Quetiapine

Decrease in testosterone and estrogen:

Hyperprolactinemia can cause suppression of the hypothalamic-pituitary gonadal axis, and can decrease gonadotropin releasing hormone and consequently lower testosterone levels in males. Decrease in testosterone can lead to delayed puberty. Secondary sexual development is impaired. It can result in poor muscle development, high pitched voice, inadequate testicular growth, small scrotum, sparse pubic and axillary hair. Low testosterone and estrogen levels result in decrease in bone mineral density and if continues, can cause osteoporosis and loss of height.7

Strategies to reduce impact on sexuality and growth:

1. Monotherapy should be preferred.

2. Psychosocial interventions should be used along with pharmacotherapy.

3. Monitor outcome in more than one settings. Expression of problems may differ

according to different settings like at home or school. Therefore, monitoring outcome in more than one setting will prevent overdiagnosing and overtreating and viceversa. Thus, dose related adverse effects can be prevented.

4. Start with low dose and go slow.

5. Monitor efficacy and adverse effects.

6. Monitor weight, height, BMI, at baseline and atleast every 3 months.

7. Psychoeducation of family members about possible adverse effects of

antipsychotics, and discussing risk and benefits of giving antipsychotics.

8. In case child presents with symptoms of hyperprolactinemia,, reassuring the child and the family, that adverse effects will disappear after stopping the offending medication. detailed examination, ruling out other possible/ primary

causes of hyperprolactinemia should be done.

9. Adequate intake of vitamin D3 and calcium to prevent long term risk to bone

mineral density.8

10. Adequate physical activity including weight bearing exercises is important to

reduce long term risk to bone mineral density.

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Sidana & Sidana: Prolonged antipsychotic use in growing children


1. Patel NC, crimson ML, Hoagwood K, et al. trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry 2005;44:548-56.

2. Halbreich U, Kinon BJ, Gilmore JA, et al. elevated prolactin levels in patients

with schizophrenia: mechanism and related adverse effects. Psychoneuroendocrinology 2003;28:53-67

3. Findling R, Kusumakar V, Daneman D, Moshang T, De Smedt G, Binder C. Prolactin levels during long term risperidone treatment in children and adolescents. J Clin Psychiatry 2003;64:1362-69.

4. Roke Y, van Harten PN, Boot AM, Buitelaar JKet al. Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects. J Child Adolesc Psychopharmacol 2009;19:403-14

5. Peuskens J, Pani L, Detraux J, De Hert M. the effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014;28(5):421-53.

6. Yasui-Furukori N, furukori H, Sugawara N, Fuji A, Kaneko S. dose dependent effects of adjunctive treatment with aripiprazole on hyperprolactinemia induced by risperidone in female patients with schizophrenia. J Clin Psychopharmacol 2010;30(5):596-9.

7. De Hert M, Detraux J, Stubbs B. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: a critical literature review. Expert Opin Drug Saf 2016; 15(6):809-23.

8. Abraham G, Paing W, Kaminski J, Joseph A, Kohegyi E, Josissen R. effects of elevated serum prolactin on bone mineral density and bone metabolism in female patients with schizophrenia: A prospective study. Am J Psychiat 2003;160:1618-20.

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Kakunje, Kini & Nishad: Hyponatremia and antidepressants

Hyponatremia and antidepressants

Anil Kakunje1, Ganesh Kini2, PMA Nishad3


Hyponatremia is one of the most commonly encountered side effects with the use of antidepressants. Hyponatremia is defined as sodium levels less than 135 mmol/L (normal range: 135-145 mmol/L). However different studies use different definitions of hyponatremia and hence it becomes difficult to compare the various studies. Nonetheless it is very important to recognize the emergence of this side effect and correct it to prevent significant morbidity and mortality, especially in the older adults who are more likely to develop hyponatremia. Even mild hyponatremia can cause clinically significant cognitiveissues. Hyponatremia can lead to development of osteoporosis. If left unrecognised it can lead to falls, seizures and even death1 Majority of the incidences of hyponatremia developed first two weeks of starting the antidepressants.


Selective Serotonin Reuptake Inhibitors (SSRIs)

Among the antidepressants the highest risk for developing hyponatremia is for the Selective Serotonin Reuptake Inhibitors (SSRIs) more than any other class of antidepressants. The initial studies were focussed on the potential of Tricyclic Antidepressants (TCAs) to cause hyponatremia. However due to safety and tolerability of SSRIs there has been a change in the prescribing pattern across the world and SSRIs have overtaken the TCAs as the most consumed antidepressant. Mirroring that development, the scientific community started investigating the SSRIs and its potential for causing hyponatremia. Among the various

In one large retrospective cohort study from Denmark done using nationwide registers,3 Citalopram had the highest incidence

rate ratio for developing hyponatremia among all the antidepressants.

1 Professor & Head; 2Assistant Professor; 3Senior Resident, Department of Psychiatry Yenepoya Medical College, University Road, Deralakatte, Mangalore – 570018 Email:

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SSRIs Citalopram,

Escitalopram, and Fluoxetine have been found to be associated with significantly

increased risks of hyponatraemia2.

and Sertraline, however, are less likely to cause hyponatremia compared to the other


SSRIs.2,4 There has been one case report suggesting vortioxetine induced

Kakunje, Kini & Nishad: Hyponatremia and antidepressants

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine has low incidence rate ratio compared to Venlafaxine.3 However some studies have been wary of reporting their findings due to low rates of administration of Duloxetine4.There are at leastfour case reports of Desvenlafaxine inducing hyponatremia.6-9 However a systematic head to head comparison with SSRIs and other SNRIs hasn’t been done.

Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

There is robust evidence to say that Mirtazapine and Mianserin have low propensity to cause hyponatremia. In a massive drug surveillance programme, 28172 patients on Mirtazapine were monitored. Only one case of hyponatremia was observed.4 Similarly in a study from Korea by Jung et al, not a single patient out of the 76 patients who were administered Mirtazapine developed hyponatremia.10 However there are case reports of Mirtazapine causing hyponatremia.11,12 Similarly the incidence rate ratio for hyponatremia by Mianserin was found to be 0.90 i.eMianserin was not associated with hyponatremia.3

Noradrenergic and specific serotonergic antidepressants (NaSSAs), perhaps, due to their unique mechanism of action when compared to SSRIs and SNRIs have low propensity to cause hyponatremia.

Tricyclic Antidepressants (TCAs)

Though the usage of TCAs has reduced in the last two decades due to its side effect profile, they continue to be utilised in especially in Treatment Refractory Depression and Psychotic Depression. There is fairly strong evidence to suggest that TCAs are less prone to cause hyponatremia than SSRIs and SNRIs. In the study by Letmaier et al. the frequency of TCAs causing hyponatremia was found to be 0.005%.4

Others antidepressants

There are very few studies and very limited evidence regarding association of

Patients taking Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) also have

high risk for developing hyponatremia. The risk of developing hyponatremia while

on Venlafaxine seems to be comparableto SSRIs, varying only marginally, with some

studies suggesting slightly higher risk4 and some suggesting a slightly lower risk.3

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hyponatremia and the package insert by the manufacturer also warns of

hyponatremia especially in the elderly.5

comparison of various classes of antidepressants it was noted that the TCAs had the

In a direct

lowest adjusted hazard ratio among all the antidepressant classes for hyponatremia.2

Kakunje, Kini & Nishad: Hyponatremia and antidepressants


hyponatremia with Monoamine Oxidase Inhibitors. Even in the studies which are

available, the confidence intervals are extremely wide and we cannot draw any

definite conclusion regarding the association.13

There are five case reports of Bupropion induced hyponatremia and in one of the

case reports the association was verified by rechallenging the patient with

bupropion.14 Nevertheless there is one case report where a patient who developed

hyponatremia while on Sertraline tolerated Bupropion well.15

There are three case reports describing hyponatremia with treatment of

Reboxetine.16-18 However there is a lack of methodologically strong observational

studies evaluating the association between Reboxetine and hyponatremia.


1. Syndrome of Inappropriate Anti Diuretic Hormone (SIADH)

The underlying mechanism for antidepressant-induced hyponatremia is the

disruption in the water homeostasis which is attributed to the development of

Syndrome of Inappropriate Anti Diuretic Hormone (SIADH).19

⦁ Hyponatremia with ECF hypo-osmolality (Posm<275 mOsm/kg H2O)

⦁ Elevated urine sodium excretion (urine sodium excretion >40 mmol/l)

Table 1: Criteria of SIADH (Batter and Schwartz) 20

⦁ Inappropriate urinary concentration (Uosm>100 mOsmol/kg H2O)

⦁ Absence of volume depletion or overload

⦁ Normal renal, adrenal, and thyroid function

Antidepressants like TCA, SSRI, and MAO inhibitors promote increased secretion of

Antidiuretic hormone (ADH) from the hypothalamus.19 It is postulated that

elevation in noradrenaline and serotonin are the basis for SIADH.21

a. Noradrenaline: Ascending neurons from lower brain stem synapse with alpha 1

receptors of the hypothalamus. The synaptic transmission of noradrenaline carried

out at this level result in ADH secretion from the hypothalamus.21

b. Serotonin: The function of the dorsal raphe nucleus is linked to serotonin

(5-hydroxytryptamine; 5-HT) which on activation increases the ADH production.

This is brought about through its synapse with 5-HT 2 and/or 5-HT 1C receptors 21.

It also acts via 5-HT7 receptors.20

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causing excessive reabsorption of water and resultant dilutional hyponatremia.

2. Increased water intake:

a. b.

Risk Factors




Kakunje, Kini & Nishad: Hyponatremia and antidepressants


ADH also called arginine vasopressin acts on V2 receptors present in the kidney

Effect of serotonin: Animal studies have revealed that serotonin enhances oral

water intake due to stimulation of thirst.21

Effect of anticholinergic: Dryness of mouth produced by TCA due to its

anticholinergic activity forces the patient to drink water.21

Even though the literature mentions the above postulations, the uncertainty about

the extent of such effects produced by antidepressants exists.21

Age: Elderly patients were seen to be affected more due to age-related

changes in their neuro-endocrine and renal function. According to

Madhusoodanan et al. about 85% of patients affected were above 65 years.22

Gender: There appears to be a female preponderance in the drug-induced

hyponatremic patients. Strachan and Shepherd deciphered that hyponatremia

was seen predominantly in females as per their study. 23

Concomitant drug use: Antipsychotics are also in the first run to cause

hyponatremia. Synergistic action of medication such as thiazides and

thiazide-like diuretics increases the risk of developing hyponatremia. Other

drugs like Carbamazepine, Angiotensin-Converting Enzyme Inhibitors,

NSAIDs, Chemotherapeutics, Laxatives, etc were also implicated. Bouman et

al reported that gender or age does not induce hyponatremia, but

concomitant drug intake has a role.24 Also, Kirchner et al. state that due to the

co-morbidities and co-medication in elderly patients age cannot be relied

upon as a sole causative.25

4. Low serum potassium

5. Low baseline serum sodium


7. Co-morbid illness. 8.

Bodyweight: Wilkinson et al prove low body weight has a strong association

with drug-induced hyponatremia.26 The same has been agreed upon by Kirby

and Ames.27

CYP2D6 poor metabolizers: This category of people on antidepressants are

said to be at higher risk as the reduced activity of this enzyme in them

increases the antidepressant concentration in blood.28

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Kakunje, Kini & Nishad: Hyponatremia and antidepressants

Signs and symptoms depend on the sodium level. Symptoms are due to osmotic

swelling of the brain cells. There can be headache, weakness, lethargy, irritability,

mood symptoms, cognitive slowing, confusion, behavioural changes, psychosis,

delirium and seizures.

Patients on antidepressants with a high chance of developing drug-induced

hyponatremia should be made aware of the symptoms and their sodium level

should be supervised. Symptoms include mild GI manifestations and depression in

mild cases whereas moderate cases can develop headache, lethargy, restlessness,

sleep disturbance, disorientation, and cognitive impairment. At sodium level <120

mmol/L, the condition can be perilous because of seizure, coma, and respiratory

arrest. Before the start of antidepressant therapy, baseline serum sodium value has

to be recorded. Thereafter repeat it at 2nd and 4th week following which monitoring

is continued once in three months.29


Withdrawal of offending drug: The condition can be corrected once the causative

drug is withdrawn. Check the serum sodium daily till it returns to its normal

value.30 It takes about two weeks to return to the pre-treatment level. The average

duration required for this was estimated to be 6.9 days with a range of 4-16 days.23

Clinical improvement takes longer compared to laboratory correction of


Symptomatic cases: Mildly symptomatic patients are advised to restrict their fluid

intake to 500-1000 ml/day. Severe cases of hyponatremia need treatment with

intravenous hypertonic sodium which has to be infused slowly. Rapid correction can

lead to central pontine osmotic myelinolysis.11

Restarting the Treatment

Restart the treatment with another antidepressant such as Mirtazapine,

Nortriptyline, or other similar drugs. Start with a lower dose and gradually increase

the drug with strict follow-up. Yet if recurrent hyponatremia occurs and the new

antidepressant cannot be discontinued, then contemplate regarding use of

Demeclocycline and restriction of fluid intake.30 ECT is another option in such cases.

Lithium is also an alternative.21

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Kakunje, Kini & Nishad: Hyponatremia and antidepressants

If the patient is also on other medication like diuretics which augments the risk of

developing hyponatremia, consider withdrawing it and change into other suitable




Hyponatremia is an under-reported and frequently missed side effect of

antidepressants. It should be carefully handled when antidepressants are prescribed

for the at-risk population.

 Hyponatremia, when unrecognized, can lead to significant morbidity and mortality.

 Antidepressants especially SSRIs and SNRIs are frequently known to induce hyponatremia,

shortly after initiation of treatment.

 There is a several fold increase in risk of developing hyponatremia in geriatric patients, patients

with concomitant drug use and co morbid illnesses.

 Withdrawal of the drug and restriction of fluid intake maybe sufficient in mild hyponatremia

with hypertonic saline infusion reserved only for cases of severe hyponatremia.

 Drugs with lower potential for inducing hyponatremia like Mirtazapine or Nortriptyline can be

considered when restarting treatment.

Take Home Points


1. Sterns RH, Silver SM. Complications and management of hyponatremia. Curr Opin Nephrol Hypertens 2016;25(2):114-9. doi:10.1097/MNH.0000000000000200


3. Leth-Møller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open 2016;6:e011200. doi: 10.1136/bmjopen-2016- 011200



6. Shetty HM, Manimekalai K, Sivaprakash B, Jagan Mohan R, Shetty PH. Hyponatremia Secondary to Antidepressant Therapy – A Post Marketing Safety Study. J Pharmacovigilance 2015;3(3):1000167. doi:10.4172/2329-6887.1000167

Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox

J. Antidepressant use and risk of adverse outcomes in older people: population

based cohort study BMJ 2011;343:d4551 doi:10.1136/bmj.d4551

Letmaier M, Painold A, Holl AK, Vergin H, Engel R, Konstantinidis A, Kasper

S, Grohmann R. Hyponatraemia during psychopharmacological treatment:

results of a drug surveillance programme. Int J Neuropsychopharmacol

2012;15(6):739-48. doi: 10.1017/S1461145711001192.

Lundbeck Limited. Summary of Product Characteristics. Brintellix

(vortioxetine). 2017. Available from:

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Kakunje, Kini & Nishad: Hyponatremia and antidepressants

7. Liew ED, Alderman CP. Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine. Int J Clin Pharm 2014;36(2):253-5. doi:10.1007/s11096-013-9870-0.

8. Lee Gt, Leung Jl. Syndrome of inappropriate secretion of antidiuretic hormone

due to desvenlafaxine. Gen Hosp Psychiatry 2013;35(5):574.e1-3. doi:10.1016/j.genhosppsych.2012.06.004.

9. García Fernández E, Ramos García DMI. Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine. Eur Psychiatry 2016;33:S469.

10. Jung YE, Jun TY, Kim KS, Bahk WM. Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder. Int J Clin Pharmacol Ther 2011;49(7):437-43. doi: 10.5414/cp201500

11. Cheah CY, Ladhams B, Fegan PG. Mirtazapine associated with profound hyponatremia: two case reports. Am J Geriatr Pharmacother. 2008;6(2):91-5. doi: 10.1016/j.amjopharm.2008.04.001.

12. Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in

an elderly hospice patient. J Palliat Med

doi:10.1089/jpm.2006.9.258. 13.




17. 18.



Siegler EL, Tamres D, Berlin JA, Allen-Taylor L, Strom BL. Risk factors for the

development of hyponatremia in psychiatric inpatients. Arch Intern Med


Bagley SC, Yaeger D. Hyponatremia associated with bupropion, a case verified

by rechallenge. J Clin Psychopharmacol 2005;25(1):98-9.


Cerimele JM, Robinson LA. Sertraline-associated hyponatremia and subsequent

tolerability of bupropion in an elderly woman. Prim Care Companion CNS

Disord 2011;13(5):PCC.11l01175. doi:10.4088/PCC.11l01175

Abdelrahman N, Kleinman Y, Rund D, Da’as N. Hyponatremia associated with

the initiation of reboxetine therapy. Eur J Clin Pharmacol 2003;59(2):177. doi:


Ranieri P, Franzoni S, Trabucchi M. Reboxetine and hyponatremia. N Engl J

Med 2000;342(3):215-6. doi: 10.1056/NEJM200001203420315

Koelkebeck K, Domschke K, Zwanzger P, Hetzel G, Lang D, Arolt V. A case of

non-SIADH-induced hyponatremia in depression after treatment with

reboxetine. World J Biol Psychiatry 2009;10(4 Pt 2):609-11.


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Kakunje, Kini & Nishad: Hyponatremia and antidepressants


Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J

Kidney Dis 2008;52(1):144-53. doi: 10.1053/j.ajkd.2008.03.004.

Egger C, Muehlbacher M, Nickel M, Geretsegger C, Stuppaeck C. A review on

hyponatremia associated with SSRIs, reboxetine and venlafaxine. Int J

Psychiatry Clin Pract 2006;10(1):17-26. doi: 10.1080/13651500500410216.

Spigset O, Hedenmalm K. Hyponatraemia and the syndrome of inappropriate

antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug

Saf 1995;12(3):209-25. doi:10.2165/00002018-199512030-00006.

Madhusoodanan S, Bogunovic OJ, Moise D, Brenner R, Markowitz S, Sotelo J.

Hyponatraemia associated with psychotropic medications. A review of the

literature and spontaneous reports. Adverse Drug React Toxicol Rev 2002;21(1-

2):17-29. doi: 10.1007/BF03256181

Strachan J, Shepherd J. Hyponatraemia associated with the use of selective

serotonin re-uptake inhibitors. Aust N Z J Psychiatry 1998;32(2):295-8.


Bouman WP, Pinner G, Johnson H. Incidence of selective serotonin reuptake

inhibitor (SSRI) induced hyponatraemia due to the syndrome of inappropriate

antidiuretic hormone (SIADH) secretion in the elderly. Int J Geriatr Psychiatry


Kirchner V, Silver LE, Kelly CA. Selective serotonin reuptake inhibitors and

hyponatraemia: review and proposed mechanisms in the elderly. J

Psychopharmacol 1998;12(4):396-400. doi:10.1177/026988119801200411

Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. Incidence and risk factors for

hyponatraemia following treatment with fluoxetine or paroxetine in elderly

people. Br J Clin Pharmacol 1999;47(2):211-7. doi:10.1046/j.1365-


Kirby D, Ames D. Hyponatraemia and selective serotonin re-uptake inhibitors

in elderly patients. Int J Geriatr Psychiatry 2001;16(5):484-93. doi:10.1002/gps.367

Kwadijk-de Gijsel S, Bijl MJ, Visser LE, van Schaik RH, Hofman A, Vulto AG,

van Gelder T, Ch Stricker BH. Variation in the CYP2D6 gene is associated with

a lower serum sodium concentration in patients on antidepressants. Br J Clin

Pharmacol. 2009;68(2):221-5. doi: 10.1111/j.1365-2125.2009.03448.x.

Arinzon ZH, Lehman YA, Fidelman ZG, Krasnyansky II. Delayed recurrent

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19. 20.







27. 28.


30. Taylor DM, Barnes TR, Young AH. The Maudsley prescribing guidelines in psychiatry. 13th ed. NY:John Wiley; 2018.

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Nair: Lithium and kidney

Lithium and kidney: Story of a long journey

Arun B Nair1


Lithium is a drug commonly used for the treatment of bipolar mood disorders for over six decades. Small amounts of lithium in the body are essential for maintaining physical and mental health. A number of persons on lithium therapy suffer from renal adverse effects including nephrogenic diabetes insipidus and end stage renal disease. But several animal studies have shown that administration of lithium in low doses helped in reversing in acute kidney injury due to various causes. This article attempts to analyse the probable mechanisms behind the impact of lithium on kidney function.

Lithium is ametal which is naturally present in soil. Intake of trace quantity of Lithium through food or water is necessary for maintaining physical and mental health of a person.1 Humans living in areas which there is high level of natural Lithium in drinking water have showed reduced mortality rate due to all causes, as well reduced rate of homicides and suicides.2,3 Lithium has been used in the treatment of bipolar mood disorders for over half a century now, and despite the availability of many newer drugs, it continues to be one of the most effective drugs for the treatment of this disorder.4

Renal adverse effects of Lithium

One of the important problems associated with Lithium use is it’srenal adverse effects ranging from nephrogenic diabetes insipidus(NDI) to end stage renal disease (ESRD).5 NDI, a disorder in urinary concentrating, characterised by polyrea, increased thirst, dehydration and compensatory polydipsia, which is seen in around 20 % of those using Lithium for a few months to years. People using Lithium for long time, especially for decades, have a 6 to 8 fold increased chance to develop End Stage Renal Disease (ESRD), depending on the dose of the medicine, and duration of treatment.5-7 Though isolated studies had reported an increased incidence of solid renal tumours in lithium users,8-9 a subsequent study by Pottegard et al which had a

1Associate Professor of Psychiatry Medical College Thiruvananthapuram Different Strokes


Nair: Lithium and kidney

bigger sample size, showed that there is no association between Lithium use and renal tumours.10-11

Is Lithium beneficial to renal health?

Some animal studies have recently shown that administration of low lithium amounts (>0.6 mM in blood), improved renal function. Single bolus injection or short term treatment with Lithium for less than one week reduced acute kidney injury related to adriamicin, gentamicin, cis platin, LPS and ischaemia, and prolonged treatment for more than a year alleviated kidney injury due to systemic lupus erythematosis, hypertension and ischaemia-reperfusion.12-21

How does kidney handle Lithium?

Lithium is freely filtered in glomerulus, and largely reabsorbed in the proximal tubules, which also reabsorbs 70% of filtered sodium. So lithium is also proposed as a quantitative marker of sodium absorption in proximal tubules.22-23 But later evidence from micropuncture studies showed that, actual delivery of Lithium at the end of proximal tubules exceed sodium by 14%, indicating that Lithium is reabsorbed to a lower extent than sodium.One third of sodium is reabsorbed through trans cellular and two third through para cellular pathways, but in case of Lithium absorption through transcellular pathway is less, explaining its lesser total proximal reabsorption.24-27 The Na +/H+ exchanger (NHE3) is responsible for most of the luminal uptake of lithium as it mediate lithium uptake at apical side of the cell. NHE1 which is expressed in basolateral membrane of epithelial cells of nephrons except macula densa and collecting duct intercalated cells, is thought to be responsible for lithium transport in all lithium transporting segments.

Another 3-10% of filtered lithium is reabsorbed in the thick ascending limb of loop of Henle. This is mediated by the para cellular pathway, and is driven by the trans epithelial voltage difference created by potassium efflux by renal outer medullary K+2 and activity of Sodium-potassium chloride cotransporter. Then at late distal tubules and collecting duct lithium is taken up from prourine by the principal cells of the collecting duct through epithelial sodium channel.

Lithium and end stage renal disease ( ESRD)

The prevalence of ESRD in people on lithium is approximately 1.5%, which is 6-8 times of that in the general population.7 Majority of those who developed ESRD had been on lithium for more than 15 years.7

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Nair: Lithium and kidney

Renal damage in people on chronic lithium therapy is characterised by proximal tubular atrophy and chronic interstitial fibrosis. Some people show glomerulosclerosis, but most animal models show that this starts mostly after interstitial fibrosis and tubular atrophy. Though it could be an indicator that glomerulosclerosis occurs from damage to other renal segments, it could be considered as an essential step in the final progression of ESRD.6 Biopsy specimen histology and MRI scan reveals renal micro cysts in many people on lithium.This could be due to lithium uptake by principal cells as they originate mainly from distal tubule and collecting duct. There is high levels of inactive GSK3 in renal tubules and cysts in animals on lithium, and this could lead to disturbance in function of primary cilium, and subsequently to renal cyst formation.

How lithium causes proximal tubular atrophy and interstitial fibrosis is poorly understood. Lithium may cause G2 arrest of principal cells, while there is some evidence that there is a direct link between G2 arrested renal cells and elevated production of TGF-beta1, which plays an important role in development of renal fibrosis. In lithium treated animals, there is increased TGF-beta1 in collecting ducts. Increased level of beta-catenin levels in principal cells also contribute to fibrosis. In mouse nephropathy models, Dickkopf-1, an antagonist of canonical Wnt signalling and ICG-001, which disrupts beta-catenin mediated gene transcription strongly reduced interstitial fibrosis.

Lithium and nephrogenic diabetes insipidus (NDI)

NDI is characterized by the inability of the kidney to concentrate prourine. Urine concentration is mediated by the principal cells of the collecting duct that express aquaporin-2 (AQP2) water channels at their apical membrane and thereby, allow transcellular water reabsorption. Lithium treatment causes dysregulation of AQP2 expression and trafficking on the short term and loss of principal cells on the long term. Lithium–induced AQP2 downregulation is a consequence of ENaC-mediated influx of lithium into principal cells, which is shown by ENaC inhibition studies on cultured collecting duct cells. In agreement, Within the cell, lithium inhibits glycogen synthase kinase type 3 (GSK3), a serine/threonine protein kinase that regulates cell cycle progression, cell differentiation, and normal epithelial function and survival. GSK3 consists of two isoforms (α and β), which are inhibited directly by lithium. How the inhibition of GSK3 by lithium ultimately leads to NDI has not been identified but may involve β-catenin, which is increased in expression in lithium- induced NDI and targeted for degradation by GSK3.

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Nair: Lithium and kidney

In lithium-induced NDI, urinary PGE2 levels are increased and contribute significantly to the disorder, because inhibition of cyclooxygenase-2 in rodents and patients strongly attenuated their lithium-induced polyuria.PGE2 activates the EP3 receptor in principal cells, leading to a reduced cAMP signaling, AQP2 expression, and plasma membrane targeting.


Lihium can easily enter proximal tubule cells, and a recent study showed that,

several days after a single lithium dose, which was below or similar to therapeutic

amounts given to patients with bipolar disorder, the proximal tubule exhibited an

enhanced expression of different proproliferative proteins. The development of NDI

can further aggravate the potential direct pathologic effect of lithium on proximal

tubules, because polyuric rats were shown to have an enhanced capacity of

transcellular proximal sodium transport and a corresponding increase in NHE3

abundance, likely as a consequence of the hypovolemia-induced activation of the

renin-angiotensin system. Considering NHE3 as the main lithium entry site of

proximal tubule cells, this likely also elevates the proximal uptake of lithium. Thus,

chronic exposure to therapeutic lithium amounts, certainly combined with NDI, will

increase lithium fluxes in proximal tubular epithelia, which may directly cause or

contribute to the proximal tubular atrophy and interstitial fibrosis. But to develop

medication to prevent or attenuate lithium–induced ESRD development, a better

understanding of the etiology is needed.18

Potential renal benefits of Lithium

Although chronic intake of high lithium amounts causes renal damage, accumulating evidence from animal studies indicates that administration of low lithium amounts is beneficial in preventing kidney disease caused by nephrotoxic compounds, inflammation, or oxidative stress. In mice, the administration of a single lithium dose 3 days after the induction of AKI by cisplatin largely prevented acute tubular necrosis and reduced serum creatinine levels. The protective effect of lithium was probably due to its stimulatory effect on tubular cell proliferation and repair, allowing the kidney to repopulate the damaged proximal epithelium. Similarly, a 6- hour pretreatment with lithium prevented adriamycin–induced podocyte injury, which was shown by a reduced albuminuria and reduced expression of podocytopathic mediators B7–1 and MCP-1. A single lithium bolus 1 hour before or simultaneously with LPS injection strongly reduced inflammation and apoptosis of renal cells in mice. Importantly, a single dose of 40 mg lithium chloride per 1 kg body wt was effective in all above–mentioned experiments. Although serum lithium

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Nair: Lithium and kidney

levels were not determined in these experiments, the used dose is well below the dose of single lithium chloride injections (200–300 mg/kg body wt) administered to mice to reach the therapeutic range of serum lithium levels in humans. Also, long– term lithium treatment of mice with lupus erythematosus, an autoimmune disease, attenuated the progression of tubulointerstitial damage and ESRD. Serum lithium levels were not determined, but the mice were injected daily with 4 mg lithium chloride (approximately 120 mg/kg body wt), which likely resulted in lithium levels within the therapeutic range (0.6–1.0 mM). It remains to be determined why this dose improved the kidney function of lupus mice, whereas it causes renal disease in other animals and humans.

Finally, rats that were injected 30 minutes before ischemia-reperfusion with lithium displayed reduced levels of renal oxidative stress, because they exhibited a diminished mitochondrial membrane depolarization and reactive oxygen species (ROS) production. In addition, a 30-day pretreatment of rats with lithium reduced renal damage induced by ischemia-reperfusion, which was shown by the reduction in BUN and serum creatinine and the improved preservation of the tubular structure. Also, lithium treatment of mice 8 hours after the onset of ischemia- reperfusion was also effective in reducing kidney injury, because these mice exhibited less necrosis and a faster recovery of serum creatinine levels. In these experiments, the applied lithium doses were below clinical levels, because they were maximally 50 mg lithium chloride per 1 kg body wt; the 30-day treatment lead to the low serum level of 0.4 mM.18

Molecular Mechanisms of the Renoprotective Effects of Lithium

Although lithium also targets inositol monophosphatase and inositol polyphosphate phosphatase, there is no evidence that these targets confer renoprotection. Instead, several GSK3–specific inhibitors other than lithium, like TDZD-8 or BIO, mimicked the protective effects of lithium.Consistently, mice carrying an inactive GSK3β mutant were protected from mercuric chloride–induced nephrotoxic injury.

During AKI, the tubular epithelium is damaged and requires repair to prevent chronic damage. Proximal tubule–specific GSK3βknockout or lithium–induced GSK3 inhibition in mice with AKI increased the ability of damaged tubules to undergo repair by enhancing their capacity to proliferate. This increased capacity might be caused by an enhanced β-catenin–mediated transcription of proliferative genes (canonical Wnt signaling), because this pathway was also activated in cultured

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Nair: Lithium and kidney

mouse proximal tubular cells treated with lithium and the GSK3 inhibitor BIO. Although canonical Wnt signaling is essential for self-repair during AKI, it is less evident whether pharmacologic repair by lithium also requires canonical Wnt signaling. In fact, the lower lithium amounts used in the AKI mice barely affected canonical Wnt signaling, whereas the expression of proliferative proteins, such as cyclinD1, c-Myc, and HIF-1α, were increased. Xu et al. suggested that a moderate GSK3 inhibition might activate the repair machinery by preventing GSK3-mediated degradation of these proliferative proteins in a Wnt-independent manner. Because prolonged canonical Wnt signaling induces kidney damage, activation of the repair machinery without activating Wnt signaling by moderate GSK3 inhibition might be an exciting potential novel therapeutic strategy in treating kidney disease. Additional research is required to confirm the existence of a Wnt-independent regulation of this repair machinery by GSK3.18

Progression of renal injury is associated with graded increases in oxidative stress. ROS mediate or accelerate renal injury by triggering inflammatory responses or promoting cell apoptosis, necrosis, senescence, and fibrosis. Different GSK3 inhibitors, including lithium, prevent ROS-induced apoptosis of mesangial cells and renal proximal epithelial cells. Although the molecular mechanism by which GSK3 inhibition prevents renal oxidative damage has not been investigated, studies on extrarenal tissues show that ROS–induced GSK3 activation induces the opening of the mitochondrial permeability transition pore, eventually resulting in cell death. Active GSK3α/β induces permeability transition pore opening by activating Bax and BIM in the cytosol and cyclophilin-D in the mitochondrion .Other than reducing the sensitivity to ROS, lithium and other GSK3 inhibitors also increase the activity of antioxidant proteins, including Bcl-2, in both animal models and humans.– Although the involved mechanisms are poorly studied, they might involve GSK3- mediated degradation of the transcription factor Nrf2, which upregulates the expression of different antioxidant proteins, like Bcl-2, and recently emerged as an important factor in protection against acute kidney injury.


1. Schrauzer GN: Lithium: Occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr 2002;21:14–21.

2. Blüml V, Regier MD, Hlavin G, Rockett IR, König F, Vyssoki B, Bschor T, Kapusta ND: Lithium in the public water supply and suicide mortality in Texas. J Psychiatr Res 2013;47:407-11.

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Nair: Lithium and kidney

3. Zarse K, Terao T, Tian J, Iwata N, Ishii N, Ristow M: Low-dose lithium uptake promotes longevity in humans and metazoans. Eur J Nutr 2011;50:387-89.

4. Malhi GS, Tanious M, Gershon S: The lithiumeter: A measured approach. Bipolar Disord 2011;13:219–26.

5. Dols A, Sienaert P, van Gerven H, Schouws S, Stevens A, Kupka R, Stek ML: The prevalence and management of side effects of lithium and anticonvulsants as mood stabilizers in bipolar disorder from a clinical perspective: A review. Int Clin Psychopharmacol 2013;28:287-96.

6. Aiff H, Attman PO, Aurell M, Bendz H, Ramsauer B, Schön S, Svedlund J: Effects of 10 to 30 years of lithium treatment on kidney function. J Psychopharmacol 2015;29:608–14.

7. Bendz H, Schön S, Attman PO, Aurell M: Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 2010;77:219–24.

8. Rookmaaker MB, van Gerven HA, Goldschmeding R, Boer WH: Solid renal tumours of collecting duct origin in patients on chronic lithium therapy. Clin Kidney J 2012;5:412–15.

9. Zaidan M, Stucker F, Stengel B, Vasiliu V, Hummel A, Landais P, Boffa JJ, Ronco P, Grünfeld JP, Servais A: Increased risk of solid renal tumors in lithium- treated patients. Kidney Int 2014;86:184–90.

10. Licht RW, Grabenhenrich LB, Nielsen RE, Berghöfer A, International Group for the Study of Lithium (IGSLi): Lithium and renal tumors: A critical comment to the report by Zaidan et al. Kidney Int 2014;86(4):857.


J Am Soc Nephrol

12. Wang Y, Huang WC, Wang CY, Tsai CC, Chen CL, Chang YT, Kai JI, Lin CF: Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis. Br J Pharmacol


13. Plotnikov EY, Kazachenko AV, Vyssokikh MY, Vasileva AK, Tcvirkun DV,

Isaev NK, Kirpatovsky VI, Zorov DB: The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney Int 2007;72:1493–1502.

14. Plotnikov EY, Grebenchikov OA, Babenko VA, Pevzner IB, Zorova LD, Likhvantsev VV, Zorov DB: Nephroprotective effect of GSK-3β inhibition by lithium ions and δ-opioid receptor agonist dalargin on gentamicin-induced nephrotoxicity. Toxicol Lett 2013;220:303–8.

Pottegård A, Hallas J, Jensen BL, Madsen K, Friis S. Long-term lithium use and

risk of renal and upper urinary tract cancers.


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15. Xu W, Ge Y, Liu Z, Gong R: Glycogen synthase kinase 3β orchestrates microtubule remodeling in compensatory glomerular adaptation to podocyte depletion. J Biol Chem 2015;290:1348–63.

16. Xu W, Ge Y, Liu Z, Gong R: Glycogen synthase kinase 3β dictates podocyte motility and focal adhesion turnover by modulating paxillin activity: Implications for the protective effect of low-dose lithium in podocytopathy. Am J Pathol 2014,184:2742–56.

17. Bao H, Ge Y, Peng A, Gong R: Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury. Kidney Int 2015;87: 1176–10.

18. Bao H, Ge Y, Wang Z, Zhuang S, Dworkin L, Peng A, Gong R: Delayed administration of a single dose of lithium promotes recovery from AKI. J Am Soc Nephrol 2014;25:488–500.

19. Lenz SP, Izui S, Benediktsson H, Hart DA: Lithium chloride enhances survival of NZB/W lupus mice: Influence of melatonin and timing of treatment. Int J Immunopharmacol 1995;17:581–92.

20. Talab SS, Emami H, Elmi A, Nezami BG, Assa S, Deroee AF, Daneshmand A, Tavangar SM, Dehpour AR: Chronic lithium treatment protects the rat kidney against ischemia/reperfusion injury: The role of nitric oxide and cyclooxygenase pathways. Eur J Pharmacol 2010;647:171–7.

21. Xu J, Scholz A, Rösch N, Blume A, Unger T, Kreutz R, Culman J, Gohlke P: Low-dose lithium combined with captopril prevents stroke and improves survival in salt-loaded, stroke-prone spontaneously hypertensive rats. J Hypertens 2005;23:2277–85.

22. Thomsen K, Schou M, Steiness I, Hansen HE: Lithium as an indicator of proximal sodium reabsorption. Pflugers Arch 1969;308:180–84.

23. Thomsen K: Lithium clearance: A new method for determining proximal and distal tubular reabsorption of sodium and water. Nephron 1984;37:217–23.

24. Boer WH, Fransen R, Shirley DG, Walter SJ, Boer P, Koomans HA: Evaluation of the lithium clearance method: Direct analysis of tubular lithium handling by micropuncture. Kidney Int 1995;47:1023–30.

25. Hartmann A, Holdaas H, Steen PA, Kiil F: Evidence for bicarbonate-dependent lithium reabsorption in dog kidneys. Acta Physiol Scand 1984;120:257–64.

26. Leyssac PP, Holstein-Rathlou NH, Skøtt P, Alfrey AC: A micropuncture study of proximal tubular transport of lithium during osmotic diuresis. Am J Physiol 1990;258:F1090–95.

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27. Leyssac PP, Frederiksen O, Holstein-Rathlou NH, Alfrey AC, Christensen P: Active lithium transport by rat renal proximal tubule: A micropuncture study. Am J Physiol 1994;267:F86–93.

28. Palmer LG, Schnermann J: Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol 2015;10:676–87.

29. Corry DB, Tuck ML, Nicholas S, Weinman EJ: Increased Na/H antiport activity and abundance in uremic red blood cells. Kidney Int 1993;44:574–8.

30. Yusufi AN, Christensen S, Dousa TP: Effect of chronic lithium treatment upon the Na(+)-coupled cotransporters in renal brush border membranes. Kidney Int 1993;43:1074–80.

31. Holstein-Rathlou NH: Lithium transport across biological membranes. Kidney Int Suppl 1990;28:S4–9.

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Das & Khanra: Hepatic adverse effects of psychotropics

Hepatic adverse effects of psychotropics: How to monitor and when to be alarmed?

BasudebDas,1 SouravKhanra2


Among all drugs causing hepatic injury, psychotropics has had its presence since decades. Due to several reasons, there are inconsistencies for prevalence of not

only psychotropics but also of drug induced hepatic adverse effects.1,2 Afterwards, several research networks and database registries were developed for drug

induced liver injury (DILI).3,4 Estimate from several national studies have shown that DILI varies from 2 to 19 cases/100,000/year.5 Among all DILI

psychotropics were responsible for 7.6% of cases.6 Several psychotropics across pharmacological classes cause hepatic adverse effects. Description of individual psychotropic is beyond scope of this chapter. Readers are advised to look into

literature cited here.2,5,7


Monitoring for DILI by psychotropics require understanding few important aspectsof etiopathogenesisofDILI.

o Aetiology of hepatic injury

Three types of hepatic injuries occur: 1) intrinsic, 2) idiosyncratic (iDILI) and 3) adaptive. There are salient differences between intrinsic and idiosyncratic injuries. Adaptive type of injury occurs when there is transient minor alteration in liver function test which resolves with continued exposure to causative drug. There

is absence of DILI symptoms too.8,9

o Mechanism of hepatic injury

Drugs may damage the liver via direct toxicity or immunological responses

depending on type of injury. During drug metabolism when active metabolites

1 Director Professor of Psychiatry & Director; 2Associate Professor of Psychiatry Central Institute of Psychiatry, Ranchi 834006, Jharkhand, India


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Das & Khanra: Hepatic adverse effects of psychotropics

accumulate, this initiates biochemical reaction cascade leading to mitochondrial dysfunction, oxidative and nitrosative stress, endoplasmic reticulum stress,

deranged bile acid homeostasis.10 Interactions among patients’ factor, environment, and causative drug often precipitate iDILI. The innate immune system gets activated by iDILI. Adaptive immune response too is involved in iDILI. Other important mechanisms are immune tolerance and immune genetic

polymorphism.10 A common pathway both for intrinsic and idiosyncratic injury are metabolism of lipophilic drugs which generate reactive metabolites. Cellular defense responses get overburdened leading to necrosis or apoptosis or

generating an adaptive immune response (haptens).11 * Pathology of hepatic injury

Based on the patterns, there can be four types of injuries: 1) hepatocellular, 2) cholestatic, 3) steatosis, and 4) mixed. Hepatocellular injury is most common and is hallmarked by raised serum alanine aminotransferase (ALT) only. Cholestatic injury is associated with raised alkaline phosphatase (ALP) only. In

steatosis there is gradual and chronic accumulation of fat in the liver.7 Several histological features are micro vesicular hepatic steatosis, necrosis of hepatic parenchyma, balloon hepatocytes, hepatic collagenization, micro or macroscopic

liver nodules etc.12

* Metabolism of psychotropic drugs

Psychotropics are metabolized by the cytochrome P450-dependent monooxygenase family of isoforms. More than 50% of all clinically used drugs are metabolized by

CYP3A4.13 Those psychotropics which are substrates of CYP450 cause it in dose independent manner while those which inhibit CYP450 cause it only at daily

higher dose.14 Sometimes more reactive metabolites produced from psychotropic metabolism bind covalently with mitochondrial proteins and alter

cellular structures and functions causing hepatic adverse effects.15

Diagnosis and Monitoring

Typical presentations

Clinical: Initial nonspecific symptoms can be fatigue, nausea, or abdominal pain. Liver specific symptoms and signs are present in severe cases only. These are pruritus, jaundice, ascites, or encephalopathy. The latter two are hallmarks of liver failure.

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Das & Khanra: Hepatic adverse effects of psychotropics

Biochemical and Histological: Marked elevation of ALT is hallmark of hepatocellular injury and same for ALP is the hallmark of cholestatic injury. Elevation of both usually indicate mixed type of hepatic injury. Serum bilirubin can be elevated across all types of injury. Few common histological features are acute fatty liver, hepatic necrosis, bland cholestasis, fibrosis/cirrhosis, nodular regeneration. With monitoring both biochemical and histological abnormalities, causative drug can be narrowed down.8,16

Atypical presentations

There can be few atypical presentations as well. Sometimes it can present without elevation or with modest elevation of hepatic enzymes. Hepatic injury can progress to fibrosis with mild elevation of enzymes over month to year. Hepatic adverseeffectsfromvalproatecanpresent inthreetypesofpresentations.1)There can be acute presentation of jaundice, encephalopathy without marked or with modest elevation of enzymes. 2) In children it can manifest with Reye’s like syndrome without elevation of enzymes but with neurological signs. 3) Lastly valproate induced hepatic adverse effects can present with hyperammonemic encephalopathy again without picture of overt liver injury. Chronic portal hypertension, sinusoidal obstructive syndrome with portal hypertension are other

atypical presentations.16

Data across DILI registries

Different DILI registries reveal that mean age ranged from 49 to 54 years while females were between 49% to 59%. Presence of jaundice varied widely from 27% to 70%. From one-fourth to two-third required hospitalization. Most common type

of injury was hepatocellular (42- 64%).1

Case definition

Case definition of DILI is one among the followings – 1) ≥ 5 x ULN elevation in ALT, 2) ≥ 2 x ULN elevation in ALP (with concurrent elevation of gamma-GGT in absence of bone pathology), 3) ≥ 3 x ULN elevation of ALT and simultaneous elevation of TBL exceeding 2 x ULN. In case of abnormal liver function test before DILI is suspected or causative drug was started, instead of ULN mean baseline values prior to initiating treatment of the suspected causative drug is to be considered. When ALT alone is increased ≥ 5 times or ratio of serum activity (measured by ULN) of ALT to ALP is ≥ 5, ‘hepatocellular’ injury is considered.

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Das & Khanra: Hepatic adverse effects of psychotropics

When there ALP alone is increased ≥ 2 or ratio of serum activity of ALP to ALT is ≤ 2, ‘cholestatic’ injury is diagnosed. In between 2 and 5 ‘mixed’ injury is

termed.11,17 Recent guidelines endorses standard biochemical tests for suspected DILI [Table 1].

Table 1: Standard liver biochemistry for suspected DILI11,18


Clinical implication to


Alanine aminotransferase

Hepatocellular damage Reasonably specific when >3 ULN (low concentrations in

Aspartate aminotransferase

Hepatocellular damage Non-specific (skeletal muscle, heart, pancreas, blood)

Cholestasis, impaired uptake, conjugation or excretion, biliary obstruction, haemolysis

Alkaline phosphatase

Cholestasis, infiltrative disease, Non-specific (bone, salivary biliary obstruction glands, intestinal, biliary)

Cholestasis, biliary obstruction

Glutamate dehydrogenase

Hepatocellular (mitochondrial) Specific, helpful to differentiate damage muscular from hepatic injury

Impaired hepatocellular function

International normalized ratio

Impaired hepatocellular function Vitamin K deficiency; anticoagulants

Muscular injury

Total bilirubin

Gamma-glutamyl transferase


Creatine kinase


tissues other than liver, e.g., skeletal muscle)

Non-specific. Two forms: indirect (unconjugated) and direct (conjugated)

Non-specific (kidney,

liver, pancreas, GI tract,


Malnutrition, nephrotic syndrome, cirrhosis (any cause)

Crucial to differentiate muscular from hepatic injury

Roussel Uclaf Causality Assessment Method (RUCAM)

RUCAM is a structured assessment tool for DIL endorsed for DILI. Based on several these factors RUCAM provides a score for causality assessment [Table

2].16, 19 The scores range from – 9 to + 14.

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Das & Khanra: Hepatic adverse effects of psychotropics

Table 2: Roussel Uclaf Causality Assessment Method (RUCAM)

a Group I, HAV, HBV, HCV (acute), biliary obstruction, alcoholism, recent hypotension (shock liver) b Group II, CMV, EBV, herpes virus infection.


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Concomitant diseases

History of drug reactions

History of alcohol use

Washout (dechallenge) data

Stepwise approach

Laboratory results

Autoimmune hepatitis serologies

Histology if available

Medications, Herbal or Dietary Supplements

Symptoms & signs Clinical outcome

Das & Khanra: Hepatic adverse effects of psychotropics

Apart from RUCAM, clinicians often have to rely upon other important clinical information fordiagnosis,monitoringandprognosisofDILI[Table3].16,21

Table 3: Clinical information essential in diagnostic evaluation for suspected DILI16,21


Viral hepatitis serologies

Indication for suspect drug or HDS use


Presence of rechallenge

Physical findings

History of hepatic disorders

Exposure time

Monitoring for DILI requires a stepwise approach for suspected DILI. The recent guideline has emphasized that. This should include assessing biochemical patterns of liver injury by R [(ALT/ULN)/(ALP/ULN)] value, searching for

alternative causes, and considering liver biopsy.11

Imaging and Liver biopsy

All patients with suspected DILI should be recommended for abdominal ultrasound. Guidelines encourage additional imaging based on clinical profile and pattern of hepatic injury. Liver biopsy is helpful to differentiate DILI from autoimmune hepatitis. Also, more severe necrosis, fibrosis, microvesicular

steatosis, and ductular reaction are associated with hepatic failure and death.11

Severity grading

Two severity grading systems are mentioned in literature [Table 5].

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Das & Khanra: Hepatic adverse effects of psychotropics

Table 4: DILI severity grading systems 11,17,22 US Drug-Induced Liver Injury Network

Category Severity


1 Mild

2 Moderate

3 Moderate- severe

5 Fatal

Elevated ALT and/or ALP with TBL <2.5 mg/dl and INR


Elevated ALT and/or ALP and TBL ≥2.5 mg/dl or INR ≥1.5

Elevated ALT, ALP, TBL and/or INR and hospitalization or ongoing hospitalization prolonged due to DILI

Death or liver transplantation due to DILI

4 Severe Elevated ALT and/or ALP and TBL ≥2.5 mg/dl and at least 1 of the following criteria:

– Hepatic failure (INR >1.5, ascites or encephalopathy) – Another organ failure due to DILI

International DILI Expert Working Group

1 Mild

2 Moderate

4 Fatal/transplan tation

ALT ≥ 5 or ALP ≥2 and TBL <2 ULN

ALT ≥ 5 or ALP ≥2 and TBL ≥2 ULN, or symptomatic


Death or liver transplantation due to DILI

3 Severe

ALT ≥ 5 or ALP ≥ 2 and TBL ≥ 2 ULN, or symptomatic hepatitis and 1 of the following criteria:

– INR ≥ 1.5

– Ascites and/or encephalopathy, disease duration <26

weeks, and absence of underlying cirrhosis – Another organ failure due to DILI

ALP, alkaline phosphatase; ALT, alanine aminotransferase; INR, international normalized ratio; TBL, total bilirubin, ULN, upper limit of normal

There has been a surge of research in search for novel biomarkers for DILI. However, the search for new biomarkers has slowed down after the European

Medicines Agency issued a retraction note for ethical concerns.23

Indication for transplantation in hepatic failure due to non-paracetamol type of injury

In search for early prognostic indicators to select patients who would most likely be benefitted fromtransplantation,fewclinicalandlaboratoryfeatureswerefoundto be of poor prognostic indicators in non-paracetamol type of hepatic injury. These were – 1) prothrombin time > 100 seconds, 2) age less than 11 years and greater

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Das & Khanra: Hepatic adverse effects of psychotropics

than 40 years, 3) aetiology of non-A/non-B hepatitis, 4) halothane hepatitis, or 5) idiosyncratic drug reactions, 6) duration of jaundice of more than 7 days before onset of encephalopathy, 7) prothrombin time > 50 seconds (INR > 3.5) and

8) serum bilirubin > 17 mg/dl (300 micro mol/l).24, 25


Though research on DILI has been conducted across the globe, specific research on psychotropic induced hepatic adverse effects or DILI is limited. Future multicentric prospective research with naturalistic design would characterize psychotropicinducedhepatic adverseeffectsmoreprecisely.


Take Home points

 Psychotropics induced hepatic adverse effects are important and several commonly used psychotropics cause hepatic adverse effects.

 It can present with varied symptoms and in subsyndromal manner.

 Idiosyncratic and intrinsic types are two types of hepatic injury.

 Hepatocellular, cholestatic and mixed types are example of hepatic pathology found in psychotropic drugs induced hepatic adverse effects.

 There are structured clinical and laboratory assessments available.

 Detaile history and high index of suspicion are required to prevent mortality.


1. Andrade RJ, Ortega-Alonso A, Lucena MI. Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge. Exp Opin Drug Metab Toxicol 2016;12(6):589-93.

2. Larrey D, Ripault M. Hepatotoxicity of Psychotropic Drugs and Drugs of

Abuse. In: Kaplowitz N, DeLeve LD, (eds.) Drug-Induced Liver Disease. 3rd

edition.Academic Press;2013.pp443-62.

3. Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, Garcia-Ruiz E,

et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the

Spanish registry over a 10-year period. Gastroenterology 2005;129(2):512-21.

4. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug- induced liver injury in the United States. Gastroenterology 2008;135(6):1924-

34. doi:10.1053/j.gastro.2008.09.011

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Das & Khanra: Hepatic adverse effects of psychotropics

5. Todorović Vukotić N, Ěorđević J, Pejić S, Ěorđević N, Pajović SB. Antidepressants- and antipsychotics-induced hepatotoxicity. Arch Toxicol 2021;95(3):767-89. doi:10.1007/s00204-020-02963-4

6. Licata A, Minissale MG, Calvaruso V, Craxì A. DILI and epidemiology. Eur Rev Med Pharmacol Sci 2017;21:112-21

7. Telles-Correia D, Barbosa A, Cortez-Pinto H, Campos C, Rocha NB, Machado S. Psychotropic drugs and liver disease: A critical review of pharmacokinetics and liver toxicity. World J Gastrointest Pharmacol Ther 2017;8(1):26-38. doi:10.4292/wjgpt.v8.i1.26

8. Chughlay MF, Blockman M, Cohen K. A clinical approach to drug-induced liver injury. Curr Allergy Clin Immunol 2015; 28(4): 252-6

9. Roth RA, Ganey PE. Intrinsic versus idiosyncratic drug-induced hepatotoxicity—two villains or one? J Pharmacol Exp Ther 2010; 332(3): 692-7. doi:10.1124/jpet.109.162651

10.Ye H, Nelson LJ, Gómez Del Moral M, Martínez-Naves E, Cubero FJ. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol 2018;24(13):1373-85. doi:10.3748/wjg.v24.i13.1373

11.European Association for the Study of the Liver. Electronic address:; Clinical Practice Guideline Panel: Chair:; Panel members; EASL Governing Board representative: EASL Clinical Practice Guidelines: Drug- induced liver injury. J Hepatol 2019;70(6):1222-61. doi:10.1016/j.jhep.2019.02.014

12. Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 2014;146(4):914-28. doi:10.1053/j.gastro.2013.12.032

13. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103-41. doi:10.1016/j.pharmthera.2012.12.007

14. Yu K, Geng X, Chen M, et al. High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury. Drug Metab Dispos 2014;42(4):744-50. doi:10.1124/dmd.113.056267

15. Hrycay EG, Bandiera SM. Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer. Adv Pharmacol 2015;74:35-84. doi:10.1016/bs.apha.2015.03.003

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16. Hayashi PH, Fontana RJ. Clinical features, diagnosis, and natural history of drug- induced liver injury. Semin Liver Dis 2014;34(2):134-44. doi:10.1055/s- 0034-1375955

17. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 2011;89:806–15.

18. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests.Gastroenterology2002;123:1367–84.

19. Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993;46(11):1323-30. doi:10.1016/0895-4356(93)90101-6.

20. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci 2016;17(1):14 doi: 10.3390/ijms17010014.

21. Agarwal VK, McHutchison JG, Hoofnagle JH; Drug-Induced Liver Injury Network. Important elements for the diagnosis of drug induced liver injury. Clin Gastroenterol Hepatol 2010; 8(5):463–70.

22. Fontana RJ, Seeff LB, Andrade RJ, Björnsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in drug induced liver injury: summary of a clinical research workshop. Hepatology 2010; 52:730-42.

23. Teschke R, Eickhoff A, Brown AC, Neuman MG, Schulze J. Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support. Int J Mol Sci 2019;21(1):212. doi:10.3390/ijms21010212

24. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-45. doi: 10.1016/0016-5085(89)90081-4.

25. Verma S, Kaplowitz N. Diagnosis, management, and prevention of drug- inducedliver injury.Gut2009;58:1555-64.

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Srivastava: Varied clinical presentations of OCD

The varied clinical presentations of obsessive compulsive disorder: Phenomenological overlaps with psychosis

Ashish Srivastava1


Obsessive-compulsive disorder (OCD) has been phenomenologically considered to be a heterogeneous psychiatric condition. Overlaps have been reported between OCD and psychotic disorders in various dimensions including biological and phenomenological. However, the underlying mechanisms for the association between OCD and psychotic disorders remain unclear to date. The differentiation between OCD and psychotic disorders can be difficult and poses a diagnostic challenge. The various aspects where overlap is noted need to be better understood. It appears that OCD and psychotic disorders are integrally related to each other and form a more complex syndrome.


Mr. Y.S., 23 year old male, presented to the outpatient department of a tertiary care psychiatry hospital with complaints of spending significant hours in a day in arranging and rearranging his personal items like books, files, clothes, etc. in a particular way. He was also reported to be smiling to self and said that he would get “vibes” from aliens. Mr. Y.S. reported that around 3 to 4 years back his friends had made fun of him, blamed him of sharing their secrets with others outside their group and ousted him from the group. Few weeks thereafter he started having repeated and intrusive thoughts of keeping his personal belongings in an orderly way and he would spend around one and half to two hours every day in doing so. He feared that if he did not do so some unwanted trouble would hurt him and his family though he admitted that those were his own thoughts and that he found them excessive and irrational. He also said that he would get “vibes” from aliens through some kind of special rays that reached his head and tongue. He could not state clearly whether these “vibes” were thoughts or experiences. He further stated that

1 Consultant Psychiatrist, Institute of Psychiatry and Human Behavior, Goa


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Srivastava: Varied clinical presentations of OCD

these “vibes” had no connection with the repeated and intrusive thoughts of arranging his things. On childhood history, some schizoid traits were elicited in him. No history of substance use or history suggestive of mood disorder was elicited in him. Diagnosis of OCD was made with a plan to watch for more psychotic symptoms. He was started on Sertraline, which was titrated up to 200 mg per day with poor response over three months. He was then tried on Escilatopram up to 40 mg per day for the next three to four months, again with a poor to minimal response. He was found to be more isolated socially. Then his diagnosis was reviewed to OCD with Psychosis NOS and he was put on Escilatopram 40 mg per day along with Risperidone titrated up to 3 mg per day. He showed partial improvement in his obsessive-compulsive symptoms and did not report “vibes” anymore. The psychiatrist added CBT (ERP) to his treatment protocol and over the next 3 to 4 months significant reduction of obsessive-compulsive symptoms was noted. However, he continued to show social isolation.


Obsessive-compulsive disorder (OCD) has been phenomenologically considered to be a heterogeneous psychiatric condition with subgroups having varied underlying biological mechanismslike early onset, tics related, with poor insight, etc. Now, DSM-V has specifiers for OCD based on insight as good or fair insight, poor insight, or absent insight (delusional OCD beliefs).Biological and phenomenological overlaps have been reported between OCD and psychotic disorders and this co- occurrence has been recognized since a long time in the history of psychiatric disorders. The differentiation between OCD and schizophrenia spectrum disorders can be difficult and poses a diagnostic challenge. Ten to fifteen percent of patients of schizophrenia are found to have OCD and up to fifty percent can have some OC symptoms (OCS)1-4,6 and up to a quarter of OCD patients show psychotic symptoms.5,6

Exploring the differentiation

Based on the scientific evidence so far, complex interactions seem to occur between OCD and psychotic spectrum disorders. Increased rates of OCD are consistently reported in patients with psychotic disorders specially schizophrenia. In OCD patients withsub-threshold or attenuated psychotic symptoms,an additional comorbid diagnosis of possibly prodromal syndrome of schizophrenia should be kept in mind. There are no biological markers to differentiate between the two syndromes. However, the probable answer can be drawn from the detailed

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Srivastava: Varied clinical presentations of OCD

phenomenology of the whole process and the evolution of symptoms. This is indeed important not only to have a right diagnosis but this also influences the treatment module as current medications available for either of the disorders may worsen the symptoms of the other for instance antipsychotics related worsening or exacerbation of OC symptoms (OCS). It also has prognostic implications for example schizophrenia with comorbid OCD or OCS has poor prognosis and higher risk of depression and suicide. Similarly, in OCD patients, presence of psychotic symptoms or poor insight implies poor prognosis when compared to only OCD diagnosis.

Schizotypal symptoms and OCD

Schizotypal symptoms along with OCD have been frequently reported and published in literature and often referred to as “schizotypal OCD”.7-9 When compared to depression, patients with OCD reported more often symptoms of schizotypal disorder.10 Schizotypal disorder shares common neurobiological and phenomenological basis with schizophrenia and has been seen to aggregate in OCD patients excessively. This combination or comorbidity displays a more severe, disabling, and deteriorative illness course. This subgroup seems to score poorer on insight and cognition and higher on SANS (Scale for the Assessment of Negative Symptoms) and GAF (Global Assessment of Functioning scale).11 Poor response to treatment is also noted in this subgroup. In addition, this subgroup also predicts higher genetic loading and more significantly at least one first-degree relative which schizophrenia is found in this subgroup.7 There also appears to be some association between OCD with schizotypal or psychotic symptoms and symptom severity.9 With increasing severity of the disorder (OCD), the symptoms of schizotypal disorder or psychotic symptoms are more frequently found in OCD. OCD with poor insight represents a subtype with ego-syntonic symptoms, which may extend to delusions.

Phenomenological differences between OCS and Delusions

Obsessions many a times involve unrealistic fear but they are not fixed, unshakable, and false belief systems unlike delusional thinking. A recurrent intrusive thought that may be ego-dystoniceven then not be considered as an obsession if it exists exclusively around delusional themes. Obsessive slowness seen in some OCD patients may be at times mistaken for prodromal symptoms of psychosis and this fact needs to be kept in mind and observed for longitudinally. Periodic assessments often are helpful.17 The OCD symptoms may appear bizarre at times but the patient recognizes them as excessive and irrational. Compulsions in OCD patients are never

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Srivastava: Varied clinical presentations of OCD

gratifying or pleasurable though they may relieve anxiety, unlike eating and sexual disorders. The distinction between primary and secondary compulsions (secondary to delusional or psychotic thinking) aids in differential diagnosis of OCD versus psychosis. A repetitive act should be considered a compulsion if it is seen in response to an obsessional thought and not secondary to delusional thinking for example paranoia leading to frequent checking. Mayer Gross has done seminal work on boundaries of obsessions, delusions and overvalued ideas that has been further reviewed by Kozak and Foa.[12] A shift from obsessional to delusional thinking is elicited in patients with OCD when the internal resistance and insight into obsessions is lost, which is often precipitated by stressful life events.13,14 Once again, this phenomenon is significantly more evident in patients with comorbid schizotypal disorder.13 This shift from obsessional to delusional thinking may also arise from disturbances of affect- the guilt associated with obsessive thinking or a compulsive act translates into persecutory delusions. It becomes difficult to discern whether psychotic features are a part of OCD or a syndromal component of the coexisting depression.

Some aspects of phenotype and timeline of evolution of symptoms come to the help of an astute clinician or professional. In both OCD and psychotic disorders, sub- syndromal symptoms frequently start in adolescence. However, if psychotic symptoms appear or become more evident after starting treatment for OCD especially SSRI drugs, it could likely be medication related. Conversely, if OCS start soon after treatment with antipsychotics, probably the OC symptom is antipsychotic induced. The content and type of thought distortions in OCD and psychotic disorders could also be helpful in distinguishing obsessions and delusional thinking. Obsessions are rarely unaccompanied by repetitive behaviors or compulsions (only in about two percent of OCD patients pure obsessions are seen)15 and content of obsessions are characteristically under the themes of contamination, symmetry, aggressive/sexual/religious impulses.16 In comparison, the content of delusions most notably are persecution, reference, grandiose or erotomanic and a similar pattern is seen in overvalued ideas especially in prodromal or attenuated psychotic symptoms stage.17 Bizarreness in thinking is seen more often in psychosis and rarely in OCD. However, it is often difficult to define what is bizarre across different cultures. Somatic and religious themes are common in both disorders. However, again bizarreness or loss of control is more characteristic of somatic delusional thinking and in terms of religious themes, obsessions of OCD have content related to blasphemy or sacrilege where as grandiose religious delusions are seen in psychotic

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Srivastava: Varied clinical presentations of OCD

disorders. The challenge with above distinctions is when they occur during prodromal stages or residual stages of the disorder. Repetitive behaviors in psychotic illness are usually independent of thought content where as these (compulsions) are subsequent to obsessions in OCD (except in one to two percent of OCD patients).15

People with marked obsessional traits are prone for decompensation into depression and specially depersonalization which many a times may mimic psychosis or a psychotic phenomenon. The threatening obsessive thinking leads to helpless state which may in turn lead to feelings of incompleteness, disgust and depersonalization. In patients with subtle psychotic symptoms with no hallucinations or disorganized speech/ behaviors, it becomes a very difficult task to differentiate psychotic beliefs and repetitive behaviors from obsessions of OCD with poor or lacking insight.[15] The overvalued ideas (yet not delusional thinking) are commonly elicited in patients with OCD and may confuse even a trained professional, especially in adolescents and young patients and at the start of OCD phenomenology.12 The terminology like “obsessive psychosis” or “delusional OCD” makes differentiation more difficult.18

Functional dysfunction is common in both disorders. However, it is more coarse or intense/ severe in psychosis and manifest during early stages of the illness and is considered a core symptom of psychosis in DSM. Negative symptoms like loss of effect, avolition, alogia, and lack of interpersonal relatedness are prominent symptoms of psychosis but rarely seen in OCD unless patients have comorbid moderate to severe depressive symptoms. Heritability is noted significantly in both, psychotic disorders and OCD but they do not appear to coseggregate. The patients of schizophrenia have more first-degree relatives with schizophrenia or psychosis and similarly patients with OCD have more family members with history of OCD or OC spectrum disorders though some evidence exists to contrary that increased diagnosis of schizophrenia is reported in offsprings of patients with OCD.

Many at times both diagnosis of OCD and psychosis need to be considered as in the case of Mr. Y.S. mentioned at the beginning of this article. Mr. Y.S. had few psychotic symptoms and clearly symptoms of OCD into which he had insight. Hence, the criteria of both disorders are met simultaneously and none of the two symptom syndromes are related to medications received. Therefore, in this case diagnosis of schizo-obsessive disorder would be appropriate. Once again, the dilemma arises when psychotic symptoms are attenuated or sub threshold or are not characteristic of schizophrenic phenomenology.13

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Srivastava: Varied clinical presentations of OCD

The underlying mechanisms for this non-chance association between OCD and psychotic disorders have been unclear to date. Patients with comorbid OCD and psychosis are more likely to report to the mental health professional and seek treatment than those with either of the disorders. Treatment of one causes increase in symptoms of the other disorder. Still both, when comorbid, require separate/ specific treatment for each symptom syndrome. One disorder’s symptoms can be seen as prodromal symptoms of the other. In view of the above observations, it appears that OCD and psychotic disorders are intrinsically related to each other and form a tangled syndrome.19


Today, there is extensive research available on OCD and psychotic disorders but the relationship between the two disorders still remains unclear to a large extent. At times, it is difficult to distinguish an obsession from a delusion despite all the distinctions in the natural course of disorders, phenomenology and treatment responses. The present clinical evidence available suggests that obsessive- compulsive symptoms in psychotic disorders specially schizophrenia spectrum disorders are more than just an expression or stage related symptoms of the ongoing psychotic process. However, careful study of phenomenology of the syndrome often is helpful.

It remains to be further evaluated whether OCS phenomenology is a part of psychosis or OC symptoms are a part of prodrome of psychosis or they are antipsychotic induced symptoms or they occur as two comorbid disorders. Conversely, is the psychotic phenomenon occurring in OCD patients a subtype of OCD (delusional or poor insight OCD) or does severe OCD with depressive symptomatology make the psychosis to be there or could it rarely be SSRI induced psychotic symptoms – they remain possibilities!!


1. Fabisch K, Fabisch H, Langs G, Huber HP, Zapotoczky HG. Incidence of obsessive–compulsive phenomena in the course of acute schizophrenia and schizoaffective disorder. Eur Psychiatry 2001;16(6):336-41.

2. Poyurovsky MD, Fuchs C, Weizman A. Obsessive–compulsive disorder in patients with first-episode schizophrenia. Am J Psychiatry 1999;156(12):1998-2000.

3. Ohta M, Kokai M, Morita Y. Features of obsessive–compulsive disorder in

patients primarily diagnosed with schizophrenia. Psychiatry Clin Neurosci 2003;57(1):67-74.

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Srivastava: Varied clinical presentations of OCD

4. Nechmad A, Ratzoni G, Poyurovsky M, Meged S, Avidan G, Fuchs C, et al. Obsessive–compulsive disorder in adolescent schizophrenia patients. Am J Psychiatry 2003;160(5):1002-4.

5. De Haan L, Dudek-Hodge C, Verhoeven Y, Denys D. Prevalence of psychotic disorders in patients with obsessive- compulsive disorder. CNS Spectr 2009;14:415–17.

6. 6.Anne Katrin Külz, Ulrich Voderholzer. Comorbid Psychiatric Disorders in Obsessive-Compulsive Disorder: The Spectrum Concept. In: De Haan L, Schirmbeck F, Zink M, editors. Obsessive-compulsive symptoms in schizophrenia. Springer, Cham; 2015,p.11-29.



9. Poyurovsky M. Obsessive-compulsive disorder with schizotypal personality disorder (schizotypal OCD). In: De Haan L, Schirmbeck F, Zink M editors. Obsessive-compulsive symptoms in schizophrenia. Springer, Cham; 2015,p.63-76.



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15. 15. Rodriguez CI, Corcoran C, Simpson HB. Diagnosis and Treatment of a Patient With Both Psychotic and Obsessive-Compulsive Symptoms. Am J Psychiatry 2010; 167:754-61.

16. 16. Bloch MH, Landeros-Weisenberger A, Rosario MC, Petenger C, Leckman JF. Meta-analysis of the symptom structure of obsessive-compulsive disorder. Am J Psychiatry 2008;165:1532-42.

Poyurovsky M, Faragian S, Pashinian A, Heidrach L, Fuchs C, Weizman R, et

al. Clinical characteristics of schizotypal-related obsessive-compulsive disorder.

Psychiatry Res 2008;159(1–2):254–8.

Sobin C, Blundell ML, Weiller F, Gavigan C, Haiman C, Karayiorgou M.

Evidence of a schizotypy subtype in OCD. J Psychiatr Res 2000;34(1):15–24.

Rossi A, Daneluzzo E. Schizotypal dimensions in normals and schizophrenic

patients- a comparison with other clinical samples. Schizophr Res 2002;54(1–


11. Rasmussen AR, Nordgaard J, Parnas J. Schizophrenia spectrum

psychopathology in obsessive-compulsive disorder: an empirical study.

European Archives of Psychiatry and Clinical Neurosciences 2020;270:993-1002.

12. Kozak MJ, Foa EB. Obsessions, overvalued ideas, and delusions in

obsessive-compulsive disorder. Behav Res Ther 1994;32(3):343–53.

13. Avasthi A, Kumar D. Phenomenology of Obsessive Compulsive Disorder.

JK Science 2004;6(1):9-14.

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disorder with psychotic features: a phenomenological study.Hong Kong

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17. 17. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM IV-TR). Washington DC, American Psychiatric Association, 1994.

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Br J Psychiatry

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O’Dwyer AM, Marks I. Obsessive–compulsive disorder and delusions



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Pabbathi: Hypoactive delirium in ICCU

How to pick up hypoactive delirium

Lokeswara Reddy Pabbathi1


Delirium has been defined as a syndrome characterised by disturbance in attention and awareness along with cognitive disturbances which develop over a short period of time (hours to days) and tends to fluctuate in severity during the course of the day.1

Types of Delirium

Delirium, based on the psychomotor activity levels, is divided into hyperactive, hypoactive and mixed subtypes.2,3

Hyperactive delirium

It is characterised by hypervigilance, restlessness, fast or loud speech, anger or irritability, combativeness, impatience, uncooperativeness, swearing, singing, laughing, euphoria, wandering, easy startling, distractibility, nightmares, persistent thoughts.

Hypoactive delirium

It is characterised by unawareness, decreased alertness, sparse or slow speech, lethargy, decreased motor activity, staring, apathy.

Mixed delirium

Both the symptoms of hyperactive and hypoactive are present in the past 24 hours.

Epidemiologyof Hypoactive Delirium

The prevalence of delirium varies across different settings ranging from 11-14% in general hospitals, about 14% in care homes, 10-11% in emergency departments and in about 45% of community elderly population within 1 month after discharge from the hospital after being diagnosed and treated for delirium.4-8When the question of how common the hypoactive delirium arise, the available data suggest that Hypoactive delirium is 56-92% in cardiac surgery patients, 7-30% of Consultation liaison psychiatry services, 12-41% of hip fracture patients,20-53% in palliative care settings, 36-100% of intensive care unit.3,8

1 Associate Professor, Guntur Medical College, Guntur, Andhra Pradesh


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Pabbathi: Hypoactive delirium in ICCU

When it comes to the detection rates of delirium in general

Risk Factors Associted with Hypoactive Delirium

Though all the factors associated with development of delirium can result in hypoactive delirium, but few factors like metabolic disturbances, organ failure, prior cognitive impairment, dehydration, increasing age are more likely to present with hypoactive delirium.3,5

Detection of Hypoactive Delirium

Need for early detection: The prognostic significance of hypoactive delirium was studied and was found that it was an independent predictor for prolonged mechanical ventilation and stay in the hospital in cardiosurgery patients.9In critically ill patients; many studies have reported higher mortality, worse functional outcomes ad worse quality of life in long-term.10-14

The higher level of mortality and morbidity would be due to late presentation and late diagnosis of hypoactive delirium and these poorer outcomes can be minimised and improve outcomes by early identification of cases, including identification of those at high risk and addressing the causes of delirium.4,15

Difficulties in detection: In one study, about 75% of the cases of delirium were missed by the admitting teams in acute medical admissions in a total of 805 consecutive admissions.16The hypoactive delirium patients can be missed because those who are docile and not disruptive may not come to the attention of care providers. In one observationalstudy of 67 elderly inpatients consecutively referredto a psychiatric consultation service with suspected depression,42% were found to be delirious.4,17

There are various reasons why hypoactive delirium can be missed: 4, 18-19

1. Nature of the condition: A withdrawn person is less likely to alert a health care provider, as the condition fluctuates, and period of near-normality can coincide with a clinical assessment.

2. The nature of health care system: A lack of continuity of care, poor access to previous treatment records and delayed assessment due to poor triage system.

3. Misunderstandings among the care providers: It is normal for elderly to be

forgetful or disoriented, hyperactive symptoms are necessary for diagnosis of

delirium, patients may be offended by testing their cognition.

4. The population at risk factors, like the elderly are likely to be isolated.

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Pabbathi: Hypoactive delirium in ICCU

Measures to improve the detection of hypoactive delirium:

 The NICE guidelines on delirium, recommends the identification of risk factors associated with the development of hypoactive delirium before further assessing for fluctuations in behaviour. 20Many elderly patients with delirium presented with hypoactive delirium.

 To ensure that history taking includes information about medication use, the presence of co-morbid conditions, and any alcohol or other illicit drug usage. 4

 DSM-5 (Diagnostic and statistical manual of mental disorders, fifth edition)

criteria for delirium gives a stepwise approach to diagnose delirium. 21

 The 4A’s test (4AT): It consists of four items (Alertness, cognition, attention and acute changes in fluctuations) with 90% sensitivity and specificity in screening for delirium. It has advantages in ease of administration, rapid screening without requiring specific training and ability to assess patients with hypoactive

delirium. 4,22

 Nursing Delirium Screening Checklist (NuDESC): It assesses patients on five

dimensions (Disorientation, inappropriate behaviour, inappropriate communication, illusions or hallucinations and psychomotor retardation), has about 86% sensitivity and specificity and can be administered by nurses.4, 22

 4AT and NuDEC are recommended in a systematic review due to their validity in hypoactive patients and their suitability for incorporation into busy clinical practice without specific training.

 In each acutely unwell patient, the approach needs to be “is there a delirium?” with the use of an appropriate screening tool for early detection and better management to improve outcomes for patients.


1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. (fifth edition). DSM-5. 2013.

2. Liptzin B, Levkoff SE: An empirical study of delirium subtypes. Br J Psychiatry 1992;161:843-5.



5. Siddiqi N, House AO, Holmes JD. Occurrence and outcome of delirium in

medical in-patients: a systematic literature review. Age Ageing 2006;35:350-64.


Meagher DJ, O’Hanlon D, O’Mahony E, Casey PR, Trzepacz PT. Relationship

between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin

Neurosci 2000;12(1):51-6.

Hosker C, Ward D. Hypoactive delirium. BMJ 2017 25;357:j2047.

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Pabbathi: Hypoactive delirium in ICCU

6. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014;383:911-22.

7. National Institute for Health and Care Excellence. Delirium: prevention, diagnosis and management (clinical guideline 103). 2010. Available from: uk/Guidance/CG103


9. et al. Hypoactive delirium after cardiac surgery as an independent risk factor for prolonged mechanical ventilation. 2011;25(6):968–74.

10. 11.




15. Siddiqi N, Harrison JK, Clegg A, et al. Interventions for preventing delirium inhospitalised non-ICU patients. Cochrane Database Syst Rev 2016;3:CD005563.

16. Collins N, Blanchard MR, Tookman A, Sampson EL. Detection of delirium in the acute hospital. Age Ageing 2010;39:131-5.

17. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill elderly patients. Arch Intern Med 1995;155:2459-64

18. Meagher D, Leonard M. The active management of delirium: improving detection and treatment. Adv Psychiatr Treat 2008; 14:292-301.


Peritogiannis V, Bolosi M, Lixouriotis C, Rizos DV. Recent Insights on

Prevalence and Correlations of Hypoactive Delirium. Behavioural neurology


Stransky M, Schmidt C, Ganslmeier P, Grossmann E, Haneya A, Moritz S,

J Cardiothorac Vasc Anesth

Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M. Motor subtypes of

postoperative delirium in older adults. Archives of surgery 2011;146(3):295-300.

Van den Boogaard M, Schoonhoven L, Van der Hoeven JG, Van Achterberg T,

Pickkers P. Incidence and short-term consequences of delirium in critically ill

patients: a prospective observational cohort study. International journal of

nursing studies 2012;49(7):775-83.

van den Boogaard M, Schoonhoven L, Evers AW, van der Hoeven JG, van

Achterberg T, Pickkers P. Delirium in critically ill patients: impact on long-

term health-related quality of life and cognitive functioning. Critical Care

Medicine 2012;40(1):112-8.

Sharma A, Malhotra S, Grover S, Jindal SK. Incidence, prevalence, risk factor

and outcome of delirium in intensive care unit: a study from India. General

hospital psychiatry 2012;34(6):639-46.

Naidech AM, Beaumont JL, Rosenberg NF, Maas MB, Kosteva AR, Ault ML,

Cella D, Ely EW. Intracerebral hemorrhage and delirium symptoms. Length

of stay, function, and quality of life in a 114-patient cohort. American journal

of respiratory and critical care medicine 2013;188(11):1331-7.

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Pabbathi: Hypoactive delirium in ICCU

19. Stephens J. Assessment and management of delirium in primary care. Prog Neurol Psychiatry 2015;19:4-5.

20.National Institute for Health and Care Excellence. Delirium: prevention, diagnosis and management (clinical guideline 103). 2010. Available from: uk/Guidance/CG103

21. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. (fifth edition). DSM-5. 2013.

22. De J, Wand AP. Delirium screening: a systematic review of delirium screening tools in hospitalized patients. Gerontologist 2015;55:1079-99.

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Sahu,Baliga & Subramanyam: High Functioning Autism

Adult high functioning autism: How to pick up the subtle shades

Samiksha Sahu1, Sachin Pradeep Baliga2, Alka Subramanyam3


Autism spectrum disorder is aneurodevelopmental disorder characterized by a wide range of impairment in areas of social interaction and communication, along with the presence of restricted/repetitive patterns of behavior. Almost three-fourth of these individuals suffer from some form of cognitive impairment or intellectual disability. However, the remaining subgroup, labeled as high functioning autism (HFA), demonstrates milder autistic symptoms and hasnormal cognitive ability or intelligence. HFA in adulthood frequently gets misdiagnosed as an atypical psychiatric disorder owing to its subtle presentation and poor awareness among clinicians. This article discusses such subtle abnormalities in HFA in adults observed not only in clinical presentation but also across various investigative modalities such as psychometric tests and imaging. Societal acceptance and better awareness among clinicians regarding the illness will go a long way in improving mental health outcomes not only for these individuals but also their families.



The word ‘autism’ was first introduced by Bleuler in relation to schizophrenia to imply detachment from reality. Later, Kanner, in the 1940s, introduced the syndrome of ‘early infantile autism’ in his paper on ‘Autistic disturbance of affective contact,’ where he described children who related better to objects than people, had autistic aloneness, echolalia, and pronoun reversal. Around the same time, Asperger described socially awkward boys having ‘autistic psychopathy,’ who showed difficulty in understanding the emotions/feelings of others and had narrow areas of interest, albeit being of normal intelligence.1 Currently, as per DSM-5 and ICD-11, the rubric of ‘autism spectrum disorder’ (ASD) is used to describe developmental disorders characterized by a wide range of impairment in areas of social interaction

1Fellow, CAMH, 2Assistant Professor, 3Associate Professor; Department of Psychiatry, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai


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Sahu,Baliga & Subramanyam: High Functioning Autism

and communication, along with the presence of restricted/repetitive patterns of behavior. Almost three-fourth of these individuals suffer from some form of intellectual disability. The label ‘High Functioning Autism’ (HFA), was first used by DeMyer, Hingtgen and Jackson in 1981 to specifically describe the subgroup of individuals with ASD who demonstrated milder symptoms and, importantly had normal intelligence.


Literature regarding the prevalence of HFA in adults is scarce. It is estimated that HFA occurs in less than 5 of 10,000 children.2 Since ASD is a lifelong condition, the same prevalence rates as that in children are generally considered even for adults.

Clinical Features

HFA is considered under the heading of ASD and, at present, is not a separate diagnostic entity. HFA is defined in individuals with autism whose full-scale IQ is > 70 and who do not have intellectual or language delays. They,however, do face some difficulty in domestic, school, occupational, or social functioning, but are generally able to maintain meaningful interpersonal relationships. Luke Y. Tsai has proposed diagnostic criteria for HFA based on the ICD-10 diagnosis of childhood autism. Taken into account the nonverbal IQ, language comprehension, social functioning and expressive language skills as assessed by standardized scales.3

Recognizing the Subtle Shades

A variety of autism detection models have been created independently using fMRI, EEG, speech and visual processing data in children and adolescents with autism with the help of machine learning approaches. Of these, fMRI-based models remain the most rigorously validated.4 However, such studies in adults with HFA are sparse. The following section covers a variety of approaches that have been specifically tried to detect subtle abnormalities in adults with HFA.

Clinical Presentation

Individuals with HFA exhibit a myriad of psychiatric symptoms which often get misdiagnosed. While HFA patients have good cognitive capacity, they face a lot of interpersonal problems due to their poor social competence. They are often perceived by others as rigid, complicated and odd who fail to understand the pragmatic aspect of language, leading to interpersonal misunderstandings and failures. These chronic problems often are a source of social withdrawal, depression, and anxiety. Their cognitive and behavioral stereotypies, along with a high need for

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Sahu,Baliga & Subramanyam: High Functioning Autism

rituals and routines, are often diagnosed as atypical OCD. Furthermore, bizarre idiosyncratic behaviors, emotional dysregulation and perceptual distortions in stressful situations are misdiagnosed as schizophrenia simplex. The typical autistic stress reaction with sensory overload, reduced pain sensitivity and self-injurious behavior as an attempt to regulate stress is often misdiagnosed as borderline personality disorder. A thorough history taking with specific focus on developmental symptoms of autism may lead to better diagnosis and understanding of atypical symptoms.5 Scales like Autism spectrum quotient (AQ) are easy to use and can be used to assess if a person lies on the autism spectrum.6

Social Cognition and Neurocognition

When compared to healthy individuals, adults with HFA have been found to demonstrate deficits in verbal and non-verbal theory of mind (ToM) and social perception. Since ToM largely depends on processes involved in perception, recognition and categorization of facial expressions, gestures, prosody and postures related to emotions, ToM deficits have been found to affect not only social interactions, but also moral reasoning.7,8. Research comparing social cognitive deficits in HFA with those in schizophrenia have shown mixed results.9,10

Adults with HFA show similar neurocognitive profiles to those with ADHD with verbal IQ (VIQ) being significantly higher than performance IQ (PIQ). However, adults with HFA tend to show superior verbal and acquired knowledge. Subsequently, the VIQ-PIQ difference is significantly higher in HFA as compared to ADHD. However, they score poorer on tests of visual perception and recognition as compared to those with ADHD.11 These findings however are not specific, and are also seen in individuals with Non Verbal learning Disability (NVLD).12


Based on mounting evidence regarding role of epigenetic mechanisms in the etiology of ASD in Paediatric age group, a candidate DNA methylation biomarker annotated to the PPP2R2C gene was recently identified in peripheral blood of adults with HFA.13 Such studies could pave a way for developing diagnostic biomarkers for adult HFA in future.


Intermittent rhythmic delta and theta activity (IRDA/IRTA) are considered as pathological EEG patterns with unknown significance. Increased rates of IRDA/ IRTA during hyperventilation (HV) have been shown in adults with HFA as compared to neurotypical individuals, with no differences in resting, pre or post-HV

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Sahu,Baliga & Subramanyam: High Functioning Autism

EEG rates.14 This IRDA/IRTA-HV- difference could be explored as a possible marker of relevant neuronal network instability, particularly in the background of a known link between ASD and EEG abnormalities and/or epilepsy.

Apart from this, individuals with ASD are known to have atypical visual processing as compared to neurotypical individuals, reflecting higher order differences in information processing. Using data obtained from eye-tracking, machine learning approaches have been successfully tried to detect HFA in adults with nearly 75% accuracy.4


Structural imaging studies have been largely inconsistent with some studies demonstrating decreased gray matter (GM) volumes in multiple regions, and others demonstrating regional increases in GM volumes along with local reductions in white matter (WM) volumes in adults with HFA. However, recent research focusing on abnormal functional connectivity (FC) patterns has helped to gain a better understanding of pathophysiology of HFA in adults. Local disruptions in the form of co-occurrence of spontaneous brain activity level and local functional connectivity have been observed in the occipital and temporal regions (especially the right fusiform gyrus and posterior middle temporal gyrus. These have been thought to underlie the social and communicative dysfunctions in adult HFA.15 Localized FC alterations in left and right insula, corresponding to sub-regions for emotional/ affective and auditory/sensory related functions respectively have also been demonstrated. These have been thought to underlie the emotional and sensory issues observed in autism.16

Some studies have specifically examined abnormalities in FC networks. Weaker integration in the resting state FC (rsFC) profile of default mode network (DMN) in transition-age males with HFA has been demonstrated. Moreover, a lack of segregation of DMN from regions belonging to the temporoparietal network has also been noted, and this has been found to correlate with the severity of autistic symptoms.17 Abnormal temporal structure in rsFC of salience network has also been shown with a relative predominance of slower over faster frequencies. This has been hypothesized to underlie the inflexible attitude and slow adaptation to unexpected changes noted in autistic individuals.18 Again, these changes are nonspecific and have been demonstrated across a variety of neurodevelopmental disorders.

Impact of HFA in Adulthood

It is seen in general that the psychosocial quality of life (QoL) of adults with HFA is

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Sahu,Baliga & Subramanyam: High Functioning Autism

lower than that of the neurotypical adult population. Presence of aggressive behaviors has particularly been shown to be associated with a poorer QoL while environmental factors, such as maternal support and early diagnosis have been associated with a better QoL.19

Considering that interpersonal and social skills form an important part of the workplace environment, it is understandable that adults with HFA experience higher rates of both unemployment and under-employment (working in an environment where one’s skills, knowledge and experience are not fully utilized). Even in those who achieve higher levels of academic achievement, a considerable proportion of individuals experience unemployment. Communication issues experienced at the workplace include difficulty in reading between the lines and a tendency to misunderstand and require additional clarification, leading to stress and anxiety at the workplace. While not exactly clear, it is likely that adult females with HFA experience more difficulties as compared to males.20

The primary caregivers of these individuals also experience stress and caregiver burden. Parents of adults with HFA continue to report high levels of worrying even as their child transitions into an adult. Their spouses, for those that progress into meaningful relationships, also report higher levels of tension, possibly as a consequence of absence of mutual reciprocal interaction. However, the severity of ASD symptoms recognized by the caregivers do not necessarily correlate with the level of burden they experience.21

Integration of Neurodiversity

In this era of diversity and acceptance, it becomes important that HFA also be looked at from a perspective of strength and variety rather than though the rigid negative lens of ‘mental illness.’ People with autism often struggle with social communication, but can excel in task requiring visual skills and routine. In many cases, they may have poor working memory but have good long-term memory. Hence, these individuals progress well in jobs like computer programming, computer animations and equipment design. Those who are good at math can pursue careers in Accounting, Statistics, Physics and Math.22

There is no direct co-relation between HFA and radicalization or anti-social behavior. However, people with HFA are more vulnerable towards victimization by extremists as they experience social isolation, naivety and are prone to develop fixation towards selective themes. As they may be aware that they have difficulty empathizing other’s perspective, they may not question the radical point of view or

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Sahu,Baliga & Subramanyam: High Functioning Autism

consequence of an action. Some lack abstract thinking and may not even question the nuances of extreme thinking, which again makes them prone towards becoming radicalized.23

In such a case, early diagnosis and social acceptance will go a long way towards improving general as well as mental health outcomes for these individuals.

Importance for Clinicians

Awareness among clinicians about subtle abnormalities in clinical presentation and investigational findings is paramount.


Take Home Message

 Presence of atypical symptoms in patients or atypical psychiatric diagnosis should be evaluated in depth to rule out High Functioning Autism (HFA) in adults.

 Recent research has shown subtle abnormalities in psychometric tests, EEG and fMRI studies.

 Early diagnosis of HFA will help in reducing the caregiver burden and improve healthcare outcome in these individuals.


1. Rinehart NJ, Bradshaw JL, Brereton AV, Tonge BJ. A clinical and neurobehavioral review of high- functioning autism and Asperger’s disorder. Aust N Z J Psychiatry. 2002;36(6):762-70

2. Gillberg C. Asperger syndrome and high-functioning autism. The British Journal of Psychiatry. 1998;172(3):200–9.

3. Tsai LY. Diagnostic Issues in High-Functioning Autism. In: Schopler E, Mesibov GB, editors. High-Functioning Individuals with Autism [Internet]. Boston, MA: Springer US; 1992 [cited 2021 Jul 24]. p. 11–40. Available from:

4. Yaneva V, Ha LA, Eraslan S, Yesilada Y, Mitkov R. Detecting High-Functioning Autism in Adults Using Eye Tracking and Machine Learning. IEEE Trans Neural Syst Rehabil Eng. 2020;28(6):1254–61.

5. Tebartz van Elst L, Pick M, Biscaldi M, Fangmeier T, Riedel A. High- functioning autism spectrum disorder as a basic disorder in adult psychiatry and psychotherapy: psychopathological presentation, clinical relevance and therapeutic concepts. Eur Arch Psychiatry Clin Neurosci. 2013;263 Suppl 2:S189-96.

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Sahu,Baliga & Subramanyam: High Functioning Autism

6. Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism- spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord. 2001;31(1):5–17.

7. Schaller UM, Biscaldi M, Fangmeier T, Tebartz van Elst L, Rauh R. Intuitive Moral Reasoning in High-Functioning Autism Spectrum Disorder: A Matter of Social Schemas? J Autism Dev Disord. 2019;49(5):1807–24.

8. Gleichgerrcht E, Torralva T, Rattazzi A, Marenco V, Roca M, Manes F. Selective impairment of cognitive empathy for moral judgment in adults with high functioning autism. Soc Cogn Affect Neurosci. 2013;8(7):780–8.

9. Veddum L, Pedersen HL, Landert A-SL, Bliksted V. Do patients with high- functioning autism have similar social cognitive deficits as patients with a chronic cause of schizophrenia? Nordic Journal of Psychiatry. 2019;73(1):44–50.

10. Chung YS, Barch D, Strube M. A Meta-Analysis of Mentalizing Impairments in Adults With Schizophrenia and Autism Spectrum Disorder. Schizophr Bull. 2014;40(3):602–16.

11. Kanai C, Hashimoto R, Itahashi T, Tani M, Yamada T, Ota H, et al. Cognitive profiles of adults with high-functioning autism spectrum disorder and those with attention-deficit/hyperactivity disorder based on the WAIS-III. Res Dev Disabil. 2017 Feb;61:108–15.

12. Fine JG, Semrud-Clikeman M, Bledsoe JC, Musielak KA. A critical review of the literature on NLD as a developmental disorder. Child Neuropsychology. 2013;19(2):190–223.

13. Kimura R, Nakata M, Funabiki Y, Suzuki S, Awaya T, Murai T, et al. An epigenetic biomarker for adult high-functioning autism spectrum disorder. Sci Rep. 2019;9(1):13662.

14. Endres D, Maier S, Feige B, Posielski NA, Nickel K, Ebert D, et al. Altered Intermittent Rhythmic Delta and Theta Activity in the lectroencephalographies of High Functioning Adult Patients with Autism Spectrum Disorder. Front Hum Neurosci. 2017;11:66.

15. Itahashi T, Yamada T, Watanabe H, Nakamura M, Ohta H, Kanai C, et al. Alterations of local spontaneous brain activity and connectivity in adults with high-functioning autism spectrum disorder. Mol Autism. 2015;6:30.

16. Yamada T, Itahashi T, Nakamura M, Watanabe H, Kuroda M, Ohta H, et al. Altered functional organization within the insular cortex in adult males with high-functioning autism spectrum disorder: evidence from connectivity-based parcellation. Mol Autism. 2016;7:41.

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Sahu,Baliga & Subramanyam: High Functioning Autism

17. Joshi G, Arnold Anteraper S, Patil KR, Semwal M, Goldin RL, Furtak SL, et al. Integration and Segregation of Default Mode Network Resting-State Functional Connectivity in Transition-Age Males with High-Functioning Autism Spectrum Disorder: A Proof-of-Concept Study. Brain Connectivity. 2017;7(9):558–73.

18. Damiani S, Scalabrini A, Gomez-Pilar J, Brondino N, Northoff G. Increased scale-free dynamics in salience network in adult high-functioning autism. NeuroImage: Clinical. 2019;21:101634.

19. Kamio Y, Inada N, Koyama T. A nationwide survey on quality of life and associated factors of adults with high-functioning autism spectrum disorders. Autism. 2013;17(1):15–26.

20. Hayward SM, McVilly KR, Stokes MA. Challenges for females with high functioning autism in the workplace: a systematic review. Disabil Rehabil. 2018;40(3):249–58.

21. Grootscholten IAC, van Wijngaarden B, Kan CC. High Functioning Autism Spectrum Disorders in Adults: Consequences for Primary Caregivers Compared to Schizophrenia and Depression. J Autism Dev Disord. 2018;48(6):1920–31.

22. USA (November, 1999) TG Ph D Assistant Professor Colorado State University Fort Collins, CO 80523. Choosing the Right Job for People with Autism or Asperger’s Syndrome: Articles: Indiana Resource Center for Autism: Indiana University Bloomington [Internet]. Indiana Resource Center for Autism. [cited 2021 Aug 13]. Available from: choosing-the-right-job-for-people-with-autism-or-aspergers-syndrome.html

23. Parental guidance – Safeguarding young people with Autistic Spectrum Conditions from extremist ideologies. [cited 2021 Aug 13] Available from: e_with_autism.pdf

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Majumder: conversion disorder


Conversion disorder: how clinictians can tackle varied presentations ?

Udayan Majumder1


Conversion disorder or conversion reaction is an acute and temporary loss or alternation of motor & sensory function that is almost incompatible with known medical or neurological conditions. It is generally characterized by the occurrence of certain signs or symptoms that are clearly inconsistent with what is known about anatomy and pathophysiology. Management of patients with conversion disorder overlaps both the neuromedicine and neuropsychiatry specialties. Sometimes it might lead a substantial gap in care.

Recent decades have seen considerable research of neuropsychology and brain imaging that have led us to get a relativelysophisticated picture of the scientific psychopathology of complexities of conversion disorder. Predominantly consistent pattern of hypoactivation in brain regions linked to the specific conversion symptoms, accompanied by primary activations in limbic, paralimbic, and basal ganglia and allied areas of brain. Apart from medications which many experts claim to have no major role in every case, cognitive-behavioral therapy looks promising as the psychological treatment of choice.


Conversion disorder, which is also known as functional neurological symptom disorder, is defined as a psychiatric illness in which symptoms and signs affecting voluntary motor or sensory function cannot be explained by a neurological or general medical condition.1Psychological factors, such as conflicts or stress, are judged to be associated with the deficits.2,3 The term conversion disorder was coined by Sigmund Freud, who hypothesized that the occurrence of certain symptoms not explained by organic diseases reflect unconscious conflict.3 The word conversion refers to the substitution of a somatic symptom for a repressed idea.3,4

Usual presentations of conversion symptoms that physicians or psychiatrist come across are blindness, paralysis, dystonia, psychogenic nonepileptic seizures (PNES), anesthesia, swallowing difficulties, motor tics, difficulty walking & anesthesia.5

1 Consultant Psychiatrist, Modern Psychiatric Hospital & De-Addiction Centre, Agartala Different Strokes


Majumder: conversion disorder

Despite the lack of a definitive organic diagnosis, the patient’s distress is veryreal and the physical symptoms the patient is experiencing cannot be controlled at will. 6 Latest and emerging concepts, theories and advanced imaging techniques have led to an more precise and comprehensive idea of involvement of CNS in generation of conversion symptoms.


Epidemiology of Conversion disorder in worldwide literature is varied and limited. Its has been estimated thatthe prevalence of such disorder is <1% in the general population, 5-14% in patients referred from medical/surgical specialties to psychiatry, and 5-25% in general psychiatry OPD. Conversion disorder is usually found more prevalent in females, though it may be found in children as young as 7-8 years of age. Although it is not very common after 35 years of age.1 Also, persons suffering from conversion disorder spend 9 times more on healthcare facilities compared to those who don’t have the disorder. In Indian setups, persons from rural areas, lack of education, lower socio-economic status, female sex, history of physical or sexual abuse are important socio-demographic factors leading to conversion disorders.7


Psychological factors: Faulty childhood learning is attributed to be one of the major factors for the development of conversion symptoms. Such learning of symptoms of illness to cope up with adverse and impossible situations from childhood leads to such disorder in adulthood. Some have hypothesized past physical or psychological trauma in childhood have a tendency to develop such symptoms in later life. 1,7

Psychoanalytic factors: Psychoanalytic theory of Freud postulate that symptoms are associated with a persons conflicts or recent stressors, when an unconscious conflict between a forbidden wish of the patient and his or her conscience ultimately leads to conversion disorder.1,7

Biological Factors: Recent neurophysiologic concepts claim that impaired cerebral hemispheric communications and excessive cortisol arousal that inhibit the individual’s awareness of bodily sensations. Subtle impairments on neuropsychological tests in conversion disorder patients also postulate involvement of CNS in generation of conversion symptoms. 1,7

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Signs & Symptoms



2.Paralysis 3.Swallowing difficulties 4. Inability to speak

5. Tremors


6. Dystonia

7. Paralysis

8. Syncope

9. Psychogenic non-epileptic seizures

Paralysis Patient looses half of the body or a single limb, but presentation of pasralysis doesn’t follow ususal anatomical apttern. Also, degree of paralysis is inconsistent on repreated examination. Hoover’s sign can be found positive

Psychogenic non-epileptic seizures




Ineffectiveness of multiple antiepileptic drugs & induced by stress or emotional upset. There are lack of physical injury, lack of headache or myalgias following convulsions & lack of incontinence. Sometimes paradoxical increase in seizures after AEDs.

Fainting attacks in absence of any identifiable autonomic problems like pallor, absence of any associated injury.

In functional deafness, the blink reflex to a loud and unexpected sound is present, thus demonstrating the intactness of the brain stem.

On asking to cough such as during auscultation of the lungs, in contrast with other aphonias, the cough is usually normal, full and loud.

Majumder: conversion disorder

1. A debilitating illness that begins suddenly

2. History of psychological problems that improve when symptoms of physical illness appear

3. Lack of concern that usually appears with a severe physical symptom

Distinguishing features of varied presentations of Conversion Disorder7-11

Tremors or psychogenic movement disorders

Abrupt onset of symptoms, character of movements atypical of recognized patterns and have inconsistent amplitude, frequency, and distribution. Characteristics of movements change over time, spontaneous remissions At time, movements disappear with distractions or increase with attention

Paraplegia No associated changes in deep tendon reflexes, rather found normal, Babinski normal. Demonstrating normal motor evoked potentials in doubtful cases can establish conversion symptoms.

Blindness Patient with functional deafness neither sustains injury while wandering around the office nor any expected bruises injury marks are found. The pupillary reflex is present, showing intactness of the optic nerve, chiasm, tract, lateral geniculate body.

Anaesthesia Functional anesthesia may occur anywhere, but it is most common on the extremities. Typical “glove and stocking” distribution might be seen sometimes, however, conversion anesthesia have a very precise and sharp boundary, often located at a joint.

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Majumder: conversion disorder

Diagnosis of Conversion Disorder

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), conversion disorder is characterized by the following:2

1. One or more symptoms of altered voluntary motor or sensory function

2. Clinical findings that show evidence of incompatibility between the

symptoms and recognized neurological or medical conditions

3. Symptoms or deficit that are not better explained by another medical or

mental disorder

4. Symptoms or deficit that cause clinically significant distress or impairment in

social, occupational, or other important areas of functioning or warrants medical evaluation

Differential Diagnosis

Differentiating the following four Psychiatric conditions are vital to stick to the diagnosis of conversion disorder or functional neurological symptom disorder: 7-11

1. Somatisation Disorder: In somatization disorder, a person experiences physical symptoms that are inconsistent with or cannot be fully explained by any underlying general medical or neurological condition.15 Preoccupation with these symptoms leads to excessive distress in the patient

2. Hypochondriasis: Also known as illness anxiety disorder in DSM-5, it is characterized by excessive preoccupancy or worry about having one (or more) serious physicalillnesses. This debilitating condition isthe result of an inaccurate perceptionof the condition of body or minddespite the absence of an actualmedical condition.16

3. Factitious disorder: Factitious disorder is a condition in which a person acts as if he or she has a physical or mental illness when he or she is not really sick and without an external gain. Factitious disorder is considered a mental illness because it is associated with severe emotional difficulties. People with factitious disorder deliberately create or exaggerate symptoms of an illness inseveral ways. 17

4. Malingering: Malingering is defined as intentionally feigning the symptoms of a physical, psychiatric, or neurological disorder in order to achieve personal or financial gain. The individual is fully aware that he or she is feigning the symptoms and has clear knowledge of why he or she is doing it. 18 Malingering is actually not a Psychiatric or mental disorder.

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Medical / Organic illness as differential diagnoses:7

1.Myasthenia gravis

(muscle weakness disorder)

2.Multiple sclerosis (blindness resulting from optic neuritis)

3.Periodic paralysis (muscle weakness)

Approach to the Patient12-14

4. Polymyositis (muscleweakness) 5. Stroke

6. Lupus

7. Spinal cord injury

Majumder: conversion disorder

Patients with conversion disorder are generally found less open to doctor than patients having definite neurological illness, the approach towards the patient should be very calculative and careful, as per understanding of the patient. Few steps could be useful, such as:

1. It is better not to inform the patient about the diagnosis on the first set up.

2. Reassuring the patient that the symptoms are real even if no definitive illness

could be established.

3. The patient should not feel that the clinician hasn’t found any wrong in him

or her.

4. Citing examples of socially acceptable diseases such as peptic ulcer disease or

hypertension which are often attributed to stress.

5. Trying to convince the patient that many a times subconscious influences

behavior like nail biting or foot tapping during anxiety.

6. Patients should be psycho-educated about the fact that, unlike many

neurological illness, such symptoms are potentially reversible and recovery

could be ful, as there is no structurally identifiable damage.

7. Explaining the patient that, accepting the diagnosisgenerally helps in further course of treatment, rather wandering what is the wrong going on or what

else are remaining to be found out.


1. Reassurance: Many patients with conversion disorder have an acute benign course and reit spontaneously with reassurance & brief psychotherapeutic intervention. Early diagnosis and intervention can avoid chronicity in such patients.

2. Hypnotherapy: One of the oldest method for treatment of conversion disorders. However, these are not widely supported by extensive research and in many time remains inconclusive because hypnotisability is often doesn’t predict treatment outcome.1


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Majumder: conversion disorder

3. Psychotherapy: Psychotherapy remains the mainstay of treatment of conversion disorders & usually aimed at dealing with the emotional root causes of symptoms. Psychotherapy can include individual or group therapy, behavioral therapy, biofeedback, relaxation therapy, couple therapy, etc. Cognitive-behavioral therapy (CBT) has shown the highest efficacy in the treatment of varied presentations of conversion symptoms, including pseudoseizures. Improving self-esteem, assertiveness skills, increasing the capacity to express emotions, different coping strategies, grounding techniques, improving the ability to communicate comfortably with others remain the objectives of behavioral modifications in such conditions.1,19

4. Physical therapy: Physical therapies are also found helpful, especially in patients with repeated and chronic conversion disorder. Iteffectively overcomes physical symptoms in many patients and is also helpful in avoiding secondary complications. Even in the absence of contractures, physical therapies help in restoring muscular symptoms and balance problems. 14

5. Pharmacological treatment: Pharmacological treatment ate most effective in co-morbid anxiety disorders, depression, phobias, and other behavioral problems. Medications may include Antidepressants, anxiolytics, hypnotics, scheduled doses of antipsychotics.20 Repeated follow-ups are necessary to avoid unnecessary tests & invasive diagnostic procedures.


Predictors of good prognosis in conversion disorders include sudden onset, brief duration, early identifiable stressors, good premorbid functioning, and absence of any comorbid psychiatric illness.


Conversion disorder is a condition where an unconscious or repressed mental or emotional stress is converted into physical symptoms, which are usually not better explained by known medical or neurological disorders. Presenting symptoms are real, and patients are not feigning the symptoms, and so it is not wise to label them as manipulative. Taking detail medical and psychiatric history, making a proper diagnosis and early arrangement for treatment remains cornerstone for management of conversion disorder. Therapeutic alliance with the patients is always a must for successful outcome.

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Majumder: conversion disorder


Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock’s Comprehensive

Textbook of Psychiatry. 10thed. New Delhi: Wolters Kluwer; 2017; pp1839-40.

2. American Psychiatric Association. DSM 5 development. Highlights of changes from DSM-IV-TR to DSM 5 [cited 2021 June 30]. Available from:

3. Ballmaier M, Schmidt R. Conversion disorder revisited. May 23, 2005. [cited 2021 June 30]. Available from:


4. Blitzstein S. Recognizing and conversion disorder. Virtual Mentor


5. Freud S. The neuro-psychoses of defense. In: Freud S, Strachey J, Freud A,

Institute of Psychoanalysis (eds). The Standard Edition of the Complete Psychological Works of Sigmund Freud. London: Hogarth Press and the Institute of Psycho-Analysis 1962:45–61.

6. Marshall S, Bienenfeld D. Conversion disorder. Medscape. Drugs and diseases.

June 26, 2013. [cited 2021 june 30]. Available from: le/287464-overview.

7. Ali S, Jabeen S, Pate R, Shahid M, Chinala S, Nathani M, Shah R. Conversion Disorder mind versus body: A review. Innov Clin Neurosci 2015;12(5-6):27-33.

8. Conversion disorder. [cited 2021 May 30]. Available from:

9. Ali S, Jabeen S, Arain A, et al. How to use your clinical judgment to screen for

and diagnose psychogenic nonepileptic seizures without video electroencephalogram. Innov Clin Neurosci2011; 8: 36–42.

10. Couprie W, Wijdicks E, Rooijmans H, et al. Outcome on conversion disorder: a follow up study. J Neurol Neurosurg Psychiatry1995;58:750–2.

11.Vuilleumier P, Chicherio C, Assal F, et al. Functional neuroanatomical correlates of hysterical sensorimotor loss. Brain 2001;124:1077–90.

12. Carson A, Best S, Postma K, et al. The outcome of neurology outpatients with medically unexplained symptoms: a prospective cohort study. J Neural Neurosurg Psychiatry 2003;74(7):897–900.

13. Stone J, Sharpe M, Dimsdale J. Conversion disorder in adults: treatment. Wolters Kluwers. Up to date. June 10, 2014. [cited 2021 June 30]. Available from:

14. Kaur J, Garnawat D, Ghimiray D, et al. Conversion disorder and physical therapy; Delhi Psychiatry J 2012;15:394–7.



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Majumder: conversion disorder

15. Spratt E, Pataki C. Somatoform disorders. Medscape. Drugs and diseases. March 4, 2014. [cited 2021 July 1]. Available from:

16. Avia M, Ruiz M. Recommendations for the treatment of hypochondriac patients. J ContempPsychother 2005;35:301–13.

17. WebMD. Mental health center. Factitious disorders. [cited 2021 june 30]. Available from:

18. Owens C, Dein S. Conversion disorder: the modern hysteria. Adv Psychiatr Treat 2006;12:152–7.

19. Ali S, Jabeen S, Arain A, et al. How to use your clinical judgment to screen for

and diagnose psychogenic nonepileptic seizures without video electroencephalogram. Innov Clin Neurosci 2011;8:36–42.

20.Stonnington C, Barry J, Fisher R. Conversion disorder. Am J Psychiatr 2006;163:1510–17.

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule


Why is clozapine an underutilized molecule in clinical practice?

Arghya Pal1, Nitu Mallik2, Rudraprasad Acharya3


Clozapine was discovered quite early, in 1958; but its usage was always fraught with controversy for its severe side effects. Currently clozapine’s efficacy and supremacy over other antipsychotics for treatment resistant schizophrenia and various other psychiatric conditions has been proved beyond doubt. Despite this, clozapine remained underused across high and low-income countries. Patients perceive the drug as problematic for its frequent hematological monitoring and disturbing side effects like constipation and sialorrhoea. On the other hand, lack of skillsets for proper clozapine use among clinicians has acted as a major deterrent against early initiation of clozapine. Lack of dedicated clozapine centers and other organizational issues also played a role. A simpler approach to monitor side effects, standardized protocol of use and proper training of health workers can solve the issue to a major extent.


The discovery of clozapine was arguably one of the most important discoveries regarding the management of schizophrenia in the last century. Clozapine was discovered in 1958, at a time when the world of psychopharmacology was into frantic research following the successful advent and approval of chlorpromazine. However, much unlike chlorpromazine, clozapine was initially snubbed, owing to two major reasons. One is the apparent lack of parkinsonian side-effects, which at that time was also believed as a proxy marker of antipsychotic potency. The second reason was the incidence of ‘severe blood disorders’ in 18 patients of Finnish sample

1Assistant Professor, Dept. of Psychiatry, All India Institute of Medical Sciences, Raebareli, India 2Resident Medical Officer cum Clinical Tutor, Department of Psychiatry, Medical College and

Hospital, Kolkata, India

3Resident Medical Officer cum Clinical Tutor, Department of Psychiatry, Medical College and

Hospital, Kolkata, India

Corresponding Author: Dr Arghya Pal, Assistant Professor, Department of Psychiatry All India Institute of Medical Sciences, Raebareli Email:


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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule

in 1975, including 9 fatalities.1 However, the scene started to change following certain organizational changes in the United States Food and Drug Administration (FDA) and the successful completion of the Sandoz-FDA study headed by Dr. John Kane in 1984 which presented solid evidence in favor of the antipsychotic property of clozapine.2 Subsequently clozapine finally re-entered the market in 1990 and gradually over years has become one of the most important components of our armory of antipsychotics.

Range of Therapeutic Role of Clozapine

In today’s practice, clozapine holds a very important position in psychopharmacology. Clozapine is considered to be most important anti-psychotic, particularly in those who had responded sub-optimally to other first or second generation antipsychotics.3 This position of clozapine is further confirmed from the results of large-scale studies like Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study (phase 2); Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 2) and the Schizophrenia Outpatient Health Outcomes (SOHO) study. Thus, to summarize, clozapine is considered to be superior than all other anti-psychotics in the treatment of treatment resistant schizophrenia. However, clozapine is also recommended for early use in young patients of psychosis, as the drug provides a substantially better chance for improvement, course stabilization and functional recovery.4 Other than this, clozapine has also been demonstrated to have the lowest mortality rates amongst all antipsychotics.5

Additionally, clozapine also plays an important role in management of other disorders like schizo-affective disorders, treatment resistant bipolar disorder, psychosis in context of Parkinson’s disease or Lewy Body Dementia and borderline personality disorder. Also, clozapine has been approved for treatment of suicidality by FDA and also plays critical role in management of aggression, psychogenic polydipsia and tardive dyskinesia.5

Problem Statement

Surprisingly, in spite of being such a unique molecule, the use of clozapine has been sub-optimal. The prescription patterns of clozapine have been shown to be diverse across the world. A study conducted in the high-income countries has confirmed that the Clozapine use is higher in centers like Finland, New Zealand, but conspicuously lower in countries like Japan 6. In addition, there is a diversity in the recommendations of hematological monitoring across the countries, the frequency of which have an inverse relation with clozapine prescription.7 However, both studies

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule

pointed out that clozapine under-use was prevalent across all the countries. In addition, it has been seen that prescription of clozapine is lower in ethnic minority groups as compared to others.8 It is speculated that the problem of under-use may be higher in low-income countries. The picture in India is also very similar. Studies have shown that clozapine prescription usually preceded by a trial of polypharmacy in at least one-fourth of the patients and there is a delay of about 2 years in clozapine initiation.9

Reasons for Underutilization of Clozapine

The reasons behind underutilization of clozapine have been a subject of close scrutiny amongst the researchers. The reasons could be classified as follows:

Barriers related to patients:

One of the major barriers that has repeatedly reported in studies is the reluctance of the patients to undergo blood tests. This has been reported in various studies surveying psychiatrists, health-care staff as well as patients.10 The other most common barrier reported by the patients is the concern of tolerating the drug. Complications like constipation, hypersalivation, neutropenia and myocarditis were often reported as offending factors for the patients as per a survey on health-care staff.11

Barriers related to clinician:

Many of the studies has shown that there is a delay in initiation of clozapine, particularly in patients who were above the age of 30 years. Additionally, patients who were previously on polypharmacy tended to be initiated on clozapine later 10. One of the major reason behind this phenomena has been the lack of adequate knowledge regarding the use of clozapine in healthcare workers 10. Studies have found that knowledge regarding the initiation of clozapine is lacking in a vast majority of consultants.12 Also, various consultants who underwent the survey declared that they had very few patients on clozapine and many could not successfully report the recommended dose of clozapine.13 Many of the consultants also displayed lack of confidence in handling the various drug-emergent side-effects. This is in spite of many of the consultants working in dedicated facilities for clozapine.

Most of the current guidelines recommend initiation of clozapine after unsuccessful trials of two antipsychotics. However, a study have found that vast majority of the clinicians tend to wait until unsuccessful trials of three antipsychotics.14 This study

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule

also found that the consultants rather preferred to try a combination of drugs rather than initiating clozapine. Additionally, another study reported that clinicians found it difficult to identify the right patients for starting clozapine.12 Patients who are considered to be candidate for clozapine are also tended to be looked as patients with poor medication adherence and likely to show resistance in complying to the instruction of regular follow-up and blood investigations.

Barriers related to health system:

A number of factors arising from the perspective of healthcare system have also been identified leading to underutilization of clozapine. These factors includes constraints of healthcare personnel to run dedicated clozapine centers, limited centers for obtaining samples for blood investigations and lack of intersectoral coordination across psychiatrists, pathologists, community health workers and other required collaborators.12

In a retrospective review conducted based on insurance claims, it was found that the chances of clozapine use was higher in countries with a higher density of psychiatrists and also with a history of higher use of clozapine.15 Lack of access to quality healthcare, poor motivation amongst stake-holders and complex paperwork were also identified as other contributors to underuse.16

To provide a solution to the current question, the National Association of State Mental Health Program Directors (NASMHPD) in the USA formed a working group to identify the major bottlenecks in use of clozapine. Other than many of the factors mentioned above, the group identified lack of standardised material for easy decision making and complex protocols as important obstacles. Additionally the group recommended early identification of benign ethnic neutropenia (BEN), to prevent side-effects from clozapine.17

The Way Forward

Since, clozapine underuse has been recognized to be a major problem in the management of psychosis, some amount of research has been invested in identifying the interventions in overcoming this issue. One of the most promising approach has been to implementing Point-of-care (POC) devices for the purpose of monitoring adverse effects. In a study comparing the subjective experiences of patients and practitioners towards traditional venous sampling versus a POC device using finger prick to obtain capillary blood to ascertain leucocyte counts, it was found that both the group of respondents appreciated POC device to be a preferable option.18

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule

A similar result was also obtained from another study which showed that POC device was a less painful and more convenient.19

Another step that was found to be beneficial was widespread educational endeavors like tools for decision-making, clinical grand rounds, internet-based programs, and scope for telephone consultations with experts. These measures when assessed using data from insurance claims showed that rates of initiation of clozapine increased significantly following these steps.20


It can be argued that clozapine is a unique molecule in the context of management of various psychotic and other disorders. It is one of the most potent antipsychotics and its adverse effect profile is very different from other antipsychotics. As a result, the use of clozapine is important to salvage very critical situations in clinical practice. But, in spite of that, clozapine continues to be ignored for very worthy patients. To solve this conundrum, fair amount of research has been done. But it can be safely said that the research in this respect has most been focused on various psychotic disorders only. As a result, the reasons of underuse in other disorders like affective disorders, psychosis in Parkinson’s disease etc. remain unknown. Additionally, existing reviews on this topic mentions that the quality of the evidence in this field is poor, due to lack of clinical trials and reliance on surveys and use of non-validated tools 10. Future studies in this regard should focus identifying the barriers of use of clozapine in other disorders and identifying clozapine should be seen as a priority area of research and use of clozapine should be increased for deserving patients.


Take Home Points

1. Clozapine is the drug of choice in treatment resistant schizophrenia.

2. It is recommended for early use in young patients of psychosis. Important role is

seen in treatment of schizoaffective disorder, psychosis in Parkinson’s disease,

borderline personality disorder, psychogenic polydipsia and tardive dyskinesia.

3. Low use is seen in both high- and low-income countries.

4. Various patient and physician factors stand barrier against early use of clozapine.

5. Improvement in knowledge about the use of the drug and ease of monitoring

systems is required for more frequent use of clozapine.

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule


1. Crilly J. The history of clozapine and its emergence in the US market: A review and analysis. History of Psychiatry 2007;18:39–60.

2. Kane J, Honigfeld G, Singer J, et al. Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine. Arch Gen Psychiatry 1988;45:789–96.

3. Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opinion on Pharmacotherapy 2012;13:1545–73.

4. Agid O, Arenovich T, Sajeev G, et al. An algorithm-based approach to first- episode schizophrenia: Response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011;72: 1439–44.



6. Bachmann CJ, Aagaard L, Bernardo M, et al. International trends in clozapine

use: a study in 17 countries. Acta Psychiatr Scand 2017; 136: 37–51.

7. Nielsen J, Young C, Ifteni P, et al. Worldwide differences in regulations of

clozapine use. CNS Drugs 2016;30:149–61.

8. Williams JC, Harowitz J, Glover J, et al. Systematic review of racial disparities

in clozapine prescribing. Schizophr Res 2020; 224: 11–8.

9. Grover S, Hazari N, Chakrabarti S, et al. Delay in initiation of clozapine: A

retrospective study from a tertiary care hospital in North India. Psychiatry Res

2015; 226:181–5.

10. Farooq S, Choudry A, Cohen D, et al. Barriers to using clozapine in treatment-

resistant schizophrenia: systematic review. BJPsych Bull 2019;43: 8–16.

11. Gee S, Vergunst F, Howes O, et al. Practitioner attitudes to clozapine initiation.

Acta Psychiatr Scand 2014;130:16–24.

12. Tungaraza TE, Farooq S. Clozapine prescribing in the UK: Views and

experience of consultant psychiatrists. Ther Adv Psychopharmacol 2015;5:88-96.


doi: 10.1186/1471-244X-4-12.

Clozapine underutilization: Addressing the barriers. National Association of

Avalable from:

State Mental Health Program Directors. 2016.

[cited 2021 June 13].


Love RC, Kelly DL, Freudenreich O, Sayer M, Sanders KM, McLean MF.

Apiquian R, Fresán A, De la Fuente-Sandoval C, Ulloa RE, Nicolini H. Survey

on schizophrenia treatment in Mexico: perception and antipsychotic

prescription patterns. BMC psychiatry. 2004;4(1):1-7.

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Pal, Mallik & Acharya: Clozaine an Umderutilized Molecule

14. Nielsen J, Dahm M, Lublin H, et al. Psychiatrists attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010;24:965–71.

15. Stroup TS, Gerhard T, Crystal S, et al. Geographic and clinical variation in Clozapine use in the United States. Psychiatr Serv 2014;65:186–92.

16. Gören JL, Rose AJ, Engle RL, et al. Organizational characteristics of veterans affairs clinics with high and low utilization of clozapine. Psychiatr Serv 2016;67:1189–96.

17. Kelly DL, Freudenreich O, Sayer MA, et al. Addressing barriers to clozapine underutilization: A national effort. In: Psychiatric Services. American Psychiatric Association, pp. 224–27.

18. Bogers JPAM, Bui H, Herruer M, et al. Capillary compared to venous blood sampling in clozapine treatment: Patients’ and healthcare practitioners’ experiences with a point-of-care device. Eur Neuropsychopharmacol 2015;25:319–24.

19. Nielsen J, Thode D, Stenager E, et al. Hematological clozapine monitoring with

a point-of-care device: A randomized cross-over trial. Eur Neuropsychopharmacol 2012;22:401–5.

20. Carruthers J, Radigan M, Erlich MD, et al. An initiative to improve clozapine prescribing in New York state. Psychiatr Serv 2016;67:369–71.

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics


Psychiatric adverse effects of antibiotics: What clinicians need to know?

Ranjan Bhattacharyya1, Kaustav Chakraborty2 Abstract

The term ‘Antibiomania’ has been described almost two decades back and commonly seen with cephalosoporins, cotrimoxazole and ofloxacin like drugs.. Manic symptoms are related to interference with GABAergic neurotransmission. Quinolones cross BBB (Blood Brain Barrier) and inhibits binding of GABA. INH inhibits GAD enzyme with catalyzes glutamate to GABA. Clarithromicin antagonizes GABA-A receptor leading to excitability.

Keywords: Antibioma, neurotoxicity, GABAergic neurotransmission, dose dependant, seizures, peripheral neuropathy


The Central nervous system (CNS) effects of Beta lactams, clarithromycin and fluroquinolones occur due to GABA-A antagonistic action. The CNS excitotoxicity can occur in a dose dependant manner by MAO inhibition, drug-drug interaction with reduced CYP2C 19 activity. More or less all antibiotics can have CNS adverse effects but with varying degree of severity. In most of the cases these CNS adverse effects are reversible. The term ‘Antibiomania’ has been described by Abouesh A et al. in 2002.1

Beta lactam antibiotics include penicillins, cephalosporins and carbapenems which causes CNS toxicity by GABA-A antagonism in a doe dependant manner. The beta lactam ring of these antibiotics is similar to GABA antagonist bicuculline.2

Antibiomania is commonly seen with antibiotics like clarithromycin ofloxacin cephalosporins. The CNS manifestations are related to GABAergic neurotransmission. Quinolones can cross BBB and binds with GABA. INH inhibits

1Associate Professor & Head, Department of Psychiatry, Murshidabad Medical College & Hospital. Director, Charak Square Diagnostic & Research Center, West Bengal, India

2Associate Professor & Head, Department of Psychiatry, College of Medicine & JNM Hospital, Kalyani, Nadia, India

Address of correspondence: 29, Anandasree, Garia, Near Boral TB Hospital, Kolkata-700084 Email:

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics

GAD enzyme which is responsible for catalyzation glutamate to GABA. Clarithromycin inhibits GABA-A receptor leading to excitability and thus clarithromycin, fluroquinolones beta-lactam antibiotics can cause antibiomania.3 The details of neurotoxic effects of antimicrobial agents have been summarized in table 1.

Table 1 Manifestations and mechanisms of neurotoxic effects of common antibiotic drugs



Ampicillin, Piperacillin/tazobactam are very notorious to cause neuropsychiatric adverse effects. The continuous infusion of piperacillin/tazobactam has shown to

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics

produce decrease level of consciousness, myoclonic jerks, hallucinatory behavoiours, prolonged sedation etc. The onset of piperacillin/tazobactam associated neurotoxicity is within seven days and renal impairment is an important risk factor. The risk of ampicillin induced neurotoxicity are low birth weight infants having more permeability of blood brain barrier.4


Cefepime and ceftazidime are most common cephalosporins which are responsible for nonconvulsive status epilepticus with altered sensorium. The myoclonus and altered consciousness are the two common manifestations of cefepime associated CNS toxicity. These neurotoxicity is aggravated in predisposed individual especially having renal impairment. 5


Carbapenems often show the seizure disorder because of the antagonism of the GABA receptor aggravated in patients having renal insufficiency, previous history of seizure disorder, CVA and advancing age. On the other hand Ertepenem has been associated with psychosis and neurotoxicity usually persists for 14 days. 6


Metronidazole can cause psychosis which is resolved within 14 days of discontinuation. This is being aggravated with concomitant use of Disulfiram, in presence of hepatic and renal insufficiency and supratherapeutic plasma levels of metronidazole. The cumulative exposure of metronidazole is more important than the single large dose. The neurotoxicity has been observed in the dose range 25-100 gm, however the seizures have been seen at a cumulative dose of more than 40 gms. Metronidazole induced encephalopathy presents with slow onset myoclonus, peripheral neuropathy, paresthesia, ataxia etc and metabolites of metronidazole inhibiting the vestibular and cerebellar symptoms are responsible for this. 7


Among the macrolide group of antibiotics, clarithromycin has been most commonly attributed to neurotoxicity and is responsible for delirium, psychosis with hallucinations (especially in patients suffering from End Stage Renal Diseases) and manic symptoms. The clarithromycin induced antibiomania has been described well in literature. Azithromycin has been reported to cause similar psychotic symptoms without any history of underlying psychiatric illnesses but with a milder intensity. The CNS manifestations of macrolides are mediated by GABA-A receptor agonism because of their potentiality to produce epileptogenic activity. The drug interaction

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics

may also have a role to play as both clarithromycin and erythromycin are CYP3A4 inhibitors.8


Fluroquinolones like macrolides are also responsible for neuropsychiatric symptoms (black box warning), the most common being delirium and psychosis by GABA antagonism and NMDA (N-methyl-d-aspartate) receptor mediated neurotoxicity. The common neuropsychiatric effects of fluoroquinolones are headache, insomnia, dizziness, nervousness, confusion, excitability etc. The severe neuropsychiatric adverse effects are antibiomania, delirium, seizure, acute psychosis with hallucination. The NSAIDS if used with fluroquinolones the chance of neurotoxicity increases especially in elderly subjects.9


Linezolid and tedizolid are oxazolidinone class of antibiotics and are used for vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus infections. Linezolid inhibits MAO enzyme which is responsible for metabolism of monoamines (dopamine, serotonin, noradrenaline). The tyramine containing food and coadministration with other serotonergic medications are avoided due to risk of hypertensive crisis and serotonergic syndrome. Tedizolid also reversibly inhibit MAO enzyme. Linezolid has also been associated with peripheral neuropathy, optic neuropathy especially when used for prolong duration (more than 4 weeks). The peripheral neuropathy is seen more commonly and the damage often becomes permanent. On the other hand, optic neuropathy seen with linezolid is often reversible. The peripheral neuropathy is often compounded by pre=existing neurologic diseases, alcohol abuse, diabetes, chemotherapy and antiviral therapy.

The mechanism of neuropathy is thought to be due to inhibition of protein synthesis and subsequent mitochondrial injury, in addition to its ability to penetrate the CNS. Several reviews indicate risk factors for developing linezolid associated-neuropathy are pre-existing neurologic disease, alcohol abuse, diabetes, chemotherapy, and antiviral therapy. 10,11


Nitrofurantoin antibiotic has been one of the most commonly used antibiotic used for cystitis and urinary tract infections. Nitrofurantoin also causes dose and duration dependant peripheral neuropathy especially in patients having anemia, impaired renal function (CrCl <60 ml/m), Type II Diabetes Mellitus, Vitamin deficiency, dyselectrolytemia and debilitating diseases which probably occurs due to axonal

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics

loss. The uremia and serum accumulation of Nitrofurantoin are two deadly combinations which can precipitate and worsen existing peripheral neuropathy. 12


Cotrimoxazole (Sulfamethoxazole-trimethoprim) acts by inhibiting folic acid synthesis which can cause acutevpsychosis. The immunocompromised individuals, geriatric patients and patients having renal impairments are more vulnerable which has been known over decades. The commonest psychotic features are hallucinations, psychosis, agitation, apathy, depression, nervousness and others. Cotrimoxazole can cause severe type I hypersensitivity reactions which is known as aseptic eosinophilic meningitis. The neurotoxic effects appear in temporal manner starts between 3-10 days following initiation of therapyz. These manifestations are too dose dependant and is reversible on discontinuation of drugs.13


Among the tetracycline group of antibiotics, minocycline has more propensities to cause neuropsychiatric adverse effects whereas doxycycline has more favourable neuropsychiatric effects. The neurotoxic effects of minocycline include blurring of vision, tinnitus, dizziness, light headedness, vertigo, tinnitus and inability to maintain balance and postures. These adverse effects are probably due to intracellular alteration of volume, ion concentration and osmolality.14

Antibiotic Associated Encephalopathy (AAE): Delirium occurs in 80% hospitalized patients according to some studies. In some cases 15% of Antibiotic Associated Encephalopathy (AAE) are attributed to 4th generation cephalosporins like cefepime.15 The different presentations of three different types of AAE s have been summarized in Table 2.

Table 2: The clinical presentation & pathophysiology of different types of AAE


Types of AAE


Clinical & laboratory features


Type 1

(Seizure predominant)


days of antibiotic initiation

Abnormal EEG,

myovlonic seizures. MRI normal

Resolution is complete in few days

Seen with penicillin & cephalosporins in a patient suffering from renal insufficiency.

Type 2 (Psychosis predominant)


Frequent psychosis, rarely seizure, infrequently abnormal EEG, normal MRI.

Resolution within days, commonly seen with use of procaine penicillin, macrolides, sulphonamides, fluroquinolones.

Type 3

(Cerebellar signs with encephalopathy)

Weeks after initiation

Predominant cerebellar dysfunction.

Rarely seizure disorders.

Seen with Metronidazole

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics


The early diagnosis, monitoring, decision and discontinuation of offending antimicrobial agent are the key steps to control neuropsychiatric adverse effects of the responsible drug. The awareness among the prescribers of possible adverse effects of antibiotics plays a crucial role to avoid these adverse reactions. The medical record and history of past allergic and adverse reactions also guides clinicians to prevent these untoward events. The repetitive exposure risks also can be minimized following this strategy. Some group of drugs potentially carries risk of adverse events like use of psychotropics with Linezolid in methicillin resistant Staph aureus infection. So, early the detection, diagnosis, decision, discontinuation and drug causing these neurotoxic adverse reactions are removed, it will be better for the patient by virtue of not experiencing further adverse effects, though most of these dose and duration dependant adverse effects are reversible on discontinuation of offending drugs.

Acknowledgement: Nil Financial interest: Nil Conflicts of interest: Nil References


3. 4. 5.




Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced mania (antibiomania):

a review of spontaneous reports. J Clin Psychopharmacol. 2002;22(1):71-81.

2. Schliamser SE. Neurotoxicity of beta-lactam antibiotics. Experimental kinetic and neurophysiological studies. Scand J Infect Dis Suppl. 1988;55:1-61. doi: 10.3109/inf.1988.20.suppl-55.01.

Zareifopoulos N, Panayiotakopoulos G. Neuropsychiatric Effects of

Antimicrobial Agents. Clin Drug Investig. 2017;37(5):423-37.

Warstler A, Bean J. Antimicrobial-induced cognitive side effects. Ment Health

Clin. 2016;29;6(4):207-14.

Diemont W, MacKenzie M, Schaap N, Goverde G, van Heereveld H, Hekster Y,

van Grootheest K. Neuropsychiatric symptoms during cefepime treatment.

Pharm World Sci. 2001;23(1):36. doi:


Velkov T, Dai C, Ciccotosto GD, Cappai R, Hoyer D, Li J. Polymyxins for CNS

infections: Pharmacology and neurotoxicity. Pharmacol Ther. 2018;181:85-90.

doi: 10.1016/j.pharmthera.2017.07.012.

Bonda C, Evans MS. Metronidazole CNS toxicity. Acta Neurol Belg.

2015;115(4):709-10. doi: 10.1007/s13760-015-0485-1.

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Bhattacharyya & Chakraborty: Psychiatric adverse effects of antibiotics


Zhang B, Kopper TJ, Liu X, Cui Z, Van Lanen SG, Gensel JC. Macrolide

derivatives reduce proinflammatory macrophage activation and macrophage-

mediated neurotoxicity. CNS Neurosci Ther. 2019;25(5):591-600. doi:


Kiangkitiwan B, Doppalapudi A, Fonder M, Solberg K, Bohner B. Levofloxacin-

induced delirium with psychotic features. Gen Hosp Psychiatry. 2008;30(4):381-

3. doi: 10.1016/j.genhosppsych.2007.11.003.

Hashemian SMR, Farhadi T, Ganjparvar M. Linezolid: a review of its

properties, function, and use in critical care. Drug Des Devel Ther.

201818;12:1759-67. doi: 10.2147/DDDT.S164515.

Hall RG 2nd, Smith WJ, Putnam WC, Pass SE. An evaluation of tedizolid for

the treatment of MRSA infections. Expert Opin Pharmacother. 2018;19(13):1489-

94. doi: 10.1080/14656566.2018.1519021.

Mattappalil A, Mergenhagen KA. Neurotoxicity with antimicrobials in the

elderly: a review. Clin Ther. 2014;36(11):1489-1511.e4. doi:


Thyagarajan B, Deshpande SS. Cotrimoxazole and neonatal kernicterus: a

review. Drug Chem Toxicol. 2014;37(2):121-9. doi:


Arnoux I, Hoshiko M, Sanz Diez A, Audinat E. Paradoxical effects of

minocycline in the developing mouse somatosensory cortex. Glia.









15. Bhattacharyya S, Darby RR, Raibagkar P, Gonzalez Castro LN, Berkowitz AL. Antibiotic-associated encephalopathy. Neurology. 2016;86(10):963-71. doi: 10.1212/WNL.0000000000002455.

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Siddiqui et al: Antipsychotic use in BPSD

Antipsychotic use in behavioral and psychological symptoms of dementia: A double edged sword?

M. Aleem Siddiqui1, Amrit Pattojoshi2, Shobit Garg3, Niska Sinha4

“They may forget but never let them be forgotten, care for those who once cared for us”


Behavioral and psychological symptoms of dementia (BPSD) are an array ofsymptoms like agitation, aggression (both verbal and physical), psychotic symptoms(hallucinations and delusions), behavioural problems like mischievous acts, hyperkinesis,wandering behaviour and sleep disturbances and is estimated to be as high as in 80% ofpatients of dementia. They are often severe and complicate clinical picture of dementiawarranting clinical attention. BPSD is associated with worse outcomes, impaired quality of life, increased rates of institutionalization and inflated cost of care with higher caregiversburden. The pharmacological management where non-pharmacological approaches fail aretried using antipsychotics, anxiolytics, antidepressants, mood stabilisers, cholinesterase inhibitors and N-methyl-D-aspartate receptor modulators. Evidences are for maximum efficacy with use of anti-psychotics which are most commonly prescribed. The risk-benefit of using antipsychotics in BPSD needs to be carefully reviewed due to reports of increased cerebrovascular side effects and mortality rates.

Keywords: Antipsychotics, behavioural and psychological symptoms, dementia, cardiovascular adverse events, efficacy, mortality


Behavioural and psychological symptoms of dementia (BPSD) include a varied range of non-cognitive symptoms and behaviours found in more than 80 % of individuals with dementia at different stages of their illness.1 BPSD is associated

1Professor, Department of Psychiatry, Era Medical college hospital, Lucknow, Uttar Pradesh

2Professor, Department of Psychiatry, Hi-tech Medical college hospital, Bhubaneshwar, Odisha 3Professor, Dept. of Psychiatry, Shri Guru Ram Rai Institute of Medical & Health Sciences, Uttarakhand 4Assistant Professor, Department of Psychiatry, Indira Gandhi Institute of Medical Sciences, Patna, Bihar


Different Strokes

Siddiqui et al: Antipsychotic use in BPSD

with worse outcomes, impaired quality of life, higher rates of institutionalization, inflated cost of care and increased care giver distress.1 BPSD as per consensus statement by Finkel and colleagues2 has replaced the term ‘behavioural disturbances’ in dementia and comprises of different clusters such as apathy, depression, mania, aggression, agitation and psychosis. Psychosis as the most severe phenotype of BPSD has been defined by various criteria like Jest and Finkel, Lyketsos and DSM 5.2,3 Fisher and colleagues have recently proposed the most comprehensive criteria for psychosis in dementia taking into the account the staging (preclinical/prodromal), grading (mild/moderate/severe) and duration (at least 4 weeks) to be clearly defined in context of BPSD.[3]The neurobiology of BPSD is unclear as of now but it has been found that they are not just a sequelae of cognitive impairment but specific brain dysfunctions with involvement of fronto-subcortical, cortico-cortical circuits and alterations of neurotransmitter systems with a complex interplay of genetic, neuropathological, and neurochemical mechanisms in their genesis. The risk factors for BPSD in dementia include the interplay of biological, psychological, and environmental factor.4 Thus, treatment of BPSD is often challenging due to the complex etiopathogenesis with an array of presentation and symptoms.

Although the use of antipsychotics in BPSD is not approved and is off-label, antipsychotics are still the best short-term treatment option and most common pharmacological agents used for BPSDrelated aggression and agitation. However, PROPER I-study has found that only 10 % of psychotropic usage is appropriate in context of BPSD.5 Moreso, there is lack of naturalistic studies taking in consideration transcultural differences, different pharmaco-genetics and diverse background which makes the picture even more unclear. The issue is compounded further by lack of updated clinical practice guidelines addressing BPSD.6 Considering the concerns for safety and wide scale use of antipsychotics in these subset of patients with a challenging management, it needs to be reviewed in detail.

When to Use Antipsychotics among Individuals with BPSD?

The evidences indicate modest efficacy but few serious adverse effects like cognitive decline, cerebrovascular adverse events and even increased mortalitywith use of antipsychotics in individuals of dementia with BPSD. Hence, their use is recommended only in those with severe or refractory symptoms where non- pharmacological approaches have proved futile. Recent American Psychiatric Association practice guideline7 says a risk-benefit ratio needs to be assessed prior to prescribing antipsychotics in BPSD and if required it should be initiated at the

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Siddiqui et al: Antipsychotic use in BPSD

lowest possible dose, gradually titrated up to the minimum effective tolerable dose with an attempt to taper and withdraw within 4 months of initiation of treatment with a careful vigilance for significant recurrence of symptoms for at least 4 months after the medication has been discontinued, to identify signs of recurrence of BPSD. Similar, explicit recommendations are in Indian guidelines6 for initiation and discontinuation time frame with an adequate trial of each antipsychotic to be not more than 4 weeks. The guideline says that in the absence of delirium, haloperidol should not be used as a first-line agent due to lack of efficacy and side effects. Also, long-acting injectable antipsychotic medications are not to be triedexcept in those with a comorbid chronic psychotic illness.

Efficacy of Antipsychotic Medications in Management of BPSD

Studies have found efficacy of both atypical and typical antipsychotic medications in BPSD. Psychosis, aggression, agitation and those with more severe symptoms are found to be responsive to the atypical antipsychotics with no better outcomes for any particular medication. It is recommended that antipsychotic dosages should be initiated at a low dose and is to be gradually titrated up to the minimum effective dose as per tolerance and response.6,7 Second generation antipsychotics (SGA) that have shown modest efficacy in BPSD (majorly Alzheimer’s and mixed) are risperidone (best evidence), aripiprazole, olanzapine and quetiapine.8 No superior efficacy has been seen with haloperidol when compared with placebo in several studies. Risperidone (0.5 mg per day titrated to a maximum dose of 2 mg per day) though not FDA approved for this indication, has attained approval in few countries like UK and Canada.8 Quetiapine (25 mg per day titrated to maximum dose of 200 mg per day) has shown to differentially improve agitation than for psychosis.[9] In Lewy Body Dementia, unlike quetiapine, olanzapine (5 mg per day) has shown efficacy in psychotic symptoms. [10]Risperidone and olanzapine have been found to have an increased risk of cardiovascular adverse events. Other SGA like clozapine, asenapine, paliperidone, ziprasidone have also been used rarely but they lack controlled data in studies for evidence for their efficacy and safety in BPSD.11,12

Adverse Events and Side Effects with Use of Antipsychotics in BPSD

Antipsychotic use among individuals with BPSD is associated with anincreased risk for cerebrovascular adverse effects (CVAEs) and deaths in comparison to placebo. Sedation and extrapyramidal symptoms are more common with risperidone and olanzapine. First-generation antipsychotics, in comparison to second-generation antipsychotics have an increased risk for cerebrovascular adverse events. There is no significant effect on cognition with the use of antipsychotics, but cognitive

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Siddiqui et al: Antipsychotic use in BPSD

impairmenthas been reported in those with longer treatment duration.[11,12]

for mortality of haloperidol, risperidone, olanzapine and quetiapine is 26, 27, 40 and 50 respectively which means that quietiapine stands safest in this respect among all others when it comes to mortality risk.13 The mortality risk does not correlate with the drug type, severity of dementia or type of symptomatology in BPSD. Prevalence of cerebrovascular adverse events (CVAE) is not as high as has been feared and is estimated to have around OR=1.31 for various antipsychotics but is found to be highest for risperidone among the SGAs.14 Other side effects with use of SGA in BPSD are falls, fractures, cardio-metabolic and extra pyramidal side effects.11,12 Citing plethora of side effects, haloperidol should not be

considered as first line in BPSD and especially in absence of delirium.12,14

Effect of Withdrawal of Antipsychotics in Individuals with BPSD?

Discontinuation of antipsychotic medications in patients with BPSD mostly does not worsen behavioural symptoms except in those individuals who had greater baseline behavioural symptoms. Also mortality rates and other side effects are considerably lower among those with timely discontinuation of antipsychotics. Discontinuation phase has been relatively safer with minimal rebound symptoms as found in several metanalysis.7,12 But concerns have been raised lately for higher relapse rates of the hallucinatory phenomenon after SGA discontinuation.8,12

Other Psychotropic Agents Used in BPSD

Other psychotropic agents studied systematically in BPSD are antidepressants, mood stabilizers, cognitive enhancers and antihypertensive agents like prazocin. Among antidepressants, Tricyclic Antidepressants (TCAs) are not recommended due to side effect burden in elderly. Among selective serotonin reuptake inhibitors (SSRIs), citalopram (not available in India) has shown efficacy in reducing agitation (CitAD trial)15 but safety concerns have been raised due to QTc prolongation. Another SSRI sertraline has shown some therapeutic benefits in BPSD.12 Trazodone, a serotonin receptor antagonist and reuptake inhibitor (SARI), citing minimal anticholinergic and significant sedating profile, has the potential role in BPSD.[16] It has also shown promise in reducing agitation in fronto-temporal dementia (FTD)[16] and as a PRN drug i.e. prescribed as the situation calls for it in dose 25 mg every hour till 150 mg per day for agitation for intermittent agitation in dementia. Other antidepressants like escitalopram, buspirone and mirtazapine have been poorly studied.12 Among mood stabilizers, carbamazapineexcept for limitations related to



Needed to Harm (NNH) is a measure of how many people need to be treated or

exposed to a risk factor for one of them to have a particular adverse effect and

studies have found that NNH

Different Strokes

Siddiqui et al: Antipsychotic use in BPSD

its CYP3A4 drug interactions holds promise when compared to valproate which is ineffective in lower doses and has significant side effects at higher dosages and similar holds true for lamotrigine and gabapentine which have not shown efficacy.12 Among cognitive enhancers, acetylcholine esterase inhibitors (AChEI) like donepezil, rivastigmine and galantamine and NMDA uncompetitive antagonists like memantine have shown slow insidious benefits in BPSD (over 6 months). The combination (AChEI and memantine) have shown superior efficacy over monotherapy in a recent metaanalysis.17 Antihypertensive agents like prazocin due to alpha-adrenoceptor blocking actions have shown benefits in agitation in Alzheimer’s dementia (dose between 1 mg and 6 mg/day) with additional benefits in associated REM sleep behavioral disorder.Benzodiazepines are not recommended due to side effects like falls, cognitive deficits, sedation and paradoxical agitation but exceptionally lorazepam can be utilized as a PRN drug (0.5 mg every 4 hours as needed, max 2 mg/24 hours).[12] Citing limited therapeutic options tailor made for BPSD, there are several ongoing trials of novel promising molecules in pipeline.


There has been lack of consensus on pharmacological management of BPSD though antipsychotics come to our rescue and are commonly prescribed. So, with current evidence base, we can define an algorithm giving attention to the type (non- pharmacological vs non-pharmacological), dose, duration of treatment for different clusters of BPSD.9 We also need naturalistic and longitudinal data to generate evidence for the same.


 Behavioral and psychological symptoms of dementia (BPSD) are quiet common and are often severe with worse outcomes, impaired quality of life, use of polypharmacy with risk of side effects in already frail individuals, increased rates of institutionalization, inflated cost of care and increased caregiver burden

 The pharmacological management where non-pharmacological approaches fail are tried using antipsychotics, anxiolytics, antidepressants, mood stabilisers andcognitive enhancers

 Evidences are for maximum efficacy with use of anti-psychotics and hence are most commonly prescribed in as high as about one-fourth of the individuals with dementia

 The risk-benefit of using antipsychotics in BPSD needs to be addressed considering serious cerebrovascular adverse events, extrapyramidal side effects and concerns for increased mortality rates

 Second generation antipsychotics that have shown modest efficacy in BPSD are risperidone (best evidence), aripiprazole, olanzapine and quetiapine while first generation antipsychotic haloperidol should not be considered as first line in BPSD especially in absence of delirium

 Recommendations are to use the lowest effective doses of these medications and for the shortest possible time, with adequate follow up for re-emergence or worsening of symptoms on withdrawal of antipsychotics use

Take Home Points

Different Strokes

Siddiqui et al: Antipsychotic use in BPSD

“My eyes do see, my ears do hear, my memory may fade, my walk may slow but I am still me, so be clear and don’t let me go”


1. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002;288(12):1475-83. doi:10.1001/jama.288.12.1475

2. Finkel SI, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr. 1996;8(Suppl 3): 497-500.

3. Fischer CE, Ismail Z, Youakim JM, Creese B, Kumar S, Nuñez N, et al. Revisiting Criteria for Psychosis in Alzheimer’s Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research. J Alzheimers Dis. 2020; 73(3):1143-56. doi:10.3233/JAD-190828.

4. Tible OP, Riese F, Savaskan E, von Gunten A. Best practice in the management of behavioural and psychological symptoms of dementia. Ther Adv Neurol Disord. 2017;10(8):297–309.

5. van der Spek K, Gerritsen DL, Smalbrugge M, Nelissen-Vrancken MH, Wetzels RB, Smeets CH, et al. Only 10% of the psychotropic drug use for neuropsychiatric symptoms in patients with dementia is fully appropriate. The PROPER I-study. Int Psychogeriatr 2016;28:1589–95.

6. Shaji K S, Sivakumar P T, Rao G P, Paul N. Clinical practice guidelines for management of dementia. Indian J Psychiatry [serial online] 2018 [cited 2020

Jun 7] 60(S3):312-28. Available from: text.asp?2018/60/7/312/224472

7. Reus VI, Fochtmann LJ, Eyler AE,Hilty DM, Horvitz-Lennon M, Jibson MD, et al. The American Psychiatric Association Practice Guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173:543–46.

8. Tampi RR, Tampi DJ, Balachandran S, Srinivasan S. Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses. Ther Adv Chronic Dis. 2016; 7(5):229-45. doi:10.1177/2040622316658463.

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Siddiqui et al: Antipsychotic use in BPSD

9. Davies SJ, Burhan AM, Kim D, Gerretsen P, Graff-Guerrero A, Woo VL, et al. Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol. 2018; 32(5): 509-23. doi:10.1177/0269881117744996.

10. Stinton C, McKeith I, Taylor J, Lafortune L, Mark E, Mioshi E. et al. Pharmacological management of lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry 2015; 172: 731–42.

11. Yunusa I, Alsumali A, Garba AE, Regestein QR, Eguale T. Assessment of reported comparative effectiveness and safety of atypical antipsychotics in the treatment of behavioral and psychological symptoms of dementia: a network meta-analysis. JAMA Netw Open. 2019;2(3):e190828.

12. Masopust J, Protopopová D, Vališ M, Pavelek Z, Klímová B. Treatment of behavioral and psychological symptoms of dementias with psychopharmaceuticals: a review. Neuropsychiatr Dis Treat. 2018;14: 1211-20. doi:10.2147/NDT.S163842

13. Maust DT, Kim HM, Seyfried LS, et al. (2015) Antipsychotics, other psychotropics, and the risk of death in patients with dementia: Number needed to harm. JAMA Psychiatry 72: 438–45.

14. Hsu WT, Esmaily-Fard A, Lai CC, Chiang C, Kavanagh J, Schneider LS, et al. Antipsychotics and the risk of cerebrovascular accident: a systematic review and meta-analysis of observational studies. J Am Med Dir Assoc. 2017;18:692-9.

15. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682-91. doi:10.1001/jama.2014.93.

16. Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord. 2004;17:355–59.

17. Chen R, Chan PT, Chu H, et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: a meta- analysis. PLoS One. 2017;12(8):e0183586.

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Dr Arabinda Brahma is currently the Director and Consultant Psychiatrist of Girindra Sekhar Bose Clinic, Kolkata. He is also Hon. Lecturer of Indian Psycho Analytical Society, Kolkata. He has received many awards of Indian Psychiatric Society & Indian Association of Private Psychiatry including Bhagwat Award, Marfatia Award & RB Davis Oration Award. Currently, Hon. Secretary of

Indian Psychiatric Society, Eastern Zone; Chairman, Publication Subcommittee of Indian Psychiatric Society and Council Member of Rehabilitation Council of India. He has published more than 50 papers in national and international medical journals including 4 Book Chapters.

Dr. George V Reddy is consultant Psychiatrist and Director of Healthy Brain Clinic and Hospital, Secunderabad, Telangana. He Worked with the editorial board of Telangana Journal of Psychiatry and was the founder and first general secretary of Indian Psychiatric Society, Telangana state.

Dr. Naren Rao is currently an Additional Professor of Psychiatry at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. After his MD Psychiatry at NIMHANS, he completed his post-doctoral fellowship at the Centre for Addiction and Mental Health, Toronto, Canada. His research focuses on schizophrenia biomarkers utilizing multi-modal neuroimaging. He has

published more than 140 peer-reviewed journal publications and book chapters.

Publication Committee Indian Psychiatric Society Headquarter: Plot 43, Sector 55 Gurugram, Haryana, India, Pin – 122003

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