Management of Bipolar Disorder (Second Edition)

Published by:
Malaysia Health Technology Assessment Section (MaHTAS)
Medical Development Division, Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Federal Government Administrative Centre
62590 Putrajaya, Malaysia

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STATEMENT OF INTENT
This clinical practice guidelines (CPG) is meant to be a guide for
clinical practice based on the best available evidence at the time of
development. The guideline should not override the responsibility of
the practitioners to make decisions appropriate to the circumstances of
the individual. This should be done in consultation with the patients and
their families or guardians, taking into account the management options
available locally.

UPDATING THE CPG

These guidelines were issued in 2024 and will be reviewed in a minimum
period of four years (2028) or sooner if there is a need to do so. When
it is due for updating, the Chairman of the CPG or National Advisor of
the related specialty will be informed about it. A discussion will be done
on the need for a revision including the scope of the revised CPG. A
multidisciplinary team will be formed and the latest systematic review
methodology used by MaHTAS will be employed. Every care is taken
to ensure that this publication is correct in every detail at the time of
publication. However, in the event of errors or omissions, corrections
will be published in the web version of this document, which is the
definitive version at all times. This version can be found on the websites
mentioned above.
 Management of Bipolar Disorder (Second Edition)

TABLE OF CONTENTS

No. Title Page

Levels of Evidence and Formulation of Recommendation i

Key Recommendations ii
Guidelines Development and Objectives iv
Development Group v
Review Committee vii
External Reviewers viii
Algorithm 1: Treatment of Acute Mania ix
Algorithm 2: Treatment of Acute Depressive Episode x

1. INTRODUCTION 1

2. RISK FACTORS 2

3. SCREENING AND DIAGNOSIS 3

3.1 Screening Tools 3
3.2 Differential Diagnoses 6
3.3 Co-Morbidities 7

4.TREATMENT 9
4.1 Pharmacotherapy 9
4.1.1 Manic Episode 9
4.1.2 Depressive Episode 11
4.1.3 Bipolar disorder with specifiers 14
4.1.4 Maintenance phase 18
4.2 Non-Pharmacological Therapy 22
4.2.1 Physical therapy 22
4.2.2 Psychosocial intervention 26
4.2.3 Psychotherapy 27

5. COMPLEMENTARY AND ALTERNATIVE THERAPIES 30

6.FOLLOW-UP/MONITORING AND REFERRAL 31

6.1 Parameters to be Monitored during 31
Maintenance Phase
6.2 Referral Criteria 31

7. RELAPSE PREVENTION AND ADHERENCE 33

7.1 Prevention of Relapse 33
7.2 Strategies to Improve Adherence 34
7.3 Collaborative Care Models 37
 Management of Bipolar Disorder (Second Edition)

TABLE OF CONTENTS

No. Title Page

8. SPECIAL POPULATION 38
8.1 Pregnancy and Lactation 38
8.2 Elderly 40
8.3 Children and Adolescents 41
8.4 People with Substance Use Disorder 44
8.5 People with Borderline Personality Disorder 45

9. SUICIDE PREVENTION 46
9.1 Risk and Protective Factors 46
9.2 Effective and Safe Intervention 47

10. IMPLEMENTING THE GUIDELINES 49

10.1 Facilitating and Limiting Factors 49
10.2 Potential Resource Implications 49

REFERENCES 51
Appendix 1 Example of Search Strategy 60
Appendix 2 Clinical Questions 62
Appendix 3 Diagnostic Criteria of Bipolar Disorder 63
based on Diagnostic and Statistical
Manual of Mental Disorders Fifth Edition,
Text Revision (DSM-5-TR) or International
Classification of Diseases Eleventh
Revision (ICD-11)
Appendix 4 List of Screening Tools in Bipolar Disorder 67
Appendix 5 Recommended Adult Medication Dosages 69
and Adverse Effects for Bipolar Disorder
Appendix 6 Psychoeducation for Bipolar Disorder 77
Appendix 7 Parameters for Monitoring during 78
Treatment of Bipolar Disorder
Appendix 8 Collaborative Care Model Core Elements 80
Appendix 9 Summary of Medications for 81
Bipolar Disorder in Pregnancy
and Lactation
Appendix 10a Annual Risk Acknowledgement Form 87
Appendix 10b Borang Pengakuan Risiko Tahunan 89
Appendix 11 Suggested Paediatric Medications Dosing 91

List of Abbreviations 96
Acknowledgment 99
Disclosure Statement 99
Source of Funding 99
 Management of Bipolar Disorder (Second Edition)

LEVELS OF EVIDENCE
Level Study design

I Properly powered and conducted randomised controlled

trial; well-conducted systematic review or meta-analysis of
homogeneous randomised controlled trials

II-1 Well-designed controlled trial without randomisation

II-2 Well-designed cohort or case-control analysis study

II-3 Multiple time series, with or without the intervention; results

from uncontrolled studies that yield results of large magnitude

III Opinions of respected authorities, based on clinical experience;

descriptive studies or case reports; reports of expert committees
SOURCE: U.S. Preventive Services Task Force. U.S. Preventive Services Task Force Procedure
Manual. Rockville, MD: USPSTF; 2015.

FORMULATION OF RECOMMENDATION

• In line with the new development in CPG methodology, the

CPG Unit of MaHTAS is adapting Grading Recommendations,
Assessment, Development and Evaluation (GRADE) in its
work process. The quality of body of evidence and related effect
size are carefully assessed/reviewed by the CPG DG.
• Recommendations are formulated based on certainty of
evidence and the wording used denotes the strength of
recommendations. This takes into account:
 quality and level of the evidence
 balance of benefits and harms of the options
 patient’s preference and values
 resource implications
 relevancy and applicability to the local target population
• The more criteria being fulfilled, the more certain is the evidence
leading to strong recommendations using the word “should”
being considered. Otherwise, weak recommendations use the
word “may” in proposing an action to be made.
• In the CPG, a yellow box highlights important message(s) in
the management while a blue box contains evidence-based
recommendation(s) for the particular condition.

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 Management of Bipolar Disorder (Second Edition)

KEY RECOMMENDATIONS

The following recommendations are highlighted by the CPG

Development Group (DG) as the key recommendations that answer
the main questions addressed in the CPG and should be prioritised for
implementation.

DIAGNOSIS

• Bipolar disorder should be diagnosed based on the Diagnostic and

Statistical Manual of Mental Disorders Fifth Edition, Text Revision
(DSM- 5-TR) or International Classification of Diseases Eleventh
Revision (ICD- 11).

TREATMENT AND MONITORING

• Antipsychotics or mood stabilisers, either as monotherapy or

combination, should be used to treat acute mania or depressive
episodes in bipolar disorder (BD).
• Antidepressants may be used as short-term adjunctive treatment but
not as monotherapy in acute bipolar depression.
• In BD with specifiers:
 atypical antipsychotics (AAPs) or mood stabilisers may be used
as monotherapy or combination therapy in mixed features
 AAPs may be used in anxious distress
 combination of mood stabilisers with AAPs or another mood
stabiliser is the preferred treatment of choice in rapid cycling
 antidepressants should be avoided in mixed features and used
with caution in rapid cycling
• For maintenance pharmacotherapy of BD:
 lithium and quetiapine are the preferred first-line monotherapy
while lithium plus quetiapine or aripiprazole are the preferred first-
line combination therapy
 antidepressant monotherapy should be avoided
 aripiprazole or risperidone long-acting injectables may be
considered in patients who have poor adherence to oral
medications especially in preventing manic episodes
• Serum lithium level should be monitored one week upon initiation or
dose change and every six months or earlier if indicated in BD.
• Electroconvulsive therapy should be considered in both bipolar
manic and depressive episodes in indicated situations.
• Psychosocial interventions and psychotherapies should be offered
as an adjunctive treatment for BD.

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 Management of Bipolar Disorder (Second Edition)

RELAPSE PREVENTION AND ADHERENCE

• Psychosocial interventions and psychotherapies should be part of

strategies in relapse prevention of bipolar disorder.

SPECIAL POPULATION

• Shared decision-making in weighing the risks versus benefits of

pharmacological treatment should be done in pregnant and lactating
women with bipolar disorder (BD).
 Atypical antipsychotics (AAPs) may be used in pregnancy.
 Valproate and carbamazepine should be avoided in pregnancy
given their teratogenic risks. Other mood stabilisers should be
used with caution.
• For children and adolescents with BD:
 AAPs monotherapy may be used in manic or mixed episodes
 lurasidone and olanzapine/fluoxetine combination may be used in
depressive episodes
• Patients with BD with co-morbid substance use disorder should be
referred to psychiatric services.

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 Management of Bipolar Disorder (Second Edition)

GUIDELINES DEVELOPMENT AND OBJECTIVES

GUIDELINES DEVELOPMENT

The members of the DG for this CPG were from the Ministry of Health
(MoH), Ministry of Higher Education and the private sector. There was
active involvement of a multidisciplinary Review Committee (RC) during
the process of the CPG development.

A systematic literature search was carried out using the following

electronic databases/platforms: mainly Medline via Ovid and others
e.g. Pubmed (refer to Appendix 1 for Example of Search Strategy).
The inclusion criteria includes everyone at risk and with bipolar disorder
(BD) regardless of study design. The first search was limited to
literature published in the last eight years (2014 until 2022) on humans
and in English. In addition, the reference lists of all retrieved literature
and guidelines were searched to further identify relevant studies.
Experts in the field were also contacted for studies related to the issues
addressed. All initial searches were conducted from 2 August 2022
to 17 August 2022. The literature search was repeated for all clinical
questions at the end of the CPG development process allowing any
relevant papers published before 31 December 2023 to be included.
Future CPG updates will consider evidence published after this cut-off
date. The details of the search strategy can be obtained upon request
from the CPG Secretariat.

References were also made to other guidelines on BD as listed below:

i. Canadian Network for Mood and Anxiety Treatments (CANMAT)
and International Society for Bipolar Disoder (ISBD) - Guidelines for
the Management of Patients with Bipolar Disorder (2018)
ii. Ministry of Health, Malaysia - Clinical Practice Guidelines on
Management of Bipolar Disorder (2014)
iii. National Institute for Health and Care Excellence (NICE) - Guideline
on the Assessment and Management of Bipolar Disorder in Adults,
Children and Young People in Primary and Secondary Care (2014)
iv. Royal Australian and New Zealand College of Psychiatrists
(RANZCP) - The 2020 RANZCP Clinical Practice Guidelines for
Mood Disorders (2020)

A total of 18 main clinical questions were developed under different

sections. Members of the DG were assigned individual questions within
these sections. Refer to Appendix 2 for Clinical Questions. The DG
members met 27 times throughout the development of these guidelines.
All literature retrieved was appraised by at least two DG members using
the Critical Appraisal Skill Programme checklist, presented in evidence
tables and further discussed in each DG meeting. All statements and

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 Management of Bipolar Disorder (Second Edition)

recommendations formulated after that were agreed upon by both the

DG and RC. Where evidence was insufficient, the recommendations
were made by consensus of the DG and RC. Any differences in opinion
were resolved consensually. The CPG was based largely on the
findings of systematic reviews/meta-analyses and clinical trials, with
local practices taken into consideration.

The literatures used in these guidelines were graded using the U.S.
Preventive Services Task Force Level of Evidence (2015) while the
grading of recommendation was done using the principles of GRADE
as much as possible (refer to the preceding page). The writing of the
CPG followed strictly the requirement of Appraisal of Guidelines for
Research and Evaluation (AGREE) II.

Upon completion, the draft CPG was reviewed by external reviewers. It

was also posted on the MoH Malaysia official website for feedback from
any interested parties. The draft was finally presented to the Technical
Advisory Committee for CPG and, the Health Technology Assessment
(HTA) and CPG Council, MoH Malaysia, for review and approval.
Details on the CPG development by MaHTAS can be obtained from the
Manual on Development and Implementation of Evidence-based
Clinical Practice Guidelines published in 2015 (available at https://
www.moh.gov.my/moh/resources/CPG_MANUAL_MAHTAS.pdf).
 Management of Bipolar Disorder (Second Edition)

OBJECTIVES

The objective of the CPG is to provide evidence-based recommendations

on the management of bipolar disorder in the following aspects:
• diagnosis and assessment
• treatment
• prevention
• monitoring and referral

CLINICAL QUESTIONS

Refer to Appendix 2.

TARGET POPULATION

Inclusion Criteria
• Persons with BD
• Special population with BD:
 pregnant and lactating women
 elderly
 children and adolescents
 persons with substance use disorder
 persons with borderline personality disorder

Exclusion Criteria
• People with BD secondary to organic conditions

TARGET GROUP/USER

This document is intended to guide health professionals and relevant

stakeholders in primary and secondary/tertiary care of both public and
private sectors in the management of BD including:
i. medical doctors
ii. allied health professionals
iii. trainees and medical students
iv. patients, caregivers and their advocates
v. professional societies
vi. policy makers

HEALTHCARE SETTINGS

Primary, secondary and tertiary care

 Management of Bipolar Disorder (Second Edition)

DEVELOPMENT GROUP

Chairperson

Dr. Melisa Abdul Aziz Psychiatrist

Hospital Ampang, Selangor

Members (alphabetical order)

Dr. Aishah Siddiqah Alimuddin Medical Dr. Lee Wen Jih

lecturer & Psychiatrist Faculty of Psychiatrist
Medicine & Health Science Hospital Bahagia Ulu Kinta, Perak
Universiti Putra Malaysia, Selangor

Dr. Asma Assa’edah Mahmud Medical Dr. Mohd. Aminuddin Mohd. Yusof
lecturer & Psychiatrist Faculty of Head of Clinical Practice Guidelines
Medicine & Defense Health Unit & Public Health Physician Health
Universiti Pertahanan Nasional Technology Assessment Section
Malaysia Kuala Lumpur Ministry of Health, Putrajaya

Dr. Azrina Mahmud Dr. Nor Faizah Ghazali

Family Medicine Specialist Medical Lecturer & Family Medicine
Kesihatan Rasa Hulu, Selangor Specialist
Faculty of Medicine & Health Science
Universiti Sains Islam Malaysia
Negeri Sembilan

Dr. Choy Seng Kit Dr. Ravivarma Rao Panirselvam

Consultant Psychiatrist Psychiatrist
Hospital Universiti Tunku Abdul Rahman Hospital Miri, Sarawak
Kampar, Perak

Dr. Christabel Esther Terence Ms. Siti Salwani Razali

Psychiatrist Pharmacist
Hospital Raja Permaisuri Bainun Perak Hospital Putrajaya, Putrajaya

Dr. Karen Sharmini Sandanasamy Ms. Umi Izzatti Saedon

Public Health Physician Clinical Psychologist
Clinical Practice Guidelines Unit Health Hospital Tengku Ampuan Rahimah
Technology Assessment Section Selangor
Ministry of Health, Putrajaya

Dr. Khadijah Hasanah Abang Abdullah Dr. Yoong Mei Theng

Lecturer & Psychiatrist Psychiatrist
Faculty of Medicine & Health Science Hospital Putrajaya, Putrajaya
Universiti Sains Islam Malaysia
Negeri Sembilan

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 Management of Bipolar Disorder (Second Edition)

REVIEW COMMITTEE

The draft CPG was reviewed by a panel of experts from both public
and private sectors. They were asked to comment primarily on the
comprehensiveness and accuracy of the interpretation of evidence
supporting the recommendations in the CPG.

Chairperson

Dr. Azizul Awaluddin

Head of Department & Consultant Psychiatrist
Hospital Putrajaya, Putrajaya

Members (in alphabetical order)

Datin Dr. Ang Kim Teng Dr. Izzuna Mudla Mohamed Ghazali
Honorary Treasurer Deputy Director & Public Health Physician
Malaysian Mental Health Association Health Technology Assessment Section
Ministry of Health, Putrajaya

Ms. Ang Wei Nei Dr. Jamilah Hanum Abdul Khaiyom

Pharmacist Clinical Psychologist
Hospital Selayang, Selangor International Islamic Universiti Malaysia
Kulliyyah of Islamic Revealed Knowledge
and Human Sciences
Selangor

Dr. Benjamin Chan Teck Ming Dr. Salina Abdul Aziz

Consultant Psychiatrist Senior Consultant Psychiatrist
Chan Specialist Clinic Hospital Kuala Lumpur
Johor Bahru, Johor Kuala Lumpur

Professor Dr. Chan Lai Fong Dr.Yusni Yusuff

Senior Lecturer & Consultant Director & Consultant Child and
Psychiatrist Adolescent Psychiatrist
Faculty of Medicine Hospital Bahagia Ulu Kinta, Perak
Universiti Kebangsaan Malaysia
Kuala Lumpur

Mr. Hasbeemasputra Abu Bakar Dr. Zainal Fitri Zakaria

Patient Advocate Family Medicine Specialist
Klinik Kesihatan Seremban
Dr. Hazli Zakaria Negeri Sembilan
Consultant Psychiatrist &
Past President
Malaysian Psychiatric Association

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 Management of Bipolar Disorder (Second Edition)

EXTERNAL REVIEWERS (in alphabetical order)

The following external reviewers provided feedback on the draft:

Dr. Anthony James Dr. Uma Visvalingam

Consultant Child & Adolescent Head of Department & Consultant
Psychiatrist Psychiatrist
Warneford Hospital Hospital Sg. Buloh, Selangor
Oxford, United Kingdom

Mr. Azmi Mohamad @ Suleiman Professor Dr. Margarita M. Maramis

Clinical Psychologist Professor of Psychiatry
Hospital Raja Permaisuri Bainun Faculty of Medicine, Airlangga University
Perak Surabaya, Indonesia

Dr. Chee Kok Yoon Dr. Nor Hayati Ali

Consultant Neuropsychiatrist Head of Psychiatric Services & Senior
Hospital Kuala Lumpur Consultant Psychiatrist (Community &
Kuala Lumpur Rehabilitation)
Hospital Selayang, Selangor

Dato’ Dr. Ding Lay Ming Dr. Norfaridah Masiran

Honorary General Secretary Family Medicine Specialist
Malaysian Mental Health Kinik Kesihatan Kampung Bandar
Association Kuala Langat, Selangor

Professor Dr. Firdaus Mukhtar Dr. Nurul Wafa Hussin

Clinical Psychologist Head of Department & Consultant Child
Faculty of Medicine and Health & Adolescent Psychiatrist
Sciences Hospital Melaka, Melaka
Universiti Putra Malaysia
Selangor

Dr. Julia Suhaimi Dr. Selvasingam Ratnasingam

Senior Lecturer & Family Medicine Consultant Child & Adolescent Psychiatrist
Specialist Hospital Tuanku Azizah, Kuala Lumpur
Faculty of Medicine
Universiti Malaya, Kuala Lumpur

Mr. Larry Lee Lian Seng Ms. Shamini Rama

Pharmacist Head of Department & Pharmacist
Hospital Tengku Ampuan Rahimah Hospital Bahagia Ulu Kinta, Perak
Selangor

Professor Dr. Roger McIntyre Assoc. Prof. Dr. Wan Salwina Wan Ismail
Professor of Psychiatry & Child & Adolescent Psychiatrist
Pharmacology Faculty of Medicine
University of Toronto & Head of Universiti Kebangsaan Malaysia
Mood Disorders Kuala Lumpur
Psychopharmacology Unit
University Health Network
Toronto, Canada

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 Management of Bipolar Disorder (Second Edition)

ALGORITHM 1. TREATMENT OF ACUTE MANIA

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 ALGORITHM 2. TREATMENT OF ACUTE DEPRESSIVE VALPROATE

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Management of Bipolar Disorder (Second Edition)
 Management of Bipolar Disorder (Second Edition)

1. INTRODUCTION

Bipolar disorder (BD) is a potentially life-long disabling condition

presenting commonly as either bipolar I disorder (BD I) or bipolar II
disorder (BD II). BD I is characterised by episodes of mania (abnormally
elevated mood or irritability and related symptoms with severe
functional impairment or psychotic symptoms for seven days or more).
On the other hand, BD II is characterised by episodes of hypomania
(abnormally elevated mood or irritability and related symptoms with
decreased or increased function for four days or more) and depressive
episodes.

BD is a severe mental disorder. Based on World Health Organisation

(WHO) statistics in 2019, its global prevalence was estimated to be
around 40 million.1 In the Global Burden of Disease Study 2019, the
prevalence of BD showed an increasing trend from 24.8 million in 1990
to 39.5 million in 2019.2 Its prevalence in Malaysia, however, is not
well-established. BD is associated with reduced functioning, cognitive
impairment and decreased quality of life (QoL). It is also one of the
leading causes of disability in young people and increased mortality,
especially by suicide.3

Diagnosis of BD may be difficult given the complexity of its clinical

presentation which may overlap with other psychiatric disorders and
change over time. Moreover, managing BD is limited by the lack of
resources including expertise and medications. Poor adherence
remains a major issue that needs to be tackled in its management.

The first edition of the CPG Management of BD in Adults was published

in 2014. Since then, there have been advances in the management
of BD which include wider medication choices and new treatment
modalities that incorporate technological advancement.

This revised edition provides updates on the evidence and related

recommendations on the current management of BD, keeping in mind
the acceptability of the treatment and availability of resources. It also
addresses the management of children and adolescents, and looks
into evidence on psychospirituality as well as complementary and
alternative medicine. Previous topics on psychosocial interventions,
suicide prevention and management in pregnant and lactating women
are further expanded.

This CPG is aimed to be used at primary, secondary, and tertiary health

care settings. It is also useful for those involved in psychiatric training. It
is hoped that this CPG will be of benefit to healthcare professionals and
help improve the management of patients with BD.

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 Management of Bipolar Disorder (Second Edition)

2. RISK FACTORS

Identifying risk factors of BD may assist in the early detection of BD.

Several factors increase the risk of people developing BD which

include:
• offspring of maternal age group ≥40 years old (OR=1.20, 95% CI
1.10 to 1.31)4, level II-2
• presence of major depression with attention-deficit hyperactivity
disorder (ADHD) (OR=1.50, 95% CI 1.30 to 1.72)5, level II-2

Apart from the above, the established risk factors for BD are:
• family history of BD6
• young age (<25 years old)7
• low educational level6
• low employment level6

Recurrence of BD means the return of symptoms e.g. mania,

hypomania or depression after a period of wellness (symptom-free
period). In a systematic review, factors associated with recurrence of BD
were:8, level II-2
• early age of onset
• low socio-economic status
• family history of BD
• history of child abuse
• low maternal warmth
• co-morbid mental health disorders (anxiety disorder, ADHD and
substance use disorders)
• inter-episode subsyndromal mood symptoms

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 Management of Bipolar Disorder (Second Edition)

3. SCREENING AND DIAGNOSIS

The diagnosis of BD relies on signs and symptoms elicited during

clinical interviews with the patient and often with corroborative history
from informants. Diagnostic and Statistical Manual of Mental Disorders
Fifth Edition, text revision (DSM-5-TR) and International Classification
of Diseases Eleventh Revision (ICD-11) classification systemfor
psychiatric disorders assist in framing operational definitions i.e.
making diagnoses for clinical work and research. Revisions of these
classifications ensure they are at pace with the recent advancements
in the field. The main changes in the new classification systems are:
• both ICD-11 and DSM-5-TR use the term bipolar disorder instead
of bipolar affective disorder as in ICD-10
• ICD-11 uses subdivision of bipolar disorder type I and II, in line
with DSM-5-TR
• definitions of manic and hypomanic syndromes and episodes are
almost identical between ICD-11 and DSM-5-TR

Refer to Appendix 3 for Diagnostic Criteria of Bipolar Disorder Based

on the Diagnostic and Statistical Manual of Mental Disorders Fifth
Edition, Text Revision (DSM-5-TR) and International Classification
of Diseases Eleventh Revision (ICD-11).

Recommendation 1
• Bipolar Disorder should be diagnosed based on the Diagnostic and
Statistical Manual of Mental Disorders Fifth Edition, Text Revision or
International Classification of Diseases Eleventh Revision.

3.1. Screening Tools

BD commonly presents as unipolar depression on the first presentation.

There is a prevalence of 17% of undiagnosed BD in primary care,
amounting to over 3 in every 20 patients.9, level II-2 This may lead to a
misdiagnosis or delayed diagnosis of BD up to 10 years, which in turn
may result in an increased risk of treatment-emergent mania/hypomania
and suicide.10 - 12 Screening tools for BD may assist healthcare
practitioners in identifying those with underlying BD. Furthermore,
identifying those who are at risk of BD allows for preventive strategies
and early interventions.

The following tools are available for the screening of BD:

• Mood disorder questionnaire (MDQ)13
• Hypomania checklist (HCL-32)14
• Bipolar spectrum diagnostic scale (BSDS)15
• Rapid mood screener (RMS)16
Refer Appendix 4 for List of Screening Tools in Bipolar Disorder.
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 Management of Bipolar Disorder (Second Edition)

In a nationwide cross-sectional study on awareness and acceptability

of RMS and MDQ in BD screening among 200 healthcare practitioners
(HCP) in both primary and secondary care, the findings were:17, level III
• only 32% of HCP used a screening tool for BD compared with 82%
for MDD
• although 85% of the HCP were aware of MDQ, only 29% reported
on its current use
• RMS was significantly better than MDQ in terms of accuracy,
brevity, practicality and easy scoring
• HCPs were significantly more likely to use RMS than MDQ (81%
vs 19%)

Bipolarity index (BI) is a tool that can increase diagnostic confidence

of BD. This tool is clinician-rated. It is useful when symptoms of mania
are difficult to elicit, patients deny the presence of manic symptoms
or manic symptoms stem from another diagnosis. The scale has five
sections; episode characteristics, age of onset, course of illness,
response to treatment and family history. In a diagnostic study using
BI to screen for BD in outpatient psychiatric practice, the sensitivity and
specificity of BI were 0.91 and 0.90, at a cut-off point of 50, PPV of 0.88,
NPV of 0.93 and AUC of 0.97.18, level III

It may be difficult to screen for BD in the general population. A group of

researchers from the University of Melbourne introduced Bipolar at-risk
(BAR) criteria which may assist in identifying those at risk of BD in the
age range of 15 - 25 years. It included sub-threshold mania, depressive
symptoms, cyclothymic features and genetic risk.19, level III Refer to Table
1 for further description of the criteria.

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 Management of Bipolar Disorder (Second Edition)

Table 1: Bipolar At-Risk Criteria

Criterion Description
Group 1: Subthreshold 2 - 4 consecutive days of abnormally and
mania persistently elevated, expansive or irritable mood
with at least two of the following:
1. inflated self-esteem or grandiosity
2. decreased need for sleep (e.g. feels rested after
only three hours of sleep)
3. more talkative than usual or pressure to keep
talking
4. flight of ideas or subjective experience that
thoughts are racing
5. distractibility
6. increased goal-directed activity (socially, at work
or sexually) or psychomotor agitation

Group 2: Depression Depression defined as at least one week of

and cyclothymic depressed mood or loss of interest/pleasure with at
features least two of the following:
1. significant weight loss
2. insomnia or hypersomnia nearly every day
3. psychomotor retardation or agitation
4. fatigue or loss of energy
5. feelings of worthlessness or excessive/inappro-
priate guilt
6. diminished ability to think or concentrate
7. recurrent thoughts of death and/or recurrent
suicidal ideation
Cyclothymic features are defined as numerous
episodes with subthreshold manic symptoms not
meeting group 1 criteria and numerous episodes
with depressive symptoms. e.g. sub-threshold
mania as defined in group

1 only for four hours within a 24-hour period and at

least four cumulative lifetime days meeting the
criteria
Group 3: Depression Depression same as for group 2; genetic risk
and genetic risk defined as first-degree relative with BD

Adapted: Bechdolf A, Nelson B, Cotton SM, et al. A preliminary evaluation of the

validity of at-risk criteria for bipolar disorders in help-seeking adolescents
and young adults. J Affect Disord. 2010;127(1-3):316-20

A cohort study assessed the association of BAR criteria and onset of

BD over 10 to 13 years of follow-up and showed that:20, level II-2
• 28.6% of subjects from BAR group developed BD over a mean
of 11.1 years whilst none developed BD in a clinically matched
comparison group. Of these:

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 Management of Bipolar Disorder (Second Edition)

 87.5% transitions were to BD II and 12.5% to BD I

 75.0% transitions occurred in those with subthreshold mania
and 25.0% in those with major depression and cyclothymic
features

• Patients with suspected unipolar depression should be screened for

BD.
• There is inadequate evidence to recommend a specific screening
tool for BD in primary care.
• Clinical diagnostic assessment should follow any positive screening
for BD.

3.2. Differential Diagnoses

Symptoms of BD can overlap with other disorders. A comprehensive

current and longitudinal history, corroborative history from informants
and relevant investigations are useful to rule out the differential
diagnoses in BD.

Below are common differential diagnoses to be considered in BD:

a) during depressive episode -
• major depressive disorder6
• major depressive disorder with mixed episode21, level III
• adjustment disorder with depressed mood6
• anxiety disorders6
• depressive disorder due to another medical condition6
• substance-induced depressive disorder6
• schizophrenia or schizoaffective disorder6
b) during mania or hypomania episode -
• substance-induced bipolar disorder6
• bipolar and related disorder due to another medical condition6
• schizophrenia or schizoaffective disorder6
• borderline personality disorder6
• attention-deficit hyperactivity disorder (ADHD)22, level III

In a narrative review comparing the overlap and differences of ADHD

and BD, the authors summarised the findings as follows:22, level III
• similarities - distractibility, irritability, insomnia, poor concentration,
talkativeness and psychomotor agitation
• differences were as follows -

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 Management of Bipolar Disorder (Second Edition)

ADHD BD
Childhood or early adolescent onset Adolescent/adult onset
Trait-like, no change from pre-morbid Episodic course, change from pre-
state morbid state
May be excitable but not grandiose/ Grandiosity/elated
elated
Reports being unable to function Reports high-level function, not
reflecting behaviour
Chronic low self-esteem Episodes of depression
Usually possesses insight Tends to lack insight
Difficulty getting off to sleep Reduced need for sleep
Complains of being unable to Subjective sense of sharpened
concentrate/focus mental abilities
Restless (fidgety, difficulty being still) Marked overactivity and agitation

Source: Asherson, P, Young AH, Eich-Höchli D et al. Differential diagnosis, comorbidity,

and treatment of attention-deficit/hyperactivity disorder in relation to bipolar
disorder or borderline personality disorder in adults. Current medical research
and opinion. 2014;30(8):1657-1672

3.3. Co-Morbidities

BD patients may have psychiatric and medical co-morbidities. The co-

morbidities cause difficulties in treatment e.g. decision on the drugs
of choice and consideration of drug interactions. It also affects the
prognosis of BD in terms of aggravating the course of illness, delaying
recovery, increasing risk of recurrence and suicide, and reducing QoL.

The prevalence of eating disorders in BD populations ranges from 1.9%

to 33.3%.23, level III The prevalence of co-morbid antisocial personality
disorder (ASPD) in BD ranges between 4.8% and 63%.It is higher in
BD I (45.1%) than

BD II (8.2%). The most commonly abused substances in BD with ASPD

are a combination of cocaine and alcohol. People with this co-morbidity
have early onset of symptoms, impulsive traits, increased episodes
of depression and mania, aggressive behaviour and high suicide
attempts.24, level I

Other psychiatric co-morbidities in BD include:25, level II-2

• drug abuse (33.5%)
• anxiety disorder (31.8%)
• borderline personality disorder (6.9%)
• ADHD (5.2%)

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 Management of Bipolar Disorder (Second Edition)

Patients with BD may have medical co-morbidities as follows:25, level II-2

• hypertension (31.1%)
• asthma (11.7%)
• diabetes mellitus (11%)
• obesity (11%)
• hypothyroidism (11%)
• migraine (5.5%)

Another co-morbidity is human immunodeficiency virus (HIV) infection

(1%).26, level II-2

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 Management of Bipolar Disorder (Second Edition)

4. TREATMENT

There are several treatment options in BD, including pharmacological

interventions, psychotherapies and physical therapies. Ideally, treatment
needs to be individualised and patient-centered, focusing on patient-
related outcomes.

4.1. Pharmacotherapy

Pharmacological treatment is one of the main pillars in the management

of BD. There is ample evidence on the effectiveness of treatment in
acute mood episodes and the prevention of relapses in the maintenance
phase.

Medications with mood-stabilising properties include lithium, antiepileptic

agents (e.g. valproate, carbamazepine, lamotrigine), haloperidol and
AAPs. Choice of medications is based on the effectiveness, safety,
availability and affordability of the medication, concomitant medications,
response to previous medication, family history of medication response,
patient preference as well as medical and psychiatric co-morbidities.
Refer to Appendix 5 on Recommended Adult Medication Dosages
and Adverse Effects For Bipolar Disorder.

• Response to treatment is defined as a ≥50% reduction of total score

in standardised rating scales.
• Remission is an outcome of effectiveness measured by varying cut-
off points in standardised scales used in clinical trials.

4.1.1. Manic episode

The manic episode in BD poses its challenges with patients potentially

having agitation, impulsivity, risky behaviour, aggression and reduced
insight. The goal of treatment is to rapidly achieve early remission and
return to baseline levels of psychosocial functioning. Pharmacotherapy
remains one of the main treatments for a manic episode.

In a large network meta-analysis on adults with acute bipolar

mania:27, level I
• most of the anti-manic agents (aripiprazole, asenapine, carbamazepine,
cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine,
risperidone, valproate and ziprasidone) were more effective than
placebo; lamotrigine was among those agents found not to be
effective

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 Management of Bipolar Disorder (Second Edition)

• only aripiprazole, olanzapine, quetiapine, risperidone and valproate

showed more acceptability (all-cause discontinuation) compared
with placebo
However, there was no mention on quality assessment of the primary
papers.

The above findings were supported by a more recent network meta-

analysis on adults with acute bipolar mania which showed:28, level I
• the following pharmacological agents as monotherapy were more
effective than placebo in term of response to treatment -
 antipsychotics (APs) - haloperidol, risperidone, paliperidone,
olanzapine, quetiapine, aripiprazole, cariprazine, ziprasidone
 mood stabilisers - lithium, valproate, carbamazepine
• aripiprazole, olanzapine, quetiapine and risperidone had better
acceptability (all-cause discontinuation) than placebo
The quality of most of the primary papers were moderate based on the
risk of bias assessment.

In a systematic review of recently published RCTs after 2017 on adults

with BD, results on acute mania/hypomania found that:29, level I
• olanzapine was more effective than asenapine as an adjunct to
valproate in reducing Young Mania Rating Scale (YMRS) and
Clinical Global Impression-Bipolar Disorder (CGI-BP) scores
• lithium was more effective than aripiprazole in reducing manic
symptoms based on Manic State Rating Scale (MSRS)
• olanzapine was associated with increased waist circumference,
waist-hip ratio and total cholesterol compared with asenapine
• reported AEs in aripiprazole were akathisia, mild stiffness and
sedation whilst tremors were seen in lithium
The risk of bias was reported to be high in most primary papers.

In another systematic review on adults with bipolar mania, lithium was

found to be:30, level I
• more effective than placebo in response, remission and
improvement of YMRS scores
• more effective when used as a combination with either risperidone,
olanzapine, quetiapine, asenapine or carbamazepine compared
with lithium monotherapy
• equally effective to valproate, carbamazepine and quetiapine
There was no mention of quality assessment done on the primary
papers.

A systematic review on the effectiveness and safety of brexpiprazole in

BD I revealed that:31, level I
• brexpiprazole showed no difference in YMRS scores at 21 days
compared with placebo
• akathisia was the only AE with an incidence of 5% being reported

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 Management of Bipolar Disorder (Second Edition)

An open-label RCT comparing the combinations of lithium with either

valproate or carbamazepine in young adults (18 - 35 years old) with BD
I showed that:32, level I
• although both groups had significant improvement in YMRS
scores at eight weeks, there was NS difference between them
• AEs reported in lithium plus valproate group were fatigue,
weight gain and decreased sexual desire while the lithium plus
carbamazepine group had significant increased rates of diarrhoea

A post-hoc analysis of three RCTs on adults with bipolar mania

comparing cariprazine vs placebo showed that the former:33, level I
• was more effective in reducing YMRS scores (SMD= -5.35, 95%
Cl -6.69 to -4.01)
• appeared to have a dose-related response in terms of extra-
pyramidal symptoms (EPS), constipation and, changes in ALT and
AST levels
• had a low incidence of serious AEs with NS difference between
groups

Recommendation 2
• Antipsychotics or mood stabilisers, either as monotherapy* or
combination**, should be used to treat acute mania in bipolar
disorder.

*Monotherapy APs:
• haloperidol, risperidone, paliperidone, olanzapine, quetiapine,
aripiprazole, cariprazine, ziprasidone or asenapine
Monotherapy mood stabilisers:
• lithium, valproate or carbamazepine

**Combination therapies:
• lithium with either valproate, carbamazepine, risperidone, olanzapine,
quetiapine or asenapine
• valproate with olanzapine

4.1.2. Depressive episode

Depressive episodes are debilitating for patients with BD and account

for much of the time spent unwell. This would include subsyndromal
presentation and long-term functional impairment. Management of
depressive episodes in BD proves to be a challenging task given the
risk of treatment-emergent manic switch and increasing choices of
treatment.

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 Management of Bipolar Disorder (Second Edition)

A network meta-analysis on bipolar depression comparing monotherapy

vs placebo showed:34, level I
• response rates were higher with tranylcypromine, venlafaxine,
fluoxetine, imipramine, valproate, olanzapine/fluoxetine
combination (OFC), lurasidone, olanzapine, quetiapine,
cariprazine and lamotrigine
• remission rates were higher with tranylcypromine, fluoxetine,
venlafaxine, OFC, quetiapine, lurasidone, olanzapine, lamotrigine
• reduction in depression severity with fluoxetine, valproate,
lurasidone,cariprazine, olanzapine and quetiapine
• NS difference in discontinuation rate due to AEs for all medications
except aripiprazole (OR=2.25, 95% CI 1.18 to 4.30) and quetiapine
(OR=1.80, 95% Cl 1.26 to 2.55)
Majority (74%) of the primary papers were of low risk of bias.

A recent large network meta-analysis on adults with bipolar depression

compared different pharmacological treatments with placebo and
reported:35, level I
• based on statistically significant effectiveness and good confidence
evidence, the medications that improved depressive symptoms in
MADRS, HAM-D (Hamilton Depression Rating Scale), Inventory
of Depressive Symptomatology (IDS) or Quick Inventory of
Depressive Symptomatology Self-Report (QIDS-SR) were OFC,
quetiapine, olanzapine, lurasidone, lumateperone, cariprazine
and lamotrigine.
• quetiapine reduced the risk of manic switch (OR=0.49, 95% CI
0.33 to 0.75) while NS risk was seen in all other individual drugs
e.g. lithium, antiepileptics, antidepressants or APs
• lumateperone (OR=2.71, 95% CI 1.29 to 5.71) and quetiapine
(OR=1.99, 95% CI 1.51 to 2.63) had a higher risk of discontinuation
due to AEs
Overall quality assessment showed a 94% low risk of bias.

In the third network meta-analysis on adults with bipolar depression

treated with atypical antipsychotic (AAP) monotherapy vs placebo
revealed:36, level I
• significant improvement in MADRS was seen with lurasidone,
olanzapine, quetiapine and cariprazine
• NS difference in discontinuation rate due to AEs among lurasidone,
cariprazine, olanzapine and ziprasidone but significantly higher
risk in aripiprazole and quetiapine
According to SUCRA analyses, lurasidone, olanzapine and quetiapine
ranked first for improvement in MADRS compared with placebo followed
by cariprazine. Based on GRADE assessment, both direct and indirect
comparisons of the above AAPs for both outcomes were of moderate
to high quality.

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 Management of Bipolar Disorder (Second Edition)

Two meta-analyses on adults with acute bipolar depression on mood

stabilisers or APs, comparison between adjunctive of mainly second-
generation antidepressants and placebo showed:37, level I; 38, level I
• small reduction in depressive symptoms in the intervention group
• NS difference in response and remission
• NS difference in affective switch at short-term (up to 26 weeks) but
a risk at long-term (52 weeks)
• NS difference in patients with at least one AE
52.6 % of included trials scored low risk on the measurement of the
outcomes. Most of the 47.4% of studies that scored high risk were
open-label studies.

A few guidelines recommend that antidepressants may be used as

short-term adjunctive treatment but not as monotherapy in acute bipolar
depression.6, 39, 40

In a Cochrane systematic review on glutamate receptor modulators in

BD, the findings were:41, level I
• IV ketamine was more effective in response than placebo at 24
hours only (OR=11.61, 95% CI 1.25 to 107.74) but showed no
difference with midazolam; however, there was no difference in
AEs between ketamine and placebo
• no difference in response between memantine and N-acetylcysteine
compared with placebo

Another systematic review of RCTs on adults with BD compared

monotherapy or adjunctive AAPs vs placebo, the findings for acute
depression were:29, level I
• cariprazine showed significant improvement in depressive
symptoms in two studies and NS changes in one study
• quetiapine showed significant improvement in depressive symptoms,
response rate and remission rate
The papers on cariprazine were of low risk while the ones on quetiapine
had high risk of bias.

For the use of lithium, existing guidelines have recommended that it

may be used in bipolar depression.39, 40

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 Management of Bipolar Disorder (Second Edition)

Recommendation 3
• Atypical antipsychotics* or mood stabilisers**, either as monotherapy
or combination, should be used to treat depressive episodes in
bipolar disorder.
• Antidepressants may be used as short-term adjunctive treatment but
not as monotherapy in acute bipolar depression.
 Occurrence of treatment-emergent manic switch should be
monitored.

*AAPs: olanzapine, quetiapine, lurasidone, cariprazine, OFC, lumateperone

**mood stabilisers: lamotrigine, valproate, lithium

4.1.3. Bipolar disorder with specifiers

Specifiers in BD are descriptive terms on different features of the

disorder. They are outlined in the International Classification of Diseases
(ICD-11) and Diagnostic and Statistical Manual of Mental Health (DSM-
5). Only the three most commonly studied specifiers will be addressed
in this CPG.

a. Mixed features
Mixed features are present in one-third of BD in either manic or
depressive episode. The presence of mixed features is associated
with poorer outcomes e.g. increased time in illness, poorer response
to treatment and suicidality.42 Management of mixed features is
challenging as it needs to address both mania/hypomania and
depressive symptoms that occur simultaneously. Despite its common
prevalence in BD, there is a paucity of RCTs on pharmacological
intervention of mixed features.43

In a systematic review of six international clinical guidelines on the

treatment of mixed states in mood disorders mainly BD among the adult
population, the recommended treatments are summarised in the table
below:

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 Management of Bipolar Disorder (Second Edition)

Phases of BD Mania/hypomania with Depression with mixed

mixed features features
Acute episode
First-line
Monotherapy Olanzapine, aripiprazole, Lurasidone, olanzapine,
asenapine, paliperidone, quetiapine, valproate
Combination Olanzapine + valproate Lurasidone + valproate
therapy Olanzapine + lithium Lurasidone + lithium
Quetiapine + lithium Olanzapine + valproate
Quetiapine + valproate Olanzapine + lithium
Asenapine + valproate Olanzapine/fluoxetine
Aripiprazole + valproate combination (OFC)
Ziprasidone + treatment as
usual

Second-line Cariprazine, ziprasidone, Aripiprazole, asenapine,

risperidone, clozapine, carbamazepine
valproate, lamotrigine,
carbamazepine

Maintenance
First-line
Monotherapy Lithium, valproate, olanzapine, quetiapine

Combination Quetiapine + valproate

therapy Quetiapine + lithium
Aripiprazole + valproate
Aripiprazole + lithium

Second-line Ziprasidone
Risperidone + lithium
Risperidone + valproate
Aripiprazole + lamotrigine

The same review recommended that antidepressants should be

avoided in mixed episodes. Clozapine was an effective option in
treatment-resistant patients.43

A systematic review on adults with BD showed that in those with mixed

episodes:30, level I
• combination of olanzapine plus lithium or valproate was effective
in acute episodes but combination of haloperidol or risperidone
plus lithium or valproate was not
• combination of quetiapine plus lithium or valproate was effective
in preventing relapse but the addition of aripiprazole on lithium or
valproate was not
• lithium monotherapy was not effective in preventing relapse Quality
assessment of primary papers however was not mentioned.

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 Management of Bipolar Disorder (Second Edition)

A post-hoc analysis of three RCTs on acute bipolar depression with

concurrent manic symptoms compared the effectiveness of cariprazine
(1.5 mg and 3 mg) vs placebo at six weeks and showed that the former
had:44, level I
• significantly more improvement of MADRS total score, CGI-S and
HAM-D scores
• significantly higher response and remission rates
• NS improvement of YMRS total score

A 6-week placebo-controlled RCT on adults with bipolar depression

demonstrated that 42 mg of lumateperone, another new AAP, in those
with mixed features had:45, level I
• significantly reduced MADRS total scores (LSMD= -4.4, 95% Cl
-7.26 to -1.52)
• significantly reduced CGI-S-Bipolar Version-Severity (CGI-BP-S)
total scores (LSMD = -0.7, 95% Cl -1.43 to -0.05)
• higher AEs of somnolence and postural dizziness but no difference
in manic switch

The summary of the 2021 CANMAT guidelines for the management of

BD patients with mixed presentations are as follows:42
• there is limited evidence for first-line treatment based on DSM-5
manic or depressive episodes with mixed features
• for DSM-IV-defined mixed episodes, asenapine and aripiprazole
are first- line while olanzapine (monotherapy or combination),
carbamazepine and valproate are second-line agents
• for maintenance treatment following a DSM-IV mixed episode,
quetiapine (monotherapy or combination) is first-line while lithium
and olanzapine are identified as second-line options

b. Anxious distress
Anxious distress is common in BD but often under-recognised by
clinicians. Its symptoms include feeling keyed up or tense, feeling
unusually restless, difficulty concentrating because of worry, feeling that
something awful may happen and feeling that one might lose control.
Prompt evaluation and treatment of its symptoms is important as it is
associated with adverse outcomes including higher suicidal risk and
persistence of bipolar symptoms compared with those without anxious
distress.

A meta-analysis evaluating the effectiveness of pharmacotherapy vs

placebo on BD patients (mostly in depressive episodes) with anxiety
symptoms revealed that:46, level I
• pharmacotherapy (primarily AAPs - cariprazine, quetiapine,
olanzapine and olanzapine-fluoxetine combination) was more
effective based on improvement of scores in Generalized Anxiety
Disorder-7 scale (GAD-7) or Hospital Anxiety and Depression

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 Management of Bipolar Disorder (Second Edition)

scale (HADS) (SMD= -0.22, 95% CI -0.34 to -0.11) and the result
remained significant even after controlling depressive symptoms
(SMD= -0.15, 95% CI -0.28 to -0.02)
• NS difference in all-cause discontinuation rate
A total of 32 out of 37 RCTs had moderate to strong quality based
on assessment with Effective Public Health Practice Project Quality
Assessment Tool.

CANMAT guidelines state that quetiapine, olanzapine-fluoxetine

combination and lurasidone improve anxiety symptoms associated with
bipolar depression.40

c. Rapid cycling
Patients who experience at least four episodes (meeting criteria for full
mania, hypomania or major depression) during a 12-month period are
classified in DSM-5 as “rapid cycling”. The lifetime prevalence of rapid
cycling is between 26% and 43% of those with BD.47 Patients with this
condition are more likely to demonstrate greater severity of illness and,
higher risk at suicide attempts and functional impairment compared
with non-rapid cycling patients.48 Successful treatment of rapid cycling
often requires several combinations of mood-stabilising agents.

A recent meta-analysis on mood stabilisers for treatment of rapid cycling

BD showed the following:49, level I
• combination of lamotrigine and lithium compared to lithium
monotherapy reported:
 better improvement in Positive and Negative Syndrome Scale
(PANSS) (MD= -16.67, 95% CI -22.98 to -10.36) and Brief
Psychotic Rating Scale (BPRS) scores (MD= -3.07, 95% CI
-5.02 to -1.12)
 better response rate (OR=4.26, 95% CI 1.65 to 10.99)
• lithium monotherapy had NS difference in remission rate compared
with any of the three combination therapies (lamotrigine, lithium
and valproate)
There was no mention of AEs. The quality of primary papers was high
based on the Agency for Healthcare Research and Quality (AHRQ)
assessment.

In another systematic review of RCTs and meta-analysis on adults with

rapid cycling BD, it was shown that:30, level I
• both lithium and short-term venlafaxine monotherapy had equal
effectiveness in acute episodes of BD-II depression
• combination of lithium and carbamazepine was more effective in
preventing relapse compared with either monotherapy
• quetiapine as an adjunct to lithium or valproate was effective and
safe in the prevention of mood episodes in BD-I
There was no mention of quality assessment on the primary papers.

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 Management of Bipolar Disorder (Second Edition)

In the third meta-analysis on adults with rapid cycling BD:47, level I

• AAPs and mood stabilisers were more effective than placebo in
 Clinical Global Impression (CGI) with Hedge’s g of 0.79 (95%
CI 0.71 to 0.86) for AAPs and 0.67 (95% CI 0.40 to 0.95) for
mood stabilisers
 Montgomery-Asberg Depression Rating Scale (MADRS)/
Hamilton Depression Rating Scale (HAM-D) score with Hedge’s
g of 0.75 (95% CI 0.56 to 0.93) for AAPs and 0.83 (95% CI 0.57
to 1.08) for mood stabilisers
• AAPs were more effective than placebo in YMRS with Hedge’s g
of 1.11 (95% CI 0.92 to 1.30)
There was a mixture of quality on the primary papers based on risk of
bias (RoB) assessment.

Canadian Network for Mood and Anxiety Treatments (CANMAT)

guidelines has no specific recommendation on the use of
antidepressants in BD with rapid cycling.40 The Royal Australian and
New Zealand College of Psychiatrists (RANZCP) guidelines recommend
antidepressant therapy should be used cautiously in the treatment of
bipolar depression when there is a history of rapid cycling.39

Recommendation 4
• In bipolar disorder with specifiers:
 atypical antipsychotics (AAPs) or mood stabilisers may be used as
monotherapy or combination therapy in mixed features o AAPs may
be used in anxious distress
 combination of mood stabilisers with AAPs or another mood stabiliser
is the preferred treatment of choice in rapid cycling
 antidepressants should be avoided in mixed features and used with
caution in rapid cycling

4.1.4. Maintenance phase

Maintenance phase focuses on prevention of recurrence after remission

of acute mood episodes.

The duration of maintenance phase in BD is debatable. In a meta-

analysis on BD I, pooled results of five RCTs showed that patients
who were stable with combination therapy of mood stabilisers and
AAP had lower recurrence rate at 12 months compared with those on
mood stabilisers and placebo (RR=0.51, 95% CI 0.41 to 0.64 with I2 of
70.03%). There was good to moderate quality of primary papers based
on risk of bias (RoB) assessment.28, level I

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 Management of Bipolar Disorder (Second Edition)

In a systematic review of five international clinical guidelines on long-

term pharmacological management of BD I in adults, the recommended
treatments are summarised below:50
Pharmacological Prevention of any Prevention of manic Prevention of
agents mood episode episode depressive episode
First line: Lithium, valproate, Lithium, valproate, Lithium, valproate,
Monotherapy lamotrigine, quetiapine, lamotrigine,
quetiapine, olanzapine, quetiapine,
olanzapine, aripiprazole, olanzapine,
aripiprazole, asenapine, asenapine
asenapine, paliperidone,
paliperidone, aripiprazole LAI
aripiprazole LAI
(long-acting
injectable/LAI)
Lithium or valproate +
Combination Lithium or valproate + Lithium or valproate + quetiapine
therapy quetiapine quetiapine
Lithium + aripiprazole Lithium + aripiprazole

Second line: Carbamazepine, Carbamazepine, Carbamazepine,

Monotherapy ziprasidone, lamotrigine, clozapine
clozapine, risperidone ziprasidone,
LAI clozapine, risperidone
LAI

Combination Valproate + Valproate + Olanzapine fluoxetine

therapy aripiprazole aripiprazole combination
Lithium or valproate + Lithium or valproate + Lithium or valproate +
olanzapine olanzapine olanzapine
Lithium or valproate + Lithium or valproate + Lithium or valproate +
ziprasidone ziprasidone lurasidone
Lithium or valproate + Lithium or valproate + Lithium or valproate +
lurasidone risperidone LAI lamotrigine
Lithium or valproate + Lithium + valproate
risperidone LAI
Lithium + valproate

The same systematic review on BD I recommended lithium or

quetiapine as the best monotherapy option in the maintenance phase.
For combination therapy, lithium + quetiapine or lithium + aripiprazole
is the first-line treatment. It also mentioned that antidepressant
monotherapy and first-generation antipsychotics (FGA) should be
avoided in the maintenance phase. Clozapine may be considered in
treatment-resistant BD.

A large network meta-analysis (NMA) of 41 RCTs assessed mood

stabilisers or APs as monotherapy or combination therapy vs placebo
in the maintenance phase of BD (mean study duration of 70.5 ± 36.6
weeks). Two categorical NMA were performed and showed the following
results:28, level I

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 Management of Bipolar Disorder (Second Edition)

Studied Lower risk ratio of Lower risk ratio of Lower risk ratio of
medications relapse into any mood relapse into manic/ relapse into
episode (from lowest hypomanic/ mixed depressive episode
to highest) episode (from lowest (from lowest to
to highest) highest)
First NMA • Asenapine • Asenapine • Aripiprazole +
(included • Aripiprazole + • Lithium + valproate
monotherapy valproate oxcarbazepine • Lamotrigine +
and combina- • Lithium + • Aripiprazole LAI valproate
tion therapy oxcarbazepine • Olanzapine, • Quetiapine
in which two • Olanzapine • Risperidone LAI • Lamotrigine
drugs used • Aripiprazole LAI • Lithium + valproate • Olanzapine
were • Lithium + valproate • Aripiprazole • Lithium
specified) • Quetiapine • Aripiprazole +
• Aripiprazole + lamotrigine
lamotrigine • Lithium
• Aripiprazole • Quetiapine,
• Lithium • Paliperidone
• Valproate • Valproate
• Risperidone LAI
• Lamotrigine

Second NMA • Quetiapine + • Aripiprazole + • Lurasidone +

(included lithium or valproate lithium or valproate lithium or valproate
combination • Lurasidone + • Quetiapine + • Quetiapine +
therapy of lithium or valproate lithium or valproate lithium or valproate
SGAs and • Aripiprazole +
lithium or lithium or valproate
valproate • Ziprasidone +
comparing lithium or valproate
with placebo
and lithium or
valproate)

• only asenapine, quetiapine, olanzapine, valproate, lithium

monotherapy and combination of lurasidone or quetiapine +
lithium or valproate had lower all-cause discontinuation rate
• significant AEs reported were:
 lithium and valproate had higher risk of EPS and nausea
 olanzapine had higher risk of somnolence
 risperidone LAI had higher risk of hyperprolactinaemia
 quetiapine had higher risk of dry mouth
 lithium had higher risk of diarrhoea
Most of the RCTs assessed had low to moderate risk of bias based on
Cochrane RoB.

In a meta-analysis of 11 RCTs on long-term effectiveness and safety

of antidepressants in BD (treatment duration ranged up from 4.4 to 36
months), the findings were:51, level I
• combination of antidepressants with mood stabilisers was more
effective than mood stabilisers and placebo for prophylaxis
of new depressive episodes (RR=0.66, 95% CI 0.47 to 0.93;
NNT=12.5), without significant increased risk of new manic/
hypomanic episodes
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 Management of Bipolar Disorder (Second Edition)

• compared with mood stabiliser monotherapy, antidepressant

monotherapy was not superior in preventing new depressive
episodes but had an increased risk of new mania/hypomania
episodes (RR=2.35, 95% CI 1.42 to 3.91; NNH=4.3)
In the subgroup analysis on the prevention of depressive episodes,
patients with BD II benefited significantly with antidepressants (used
as combination or monotherapy) at long-term but not those with BD I.
Apart from that, only second-generation antidepressants were found
to be significantly effective. Three out of 11 RCTs had high risk of bias
based on Cochrane RoB.

However, CANMAT states that usage of antidepressants in BD II

remains controversial due to safety and effectiveness concerns.40

A meta-analysis on SGA LAI on BD, four RCTs found that risperidone

LAI compared with oral active control (olanzapine, aripiprazole,
quetiapine, ziprasidone) had:52, level I
• similar relapse rate for overall and manic/hypomanic episodes
• higher relapse rate of depressive episodes (RR=1.83, 95% CI
1.05 to 3.19)
• similar all-cause discontinuation rate
• comparable risk of EPS and weight gain but higher risk of
hyperprolactinemia (RR=5.75, 95% CI 2.03 to 16.29)
Quality assessment based on the Jadad scores of the RCTs were 3 - 5.

CANMAT guidelines recommend that psychosocial strategies should

be used to improve treatment adherence. If ineffective, LAI medications
e.g. risperidone or aripiprazole LAI should be offered. They are effective
in preventing relapse of any mood episode and mania.40

In a systematic review on BD, clozapine:53, level I

• was as effective as other APs (chlorpromazine, risperidone,
olanzapine and quetiapine) in the improvement of Bech-Rafaelsen
Mania Scale (BRMS) or YMRS scores
• when used as add-on treatment for treatment-resistant BD, was
superior than the treatment as usual (lithium, valproate or APs)
in all outcome measures (BPRS, CGI and BRMS) except for the
HAM-D
• had common AEs of sedation, constipation and tachycardia whilst
severe AEs were reduced white blood cells (5.3%) and seizures
(2%)

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 Management of Bipolar Disorder (Second Edition)

• General principles of maintenance pharmacotherapy in BD are as

follows:50
 medications effective and safe in acute episodes should be
continued
 monotherapy should be preferred
 for combination therapy, pharmacological agents with different
mechanisms of action should be used and, benefits and risks
should be re-evaluated every six months or earlier if indicated

Recommendation 5
• For maintenance pharmacotherapy of bipolar disorder (BD),
 lithium and quetiapine are the preferred first-line monotherapy
while lithium plus quetiapine or aripiprazole are the preferred first-
line combination therapy
 antidepressant monotherapy should be avoided
 aripiprazole or risperidone long-acting injectables may be
considered in patients who have poor adherence to oral
medications especially in preventing manic episodes

4.2. Non-Pharmacological Therapy

Non-pharmacological treatment in BD includes physical therapies,

psychosocial interventions and psychotherapies which are discussed
further below.

4.2.1. Physical therapy

Physical therapies are increasingly common in the treatment of BD and

newer strategies have been developed in recent years. In comparison
to pharmacological treatment, the evidence on the effectiveness and
safety of physical therapies is diverse. Despite this, the use of physical
therapies would be a good complement to the management strategies
and provide alternatives to treatment options.

a. Electroconvulsive therapy
In a systematic review of six international clinical guidelines on the
treatment of mainly mixed states in BD among adult population, ECT was
an effective option in patients with poor response to pharmacological
treatment.43

In another systematic review of five international clinical guidelines on

long-term management of BD I in adults, ECT was an effective second-
line treatment option in prevention of any mood episode.50

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 Management of Bipolar Disorder (Second Edition)

In a 6-week RCT on adults with treatment-resistant bipolar depression,

right unilateral electroconvulsive therapy (ECT) showed lower MADRS
score (MD=6.6 points, 95% CI 2.5 to 10.6) and higher response rate
(p=0.01) compared with pharmacological treatment.54, level I Based on
the same study, there were NS differences in neurocognitive functioning
between the two groups apart from worsening autobiographical memory
in the ECT group.55, level I

Observational studies on patients treated with ECT showed:

• NS difference in number of admissions in one year between pre-
and post-ECT in bipolar patients in a pre-post study on mood
disorder56, level II-3
• increased illness-free interval and, reduced number of mood
episodes and admission in non-rapid cycling BD in a 5-year pre-
and post-ECT57, level II-3
• reduced risk for serious AEs e.g. hospitalisation due to medical
events, non-suicidal death or transfer to a medical bed (HR=0.42,
95% CI 0.20 to 0.92) compared with no ECT on bipolar depression
in a cohort study58, level II-2

RANZCP guidelines recommend the use of ECT as first-line treatment

in mood disorders with severe melancholic depression, imminent risk
of suicide, severe levels of distress, psychotic depression, catatonia,
previous responded to ECT and patients’ preference. It is also
recommended as second-line in patients who fail to respond to one or
more adequate course of medication. Potential AEs on cognition need
to be considered before offering ECT. Adverse memory changes are
short-lived and reversible; more common with bitemporal placement,
higher doses, greater number of treatments and three times weekly
treatment compared with twice weekly.39

MOH guideline on ECT recommends the use of ECT as first-line in

mental disorders when rapid definitive response is required, the risk of
other alternatives outweighs the risk of ECT, previous good response to
ECT, and patients’ preference. ECT may also be considered as second-
line treatment in treatment- resistant cases, patients with severe AEs
to medication and deterioration of psychiatric conditions e.g. severe
or prolonged mania with persistent or life- threatening symptoms.
The same guideline recommends bitemporal ECT for rapid response,
bifrontal placement for those with ischaemic heart disease or cardiac
arrhythmias and unilateral ECT for patients susceptible to profound
confusional state.59

b. Repetitive transcranial magnetic stimulation

A meta-analysis on adults with bipolar depression comparing repetitive
transcranial magnetic stimulation (rTMS) with sham treatment showed
that the former was more effective in achieving clinical response as

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 Management of Bipolar Disorder (Second Edition)

measured by HAM-D or MADRS (OR=2.72, 95% CI 1.44 to 5.14). In

terms of safety, there was only one case of hypomania and one case of
mania. Majority of the primary papers had low RoB.60, level I

A systematic review on adults with BD found that:61, level I

• left rTMS, when compared with sham treatment, was more
effective in improving working memory and processing speed but
not in reducing depressive or manic symptoms while side effects
were comparable between the two groups
• right rTMS, when compared with sham treatment, was more
effective in reducing HAM-D scores at two weeks post-treatment
but conflicting results in its effectiveness in mania
• right rTMS and left rTMS showed similar response and remission
rates in depressive episodes
• bilateral rTMS was more effective than right rTMS in proportion of
responders but equally effective in remission rates in depressive
episodes
The RoB of the primary papers was heterogeneous.

A sham-controlled RCT on adults with BD at a clinically remitted or

non-acute state found that rTMS was more effective in improving
verbal learning but not in areas of processing speed, attention, working
memory, visual learning, reasoning and social cognition. In fact, there
was no dyscognitive effect seen across subdomains.62, level I

c. Deep transcranial magnetic stimulation

In the same systematic review as above, deep transcranial magnetic
stimulation (TMS) was more effective than sham treatment in reducing
HAM-D scores at end-point (four weeks) but not at follow-up (eight
weeks). There were no AEs reported.61, level I

A sham-controlled RCT on adults with treatment-resistant bipolar

depression found that deep TMS was more effective in improving
depressive symptoms (based on HAM-D) but showed NS difference in
response rate, remission rate and cognitive measures at six weeks. There
were no serious AEs.63, level I

d. Theta burst stimulation

A systematic review on adults with BD found that theta burst stimulation
(TBS) showed NS difference in response and remission rates based on
MADRS score compared with sham treatment.61, level I

A sham-controlled RCT on adults with bipolar depression with mixed

features found that TBS as an adjunct showed NS difference in
effectiveness (response and remission rates based on MADRS scores)
and safety.64, level I

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 Management of Bipolar Disorder (Second Edition)

e. Transcranial direct current stimulation

Transcranial direct current stimulation on adults with bipolar depression
demonstrated:
• NS difference in response and remission rate compared with sham
treatment in an 8-week RCT and reported AEs included increased
suicidality, headaches and blurred vision65, level I
• It was more effective as adjunct than sham treatment in response
rate (NNT=2.69, 95% CI 1.84 to 4.99) and remission (NNT=5.46,
95% CI 3.38 to 14.2) in a 6-week RCT but with higher incidences
of skin redness being reported66, level I
• NS difference in cognitive outcomes compared with sham
treatment with no dyscognitive effects reported67, level I

f. Bright light therapy

Adjunct bright light therapy on adults with bipolar depression showed:
• higher response rate (p<0.01) and improvement in HAM-D score
reduction (p<0.01) compared with control in a 2-week RCT while
reported AEs included dizziness, fatigue and sleep disturbance;
no manic switch was reported68, level I
• higher rate of remission (OR=12.64, 95% CI 2.16 to 74.08)
compared with control in a 6-week RCT with no AEs including
manic switch reported69, level I

g. Magnetic seizure therapy

A pre-post study on adults with treatment-resistant bipolar depression
showed that adjunct magnetic seizure therapy led to a reduction in
HAM-D scores (Cohen’s d=1.25, 95% CI 0.42 to 1.57) with a response
rate of 38.5% and a remission rate of 23.1%. Serious AEs reported
were hypomanic episode and hospitalisation due to fall.70, level II-3

h. Vagus nerve stimulation

In a 5-year cohort study involving patients with treatment-resistant
bipolar depression, adjunctive vagus nerve stimulation showed
significant higher cumulative percentages of response based on
MADRS scores from 12 months to 60 months compared with
TAU.71, level II-2.

There is no retrievable evidence on the comparison of physical

therapies.

• The use of ECT in the maintenance phase of BD should be

individualised based on a thorough risk vs benefit analysis, given the
current limited robust evidence.

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 Management of Bipolar Disorder (Second Edition)

Recommendation 6
• Electroconvulsive therapy should be considered in both bipolar
manic and depressive episodes with the following indications:
 rapid definitive response is required
 risk of other alternatives outweighs risk of ECT
 previous good response to ECT
 patient’s preference
 treatment-resistant cases
• Repetitive transcranial magnetic stimulation may be considered in
the treatment of bipolar depression.

4.2.2. Psychosocial intervention

In the treatment of BD, psychosocial interventions may play a crucial

role. A combination of pharmacotherapy and psychosocial intervention
has been recommended in the management of BD.39

A meta-analysis on 11 RCTs investigated the effectiveness of

psychoeducation modules compared with TAU/psychological placebo
(non-specific or shared component of psychological treatment) in
reducing bipolar depression in adults. There was NS difference between
the intervention and comparators at post-treatment and 3 - 12 months
follow-up. GRADE assessment revealed low quality of evidence.72, level I

In summary, established guidelines recommend psychoeducation

in all phases of BD especially in the maintenance phase to patients
and caregivers if appropriate.39, 40, 73 Refer to Appendix 6 on
Psychoeducation for Bipolar Disorder.

In a meta-analysis of seven RCTs comparing smartphone-based

interventions vs control on adults with BD, the findings were:74, level I
• the former (specifically phone call-based and web-based) were
more effective in reducing manic (SMD= -0.19, 95% CI -0.33 to
-0.04) and depressive symptoms (SMD= -0.38, 95% CI -0.61 to
-0.14)
• self-monitoring using smartphone apps was effective in reducing
manic symptoms (SMD=0.27, 95% CI 0.02 to 0.51) compared with
baseline but NS difference for depressive symptoms
Generally, the risk of bias was low based on Cochrane RoB except for
inadequate blinding of participants and personnel in two RCTs.

In another meta-analysis of five RCTs (different RCTs from the earlier

meta- analysis) with more defined use of smartphone-based intervention
on adults with BD, the smartphone-based interventions showed NS
difference in effectiveness in reducing depressive or manic symptoms

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 Management of Bipolar Disorder (Second Edition)

compared with controls. Although the primary papers were of low risk
of bias based on RoB2, there was considerable heterogeneity among
them.75, level I

A 2-years cohort study examining effects of religiosity/spirituality beliefs

and practices on adults with BD showed a reduction in symptoms of
mania (p<0.001) and depression (p=0.001) based on YMRS and
MADRS respectively. Positive religious coping predicted better QoL
across physical, mental, social and environmental domains.76, level II-2

There is limited evidence available on psychospirituality in BD.

Supported employment is an intervention to help individuals with

severe mental illness including BD to secure and maintain meaningful
work. Its principles include competitive employment, rapid job search
and attention to patients’ preferences, among many others.77 NICE
guideline recommends that people with severe mental illness including
BD who wish to find work receive supported employment services.73
These services are available in places e.g. community mental health
centres (MENTARI) or in local psychiatric services. List of available
MENTARI can be accessed via https://mentari.moh.gov.my/ mentari-
minds/.

4.2.3. Psychotherapy

Psychotherapy has been used as adjunctive to pharmacotherapy for

BD. These include cognitive behavioural therapy (CBT), family-focused
therapy (FFT), interpersonal and social rhythms therapy (IPSRT),
mindfulness-based cognitive therapy (MBCT) and dialectical behaviour
therapy (DBT). Different types of psychotherapies can address various
aspects of the condition, helping patients cope with mood swings,
manage stress and improve overall functioning.

A meta-analysis of 11 RCTs on adults with bipolar depression examined

the effectiveness of psychotherapies in reducing depressive symptoms.
The study found that:72, level I
• at post-treatment -
 CBT was more effective in reducing depressive symptoms
compared with TAU (SMD= -0.51, 95% CI -0.75 to -0.27)
 MBCT group therapy was more effective in reducing depressive
symptoms compared with TAU (SMD= -0.47, 95% CI -0.88 to
-0.06) but not with waiting list
 DBT group therapy was more effective in reducing symptoms
of depression compared with waiting list (SMD= -1.18, 95% CI
-2.06 to -0.30)

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 Management of Bipolar Disorder (Second Edition)

 both group therapy for family therapy and IPSRT were not
effective in reducing depressive symptoms compared with
placebo
• at 3 - 12 months follow-up, both CBT and MBCT group therapy
had NS effect on reducing symptoms of depression compared
with TAU or placebo
Overall, the quality of studies was low, other than for studies examining
psychoeducation vs placebo in which the quality was moderate based
on GRADE.

However, in a large network meta-analysis on adjunctive psychotherapy

vs TAU on adults with BD, evidence showed that CBT (individual and
group) was more effective compared with TAU at 12 months follow-
up in reducing depressive symptoms (SMD= -0.32, 95% CI -0.64 to
-0.01). The overall quality of studies was mixed based on Cochrane
RoB assessment.78, level I

Another meta-analysis of three RCTs on adults with BD explored the

effectiveness of group CBT vs TAU/individualised therapy in reducing
depressive and manic symptoms. The study revealed that group CBT
was not effective in reducing depressive or manic symptoms. The
overall RoB 2 of the primary studies was of some concern.79, level I

In a meta-analysis of five RCTs on adults with BD using IPSRT as an

adjunct treatment vs control, evidence found that IPSRT was more
effective in improving:80, level I
• depressive symptoms [Longitudinal Interval Follow-up Evaluation
(LIFE)] (Hedge’s g= -0.23, 95% CI -0.62 to 0.16)
• recovery rate of depression (MADRS) (Hedge’s g= -0.29, 95% CI
-0.55 to -0.03)
• stability of social rhythm [Social Rhythm Metrics (SRM)] (Hedge’s
g= -0.69, 95% CI -1.33 to -0.04)
• occupational, social and impaired functioning score (UCLA Social
Attainment Scale, Social Adjustment Scale (SAS) and Longitudinal
Interval Follow-Up Evaluation-Range of Impaired Functioning
Tool (LIFE-RIFT) respectively] (Hedge’s g= -0.34, 95% CI -0.55 to
-0.14)
The overall quality of the primary papers was mixed based on RoB.

The above findings were supported by a recent RCT on adults with BD

receiving IPSRT as an adjunct treatment. It showed that compared with
control, IPSRT reported a significant improvement in:81, level I
• anxiety symptoms [Hamilton Rating Scale for Anxiety (HAM-A)]
• manic symptoms [Mania Rating Scale (MRS)]
• depressive symptoms [Inventory of Depressive Symptomatology
Self- Report (IDS-SR)
• global functioning [Global Assessment of Functioning (GAF)]

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 Management of Bipolar Disorder (Second Edition)

• response to mood stabilisers [Retrospective Criteria of Long-term

Treatment Response in Bipolar Disorder (ALDA Scale)]
• psychological functioning [Affective Morbidity Index (AMI)]

A meta-analysis on adults with BD compared MBCT vs TAU/waitlist

and found NS difference in improvement of depressive and anxiety
symptoms. The three related RCTs had mixed RoB.82, level I

The evidence on the effectiveness of Acceptance and Commitment

Therapy (ACT) in managing BD is limited. A single-group clinical
trial of adults with BD receiving group ACT as an adjunct treatment
showed significant change in the following outcomes compared with
baseline:83, level II-3
• decrease in anxiety symptoms [Beck Anxiety Inventory (BAI)]
• decrease in depressive symptoms [Beck Depression Inventory
(BDI- II)]
• increase in QoL [The Quality of Life Inventory (QOLI)]
• increase in psychological flexibility [The Acceptance and Action
Questionnaire (AAQ-2)]

In a narrative review on the management of BD based on well-

established guidelines, adjunctive psychosocial interventions and
psychotherapies that had been recommended in acute depression
and maintenance were CBT, IPSRT, FFT ± psychoeducation.84, level
III In the first edition of local CPG, psychosocial interventions were

recommended to be incorporated into patients’ care in addition to

pharmacological treatment in BD.6 The CPG DG opines that this should
be maintained in the treatment of BD despite the mixed results and
quality of the latest evidence.

Recommendation 7
• Psychosocial interventions and psychotherapies should be offered
as an adjunctive treatment for bipolar disorder.

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 Management of Bipolar Disorder (Second Edition)

5. COMPLEMENTARY AND ALTERNATIVE THERAPIES

Persons with BD often self-medicate themselves with complementary

and alternative medicine (CAM) despite limited evidence supporting
their use.85

Complementary therapies mentioned in RANZCP include regular

exercise being associated with improved QoL, although its benefits in
BD remain less clearly defined.39 Meanwhile, in a systematic review
of nutraceuticals use in BD, there was promising, albeit conflicting
evidence for omega-3 fatty acids, N-acetylcysteine and coenzyme
Q10.86

Meanwhile, in Malaysia, among the common alternative therapies

used are cannabis and kratom (ketum).87, level III Interactions between
cannabis use (CU) and BD are complex and bidirectional whereby one
may contribute to the other. The prevalence of CU is increasing globally
and yet there’s limited research done on the treatment options for co-
morbid BD and CU.40

In a systematic review, a case series on patients diagnosed with BD and

treated with cannabidiol (CBD) monotherapy showed no therapeutic
benefits in improving manic symptoms compared with the combination
of olanzapine and CBD.88, level III

Moreover, the CANMAT Task Force Report 2022 showed that CU in BD

was associated with a worsened illness course, decreased functionality
and increased mortality through suicide.89

• There is insufficient evidence for the use of cannabis and kratom in

the treatment of BD.

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 Management of Bipolar Disorder (Second Edition)

6. FOLLOW-UP/MONITORING AND REFERRAL

When managing BD, exploring several key aspects to provide effective

care during follow-up is crucial. Monitoring symptoms over time is
essential to assess the response to treatment and the current state,
whether in stable, remission or relapse. Besides that, it is important to
review the compliance with medication and presence of AEs.

6.1. Parameters to be Monitored during Maintenance Phase

Parameters recommended to be monitored during the maintenance

phase of BD at regular intervals are:6
• weight
• height
• waist circumference
• blood pressure
• electrocardiogram (ECG)
• full blood count
• fasting blood sugar
• renal function
• liver function
• lipid profile
• thyroid function
• serum calcium level
• drug serum level

• Lithium has a narrow therapeutic index and a risk of toxicity. In the

first edition of the MoH CPG on BD, lithium monitoring has been
recommended to be carried out at least every six months.6 Monitoring
should also be done earlier in dose adjustment or suspected toxicity.

Recommendation 8
• Serum lithium level should be monitored one week upon initiation or
dose change, and every six months or earlier if indicated.

Refer to Appendix 7 on Parameters for Monitoring during Treatment

of Bipolar Disorder

6.2. Referral Criteria

There is no direct evidence on referral criteria for BD. Existing

guidelines state that BD can be managed in primary care except in the
following conditions where the cases need to be referred to psychiatric
services:6, 73

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 Management of Bipolar Disorder (Second Edition)

• unsure of diagnosis
• complex presentation of mood episodes
• acute exacerbation of symptoms
• increased risk of harm to self or others
• marked impairment in social or occupational functioning
• poor or partial response to treatment
• poor treatment adherence
• intolerable or medically important AEs of medication
• psychiatric co-morbidities
• psychotherapeutic needs
• ambivalent or wanting to stop any medication after a period of
relatively stable mood
• special population-
 pregnant or planning a pregnancy
 children and adolescents
 co-morbidity with alcohol or substance misuse

People with BD whose symptoms have responded effectively to

treatment and remain stable may have the option to return to primary
care for further management. Care plans for this group of people
include the following:73
• latest mental state assessment and diagnosis
• detailed medication plan for review and monitoring by primary care
providers
• concise and individualised recovery plan
• crisis alert plan on early warning symptoms, triggers of relapse
and referral pathways

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 Management of Bipolar Disorder (Second Edition)

7. RELAPSE PREVENTION AND ADHERENCE

7.1. Prevention of Relapse

In BD, relapse is defined as a new mood episode occurring within

8 weeks after having achieved remission from the index episode.90
Adjunctive psychosocial interventions and psychotherapies e.g.
psychoeducation, cognitive behavioural therapy (CBT) and family
therapy are useful to prevent relapse. These interventions vary in
method of delivery (e.g. individual vs group format), its contents and
duration of intervention.

A meta-analysis on adults with BD demonstrated that psychoeducation:91, level I

• was more effective than TAU in not relapsing (preventing relapse)
into any episode (OR=1.98, 95% CI 1.09 to 3.58; NNT=7, 95% CI
4 to 25)
• subgroup analysis showed that group delivery was effective in not
relapsing (preventing relapse) into:
 any episode (OR=2.80, 95% CI 1.63 to 4.82; NNT=4, 95% CI 3
to 7)
 manic episode (OR=2.07, 95% CI 1.11 to 3.85; NNT=6, 95% CI
3 to 39)
 depressive episode (OR=2.08, 95% CI 1.05 to 4.12; NNT=6,
95% CI 3 to 77)
• subgroup analysis also showed that individual delivery was not
effective in not relapsing (preventing relapse) into any mood,
manic and depressive episodes
The quality of most of the primary papers was moderate based on RoB.

The above was supported by another meta-analysis of patients with BD

on pharmacotherapy where the following adjuvant group interventions
were more effective than TAU in the prevention of relapse:92, level I
• psychoeducation (RR=0.65, 95% CI 0.55 to 0.77)
• CBT (RR=0.68, 95% CI 0.50 to 0.94)
Quality assessment of primary papers however was not mentioned.

Another meta-analysis, however, on relapse prevention in a similar

study population showed effectiveness in group psychoeducation
(OR=0.43, 95% CI 0.28 to 0.62) but not in group CBT (OR = 0.72, 95%
CI 0.19 to 2.66) when compared with control. The authors concluded
that studies included in group CBT were of small size and hence
might not achieve adequate statistical power to detect the differences
between the groups.79, level I Most of the primary papers used in this
meta-analysis had some concern of bias based on Cochrane RoB2.

In a large NMA on adults with BD on adjunctive psychosocial interventions,

two high-quality RCTs showed carer-focused interventions e.g.

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 Management of Bipolar Disorder (Second Edition)

psychoeducation was more effective than TAU in relapse prevention

(RR=0.61, 95% CI 0.44 to 0.86).93, level I

In another large NMA on patients with BD, the following adjunctive

psychotherapies were more effective than TAU for relapse
prevention:78, level I
• standard psychoeducation ≥6 group or individual sessions
(OR=0.52, 95% CI 0.32 to 0.84)
• brief psychoeducation ≤3 group or individual sessions (OR=0.34,
95% CI 0.16 to 0.74)
• family or conjoint therapy (OR=0.30, 95% CI 0.17 to 0.53)
• CBT (OR=0.52, 95% CI 0.34 to 0.79)
Most of the primary papers were rated to have low to moderate risk of
bias.

Meanwhile, in a small RCT on adults with BD, adjunctive mindfulness-

based cognitive therapy was not effective compared with TAU in
preventing the recurrence of depressive or hypo/manic episodes over a
12-month follow-up period.94, level I

7.2. Strategies to Improve Adherence

Adherence to treatment within patients with BD may change over time

and vary between different pharmacotherapies. About half of patients
with BD become non-adherent during long-term treatment.95, level I Non-
adherence in BD is a complex phenomenon determined by a multitude
of factors.

Significant risk factors for non-adherence are:6

• difficulties with medication routines
• negative attitudes towards drugs in general
• depressive polarity of the last acute episode
• presence of subsyndromal symptoms
• co-morbid obsessive-compulsive disorder
• current acute episode
• substance abuse/dependence
• younger age
• AEs

Enhancing adherence involves employing various approaches, which

are psychological interventions, personalised adherence enhancement,
technology- assisted strategies and community-based care which are
discussed below.

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 Management of Bipolar Disorder (Second Edition)

7.2.1. Psychological interventions

The most frequently studied intervention for enhancing adherence is

psychoeducation.

In a large NMA assessing non-adherence in patients with BD on

pharmacotherapy, a lower risk of non-adherence was found among
those who received psychoeducation alone (RR=0.27, 95% CI 0.14 to
0.53) or a combination of psychoeducation and CBT (RR=0.14, 95%
CI 0.02 to 0.85) compared with TAU. The author concluded that many
adjunctive psychosocial interventions lacked high-quality evidence to
support their effectiveness which includes adherence.93, level I

A meta-analysis of 18 RCTs among adults with BD on pharmacotherapy,

psychological interventions (e.g. family-focused therapy, CBT, cognitive
psychoeducation therapy (CPT), psychoeducation] were more effective
than control in improving medication adherence (OR=2.27, 95% CI
1.45 to 3.56).23, level I There was a mixture of quality of primary papers
based on RoB.

In an RCT of adults with BD on mood stabilisers, multifaceted interventions

that include motivational interviewing and psychoeducation were more
effective than control in improving adherence at 1- and 6-month post-
intervention as indicated by a higher Medication Adherence Rating
Scale (MARS) score and plasma level of mood stabilisers.96, level I

7.2.2. Customised adherence enhancement

Customised adherence enhancement (CAE) is a module that combines

the following strategies:97, level II-3
• psychoeducation which includes information on BD and its
neurobiological facets, medication management and creation of
an individualised symptom profile to detect early signs of relapse
• modified motivational enhancement therapy where the overall
goal is to enhance personal motivation to increase the likelihood
of medication adherence
• communication with providers where individuals are supported
with discussions on the crucial aspects of treatment planning
including expectations for medication response and concerns
about medication AEs
• medication routines that aim to help individuals adjust their
treatment plans as needed and engage in discussions with
healthcare providers.

In an RCT among poorly adherent individuals with BD, CAE had

significantly improved adherence at six months based on a reduction in

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 Management of Bipolar Disorder (Second Edition)

Tablet Routine Questionnaire (TRQ) mean score when compared with

BD-specific educational program. No AEs reported.98, level I

7.2.3. Technology-assisted strategies

The technology-assisted strategies that are explored in adherence-

related intervention studies include medication event monitoring system
(MEMS), short messaging service (SMS) and android smartphone-
based self-monitoring system (MONARCA System) which are described
below.

In an RCT on medication adherence among poorly adherent individuals

with BD, MEMS bottle caps detected worse adherence compared with
self-report TRQ (66.43% vs 46.61%) with a correlation between them of
0.47 (p<0.01). The findings showed that both self-report and automated
medication monitoring were reasonable methods of evaluating
adherence, although the latter was likely to provide a more sensitive
assessment on the missed drug.99, level I

In another RCT on treatment adherence in adults with BD I, those

who received a twice-weekly mobile phone-based SMS reminder
intervention for three months showed better adherence and attitude
towards the medication, based on the Morisky Medication Adherence
Scale and Drug Attitudes Inventory respectively, compared with
TAU.100, level I

In two RCTs comparing MONARCA system vs control, the findings were:

• NS difference in medication adherence based on plasma
concentration of medications on adults with BD I at six months.
However, patients in the intervention group had significantly more
depressive symptoms.101, level I
• NS difference in medication adherence measured by MARS on
BD patients at nine months. However, the intervention group
had higher depressive episodes (HR=2.89, 95% CI 1.02 to
8.23).102, level I

7.2.4. Community-based care

There was limited evidence on adherence interventions for BD patients

conducted in the community setting.

A pre-post study of a Life Goal Program (a structured group psychotherapy

programme) delivered at three community mental health centres
demonstrated a significant increase in knowledge about BD among the
participants with a large effect size (Cohen’s d= 0.85) compared with
baseline. However, there is NS difference in medication adherence as
measured by MARS.103, level II-3

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 Management of Bipolar Disorder (Second Edition)

A cohort study that included patients with BD I with psychotic features

revealed that ACCESS model (assertive community treatment) reported
full adherence measured using an expert consensus panel criteria in
the majority of BD patients (91.3%) at 24 months.104, level II-2

Recommendation 9
• Psychosocial interventions (e.g. psychoeducation) and psychotherapies
(e.g. cognitive behavioural therapy) should be part of strategies in
relapse prevention of bipolar disorder.

7.3. Collaborative Care Models

Collaborative care is an intervention that aims to facilitate communication

and joint working relationships between health professionals (e.g. family
physicians, psychiatrists, psychologists, pharmacists, nurses, etc.) in
delivering integrated and comprehensive care to patients in various
healthcare settings. It can be done in several ways and incorporates
at least three of the following components i.e. patient self-management
support, delivery system redesign, use of clinical information systems,
provider decision support, health care organisation support and linkage
to community resources.105, level III Refer to Appendix 8 for Collaborative
Care Model Core Elements.

In a systematic review of six RCTs comparing the effectiveness of

collaborative care with TAU on adults with BD, the findings were:106, level I
• NS difference in 2-year relapse rate of manic/hypomanic and
depressive episodes
• mixed effects on depression, mania and functionality
The RCTs assessed by the Cochrane RoB tool were of mixed quality.

A recent RCT compared collaborative care model vs TAU using

telepsychiatry services in primary care over a 12-months period on
adult patients. Adults with BD showed improvement in the following
outcomes with NS differences between groups:107, level I
• mental health QoL (measured with Veterans RAND 12-Item Health
Survey Mental Health Component Summary)
• depression (measured with Hopkins Symptom Checklist
Depression Scale)
• anxiety (measured with GAD-7)

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 Management of Bipolar Disorder (Second Edition)

8. SPECIAL POPULATION

8.1. Pregnancy and Lactation

There is a high risk of relapse of BD during pregnancy or the post-

partum period especially in patients not on treatment. There is,
however, the issue of specific considerations to be given on the use
of medications during these periods based on the new Pregnancy and
Lactation Labelling Final Rule of the US Food and Drug Administration
(FDA) as shown in Appendix 9. If medications are deemed necessary,
preference should be given to monotherapy using the lowest effective
dose.40

Given the complexity of BD management in this group of women, it is

advisable to co-manage them with the obstetrics team. Risks-benefits
analysis of medications on both women and the developing foetus and
infant should be done with the patients using a shared decision-making
approach.

The Guidelines on Pre-Pregnancy Care in MOH Specialist Hospital

suggest that all women of reproductive age with BD should be referred
to a pre-pregnancy care team to optimise their mental health condition
before conception, pregnancy and lactation.108

In a large meta-analysis of six cohort studies, the use of lithium in

pregnancy showed NS difference in risk of:109, level II-2
• diabetes in pregnancy
• pre-eclampsia
• small for gestational age
• major malformations including cardiac malformations
• foetal distress
• caesarean section
• preterm birth
• low birth weight
• post-partum hemorrhage
However, there was a small risk of neonatal admission to a special care
baby unit prior to 28 days of age (OR=1.28, 95% CI 1.12 to 2.33). There
was no mention on quality assessment of the primary papers.

• The use of lithium in pregnancy should be cautioned given small

studies, heterogeneity of results and no report on quality assessment
of primary papers in the meta-analysis mentioned above.
• However, lithium may be used on a case-to-case basis after careful
consideration of risk and benefits e.g. women with high risk of relapse
without lithium.

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 Management of Bipolar Disorder (Second Edition)

A systematic review of observational studies on the use of mood

stabilisers in pregnancy showed the following outcomes:110, level II-2
• Lamotrigine had a favourable reproductive risk profile and was
a preferred option for women of childbearing age, although an
increased risk of cleft lip and palate, heart malformations and
hypospadias were reported (more frequent with doses over 300
mg/day).
• Valproate and carbamazepine were classified by FDA as drugs
contraindicated during pregnancy with the following adverse
outcomes.
 Valproate was considered the most teratogenic drug since it
had a 1 - 5% rate of foetal abnormalities, particularly neural
tube defects and especially with doses over 1,000 mg/
day. Additionally, children exposed to valproate prenatally
showed higher rates of low Intelligence Quotient (IQ),
neurodevelopmental deficits, reduced verbal abilities, attention
deficit hyperkinetic disorder and autism spectrum disorder.
 Carbamazepine use was associated with teratogenicity e.g.
neural tube defects, craniofacial abnormalities, etc.

Since 2020, the National Pharmaceutical Regulatory Agency (NPRA)

has endorsed the use of the Annual Risk Acknowledgment form for
valproate in women with BD in child-bearing ages (refer to Appendix
10a and 10b).

There is insufficient evidence on the safety profile of APs use in BD

with pregnancy. However, RANZCP guidelines state that AAPs e.g.
quetiapine or olanzapine can be used in the treatment of BD with
pregnancy as they are generally considered to be safe aside from a
risk of gestational diabetes and having a large baby.39

In a systematic review of case series/reports, ECT use in first trimester

of pregnancy showed no safety concerns for the mother or foetus
including teratogenicity.111, level III

In another systematic review of mainly case series/reports on mood

stabilisers and APs use in lactation, the findings were:112, level II-2
• carbamazepine, valproate, quetiapine, olanzapine and risperidone
were relatively safe either due to their limited passage into breast
milk or low infant plasma concentrations
• lamotrigine had high variability in infants’ plasma concentration but
no serious AEs and thus can be considered for individual cases
• lithium was a possible treatment option although there was high
variability of transfer into breast milk
• other AAPs e.g. aripiprazole, paliperidone, lurasidone, ziprasidone
and asenapine were not recommended due to the scarcity of data

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 Management of Bipolar Disorder (Second Edition)

Recommendation 10
• Shared decision-making in weighing the risks versus benefits of
pharmacological treatment should be done in pregnant and lactating
women with bipolar disorder.
 Atypical antipsychotics e.g. olanzapine and quetiapine may be
used in pregnancy.
 Valproate and carbamazepine should be avoided in pregnancy
given their teratogenic risks. Other mood stabilisers should be
used with caution.

8.2. Elderly

Older adults make up 25% of all bipolar patients and this number is
expected to increase along with the world’s ever-aging population.97
Older age bipolar disorder (OABD) includes both elderly patients
whose bipolar disorder has commenced earlier in life and those who
present for the first time in later life. There is sparse data on OABD, thus
current guidelines recommend that first- line treatment of OABD should
be similar to that for the general population with BD, whilst specifically
paying attention to side effects, co-morbidities and specific risks in
elderly patients.113 In particular, careful consideration must be given
to the pharmacokinetic and pharmacodynamic changes that occur in
elderly patients.

A double-blind RCT comparing lithium and valproate in older patients

with BD reported that:114, level I
• lithium was more effective than valproate based on YMRS scores
at week nine (Cohen’s d=0.54, 95% CI 0.17 to 0.91)
• both lithium and valproate were equally tolerated with slightly more
tremor with lithium

On the other hand, a cohort study on lithium vs AAPs which included

aripiprazole, quetiapine, risperidone, olanzapine and lurasidone for BD
in older war veterans showed:115, level II-2
• all-cause discontinuation rate (lack of effectiveness, loss to follow-
up and AEs) was significantly higher in lithium compared with
AAPs
• NS difference in discontinuation rate due to AEs
• tremor, renal failure, toxicity and bloating/swelling were more
often reported with lithium whilst extrapyramidal symptoms (EPS),
sedation, restlessness and hallucinations were more with AAPs

In an RCT comparing lurasidone and placebo in older adults with bipolar

I depression, the findings were:116, level I

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 Management of Bipolar Disorder (Second Edition)

• in monotherapy -
 those on placebo who switched to lurasidone had better
improvement in depressive symptoms (reduction in MADRS
score)
 no increase in mean weight or glycaemic indices and low rates
of switching to hypomania or mania
• in adjunct with lithium or valproate -
 NS difference in reduction of MADRS score
 higher rate of akathisia and tremor were noted
• common AEs for both monotherapy and adjunctive lurasidone
therapy include headache, nasopharyngitis and insomnia

8.3. Children and Adolescents

Paediatric bipolar disorder (PBD) is a diagnostic challenge as children

have yet to achieve emotional, neurocognitive and physical maturity. A
meta-analysis of 19 studies showed that the prevalence rate of bipolar
spectrum disorders among young people below 21 years of age was
3.9% (95% CI 2.6% to 5.8%).117, level III Early diagnosis of BD is crucial
but over-diagnosis comes with its risks of medical-related AEs and
stigmatisation.

Signs and symptoms of BD may overlap with symptoms of other

psychiatric disorders that may occur in young people e.g.:40
• ADHD
• conduct disorder
• disruptive mood dysregulation disorder
• oppositional defiant disorder
• schizophrenia
• substance use disorder
• unipolar depression

• Proper clinical assessment by a psychiatrist is important to rule out

co- morbidities in children and adolescents presenting with symptoms
of BD.

Family history of BD, especially if the parents developed BD early in

life and the young person has a history of prominent mood lability,
depression/anxiety and subsyndromal manic/hypomanic symptoms
suggest a risk of developing BD.118, level III

The role of pharmacotherapy in paediatric mental health remains the

object of debate and controversy. Careful consideration of treatment
options should be given after weighing the benefits and risks.

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 Management of Bipolar Disorder (Second Edition)

In a meta-analysis of RCTs on the use of lithium vs active comparators/

placebo for acute mania in children with BD, it was shown that:119, level I
• lithium was less effective than risperidone in treating manic/mixed
episodes among young people aged 6 - 15 years (SMD= 0.85,
95% CI 0.54 to 1.15) but had NS difference vs valproate or placebo
• majority of the AEs were described as mild to moderate
• high rates of psychiatric co-morbidity across all studies with the
highest being ADHD
There was a potential high or unclear risk of bias in the included primary
papers based on RoB.

An RCT of lithium vs quetiapine for the treatment of acute mania in young

people of 10 -17 years of age with BD reported that quetiapine:120, level I
• showed a greater reduction in YMRS score (-11.0 vs -13.2,
p<0.001)
• had a higher response rate (72% vs 49%, p=0.012)
• showed NS difference in remission rates
• had more somnolence (p<0.001), dizziness (p<0.05) and weight
gain (p=0.02)

In an RCT in the treatment of adolescents with BD in manic or mixed

episodes, compared with placebo, olanzapine:121, level I
• showed a greater reduction in YMRS score (p<0.001)
• had higher response (RR=2.19, 95% CI 1.28 to 3.74; NNT=3.80)
and remission (RR=3.17, 95% CI 1.43 to 7.04; NNT=4.14) rates
• had shorter times-to-reach response (p=0.003) and remission
(p=0.002) criteria
• had significantly higher common AEs with a frequency ≥5% for
increased appetite, weight gain and somnolence and sedation

In a 3-week RCT on acute treatment of manic or mixed episodes in 10 -

17-year- old patients with BD I, asenapine of three different doses was
significantly more effective than placebo (MDs for YMRS were -3.2,
-5.3 and -6.2 for asenapine 2.5 mg, 5 mg and 10 mg bd respectively).
The treatment-emergent AEs (≥5%) were somnolence, sedation, oral
hypoaesthesia/paraesthesia and increased appetite.122, level I An open-
label extension study of the same RCT demonstrated that most AEs
were mild or moderate in severity at 50 weeks. The additional reported
AEs (≥5%) were increased weight, headache, nausea, vomiting, fatigue
and upper abdominal pain.123, level I

In a 30-week RCT on manic/mixed episode of 10-17-year-old patients

with BD I, compared with placebo, aripiprazole:124, level I
• was significantly more effective (mean change from baseline for
YMRS was 14.1 and 14.9 for aripiprazole with daily doses of 10
mg and 30 mg respectively); the findings were consistent in a
subgroup analysis of 10

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 Management of Bipolar Disorder (Second Edition)

- 12-year-old and 13 - 17-year-old study subjects with or without

prior bipolar treatment
• showed greater response rates with both doses (p<0.01)
The commonly reported AEs were somnolence, headache and EPS.

In a recent RCT on 10 - 17-year-old patients with BD I in manic/mixed

episodes, ziprasidone was more effective than placebo (MD in YMRS
total score= -4.23, 95% CI -7.14 to -1.32). The common AEs were
somnolence, fatigue and nausea.125, level I

A double-blinded RCT on 10 - 17-year-old with BD I with manic/mixed

episodes showed NS difference in effectiveness and safety between
valproate ER monotherapy and placebo.126, level I

A meta-analysis of three RCTs on quetiapine monotherapy vs placebo in

children and adolescents with bipolar depression showed NS difference
in the following outcomes:127, level I
• Children’s depression rating scale revised (CDRS-R), CGI-BP-S
scores, response and remission rates
• discontinuation rate due to AEs
Based on the GRADE assessment, all outcome qualities were moderate
to high.

In an NMA of four RCTs on 10 - 18-year-old young persons with bipolar

depression, the effectiveness and safety of AAPs (lurasidone, OFC and
quetiapine) were compared with placebo. The findings were:128, level I
• improvement in CDRS-R with lurasidone (MD = -5.70, 95% CI
-8.66 to -2.76) and OFC (MD= - 5.0, 95% CI -8.63 to -1.38) but
not with quetiapine
• improvement in CGI-BP-S depression scores with lurasidone
(MD= -0.40, 95% CI -0.68 to -0.12) but not with OFC
• improvement in CGI-BP-S overall scores with lurasidone (MD=
-0.40, 95% CI -0.68 to -0.12) but not with OFC and quetiapine
• improvement in response rate with lurasidone (OR=2.64, 95% CI
1.67 to 4.01; NNT=5) and OFC (OR=2.64, 95% CI 1.43 to 4.50;
NNT=6) but not with quetiapine
• improvement in remission rate with OFC (OR=1.93, 95% CI 1.10
to 3.17; NNT=7) but not with lurasidone and quetiapine
• discontinuation due to AEs, quetiapine had fewer discontinuation
vs placebo (OR=0.32, 95% CI 0.07 to 0.83) whereas OFC had
more discontinuation vs placebo (OR=3.31, 95% CI 1.08 to 8.75)
and quetiapine (OR=15.08, 95% CI 2.32 to 56.84)
Based on SUCRA rankings, lurasidone had the highest rank followed
by OFC and quetiapine in terms of effectiveness. For safety, quetiapine
was ranked first followed by lurasidone, placebo and OFC. GRADE
assessment gave mixed quality on the various outcomes.

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 Management of Bipolar Disorder (Second Edition)

Recommendation 11
• For children and adolescents with bipolar disorder:
 atypical antipsychotics* monotherapy may be used in manic or
mixed episodes
 lurasidone and olanzapine/fluoxetine combination may be used in
depressive episodes

*aripiprazole, asenapine, lurasidone, olanzapine, quetiapine, risperidone

and ziprasidone

Refer to Appendix 11 for Suggested Paediatric Medications Dosing.

8.4. People with Substance Use Disorder

Substance use disorder (SUD) is a common co-morbidity of BD.

Substance use may cause, mimic, underlie or complicate mental health
disorders. Empirical evidence to guide optimal management of BD and
co-morbid SUD is scarce, partly because such patients are difficult to
engage in clinical trials.

NICE guidelines have recommended that the use of alcohol, tobacco,

prescription and non-prescription medication, and illicit drugs should be
discussed with people with BD to address the negative effects of these
substances.73

In a guidelines on the pharmacological and psychological management

of adult patients with BD and co-morbid SUD, the following are
recommended:129
• adjuvant valproate or naltrexone may improve symptoms of
alcohol use disorder
• lamotrigine add-on therapy may reduce cocaine use
• varenicline may improve nicotine abstinence
• integrated group therapy may reduce substance use and BD
symptoms
The strength of recommendations was weak to moderate based on
GRADE.

An RCT on adjunctive psychosocial intervention for BD patients with

co-morbid substance use found that Integrated Treatment Adherence
Program (which combined elements of CBT and Acceptance and
Commitment Therapy) significantly improved depression, mania,
functioning and values-consistent living compared with those on
Enhanced Assessment and Monitoring (enhanced TAU). There was
also a trend for increased treatment adherence.130, level I

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 Management of Bipolar Disorder (Second Edition)

8.5. People with Borderline Personality Disorder

Borderline personality disorder (BPD) is a co-morbid of BD, each

amplifying the symptoms of the other hence delaying time to remission.

NICE and CANMAT guidelines state that drug treatment should not be
used specifically for symptoms or behaviour of BPD. However, AAPs
and mood stabilisers are valuable in treating BPD with co-morbid
BD.40, 73 Meanwhile, the RANZCP guidelines recommend psychotherapy
as the fundamental management of BPD and is of considerable
importance in the management of BD.39

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 Management of Bipolar Disorder (Second Edition)

9. SUICIDE PREVENTION

Annually, WHO estimates that 703,000 people die by suicide.131 In low-

and middle-income countries, 58% of those who died by suicide and 45%
of those who engaged in non-fatal suicidal behaviour had a psychiatric
disorder.132 Among those living with mental illnesses, people with BD
have been associated with the highest risk of suicide.133 In children
and adolescents (<18 years of age) with BD, the prevalence of suicidal
ideation was 50 - 60% and suicide attempt was 20 - 25%.134, level II-2

A large number of people are bereaved by suicide deaths and often

require psychosocial support.135

While there is extensive evidence on risk formulation and management

of suicidal behaviour, paucity of high-quality studies focused on
individuals with BD limits the synthesis of recommendations.

9.1. Risk and Protective Factors

The risk factors for suicide in BD in adults are:6

• sociodemographic
 younger age
 male
 unemployed
 disabled
• symptomatology
 suicidal ideation
 rapid cycling
 psychotic symptoms
 depressive phase
 hopelessness
 mixed state
• clinical characteristics
 early onset of mood disorder
 previous suicide attempts
 multiple hospitalisations
 early sexual abuse
 stressful life events
 lack of confidant
 family history of suicide
• co-morbidity
 anxiety disorder
 Cluster B personality (antisocial/borderline/histrionic/narcissistic
personality disorder)
 substance misuse
• treatment
 duration of treatment (<5 years)

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 Management of Bipolar Disorder (Second Edition)

A systematic review of 14 observational studies on children and

adolescents (<18 years of age) with BD showed that the risk factors for
suicide attempt were:134, level II-2
• early illness onset
• severe illness characteristics e.g. psychosis, hospitalisation,
hopelessness etc
• mixed episode
• co-morbid disorders e.g. ADHD, substance use disorder, panic
disorder, oppositional defiant disorder
• past self-injurious behaviour
• past suicide ideation/suicide attempt
• past physical/sexual abuse
• parental depression
• family history of suicidality
• poor family functioning

Evidence for protective factors in suicidal behaviour in BD is limited. A

small cross-sectional study on euthymic adult outpatients with BD found
that personal religious activities (e.g. meditation, prayers and religious
studies) and religious integration in daily living exerted a protective
effect against suicide attempts.136, level III

9.2. Effective and Safe Intervention

Suicidal behaviour in BD has to be managed in a person-centered

collaborative approach requiring both clinical and community-based
strategies.132, level III

Specific attention is drawn to the role of lithium in preventing suicidal

behaviour in BD. A systematic review of adults with BD showed:30, level I
• combination of olanzapine and lithium significantly reduced
suicidal item score of HAM-D vs lithium alone
• lithium and valproate were equally effective in reducing suicide
ideation among suicidal attempters
• no definitive evidence on anti-suicidal effect of lithium

A meta-analysis of RCTs on adults with mood disorders showed NS

difference between lithium and placebo in suicide and non-fatal suicidal
behaviour between the groups.137, level I The primary papers were of
moderate quality based on RoB.

In a cohort study on patients >10 years of age with BD, ECT

reduced suicide risk in depressive state (HR=0.805, 95% CI
0.514 to 0.987) but not in mania or mixed states compared with
psychopharmacotherapy.138, level II-2

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 Management of Bipolar Disorder (Second Edition)

In a systematic review, a small RCT on the effectiveness of IV ketamine

vs placebo in bipolar depression found that suicidal ideation scores in
MADRS reduced within 40 minutes in subjects of the ketamine arm
(Cohen’s d=0.98, 95% CI 0.64 to 1.33) and remained significant to
Day 3.139, level I

Evidence on psychological interventions for suicidal behaviour in BD

population is limited. Safety Planning is a personalised and prioritised
list of coping strategies and resources to reduce suicide risk and
improve help-seeking.

Components of Safety Planning include:140, level III

• recognising warning signs of impending suicidal crisis
• identifying and employing internal coping strategies without
needing to contact another person
• utilising contacts with people as a means of distraction from
suicidal thoughts and urges
• contacting family members or friends who may help to resolve a
crisis and with whom suicidality can be discussed
• contacting mental health professionals or agencies
• reducing the potential use of lethal means

A meta-analysis of trials on safety planning interventions (cognitive

therapy and CBT for suicide prevention) vs control (TAU or other
treatment modalities) among adults with suicidal behaviour (including
those with affective disorders) showed mixed results where two RCTs
found significant reduction in suicidal behaviour while another two did
not. The overall bias of primary papers was considered high based on
RoB2.141, level I

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 Management of Bipolar Disorder (Second Edition)

10. IMPLEMENTING THE GUIDELINES

10.1. Facilitating and Limiting Factors

Existing facilitators for the application of the recommendations in the

CPG include:
• wide dissemination of the CPG to healthcare providers
• training and updates on the management of BD in relevant
scientific and professional meetings, seminars, conferences, etc.
• public awareness programmes on the importance of BD e.g.
World Bipolar Day, World Mental Health Day, Suicide Prevention
Day, etc
• peer support and psychosocial support services by non-
governmental organisations and patient advocates

Existing barriers for application of the recommendations of the CPG

are:
• limited awareness and knowledge among healthcare providers on
BD and its management
• lack of awareness of symptoms of BD among families/carers and
community
• variation in treatment practice and preferences due to limited
accessibility to resources e.g. medications
• no national clinical registry for BD for planning services

10.2 Potential Resource Implications

BD is a complex mental disorder that is challenging to diagnose and treat.

Those with BD need to be referred to psychiatric services for accurate
diagnosis and further management. The pharmacological treatment that
had been recommended by the CPG is not readily available in some
healthcare facilities. The financial burden of psychotropic treatments
restricts treatment options and distribution, while a scarcity of clinical
psychologists limits access to essential psychosocial interventions. The
available psychoeducational materials for patients fall short in effectively
fostering early help-seeking tendencies and offering comprehensive
management strategies.

In line with the key recommendations in this CPG, the following are
proposed as clinical audit indicators for quality management of BD:
Percentage of
patients with bipolar Number of patients with bipolar disorder
disorder not on not on antidepressant monotherapy in a period
antidepressant = x100%
Number of patients with bipolar disorder
monotherapy
in the same period
(Target of ≥80%)

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 Management of Bipolar Disorder (Second Edition)

Percentage of
patients with bipolar Number of patients with bipolar disorder on
disorder on lithium lithium monitoring every six months within a period
monitoring every six = x100%
Total number of patients with bipolar disorder on
months
lithium within the same period
(Target of ≥80%)

Implementation strategies will be developed following the approval

of the CPG by MoH which include a Quick Reference and a Training
Module.

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 Management of Bipolar Disorder (Second Edition)

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Appendix 1

EXAMPLE OF SEARCH STRATEGY

Clinical Question: What are the safe and effective pharmacotherapy in

the management of manic episode in BD?

1. BIPOLAR DISORDER/
2. (bipolar adj2 affective psychos#s).tw.
3. (bipolar adj1 (depressi* or disorder*)).tw.
4. (bipolar adj2 mood disorder*).tw.
5. (manic adj1 (depressi* or disorder*)).tw.
6. (manic depressi* adj2 psychos#s).tw.
7. (manic-depressi* adj1 psychos#s).tw.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. MANIA/
10. (manic adj1 (state* or episode*)).tw.
11. hypomani*.tw.
12. (hypomanic adj1 (episode* or state*)).tw.
13. mania*.tw.
14. 9 or 10 or 11 or 12 or 13
15. DRUG THERAPY/
16. (drug adj1 therap*).tw.
17. pharmacotherap*.tw.
18. mood stabilizer*.tw.
19. ANTIPSYCHOTIC/
20. (antipsychotic* adj1 (agent* or drug* or effect* or medication* or
therap*)). tw.
21. antipsychotic*.tw.
22. (neuroleptic adj1 (agent* or drug* or medication* or therap*)).tw.
23. neuroleptic*.tw.
24. (major adj1 tranquili*).tw.
25. (major tranquili#ing adj2 (agent* or medication* or therap*)).tw.
26. ANTIMANIC AGENTS/
27. (antimanic adj1 (agent* or drug* or effect* or medication* or
therap*)).tw.
28. antimanic*.tw.
29. ANTIDEPRESSANTS/
30. (antidepress* adj1 (agent* or drug*or medication* or therap*)).tw.
31. antidepressant*.tw.
32. thymoanaleptic*.tw.
33. thymoleptic*.tw.
34. PSYCHOTROPIC DRUGS/

60
 Management of Bipolar Disorder (Second Edition)

35 (psychotropic* adj1 (drug* or agent* or medication* or therap*)).tw.

36. psychotropic*.tw.
37. (psychoactive adj1 (agent* or drug* or medication* or therap*)).tw.
38. psychopharmaceutical*.tw.
39. (psychopharmaceutical adj1 (agent* or drug* or medication* or
therap*)). tw.
40. ANTICONVULSANTS/
41. (anticonvuls* adj1 (agent* or drug* or medication* or therap*)).tw.
42. (antiepileptic* adj1 (agent* or drug* or medication* or therap*)).tw.
43. antiepileptic*.tw.
44. anticonvulsant*.tw.
45. BENZODIAZEPINES/
46. benzodiazepine*.tw.
47. (benzodiazepine adj1 compound*).tw.
48. 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26
or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or
38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47
49. 8 and 14 and 48
50. limit 49 to (english language and humans and “all adult (19 plus
years)” and last 9 years)

61
 Management of Bipolar Disorder (Second Edition)

Appendix 2

CLINICAL QUESTIONS

1. What are the risk and protective factors for bipolar disorder?
2. What are the accurate screening and diagnostic tools in bipolar
disorder?
3. What are the differential diagnoses in bipolar disorder?
4. What are the indicators of bipolarity in patients with depression?
5. What are the co-morbidities in bipolar disorder?
6. What are the effective and safe pharmacotherapy in the
management of
● manic episode in bipolar disorder?
● depressive episode in bipolar disorder?
● bipolar disorder with specifiers (mixed features, anxious distress
and rapid cycling)?
● maintenance phase of bipolar disorder?
7. What are the effective and safe physical therapies in bipolar
disorder?
8. What are the effective and safe psychosocial interventions in
bipolar disorder?
9. What are the effective and safe psychotherapies in bipolar disorder?
10. What are the effective and safe complementary and alternative
therapies in bipolar disorder?
11. What are the parameters to be monitored during the maintenance
phase of bipolar disorder?
12. What are the referral criteria for patients with bipolar disorder?
13. What are the effective and safe strategies in the prevention of
bipolar disorder?
14. What are the effective strategies to improve adherence in bipolar
disorder?
15. How effective are Collaborative Care Models in the management of
bipolar disorder?
16. What are the effective and safe treatments in the following special
population with bipolar disorder?
● pregnancy and lactation
● elderly
● children and adolescents
● people with addictions (behavioural and substance)
● borderline personality disorder
17. What are the risk and protective factors for suicide in bipolar
disorder?
18. What are the effective and safe interventions in suicide prevention
in bipolar disorder?

62
 Management of Bipolar Disorder (Second Edition)

Appendix 3

DIAGNOSTIC CRITERIA OF BIPOLAR DISORDER BASED ON

DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS
FIFTH EDITION, TEXT REVISION (DSM-5-TR) AND
INTERNATIONAL CLASSIFICATION OF DISEASES
ELEVENTH REVISION (ICD-11)

ICD-11 DSM-5-TR
Hypomanic Episode Hypomanic Episode

A persistent mood state lasting for Abnormally and persistently elevated,

at least several days characterised expansive or irritable mood along AND
by persistent elevation of mood or persistently increased energy or activity
increased irritability as well as increased lasting at least four days accompanied by
activity or a subjective experience of three or four (if mood is only irritable):
increased energy, accompanied by other • inflated self-esteem or grandiosity
characteristic symptoms e.g.: • decreased need for sleep
• increased talkativeness • increased talkativeness or pressure
• rapid or racing thoughts of speech
• increased self-esteem • flight of ideas
• decreased need for sleep • distractibility
• distractibility • increased in goal-directed activity
• impulsive or reckless behaviour • excessive involvement in activities
with negative consequences

Manic Episode Manic Episode

An extreme mood state lasting at Abnormally and persistently elevated,

least one week unless shortened by a expansive or irritable mood along AND
treatment intervention characterised by persistently increased energy or activity
euphoria, irritability or expansiveness lasting at least one week accompanied by
and by increased activity or a subjective three or four (if mood is only irritable):
experience of increased energy, • inflated self-esteem or grandiosity
accompanied by other characteristic • decreased need for sleep
symptoms e.g.: • increased talkativeness or pressure
• rapid or pressured speech of speech
• flight of ideas • flight of ideas
• increased self-esteem or grandiosity • distractibility
• decreased need for sleep • increased in goal-directed activity or
• distractibility excessive involvement in activities
• impulsive or reckless behaviour with negative consequences
• rapid changes among different mood
states (i.e. mood lability)

At least one manic episode is not better explained by schizoaffective disorder and is
not superimposed on schizophrenia or other psychotic disorders.

63
 Management of Bipolar Disorder (Second Edition)

ICD-11 DSM-5-TR

A manic/hypomanic episode during antidepressant treatment is accepted as evidence

of BD.
The symptoms in hypomania represent a change from the individual’s typical mood,
energy level and behaviour but are not severe enough to cause marked impairment
in functioning.
There are similarities between mania and hypomania symptoms; however the diagnosis
of manic episode necessitates that the disturbance is severe enough:
• causing impairment in social or occupational functioning or
• requiring hospitalisation or
• with psychotic features

Depressive Episode Major Depressive Episode

A period of depressed mood or diminished For at least two weeks, presenting with
interest in activities occurring most of the five or more of the following symptoms,
day, nearly every day during a period of which, at least one must be depressed
lasting at least two weeks accompanied mood or loss of interest or pleasure. The
by other symptoms e.g.: other symptoms include:
• changes in appetite or sleep • disruption in appetite with
• psychomotor agitation or retardation accompanying weight loss or gain
• fatigue • sleep disturbance
• worthlessness or excessive or • psychomotor agitation or retardation
inappropriate guilt feelings or • fatiguability
hopelessness • feeling worthless or guilty
• difficulty concentrating • reduced concentration or indecisiveness
• suicidality • recurrent thoughts of death or suicidal
ideas or acts

6A60 Bipolar Type I Disorder Bipolar I Disorder

An episodic mood disorder defined by Having met the criteria for at least one
the occurrence of one or more manic or manic episode.
mixed episodes. • Current or most recent episode manic:
• 6460.0 Bipolar type I disorder, current ○ F31.11 Mild
episode manic without psychotic ○ F31.12 Moderate
symptoms ○ F31.13 Severe
• 6460.1 Bipolar type I disorder, ○ F31.2 With psychotic features
current episode manic with psychotic ○ F31.73 In partial remission
symptoms ○ F31.74 In full remission
• 6A60.2 Bipolar type I disorder, • Current or most recent episode
current episode hypomanic depressed:
• 6460.3 Bipolar type I disorder, ○ F31.31 Mild
current episode depressive, mild ○ F31.32 Moderate
• 6460.4 Bipolar type I disorder, current ○ F31.4 Severe
episode depressive, moderate ○ F31.5 With psychotic features
without psychotic symptoms ○ F31.75 In partial remission
○ F31.76 In full remission

64
 Management of Bipolar Disorder (Second Edition)

ICD-11 DSM-5-TR

• 6460.5 Bipolar type I disorder, current F31.81 Bipolar II Disorder

episode depressive, moderate with
psychotic symptoms Having met the criteria for hypomanic
• 6460.6 Bipolar type I disorder, episodes at least once and major
current episode depressive, severe depressive episode at least once,
without psychotic symptoms
• 6460.7 Bipolar type I disorder, Specify current or most recent episode:
current episode depressive, severe Hypomanic
with psychotic symptoms Depressed

6A61 Bipolar Type II Disorder Current or most recent episode

hypomanic
An episodic mood disorder is defined by F31.0 Not in remission
the occurrence of one or more hypomanic F31.71 In partial remission
episodes and at least one depressive F31.72 in full remission
episode.
Specifiers (both BD I and II):
Refer to ICD-11 for more coding. With anxious distress
With mixed features
With rapid cycling
With melancholic features
With atypical features
With mood-congruent psychotic
features
With mood-incongruent psychotic
features
With catatonia
With peripartum onset
With seasonal pattern

Refer to DSM-5-TR for more coding.

6A62 Cyclothymia F34.0 Cyclothymic disorder

A persistent instability of mood over a At least two years (for children, a full
period of at least two years, involving year) of both hypomanic and depressive
numerous periods of hypomanic and symptoms without ever fulfilling the criteria
depressive symptoms that are present for an episode of mania, hypomania or
during more of the time than not, but major depressive disorder.
not sufficient to meet the full criteria for
an episode. Specify
With anxious distress

Mixed Episode Mixed features

A mixed episode is characterised by the Manic or hypomanic episode, with

presence of several prominent manic and mixed features
several prominent depressive symptoms
consistent with those observed in manic Full criteria are met for a manic or
episodes and depressive episodes, which hypomanic episode, and at least three
either occur simultaneously or alternate depressive symptoms are present.
very rapidly.

65
 Management of Bipolar Disorder (Second Edition)

ICD-11 DSM-5-TR

Depressive episode, with mixed

features

Full criteria are met for a depressive

episode, and at least three manic/
hypomanic symptoms are present.

Rapid cycling Rapid cycling

High frequency of mood episodes (at At least four mood episodes in the
least four) over the past 12 months previous 12 months that met the criteria
for manic, hypomanic or major depressive
episodes.

An interval of at least two months free of symptoms is required to

distinguish between episodes.

Source:
1. ICD-11 International Classification of Diseases 11th Revision. The global standard
for diagnostic health information (Available at: https://icd.who.int/).
2. American Psychiatric Association. Bipolar and Related Disorders. In Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision.
Washington DC: APA; 2022.

66
 Management of Bipolar Disorder (Second Edition)

Appendix 4

LIST OF SCREENING TOOLS IN BIPOLAR DISORDER

Screening No. of Rater Cut-off Sensiti- Specifi- Comments

tool items points vity city
Mood 17 Self- 7 80% 70% Screens for lifetime
disorder rated (range history of (hypo) mania.
question- 3 - 7) There was no evidence
naire o f a d i ff e r e n c e i n
(MDQ) diagnostic accuracy
between Asian and
non-Asian studies for
both the MDQ and
HCL-32.1
Hypomania 32 Self- 14 82% 57% Screens for lifetime
checklist rated (range history of hypomania.
(HCL-32) 7 - 18) More significantly
accurate than MDQ to
detect BD II in mental
healthcare centre.2
Bipolar 19 Self- 13 69% 86% Uses 19 sentences
spectrum rated describing
diagnostic manifestations of
scale bipolar disorder.3
(BSDS)
Rapid mood 6 Self- 4 88% 80% Validated for BD I
screener rated only.
(RMS)
Rapid mood 6 Self- 4 88% 80% Validated for BD
screener rated I only. RMS is
(RMS) significantly better
than MDQ in the
following:4
1. sensitivity/
specificity
2. brevity
3. practicality
4. easy scoring

Bipolarity 5 Clinic- 50 91% 90% High score

index (BI) cian- suggests likelihood
rated of a true bipolar
diagnosis.
Score 50: BD
Score 40 - 50: at
risk of conversion
to BD, thus careful
monitoring.5

Only 1 study done

in unselected
clinical patients.

67
 Management of Bipolar Disorder (Second Edition)

Reference:
1. Wang YY, Xu DD, Liu R, et al. Comparison of the screening ability between the
32-item Hypomania Checklist (HCL-32) and the Mood Disorder Questionnaire
(MDQ) for bipolar disorder: A meta-analysis and systematic review. Psychiatry
Res. 2019;273:461-466.
2. Carvalho AF, Takwoingi Y, Sales PM, et al. Screening for bipolar spectrum
disorders: A comprehensive meta-analysis of accuracy studies. J Affect Disord.
2015;172:337-46.
3. Ghaemi SN, Miller CJ, Berv DA, et al. Sensitivity and specificity of a new bipolar
spectrum diagnostic scale. Journal of affective disorders. 2005;84(2- 3):273-7.
4. McIntyre RS, Patel MD, Masand PS, et al. The Rapid Mood Screener (RMS): a
novel and pragmatic screener for bipolar I disorder. Current Medical Research
and Opinion. 2021;37(1):135-44.
5. Aiken CB, Weisler RH, Sachs GS. The Bipolarity Index: a clinician-rated measure
of diagnostic confidence. J Affect Disord. 2015;177:59-64.

68
 Appendix 5

RECOMMENDED ADULT MEDICATION DOSAGES AND ADVERSE EFFECTS FOR BIPOLAR DISORDER

MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS

ADVERSE EFFECTS
MOOD STABILISERS
Lithium Acute mania, acute episodes CrCl <30 mL/min: No dosage adjustment Cardiac: cardiac arrhythmia, • Therapeutic Drug Monitoring
with mixed features, acute Use not provided in the T-wave inversion, oedema, (TDM)
hypomania, acute bipolar recommended manufacturer’s hypotension ○ Steady state: 4 - 5 days
depression labelling CNS: drowsiness, abnormal ○ Sampling time: before next
Oral - EEG, confusion, memory morning dose OR 12 hours from
Initial: 600 - 900 mg/day in 2 - 3 impairment, tremor last evening dose
divided doses. Titrate in Dermatologic: acne, ○ Therapeutic range:
increment of 300 - 600 mg to exacerbation psoriasis
usual therapeutic dose range of GI: dyspepsia, nausea, Indication Plasma trough
900 - 1800 mg/day in divided vomiting, abdominal pain, concentration

69
doses. diarrhoea, dysgeusia (mmol/L)
(Max dose: 1.8 g/day in 1 to 3 Renal: changes in eGFR Acute mania 0.8 - 1.2
divided doses) Endocrine and metabolic: Maintenance 0.8 - 1.0
polydipsia and polyuria,
weight gain, • May be taken with meals to avoid GI
hyperparathyroidism, upset
hypercalcemia, • Caution use during periods of
hypothyroidism, diabetes dehydration e.g. acute
insipidus gastroenteritis, fasting and intense
Others: sexual dysfunction exercise
Lithium toxicity: tremor, • Drug interaction with SGLT2
tinnitus, seizure, ataxia inhibitor:
Reduced serum lithium
concentration. Monitor serum
lithium concentration more
frequently during treatment with an
SGLT2 inhibitor, particularly
following initiation or dose changes.
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
Valproate Acute manic or acute CrCl <10 mL/min: Severe impairment: CNS: dizziness, drowsiness, • TDM:
episodes with mixed features, No specific dosage Use is contraindicated Hematologic: ○ Therapeutic range: 50 - 125 mg/L
depressive episodes adjustment thrombocytopenia, ○ Steady state: 2 - 4 days
necessary. However, decreased platelet ○ Sampling time: 30 minutes OR
Oral - free valproate aggregation just before next dose
IR: 600 mg daily and increase clearance may be Liver: hepatotoxicity/hepatic ○ Therapeutic serum levels
by 200 mg/day at 3-day interval reduced up to ~30%. failure, hyperammonaemia, generally occur with total daily
until control is achieved. hepatic encephalopathy doses of 1.5 - 2.5 g
Dermatologic: SJS, TEN, • Valproate administration may also
ER: 1000mg daily (in once or DRESS impair fertility in men. Fertility
twice daily regimen) GI: abdominal pain, dysfunctions are in some cases
diarrhoea, nausea, vomiting, reversible at least 3 months after
Usual dose range : 1000 to 2000 pancreatitis treatment discontinuation, however,
mg/day (i.e 20 - 30 mg/kg/day) Psychiatric: suicidal the reversibility of male infertility was
Ideation unknown. Offspring of men on
(Max dose: 2500mg/day or 60 valproate have an increased risk of
mg/kg/day) learning or behavioural problems

70
• Valproate is highly albumin-bound
(~90%). Cautious use of valproate in
patients with hypoalbuminaemia as
free valproate levels are elevated.
Lamotrigine Acute bipolar depression CrCl <30 mL/min: Moderate to severe Hematologic: • Periodically reassess needed for
Oral - Titrate with caution impairment agranulocytosis, continued use after 16 weeks
Patients not taking any as some WITHOUT ascites: neutropaenia, pancytopenia, • Restarting therapy: If lamotrigine
interacting medications: pharmacokinetics Decrease doses by pure red cell aplasia, aplastic has been discontinued for >5 half-
Week 1 and 2: 25 mg once daily parameters (e.g. half ~25% anaemia lives (half-life varies depending on
Week 3 and 4: 50 mg/day in 1 - life) may vary Dermatologic: skin rash, concomitant antiepileptics), reinitiate
2 divided doses considerably Moderate to severe SJS, TENS, DRESS with initial dosage. The greater the
Week 5: 100 mg/day in 1 - 2 impairment WITH GI: nausea, vomiting, interval of time since previous
divided doses ascites: diarrhoea dosage, the greater the
Week 6 and maintenance: 200 Decrease doses by Ophthalmic: blurred vision, consideration should be given to
mg/day in 1 - 2 divided doses ~50% diplopia restarting with initial dosing
(up to 400 mg/day) CNS: ataxia, dizziness, recommendations.
drowsiness, headache,
Management of Bipolar Disorder (Second Edition)

tremor, aseptic meningitis

 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
Patients taking valproate
Week 1 and 2: 25 mg every
other day
Week 3 and 4: 25 mg once
daily
Week 5: 50 mg/day in 1 - 2
divided doses
Week 6 and maintenance: 100
mg/day in 1 - 2 divided doses
Patients taking drug(s) that
induce lamotriginine
metabolism but not taking
valproate
Week 1 and 2: 50 mg/day in 1 -
2 divided doses
Week 3 and 4: 100 mg/day in 1 -
2 divided doses
Week 5: 200 mg/day in 1 - 2

71
divided doses
Week 6 and maintenance: 300
mg/day in 1 - 2 divided doses
Carbamazepine Bipolar I disorder, acute No dosage No dosage adjustment Hematologic: Aplastic • TDM
manic or mixed episodes, adjustment provided in the anaemia, leukopenia, ○ Steady state:
depressive episodes necessary manufacturer’s neutropenia, Initiation: 2 - 3 weeks
labelling. Use with thrombocytopenia Dose adjustment: 2 - 5 days
Oral - caution and consider Cardiac: sinus tachycardia ○ Sampling time: 0 - 30 min before
dose reduction as it is Liver: Hepatotoxicity/hepatic dose; after steady state achieved
IR: 200 mg twice daily; may metabolised primarily failure, increased serum ○ Therapeutic range: 4 - 12 µg/ml
increase in increment of 200 in the liver. transaminases
mg/day every 1 to 4 days. Dermatologic:
maculopapular rash, SJS,
ER: To be given in twice daily TEN, DRESS, AGEP
regimen Electrolytes:
hyponatraemia, SIADH
Usual dose range: 400 -1600 CNS: ataxia, dizziness,
mg/day in 2 to 3 divided doses drowsiness
Management of Bipolar Disorder (Second Edition)

(Max dose: 1.6 g/day)

 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
GI: Nausea, vomiting,
constipation, xerostomia
ENT: tinnitus
ANTIPSYCHOTICS
Aripiprazole Acute mania or episodes with No dosage No dosage adjustment Endocrine and metabolic: For long acting injectable, consider
mixed features, acute adjustment necessary weight gain, reduce the dose to 300mg once
hypomania and maintenance necessary hypertriglyceridaemia, monthly if there are adverse reactions
treatment hypercholesterolaemia, with dose of 400mg once monthly
Oral - hyperglycaemia
10 - 15 mg once daily; increase CNS: drowsiness,
dose in 5 - 10mg/day increment extrapyramidal reaction,
at intervals of >1 week headache, insomnia
(Max dose: 30 mg/day) Hematologic: neutropenia
LAI -
400 mg once monthly
Asenapine Acute mania or episodes with No dosage Child-Pugh class C: CNS: drowsiness, insomnia,
mixed features adjustment Use is contraindicated akathisia, extrapyramidal

72
Oral - necessary reaction, headache,
5 - 10 mg twice daily dizziness
(Max dose: 10 mg twice daily) Endocrine and metabolic:
weight gain,
hypertriglyceridemia,
hypercholesterolemia,
hyperglycaemia,
GI: oral hypoesthesia
Cariprazine Acute mania and acute CrCl <30 mL/min: Child-Pugh class C: GI: nausea, vomiting,
episodes with mixed features Use not Use not recommended constipation
Oral - recommended CNS: akathisia, dizziness,
Initial: 1.5 mg once daily; titrate extrapyramidal reaction,
in increment of 1.5 or 3 mg. insomnia, somnolence,
Recommended dosing range: 3 headache
- 6 mg once daily Endocrine and metabolic:
(Max dose: 6 mg/day) hyperglycaemia, weight gain

Bipolar major depression

Management of Bipolar Disorder (Second Edition)

Oral -
 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
Initial 1.5 mg once daily;
increase to 3 mg on day 15.
(Max dose: 3 mg/day)
Clozapine Maintenance/treatment No dosage Dose reduction may Cardiac: hypotension,
resistant adjustment provided be necessary with syncope, tachycardia
Oral - in the manufacturer’s significant impairment Endocrine metabolic:
Initial: 25 mg daily; titrate in labelling sweating, increased weight,
increments of 25 mg at intervals hyperglycaemia
>1 day GI: constipation, excessive
(Max dose: 550 mg/day in salivation, nausea,
divided doses) xerostomia
CNS: dizziness, headache,
somnolence
Ophthalmic: visual
disturbance
Other: fever
Haloperidol Acute mania, episodes with No dosage No dosage adjustment Cardiac: hypotension May worsen depressive symptoms

73
mixed features and acute adjustment provided in the GI: constipation, xerostomia
hypomania necessary manufacturer’s CNS: akathisia,
Oral - labelling. extrapyramidal reaction,
2 - 15 mg/day or 0.2 mg/kg/day Concentrations may somnolence
(up to 15 mg/day), in 1 or 2 increase in patients Ophthalmic: blurred vision
divided dose. Titrate in with hepatic
increment of <5 mg every 2 impairment as it is
days metabolised primarily
(Max dose: 30 mg/day) in liver and protein
binding may decrease.
Lumateperone Depressive episodes No dosage Child-Pugh class B GI: nausea, xerostomia Currently not registered with NPRA
Oral - adjustment and C: CNS: dizziness, somnolence,
42 mg once daily necessary Max: 21 mg once daily extrapyramidal reaction
Lurasidone Depressive episodes CrCl <50 mL/min: Child-Pugh class B: Endocrine and metabolic: Take with meals (>350 calories) for
Oral - Max: 80 mg/day Max: 80 mg/day dyslipidaemia, adequate absorption
Initial, 20 mg once daily. Titrate hyperglycaemia, weight gain
in increment of 20 mg every >2 Child-Pugh class C: GI: diarrhoea, nausea,
days. Max: 40 mg/day vomiting
Management of Bipolar Disorder (Second Edition)

(Max dose: 120 mg once daily)

 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
CNS: akathisia,
extrapyramidal reaction,
parkinsonism, somnolence
Psychiatric: anxiety
Olanzapine Acute mixed or manic No dosage When used in Cardiac: orthostatic • Take at bedtime to help reduce
episodes adjustment combination with hypotension, peripheral daytime sedation
Oral - necessary fluoxetine: oedema • Only oral formulations registered
Initial: 10 - 15 mg once daily, Initial: 2.5 - 5 mg daily Endocrine and metabolic: with NPRA
titrate in increment of 5 mg at hypercholesterolaemia,
intervals of ≥1 day hyperglycaemia,
(Max dose: 20 mg/day) hyperprolactinaemia,
increased appetite,
Acute depressive episode hypertriglycerides, weight
Oral - gain
Initial: 5 mg once daily; titrate in GI: constipation, xerostomia
increment of 5 mg every 1 - 7 CNS: akathisia, asthenia,
days dizziness, tremor, dystonia

74
(Max dose: monotherapy = 20
mg/day; combination = 15
mg/day)
Paliperidone Acute manic and mixed CrCl 50 - <80 mL/min: No adjustment Cardiac: tachycardia,
episodes Initial: 3 mg OD provided in the prolonged QT interval
Oral - Max: 6 mg OD manufacturer’s Endocrine and metabolic:
Initial, 6 mg once daily; titrate in labelling. weight gain,
increment of 3 mg/day every ≥5 CrCl 10 - <50 mL/min: hyperprolactinaemia,
days Initial: 1.5 mg OD GI: constipation, indigestion
(Max dose: 12 mg/day) Max:3 mg OD CNS: akathisia, dyskinesia,
dystonia, extrapyramidal
CrCl <10 mL/min: reaction, parkinsonism
Not recommended somnolence, tremor
Psychiatric: anxiety
Quetiapine Acute mania, acute episodes No dosage Child-Pugh class A Cardiac: orthostatic
with mixed features and acute adjustment and B: hypotension
hypomania necessary Initial: 25 mg once
IR - daily; may increase by
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
100 - 200 mg once daily at 25 - 50 mg/day based Endocrine and metabolic:
bedtime or in 2 divided doses; on response and hypercholesterolemia,
titrate in increment of <200 tolerability until hpertriglycerides, weight gain
mg/day effective dose GI: xerostomia
achieved, dividing total CNS: asthenia, dizziness,
ER - daily dose into 1 - 3 extrapyramidal reaction,
300 mg once daily on Day 1, divided doses headache, insomnia,
increase to 600 mg once daily somnolence
on Day 2, then adjust Child-Pugh class C: Psychiatric: agitation
accordingly Avoid use
(Max dose: 800 mg/day)

Acute depressive episode

IR, ER -
50 mg once daily at bedtime;
increase to 100 mg once daily
on Day 2. Further increase by

75
50 - 100 mg/day to reach usual
target dose of 300 mg OD by
Day 4 - 7.
(Max dose: 300 mg/day)
Risperidone Acute mania, acute episodes CrCl 30 - 60 mL/min: Child-Pugh class C: Endocrine and metabolic: Risperdal CONSTA is discontinued in
with mixed features and acute Administer 50 - 75% 0.5 mg twice daily; weight gain, Malaysia effective 31.07.2024
hypomania of usual indication- titration in increment of hyperprolactinaemia
Oral - specific dose no more than 0.5 mg GI: constipation, excessive
1 - 3 mg/day in 1 or 2 divided twice daily. Increase to salivation, indigestion,
doses, increase 1 mg/day at CrCl 10 - 30 mL/min: dosages above 1.5 mg nausea, abdominal pain,
interval >24 hours Administer 50% of twice a day occurring vomiting, xerostomia
(Max dose: 8 mg/day) usual indication- at interval of at least 1 CNS: akathisia, dizziness,
specific dose week. dystonia, sedation,
LAI - parkinsonism, tremor
25 mg every 2 weeks; may CrCl <10 mL/min: Ophthalmic: blurred vision
increase dose in increment of Consider alternative Psychiatric: anxiety
12.5 mg no sooner than every 4 agent. If necessary,
weeks administer 25% of
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL DOSE HEPATIC DOSE COMMON/SIGNIFICANT REMARKS
ADVERSE EFFECTS
(Max dose: 50 mg every 2 usual indication-
weeks) specific dose
Ziprasidone Acute mania, acute episodes No dosage No dosage adjustment Endocrine and metabolic: • Oral dose needs to be taken with a
with mixed features and acute adjustment is provided in the weight gain ≥
meal (>500 calories) to be
hypomania necessary manufacturer’s GI: constipation, indigestion, adequately absorbed
Oral - labelling. Use with nausea • Only oral forms are registered under
Initial: 40 mg twice daily; caution as it CNS: akathisia, dizziness, NPRA
increase to 60 or 80 mg twice undergoes extensive extrapyramidal reaction,
daily. If indicated, maximum hepatic metabolism headache, somnolence,
recommended dose may be and systemic exposure tremor
reached as early as Day 2 of may be increased. Cardiac: prolong QTc
treatment. interval
(Max dose: 80 mg twice daily)
SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI)
Fluoxetine Acute depressive episode No dosage Use lower dose (up to GI: diarrhoea, indigestion,
Oral - adjustment 50%) reduction and loss of appetite, nausea,
Initial: 20 mg once daily in the necessary less frequent interval xerostomia

76
evening with another AAP (e.g. in patients with CNS: asthenia, dizziness,
olanzapine) or mood stabilisers; cirrhosis and chronic insomnia, somnolence,
titrate in increment of 10 - 20 liver disease tremor
mg every 1 - 7 days Psychiatric: anxiety, suicidal
(Usual dose range: 20 - 50 ideation
mg/day) Respiratory: pharyngitis,
rhinitis
Other: influenza-like illness

Source:
1. Individual product information leaflet.
2. Clinical Drug Information, Inc. Wolters Kluwer. UpToDate® [Mobile application software].
3. Micromedex® Solution [Mobile application software].
4. MOH Clinical Pharmacy Working Committee. Clinical Pharmacokinetics Pharmacy Handbook. 2nd ed. Petaling Jaya: Pharmacy Practice &
Development Division, MOH; 2019.
5. PDSB. Quest3+ Product Search Sistem Pendaftaran Produk & Perlesenan (Available at: https://quest3plus.bpfk.gov.my/pmo2/index.php).
6. Medicines and Healthcare Products Regulatory Agency (MHRA), UK:(Available at: https://www.gov.uk/drug-safety-update/valproate-re-analysis- of-
Management of Bipolar Disorder (Second Edition)

study-on-risks-in-children-of-men-taking-valproate).
.7. National Health Service (NHS).Sodium Valproate: Medicine to treat epilepsy and BD (Available at: https://www.nhs.uk/medicines/sodium-valproate/).
 Management of Bipolar Disorder (Second Edition)

Appendix 6

PSYCHOEDUCATION FOR BIPOLAR DISORDER

Duration 90 minutes per session

Total number of sessions 21 sessions, weekly
Methods of delivery Individual or group (8 to 12
participants per group)

Major components
a. Information on illness features
b. Importance of treatment compliance
c. Early detection of prodromal signs of recurrence
d. Management of mood symptoms or co-morbid conditions
e. Lifestyle regularity

List of sessions and its description

1. Introduction
2. What is bipolar illness?
3. Causal and triggering factors
4. Symptoms (I): mania and hypomania
5. Symptoms (II): depression and mixed episodes
6. Course and outcome
7. Treatment (I): mood stabilisers
8. Treatment (II): antimanic agents
9. Treatment (III): antidepressants
10. Serum levels: lithium, carbamazepine and valproate
11. Pregnancy and genetic counselling
12. Psychopharmacology vs alternative therapies
13. Risk associated with treatment withdrawal
14. Alcohol and street drugs: risks in bipolar illness
15. Early detection of manic and hypomanic episodes
16. Early detection of depressive and mixed episodes
17. What to do when a new phase is detected?
18. Regularity
19. Stress management techniques
20. Problem-solving techniques
21. Final sessions

Source: Colom F, Vieta E, Martínez-Arán A, et al. A Randomized Trial on the

Efficacy of Group Psychoeducation in the Prophylaxis of Recurrences in
Bipolar Patients Whose Disease Is in Remission. Arch Gen Psychiatry.
2003;60(4):402-407.

77
 Management of Bipolar Disorder (Second Edition)

Appendix 7

PARAMETERS FOR MONITORING DURING TREATMENT OF

BIPOLAR DISEASE

Relevant physical examination and laboratory investigations should

be performed before initiation of pharmacological treatment and at
regular interval thereafter

For all
Anti-
Parameter patients at Lithium Valproate Carbamazepine
psychotics
first visit

Weight (include Yes Monthly for Every 6 Every 3 Every 6 months

waist size and the first 3 months and months for and annually
BMI, if possible) months and annually the first year thereafter*
*closer annually thereafter* and annually
monitoring if thereafter* thereafter*
rapid weight
gain

Blood pressure Yes At every visit

Fasting blood Yes Every 3 - 6 Annually
sugar months and
annually
thereafter
Electrocardiogram Yes If relevant abnormalities are If clinically If relevant
detected, recheck after each indicated abnormalities
dose increase are detected,
recheck after
each dose
increase
Full blood count Yes Annually If clinically Every 3 Monthly for the
indicated months for first 3 months
the first year and annually
and annually thereafter
thereafter
Thyroid function Yes Annually Every 6 NA
months, more
often if
indicated

Renal function Yes Annually Every 6 Annually Every 6

months, more months
often if
indicated

Liver function Yes Annually Every 3 Monthly for the

months for first 3 months
the first year and annually
and annually thereafter
thereafter

78
 Management of Bipolar Disorder (Second Edition)

For all
Anti-
Parameter patients at Lithium Valproate Carbamazepine
psychotics
first visit

Lipid profile Yes Every 3 Annually

months for
the first year
and annually
thereafter
Drug serum level NA 1 week after Every 6 months
initiation and only if there is ineffectiveness,
1 week after poor adherence, or toxicity
every dose
change until
the level is
stable, then
every 3 - 6
months
Serum calcium Yes for Annually Every 6 NA
level Lithium months
initiation

Adapted from:
1. Ministry of Health. Clinical Practice Guidelines on Management of Bipolar Disorder.
Putrajaya: MoH; 2014
2. Taylor DM, Gaughran F, Pillinger T. Maudsley Practice Guidelines for Physical
Health Conditions in Psychiatry. London: Wiley Blackwell; 2020
3. Clinical Drug Information, Inc. Wolters Kluwer. UpToDate® [Mobile application
software].
4. Micromedex® Solution [Mobile application software]

79
 Management of Bipolar Disorder (Second Edition)

Appendix 8

COLLABORATIVE CARE MODEL CORE ELEMENTS

Element Focus Example

Patient self- Coaching, problem-solving, or Behavioural change strategies or coaching,
management skills-focused psychotherapy illness-specific psychoeducation,
support or psychoeducation targeting shared decision-making interventions,
ability to self-manage symptoms cognitive-behavioural or problem-solving
and participate more effectively therapies.
in clinical care and decision-
making.

Clinical Facilitation of information flow Case registries, reminder systems,

information from relevant clinical sources provision of timely clinical information
systems use to treating clinicians for optimal (e.g. laboratory and study results)
management of individuals, regarding individuals in treatment and/
panels or populations. or feedback to providers.

Delivery Redefinition of work roles for Licensed clinical staff or health educators
system physicians and support staff to provide psychoeducation, ensure
redesign to facilitate anticipatory or provision of appropriately timed clinical
preventive rather than reactive information for specific cases, or review
care; allocation of staff to of panel or population data for anticipatory
implement other CCM elements and preventive management needs.
e.g. self-management support
and information flow.

Provider Facilitated provision of expert- On-site or facilitated expert consultation

decision level input to generalist clinicians or provision of simplified clinical practice
support managing cases without need for guidelines supported by local clinician
specialty consultation separated champions.
in time and space from clinical
needs.

Community Support for clinical and non- Referral to peer support groups, exercise
resource clinical needs from resources programmes, housing resources, home
linkage outside the health care care programmes.
organisation proper.

Health care Organisation-level leadership Provision of adequate clinical staff for

organisation and tangible resources to support CCM training and implementation;
support CCM goals and practices. support from key non-clinical services e.g.
informatics; championship by organisation
leadership, optimally with a commitment
to sustainability after the research phase
of the intervention ends.

Adapted:
1. Bauer MS, McBride L, Williford WO, et al. Collaborative care for bipolar disorder:
part I. Intervention and implementation in a randomized effectiveness trial.
Psychiatr Serv. 2006;57(7):927-36
2. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients
with chronic illness. JAMA. 2002;288(14):1775-9

80
 Appendix 9

SUMMARY OF MEDICATIONS FOR BIPOLAR DISORDER WITH PREGNANCY AND LACTATION

MEDICATION PREGNANCY LACTATION
Aripiprazole* • HUMAN DATA SUGGEST LOW RISK. • NOT RECOMMENDED DURING LACTATION.
• Aripiprazole crosses placenta. • An alternate drug may be preferred, especially while nursing a
• Due to limited data, avoid use in pregnancy. However, if the newborn or preterm infant due to limited information available.
mother’s condition requires treatment with aripiprazole, the • Aripiprazole can lower serum prolactin in a dose-related manner.
lowest effective dose, avoiding the first trimester if possible, Cases of lactation cessation have occurred, but cases of
should be used. gynecomastia and galactorrhea have also been reported.
• Weight loss and poor weight gain have been reported in breastfed
infants whose mothers were taking aripiprazole.
• **Relative Infant Dose (RID): 0.7 - 8.3%.
Asenapine* • NO HUMAN DATA - ANIMAL DATA SUGGEST MODERATE • Manufacturer’s labelling recommends that women receiving
RISK. asenapine should not breastfeed.
• There are no adequate data from the use of asenapine in • If asenapine is required by the mother, it is not a reason to
pregnant women. However, maternal and embryo-foetal toxic discontinue breastfeeding. However, an alternate drug may be

81
effects were found in animal studies. preferred, especially while nursing a newborn or preterm infant.
• Should not be used during pregnancy unless clearly necessary
and only if the potential benefit outweighs potential risk to the
foetus.
Cariprazine* • NO HUMAN DATA - ANIMAL DATA SUGGEST MODERATE • No information is available on the use of cariprazine during lactation.
RISK. An alternate drug may be preferred until more data become

ANTIPSYCHOTICS
• Absence of human pregnancy data prevents a better assessment available.
of the embryo-foetal risk.
Clozapine* • COMPATIBLE - MATERNAL BENEFIT >> EMBRYO-FOETAL • NOT RECOMMENDED DURING LACTATION.
RISK. • Due to limited information with clozapine during breastfeeding, and
• Clozapine crosses placenta and can be detected in foetal blood sedation and adverse haematologic effects have been reported in
and amniotic fluid. breastfed infants, other agents are preferred.
• Other agents are preferred for use in pregnancy; however, if • Monitoring:
indicated, may be used in women who cannot be switched to ○ Monitor infant for excessive sedation and periodic monitoring of
recommended APs. the infant's white blood cell count is advisable.
Haloperidol* • LIMITED HUMAN DATA - ANIMAL DATA SUGGEST • POSSIBLE TO USE CAUTIOUSLY DURING LACTATION.
MODERATE RISK • Limited information indicates that maternal doses of haloperidol up
Management of Bipolar Disorder (Second Edition)

• Neonatal tardive dyskinesia may be an uncommon complication to 10 mg daily produce low levels in milk and usually do not affect
of exposure throughout gestation. the breastfed infant. Very limited long-term follow-up data indicate no
 MEDICATION PREGNANCY LACTATION

•
Aripiprazole* • Avoid
HUMAN trimester
firstDATA exposure
SUGGEST if possible.
LOW RISK. adverse
NOT RECOMMENDED developmental DURING effects when haloperidol is used alone.
LACTATION.
Aripiprazole
• Preferred crosses
drug placenta.
if first generation APs is needed in pregnant However,
An alternate use drugwith other
may APs be occasionally might negatively
preferred, especially affect the
while nursing a
patients. However,
Due to limited data,minimum
avoid useeffective dose should
in pregnancy. be used
However, if the infant.
newborn or preterm infant due to limited information available.
mother’s
to reducecondition
risk of AEs. requires treatment with aripiprazole, the • Monitoring:
Aripiprazole can lower serum prolactin in a dose-related manner.
lowest effective dose, avoiding the first trimester if possible, ○
Cases Monitor of infant
lactation for drowsiness
cessation have and developmental
occurred, but milestones,
cases of
should be used. gynecomastia
especially ifand other APs are used
galactorrhea haveconcurrently.
also been reported.
Lumateperone* • Insufficient data to establish any drug-associated risk for birth No information
• Weight loss andispoor available
weightongain clinical
haveuse been lumateperone
of reported during
in breastfed
defects, miscarriage, maternal or foetal outcomes. breastfeeding.
infants whose mothers were taking aripiprazole. Appendix 9
• **Relative
However, Infant amounts Doseof(RID): lumateperone
0.7 - 8.3%. and its metabolites in
Asenapine* SUMMARY
NO HUMANOF DATA MEDICATIONS
- ANIMAL DATA FORSUGGEST DISORDER WITH
BIPOLARMODERATE PREGNANCY
breastmilk
Manufacturer’s appear toAND
labelling be low LACTATION
recommends
and would that not bewomenexpected
Appendix to cause
receiving
9
RISK. asenapine
any AEs inshould breastfed not infants.
breastfeed.
MEDICATION There are no PREGNANCY
data from use of asenapine lumateperone
• IfIf asenapine is required
is required LACTATION
by by thethemother,
mother,it itisis not reason to
not aa reason to
SUMMARY OFadequate
MEDICATIONS FOR theBIPOLAR DISORDER in WITH PREGNANCY AND LACTATION
Aripiprazole* HUMAN
pregnant DATAwomen. SUGGEST
However,LOW maternal
RISK. and embryo-foetal toxic discontinue
NOT RECOMMENDED
discontinue breastfeeding
breastfeeding. DURING
However, LACTATION.
an alternate drug may be
Lurasidone* Aripiprazole
• LIMITED
effects were crosses
HUMAN
found inDATAplacenta.
animal - POTENTIAL RISK IN THIRD • An
studies. alternate
Lurasidone
preferred, is drug
>99%may
especially bound
while topreferred,
benursingplasma especially
proteins,
a newborn orso itwhile nursing
is unlikely
preterm infant.thata
MEDICATION PREGNANCY LACTATION
TRIMESTER.
Should
Due to notlimitedbe useddata,during use in pregnancy.
avoid pregnancy However,
unless clearly if the
necessary newborn
it would or bepreterm
excreted infant
intoduemilkto limited information
in sufficient amounts available.
to affect a
Aripiprazole* HUMAN DATA SUGGEST LOW RISK. NOT RECOMMENDED DURING LACTATION.
mother’s
and only condition
if the potential requires treatment
benefit outweighs aripiprazole,
withpotential risk tothethe breastfed infant.
Aripiprazole can lower serum prolactin in a dose-related manner.
Aripiprazole
lowest crosses placenta. An
Duealternate
to limited drug
of lactation may
information,cessation
be an preferred,
have especially
alternate occurred,
drug may while
but nursing
cases of
be preferred, a
foetus. effective dose, avoiding the first trimester if possible, • Cases
Due
shouldto limited
be used. data, avoid use in pregnancy. However, if the newborn
gynecomastia
especially or preterm
while and galactorrhea
nursing
infanta due limited
tohave
newborn oralsoinformation
preterm available.
reported.
beeninfant.
Cariprazine* NO HUMAN DATA - ANIMAL DATA SUGGEST MODERATE No information is available on the use of cariprazine during lactation.

82
Olanzapine* mother’s condition requires treatment with aripiprazole, the Aripiprazole
Weight loss and can poorlowerweightserumgain prolactin
have beenin a dose-related manner.
in breastfed
• COMPATIBLE
RISK. - MATERNAL BENEFIT >> EMBRYO-FOETAL • An ACCEPTABLE
alternate drug DURING may LACTATION.
be preferred until reported data become
lowest effective dose, avoiding the first trimester if possible, Cases of lactation cessation occurred,more but cases of

ANTIPSYCHOTICS
RISK.
Absence of human pregnancy data prevents a better assessment • infants
First-line
available. whose mothers
of AAPs during takinghave
werebreastfeeding. aripiprazole.
should be used. gynecomastia and galactorrhea have also been reported. Appendix 9
• Olanzapine crosses placenta.
of the embryo-foetal risk. • **Relative
Maternal doses InfantofDose (RID): 0.7
olanzapine up to - 8.3%.
20 mg daily produce low levels

ANTIPSYCHOTICS
Weight loss and poor weight gain have been reported in breastfed
Asenapine*
Clozapine* • No
NO established
HUMAN DATA
COMPATIBLE olanzapine-associated
MATERNAL
- ANIMALBENEFIT DATArisk SUGGEST
>> major birth defects,
MODERATE
of EMBRYO-FOETAL Manufacturer’s
in milk
NOT and undetectable
RECOMMENDED labellingDURING recommends
levels in the serum thatof women
breastfedreceiving
infants.
SUMMARY MEDICATIONS FOR BIPOLAR DISORDER infants whose mothers
PREGNANCY were takingLACTATION.
LACTATION aripiprazole.
miscarriage or • asenapine should notAND breastfeed.
RISK. OF-adverse maternal or foetal outcomes following WITH **RID: - 4%.
Due to 0.3
**Relative limited
Infant information
Dose (RID): with0.7clozapine
- 8.3%. during breastfeeding, and
maternal
There
Clozapineareuse. no adequate
crosses placenta data
andfromcan be thedetected
use of inasenapine
foetal blood asenapine
IfMonitoring:
in • sedation is required
and adverse by the mother,
haematologic effects ithave is not reason to
beena reported in
Asenapine*
MEDICATION NO HUMAN
pregnant women.
• Pharmacokinetics - ANIMAL
DATAHowever, PREGNANCY DATA
maternal
of olanzapine SUGGEST
and areembryo-foetal
notMODERATE toxic
significantly Manufacturer’s
discontinue labelling LACTATION
breastfeeding. recommendsanthat alternate
womendrug receiving
may be
and amniotic fluid. properties ○ Monitor
breastfed neonates
infants, other agentsforHowever,
extrapyramidal
are preferred. and/or withdrawal
Aripiprazole* RISK.
HUMAN
effects
altered were
byDATA found
pregnancy.SUGGEST
in animal LOW
However, RISK.
studies. may change asenapine
NOT
preferred, should
RECOMMENDED
especially not breastfeed.
DURING
nursing LACTATION. or preterm infant.
Other agents are preferred for serum
use inlevels
pregnancy; however,(evenif symptoms
Monitoring: and while manage symptoms
a newbornappropriately. Some
There
at are
Aripiprazole
a stable
Should no
dose,
be adequate
crosses
used during data
placenta. due from
to decreased of asenapine
the use clearly activity
necessary in If
Anasenapine
alternate
neonates is
drug required
recovered be bypreferred,
within thehoursmother, or it is notwhile a reason
without nursing to
specifica
indicated,
notmay be possibly
used in pregnancy
women whounless
cannotCYP1A2
be switched to o Monitor infant formayexcessive sedationespecially
anddaysperiodic monitoring of
pregnant
Due
during
and women.
limited
tosecond
only if theand However,
data,
third
potentialavoid maternal
use in
trimester.
benefit and
pregnancy.
outweighs embryo-foetal
However,
potential risk to toxic
if the discontinue
newborntreatment; breastfeeding.
or preterm
others required However,
due to limited an alternate
information
hospitalisation. drug may
available. be
recommended APs. the infant's white infant
blood cell prolonged
count is advisable.
effects
foetus.
• Potentialwere
mother’s condition found in
for excessive animal
requires studies. with aripiprazole,
weight gain theand preferred,
Aripiprazole especially
can
infant lower while
forserum nursing a
prolactin
drowsiness, newborn or preterm
in a dose-related
irritability, infant.
poor manner.
feeding,
Haloperidol* LIMITED HUMAN DATA treatment
-maternal
ANIMAL DATA SUGGEST POSSIBLE
○ Monitor TO USE CAUTIOUSLY DURING LACTATION.
Cariprazine* Should
lowest effective
development
NO HUMAN
not beDATA used
of dose,
gestational
ANIMAL
-during pregnancy
avoiding the first
diabetes.
DATA unless
SUGGEST clearly
trimester ifnecessary
possible,
MODERATE Cases of lactation
extrapyramidal cessation
symptoms have cases
but milestones, of
MODERATE RISK No information
Limited information is available
indicates the and
on that use ofdevelopmental
maternalcariprazine
occurred, during
doses of haloperidol lactation.
up
and only
should if
be used.the potential benefit outweighs potential risk to the gynecomastia
especially galactorrhea
other APs are have
used also been reported.
RISK.
Neonatal tardive dyskinesia may be an uncommon complication An
to 10 alternate
mg dailyifand drug
produce may low preferred
belevels inconcurrently.
milkuntil
and more
usually data
do notbecome
affect
foetus.

ANTIPSYCHOTICS
Paliperidone* • LIMITED
Absence
of exposure ofHUMAN
human DATA
pregnancy
throughout - ANIMAL
data prevents
gestation. DATA SUGGEST
a better assessment Weight
POSSIBLE
LOW • available.
the loss TO
breastfed and poor
USE
infant. Very weight
CAUTIOUSLY
limited gain have
long-term been
DURING reported
LACTATION.
follow-up breastfed
datainindicate no
Cariprazine* NO
RISK.HUMAN - ANIMAL DATA SUGGEST MODERATE • No information
infants is available
mothers were the
ontaking use of cariprazine
aripiprazole. during lactation.
of the embryo-foetalDATA risk. Due to whose
little long-term follow-up data, other agents may be preferred,
RISK.
• Information specific to paliperidone pregnancy is limited. An alternate
**Relative
especially Infant
while drug Dose
nursingmay(RID):
a be preferred
newborn - 8.3%. until more
or preterm infant. data become
Clozapine* COMPATIBLE - MATERNAL BENEFIT in >> EMBRYO-FOETAL NOT RECOMMENDED DURING 0.7LACTATION.

ANTIPSYCHOTICS
Asenapine* Absence
NO HUMAN
However,
RISK. DATA
ofif human
the pregnancy
- ANIMAL
mother requiresdata
DATA a better
SUGGEST
itsprevents
use, the assessment
MODERATE
benefits Manufacturer’s
60probably • available.
Monitoring: labelling recommends
Due to limited information with clozapinethat duringwomen
breastfeeding,
receivingand
Management of Bipolar Disorder (Second Edition)

of the embryo-foetal
RISK.
outweigh foetal risk. asenapine
○ Monitor should
breastfed not breastfeed.
infants for drowsiness, adequate and
Clozapine crosses risk.placenta and can be detected in foetal blood sedation and adverse haematologic effects have been growth
reported in
Clozapine* COMPATIBLE
There - MATERNAL
adequate dataBENEFIT
from the>> use EMBRYO-FOETAL
of asenapine in NOT RECOMMENDED
If asenapine
weight gain, required
is jitteriness, DURING
by the
tremors mother,
and abnormal not a reason to
it is movements.
and amniotic
are nofluid. breastfed infants, other agents areLACTATION.
preferred.
RISK.
pregnant women. However, maternal and embryo-foetal toxic Due to limited
discontinue information with
breastfeeding. clozapine
However, an during
alternatebreastfeeding,
drug mayand be

YCHOTICS
 Appendix 9

SUMMARY OF MEDICATIONS FOR BIPOLAR DISORDER WITH PREGNANCY AND LACTATION

MEDICATION PREGNANCY
Aripiprazole crosses placenta. An alternate drug may be LACTATION
preferred, especially while nursing a
Aripiprazole*
Quetiapine* HUMAN
• COMPATIBLE
Due to limited SUGGEST
MATERNAL
DATA -data, avoid LOW
use RISK.
BENEFIT
in >> EMBRYO-FOETAL
pregnancy. However, if the • newborn
NOT
POSSIBLE or preterm
RECOMMENDED
TO USEinfant due to
DURING
DURING limited information available.
LACTATION.
LACTATION.
mother’s condition requires treatment with aripiprazole, the
RISK. • Aripiprazole can lower serum
First- or second-choice agentprolactin in a dose-related manner.
during breastfeeding.
lowest effective
• Quetiapine dose,
crosses avoiding the first trimester if possible,
placenta. • Cases
Limited oflong-term
lactationfollow-up cessationof have infantsoccurred,
exposed but cases of
to quetiapine
should
• If be used.
treatment with AAPs is needed in a woman planning a gynecomastia and galactorrhea
indicates that infants generally developed been have also reported.
normally.
pregnancy, use of quetiapine may be considered. • Weight
Cases of loss and poor weight
galactorrhoea and milk have been
gainejection have reported in breastfed
been reported rarely.
• infants mothers were taking aripiprazole. Appendix 9
0.02 - 0.1%.
**RID: whose
• **Relative
Monitoring:Infant Dose (RID): 0.7 - 8.3%.
Asenapine* SUMMARY
NO HUMANOF DATA MEDICATIONS
- ANIMAL DATA FORSUGGEST DISORDER WITH
BIPOLARMODERATE PREGNANCY
Manufacturer’s
○ Monitor infant labelling
forAND LACTATION
recommends
drowsiness that women
and developmental Appendixreceiving
milestones,
9
RISK. asenapine
especiallyshould
if othernot APsbreastfeed.
are used concurrently.
MEDICATION
Risperidone* There are no
COMPATIBLE
• SUMMARY MATERNAL PREGNANCY from
dataBENEFIT >>use of asenapine
EMBRYO-FOETAL asenapine
• IfPOSSIBLE TO is USErequired LACTATION
by the mother,
CAUTIOUSLY is not a reason to
DURINGit LACTATION.
OF-adequate
MEDICATIONS FOR theBIPOLAR DISORDER in WITH PREGNANCY AND LACTATION
Aripiprazole* HUMAN
pregnant DATA
RISK. women. SUGGEST
However,LOW maternal
RISK. and embryo-foetal toxic • NOT Second RECOMMENDED
discontinue linebreastfeeding.
of AAPs DURING However,
during LACTATION.
an alternate
breastfeeding due todruglimited
maydatabe
Aripiprazole
effects were crosses
• Risperidone found
and placenta.
animal
itsinmetabolite studies.
cross placenta. An alternate
preferred,
available and drug
especially
higher maywhile
excretionpreferred,
benursing especially
intoa newborn
milk relative while
or preterm
to othernursing
infant.
agents. a
MEDICATION PREGNANCY LACTATION
Due
Should limited
to not
• Risperidone becan data,
used during
avoid pregnancy
increase serum pregnancy.
use in prolactin However,
clearly
unlesslevels necessary
which the
ifmay newborn or preterm infant
agents may be preferred, due to limited information available.
while nursing a newborn
Aripiprazole* HUMAN DATA SUGGEST LOW RISK. NOT
OtherRECOMMENDED DURINGespeciallyLACTATION.
mother’s
and only condition
decrease the potential
iffertility requires
in females benefit outweighs
ontreatment
risperidone. aripiprazole,
withpotential risk tothethe Aripiprazole
or preterm infant can lower serum prolactin in a dose-related manner.
Aripiprazole
lowest crosses placenta. An alternate drug may
lactation be preferred,
cessation have especially while
but nursing
cases a
of
foetus. effective dose, avoiding the first trimester if possible, • Cases Sedation, of failure thrive, jitteriness, tremors,
occurred,abnormal muscle
Due to limited data, avoid use in pregnancy. However, if the newborn or preterm toinfant due limited information available.

83
Cariprazine* should
NO be used.
HUMAN DATA - ANIMAL DATA SUGGEST MODERATE gynecomastia
movements
No information and
and is galactorrhea
respiratory
available on
tohave
depression
the use also
of been
havereported.
cariprazine been
during reported in
lactation.
mother’s condition requires treatment with aripiprazole, the Aripiprazole
Weight loss and
can poor serum prolactin
lowerweight in a dose-related
have been manner.
in breastfed
RISK. infants
An exposed
alternate drug to risperidone
may be gain in milk.
preferred until reported data become
lowest effective dose, avoiding the first trimester if possible, Cases of lactation occurred,more but cases of

ANTIPSYCHOTICS
Absence of human pregnancy data prevents a better assessment • infants
Monitoring:
available. whose mothers cessation
were takinghave aripiprazole.
should be used. gynecomastia and galactorrhea have also been reported.

ANTIPSYCHOTICS
Appendix 9
of the embryo-foetal risk. **Relative
○ MonitorInfant infantDose for drowsiness,
(RID): 0.7 - weight8.3%. gain, tremors, abnormal
Weight loss and poor weight gain have been reported in breastfed
Asenapine*
Clozapine* NO HUMAN DATA
COMPATIBLE MATERNAL
- ANIMALBENEFIT DATA SUGGEST MODERATE
>> EMBRYO-FOETAL Manufacturer’s
NOT respiratory
RECOMMENDED labelling
rate, DURING recommends
abnormal that women
muscle movements receiving and
SUMMARY OF- MEDICATIONS FOR BIPOLAR DISORDER WITH infants whose mothers
PREGNANCY ANDwere takingLACTATION.
LACTATION aripiprazole.
RISK. asenapine
Duedevelopmental should
to limited not
information breastfeed.
milestones,
with0.7 clozapine
especiallyduring if other APs are used
breastfeeding, and
**Relative Infant Dose (RID): - 8.3%.
There
Clozapine no adequate
are crosses placenta data
andfrom can be thedetected
use of inasenapine
foetal blood in If concurrently.
asenapine
sedation is required
and adverse by the mother,
haematologic effects ithave is not reason to
beena reported in
Asenapine*
MEDICATION NO HUMAN
pregnant women.DATA - ANIMAL
PREGNANCY DATA SUGGEST MODERATE Manufacturer’s
**RID: 2.3% labelling
- 4.7%.
breastfeeding. recommends
LACTATION
However, that women
an alternate drug may be receiving
and amniotic fluid. However, maternal and embryo-foetal toxic • discontinue breastfed infants, other agents are preferred.
Aripiprazole* RISK.
HUMAN
effects DATA
were found SUGGEST
in animal LOW
studies.RISK. asenapine
NOT
preferred, should
RECOMMENDED not breastfeed.
DURING LACTATION. or preterm infant.
Ziprasidone* • LIMITED
Other agents HUMAN are DATA
preferred- ANIMAL
for useDATA SUGGEST
in pregnancy; however, POSSIBLEespecially
RISK. if • Monitoring: TO USE CAUTIOUSLY
while nursing a DURING newborn LACTATION.
There are
Aripiprazole
Should no adequate
crosses
be data from the
placenta.
during of asenapine
use clearly necessary in If
An asenapine
alternate is required
drug the mother,
bypreferred, it is notwhilea reason
nursing to
a
• Safest course
indicated,notmay isused
to avoid
be used ziprasidone
in pregnancy
women who in unless
pregnancy
cannot bedue to limited
switched to • o Due to limited
Monitor infant data,
formayexcessive
other beAPs sedation and periodic
may be especially
preferred, especially
monitoring while
of
pregnant
Due
and to
only women.
limited data,However,
avoid usematernal
in and
pregnancy. embryo-foetal
potential benefit outweighs potential risk to However, iftoxic
the discontinue
newborn or breastfeeding.
preterm infant However,
due to limited an alternate
information drug may be
human data.
recommended if theAPs. nursing a newborn
the infant's whiteor preterm
blood cell count
infant.is advisable. available.
effects
mother’s
foetus. were found inrequires animal studies.
treatment aripiprazole, the preferred, especially lower while
serumnursing a newborn
prolactin or preterm infant.
in a dose-related
Haloperidol* • However,
LIMITED conditionif a woman
HUMAN DATArequires
- ANIMAL treatment
with DATA in pregnancy,
SUGGEST • Aripiprazole
POSSIBLE
Monitoring: TO canUSE CAUTIOUSLY DURING LACTATION.manner.
Cariprazine* Should
lowest
NO effective
HUMAN
not beDATA useddose,during
ANIMAL pregnancy
avoiding the
DATA unless
first
SUGGEST clearly
trimester ifnecessary
possible,
MODERATE Cases of lactation cessation have occurred, but cases of
medication
MODERATE should
RISK not- be withheld. Instead, an informed consent No
LimitedBreastfed
○ information
informationinfants
is available should
indicates the
be use
on that monitored for excess
of cariprazine
maternal doses ofduring sedation,
lactation.
haloperidol up
and only
should the potential benefit outweighs potential risk to the
beifused. gynecomastia and galactorrhea have also been reported.
RISK.
on the unknown
Neonatal tardive risk to her embryo-foetal
dyskinesia may be an uncommon obtained.
should be complication An
to 10irritability,
alternate
mg daily poor
drug
produce feeding
maylow and
belevels EPS
preferred
in e.g.
milk tremors
until
and more
usuallyand
data
do abnormal
become
not affect
foetus.

ANTIPSYCHOTICS
Absence
of exposure of human
throughout pregnancy data prevents a better assessment
gestation. Weight muscle
available.
the breastfed and
lossmovements.
infant.poor Veryweight
limitedgain have been
long-term reported
follow-up breastfed
datainindicate no
Cariprazine* NO HUMAN - ANIMAL DATA SUGGEST MODERATE No information
infants whose mothersis available were the use
ontaking of cariprazine during lactation.
aripiprazole.
of the embryo-foetalDATA risk.
RISK. An alternate
**Relative Infantdrug Dose be preferred
may(RID): 0.7 - 8.3%.until more data become

ANTIPSYCHOTICS
Management of Bipolar Disorder (Second Edition)

Clozapine* COMPATIBLE - MATERNAL BENEFIT >> EMBRYO-FOETAL NOT RECOMMENDED DURING LACTATION.
Asenapine* Absence
NO
RISK.HUMANof human
DATApregnancy
- ANIMAL data prevents
DATA SUGGEST assessment
60
a betterMODERATE available.
Manufacturer’s labelling recommends
Due to limited information with clozapinethat
duringwomen
breastfeeding,
receivingand
of the embryo-foetal risk.
RISK. should not breastfeed.
Clozapine crosses placenta and can be detected in foetal blood sedation
asenapineand adverse haematologic effects have been reported in
Clozapine* COMPATIBLE
There - MATERNAL BENEFIT >> EMBRYO-FOETAL
adequate data from the use of asenapine in NOT
If RECOMMENDED
asenapine is required DURING
by theLACTATION.
mother, it is not a reason to
and amniotic
are nofluid. breastfed infants, other agents are preferred.
RISK.
pregnant women. maternal embryo-foetal toxic Due to limited
discontinue information with
breastfeeding. clozapine
However, an during breastfeeding,
alternate drug mayand be
Other agents are preferred
However, for use in and
pregnancy; however, if Monitoring:

ICS
Clozapine
indicated, crosses
effects were
mayfound placenta
be in animal
used and
studies.
in women be detected
canwho in foetal
cannot be blood
switched to sedation
preferred,and adverse
o Monitor especially haematologic
while nursing
infant for excessive a effects
newborn
sedation andhave been
or preterm
periodic reported
monitoring in
infant. of
 MEDICATION PREGNANCY LACTATION
Carbamazepine • NOT RECOMMENDED FOR TREATMENT OF BIPOLAR • POSSIBLE AND COMPATIBLE TO USE IN LACTATION.
DISORDER. • Breastfeeding during carbamazepine monotherapy does not appear
• Carbamazepine and its active metabolite cross the placenta; to adversely affect infant growth or development.
concentrations are variable. • Carbamazepine and its active metabolite have relatively high levels
• May be associated with teratogenic effects, including spina bifida, in breastmilk and breastfed infants have serum levels that are
craniofacial defects, cardiovascular malformations and sometimes measurable, but usually well below the therapeutic
developmental delays. Risk of congenital malformations range.
increases with higher doses. • Most infants have no adverse reactions, but sedation, poor sucking,
• Foetal carbamazepine syndrome has been proposed consisting withdrawal reactions and cases of hepatic dysfunction have been
of minor craniofacial defects, fingernail hypoplasia and reported.
developmental delay. • Monitoring:
○ Monitor infant for jaundice, drowsiness, adequate weight gain
and developmental milestones, especially in younger,
exclusively breastfed infants and when using combinations of
anticonvulsant or psychotropic drugs.
○ Measuring infant serum carbamazepine levels is not

84
recommended; however breastfeeding should be discontinued if
AEs are observed.
Lamotrigine • COMPATIBLE - MATERNAL BENEFIT >> EMBRYO-FOETAL • POSSIBLE TO USE IN LACTATION.
RISK. • Lamotrigine monotherapy does not appear to adversely affect
• Crosses the human placenta and can be measured in the plasma growth or development in most infants.
of exposed newborns. • However, neonates and young infants are at risk for high serum

MOOD STABILISERS
• Significant risk for oral clefts following first trimester exposure. levels because maternal serum and milk levels can rise to high
• Increased risk of malformations may be associated with larger levels postpartum if lamotrigine dosage has been increased during
doses. pregnancy but not reduced after delivery to the pre-pregnancy
• Clearance of lamotrigine increases by >50% starting early in dosage.
pregnancy and reverts to the non-pregnant state quickly after • If an infant rash occurs, breastfeeding should be discontinued until
delivery. Pregnant women may require dose adjustments in order the cause can be established.
to maintain clinical response. • Breastfeeding should be discontinued in infants with lamotrigine
• Monitoring: toxicity.
○ Where facilities are available, baseline serum concentrations • Monitoring:
should be measured once or twice prior to pregnancy. ○ Breastfed infants should be carefully monitored for side effects
Monitoring can then be continued up to monthly during e.g. apnoea, rash, drowsiness or poor sucking, including
Management of Bipolar Disorder (Second Edition)

pregnancy and every second day during the first week post- measurement of serum levels to rule out toxicity if there is a
partum. concern.
 MEDICATION PREGNANCY LACTATION
Carbamazepine NOT RECOMMENDED FOR TREATMENT OF BIPOLAR ○ Monitoring
POSSIBLE AND of COMPATIBLE
infant’s plateletTO count,
USE liver function and serum
IN LACTATION.
DISORDER. concentrations
Breastfeeding duringbefore and after increases
carbamazepine monotherapy in maternal
does lamotrigine
not appear
Carbamazepine and its active metabolite cross the placenta; dosage might
to adversely affectalsoinfant advisable.
be growth or development.
concentrations are variable. • **RID: 5 - 31%. and its active metabolite have relatively high levels
Carbamazepine
Lithium • May
HUMANbe associated
DATA SUGGEST with teratogenic
RISK. effects, including spina bifida, • in breastmilk
POSSIBLE TOand USEbreastfed
CAUTIOUSLY infantsINhave serum levels that are
LACTATION.
• craniofacial defects, cardiovascular
Foetal echocardiography between 16 and malformations
20 weeks gestation and • sometimes
Lithium excretion measurable, but usually
into breastmilk well below the
and concentrations therapeutic
in infant serum
developmental
should be considered delays.in Risk
a womanof congenital malformations
with first-trimester lithium range.
are highly variable; most sources do not consider it an absolute
increases
exposure with
because
higherofdoses.
the potential increased risk of cardiac Most
contraindication
infants haveinno adverse
healthy reactions,
full-term but sedation,
infants, especiallypoor sucking,
in infants >2
Foetal .
carbamazepine
malformations. syndrome has been proposed consisting withdrawal
months of age reactions
and during cases of
and lithium hepatic dysfunction have been
monotherapy.
• of
Incidence
minor ofcraniofacial defects, fingernail
AEs may be associated with higherhypoplasia
maternal doses. and • reported.
Long-term effects of lithium on infants are not certain; however,
• developmental delay.
Due to pregnancy-induced physiologic changes, maternal serum Monitoring:
limited data indicate no obvious problems in growth and
concentrations should be monitored and dosage adjusted during o Monitor infant for jaundice, drowsiness, adequate weight gain
development.
MEDICATION PREGNANCY LACTATION
pregnancy. • Lithium
and indevelopmental
milk can adversely milestones,
affect theespecially
infant acutely younger,
in when its
Carbamazepine NOT RECOMMENDED FOR TREATMENT OF BIPOLAR POSSIBLE AND COMPATIBLE TO USE IN LACTATION.
• Discontinuing lithium 24 - 48 hours before Caesarean section exclusively
elimination is impaired infants and when using combinations
breastfed (dehydration/newborn/premature infants).of
DISORDER. Breastfeeding during carbamazepine monotherapy does not appear
MEDICATION delivery or at the onset of PREGNANCY
spontaneous labour and resuming the anticonvulsant
Infants who are preterm,or psychotropic
dehydrated
LACTATION drugs.or have an infection should
Carbamazepine and its active metabolite cross the placenta; to
o adversely
Measuring affect infant growth or development.
carbamazepine levels is not
Carbamazepine pre-pregnancy
NOT RECOMMENDED lithium dose immediately after delivery should receive
POSSIBLE hydration
ANDinfantand beserum
COMPATIBLE assessed TO for
USElithium toxicity.
IN LACTATION.
concentrations are variable.FOR TREATMENT OF BIPOLAR Carbamazepine and its active
however metabolite have
breastfeeding should relativelydiscontinued
high levelsif

85
minimise the infant's serum lithium concentration at birth.
DISORDER. • As recommended;
maternal lithium
Breastfeeding during requirements
carbamazepine and dosage
monotherapy may
bedoes be increased
appear
May be associated with teratogenic effects, including spina bifida, in breastmilk and
are observed. breastfed infants have serum levelsnotthat are
• Use of drug near
Carbamazepine andterm may produce
its active metabolitesevere
cross toxicity in the
the placenta; during
to AEs pregnancy,
adversely affect maternal
infant growth serum
or levels should be monitored
development.
Lamotrigine craniofacial
COMPATIBLE defects,
- MATERNAL cardiovascular
BENEFIT >>malformations
EMBRYO-FOETAL and sometimes
POSSIBLE measurable,
TO USE but usually
LACTATION. well below the therapeutic
concentrations
newborn which are is usually reversible.
variable. frequently postpartum
Carbamazepine and INand
its dosage
active reduced
metabolite have necessary
asrelatively high avoid
to levels
developmental delays. Risk of congenital malformations range.
RISKbe associated with teratogenic effects, including spina bifida,
May excessive
Lamotrigine
in breastmilkinfant andexposure
monotherapy
breastfed via
doesbreastmilk.
infants appear
not have serumto adversely
levels affect
are
increases with higher doses. Most infants have no adverse reactions, but sedation, poor that
sucking,
Crosses the human
craniofacial defects,placenta and can be measured
cardiovascular in the plasmaand • growth
If infant’s
sometimes development
or serum lithium level
measurable, in most elevated,
is usually
infants. well reducing
belowthe the percentage
therapeutic of
Foetal carbamazepine syndrome has beenmalformations
proposed consisting withdrawal reactions and but
cases of hepatic dysfunction have been
of exposed newborns. breastfeeding
However, can decrease
neonates and young it. infants are at risk for high serum

MOOD STABILISERS
developmental
of minor craniofacial delays. defects,
Risk of fingernail malformations
congenitalhypoplasia and range.
reported.
Significant
increases with
risk higher clefts following first trimester exposure.
for oraldoses. • levels
Most because
0 - 30%.
**RID:infants have maternal
no adverse serum and milk
reactions, but levels
sedation, canpoor to high
risesucking,
developmental delay. Monitoring:
Increased
Foetal risk of malformations
carbamazepine syndromemay be associated
has been proposedwith larger
consisting • levels
withdrawalpostpartum if lamotrigine
Monitoring: dosage
of hepatic been increased
has dysfunction haveduring
been
o Monitor reactions
infant for and jaundice,
casesdrowsiness, adequate weight gain
doses.
of minor craniofacial defects, fingernail hypoplasia and pregnancy
○ Monitor infant
reported. but not for reduced after delivery
lethargy, growth and feeding to the pre-pregnancy
problems.
and developmental milestones, especially in younger,
Clearance of lamotrigine
developmental delay. increases by >50% starting early in dosage.
○ Monitor infant serum lithium, serum creatinine, BUN and TSH if
Monitoring:
exclusively breastfed infants and when using combinations of
pregnancy and reverts to the non-pregnant state quickly after If
o an clinical
Monitor rash
infantconcerns
infantoccurs,
forarise. breastfeeding
jaundice, drowsiness, be discontinued
shouldadequate weight gainuntil
anticonvulsant or psychotropic drugs.
Valproate • delivery. Pregnant women
CONTRAINDICATED andmayan alternative adjustments
require dosetreatment in order
should be • the and can
causedevelopmental
POSSIBLE TObe USEestablished. milestones, in younger,
o Measuring infantIN LACTATION.
serum carbamazepineespecially levels is not
to maintain
decided on,clinical
withresponse.
appropriate specialist consultation, for • Breastfeeding
exclusively
Valproate levelsshould
breastfed discontinued
be infants
breastmilk are
andlowwhen infants
inand using
infant’s lamotrigine
combinations
withserum of
levels
recommended; inhowever breastfeeding should be discontinued if
Monitoring:
women planning pregnancy. toxicity.
rangeanticonvulsant or psychotropic
undetectable to low. drugs.
Breastfeeding during valproate
AEsfromare observed.
Lamotrigine • o
HighWhere
teratogenic are available,
facilities potential and baseline serum
exposed concentrations
in-utero to o
Monitoring:
Measuring
monotherapy infant
does not serum
appear to carbamazepine
adversely affect levels
infant is
growth not
or
COMPATIBLE - MATERNAL BENEFIT
children>> EMBRYO-FOETAL POSSIBLE TO USE IN LACTATION.

STABILISERS
valproate be measured
should have a high once or twice prior
risk congenital to pregnancy.
malformations and o Breastfed infants
recommended;
development. however be carefully monitored
should breastfeeding should befor side effects
discontinued if
RISK Lamotrigine monotherapy does not appear to adversely affect
Monitoring can then
neurodevelopmental be continued up to monthly during
disorders. • AEs
suchare
Combination apnoea,
as observed.
therapy with drowsiness
rash,sedating or poor sucking,
anticonvulsants including
or psychotropics
Crosses the human placenta and can be measured in the plasma growth or development in most infants.
pregnancy and every second day during the first week post- measurement of serum levels to rule out toxicity if there is a
Management of Bipolar Disorder (Second Edition)

Lamotrigine COMPATIBLE - MATERNAL BENEFIT >> EMBRYO-FOETAL POSSIBLE TO USE IN LACTATION.

STABILISERS
of exposed newborns. However, neonates and young infants are at risk for high serum
RISKpartum. concern.
Lamotrigine monotherapy appear adversely
Significant risk for oral clefts following first trimester exposure. levels because maternal serum does and not milk levelsto can rise toaffect
high
Crosses the human placenta and can be measured in the plasma growth or development
levels postpartum in most infants.
if lamotrigine dosage has been increased during
Increased risk of malformations may be associated with larger
of exposed newborns. However, neonates and young infants are at risk for high serum

MOODMOOD
doses. pregnancy but not reduced after delivery to the pre-pregnancy
Significant risk for oral clefts following first trimester exposure. levels
dosage. because maternal serum and milk levels can rise to high
Clearance of lamotrigine increases by >50% starting early in
Increased malformations may be associated with
63 larger levels postpartum
If an infant if lamotrigine
rash occurs, breastfeeding
dosageshould has been increased during
be discontinued until
pregnancy riskandofreverts to the non-pregnant state quickly after
pregnancy
the cause can butbenot reduced after delivery to the pre-pregnancy
established.
doses. Pregnant women may require dose adjustments in order
delivery.
 MEDICATION PREGNANCY LACTATION
Valproate CONTRAINDICATED and an alternative treatment should be • POSSIBLE TO USE IN LACTATION.
decided on, with appropriate specialist consultation, for • Valproate levels in breastmilk are low and infant’s serum levels
women planning pregnancy. range from undetectable to low. Breastfeeding during valproate
High teratogenic potential and children exposed in-utero to monotherapy does not appear to adversely affect infant growth or
valproate have a high risk congenital malformations and development.
neurodevelopmental disorders. • Combination therapy with sedating anticonvulsants or psychotropics
Pregnancy test may result in infant’s sedation or withdrawal reactions.
Treatment must not be initiated in women of child bearing • Monitoring:
potential without a negative pregnancy test to rule out unintended ○ Breastfed infants should be monitored for jaundice.
use in pregnancy. ○ Breastfed infants should be monitored for jaundice unusual
Contraception bruising or bleeding and other signs of liver damage during
Patients must be provided with comprehensive information on maternal therapy.
pregnancy prevention and should be referred for contraceptive
advice if they are not using effective contraception.
Pregnancy Planning
Treatment with valproate should be discontinued prior to
conception and before contraception is discontinued. If needed,

86
alternative treatment options should be considered.
In case of pregnancy
Refer to a specialist to re-evaluate treatment with valproate and
consider alternative options.

* Risk of EPS and/or withdrawal symptoms in newborns if APs is used in the third trimester.
** In general, RID <10% is considered compatible with breastfeeding. However, worth noting that some sources recommend that for psychotropic agents,
breastfeeding is considered acceptable if RID is <5%.4,5

Source:
1. Briggs GG, Towers CV, Forinash AB. Briggs Drugs in Pregnancy and Lactation 14th ed. Wolters Kluwer; 2022.
2. Drugs and Lactation Database (Lactmed) (Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/).
3. Uguz F. A New Safety Scoring System for the Use of Psychotropic Drugs During Lactation. Am J Ther. 2021;28(1):e118-e126.
4. Larsen ER, Damkier P, Pedersen LH, et.al. Use of psychotropic drugs during pregnancy and breastfeeding. Acta Psychiatr Scand Suppl. 2015;(445):
1-28.
Management of Bipolar Disorder (Second Edition)

5. Clinical Drug Information, Inc. Wolters Kluwer. UpToDate® [Mobile application software].
 Management of Bipolar Disorder (Second Edition)

Appendix 10a

BPFK/PPP/07/25 (21) Jld 3

ANNUAL RISK ACKNOWLEDGEMENT FORM

PART A. TO BE COMPLETED AND SIGNED BY THE PRESCRIBER

Patient’s name : ______________

MRN/IC No. : ______________
Address : ______________

For girls and women of childbearing age treated with Sodium Valproate < Product Name
>. Please read, complete and sign this form during a visit with the prescriber: at treatment
initiation, during annual visit and when the woman plans pregnancy or is pregnant.

Name of patient or care-giver:

I confirm the above-named patient needs sodium valproate because:
□ this patient does not respond adequately to other treatments, or
□ this patient does not tolerate other treatments,
□ that this patient is stable on.........dose and she is reluctant to change to other,
□ other reasons .......................................................(to specify)

I have discussed the following information with the above-named patient or caregiver:
□ The overall risk to fetus and children whose mothers are exposed to sodium valproate
during pregnancy are :
• approximately 10% chance of birth defects and
• up to 30% to 40%, chance of a wide range of early developmental problems that can
lead to learning difficulties.
□ Sodium valproate should not be used in pregnancy (except in rare situations such as
epileptic patients that are resistant or intolerant to other treatments)
□ The need for regular (at least annually) review and the need to continue sodium valproate
treatment by the prescriber
□ The need for a negative pregnancy test at treatment initiation and as required there-after
(if child-bearing age)
□ The need for an effective contraception without interruption during the entire duration of
sodium valproate (if childbearing age).
□ To need to arrange an appointment with her doctor as soon as she is planning pregnancy
to ensure timely discussion and switching to alternative treatment options prior to
conception, and before contraception is discontinued.
□ The need to contact her doctor immediately for an urgent review of the treatment in case
of suspected or inadvertent pregnancy
□ In case of pregnancy, I confirm that this patient:
• receives the lowest possible effective dose of sodium valproate to minimise the
possible harmful effect on the unborn
• is informed about the possibilities of pregnancy support or counselling and appropriate
monitoring of her baby if she is pregnant

Name of Prescriber : Signature Date

Part A and B shall be completed. All boxes shall be ticked, and the form signed by the prescriber. This is to
make sure that all the risks and information related to the use of sodium valproate during pregnancy have
been understood.
Part A - to be kept by the prescriber

87
 Management of Bipolar Disorder (Second Edition)

ANNUAL RISK ACKNOWLEDGEMENT FORM

PART B. TO BE COMPLETED BY THE PRESCRIBER AND SIGNED
BY THE PATIENT OR CAREGIVER

Patient’s name : ______________

MRN/IC No. : ______________
Address : ______________

For girls and women of childbearing age treated with Sodium Valproate < Product Name >.
Please read, complete and sign this form during a visit with the prescriber: at treatment
initiation, during annual visit and when the woman plans pregnancy or is pregnant.

I discussed the following with my doctor and understand

□ Why I need sodium valproate rather than other medicine.
□ I have decided to continue with the treatment after being advised of the risk.
□ That I should visit the prescriber regularly (at least annually) to review whether sodium
valproate treatment remains the best option for me.
□ The overall risk to fetus and children whose mothers took sodium valproate during
pregnancy are:
• an approximately 10% chance of birth defects
• up to 30 to 40 % chance of a wide range of early developmental problems that can
lead to significant learning difficulties
□ Why I need a negative pregnancy test at testament initiation and if needed thereafter (if
childbearing age).
□ That I must use effective contraception without interruption during the entire duration of
treatment with sodium valproate (if childbearing age).
□ We discussed the possibilities of effective contraception or we planned a consultation
with a professional who is experienced in advising on effective contraception.
□ The need for regular ( at least annually) review and the need to continue sodium
valproate treatment by the prescriber.
□ The need to consult my doctor as soon as I am planning to become pregnant to ensure
timely discussion and switching to alternative treatment options prior to conception, and
before conception is discontinued.
□ That I should request an urgent appointment if I think I am pregnant.
In case of a pregnancy I have discussed the following with my doctor and understand:
• the possibilities of pregnancy support or counseling
• the need to appropriate monitoring of my baby if I am pregnant.

Name of Patient/Caregiver : Signature Date

Name of Prescriber : Signature Date

Part B shall be completed. All boxes shall be ticked, and the form signed by the prescriber and the patient.
This is to make sure that all the risks and information related to the use of sodium valproate during
pregnancy have been understood.
Part B - to be given to the patient
- a copy kept by the prescriber

88
 Management of Bipolar Disorder (Second Edition)

Appendix 10b

BORANG PENGAKUAN RISIKO TAHUNAN

BAHAGIAN A: UNTUK DILENGKAPKAN DAN DITANDATANGANI
OLEH PEGAWAI PERUBATAN

Nama Pesakit : ______________

MRN/No. Kad pengenalan : ______________
Alamat : ______________

Untuk kanak-kanak perempuan dan wanita yang dalam lingkungan umur boleh melahirkan anak
dan dirawat dengan Sodium Valproate. Sila baca, lengkapkan dan tandatangan borang ini
sebelum memulakan rawatan,semasa rawatan tahunan dan apabila wanita tersebut bercadang
untuk mengandung atau sedang mengandung.

Nama pesakit atau penjaga: saya

mengesahkan bahawa penama di atas memerlukan rawatan sodium valproate kerana
□ pesakit tidak respon dengan secukupnya terhadap rawatan ubat yang lain, Atau
□ pesakit tidak serasi dengan rawatan yang lain, Atau
□ pesakit telah stabil dengan ......... dos dan enggan untuk menukar ubat yang lain, Atau
□ sebab-sebab lain ................................. (jelaskan)

Saya telah berbincang mengenai maklumat dengan pesakit atau penjaga:

□ Risiko keseluruhan terhadap janin dan kanak-kanak di mana ibunya terdedah kepada
sodium valproate semasa mengandung adalah lebih kurang 10% risiko untuk mendapat
kecacatan kelahiran manakala risiko sebanyak 30% ke 40% untuk mendapat masalah
perkembangan awal yang boleh menyebabkan masalah pembelajaran.
□ Sodium valproate tidak sepatutnya diberikan kepada ibu mengandung kecuali dalam
situasi tertentu seperti pesakit epilepsi yang sukar dirawat dengan ubatan lain.
□ Keperluan untuk pemantauan secara berkala (sekurangnya setiap tahun) dan keperluan
untuk melihat samada rawatan sodium valproate perlu diteruskan.
□ Keperluan untuk memastikan ujian kehamilan adalah negatif sebelum dan selepas
rawatan dimulakan.
□ Keperluan untuk mengambil langkah kontraseptif yang berterusan sepanjang rawatan
sodium valproate diberikan.
□ Untuk memastikan pesakit dibawah pemantaun doktor obstetrik jika merancang untuk
hamil dan berbincang untuk rawatan alternatif serta pilihan ubatan psikiatri yang lain
sebelum mengandung atau sebelum perancang kehamilan dihentikan.
□ Pesakit perlu memberitahu doktor dan berjumpa untuk temujanji susulan secepat
mungkin sekiranya didapati atau disyaki hamil.
□ Untuk kes pesakit yang sudah hamil. Saya sahkan pesakit yang hamil ini:
- Hanya menerima dos efektif yang minimum untuk mengurangkan risiko kecacatan
janin.
- Telah dimaklumkan tentang sokongan kaunseling dan pemantauan rapi terhadap
kandungan sepanjang semasa proses kehamilan.

Nama Penerima : Tarikh tandatangan :

Bahagian A dan B hendaklah dilengkapkan. Kesemua kotak hendaklah ditanda dan borang perlu
ditandatangan oleh pegawai perubatan. Ini untuk memastikan semua risiko dan maklumat tentang
penggunaan sodium valproate semasa mengandung telah difahami.
Bahagian A - untuk simpanan pegawai perubatan.

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BORANG PENGAKUAN RISIKO TAHUNAN

BAHAGIAN B: UNTUK DILENGKAPKAN OLEH PEGAWAI
PERUBATAN DAN DITANDATANGANI OLEH PESAKIT
ATAU PENJAGA
Nama Pesakit : ______________
MRN/No. Kad pengenalan : ______________
Alamat : ______________

Untuk kanak-kanak perempuan dan wanita yang dalam lingkungan umur melahirkan anak
dan dirawat dengan Sodium Valproate .Sila baca, lengkapkan dan tandatangan borang ini
sebelum memulakan rawatan,semasa rawatan tahunan dan apabila wanita tersebut bercadang
untuk mengandung atau sedang mengandung.

Saya telah berbincang dengan pegawai perubatan mengenai maklumat berikut:

□ Keperluan untuk saya mengambil sodium valproate berbanding ubatan lain.
□ Saya telah memutuskan untuk meneruskan rawatan dengan sodium valproate selepas
dimaklumkan mengenai risiko.
□ Saya akan hadir untuk temujanji secara berkala (sekurangnya setahun sekali) untuk
memantau samada rawatan sodium valproate kekal sebagai pilihan terbaik untuk
rawatan saya.
□ Risiko keseluruhan terhadap janin dan kanak-kanak di mana ibunya terdedah kepada
sodium valproate semasa mengandung adalah lebih kurang 10% risiko untuk mendapat
kecacatan kelahiran manakala risiko sebanyak 30% ke 40% untuk mendapat masalah
perkembangan awal yang boleh menyebabkan masalah pembelajaran.
□ Kenapa saya perlu pastikan ujian kehamilan sebelum dan selepas memulakan rawatan
(untuk wanita dalam lingkungan umur melahirkan anak).
□ Saya perlu menggunakan kaedah kontraseptif yang efektif tanpa gangguan sepanjang
rawatan saya dengan sodium valproate (untuk wanita dalam lingkungan umur
melahirkan anak).
□ Kami telah berbincang mengenai kebarangkalian kontraseptif yang efektif atau kami
akan mendapatkan konsultasi dengan pegawai kesihatan yang arif dengan kontraseptif.
□ Saya perlu pemantauan secara berkala (sekurangnya setiap tahun) dan keperluan
untuk melihat samada rawatan sodium valproate perlu diteruskan.
□ Saya perlu memastikan saya dibawah pemantaun doktor obstetrik jika merancang
untuk hamil dan berbincang untuk rawatan alternatif serta pilihan ubatan psikiatri yang
lain sebelum mengandung atau sebelum perancang kehamilan dihentikan.
□ Saya perlu mendapatkan temujanji serta merta jika didapati saya mengandung.
□ Sekiranya saya mengandung, saya akan berbincang dengan pegawai perubatan
mengenai:
- Kebarangkalian untuk mendapatkan sokongan dan kaunseling semasa mengandung
- Keperluan untuk mendapatkan pemantauan bayi saya sekiranya saya mengandung

Nama Pesakit/Penjaga: Tarikh tandatangan:

Nama Penerima: Tandatangan: Tarikh:

Bahagian B hendaklah dilengkapkan: semua kotak perlu ditanda dan borang perlu ditandatangani oleh
pegawai perubatan dan pesakit. Ini untuk memastikan semua risiko dan maklumat tentang penggunaan
sodium valproate semasa mengandung telah difahami.
Bahagian B - untuk simpanan pesakit, satu salinan untuk simpanan pegawai perubatan.

90
 Appendix 11

SUGGESTED PAEDIATRIC MEDICATIONS DOSING

MEDICATION DOSING GUIDE RENAL HEPATIC REMARKS
ATYPICAL ANTIPSYCHOTICS
Aripiprazole Acute mania or episodes with mixed features No dosage adjusment No dosage • Only strength 5 mg,10 mg and
necessary. adjusment 15 mg are registered with
10 to 17 years old: necessary. NPRA.
Oral • Commonly seen ADR in
D1: 2 mg once daily for 2 days; paediatric populations:
D3: 5 mg once daily for 2 days; somnolence, extrapyramidal
D5: 10 mg once daily; may titrate subsequent dose in reaction, fatigue, nausea,
increment of 5 mg/day) akathisia, blurred vision,
salivary hypersecretion,
(Usual target dose: 10 mg once daily) dizziness.
(Max dose: 30 mg daily)

91
Asenapine Acute mania or episodes with mixed features No dosage adjusment Severe hepatic • Only strength 5 mg and 10 mg
necessary. impairment (Child- are registered with NPRA.
10 to 17 years old: Pugh Class C): • Commonly seen ADR in
Sublingual Use is paediatric populations:
D1: 2.5 mg twice daily; contraindicated. somnolence, dizziness,
D4: May increase to 5 mg twice daily; dysgeusia, oral paraesthesia,
D7: May increase to 10 mg twice daily nausea, increased appetite,
(Max dose: 10 mg twice daily) fatigue, increased weight.

Lurasidone Bipolar disorder (depressive episodes) CrCl <50 mL/minute: Moderate • Take with a meal (>350
Reduce initial dose. impairment: calories) for adequate
10 to 17 years old Do not exceed an Reduce initial dose. absorption.
Oral initial dose of 20 mg Do not exceed an • Commonly seen ADR in
20 mg once daily; may titrate after 1 week based on daily initial dose of 20 mg paediatric populations:
response although dose titration is not required (Max dose: 80 daily nausea, weight gain,
mg/day). (Max dose: 80 insomnia.
(Usual target dose: 20 mg - 40 mg once daily) mg/day)
(Max dose: 80 mg/day)
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL HEPATIC REMARKS
Severe impairment:
Reduce initial dose.
Do not exceed an
initial dose of 20 mg
daily
(Max dose: 40
mg/day)
Olanzapine Acute mania or episodes with mixed features No dosage Use with caution. • Only strength 5 mg and 10 mg
adjustment is Dosage adjustment are registered with NPRA.
13 to 17 years old necessary as not may be necessary; • Commonly seen ADR in
Oral removed by dialysis. however, no specific paediatric populations:
Initial: 2.5 - 5 mg once daily recommendations sedation,weight gain,
Dose titration: Increment/decrement of 2.5 or 5 mg at exist. increased appetite, headache,
weekly interval fatigue, dizziness, dry mouth,
abdominal pain.
(Usual target dose: 10 mg/day) • Fixed dose OFC capsule is
(Max dose: 20 mg/day) not available in Malaysian
market.
Depressive episodes (in combination with fluoxetine)

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10 to 17 years old
Oral
Initial: 2.5 mg of oral olanzapine and 20 mg of oral
fluoxetine once daily
(Max dose: 12 mg olanzapine/50 mg fluoxetine)

Quetiapine Mania or episodes with mixed features No dosage Immediate release • Commonly seen ADR in
adjustment is 25 mg once daily; paediatric populations:
10 to 17 years old necessary. titrate by 25 - 50 somnolence, dizziness,
Oral, immediate release (IR) mg/day to effective fatigue, increased appetite,
D1: 25 mg twice daily dose based on nausea, vomiting, dry mouth,
D2: 50 mg twice daily individual clinical tachycardia, weight gain.
D3: 100 mg twice daily response and • Switching from IR to ER:
D4: 150 mg twice daily tolerability. May convert at the equivalent
D5: 200 mg twice daily total daily dose and administer
Dose titration: Increment of ≤100 mg/day based on Extended release once daily; individual dosage
Management of Bipolar Disorder (Second Edition)

clinical response and tolerability 50 mg once daily; adjustments may be

(Usual dosage range: 200 - 300 mg twice daily) titrate by 50 mg once necessary.
 MEDICATION DOSING GUIDE RENAL HEPATIC REMARKS
(Max dose: 600 mg/day) daily to effective
**Total daily doses may also be divided into 3 doses per dose based on
day individual clinical
response and
Oral, extended release (ER) tolerability.
D1: 50 mg once daily
D2: 100 mg once daily
D3: 200 mg once daily
D4: 300 mg oce daily
D5: 400 mg once daily

(Usual dosage range: 400 - 600 mg once daily)

(Max dose: 600 mg/day)
Risperidone Mania No pediatric-specific No pediatric-specific • No specific FDA/ NPRA
dosage dosage approved dose in
10 to 17 years old recommendations. recommendations. children/adolescent population
Oral for use of risperidone LAI in

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Initial: 0.5 mg once daily Based on experience Based on bipolar disorder.*
Titrate in increment of 0.5 - 1 mg/day at intervals >24 in adult patients, experience in adult • In patients with persistent
hours dosing adjustments patients, dosing somnolence, administering
Usual target dose: 1 - 2.5 mg/day suggested. adjustments half the daily dose twice daily
suggested. may be beneficial.
**Doses >2.5mg/day do not confer additional benefit and • Well accepted for treatment of
are associated with increased adverse events. behavioural symptoms in
children and adolescents, but
may have more sedation and
weight gain in paediatric
populations than in adult
populations.
• Other commonly seen side
effects in paediatric population
include cough, nasal
congestion, nasopharyngitis,
fatigue.
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL HEPATIC REMARKS
Ziprasidone • No specific FDA/ NPRA
approved dose in
children/adolescent population
for use of ziprasidone in
bipolar disorder*.
ANTIDEPRESSANT
Fluoxetine Depressive episodes (in combination with ≥7 years old and ≥7 years old and • Fixed dose OFC capsule is
olanzapine) adolescents: adolescents: not available in Malaysian
Adjusment not Lower doses or less market.
Oral routinely needed frequent
≥10 years old and adolescents administration are
20 mg orally once daily in the evening in combination *With chronic recommended.
with olanzapine 2.5 mg; titrate to clinical effect and administration,
tolerability additional *Elimination half-life
(Max: 50 mg/day) accumulation of of fluoxetine is
fluoxetine or prolonged in patients
norfluoxetine may with hepatic

94
occur in patients with impairment.
severely impaired
renal function.
MOOD STABILISERS
Lithium Acute mania or episodes with mixed features CrCl 30 - 89 ml/min: No dosage • Commonly seen ADR in
Initiate therapy with adjustments paediatric populations:
Oral low dose. provided in the nausea/vomiting, polyuria,
≥7 years old, weight <30 kg: manufacturer’s thyroid abnormalities, tremor,
Initial: 300 mg twice daily; CrCl <30 ml/min: labeling. thirst/polydipsia, dizziness,
Dose titration: Increment of 300 mg/weekly Avoid use. rash/dermatitis, ataxia/gait
disturbance, reduced appetite,
7 years old, weight >30 kg blurry vision.
Initial: 300 mg 3 times daily; • Only immediate release
Dose titration: Increment of 300 mg every 3 days lithium carbonate formulation
is registered with NPRA.
Management of Bipolar Disorder (Second Edition)
 MEDICATION DOSING GUIDE RENAL HEPATIC REMARKS
Usual Dose Range: • Prior to treatment initiation:
>7 years old, >7 years old, ensure prompt and accurate
wt <30 kg weight >30 kg serum lithium levels can be
Acute therapy 600 - 1500 mg 1200 - 1800 mg determined since toxicity can
dose range in divided daily in divided daily occur at doses closes to
dose dose therapeutic levels.

* At the time of writing, there is no specific FDA/NPRA approval dose for use in children/adolescent population

Source:
1. Clinical Drug Information, Inc. Wolters Kluwer. UpToDate® [Mobile application software]
2. Micromedex® Solution [Mobile application software]
3. Invidual product information leaflet
4. Stahl SM. Stahl’s essential psychopharmacology: Prescriber’s guide. Cambridge University Press; 2014
5. Quest3+ Product Search Sistem Pendaftaran Produk & Perlesenan (Available at: https://quest3plus.bpfk.gov.my/pmo2/index.php)

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Management of Bipolar Disorder (Second Edition)
 Management of Bipolar Disorder (Second Edition)

LIST OF ABBREVIATIONS

AD anti-depressant
ADHD attention-deficit hyperactive disorder
AE(s) adverse event(s)
AP antipsychotic
AAP atypical antipsychotic
ACT Acceptance and Commitment Therapy
ALT alanine aminotransferase
ASPD antisocial personality disorder
AST aspartate aminotransferase
BAI Beck Anxiety Inventory
BD bipolar disorder
BD I bipolar I disorder
BD II bipolar II disorder
BI bipolarity index
BSDS Bipolar spectrum diagnostic scale
BPD Borderline personality disorder
BPRS Brief Psychotic Rating Scale
BW birth weight
CAE customised adherence enhancement
CAM complementary and alternative medicine
CANMAT Canadian Network for Mood and Anxiety Treatments
CBD cannabidiol
CBT cognitive behavioural therapy
CGI-BP Clinical Global Impression-bipolar disorder
CGI-BP-S CGI-S-Bipolar Version-Severity
CU cannabis use
DBT dialectical behaviour therapy
DSM-5-TR Diagnostic and Statistical Manual of Mental Disorders Fifth
Edition, text revision
ECG electrocardiogram
ECT electroconvulsive therapy
EPA eicosapentaenoic acid
EPS extra-pyramidal symptoms
ER extended release
FDA Food and Drug Administration
FFT family-focused therapy
FGA first generation antipsychotic
GAD-7 Generalized Anxiety Disorder-7 Scale

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 Management of Bipolar Disorder (Second Edition)

GRADE Grading of Recommendations, Assessments, Development

and Evaluations
HADS Hospital Anxiety and Depression Scale
HCL-32 Hypomania checklist
HCP healthcare practitioner
ICD-11 International Classification of Diseases Eleventh Revision
IDS Inventory of Depressive Symptomatology (IDS)
IPSRT Interpersonal and Social Rhythm Therapy (IPSRT)
MSRS Manic State Rating Scale
MARS Medication Adherence Rating Scale
MDQ Mood disorder questionaire
NMA network meta-analysis
HAM-D Hamilton Depression Rating Scale
HR hazard ratio
IDS Inventory of Depressive Symptomatology
IQ Intelligence Quotient
IR immediate release
LAI long-acting injectable
Li lithium
LSMD least squares mean difference
MA meta-analysis
MADRS Montgomery-Asberg Depression Rating Scale
MBCT mindfulness-based cognitive therapy
MDQ Mood disorder questionnaire
MEMS medication event monitoring system
mg milligramme
MSRS Manic State Rating Scale
NMA
NMA network meta-analysis
network meta-analysis
NOS Newcastle-Ottawa Scale
NPRA National Pharmaceutical Regulatory Agency
NS non-significant
OFC olanzapine/fluoxetine combination
QoL quality of life
QIDS-SR Quick Inventory of Depressive Symptomatology Self-Report
OR odds ratio
PANSS Positive and Negative Syndrome Scale
RANZCP Royal Australian and New Zealand College of Psychiatrist
RCT(s) randomised controlled trial(s)
RID Relative Infant Dose
RMS Rapid mood screener

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 Management of Bipolar Disorder (Second Edition)

RoB risk of bias

rTMS repetitive transcranial magnetic stimulation
SGA second generation antipsychotic
SMD standard mean difference
SMS short messaging service
SR systematic review
SUCRA Surface Under the Cumulative Ranking Curve
SUD substance use disorder
TAU treatment as usual
TBS theta burst stimulation
TRQ Tablet Routine Questionnaire
WHO World Health Organisation
YMRS Young Mania Rating Scale

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 Management of Bipolar Disorder (Second Edition)

ACKNOWLEDGEMENT

The members of CPG DG would like to express their gratitude and

appreciation to the following for their contributions:
• Panel of external reviewers who reviewed the draft technically
• Technical Advisory Committee of CPG for their valuable input and
feedback
• Health Technology Assessment and Clinical Practice Guidelines
Council for approval of the CPG
• Ms. Subhiyah Ariffin for the retrieval of evidence
• Hanan Mikhael, person of lived experience, on the cover design of
the CPG
• All those who have contributed directly or indirectly to the
development of the CPG

DISCLOSURE STATEMENT

The panel members of both Development Group and Review Committee

had completed disclosure forms. None hold shares in pharmaceutical
firms or act as consultants to such firms. Details are available upon
request from the CPG Secretariat.

SOURCE OF FUNDING

The development of the CPG on Management of Bipolar Disorder

(Second Edition) was supported mainly by the MoH Malaysia and partly
by the Psychiatry Department, Hospital Putrajaya.

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Management of Bipolar Disorder (Second Edition)

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