CPG 2021 Management of Schizophrenia (Second Edition) For Reviewers

CLINICAL PRACTICE GUIDELINES
2021 MOH/P/PAK/xxxxxx
MANAGEMENT OF
SCHIZOPHRENIA
(SECOND EDITION)
Ministry of Health Malaysian Psychiatric Academy of Medicine

Malaysia Association Malaysia
i
Published by:
Malaysian 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
Copyright
The copyright owner of this publication is MaHTAS. Content may be reproduced in any number
of copies and in any format or medium provided that a copyright acknowledgement to
MaHTAS is included and the content is not changed, not sold, nor used to promote or endorse
any product or service, and not used in an inappropriate or misleading context.
ISBN:
Available on the following websites:

http://www.moh.gov.my
http://www.acadmed.org.my
https://www.psychiatry-malaysia.org
Also available as an app for Android and IOS platform: MyMaHTAS
STATEMENT OF INTENT
These clinical practice guidelines (CPG) are meant to be guides for clinical practice, based on
the best available evidence at the time of development. Adherence to these guidelines may
not necessarily guarantee the best outcome in every case. Every healthcare provider is
responsible for the management of his/her unique patient based on the clinical picture
presented by the patient and the management options available locally.
UPDATING THE CPG
These guidelines were issued in 2021 and will be reviewed in a minimum period of four years
(2025) or sooner if new evidence becomes available. When it is due for updating, the
Chairperson 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 will be the definitive version at all times. This version can
be found on the websites mentioned above.
ii
TABLE OF CONTENTS
No. Title Page
Levels of Evidence and Formulation of Recommendation i
Key Recommendations ii
Guidelines Development and Objectives iv
Development Group vi
Review Committee vii
External Reviewers viii
Algorithm 1. Management of Schizophrenia ix
Algorithm 2. Pharmacotherapy for Schizophrenia x
1. INTRODUCTION 1
2. EARLY DETECTION AND REFERRAL 2

2.1 Risk Factors 2
2.2 Screening 2
2.3 Referral
3. ASSESSMENT AND DIAGNOSIS 3

3.1 Bio-psychosocial Assessment 3
3.2 Criteria of Diagnostic Classifications 6
4. TREATMENT 7
4.1 Pharmacological Intervention 7
4.1.1 Pharmacological agents 8
4.1.2 Rapid tranquilisation in acute exacerbation 9
4.1.3 Depot/long-acting injectable antipsychotics in achieving
10
remission
4.1.4 Antipsychotics in relapse prevention 11
4.1.5 Intermittent treatment in relapse prevention 12
4.1.6 Treatment for extrapyramidal signs, sedation and weight gain
13
associated with antipsychotics
4.2 Physical Intervention 18
4.2.1 Electroconvulsive therapy 18
4.2.2 Transcranial magnetic stimulation 18
4.2.3 Transcranial direct current stimulation 18
4.3 Psychosocial intervention 18
4.3.1 Psychoeducation 18
4.3.2 Supported Employment 19
4.3.3 Cognitive Remediation Therapy 20
4.3.4 Social Skills Training 20
4.3.5 Peer Support Services 20
4.3.6 Family Therapy 21
4.3.7 Cognitive Behaviour Therapy 21
4.3.8 Supportive psychotherapy/Counselling 22
4.3.9 Others 22
5. SERVICE LEVEL INTERVENTION 23

5.1 Crisis and Emergency Service 23
5.2 Assertive Community Treatment 24
5.3 Intensive Case Management 24
5.4 Community-based Service Intervention 25
5.5 Day Hospitalisation/Day Treatment 25
5.6 Residential Services 25
iii
No. Title Page
5.7 Early Intervention in Psychosis 26
6. TRADITIONAL AND COMPLEMENTARY MEDICINE 27
7. CHALLENGES IN MANAGEMENT 27
7.1 Treatment-Resistant Schizophrenia 27
7.1.1 Definition 27
7.1.2 Predictors 28
7.1.3 Treatment 28
7.2 Treatment in Special Population 30
7.2.1 Comorbid substance use and tobacco use disorders 30
7.2.2 Pregnancy and breastfeeding 32
7.2.3 Suicide 33
7.3 Social issues 34
8. IMPLEMENTING THE GUIDELINES 36

8.1 Facilitating and Limiting Factors 36
8.2 Potential Resource Implications 36
References 38
Appendix 1. Example of Search Strategy 42
Appendix 2. Clinical Questions 43
Appendix 3. Diagnostic Criteria for Schizophrenia (DSM-5) 45
Appendix 4. International Statistical Classification of Diseases and
46
Related Health Problems, 10th Revision (ICD 10)
Appendix 5. Dosing Regimen for Oral Antipsychotics 47
Appendix 6. Dosing Regimen for Depot Injections of Antipsychotic 49
Appendix 7. Clozapine Initiation and Titration Regimen for In-Patient 51
Appendix 8. Monitoring Parameters for Antipsychotics 54
Appendix 9. Consensus Criteria for Assessment and Definition of
57
Treatment-Resistant Schizophrenia
List of Abbreviations 59
Acknowledgement 61
Disclosure Statement 61
Source of Funding 61
iv
LEVELS OF EVIDENCE
Level Study design
I Evidence from at least one properly randomised controlled trial
II-1 Evidence obtained from well-designed controlled trials without randomisation
II-2 Evidence obtained from well-designed cohort or case-control analytic studies,

preferably from more than one centre or group
II-3 Evidence from multiple time series with or without intervention. Dramatic results
in uncontrolled experiments (such as the results of the introduction of penicillin
treatment in the 1940s) could also be regarded as this type of evidence
III Opinions of respected authorities based on clinical experience; descriptive

studies and case reports; or reports of expert committees
SOURCE: US / CANADIAN PREVENTIVE SERVICES TASK FORCE 2001
FORMULATION OF RECOMMENDATION
In line with the current development in CPG methodology, the CPG Unit of MaHTAS is in the
process of adapting Grading Recommendations, Assessment, Development and
Evaluation (GRADE) in its work process. The quality of each retrieved evidence and its effect
size are carefully assessed and reviewed by the CPG Development Group. In formulating the
recommendations, overall balances of the following aspects are considered in determining the
strength of the recommendations:
• overall quality of evidence
• balance of benefits versus harms
• values and preferences
• resource implications
• equity, feasibility and acceptability
i
KEY RECOMMENDATIONS
The following recommendations are highlighted by the CPG Development Group as the key
recommendations that answer the main questions addressed in the CPG and should be
prioritised for implementation.
REFERRAL
• Early referral to psychiatric service should be considered for people with schizophrenia
having diagnosis and treatment issues.
ASSESSMENT AND DIAGNOSIS
• People with possible schizophrenia should be assessed thoroughly by history taking,

physical examination and mental state examination.
• Schizophrenia should be diagnosed using either Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5) or International Classification of Diseases and
Related Health Problem 10th Revision (ICD-10).
TREATMENT
a. Pharmacological Intervention
• Antipsychotics (APs) should be considered in the treatment of schizophrenia.

• Default from treatment in schizophrenia should be addressed and avoided.
• Depot/long-acting injectable AP in schizophrenia:
o should be offered when there is medication adherence issue
o may be considered on patient’s preference
• APs should be offered to prevent relapse in schizophrenia.
o Second-generation APs is the preferred choice.
o Standard dose of APs should be considered as maintenance treatment.
• Intermittent treatment using APs should be avoided in schizophrenia.
• Electroconvulsive therapy may be considered in schizophrenia to achieve rapid and
short-term improvement of severe symptoms after an adequate trial of AP is proven
ineffective and in treatment-resistant schizophrenia.
b. Psychosocial intervention
• Psychoeducation which includes early warning signs interventions should be given in

addition to other interventions in schizophrenia.
• Supported employment should be offered in schizophrenia.
• Cognitive remediation therapy may be considered as intervention for cognitive difficulties
in schizophrenia.
• The following may be offered in schizophrenia:
o social skills training
o peer support
o family therapy
o cognitive behaviour therapy for psychosis
ii
SERVICE LEVEL INTERVENTION
• Crisis intervention services should be offered in schizophrenia with acute psychiatric

symptoms.
• Assertive community treatment should be provided for people with schizophrenia who
has difficulty engaging with the mental health services.
• Intensive case management should be considered for people with schizophrenia who
are at risk of defaulting treatment.
• Early intervention in psychosis service should be provided in people with first episode of
psychosis.
TREATMENT OF TRS
• Clozapine should be offered in treatment-resistant schizophrenia.
CHALLENGES IN MANAGEMENT
• People with schizophrenia and comorbid substance use disorder should be referred to
the psychiatrist for further management.
• People with schizophrenia and smoking should be offered help in smoking cessation.
• Pre-pregnancy care which includes counselling should be offered to all women with
schizophrenia.
• Multidisciplinary care should be offered in the management of pregnant women with
schizophrenia.
• Clozapine may be considered in schizophrenia with persistent suicidal risk.
iii
GUIDELINES DEVELOPMENT AND OBJECTIVES
GUIDELINES DEVELOPMENT
The members of the Development Group (DG) for these Clinical Practice Guidelines (CPG)
were from the Ministry of Health (MoH) and Ministry of Higher Education. 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: mainly
Medline via Ovid and Cochrane Database of Systemic Reviews and others e.g. PubMed and
Guidelines International Network (refer to Appendix 1 for Example of Search Strategy). The
search was limited to literature published on humans, "all adults (19 plus years)", publication
from year "2009 to Current" and English language. In addition, the reference lists of all
retrieved literature and guidelines were searched and, experts in the field contacted to identify
relevant studies. All searches were conducted from 19 Nov 2018 to 26 Feb 2019. Literature
searches were repeated for all clinical questions at the end of the CPG development process
allowing any relevant papers published before 30 June 2021 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 CPGs on schizophrenia e.g.:

• Practice Guideline for The Treatment of Patients with Schizophrenia (Third Edition) [The
American Psychiatric Association (APA), 2019]
• Psychosis and Schizophrenia in Adults [National Institute for Health and Care
Excellence (NICE), 2018]
• Management of Schizophrenia [Scottish Intercollegiate Guidelines Network (SIGN),
2013]
These CPGs were evaluated using the Appraisal of Guidelines for Research and Evaluation
(AGREE) II prior to them being used as references.
A total of 35 clinical questions (CQ) 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 33 times throughout the development of these guidelines.
All literature retrieved were appraised by at least two DG members using Critical Appraisal
Skill Programme checklist, presented in evidence tables and further discussed in each DG
meetings. All statements and 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. This CPG was developed largely based on the findings of
systematic reviews, meta-analyses and clinical trials, with local practices taken into
consideration.
The literature used in these guidelines were graded using the US/Canadian Preventive
Services Task Force Level of Evidence (2001), while the grading of recommendation was
done using the principles of GRADE (refer to the preceding page). The writing of the CPG
follows strictly the requirement of AGREE II.
On completion, the draft of the 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 HTA and CPG Council
MoH Malaysia for review and approval. Details on the CPG development methodology by
MaHTAS can be obtained from Manual on Development and Implementation of Evidence-
based Clinical Practice Guidelines published in 2015 (available at
http://www.moh.gov.my/moh/resources/CPG_MANUAL_MAHTAS.pdf?mid=634).
iv
OBJECTIVES
The objectives of the CPG are to provide recommendations on the management of

schizophrenia on following aspects:
a) early detection and referral
b) assessment and diagnosis
c) treatment and follow-up
d) challenges in management including special groups
CLINICAL QUESTIONS
Refer to Appendix 2.
TARGET POPULATION
Inclusion Criteria
Adults with a diagnosis of schizophrenia
TARGET GROUP/USERS
This document is intended to guide those involved in the management of schizophrenia at any
healthcare level including:
i. doctors
ii. allied health professionals
iii. trainees and medical students
iv. patients and their advocates
v. professional organisations
HEALTHCARE SETTINGS
Primary, secondary and tertiary care settings
v
DEVELOPMENT GROUP
Chairperson
Dr. Siti Nor Aizah Ahmad
Consultant Psychiatrist
Hospital Pulau Pinang, Pulau Pinang
Members (in alphabetical order)
Dr. Ahmad Zabidin Zakaria Dr. Parveen Thanabalen

Consultant Psychiatrist Senior Principal Assistant Director
Hospital Pakar Sultanah Fatimah, Johor Malaysian Health Technology Assessment
Section, Ministry of Health, Putrajaya
Dr. Hilwa Abdullah @ Mohd. Nor Dr. Ranimah Yahya

Senior Lecturer & Clinical Psychologist Family Medicine Specialist
Universiti Kebangsaan Malaysia, Selangor Klinik Kesihatan Rahmat, Terengganu
Dr. Izyan A. Wahab Associate Prof. Dr, Salina Mohamed

Senior Lecturer & Pharmacist Senior Lecturer & Consultant Psychiatrist
Universiti Malaya, Kuala Lumpur Universiti Teknologi Mara, Selangor
Dr. Mohd Aminuddin Mohd Yusof Dr. Sharifah Nurul Aida Syed Ghazaili
Head of CPG Unit & Public Health Physician Family Medicine Specialist
Malaysian Health Technology Assessment Klinik Kesihatan Bestari Jaya, Selangor
Prof. Dr, Muhammad Najib Mohamad Alwi Dr. Siti Hazrah Selamat Din
Senior Lecturer & Consultant Psychiatrist Psychiatrist (Community & Rehabilitation)
International Medical School Hospital Tuanku Ja'afar, Negeri Sembilan
Management & Science University
Selangor
Ms. Nor Asmawati Mohamad Ali Abdul Dr. Suhaila Mohd Som
Rahman Psychiatrist
Medical Social Worker Hospital Permai, Johor
Hospital Umum Sarawak, Sarawak
Ms. Norhameza Ahmad Badruddin

Clinical Psychologist
Hospital Permai, Johor
vi
REVIEW COMMITTEE
The draft guidelines were reviewed by a panel of experts. They were asked to comment
primarily on the comprehensiveness and accuracy of the interpretation of evidence supporting
the recommendations in the guidelines.
Chairperson
Professor Dr. Ahmad Hatim Sulaiman
Head of Department & Consultant Psychiatrist
Pusat Perubatan Universiti Malaya, Kuala Lumpur
Members (in alphabetical order)

Dr. Abdul Kadir Abu Bakar Dr. Hazli Zakaria
Consultant Psychiatrist President
Johor Malaysia Psychiatric Association
Datin Dr. Ang Kim Teng Ms. Noor Ratna Naharuddin

Secretary General Pharmacist
Malaysia Mental Health Association Hospital Sultanah Aminah, Johor
Ms. Anita Abu Bakar Dr. Noraini Darus

President Clinical Psychologist
Mental Illness Awareness and Support Hospital Kuala Lumpur, Kuala Lumpur
Association
Dr. Baizury Bashah Dr. Norhayati Nordin

Consultant Family Medicine Specialist Director & Senior Consultant Psychiatrist
Putrajaya Hospital Bahagia Ulu Kinta, Perak
Dr. Izzuna Mudla Mohamed Ghazali Mr. Zulhan Ambi

Deputy Director & Public Health Physician Head of Medical Social Work
Malaysian Health Technology Assessment Hospital Kuala Lumpur, Kuala Lumpur
vii
EXTERNAL REVIEWERS (in alphabetical order)
The following external reviewers provided feedback on the draft:
viii
ALGORITHM 1. MANAGEMENT OF SCHIZOPHRENIA
Diagnosis of
schizophrenia
Acute phase/exacerbation Stable phase/relapse prevention *Cases to be referred

urgently to psychiatric
services
**Adequate response: A
• Oral SGA if patient is
No cooperative* reduction in symptoms
Need for rapid Yes
• Intramuscular haloperidol + as a result of treatment
stabilisation that is associated with
parenteral benzodiazepine if
patient is not cooperative* clinically significant
benefit in functioning
and/or quality of life
• Offer AP, preferably SGA***
• Psychoeducation
• Monitor clinical response,
side effect and treatment ***Prevention and
adherence management of side
Refer to hospital with psychiatric services
effect of AP at all phases
• Exclude substance use disorder,
• Monitor EPS/akathisia/
treatment non-adherence and co-
morbidities weight gain/diabetes/
• Optimise AP usage (adequate dose heart disease/
No and duration) sexual dysfunction
Adequate No Adequate
• Optimise psychosocial interventions • Follow schedule of
response** response** physical care
• Rule out treatment-resistant
schizophrenia
Yes Yes
AP = antipsychotic
SGA = second-generation
AP
Follow-up at • Plan for recovery (psychoeducation, ACT, family intervention, social skill ACT = assertive community
health/psychiatric training and supported employment) treatment
clinic • AP monotherapy; use depot when non-adherent EPS = extrapyramidal side
• Monitor for clinical response, side effect and treatment adherence effects
ix
ALGORITHM 2. PHARMACOTHERAPY FOR SCHIZOPHRENIA
Initial Phase Follow-Up Phase

Primary/Secondary Care
Diagnosis of
schizophrenia Relapse prevention
management
Start AP PR/SE No
Adequate
for 2 - 6 present? response
weeks
Yes
No
PR/SE
Persistent No present?
suicidal risk present?
Yes
Psychiatric Service
No
No
Start PR/SE
Yes
different AP PR/SE
present?
for 6 weeks present?
PR/SE: Poor response or Yes

Yes Augment
intolerable side effect clozapine with
Start clozapine another AP for >8
AP = antipsychotic for >8 weeks - 10 weeks or
ECT = electroconvulsive ECT
therapy
x
1. INTRODUCTION
Schizophrenia is a term that describes a major psychiatric disorder that alters an individual’s
perception, thought, affect and behaviour. Globally, It was ranked as the 11th leading cause
of disability in 2013.GBDS, 2013 In the Second Report of the National Mental Health Registry on
Schizophrenia in 2003 to 2005, the incidence rate of schizophrenia in Malaysia was stated as
5 cases/100,000 population/year. However, the expected rate was 100 cases/100,000
population/year and possible reasons for low reported incidence were delayed or under
reporting and administrative reasons. The duration of untreated psychosis (DUP) was long
with a mean of 28.7 months and longer among females. The clinical importance of DUP was
that it was one of the few prognostic factors which can be altered through changes in health
service delivery.NMHR, 2008 This emphasises the value of early recognition and the necessity for
prompt delivery of early referral and intervention including during prodromal period.
Although the prevalence of schizophrenia worldwide was low,Saha S et al., 2005 its impacts on
health, social and economy are tremendous for patients, families/caregivers and society. In
an economic evaluation in Malaysia, based on total estimated number of treated cases of
15,104, the total economic burden of treatment for schizophrenia stood at USD100 million
which was equivalent to 0.04% of the national gross domestic product. On average, the mean
cost per patient was USD6,594. Of the total economic burden, 72% was attributed to indirect
cost (USD72 million), followed by direct medical cost at 26% and the remaining on direct non-
medical cost.Teoh SL et al., 2017 This huge magnitude of this disease burden is important for
policymakers to prioritise service for schizophrenia.
Worldwide, mental health services have experienced a series of paradigm shifts along with
the development of medical technologies and the human rights movements where the services
are delivered in the community.Thornicoft G et al., 2008; Thornicroft G et al., 1989 The community-based mental
health service takes into account the facts that people with schizophrenia face difficulties in
vital issues e.g. unemployment, poverty, housing, and relationship with families and
friends.Thornicroft G et al., 1989; Russo G, 2009 Ideally, such service should include care and treatment
delivered close to home.Abdul Kadir AB, 2011, level III In Malaysia, efforts on integrating the care for
mentally ill patients in the community have started since 1997 as outlined in the National
Mental Health policy.Haque A, 2005; Jamaiyah H, 2000 Subsequently, the development of community
mental health centre (CMHC) begun in 2011. CMHC, or Mentari as it is branded in Malaysia,
is a centre for treatment and care of mental health that offer screening, diagnosis, treatment
and rehabilitation of any person suffering from any mental disorder in accordance with the
Mental Health Act 2001 and Mental Health Regulation 2010.CMHIG, 2013
The holistic management of schizophrenia encompasses biological-psychosocial-spiritual

approach to various dysfunction domains i.e. positive symptoms, negative symptoms,
cognitive dysfunction, mood symptoms and motor symptoms. Since the first edition of
Management of Schizophrenia in Adults in 2009, numerous advances in the management of
mental disorder have developed including treatment targeting those who are difficult to treat
or have intolerable to medications and non-adherence to treatment. In this edition of CPG,
more clinical questions were added to address the advances. New issues being addressed
are screening, early intervention in psychosis, special population and social issues. The
summary on management and pharmacotherapy of schizophrenia are illustrated in Algorithm
1 and 2.
2. EARLY DETECTION AND REFERRAL

2.1 Risk Factor
The risk factors of schizophrenia include:

• family history of schizophreniaMoH, 2009
1
• history of obstetric complications e.g. pre-eclampsia and extreme prematurityMoH, 2009
• cannabis useMoH, 2009
• history of childhood central nervous system infectionMoH, 2009
• refugee and migrant status with HR of 2.90 (95% CI 2.31 to 3.64) and 1.75 (95% CI 1.51
to 2.02) respectively(Hollander et al., 2016) level II-2
Latest meta-analysis/systematic review showed significant risk factors for schizophrenia were:
a. increasing paternal age (≥30 years of age) with RR ranging from 1.05 to 1.79Miller B et al., 2011,
level II-2
b. most urban environment compared with most rural environment (OR=2.37, 95% CI 2.01 to
2.81)Vassos E et al., 2012, level II-2
c. prenatal exposure to a range of infections and inflammatory responses may be a risk factor
e.g. Herpes Simplex (HSV-2) with OR ranging from 1.5 to 1.8 and toxoplasma gondii
(OR=1.79, 95% CI 1.01 to 3.15)Khandaker GM et al., 2013, level II-2
2.2 Screening
A new 32-items self-rating screening tools (SPro) was developed for pre-psychotic states.
SCL-90-R-PARA/PSYC was generated based on “Paranoid Ideation” (PARA) and
“Psychoticism” (PSYC) subscales of Symptom-Checklist-90-Revised (SCL-90-R) to explore
psychosis-like symptoms. A study examining predictive validity of SPro against SCL-90-R-
PARA/PSYC on military men showed an AUC of 0.74 (95% CI 0.65 to 0.84).Müller M et al., 2010, level
III
In another study on preliminary validity of the brief version self-report Prodromal Questionnaire
(PQ-B) among adolescents and young adults at two prodromal psychosis research clinics
showed good validity of prodromal psychosis syndromes (AUC=0.78, 95% CI 0.70 to
0.84).Loewy RL et al., 2011, level III
A two-stage study to screen relatives of people with schizophrenia and general individuals for
sub-threshold psychosis used Screening Questionnaire (SQ) and General Health
Questionnaires-12 (GHQ-12) were in the initial stage. Those who screened positive were
reassessed using the Comprehensive Assessment of At-Risk Mental State in the second
stage. Of 29% people initially screened positive by both SQ and GHQ-12, only 4% were
positive after final assessment. These indicated that both SQ and GHQ-12 were not suitable
for screening early psychosis.Razali SM et al., 2015, level III
• More evidence is warranted before screening tools for pre-psychosis in schizophrenia

can be recommended.
• Prodromal phase is characterised by impairments in psychosocial functioning, odd and
eccentric behaviour, poor communication and motivation, blunted or flattened affect and
neglect of personal hygiene.
• People with risk factors* in developing schizophrenia and with prodromal symptoms may
require further assessment to rule out schizophrenia; this may be repeated if indicated
over time.
*Refer to Subchapter 2.1
2.3 Referral
Most health facilities in Malaysia provide Mental Health Services that focus on mental health
promotion and provide early detection and treatment for people with mental disorder.
2
• For people with schizophrenia treated in primary care, early referral to psychiatric service
should be considered in the following circumstances:NICE, 2015; MoH, 2009
o presence of prodromal or attenuated symptoms
o unclear diagnosis
o plan for psychosocial rehabilitation
o treatment adherence issues
o poor response to treatment
o potential violent behaviour to self or others
o intolerable side effects from medication
o co-morbid substance use disorder
o special group e.g. pregnancy, paediatric and geriatric age
However, there is also a group of people at high risk of developing psychosis that should be
referred for mental health assessment preferably early intervention services, e.g. person in
distress with declining social function plus any of the following:NICE, 2015
• transient or attenuated psychotic symptoms
• experiences or behaviour suggestive of possible psychosis
• a first-degree relative with psychosis or schizophrenia
Recommendation 1
• Early referral to psychiatric service should be considered for people with schizophrenia
having diagnosis or treatment issues*.
*Refer to the preceding yellow box
3. ASSESSMENT AND DIAGNOSIS

3.1 Bio-Psychosocial Assessment
Bio-psychosocial assessment is essential in the diagnosis of schizophrenia. Established tools

e.g. Mini International Neuropsychiatric Interview (MINI) and Structured Clinical Interview for
DSM Disorders (SCID) are used for diagnosis, while Brief Psychiatric Rating Scales (BPRS)
and Positive and Negative Symptoms Scale for Schizophrenia (PANSS) are performed for
severity assessment.
In two cross-sectional studies, Structured Clinical Interview for DSM-5 Disorders-Clinician

Version (SCID-5-CV) showed  value of >0.8 for diagnosis of schizophrenia with sensitivity
and specificity >0.70.Shabani A et al., 2020, level III; Osório FL et al., 2019, level III
New evidence on psychosocial assessment for people with schizophrenia are discussed
below:
• A small cross-sectional study showed Self-evaluation of Negative Symptoms had excellent
psychometric properties in measuring the symptoms (Cronbach’s α of 0.867 at baseline
and 0.897 at 4 - 8 weeks).Dollfus S et al., 2019, level III
• The 4-item Negative Symptom Assessment (NSA-4) on speech quantity, emotion, social
drive and interest was effective in rapidly assessing negative symptoms in people with
schizophrenia. It was not affected by geographic regions of practice, professional
credentialing or their familiarity with the use of schizophrenia symptom rating
instruments.Alphs L et al., 2010, level III
• A small validation study demonstrated that Personal and Social Performance (PSP) scale
was significantly correlated with other similar functioning measures such as PANSS, Global
Assessment of Functioning (GAF), Quality of Life Scale (QLS) and Clinical Global
Impression Scale (CGI-S) with r of -0.31, 0.35, 0.37 and -0.27 respectively for construct
3
validity at baseline. A stronger correlation between PSP and CGI-S at follow-up was noted
with r= -0.60 in test-retest reliability.Nafees B et al., 2012, level III In another study on those with acute
symptoms, PSP had good interclass reliability of 0.87. The correlations between baseline
severity based on PANSS and CGI-S with PSP were also significant.Patrick DL et al., 2019, level I
• Among neurocognitive assessments, Brief Cognitive Assessment Tool for Schizophrenia
(B-CATS) had an administration time of approximately 10 minutes. It correlated significantly
(r=0.76) with the gold standard neurocognitive battery Measurement and Treatment
Research to Improve Cognition in Schizophrenia (MATRICS).Hurford IM et al, 2018, level III
• In a large multicentre, validation study in people with schizophrenia, Brief Negative
Symptom Scale showed excellent internal consistency (Cronbach’s α=0.94), strong
correlation with the PANSS negative subscale score (ρ=0.76) but weak correlations with
the PANSS positive subscale (ρ=0.21) and Calgary Depression Rating Scale for
schizophrenia (CDSS) total score (ρ=0.27).Mucci A et al., 2019, level III
Assessment of people with possible schizophrenia consists of thorough history taking,

physical examination, mental state examination (MSE) and investigations where indicated.
This is summarised in Table 1.
Table 1. Initial Psychiatric Assessment

History taking
History of present Reason for current visit
illness Current symptom
Precipitating factor
Past psychiatric Hospitalisation and emergency visit for psychiatry issues
history including substances abuse
Psychiatric treatment including type and duration, treatment
setting, dose of medication and, response and adherence to
treatment
Prior psychiatric diagnosis and symptom including hallucination,
delusion, negative symptom, aggressive idea or behaviour,
suicidal idea or attempt, impulsivity
Substance use history Tobacco, alcohol or illicit substance
Recent or current substance use
Medical history Allergy or drug sensitivity
All current medication use and side effect including non-
prescribed medication or supplement
Current or past medical/surgical illness including related
hospitalisation e.g.
• endocrine disease e.g. diabetes mellitus, thyroid disorder
• cardiovascular disease e.g. hypertension
• neurological disease
• connective tissue disease e.g. systemic lupus erythematosus
• infectious disease e.g. human immunodeficiency virus,
tuberculosis, sexually transmitted infections
• physical trauma or head injury
Traditional and complementary medicine
Family history History of mental illness including history of suicidal, aggressive
behaviour
Social history Presence of psychosocial stressors e.g. financial, housing, legal,
school/occupation, interpersonal relationship, social support,
disfiguring or terminal illness
Exposure to physical, sexual or emotional trauma or childhood
abuse
4
Premorbid personality Temperament, stress management, interest or hobby,
relationship, beliefs and personality traits
Physical examination Full physical examination including height, weight and body mass
index (BMI), vital signs, cardiovascular and neurological
examinations
MSE
Appearance and • Level of consciousness
behaviour • General appearance - body build, posture, cleanliness,
dressing, evidence of weight loss, self-harm
• Face - eye contact, emotional expression
• Posture and movement - posture of depressed or anxious
person, agitated, restless, biting nails etc.
• Motor - speed or slow movement, choreoatheosis, tardive
dyskinesia, odd movement (e.g. grimacing, echopraxia, tics,
mannerism/stereotyped movement)
• Attitude to examination or social behaviour - friendly, hostile,
suspicious
Speech • Production - spontaneity, speed (pressured or retarded),
loudness, quantity, tone, quality (dysarthria)
• Forms - neologism, punning and clang association, expressive
dysphasia
• Content - obscene word, poor fluency (shyness, poor education,
thought disorder or circumstantiality, receptive dysphasia,
echolalia, perseveration), coherence, relevance
Mood and affect • Mood (by asking the patient about predominant mood) -
euthymic, depressed, elevated
• Affect (by observation of the expression) - types (anxious, sad,
happy, angry, euphoria, elation), range (broad, restricted,
blunted, flat), stability/lability (labile, non-labile),
appropriateness/congruity (congruent/incongruent)
Thought disturbances Abnormal thought content - delusional, non-delusional
a. Delusion
• primary delusion (delusional mood, delusional perception,
autochthonous delusion)
• possession of thought (thought withdrawal, insertion,
broadcast)
• passivity phenomena (experience of action, thought,
feeling under control)
• theme/content (persecutory, grandiose, nihilistic, somatic)
• secondary delusion (mood congruence/ incongruence)
b. Non-delusional
• phobia, obsession, suicidal ideation
Abnormal thought form
• fluency (circumstantiality, loosening of association)
• flow (pressured, poverty of thought, thought blocking,
perseveration, derailment, tangential, flight of idea)
• word (punning, neologism)
Suicidal thought
Homicidal thought
Perceptual • Hallucination - auditory, visual, olfactory, gustatory, tactile
disturbance • Illusion
• Pseudo-hallucination
• Depersonalisation, derealisation
5
Cognitive function Orientation/memory/attention and concentration/abstract
thinking/general knowledge
Judgement Patient’s recognition of consequences of action
Insight Patient’s awareness and understanding of illness and need for
treatment
To date, there is no evidence found on biological assessment for schizophrenia.
3.2 Criteria of Diagnostic Classifications
The diagnosis and classification of schizophrenia is important and based on Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) or International Classification of
Diseases and Related Health Problem 10th Revision (ICD-10). Refer to Appendix 3 on
Diagnostic Criteria for Schizophrenia:(DSM-5) and Appendix 4 on International
Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD
10)
The ICD-11 was released on June 18, 2018 and was officially presented at the World Health
Assembly in May 25, 2019. It will be used as the official reporting system by member states
on January 1, 2022.
Issues arise on the sufficiency of current ICD-10 or DSM-5 on therapeutic and prognostic
management of schizophrenia. The stability of the diagnostic criteria are as below.
• A large randomised controlled trials (RCTs) on second-generation antipsychotic (SGA) in
acute schizophrenia showed 99.5% of the patients with DSM-IV met DSM-5 diagnostic
criteria for schizophrenia.Mattila T et al., 2015, level I
• In a small prevalence study on individuals with DSM-IV schizophrenia, DSM-5 changes in
criteria A showed a negligible effect on the prevalence of schizophrenia as over 98% of
individuals continued to receive a DSM-5 diagnosis of schizophrenia.Tandon R et al., 2013, level III
• A meta-analysis of 42 studies showed a high diagnostic stability in schizophrenia spectrum
using either DSM-IV or ICD-10.Fusar-Poli P et al., 2016, level II-2
In a Cochrane systematic review of 21 studies of old and limited qualities, first rank symptoms
correctly identified schizophrenia 75% to 95% of the times.Soares Weiser K et al., 2015, level III
• Disease severity is assessed based on presenting psychopathology and risk

assessment (risk to self and/or others). The psychopathology may be assessed using
the severity scale e.g. PANSS and BPRS by trained personnel.
Recommendation 2
• People with possible schizophrenia should be assessed thoroughly by history taking,
physical examination and mental state examination.
• Schizophrenia should be diagnosed using either Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5) or International Classification of Diseases and
Related Health Problem 10th Revision (ICD-10).
4. TREATMENT
The modalities of treatment in schizophrenia are:

• pharmacological intervention
• physical intervention
6
• psychosocial intervention
• service level intervention
These are offered both in acute and relapse prevention phases.
People with schizophrenia who present early and for the first time at primary care should be
provided with the following:MoH. 2009
• assessment and early treatment
• early referral to specialist care in the following circumstances (refer to Subchapter 2.3)
• initial treatment and urgent referral in the acutely-ill cases
• collaboration with hospital-based psychiatric services
• registration of cases at health clinics and the National Mental Health Registry
• Current available guidelines for mental health services in primary care:

o Garispanduan Perkhidmatan Rawatan Susulan Pesakit Mental di Klinik Kesihatan
2009
o Garispanduan Pelaksanaan Perkhidmatan Pemulihan Psikososial Bagi Pesakit
Mental Di Penjagaan Kesihatan Primer 2000
4.1 Pharmacological Intervention
Antipsychotics (APs) treat the symptoms of schizophrenia and since the advent of
chlorpromazine in 1952, remains the cornerstone of both acute and maintenance therapy for
the mental disorder. APs derive their effect on positive symptoms of schizophrenia from the
blocking of D2 dopamine receptors. These medications are described as first-generation APs
(FGAs) or second-generation APs (SGAs) but the individual properties of each agent varies.
Most FGAs are high-potency D2 dopamine blockers that are tightly bound to dopamine
receptors and often cause debilitating extrapyramidal side effects (EPS). Clozapine, an
example of SGA, acts on other receptors e.g D1, D4, serotonergic, adrenergic and
histaminergic receptors. Although there may be clinically meaningful distinctions in response
to and tolerability of different APs in an individual patient, there is no definitive evidence that
one AP will have consistently superior effectiveness compared with another, with the possible
exception of clozapine.
EPS, akathisia and tardive dyskinesia can occur with both FGAs and SGAs, although in
general these tend to be more common with former. IFn addition, some of the SGAs have
metabolic and cardiac side effects.
It is essential for clinicians to discuss with the patients on the best possible medication for
them in terms of both effectiveness and tolerability and, develop a dosing regimen that will
minimise the impact of side effects on daily functions. Their previous experiences with
medication should also be considered. An evidence-based ranking of FGAs and SGAs or an
algorithmic approach to AP selection is not possible because of the significant heterogeneity
in clinical trial designs and, limited numbers of head-to-head comparisons of APs and clinical
trial data for a number of APs.
The APs registered in Malaysia, either in oral, intramuscular (IM) or long-acting depot IM
preparations in alphabetical orders are listed below:
FGAs SGAs
• Chlorpromazine • Amisulpride
• Flupenthixol • Aripiprazole
7
• Fluphenazine • Asenapine
• Haloperidol • Brexipiprazole
• Perphenazine • Cariprazine
• Sulpiride • Clozapine
• Trifluoperazine • Olanzapine
• Zuclopenthixol • Paliperidone
• Quetiapine
• Risperidone
• Ziprasidone
In the treatment of acute phase of schizophrenia, the recommended optimal oral dose of AP
is two or three times minimum effective dose (MED) and adverse effects (AEs) should be
closely monitored.Takeuchi H et al., 2020, level I In relapse prevention, the standard doses should be
used.MoH, 2009APs should be used for at least 6 - 8 weeks with adequate dosage before
switching to other APs.Gardner KN et al., 2012, level III
Refer to:
i. Appendix 5 (Dosing Regimen for Oral Antipsychotics) and Appendix 6 (Dosing
Regimen for Depot Injections of Antipsychotic).
ii. Table 2 (Relative AEs of APs) and Table 3 (Common AEs of APs and their
management strategies)
iii. Appendix 8 on Monitoring Parameters for Antipsychotics
4.1.1 Pharmacological agents

In a meta-analysis of 20 RCTs on people with schizophrenia with follow-up from 5 to 14 years,
those on any APs had lower mortality risk compared with those without the treatment
(RR=0.57, 95% Cl 0.46 to 0.76). Causes of death reported were cardiovascular disease in
15.7% and suicide in 6.7%. The remaining causes were described as other natural, unnatural
or undetermined. However, reasons for the increased risk of death for those without APs
required further research. Quality of the primary studies was variable but most scored as
moderate.Vermeulen J et al., 2017, level I
A network meta-analysis on schizophrenia showed that APs reduced overall symptoms

compared with placebo, with SMD ranged from -0.89 (95% CrI -1.08 to -0.71) for clozapine to
-0.03 (95% CrI -0.59 to 0.52) for levomepromazine. The efficacy differences between APs
were mostly small. Regarding side effects, the differences were more marked for:Huhn M et al., 2019,
level I
• sedation with RR ranged from 0.92 (95% CrI 0.17 to 2.03) for pimozide to 10.20 (95% CrI
4.72 to 29.41) for zuclopenthixol
• weight gain with MD ranged from -0.16 kg (-0.73 to 0.40) for ziprasidone to 3.21 kg (2.10
to 4.31) for zotepine
• prolactin elevation with MD ranged from -77.05 ng/mL (-120.23 to -33.54) for clozapine to
48.51 ng/mL (43.52 to 53.51) for paliperidone
• QTc prolongation with MD ranged from -2.21 ms (-4.54 to 0.15) for lurasidone to 23.90 ms
(20.56 to 27.33) for sertindole
In addition, RR on the use of antiparkinson medication as a measure of extrapyramidal side-
effects ranged from 0.46 (0.19 to 0.88) for clozapine to 6.14 (4.81 to 6.55) for pimozide. The
certainty of the evidence in this network meta-analysis was generally low.
In a Cochrane systematic review, AP combination may improve clinical response compared

with AP monotherapy in schizophrenia (RR=0.73, 95% CI 0.64 to 0.83). There were no
significant difference in relapse (RR=0.63, 95% CI 0.31 to 1.29) and rate of hospitalisation
(RR=0.96, 95% CI 0.36 to 2.55). There was also no significant difference for serious AEs,
8
movement disorders and weight gain. Most evidence was from short-term trials and graded
very low in quality.Ortiz-Orendain J et al., 2017, level I
American Psychiatric Association recommends that patients with schizophrenia be treated

with an AP and monitored for effectiveness and side effects.APA, 2019
In a network meta-analysis of 19 RCTs on acute treatment in first episode of schizophrenia:Zhu

Y et al., 2017, level I
• for overall reduction of symptoms, amisulpride (SMD= -0.37, 95% CI -0.61 to -0.14),
olanzapine (SMD= -0.25, 95% CI -0.39 to -0.12), ziprasidone (SMD= -0.25, 95% CI -0.48
to -0.01) and risperidone (SMD= -0.14, 95% CI -0.27 to -0.01) were more effective than
haloperidol
• in improvement of negative symptoms, olanzapine was more effective than risperidone
(SMD= 0.20, 95% CI 0.03 to 0.37) and haloperidol (SMD= 0.31, 95% CI 0.13 to 0.48)
• in treatment of parkinsonism,
o olanzapine showed less frequent use of drugs compared with haloperidol (OR=0.10,
95% CI 0.03 to 0.29), zuclopenthixol (OR=0.02, 95% CI 0.00 to 0.37) and risperidone
(OR=0.24, 95% CI 0.07 to 0.78)
o quetiapine showed less frequent use of drugs compared with haloperidol (OR=0.10,
95% CI 0.01 to 0.75) and zuclopenthixol (OR=0.02, 95% CI 0.00 to 0.66)
• haloperidol showed less weight gain compared with olanzapine (SMD=0.63, 95% CI 0.11
to 1.16)
The primary evidences were of very low to moderate quality.
There was no RCT found on the use of depot AP on first episode of schizophrenia.
• APs are the mainstay of pharmacological treatment in schizophrenia.

• All APs are different in their effectiveness and side effects profiles.
• Reasons to switch include lack of clinical response, intolerability and drug interaction.
• SGAs are generally associated with a lower risk of EPS than FGAs e.g. haloperidol.
• SGAs have a different side effects profile i.e. metabolic syndrome (weight gain,
dyslipidaemia and glucose intolerance).
• The EPS produced by FGAs have been shown to be dose dependent.
• The choice of APs depends on their differences in side-effect profiles.
• APs should be used at least 1 - 2 years for the first episode and for a longer duration in
those with chronic schizophrenia.
• If AP is to be withdrawn, it should be done gradually whilst symptoms of potential relapse
are monitored for at least two years.
Recommendation 3
• Antipsychotics should be considered in the treatment of schizophrenia.
4.1.2 Rapid tranquilisation in acute exacerbation

In rapid tranquilisation, medications are used to calm the patient and not to induce sleep, so
that he/she can be more accurately assessed by healthcare providers when stable. The
medications commonly used are FGA, SGA and benzodiazepines. Side effects should be
anticipated and antidotes should be readily available. The choice of medication depends on
the underlying cause of the aggression.MoH, 2016
Parenteral [intramuscular (IM) or intravenous (IV)] medications are used during acute
exacerbation of schizophrenia to stabilise the aggressiveness of the patients. Evidence
supporting the effectiveness and safety of these clinical practice are as follow:
9
• A meta-analysis of 167 RCTs showed that APs were more effective than placebo in
reducing positive symptoms (SMD=0.45, 95% CI 0.40 to 0.50) and negative symptoms
(SMD=0.35, 95% CI 0.31 to 0.40). However, they had more movement disorders (RR=1.93,
95% CI 1.65 to 2.29), sedation (RR=2.80, 95% CI 2.30 to 3.55) and weight gain (SMD=
-0.40, 95% CI -0.47 to -0.33).Leucht S et al., 2017, level I
• In a Cochrane systematic review, IM aripiprazole:Ostinelli EG et al., 2018, level I
o prevented the need of additional injection to achieve tranquilisation by 31% compared
with placebo at 24 hours (RR=0.69, 95% CI 0.56 to 0.85); in addition, it was more
effective in reducing agitation in two hours (RR=1.50, 95% CI 1.17 to 1.92)
o showed no difference with IM haloperidol in the need of additional injection to achieve
tranquilisation and reducing agitation in two hours
o was less effective in reducing agitation in two hours compared with IM olanzapine
(RR=0.77, 95% CI 0.60 to 0.99)
o showed no difference in adverse effects with placebo, IM haloperidol and IM olanzapine
The primary evidences were of very low quality.
• In another Cochrane systematic review, IM haloperidol compared with placebo:Ostinelli EG et al.,
2017, level I
o prevented non-tranquillisation by 12% at two hours (RR=0.88, 95% CI 0.82 to 0.95)

o reduced the need of repeated injection by 49% at 24 hours (RR=0.51, 95% CI 0.42 to
0.62)
o was more effective in reducing agitation in two hours (RR=1.62, 95% CI 1.28 to 2.07)
o had more overall adverse events at 72 hours (RR=1.78, 95% CI 1.23 to 2.59)
The primary papers were mainly on schizophrenia and of very low quality.
• In an RCT, oral haloperidol 15 mg, olanzapine 20 mg and risperidone 2 - 6 mg improved
PANNS psychotic agitation subscale score significantly as early as two hours from baseline
and sustained until day five in acute severe psychotic agitation in schizophrenia. However
there was no difference between the three medications.Walther S et al., 2014, level I
• NICE recommends IM haloperidol combined with promethazine for rapid tranquilisation in
adults.NICE, 2015
• In the previous MoH CPG, IM preparations recommended for rapid tranquillisation are
lorazepam, midazolam, haloperidol, olanzapine, ziprasidone and zuclopenthixol acetate.
Wherever possible, a single agent is preferred. When rapid tranquillisation is urgently
needed, a combination of IM haloperidol plus lorazepam or promethazine should be
considered.MoH, 2009
• If patient is cooperative, oral medications e.g. olanzapine, risperidone and haloperidol is

preferred.
• If patient is uncooperative, parenteral medications e.g. IM haloperidol and IM midazolam
or IV diazepam are commonly used.
4.1.3 Depot/long-acting injectable antipsychotics in achieving remission

Treatment adherence is a widely recognised problem in schizophrenia but knowledge on
improving it is still limited. About 50 - 70% of people with schizophrenia had treatment non-
adherence which includes failure to enter a treatment programme, default outpatient clinic
appointment and incomplete implementation of instructions (including prescriptions).MoH, 2009;
NICE, 2014
Clinically effective management will result in low defaulter rate as patient develop compliance
and adherence to treatment. Studies have shown that high defaulter rate in psychiatric patients
resulted in high morbidity and mortality.
In a prospective cohort study, clinic defaulters had lower social functioning and more severe
mental disorder e.g. schizophrenia (38%) than those who attended the clinic. Patients who
10
missed their appointment more than 12 months were more likely to have been admitted than
clinic attendees.Killaspy, H et al., 2000, level II-2
Depot or long-acting injectable APs may be considered based on patient’s preference or when
there is medication adherence issue for maintenance treatment in schizophrenia. APA, 2019; NICE,
2014; SIGN, 2013
Available such preparations in Malaysia are:
• fluphenazine decanoate
• flupenthixol decanoate
• zuclopenthixol decanoate
• risperidone microspheres
• paliperidone palmitate
• aripiprazole
A meta-analysis of five RCTs showed that depot AAPs had higher remission rate than oral
AAPs for follow-up lasting ≥1 year (RR=1.42, 95% CI 1.18 to 1.71). However, extrapyramidal
symptoms (RR=1.61, 95% CI 1.27 to 2.04) and prolactin-related adverse effects (RR=2.48,
95% CI 1.60 to 3.84) occurred more frequently in the depot preparation.Park SC et al., 2018, level I The
primary evidences were of moderate to high quality.
A cross-sectional study showed that 17.6% of psychiatrists initiated depot APs for people with
schizophrenia having non-adherence on treatment. The initiation was significantly and
positively associated with public insurance, prior inpatient admission, longer time of non-
adherence, average or above average intellectual functioning and living in a mental health
residence. The use of depot was inversely associated with SGA and other oral psychotropic
medications prior to medication non-adherence.West JC et al., 2008, level III
Recommendation 4
• Default from treatment in schizophrenia should be addressed and avoided.
• Long-acting (depot) injectable antipsychotic in schizophrenia:
o should be offered when there is medication adherence issue
o may be considered on patient’s preference
4.1.4 Antipsychotics in relapse prevention

In a large Cochrane systematic review of 75 RCTs, APs were better than placebo in preventing
relapse in schizophrenia at 12 months (RR=0.38, 95% CI 0.32 to 0.45; NNTB=3). Furthermore,
they also:Ceraso A et al., 2020, level I
• reduced hospitalisation (RR=0.43 95% CI 0.32 to 0.57; NNTB=8)
• lessen aggressive behaviour (RR=0.35, 95% CI 0.19 to 0.66; NNTB=50)
• improved quality of life (QoL) (SMD= -0.32, 95% CI -0.57 to -0.07)
However, they increased movement disorders (RR=1.52, 95% CI 1.25 to 1.85; NNTH=20),
sedation (RR=1.52, 95% CI 1.24 to 1.86) and weight gain (RR=1.69, 95% CI 1.21 to 2.35;
NNTH=25). The evidence for relapse prevention and hospitalisation were of high quality.
A meta-analysis showed that SGA was more effective than FGA in preventing relapse in
schizophrenia (RR=0.80, 95% CI 0.70 to 0.91; NNT=17).Kishimoto T et al., 2013, level I There was no
quality assessment of primary paper mentioned. However, in the recent Cochrane systematic
review, subgroup analysis found no significant difference in reduction of relapse risk in
schizophrenia between FGA (RR=0.35, 95% CI 0.25 to 0.48) and SGA (RR=0.39, 95% CI
0.32 to 0.48).Ceraso A et al., 2020, level I
In a network meta-analysis on schizophrenia, olanzapine was more effective than

chlorpromazine (OR=0.35, 95% CI 0.14 to 0.88) and haloperidol (OR=0.50, 95% CI 0.30 to
0.82) in reducing relapses. The primary papers were of moderate quality.Zhao YJ et al., 2016, level I
11
In another meta-analysis, studies before 1991 which were exclusively on long-acting injection
(LAI) fluphenazine showed that the medication was more effective in preventing relapse
compared with oral FGA in schizophrenia (RR=0.79, 95% CI 0.65 to 0.96). There was no
difference in effectiveness between SGA LAI and oral SGA.Kishimoto T et al., 2012, level I However,
there was no quality assessment of primary paper mentioned. Depot preparations may be
considered when treatment adherence issue arises.MoH, 2009
A large meta-analysis of 24 RCTs compared the effectiveness and safety of standard vs

reduced dose of APs. The median duration of follow-up was 52 weeks (IQR 46 - 53). Doses
were classified as:
• standard dose (above or equal to the lower limit of the recommended target dose range for
acute treatment)
• low dose (50 - 99% of the lower limit)
• very low dose (<50% of the lower limit)
Compared with standard dose:
• low dose increased risk of relapse by 44% (RR=1.44, 95% CI 1.10 to 1.87) and all-cause
discontinuation by 12% (RR=1.12, 95% CI 1.03 to 1.22)
• very low dose increased risk of relapse by 72% (RR=1.72, 95% CI 1.29 to 2.29) and all-
cause discontinuation by 31% (RR=1.31, 95% CI 1.11 to 1.54)
In term of safety, there were no significant differences between different doses in intolerability
-related discontinuations, anticholinergic use and rating scale-based assessments of
akathisia, dyskinesia and parkinsonism. Most primary studies in the meta-analysis were
classified as having some concerns in risk of bias assessment.Højlund M et al., 2021, level I
Recommendation 5
• Antipsychotics (APs) should be offered to prevent relapse in schizophrenia.
o Second-generation APs is the preferred choice.
o Standard dose of APs should be considered as maintenance treatment.
4.1.5 Intermittent treatment in relapse prevention

In a Cochrane systematic review on people with schizophrenia, intermittent AP treatment
compared with maintenance treatment at ≥26 weeks follow-up showed:Sampson S et al., 2013, level 1
• higher relapse (RR=2.46, 95% CI 1.70 to 3.54)
• higher hospitalisation rate (RR=1.65, 95% CI 1.33 to 2.06)
• no difference in tardive dyskinesia (RR=1.15, 95% CI 0.58 to 2.30)
The quality of evidence in the first two outcomes was moderate while the last outcome low.
In later meta-analysis of ten studies, stabilised people with schizophrenia who had been
exposed for at least six months to intermittent or placebo strategies had higher risk of relapse
compared with those on continuous treatment with OR of (3.36, 95% CI 2.36 to 5.45) and 5.64
(95% CI 4.47 to 7.11) respectively.De Hert M et al., 2015, level I
Recommendation 6
• Intermittent treatment using antipsychotics should be avoided in schizophrenia.
4.1.6 Treatment for extrapyramidal signs, sedation and weight gain associated with
antipsychotics
There are several common adverse effects of APs e.g. constipation, EPS, cardiovascular
complications and metabolic syndrome. These adverse effects can happen at any point of
time and majority are dose dependent.
12
Summary of Relative AEs of APs and Common AEs of APs with their management
strategies are shown in Table 2 and Table 3.
• NMS is a rare medical emergency but potentially life-threatening condition caused by

APs. It is characterised by fever, rigidity, tremors, sympathetic nervous system
dysregulation and creatinine kinase elevation. Immediate diagnosis and treatment are
essential and this condition should be referred to the medical team.
13
Table 2. Relative AEs of APs
APs Tardive QT
Constipa- Weight Parkinso- Anticholi- Hypoten- Prolactin
Sedation Akathisia dyskinesia prolonga-
tion gain nism nergic sion elevation
tion
Amisulpride ++ - + + + + - - ++ +++
Aripiprazole + - - + - + - - + -
Asenapine + + + + - + - - + +
Chlorproma- ++ ++ ++
+++ ++ + ++ ++ +++ +++
zine
Clozapine +++ +++ +++ - - - +++ +++ - -
Flupentixol + + ++ ++ ++ + ++ + + +++
Fluphenazine + + + ++ +++ + + + + +++
Haloperidol ++ + + +++ +++ ++ + + ++ ++
Olanzapine ++ ++ +++ - - + + + + +
Paliperidone ++ + ++ + + + + ++ + +++
Perphenazine + + + ++ +++ ++ + + + +++
Quetiapine ++ ++ ++ - - + + ++ ++ -
Risperidone ++ + ++ + + + + ++ + +++
Sertindole - - + + - + - +++ +++ -
Sulpiride ++ - + + + - - - + +++
Trifluoperazine - + + + +++ + + + - +++
Ziprasidone + + - + - + - + ++ +
Zuclopenthixol ++ ++ ++ ++ ++ ++ + - +++
+++ High incidence/severity
++ Moderate incidence/severity
+ Low incidence/severity
- Very low incidence/severity
Source:
1. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (13th Edition). London: Wiley Blackwell; 2018
2. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341-35
14
Table 3. Common AEs of APs and their management strategies
Dose Management strategies

Adverse effects Onset Comments
dependent First choice Second choice Third choice
• Ensure adequate Clozapine-induced

Within the first four Change to AP with
fibre, fluid and gastrointestinal hypomotility
Constipation months of AP  exercise lower risk (refer to - is a common adverse effect,
administration • Bulk-forming Table 2) three times that seen with
laxatives other APs
Where symptoms do not
Within hours to Anticholinergic respond to simpler
Antihistaminic Benzodiazepine
measures, including
EPS: Dystonia
days of AP
administration or  medication (e.g.
trihexyphenidyl,
medication (e.g. (e.g. clonazepam, switching to an AP with low
diphenhydramine) diazepam) propensity for EPS,
dose increase procyclidine)
botulinum toxin may be
effective
• Majority of patients do not
EPS: Days to weeks
Change to AP with Anticholinergic require long-term
Pseudoparkinsonism
(tremor, rigidity,
after AP
administration or  Reduce dose lower risk (refer to medication (e.g. anticholinergic medication
• Use should be reviewed at
Table 2) benztropine)
bradykinesia) dose increase least every 3 months
• Do not prescribe at night
• 5-HT2 antagonists e.g.
cyproheptadine,
Within hours to mirtazapine, trazodone,
Change to AP with
and mianserin may help
Akathisia
weeks of AP
administration or  Reduce dose lower risk (refer to
Beta-blockers (e.g.
propranolol) • Antimuscarinic or
Table 2) benzodiazepine may also
dose increase
be useful
• Anticholinergics are
generally unhelpful
Valbenazine, • Clozapine is the AP most
After months to • Lower dose Change to AP with
tetrabenazine or likely to be associated with
Tardive dyskinesia years of AP  • Stop
anticholinergic if
lower risk (refer to deutetrabenazine resolution of symptoms
administration Table 2) (not available in • Quetiapine may also be
prescribed
Malaysia yet) useful
15
Within hours to Change to less

Sedation days of AP  Dose at night
before sleep
1 sedating APs
Stimulants have unclear
benefit
administration (refer to Table 2)
Change to AP with Treat accordingly and refer to Clinical
Within one month lower risk Practice Guidelines Management of Type
Diabetes mellitus of AP  (haloperidol,
aripirazole,
2 Diabetes Mellitus (6th Edition)* -
administration
amisulpride,
ziprasidone)
Pharmacological medication
e.g. metformin should be
Within three Behavioural Behavioural considered only where
Weight gain months of AP  modification (diet, modification +
Add aripiprazole to
existing treatment
behavioural methods,
switching of AP have failed
administration exercise) change AP
or where obesity presents
clear, immediate physical
risk to the patient
Within three Behavioural
Increased lipids months of AP  modification (diet,
exercise) + change
Statins - -
administration
AP
Consider Metformin has been shown
Change to dopamine agonists to improve prolactin related
Within hours to
‘prolactin-sparing’ (cabergoline,
Hyperprolactinaemia months of AP  APs (aripiprazole, Add aripiprazole bromocriptine,
symptoms and levels
respectively
administration quetiapine, amantadine) or
clozapine) referral to
endocrinologist
Avoid APs that are potent α1-
Within hours to adrenergic receptor
Change to AP with
antagonist (clozapine,
Orthostatic
hypotension
days of AP
administration or  Adjust dose or slow
dose titration
Adequate hydration lower risk (refer to quetiapine) and/or
Table 2) concomitant intake of
dose increase
medications that can reduce
BP
16
• >440 ms (men)/
>470 ms
(women) but
<500 ms: reduce
dose or switch
AP with lower risk
(refer to Table 2
below
• >500 ms:
o repeat ECG
Risk is high with any IV AP
After 2 - 4 weeks o stop suspected
ECG changes - QT
prolongation
of AP  causative
drugs and
= =
or combination of APs with
doses exceeding
administration
switch to lower recommended maximum
risk AP
o immediately
refer to
cardiologist
Abnormal T-wave
morphology: review
treatment, consider
reduce dose or
switching to lower
risk AP
*Available at https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Endocrine/CPG_T2DM_6th_Edition_2020_13042021.pdf
Adapted:
2. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341-35
17
4.2 Physical Intervention
4.2.1 Electroconvulsive therapy
Electroconvulsive therapy (ECT) may be a useful adjunct to AP when there is a need for rapid
improvement and reduction of symptoms or limited response to AP in schizophrenia.APA, 2021;
RANZ, 2016; SIGN, 2013; MoH, 2009
ECT in combination with AP may be beneficial in people with
treatment-resistant schizophrenia (refer to Subchapter 7.4.3 on Treatment for treatment-
resistant schizophrenia)
4.2.2 Transcranial magnetic stimulation

In a Cochrane SR of 41 RCTs on schizophrenia or schizoaffective/related disorder,
temporoparietal transcranial magnetic stimulation (TMS) compared with sham TMS or others
showed:Dougall N et al., 2015, level I
• improved global state on CGI scale (MD= -0.5, 95% CI -0.76 to -0.23)
• positive symptoms on PANSS scale (MD= -6.09, 95% CI -10.95 to -1.22)
However, study subjects showed no significant clinical improvement in global state or early
withdrawal from study when TMS was used as adjunctive therapy.
4.2.3 Transcranial direct current stimulation

A meta-analysis of 10 RCTs found no effect of transcranial direct current stimulation compared
with sham treatment on auditory hallucinations, positive symptoms or negative symptoms in
schizophrenia or schizoaffective disorder.Kim J et al., 2019, level I
Recommendation 7
• Electroconvulsive therapy may be considered in schizophrenia to achieve rapid and
short-term improvement of severe symptoms after an adequate trial of antipsychotic is
proven ineffective and in treatment-resistant schizophrenia.
4.3 Psychosocial Intervention
There are various forms of psychosocial intervention which are not limited to psychotherapy
and psychological techniques in the management of people with schizophrenia. The aim of
these psychosocial intervention varies depending on the treatment goal. The commonly used
interventions are discussed below.
4.3.1 Psychoeducation
Psychoeducation improves understanding of mental health issues, recognising early warning
signs of relapse and understanding psychiatric services work.NICE, 2014 A psychoeducation
programme includes key information about diagnosis, symptoms, psychosocial interventions,
medications and side effects as well as information about stress and coping, crisis plans, early
warning signs (EWS) and, suicide and relapse prevention.APA, 2019
In a Cochrane systematic review of low-quality evidence on people with schizophrenia, brief

psychoeducation was better than routine care in prevention of:Zhao S et al., 2015, level I
• non-compliance with medication at short-term (RR=0.63, 95% CI 0.41 to 0.96) and
medium-term (RR=0.17, 95% CI 0.05 to 0.54)
• relapse at medium-term (RR=0.70, 95% CI 0.52 to 0.93)
Another Cochrane systematic review on promoting well-being and reducing distress of siblings
of people with schizophrenia, psychoeducation was better than standard care in coping with
(family) burden at 12 months (MD= -8.80, 95% CI -15.22 to -2.34).Sin J et al., 2015, level I
In an RCT looking on community-based comprehensive intervention which included

psychoeducation, social skills training, cognitive behaviour therapy (CBT) and, strategies
against stigma and discrimination (SASD) vs control for people with schizophrenia, the
18
intervention was significantly effective at nine months on the following outcomes:Li J et al., 2018,
level I
• overcoming stigma
• anticipated discrimination
• functioning based on GAF total score
• reduction in BPRS total score
• reduction in PANSS negative score
EWS are early symptoms that are distinctive to the person with schizophrenia and often
precede acute psychotic relapse. Examples are change in sleep pattern, irritability, social
withdrawal, difficulty in concentration and decline in self-care. Thus, intervention on EWS aims
to detect and manage these signs for prevention of relapse. A Cochrane systematic review
showed that training to recognise EWS of relapse in schizophrenia was better compared with
treatment as usual in:Morriss et al., 2013, level I
• preventing relapses (RR=0.53, 95% CI 0.36 to 0.79)
• preventing re-hospitalisation (RR=0.48, 95% CI 0.35 to 0.66)
• improving medication compliance (MD=0.57, 95% CI 0.42 to 0.77)
In subgroup analysis, time taken to relapse after treatment was longer if EWS intervention was
delivered to patients only compared with treatment as usual (HR=0.26, 95% CI 0.13 to 0.53),
but no difference was shown when EWS intervention was delivered to both patient and their
carer/health professionals. Apart from that, time to re-hospitalisation after treatment was
longer (HR=0.62, 95% CI 0.46 to 0.83) when the intervention was delivered to both patients
and their carer/health professional. In this review, the overall quality of 34 RCTs was very low.
SIGN recommends that psychoeducation should not be offered as a stand-alone intervention

to people with schizophrenia and professionals should ensure that people with schizophrenia
and their families/carers are informed about the illness.SIGN, 2013 APA recommends that people
with schizophrenia receive psychoeducation.APA, 2019
Recommendation 8
• Psychoeducation which includes early warning signs interventions should be given in
addition to other interventions in schizophrenia.
4.3.2 Supported employment

In a Cochrane systematic review for adults with severe mental illness where schizophrenia
disorders were well represented, supported employment increased levels of any employment
compared with other vocational approaches (RR=3.24, 95% CI 2.17 to 4.82). It also showed
some advantages in other secondary outcomes e.g. duration of any form of paid employment,
job tenure for competitive employment and time to first competitive employment in long-term.
However the primary papers were of very low quality.Kinoshita Y et al., 2013, level I
NICE recommends to offer supported employment programmes to people with psychosis or

schizophrenia who wish to find or return to work. Apart from that, it is recommended to
consider other occupational or educational activities, including pre-vocational training, for
people who are unable to work or unsuccessful in finding employment.NICE, 2014
APA also recommends that patients with schizophrenia receive supported employment
services.APA, 2019
Recommendation 9
• Supported employment should be offered in schizophrenia.
19
4.3.3 Cognitive remediation therapy
Cognitive impairment is a core feature of schizophrenia that is fully evident at the time of first
episode and the most affected areas are attention, verbal memory and executive functioning.
Cognitive deficits in schizophrenia influence functional outcomes in work, independent living,
social functioning and illness management. Cognitive remediation therapy (CRT) is a
behavioural treatment intervention aims to improve the cognitive processes e.g. memory,
attention, executive function, metacognition and social cognition. It uses techniques which
modify cognition in people with schizophrenia e.g. errorless learning, repetition and positive
reinforcement.Reeder C et al., 2006
A meta-analysis of 38 moderate quality RCTs demonstrated a moderate effect of CRT on

global cognition in people with schizophrenia (Cohen’s d=0.45, 95% CI 0.31 to 0.59). The CRT
also showed significant effect on all cognitive domains i.e. attention/vigilance (Cohen’s
d=0.25), processing speed (Cohen’s d=0.258), verbal working memory (Cohen’s d=0.346),
verbal learning and memory (Cohen’s d=0.410), reasoning/problem solving (Cohen’s
d=0.572) and social cognition (Cohen’s d=0.651).Wykes T et. al, 2011, level I
The meta-analysis also suggested that functioning outcomes were best achieved by adding
cognitive remediation to other rehabilitation programmes. The cognitive remediation
programmes on psychosocial functioning reported significant stronger effects in studies that
provided adjunctive psychiatric rehabilitation (Cohen’s d=0.59, 95% CI 0.30 to 0.88) compared
with those on cognitive remediation alone (Cohen’s d=0.28, 95% CI -0.02 to 0.58).Wykes T et. al,
2011, level I
CRT has been suggested for people with schizophrenia.APA, 2019 It may be may be offered as
part of a multimodal psychosocial intervention.MoH, 2008 in schizophrenia with persisting
problems associated with cognitive difficulties.SIGN, 2013
Recommendation 10
• Cognitive remediation therapy may be considered as intervention for cognitive difficulties
in schizophrenia.
4.3.4 Social skills training

Social skills training (SST) is a psychosocial intervention, whether group or individual, aimed
at enhancing the social performance and, reducing the distress and difficulty in social
situations. A Cochrane systematic review of 13 studies found that in people with
schizophrenia, compared with standard care, SST:Almerie MQ et al., 2015, level I
• significantly improved social functioning based on various rating scale
• significantly improved mental state based on various severity rating scale
• prevented relapse (RR=0.52, 95% CI 0.34 to 0.79)
The primary papers were of very low quality.
Existing evidence-based guidelines do not strongly recommend SST in the management of

schizophrenia.APA, 2019; NICE, 2014; SIGN, 2013
Recommendation 11
• Social skills training may be offered in schizophrenia.
4.3.5 Peer support services

Peer support is a social emotional support which is mutually provided by persons having a
mental health condition to others sharing a similar problem in order to bring about a desired
social or personal change.NICE, 2014
20
A Cochrane systematic review found very limited and very low quality of evidence on the
effectiveness of peer support for people with schizophrenia. In view of that, it could not be
recommended as yet.Chien WT et al., 2019, level I
NICE recommends to consider peer support for people with schizophrenia to improve their
experience and quality of life. It should be delivered by a trained peer support worker who has
recovered from schizophrenia and remains stable. The workers should receive support from
their whole team and, support and mentorship from experienced peer workers.NICE, 2014
Recommendation 12
• Peer support may be offered in schizophrenia.
4.3.6 Family therapy

Family therapy is a form of psychotherapy involving significant family members together with
the person with schizophrenia based on individual family need. It focuses on relationship in
which the problem is manifested by providing support, skills and education through solution-
oriented approach. It aims to reduce level of distress and improve communication within
family.SIGN, 2013
In a Cochrane systematic review of 53 studies on schizophrenia, family therapy:Pharoah F et al.,

2010, level I
• decreased frequency of relapse at 7 to 12 months (RR=0.55, 95% CI 0.48 to 0.62; NNT=7,

95% CI 6 to 8)
• reduced hospital admission at 7 to 12 months (RR=0.78, 95% CI 0.63 to 0.98; NNT 8 CI 6
to 13)
• improved non-compliance with medication (RR=0.60, 95% CI 0.49 to 0.73; NNT 6 CI 5 to
9)
However, there is no evidence on suicide prevention. The primary papers in the review were
of poor methodological quality.
Recommendation 13
• Family therapy may be offered in schizophrenia.
4.3.7 Cognitive behaviour therapy

Cognitive behaviour therapy (CBT) is a structured, short-term, present-oriented
psychotherapy, It focuses on problem solving and modifying dysfunctional thinking and
behaviour. The application of CBT is based on conceptualisation of individual person’s belief,
behaviour and emotional experience.
Two meta-analyses on CBT against two different comparisons (other psychosocial
intervention and standard care) showed:
• favourable outcomes in relapse, mental state, hospitalisation, social functioning and QoL
in CBT added to standard care compared with standard care alone at long-term although
non-significant in a Cochrane systematic review of 60 RCTs. However, the risk of adverse
event was reduced in the combined treatment (CBT plus standard care) (RR=0.44, 95% CI
0.27 to 0.72). The quality of primary papers included was low.Jones C et al. (a), 2018, level I
• no significant difference between combination of CBT and standard care vs standard care
and other psychosocial therapies in relapse, mental state, hospitalisation, adverse event,
social functioning and QoL in another Cochrane systematic review. The quality of primary
papers included was low.Jones C et al.(b), 2018, level I
21
CBT for psychosis (CBT-p) aims to normalise and make sense of individual’s psychotic
experiences and also reduce the associate distress and impact on functioning. In a meta-
analysis, CBT-p comparing with treatment as usual (TAU), CBT-p showed:Laws KR et al., 2018, level I
• improved functioning at end-point of intervention (Hedges's g=0.25, 95% CI 0.14 to 0.33)
but not sustained at follow-up (Hedges's g=0.10, 95% CI -0.07 to 0.26)
• reduced distress (Hedges's g=0.37, 95% CI 0.05 to 0.69)
• did not improve QoL (Hedges's g=0.04, 95% CI -0.12 to 0.19)
However, there was no report on quality of primary papers included in this study.
An RCT comparing Recovery-Oriented Cognitive Therapy (CT-R) with TAU showed that CT-
R had earlier improvement in global functioning for people with low functioning schizophrenia
with shorter duration of illness ≤12 years (Cohen’s d 0.53).Grant PM et al., 2017
Guidelines recommend CBTp in schizophrenia with persistent positive symptoms and/or

depression.APA, 2019; SIGN, 2013; MOH, 2009
Recommendation 14
• Cognitive behaviour therapy for psychosis may be offered in schizophrenia.
4.3.8 Supportive psychotherapy/Counselling

Supportive psychotherapy/counselling relies on therapeutic alliances with the aim to assist
change in attitude and behaviour and, reinforce the ability to cope.
A Cochrane systematic review of 24 very low quality RCTs found no significant differences in
the relapse, hospitalisation and general functioning between supportive therapy and standard
care in schizophrenia on medium- and/or long-term follow-up. However, supportive therapy
had poorer outcomes compared with other psychological or psychosocial treatments at long-
term follow-up:Buckley LA et al., 2015, level I
• increased hospitalisation rates (RR=1.82, 95% CI 1.11 to 2.99)
• no clinical improvement in mental state (RR=1.27, 95% CI 1.04 to 1.54)
• dissatisfaction of treatment for the recipient of care (RR=3.19, 95% CI 1.01 to 10.7)
4.3.9 Others
• Life skills training
Life skills programmes for serious mental illness are rehabilitation programmes that address
the needs associated with independent functioning e.g. financial awareness, communication,
domestic care, personal self-care and community living skills.
A Cochrane systematic review found no good evidence to suggest that life skills programmes
were effective for people with chronic mental illnesses which were mostly
schizophrenia.Tungpunkom P et al., 2012, level I
• Exercise therapy
A Cochrane systematic review of small RCTs looked into the effectiveness of exercise therapy
on people with schizophrenia. The therapy was defined as any intervention either used alone
or in conjunction with others where physical activity or exercise was considered to be the main
or active element. Compared with standard treatment, exercise therapy improved depression,
anxiety, both negative and positive PANSS scores and also physical fitness. However, it was
less effective than yoga in total and negative PANSS scores.Gorczynski P et al., 2010, level I
• Dance therapy
Dance therapy uses movement and dance to explore a person’s emotion in a non-verbal way
by interpreting their dance to personal feelings.
22
In a Cochrane systematic review on schizophrenia, a moderate quality RCT showed that
dance therapy was more effective than standard care in reducing PANSS negative symptoms
score by 20 - 40% (RR=0.62, 95% CI 0.39 to 0.97).Ren J et al., 2013, level I.
• Music therapy
Music therapy is a systematic process of intervention promoting health using expression of
music.
A Cochrane systematic review on schizophrenia, compared with standard care, showed that
music therapy improved:Geretsegger M et al., 2017, level I
• global state at medium-term (NNTB=2, 95% CI 2 to 4)
• general mental state on PANSS at medium-term (SMD= -0.97 95% CI -1.31 to -0.63)
• negative symptoms on SANS at short-term (SMD= -0.5 95% CI -0.73 -0.27) and medium-
term (SMD= -0.55 95% CI -0.87 to -0.24)
• social functioning on Social Disability Screening Schedule (SDSS) at medium-term (SMD=
-0.72, 95% CI -1.04 to -0.40)
The quality of primary papers used in the review was low to moderate.
• Religion/spiritual activities
Religious/spiritual activities are multidimensional approaches that promote positive coping. It
provides sense of meaning and purpose, emotional comfort, personal control and connection
with others and higher power.
In a small cross-sectional study on schizophrenia, there was a modest correlation between

positive religious coping and psychological aspect in QoL (r=0.28, p=0.03).Nolan J et al., 2013, level III
5. SERVICE LEVEL INTERVENTION
Following the global paradigm shifts from institutionalisation to community-based mental

health services, Malaysia is steadily progressing towards developing more community-based
psychiatric services. Hence this chapter addresses this issue based on common service level
interventions provided in the management of schizophrenia.
5.1 Crisis and Emergency Service
Crisis and Emergency Mental Health Service provides intensive care in the community for
people with acute psychiatric symptoms, thus avoiding the need for hospitalisation. A
Cochrane systematic review of mixed quality RCTs on mainly schizophrenia showed that
those receiving crisis intervention services compared with standard care had: Murphy SM et al., 2015,
level I
• fewer re-admission after initial crisis (RR=0.53, 95% CI 0.41 to 0.68)

• fewer days in acute care post-crisis (MD= -10.30, 95% CI - 14.77 to -5.83)
• lesser family burden at three months (RR=0.57, 95% CI 0.41 to 0.80) and six months
(RR=0.34, 95% CI 0.20 to 0.59)
• higher family satisfaction with treatment at three months (RR=0.63, 95% CI 0.44 to 0.89)
and six months (RR=0.57, 95% CI 0.42 to 0.78)
• significantly higher patient satisfaction with treatment at 6 - 20 months
• Crisis resolution and home treatment team provides the following:NICE, 2014
o assessment for admission to acute psychiatric wards
o initiation of home treatment programme with frequent visits as an alternative to hospital
treatment
23
o continuation of home treatment until the crisis has resolved and subsequently transfer
to other services for further care
o facilitate early discharge from acute wards
NICE recommends offering crisis resolution and home treatment teams as a first-line service
to support people with schizophrenia during an acute episode in the community and should
be considered before admission to the hospital and as a mean to enable timely discharge.NICE,
2014
Recommendation 15
• Crisis intervention services should be offered in schizophrenia with acute psychiatric
symptoms.
5.2 Assertive Community Treatment
Assertive community treatment (ACT) is a service that provides continuous care for people
with serious mental illness in the community especially those who have difficulty engaging with
the mental health services. The Assertive Community Treatment in Schizophrenia Spectrum
Disorders (ACCESS II) study showed positive outcomes for those receiving ACT which
sustained even after four years:Schottle et al., 2018, level II-3
• 75.7% were fully adherent to medications compared with baseline (p < 0.001)
• 73.0% received psychotherapeutic treatment conducted by the ACT team or private
psychotherapists
• significant reduction of inpatient treatment from 22.4 days at year one to 4.7 days at year
four
• significant clinical improvement based on BPRS, CGI-S, GAF and Q-LES-Q
• Key elements of ACT are as follows:NICE, 2014

o a multidisciplinary approach involving a dedicated psychiatrist
o care for people with serious mental illness
o shared responsibility for the same client by team members
o provision of all psychiatric and social care for each client
o care is provided at home or work place
o emphasised on medication concordance
People with schizophrenia should receive ACT if there is a history of poor engagement with
services leading to frequent relapse or social disruption, high use of inpatient services and
presence of residual psychotic symptoms.APA, 2019; SIGN 2013
Recommendation 16
• Assertive community treatment should be provided for people with schizophrenia who
have difficulty engaging with the mental health services.
5.3 Intensive Case Management
Intensive case management (ICM) is a small case-load (up to 20 people) of community-based

psychiatric service for people with serious mental illness that may follow many models e.g.
ACT, case management etc. In a large Cochrane systematic review, compared with standard
care, people (majority with schizophrenia) receiving ICM had:Dieterich M et al., 2017, level I
• reduced number of days in hospital per month at 24 months (MD= -0.86, 95% CI -1.37 to -
0.34)
24
• reduced number of people living dependently at medium-term (RR=0.80, 95% CI 0.66 to
0.97) and long-term (RR=0.65, 95% CI 0.49 to 0.88)
• improved functioning outcomes based on GAF at long-term (MD=3.41, 95% CI 1.66 to
5.16).
• less likely to be lost to psychiatric services (RR=0.43, 95% CI 0.30 to 0.61)
• significantly higher client satisfaction at short-, medium- and long-term
A recent large cohort study investigated the change in medical utilisation of case management
(CM) for psychiatric home care among mainly people with schizophrenia. CM led to a
significant decrement of psychiatric and involuntary admissions, and the utilisation shifted
toward psychiatric outpatient service. The effect persisted after two years of intervention.
However, CM showed no impact on lowering the admission rate for comorbid physical
illnesses.Chen WY et al., 2019, level II-2
In another cohort study with a long follow-up, ICM significantly improved treatment adherence
and reduced suicide and suicidal attempts compared with previous standard treatment
received in mental health units. Apart from that, combination of ICM and LAI treatment
improved the outcomes.Díaz-Fernández S et al., 2019 level II-2
NICE recommends for consideration of ICM for people with psychosis or schizophrenia who
are likely to disengage from treatment or services.NICE, 2014
Recommendation 17
• Intensive case management should be considered for people with schizophrenia who
are at risk of defaulting treatment.
5.4 Community-based Service Intervention
An RCT compared collaborative community-based care delivered through community health

workers plus standard facility-based care with standard facility-based care alone in
schizophrenia. The community health workers were defined as non-healthcare workers who
had at least 10 years of schooling, good interpersonal skills, systematic training over six weeks
and assessment for competency. The community-based intervention had better score in the
general subscale of PANNS (MD= -2.16, 95% CI -4.23 to -0.09) and locally validated Indian
Disability Evaluation and Assessment (MD= -0.95, 95% CI -1.68 to -0.23) at 12 months.Chatterjee
S et al., 2014, level I
• Community-based service intervention may be beneficial for people with schizophrenia.
5.5 Day Hospitalisation/Day Treatment
Day hospital or day treatment centre is an ambulatory treatment programme that emphasises
psychosocial and pre-vocational treatment modalities designed for people with serious mental
disorders who require co-ordinated, intensive, comprehensive and multi-disciplinary treatment
not provided in an outpatient clinic setting.
A Cochrane systematic review found that people with schizophrenia allocated to day hospital
care had less admission to hospital beyond one year compared with those receiving out-
patient care (RR=0.71, 95% CI 0.56 to 0.89). The heterogeneity was significant while the
quality of primary papers was moderate.Shek E et al., 2009, level I
25
5.6 Residential Services
A quasi-experimental study on people with serious mental illnesses (predominantly

schizophrenia spectrum disorders) compared those who were under the Full Service
Partnerships (FSP) programme, which provided a combination of subsidised permanent
housing and full-fidelity assertive community treatment, and those receiving public mental
health services. FSP participants had significant increase in:Gilmer TP et al., 2010 level II-1
• number of days spent in either independent or congregate/residential living situations
• case management
• medication management
• therapy/rehabilitation
• total outpatient visits
There was also significant decline in:
• mean number of days spent homeless per year
• use of inpatient, emergency and justice system services
On quality of life, FSP clients gave significantly more favorable responses in all domains
especially the living situation domain.
In a recent large RCT, there was no significant difference in number of ED visit and hospital
admission between immediate access to independent housing and support from the ACT team
also known as Housing First group and TAU group for people who were homeless with severe
mental disorders with predominantly schizophrenia. However, the housing first group showed
less inpatient days (RR=0.62, 95% CI 0.48 to 0.80).Tinland A et al., 2020, level I
• Residential services may be useful in schizophrenia to reduce homelessness.
5.7 Early Intervention in Psychosis
Psychosis can lead to persistent disability, increased cost in treatment, social inequalities and
suicide if not intervened early. McGorry et. al., 2016; NICE, 2010 The initial 3 - 5 years from a first episode
of psychosis is a critical period whereby early intervention improves outcomes and alters the
trajectory of illness and disability.NICE, 2014 Early intervention in psychosis consists of early
detection of people at risk and phase-specific treatment.Orygen, 2016; Marshall M et al., 2011
Specialised high-risk service is a psychiatric service meant for those at risk of psychosis e.g.
in Outreach and Support in South London (OASIS). In a cohort study on patients with first
episode psychosis which mainly consisted of schizophrenia at 24 months follow-up, compared
with conventional service, OASIS showed significant:Fusar-Poli P et al., 2016, level II-2
• fewer days in hospital
• shorter median referral-to-diagnosis time
• reduced likelihood of compulsory hospital admission
• lower frequency of admission
In a recent Cochrane systematic review of three RCTs, extended specialised early intervention
(SEI) resulted in fewer disengagements from mental health treatment compared with standard
SEI + TAU for people with recent-onset psychosis (RR=0.45, 95% CI 0.27 to 0.75). However,
there was no significant difference in remission.Puntis S et al., 2020, level I
People with schizophrenia experiencing first episode of psychosis should receive treatment
from the early intervention services which provide a full range of pharmacological,
psychological, social, occupational and educational interventions.APA, 2019; NICE, 2015; SIGN, 2013
26
• Key elements in early intervention in psychosis services are:NICE, 2014
o swift assessment through a readily accessed point of contact by a practitioner
competent in recognising first episode psychosis
o staff who build up trust and confidence
o provision of good information on psychosis and treatment options
o a care coordinator who will support throughout their time in the service, including
helping them with self-management skills, social care issues e.g. housing or debt
management, and relapse prevention work
o a choice of psychological and pharmacological interventions
o support, information and advice for families and carers, including carers’ assessments
where required
o support with employment, training and/or education
o regular physical health checks, monitoring and appropriate treatment, with support
and/or education
o regular monitoring of risk
o routine monitoring of other co-existing conditions, including depression, anxiety and
substance misuse, particularly in the early phases of treatment
o a crisis plan and prompt service response in crisis
Recommendation 18
• Early intervention in psychosis service should be provided in people with first episode of
psychosis.
6. TRADITIONAL AND COMPLEMENTARY MEDICINE
In a Cochrane systematic review, acupuncture added to standard AP may prevent no clinical

response compared with standard AP in people with schizophrenia at 3 - 12 months follow-up
(RR=0.44, 95% CI 0.28 to 0.57). In addition, adverse effects were less in combined treatment
(RR=0.30, 95% CI 0.11 to 0.83). However, the certainty of evidence in this review was
generally low and of short duration.Shen X et al., 2014, level I
In another Cochrane review, yoga as part of a package of care compared with standard care
in schizophrenia may have a better QoL at <6 months follow-up (MD=22.93, 95% CI 19.74 to
26.12). This review included small number of small studies with lacked many key
outcomes.Broderick J et al., 2017, level I
In a meta-analysis of eight RCTs, extracted Gingko Biloba used as adjunct therapy to AP may
improve symptoms of schizophrenia compared with AP alone (SMD= - 0.49, 95% CI -0.69 to
-0.30). The certainty of evidence was generally low because most evidence was from short-
term trial and graded very low in quality.Chen X et al., 2015, level I
• There is insufficient evidence to recommend traditional and complementary medicine in

schizophrenia.
7. CHALLENGES IN MANAGEMENT
7.1 Treatment-Resistant Schizophrenia
7.1.1 Definition
The definition for treatment-resistant schizophrenia (TRS) in guidelines on schizophrenia is
varied. For clinical purposes, TRS is defined as a condition when patient’s symptoms show
27
no response or partial and suboptimal response to trial of two different APs for at least six
weeks with each medication used at an adequate dosage of medication. Some definitions
specify on using medications from different classes.APA, 2019
Due to lack of uniformity in the definition of TRS, the Treatment Response and Resistance in
Psychosis (TRRIP) Working Group has conducted a systematic review and established
minimum and optimum criteria to identify TRS for future trials. Howes OD et al., 2017 level I Refer to
Appendix 9 on Consensus Criteria for Assessment and Definition of Treatment-
Resistant Schizophrenia. TRS occurs in up to 23% of people with schizophrenia.Demjaha A et
al., 2017 level II-2; Wimberley T et al., 2016, level II-2
7.1.2 Predictors
In the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP-10) study on
first episode psychosis in United Kingdom, predicted odds of treatment-resistant
schizophrenia (TRS) were 1.09 higher in people with negative symptoms compared with those
without negative symptoms. Predicted odds of TRS for people with four and nine negative
symptoms were 1.40 and 2.13 respectively.Demjaha A et al, 2017, level II-2
A systematic review of 47 studies showed that clinical predictive factors of TRS were:Bozzatello P
et al., 2019, level I
• poor premorbid functioning

• male gender
• younger age at onset
• presence of neurobiological factors
• lower educational level
• single marital status
• negative symptoms
• substance use disorder
• non-adherence
• non-response within two weeks of initiation of treatment
• duration of untreated psychosis
However, there was no mention of quality assessment in this review.
A Danish cohort study of 4,674 person-years follow-up showed no evidence in polygenic risk
score for TRS.Wimberley T et al., 2017, level II-2
7.1.3 Treatment
Four Cochrane systematic reviews studied on treatment of TRS. The summary findings on
effectiveness of pharmacological treatment from three reviews were:
• clozapine was more effective than typical AP in improvement in BPRS endpoint scores at
short-term (WMD= -7.83, 95% CI -10.0 to -5.6) and reduction of relapse rate at long-term
(RR=0.17, 95% CI 0.1 to 0.3)Adip Essali et al., 2009, level I
• clozapine showed inconclusive efficacy compared with AAPs which required further trials
to confirm the findingsAsenjo Lobos C et al., 2010, level I
• no significant difference of effect on mental state between very low, low and standard dose
of clozapineSubramaniam S et al., 2017, level I
For adverse events, the reviews showed:

• comparing with typical AP, clozapine caused less movement disorder (RR=0.77, 95% CI
0.7 to 0.9) but more hypersalivation (RR=2.01, 95% CI 1.7 to 2.3) and weight gain
(RR=1.33, 95% CI 1.1 to 1.6)Adib E et al., 2009, level I
• comparing with AAPs, clozapine produced fewer EPS than risperidone (RR=0.39, 95% CI
0.22 to 0.68) and zotepine (RR=0.05, 95% CI 0.00 to 0.86); however, it caused more
28
reduction in white blood cells count, hypersalivation, sedation, weight gain and seizures
than other AAPsAsenjo LC et al., 2010, level I
• lower dose of clozapine was associated with less weight gain (MD= -1.60, 95% CI -2.90 to
-0.30), lower glucose level after meal (MD= -1.6, 95% CI -2.90 to -0.30) and lower
Treatment Emergent Side Effect Scale score (MD= -3.99, 95% CI -5.75 to -
2.24)Subramaniam S et al., 2017, level I
The quality of primary papers in the reviews varied from moderate to low quality.
Guidelines of SIGN, NICE and APA recommend to offer clozapine to TRS.APA, 2019; NICE, 2014; SIGN,
2013
Refer to Appendix 7 on Suggested titration regimen for clozapine initiation in the
community and Clozapine initiation and titration regimen for in-patient.
Recommendation 19
• Clozapine should be offered in treatment-resistant schizophrenia.
• Clozapine augmentation with another medications

For people with schizophrenia whose illness has not responded adequately to clozapine at an
optimised dose, healthcare providers should consider the followings before adding a second
AP to augment treatment with the clozapine:NICE, 2014
o review the diagnosis
o ensure adherence to AP (adequate dose and duration)
o review engagement with psychosocial intervention
o consider other causes of non-response e.g. co-morbid substance misuse disorder
(including alcohol, nicotine), concurrent use of other prescribed medication or physical
illness
In a Cochrane systematic review, augmentation of clozapine with another APs in five different
RCTs (low to very low quality) showed the following results:Barber S et al., 2017, level I
o clozapine + aripiprazole vs clozapine + haloperidol
- no significant differences in mental state based on BPRS at 12, 24 and 52 weeks
- less side effects in clozapine + aripiprazole based on Liverpool University Neuroleptic
Side Effects Rating Scale (LUNSERS) at 12 (MD= -4.90, 95% CI -8.48 to -1.32) and 24
(MD= -4.90, 95% CI -8.25 to -1.55) weeks
o clozapine + amisulpride vs clozapine + quetiapine
- clozapine + amisulpride showed better CGI score (MD= -0.90, 95% CI -1.38 to 0.42),
BPRS score (MD= -4.00, 95% CI -5.86, -2.14), SAPS score (MD= -6.90, 95% CI -12.82
to -0.98) and SANS score (MD= -5.20, 95% CI -7.14 to -3.26) at eight weeks
- no report on side effects
o clozapine + risperidone vs clozapine + sulpiride
- clozapine + risperidone had better PANSS positive score at eight weeks (MD= -2.55,
95% CI -4.64 to -0.46)
- no significant differences in PANSS total score (20% to 50% reduction and mean at end
point) and PANSS negative score
- no significant differences in weight gain and hypersalivation
o clozapine + risperidone vs clozapine + ziprasidone
- clozapine + risperidone had better HAMD score at six weeks (MD= -3.40, 95% CI -6.71
to -0.09) but not 26 weeks
- no significant differences in PANSS, CGI and GAF scores
- no significant differences in EPS and CGI adverse effect scores
o clozapine + ziprasidone vs clozapine + quetiapine
- clozapine + ziprasidone had better CGI-S (MD= -0.70, 95% CI -1.18 to -0.22), PANSS
total score (MD= -12.30, 95% CI -22.43 to -2.17) and PANSS positive score (MD= -3.10,
95% CI -5.52 to -0.68) at 12 weeks
29
- no significant difference in PANSS negative score
- no significant differences in EPS and overall adverse effect rate
Recommended duration of augmentation to clozapine varies i.e. 8 - 10 weeksNICE, 2014

or
minimum of 10 weeks.SIGN, 2013
• The risks and benefits should be weighed if an augmentation treatment is introduced.

• It is important to monitor side effects and potential drug-drug interactions.
• Regular review of the medication regimen should be carried out to justify the continuity
of treatment.
• Electroconvulsive therapy
A Cochrane systematic review of 15 moderate to low quality RCTs on ECT for TRS
showed:Sinclair DJM et al., 2019, level I
o no significant difference in clinical response compared with clozapine
o improvement in clinical response at short-term (RR=1.91, 95% CI 1.09 to 3.36) and long-
term (RR=2.06, 95% CI 1.75 to 2.42) compared with standard care; however, ECT was
associated with more memory deterioration (RR=27.00, 95% CI 1.67 to 437.68)
o fewer readmission (RR=0.29, 95% CI 0.10 to 0.85) compared with sham ECT
In two meta-analyses of moderate to low quality RCTs which compared combination of ECT
and AP vs AP alone in patients with TRS, the former had:
o better endpoint improvement in total score of PANSS (SMD= -0.67, 95% CI -0.95 to -
0.39)Zheng W et al., 2016, level I and BPRS (RR=1.25, 95% CI 1.14 to 1.37)Wang W et al., 2015, level I
o more side effects
- headache with NNH of 6 (95% CI 4 to 11)Zheng W et al., 2016, level I and OR of 9.1 (95% CI 3.97
to 20.86) Wang W et al., 2015, level I
- memory impairment with NNH of 3 (95% CI 2 to 5)Zheng W et al., 2016, level I and OR of 6.48
(95% CI 3.54 to 11.87)Wang W et al., 2015, level I
• ECT in combination with AP may be beneficial in people with treatment-resistant

schizophrenia.
• Common adverse reactions e.g. headache and memory impairment should be monitored.
• Cognitive behaviour therapy

A large multicentre RCT studied the effectiveness and safety of CBT in clozapine-resistant
schizophrenia. The CBT was more effective than TAU in reduction of symptoms severity
(PANSS total score) at nine months (MD= -2.40 points, 95% CI -4.79 to -0.02) but showed no
difference at 21 months. There was no significant difference in at least one AE between the
two groups.Morrison AP et al., 2019, level I
7.2 Treatment in Special Population

7.2.1 Comorbid substance use and tobacco use disorders
People with schizophrenia has been found to have higher rates of substance use disorders
(SUD). In a meta-analysis of 123 studies with 165,811 subjects and excluding nicotine
dependence, the pooled prevalence of any SUD was 41.7%, with specific prevalence of 27.5%
for illicit drugs, 26.2% for cannabis, 24.3% for alcohol and 7.3% for stimulants. The prevalence
varies according to geographical distribution and type of substance use.Hunt GE et al., 2018, level II-2
The comorbid of SUD among people with schizophrenia carries poorer prognosis and more
complex management. Referral to psychiatrist should be considered for these people. Apart
30
from that, SUD should always be considered and monitored across all phases of care for
people with schizophrenia.NICE, 2014
Evidence on treatment of schizophrenia with comorbid SUD is limited by scarcity of relevant

and high-quality studies. The best option is to offer comprehensive treatment using both
pharmacological and psychosocial interventions in treating these patients.
A Cochrane systematic review of eight very low quality RCTs on people with schizophrenia
and co-occuring substance misuse showed the following results:Temmingh HS et al., 2018, level I
o risperidone vs clozapine
- clozapine had lower score for endpoint negative symptoms in PANSS (MD=4.00, 95%
CI 0.79 to 7.21) but no difference in positive symptoms (MD=0.90, 95% CI -2.21 to 4.01)
- clozapine had lower scores in craving for substance in Marijuana Craving Questionnaire
(MD=7.00, 95% CI 2.37 to 11.63) and Obsessive-Compulsive Craving Scale (MD=14.2,
95% CI 4.45 to 23.95)
- no significant difference in adherence to AP, EPS and reduction in substance use
o risperidone vs olanzapine
- no significant difference in reduction of positive symptoms, cannabis use, craving for
cannabis and parkinsonism
In a systematic review of 14 studies on patients with schizophrenia and co-morbid substance

use disorder, clozapine use in SUD (other than nicotine) was superior than FGA and
risperidone in substance use reduction and abstinence. However, it was not superior to
olanzapine and ziprasidone. Findings on nicotine use was scarce.Arranz B et al., 2017, level I
Another meta-analysis involving 19 RCTs on schizophrenia subjects with SUD found that
clozapine showed reduction of substance use compared with any APs (MD= -1.08, 95% CI
-1.84 to -0.32) while risperidone showed reduction for craving compared with olanzapine
(SMD= 0.82, 95% CI 0.18 to 1.46). In terms of symptom reduction, olanzapine, clozapine and
risperidone were more effective than other APs. The reported side effects followed the
established patterns of each APs. Overall quality of primary studies was of low quality. Krause M
et al., 2018, level I
Based on a Cochrane systematic review, there was absence of high-quality evidence to

support any psychosocial treatment over standard care for important outcomes e.g. remain in
treatment, reduction in substance use or improved mental or global state in people with serious
mental illnesses and substance misuse. This indicated the complexities in treatment of dual
diagnosis.Hunt GE et al., 2018, level I
A meta-analysis of worldwide studies demonstrated an association between schizophrenia

and current smoking (OR=5.9, 95% CI 4.9 to 5.7).de Leon & Diaz, 2005, level II-2 A local study showed
the prevalence of nicotine dependence (smoking) among people with schizophrenia in a
hospital at 38.1%.Yee A et al., 2015, level III This was higher than the overall prevalence of smoking of
any tobacco products at 21.3% among Malaysian adults in the National Health and Morbidity
Survey 2019.NHMS, 2019 level III
Guidelines recommend that attending doctor have to assess the smoking status of all people
with schizophrenia.APA, 2019, MOH Tobacco, 2016 People with schizophrenia should be offered help to
stop smoking, even if previous attempts have been unsuccessful.NICE, 2014
• Tobacco cessation
o Smoking of tobacco and tobacco products (cigarette, electronic cigarette/vape, shisha,
pipe, cigar etc.) can lead to various non-communicable diseases (NCDs). Worldwide,
more than eight million people die every year because of this habit.WHO Tobacco Fact Sheet,
2020
31
o Hence, the decision to integrate smoking treatment with NCDs is important to reduce
the prevalence of NCDs and their complications. This decision was made during the
World Health Organization Framework Convention on Tobacco Control (WHO FCTC)
Steering Committee Meeting in December 2019 chaired by the Honourable Health
Minister of Malaysia.
o The treatment for smoking should be initiated by the treating doctor based on the
assessment and treatment of tobacco use disorder as in Table 4. Details on this can
be found in the CPG on Treatment of Tobacco Use Disorder 2016, available at:
https://www.moh.gov.my/moh/resources/Penerbitan/CPG/Respiratory/CPG_TobacoDisorder
.pdf
Table 4. Assessment and Treatment of Tobacco Use Disorder
ASSESSMENT AND TREATMENT

1. Ask and document smoking status for all patients.
2. Provide brief advice on quit smoking at every visit to all smokers.
3. Assess level of nicotine addiction using Modified Fagerström Test for Cigarette
Dependence Questionnaire (COMPULSORY) and verify smoking status using carbon
monoxide breath analyser (IF AVAILABLE).
4. Offer pharmacotherapy to all smokers who are attempting to quit, unless
contraindicated.
5. If selected, use nicotine replacement therapy (NRT) for at least eight to twelve weeks,
whereas varenicline should be used for at least twelve weeks.
6. Combination therapy (e.g. two NRTs, a non-NRT, e.g. bupropion with an NRT) is
better than monotherapy in smoking cessation treatment and may be most useful for
those smokers at highest risk of relapse.
7. Use smoking cessation medications with caution in special populations (e.g. children
and adolescents, pregnant, breastfeeding women, psychiatric and substance abuse
disorder patients).
8. Arrange a minimum of six to eight face to face follow-up sessions for smoking
cessation interventions in six months through counselling support team (health
education officer, pharmacists or any officer trained for quit smoking services).
Recommendation 20
• People with schizophrenia and comorbid substance use disorder should be referred to
the psychiatrist for further management.
• People with schizophrenia and smoking should be offered help in smoking cessation.
7.2.2 Pregnancy and breastfeeding

The principles of treatment for pregnant women with schizophrenia should be based on risk-
benefit analysis to optimise outcomes for both mothers and their babies. The management
can be of a great challenge due to limited availability of evidence. Cohort studies showed that
women with schizophrenia had increased risk of complications in pregnancy and delivery, and
neonatal morbidity.Simoila L et al., 2018; Vigod SN et al., 2014 Postpartum relapse in mothers with
schizophrenia in a cohort study was:Munk-Olsen T et al., 2009, level II-2
• highest in 0 to 9 days following childbirth (RR=5.67, 95% CI 3.23 to 9.96), followed by 10
to 19 days after childbirth (RR=4.58, 95% CI 2.48 to 8.48) compared with 180 days after
childbirth
• increased if there was admission during pregnancy (RR=6.83, 95% CI 3.58 to 13.04)
• increased when the child’s father had mental disorder (RR=1.80, 95% CI 1.21 to 2.69)
Women with schizophrenia in their reproductive age should receive pre-pregnancy care (PPC)
in a nearby health clinic or an obstetric and gynaecology clinic at least three months prior to
conception.Garispanduan Perkhidmatan Prakehamilan, 2019, level III In PPC, treatment of pre-existing
32
schizophrenia must be optimised and contraception should be offered. The risks and benefits
of continuing AP and consequences of changing treatment must also be discussed, taking
into consideration the severity of schizophrenia, risk of relapse, past response to treatment
and individual’s preference. It is essential to collaborate with the patient, partner and
multidisciplinary team in the management of patient throughout the pregnancy and postpartum
period.
Pregnant women with schizophrenia should be managed with lowest effective dose using a
single AP.APA, 2019 Continuing APs in pregnant women with schizophrenia is preferable
considering the risk of relapse when they are discontinued, which can further impair the
antenatal care, health and social functioning, and mother-infant relationship.Maudsley, 2021, level III;
APA, 2019; NICE, 2014
Change of treatment is not advisable when a pregnant woman is stable on a
specific AP and she is likely to experience relapse of schizophrenia without it.APA, 2019 Changing
of APs may expose the foetus to two different medications and increases possibilities of
relapse in mother.Maudsley 2021, level III; APA, 2019
Limited evidence suggest that FGAs and SGAs have minimal teratogenic risk or toxic effects
to the foetus.Maudsley, 2021, level III In a cohort study, women with schizophrenia who received:Lin HC
et al., 2010, level II-2
• FGA and SGA did not show higher odds of babies with LBW, SGA or LGA compared with
those not receiving APs during pregnancy
• FGA during pregnancy had higher odds of preterm birth (OR=2.46, 95% CI 1.50 to 4.11)
All APs that have been studied to date cross the placenta, present in amniotic fluid and
excreted in breast milk.AAP & ACOG, 2017 Hence, APs withdrawal symptoms can occur in the
newborns when they are used in the third trimester. The symptoms are crying, agitation,
increased suckling, abnormal increased in tone, tremors, sleepiness, difficulty in feeding and
difficulty in breathing which alleviate within hours or days and do not require specific treatment.
However, the benefits of treatment for the mothers and newborns superseded the harm of
discontinuing APs and generally favours continuation of APs.FDA, 2017
Decisions about breastfeeding on exposure of APs in infants and associated benefits and
harms should be discussed with all women with schizophrenia.NICE, 2019 Women taking APs are
usually advised to continue the treatment used during pregnancy.Maudsley, 2021, level III; APA, 2021
Mothers on clozapine should continue the treatment but advised not to breastfeed.Maudsley, 2021,
level III; SIGN, 2013
• For lactating mothers on clozapine, the benefits and risks of treatment are important to
be discussed. If they want to continue lactation while on clozapine, advice on medication
intake should be given accordingly. For those who don’t want to continue lactating, the
formulae supplementation should be offered to the infants.
Refer to Appendix 5 (Dosing Regimen for Oral Antipsychotics) and Appendix 6 (Dosing
Regimen for Depot Injections of Antipsychotic) during pregnancy and breastfeeding.
NICE recommends considering psychological intervention (CBT or family intervention) for

women with psychosis or schizophrenia who become pregnant and are at risk of relapse due
to:NICE, 2014
• stress associated with pregnancy or postnatal period
• change in medication, including stopping APs
33
Recommendation 21
• Pre-pregnancy care which includes counselling should be offered to all women with
schizophrenia.
• Multidisciplinary care should be offered in the management of pregnant women with
schizophrenia.
7.2.3 Suicide
• Prevalence
The worldwide overall prevalence of suicide in the general population is about 9.0 per 100,000
population (range 2 to 80 per 100,000 population) and it is 2.3 times more common in men
compared to womenWHO, 2021, level III
For schizophrenia and related disorders (including schizoaffective disorder or psychosis not
otherwise specified), a case-control study among 5,650 completed suicides concluded that
the overall prevalence of suicide was 11.7% with 10.3% in males and 15.7% in females. In
terms of age group, the prevalence was 21.7% in young adults (25 - 34 years old) and 7.7%
in elderly (65 years of old).Zaheer et al., 2018, level II-2
The patients who committed suicide were also most likely coming from the urban poor
neighbourhoods.
• Patients with schizophrenia comprise of about 12% of all completed suicide.

• The highest prevalence of suicide among patients with schizophrenia is in urban poor
neighbourhoods.
• Risk factors
A meta-analysis of 96 observational studies concluded that significant risk factors associated
with suicide related behaviours in patients with schizophrenia were:Cassidy et al., 2018, level II-2
o suicidal ideation
- presence of depressive symptoms
- higher PANSS general score
- higher number of psychiatric hospitalisations
o suicide attempts
- history of alcohol use
- family history of psychiatric illness
- physical comorbidity
- history of depression
- family history of suicide
- history of drug use
- history of tobacco use
- presence of depressive symptoms
o completed suicide:
- male gender
- history of attempted suicide
- younger age
- higher intelligence quotient
- poor adherence to treatment
- presence of hopelessness
• The highest risk for suicide in people with schizophrenia is among those who have
symptoms of self-devaluation and hopelessness.
34
• Suicide prevention strategy
Clozapine is indicated in the treatment of persistent suicidal thoughts or behaviours.MoH, 2009
APA recommends patients with schizophrenia to be treated with clozapine if the risk for suicide
attempts or suicide remains substantial despite other treatments.APA, 2021
Refer to Appendix 7 on Suggested Titration Regimen for Clozapine Initiation in The

Community and Clozapine Initiation and Titration Regimen for In-Patient.
Recommendation 22
• Clozapine may be considered in schizophrenia with persistent suicidal risk.
7.3 Social Issues
In a cross-sectional study, the prevalence of perceived stigma was noted to be high at 83.5%.
Education status (not able to read and write), difficulties of adherence to AP and duration of
illness <1 year were associated factors of the stigma with OR of 2.64 (95% CI 1.12 to 6.23),
4.49 (95% CI 2.31 to 8.73) and 3.48 (95% CI 2.24 to 5.42) respectively.Bifftu BB et al., 2014, level III
An RCT showed that psychoeducation programme significantly reduced stigma, improved

QoL and medication compliance apart from increased consumer satisfaction of people with
schizophrenia and their families, beyond the effects of AP.Ngoc TN et al., 2016, level I
Factors that affect and impact social engagement, QoL and life satisfaction for people with
schizophrenia were studied a systematic review of 41 observational studies. Decreased in
QoL and social relationships was found due to several factors:Stevens AK et al., 2009, level II-2
• interpersonal relationship status
• employment status
• effects of stigma
• neuro-cognitive skills and functioning
• effectiveness of intervention
However, there was no quality assessment done on the primary papers in the review.
In a cross-sectional study on people with schizophrenia in a hospital, the overall prevalence

of psychosocial disabilities was high at 98.1%. The highest prevalence was in social
disabilities, followed by vocational, self-hygiene, educational and family-related
disabilities.Goreishizadeh MA et al., 2012, level III
A population-based study looked into the crime rates in schizophrenia. The overall crime
prevalence of people with schizophrenia was 72.7 to 90.3 per 10,000 from 2012 through 2016,
which was about one fifth that of the general population. Further analysis showed that the
rates of most types of crimes including violence, intellectual crimes and theft were lower in
schizophrenia than general population. However, the prevalence of murder, arson, and drug-
related crimes was about five, six and two times higher in schizophrenia respectively.Kim AM,
2019, level III
QualityRights is WHO’s global initiative to increase access to good quality mental health
services and to promote the human rights of people with psychosocial, intellectual and
cognitive disabilities. It offers a new approach to mental health care which is rights-based and
recovery-oriented. A pragmatic trial over a 12-month period used QualityRights as intervention
public mental health services. The core elements of the intervention comprised of:
• WHO QualityRights toolkit for service assessment
• introduction of service-level policy and processes to protect against inhumane/degrading
treatment, violence and abuse (including use of restraints)
35
• improvements of service environment within existing service and government resources
• training for healthcare professionals, family members and service users
• peer support volunteers to encourage participation of family members and service users
Compared with usual care, the intervention improved significantly the quality of services in:
• theme 1 (right to adequate standard of living)
• theme 2 (right to enjoyment of highest attainable standards of physical and mental health)
• theme 4 (freedom from torture or cruel, inhumane or degrading treatment or punishment
and from exploitation, violence and abuse)
Apart from that, staff in these services showed substantially improved attitudes towards
service users (Hedges’ g of -0.50 to 0.17).Pathare S et al., 2019, level I
• Malaysian Mental Health Regulations 2010 mandated every psychiatric hospital to

display statements of patient rights in a conspicuous part of the hospital.
8. IMPLEMENTING THE GUIDELINES
The management of schizophrenia should be guided by an evidence-based approach, in order

to provide quality care to the people with schizophrenia. Several factors may affect the
implementation of recommendations in the CPG.
8.1 Facilitating and Limiting Factors
Existing facilitators for application of the recommendations in the CPG include:

• wide dissemination of the CPG (soft- and hardcopies) to healthcare providers
• training and updates in relation to schizophrenia to healthcare providers
• accessibility to relevant multidisciplinary teams
• public awareness campaigns related to mental health and mental disorders including
schizophrenia
• inter-ministerial collaboration and involvement of non-governmental organisations to
support the people with schizophrenia and their caregivers
Existing barriers for application of the recommendations of the CPG are:

• limited exposure and training among healthcare providers on management of
schizophrenia
• variation in availability of expertise and access to service provision
• insufficient resources in terms of budget, expertise, medications, psychosocial intervention
• stigma and lack of awareness among patients, families, community and healthcare
providers
• lack of local data on schizophrenia, e.g. research, registry, etc., for planning on services
8.2 Potential Resource Implications
This CPG recommends early detection and referral, comprehensive assessment and
treatment of schizophrenia. These requires increased awareness among public, healthcare
providers and other stakeholders to establish early diagnosis and uninterrupted various form
of treatment as well as support to the patients and their caregivers.
However, treatment non-adherence is a widely recognised problem in schizophrenia. This

includes failure to start treatment programme, default in outpatient clinic appointments and
failure to medicate with prescribed APs. The outcome of this heart-breaking situation is
increase in relapse of psychotic symptoms, hospitalisation, aggression, poor QoL,
stigmatisation and premature death.
36
Accordingly, Key Performance Index on psychiatrist service of outpatient defaulter rate is
being monitored in both primary and secondary/tertiary care under MoH. By doing so, effective
psychosocial intervention e.g. psychoeducation can be targeted to them. This CPG also
recommends that depot APs to be prescribed in patients with history of non-adherence in
order to improve their outcomes. Simultaneously, data on depot prescriptions can be captured
easily along with the KPI of defaulted patients as surrogate maker of CPG utilisation based on
the recommendation on depot. Moreover, the slightly expensive SGA depots with few
intolerance issues and longer injection interval should be used more widely in the country.
Based on the key recommendations, the following are proposed as clinical audit indicators for
quality management of schizophrenia:
Percentage of Number of defaulters among patients with

defaulters* among schizophrenia in outpatient clinic at primary or
patients with secondary/tertiary care in a period
schizophrenia in Number of patients with schizophrenia in outpatient
= x 100%
outpatient clinic at clinic at primary or
primary or secondary/tertiary care in the same period
secondary/tertiary
care
(Target of ≤10%)
*patients who default
one month follow-up
Percentage of patients Number of patients with schizophrenia having

with schizophrenia treatment non-adherence prescribed with
having treatment non- = depot AP in a period x 100%
adherence prescribed Number of patients with schizophrenia having
with depot AP treatment non-adherence in the same period
(Target of ≥30%)
Implementation strategies will be developed following the approval of the CPG by MoH which
include launching of the CPG, Quick Reference and Training Module.
37
REFERENCES
1. Abdul Kadir AB. Community Psychiatric Services in Malaysia: Where do we go from here?
Malaysian Journal of Psychiatry. 2011;Vol. 20, No. 1
2. Almerie MQ, Okba Al Marhi M, Jawoosh M, et al. Social skills programmes for schizophrenia.
Cochrane Database Syst Rev. 2015;(6):CD009006
3. Alphs L, Morlock R, Coon C, et al. Negative Symptom Assessment (NSA-4) Instrument: A Simple
Tool for Evaluating Negative Symptoms in Schizophrenia Following Brief Training. Psychiatry
(Edgmont). 2010;7(7):26-32
4. Arranz B, Garriga M, García-Rizo C, et al. Clozapine use in patients with schizophrenia and a
comorbid substance use disorder: A systematic review. Eur Neuropsychopharmacol.
2018;28(2):227-242
5. Asenjo Lobos C, Komossa K, Rummel-Kluge C, et al. Clozapine versus other atypical
antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2010, Issue 11. Art.
No.: CD006633.
6. Aziz AA, Salina AA, Abdul Kadir AB, et al. The National Mental Health Registry (NMHR). Med J
Malaysia. 2008;63 Suppl C:15-7.
7. Barber S, Olotu U, Corsi M, et al. Clozapine combined with different antipsychotic drugs for
treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2017;3(3):CD006324.
8. Bozzatello P, Bellino S, Rocca P. Predictive Factors of Treatment Resistance in First Episode of
Psychosis: A Systematic Review. Front Psychiatry. 2019:26;10:67.
9. Broderick J, Vancampfort D. Yoga as part of a package of care versus standard care for
schizophrenia. Cochrane Database Syst Rev. 2017:29;9:CD012145.
10. Buckley LA, Maayan N, Soares-Weiser K, et al. Supportive therapy for schizophrenia. Cochrane
Database Syst Rev. 2015;(4):CD004716.
11. Chatterjee S, Naik S, John S, et al. Effectiveness of a community-based intervention for people
with schizophrenia and their caregivers in India (COPSI): a randomised controlled trial. Lancet.
2014;383(9926):1385-94
12. Chen LP, Murad MH, Paras ML, et al. Sexual abuse and lifetime diagnosis of psychiatric disorders:
systematic review and meta-analysis. Mayo Clin Proc. 2010;85(7):618-29
13. Chen WY, Hung YN, Huang SJ, et al. Nationwide analysis of medical utilization in people with
severe mental illness receiving home care case management. Schizophr Res. 2019;208:60-66.
14. Chien WT, Clifton AV, Zhao S, et al. Peer support for people with schizophrenia or other serious
mental illness. Cochrane Database Syst Rev. 2019;4(4):CD010880
15. Demjaha A, Lappin JM, Stahl D, et al. Antipsychotic treatment resistance in first-episode
psychosis: prevalence, subtypes and predictors. Psychol Med. 2017;47(11):1981-1989
16. Díaz-Fernández S, Frías-Ortiz DF, Fernández-Miranda JJ. Suicide attempts in people with
schizophrenia before and after participating in an intensive case managed community program: A
20-year follow-up. Psychiatry Res. 2020;287:112479.
17. Dieterich M, Irving CB, Bergman H, et al. Intensive case management for severe mental illness.
Cochrane Database Syst Rev.2017;1:CD007906
18. Dollfus S, Mach C, Morello R. Self-Evaluation of Negative Symptoms: A Novel Tool to Assess
Negative Symptoms. Schizophr Bull. 2016;42(3):571-8
19. Dougall N, Maayan N, Soares-Weiser K, et al. Transcranial magnetic stimulation (TMS) for
schizophrenia. Cochrane Database Syst Rev. 2015;(8):CD006081.
20. Adib Essali, Nahla Al-Haj Haasan, Chunbo Li, et al. Clozapine versus typical neuroleptic
medication for schizophrenia Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.:
CD000059
21. Fusar-Poli P, Cappucciati M, Rutigliano G, et al. Diagnostic Stability of ICD/DSM First Episode
Psychosis Diagnoses: Meta-analysis. Schizophr Bull. 2016;42(6):1395-1406
22. Fusar-Poli P, Díaz-Caneja CM, Patel R, et al. Services for people at high risk improve outcomes
in patients with first episode psychosis. Acta Psychiabitr Scand. 2016;133(1):76-85
23. Gardner KN, Bostwick JR. Antipsychotic treatment response in schizophrenia. Am J Health Syst
Pharm. 2012 Nov 1;69(21):1872-9
24. Geretsegger M, Mössler KA, Bieleninik Ł, et al. Music therapy for people with schizophrenia and
schizophrenia-like disorders. Cochrane Database Syst Rev. 2017;5(5):CD004025
25. Gilmer TP, Stefancic A, Ettner SL, et al. Effect of full-service partnerships on homelessness, use
and costs of mental health services, and quality of life among adults with serious mental illness.
Arch Gen Psychiatry. 2010;67(6):645-52
38
26. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence,
prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188
countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet.
2015;386(9995):743-800
27. Grant PM, Bredemeier K and Beck AT. Six-Month Follow-Up of Recovery-Oriented Cognitive
Therapy for Low-Functioning Individuals With Schizophrenia. Psychiatr Serv. 2017;68(10):997-
1002.
28. Gomar JJ, Valls E, Radua J, et al. Cognitive Rehabilitation Study Group. A Multisite, Randomized
Controlled Clinical Trial of Computerized Cognitive Remediation Therapy for Schizophrenia.
Schizophr Bull. 2015;41(6):1387-96
29. Gorczynski P, Faulkner G. Exercise therapy for schizophrenia. Schizophr Bull. 2010 Jul;36(4):665-
6
30. Guidelines on Management of Aggressive Patients in Ministry of Health Facilities. 2016
31. Haque A. Mental health concepts and program development in Malaysia. Journal of Mental Health,
2005; 14(2): 183-195
32. De Hert M, Sermon J, Geerts P, et al. The Use of Continuous Treatment Versus Placebo or
Intermittent Treatment Strategies in Stabilized Patients with Schizophrenia: A Systematic Review
and Meta-Analysis of Randomized Controlled Trials with First- and Second-Generation
Antipsychotics. CNS Drugs. 2015:637-58
33. Højlund M, Kemp AF, Haddad PM, et al. Standard versus reduced dose of antipsychotics for
relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of
randomised controlled trials. Lancet Psychiatry. 2021(6):471-486
34. Hollander AC, Dal H, Lewis G, et al. Refugee migration and risk of schizophrenia and other non-
affective psychoses: cohort study of 1.3 million people in Sweden. BMJ. 2016 Mar 15;352:i1030.
Erratum in: BMJ. 2016;353:i2865
35. Howes OD, McCutcheon R, Agid O, et al. Treatment-Resistant Schizophrenia: Treatment
Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on
Diagnosis and Terminology. Am J Psychiatry. 2017;174(3):216-229
36. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32
oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic
review and network meta-analysis. Lancet. 2019:14;394(10202):939-951
37. Hunt GE, Large MM, Cleary M, et al. Prevalence of comorbid substance use in schizophrenia
spectrum disorders in community and clinical settings, 1990-2017: Systematic review and meta-
analysis. Drug Alcohol Depend. 2018;191:234-258
38. Hurford IM, Ventura J, Marder SR, et al. A 10-minute measure of global cognition: Validation of the
Brief Cognitive Assessment Tool for Schizophrenia (B-CATS). Schizophr Res. 2018;195:327-333
39. Jamaiyah H. Community Mental Health In Malaysia: Marriage of Psychiatry and Public Health.
Buletin Kesihatan Masyarakat Isu Khas 2000 155-167
40. Jones C, Hacker D, Meaden A, et al. Cognitive behavioural therapy plus standard care versus
standard care plus other psychosocial treatments for people with schizophrenia. Cochrane
Database Syst Rev. 2018;11(11):CD008712
41. Killaspy H, Banerjee S, King M, et al. Prospective controlled study of psychiatric out-patient non-
attendance. Characteristics and outcome. Br J Psychiatry. 2000;176:160-5
42. Kim J, Iwata Y, Plitman E, et al. A meta-analysis of transcranial direct current stimulation for
schizophrenia: "Is more better?" J Psychiatr Res. 2019;110:117-126
43. Kinoshita Y, Furukawa TA, Kinoshita K, et al. Supported employment for adults with severe mental
illness. Cochrane Database Syst Rev. 2013;(9):CD008297
44. Kishimoto T, Agarwal V, Kishi T, et al. Relapse prevention in schizophrenia: a systematic review
and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol
Psychiatry. 2013;18(1):53-66
45. Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for
relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull.
2014;40(1):192-213
46. Laws KR, Darlington N, Kondel TK, et al. Cognitive Behavioural Therapy for schizophrenia -
outcomes for functioning, distress and quality of life: a meta-analysis. BMC Psychol. 2018;6(1):32
47. de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between
schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76(2-3):135-57
48. Leucht S, Leucht C, Huhn M, et al. Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in
Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of
Efficacy Predictors. Am J Psychiatry. 2017;174(10):927-942
39
49. Leucht S, Tardy M, Komossa K, , et al. Maintenance treatment with antipsychotic drugs for
schizophrenia. Cochrane Database Syst Rev.2012;(5):CD008016
50. Li J, Huang YG, Ran MS, et al. Community-based comprehensive intervention for people with
schizophrenia in Guangzhou, China: Effects on clinical symptoms, social functioning, internalized
stigma and discrimination. Asian J Psychiatr. 2018;34:21-30
51. Mattila T, Koeter M, Wohlfarth T, et al. Impact of DSM-5 changes on the diagnosis and acute
treatment of schizophrenia. Schizophr Bull. 2015;41(3):637-43
52. Miller B, Messias E, Miettunen J, et al. Meta-analysis of paternal age and schizophrenia risk in
male versus female offspring. Schizophr Bull. 2011;37(5):1039-47
53. Morrison AP, Pyle M, Gumley A, et al. Cognitive-behavioural therapy for clozapine-resistant
schizophrenia: the FOCUS RCT. Health Technol Assess. 2019;(7):1-144
54. Morriss R, Vinjamuri I, Faizal MA, et al. Training to recognize the early signs of recurrence in
schizophrenia. Schizophr Bull. 2013;39(2):255-6
55. Mucci A, Vignapiano A, Bitter I, et al. A large European, multicenter, multinational validation study
of the Brief Negative Symptom Scale. Eur Neuropsychopharmacol. 2019;29(8):947-959
56. Murphy SM, Irving CB, Adams CE, et al. Crisis intervention for people with severe mental illnesses.
57. Nafees B, van Hanswijck de Jonge P, Stull D, et al. Reliability and validity of the Personal and
Social Performance scale in patients with schizophrenia. Schizophr Res. 2012;140(1-3):71-6
58. National Institute for Health and Care Excellence. Psychosis and Schizophrenia in adults;
treatment and management. London: NICE 2014.
59. Nolan JA, McEvoy JP, Koenig HG, et al. Religious coping and quality of life among individuals
living with schizophrenia. Psychiatr Serv. 2012;63(10):1051-4
60. Ortiz-Orendain J, Castiello-de Obeso S, Colunga-Lozano LE, et al. Antipsychotic combinations for
schizophrenia. Cochrane Database Syst Rev. 2017:28;6:CD009005
61. Osório FL, Loureiro SR, Hallak JEC, et al. Clinical validity and intrarater and test-retest reliability
of the Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV). Psychiatry Clin
Neurosci. 2019;73(12):754-760
62. Ostinelli EG, Brooke-Powney MJ, Li X, et al. Haloperidol for psychosis-induced aggression or
agitation (rapid tranquillisation). Cochrane Database Syst Rev. 2017;7(7):CD009377
63. Ostinelli EG, Jajawi S, Spyridi S, et al. Aripiprazole (intramuscular) for psychosis-induced
aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev.2018:8;1:CD008074
64. Park SC, Choi MY, Choi J, et al. Comparative Efficacy and Safety of Long-acting Injectable and
Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review
and Meta-analysis. Clin Psychopharmacol Neurosci. 2018;16(4):361-375
65. Pathare S, Funk M, Drew Bold N, et al. Systematic evaluation of the QualityRights programme in
public mental health facilities in Gujarat, India. Br J Psychiatry. 2019:1-8.
66. Patrick DL, Burns T, Morosini P, et al. Reliability, validity and ability to detect change of the
clinician-rated Personal and Social Performance scale in patients with acute symptoms of
schizophrenia. Curr Med Res Opin. 2009;25(2):325-38
67. Pharoah F, Mari J, Rathbone J, et al. Family intervention for schizophrenia. Cochrane Database
Syst Rev. 2010;(12):CD000088
68. Puntis S, Minichino A, De Crescenzo F, et al. Specialised early intervention teams (extended time)
for recent-onset psychosis. Cochrane Database Syst Rev. 2020;11(11):CD013287
69. Reeder C, Smedley N, Butt K, et al. Cognitive predictors of social functioning improvements
following cognitive remediation for schizophrenia. Schizophr Bull. 2006;32 Suppl 1(Suppl 1):S123-
31
70. Ren J, Xia J. Dance therapy for schizophrenia. Cochrane Database Syst Rev.
2013;(10):CD006868
71. Russo G. Dismantling Asylums: The Italian Job. London Journal Primary Care, 2009
72. Saha S, Chant D, Welham J, et al. A systematic review of the prevalence of schizophrenia. PLoS
Med. 2005;2(5):e141.
73. Sampson S, Mansour M, Maayan N, et al. Intermittent drug techniques for schizophrenia.
74. Schöttle D, Schimmelmann BG, Ruppelt F, et al. Effectiveness of integrated care including
therapeutic assertive community treatment in severe schizophrenia-spectrum and bipolar I
disorders: Four-year follow-up of the ACCESS II study. PLoS One. 2018;13(2):e0192929
75. Scottish Intercollegiate Guidelines Network. Management of schizophrenia: A national clinical
guidelines. Edinburgh: SIGN; 2013.
40
76. Shabani A, Masoumian S, Zamirinejad S, et al. Psychometric properties of Structured Clinical
Interview for DSM-5 Disorders-Clinician Version (SCID-5-CV). Brain Behav. 2021;11(5):e01894
77. Shek E, Stein AT, Shansis FM, et al. Day hospital versus outpatient care for people with
schizophrenia. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003240
78. Shen X, Xia J, Adams CE. Acupuncture for Schizophrenia (Review). Cochrane Database for
Systematic Review, 2014
79. Sin J, Jordan CD, Barley EA, et al. Psychoeducation for siblings of people with severe mental
illness. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD010540
80. Sinclair DJM, Zhao S, Qi F, et al. Electroconvulsive Therapy for Treatment-Resistant
Schizophrenia (Review). Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.:
CD011847
81. Soares-Weiser K, Maayan N, Bergman H, et al. First rank symptoms for schizophrenia. Cochrane
Database Syst Rev. 2015 25;1:CD010653
82. Subramanian S, Völlm BA, Huband N. Clozapine dose for schizophrenia. Cochrane Database of
Syst Rev. 2017, Issue 6. Art. No.: CD009555
83. Takeuchi H, MacKenzie NE, Samaroo D, et al. Antipsychotic Dose in Acute Schizophrenia: A Meta-
analysis. Schizophr Bull. 2020;46(6):1439-1458
84. Tandon R, Bruijnzeel D, Rankupalli B. Does change in definition of psychotic symptoms in
diagnosis of schizophrenia in DSM-5 affect caseness? Asian J Psychiatr. 2013;6(4):330-332
85. Temmingh HS, Williams T, Siegfried N, et al. Risperidone versus other antipsychotics for people
with severe mental illness and co-occurring substance misuse (Review). Cochrane Database of
Systematic Reviews 2018, Issue 1. Art. No.: CD011057
86. Teoh SL, Chong HY, Abdul Aziz S, et al. The economic burden of schizophrenia in Malaysia.
Neuropsychiatr Dis Treat. 2017;13:1979-1987
87. The American Psychiatric Association. Practice guideline for the treatment of patients with
schizophrenia 3ed. Washington, DC: APA; 2021
88. Thornicroft G, Bebbington P. Deinstitutionalisation-from hospital closure to service development.
Br J Psychiatry. 1989;155:739-53
89. Thornicroft G. & Tansella M. Better Mental Health Care. Better Mental Health Care. 2008;1-184.
10.1017/CBO9780511544347
90. Tobacco (Available at https://www.who.int/news-room/fact-sheets/detail/tobacco)
91. Tungpunkom P, Maayan N, Soares-Weiser K. Life skills programmes for chronic mental illnesses.
Cochrane Database Syst Rev. 2012;1:CD000381
92. Vassos E, Pedersen CB, Murray RM, et al. Meta-analysis of the association of urbanicity with
schizophrenia. Schizophr Bull. 2012;38(6):1118-23
93. Vermeulen J, van Rooijen G, Doedens P, et al. Antipsychotic medication and long-term mortality
risk in patients with schizophrenia; a systematic review and meta-analysis. Psychol Med 2017; 47:
2217-28
94. Wang W, Pu C, Jiang J, et al. Efficacy and safety of treating patients with refractory schizophrenia
with antipsychotic medication and adjunctive electroconvulsive therapy: a systematic review and
meta-analysis.Shanghai Arch Psychiatry. 2015:25;27(4):206-19
95. West JC, Marcus SC, Wilk J, et al. Use of depot antipsychotic medications for medication
nonadherence in schizophrenia. Schizophr Bull. 2008;34(5):995-1001
96. Wimberley T, Gasse C, Meier SM, et al. Polygenic Risk Score for Schizophrenia and Treatment-
Resistant Schizophrenia. Schizophr Bull. 2017:1;43(5):1064-1069
97. Wykes T, Huddy V, Cellard C, et al. A meta-analysis of cognitive remediation for schizophrenia:
methodology and effect sizes. Am J Psychiatry. 2011;168(5):472-85
98. Yee A, Bt Nek Mohamed NN, Binti Hashim AH, et al. The effect of nicotine dependence on
psychopathology in patients with schizophrenia. Biomed Res Int. 2015;2015:730291
99. Zhao S, Sampson S, Xia J, et al. Psychoeducation (brief) for people with serious mental illness.
Cochrane Database of Systematic Reviews 2015, Issue 4. Art. No.: CD010823
100. Zhao YJ, Lin L, Teng M, et al. Long-term antipsychotic treatment in schizophrenia: systematic
review and network meta-analysis of randomised controlled trials. BJPsych Open. 2016;2(1):59-
66
101. Zheng W, Cao XL, Ungvari GS, et al. Electroconvulsive Therapy Added to Non-Clozapine
Antipsychotic Medication for Treatment Resistant Schizophrenia: Meta-Analysis of Randomized
Controlled Trials. PLoS One. 2016;11(6):e0156510
41
102. Zhu Y, Krause M, Huhn M, et al. Antipsychotic drugs for the acute treatment of patients with a first
episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet
Psychiatry. 2017;4(9):694-705
42
Appendix 1
EXAMPLE OF SEARCH STRATEGY
Clinical Question: Is intermittent treatment safe and effective compared with continuous
treatment for relapse prevention in schizophrenia?
1. SCHIZOPHRENIA/
2. (schizophrenic adj1 disorder*).tw.
3. schizophrenia*.tw.
4. 1 or 2 or 3
5. ANTIPSYCHOTIC AGENTS/
6. (antipsychotic adj1 (agent* or drug* or effect*)).tw.
7. (major tranquili* adj2 agent*).tw.
8. (neuroleptic adj1 (agent* or drug*)).tw.
9. (major adj1 tranquili*).tw.
10. antipsychotic*.tw.
11. neuroleptic*.tw.
12. 5 or 6 or 7 or 8 or 9 or 10 or 11
13. intermittent.tw.
14. continuous.tw.
15. 13 or 14
16. 12 and 15
17. 4 and 16
18. limit 17 to (english language and humans and yr="2009 -Current" and "all adult (19 plus
years)")
43
Appendix 2
CLINICAL QUESTIONS
1. What are the risk factors for schizophrenia?

2. What are the accurate screening tools for schizophrenia?
3. What are the cost-effective screening tools for schizophrenia?
4. Is early referral to psychiatric service more effective and safe compared with treatment
in primary care?
5. What are the accurate bio-psychosocial assessments in schizophrenia?
6. What are criteria of diagnostic classification of schizophrenia?
7. Is the current diagnostic classification sufficient for therapeutic and prognostic
management of schizophrenia?
8. Are the following service level interventions effective and safe in schizophrenia?
• crisis and emergency service
• intensive care management
• assertive outreach team
• early intervention service
• community mental health teams
• day hospitalisation/day care
• residential care
• integrating mental health to primary care
• services in primary care
9. Are the following pharmacological agents safe and effective in schizophrenia?
• single atypical antipsychotic (AP)
• single conventional AP
• combined AP
10. Is rapid escalation of AP/other agents safe and effective in acute exacerbation of
schizophrenia?
11. Is depot AP/AAP safe and effective in achieving remission in schizophrenia?
12. Is depot AP/AAP safe and effective in first episode in schizophrenia?
13. Are AAPs more effective and safe compared with conventional APs to prevent relapse
in schizophrenia?
14. Is early initiation of AP safe and effective for first episode or early schizophrenia?
15. Is intermittent treatment safe and effective compared with continuous treatment for
relapse prevention in schizophrenia?
16. What is the safe and effective treatment for extrapyramidal signs, sedation and weight
gain associated with AP?
17. What are the safe and effective physical therapies in schizophrenia?
18. Are the following psychosocial interventions safe and effective (improving function or
quality of life) in schizophrenia?
• family therapy
• psychoeducation
• problem solving skill
• counseling and psychotherapy
• Cognitive Behaviour Therapy
• Cognitive Remediation Therapy
• social skills training
• supported employment
• social enterprise
• physical exercise
• peer support services
• life skills training (social and academic)
44
• creative and expressive art therapy
• religion and spiritual
19. Is traditional and complementary medicine safe and effective in schizophrenia?
20. What is the predictor for treatment-resistant schizophrenia (TRS)?
21. What is the safe and effective AP in TRS?
22. Is augmentation of clozapine with other medication safe and effective in patients who do
not respond to clozapine monotherapy?
23. Does pregnancy increase the risk of psychosis development or relapse of
schizophrenia?
24. Is AP safe and effective in pregnancy, post-partum and breastfeeding in schizophrenia?
25. Is psychosocial treatment safe and effective in pregnancy, post-partum and
breastfeeding in schizophrenia?
26. What is the prevalence of substance-related disorder in schizophrenia?
27. Are the following safe and effective in schizophrenia with substance-related disorder
(dual diagnosis):
• dual diagnosis service vs usual care
• AP
• psychosocial treatment
28. What is the prevalence of suicide in schizophrenia?
29. What is the risk factor of suicide in schizophrenia?
30. What is the safe and effective suicide prevention strategy in schizophrenia?
31. What is the prevalence of stigma against schizophrenia?
32. What are the safe and effective strategies to combat stigma in schizophrenia?
33. What is the mental health literacy of schizophrenia among service users?
34. What are the common social problems in schizophrenia?
35. What are the safe and effective interventions for social problems in schizophrenia?
45
Appendix 3
DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA (DSM-5)
The following criteria, as outlined by the DSM-5, must be met in order for schizophrenia to be
accurately diagnosed:
1. The individual experiences two or more of the following for a significant portion of time
during a 1-month period. And at least one of these must be (1), (2), or (3):
• Delusions
• Hallucinations
• Disorganized speech (incoherence or derailment)
• Completely disorganized or catatonic behavior
• Negative symptoms, such as diminished emotional expression
2. For a significant amount of time since the disturbance began, level of functioning in one
or more major areas (e.g., work, interpersonal relations, or self-care) is clearly below the
level achieved prior to onset.
• In children or adolescents, there is a failure to achieve the expected level of
interpersonal, academic, or occupational functioning.
3. Signs of the disturbance continue for 6 months or longer. This period must include at least
1 full month of symptoms that meet the first criteria and may include periods of residual
symptoms. During these residual periods, the signs of the disturbance may be manifested
only by negative symptoms or by two or more symptoms outlined in the first criteria, only
in a lesser form.
4. The disturbance cannot be better explained by schizoaffective disorder, depressive or

bipolar disorder because either:
• No major depressive or manic episodes have occurred concurrently with the active-
phase symptoms or if mood episodes have occurred during active phase symptoms,
it’s been for a minor amount of time.
5. The disturbance cannot be attributed to the physiological effects of a substance (e.g., a

drug of abuse or medication) or another medical condition.
6. If the individual has a history of autism spectrum disorder or a communication disorder of

childhood onset, the additional diagnosis of schizophrenia is only made if delusions or
hallucinations as well as the other required symptoms of schizophrenia are present for a
month or more.
7. There are a few specifications that should be made when it comes to diagnosing
schizophrenia. This includes specifying the severity, if it is with catatonia, as well as
categorizing it episodically:
• First episode, currently in partial remission: Partial remission refers to a period of time
in which the individual has improved after a previous episode is maintained and the
criteria are only partially met.
• First episode, currently in full remission: Full remission refers to a period of time after
a previous episode during which no symptoms are present.
• Multiple episodes, currently in acute episode: Several episodes may be determined
after a minimum of two.
• Multiple episodes currently in partial remission
• Multiple episodes, currently in full remission
• Continuous: Symptoms of the disorder remain for the majority of the illness.
• Unspecified
46
Appendix 4
INTERNATIONAL STATISTICAL CLASSIFICATION OF DISEASES AND

RELATED HEALTH PROBLEMS, 10TH REVISION (ICD 10)
Schizophrenia is coded under F20.

General criteria for Paranoid, Hebephrenic, Catatonic and Undifferentiated type of
Schizophrenia:
G1. Either at least one of the syndromes, symptoms and signs listed below under (1), or at
least two of the symptoms and signs listed under (2), should be present for most of the
time during an episode of psychotic illness lasting for at least one month (or at some time
during most of the days).
1. At least one of the following:
a. Thought echo, thought insertion or withdrawal, or thought broadcasting.
b. Delusions of control, influence or passivity, clearly referred to body or limb
movements or specific thoughts, actions, or sensations, delusional perception.
c. Hallucinatory voices giving a running commentary on the patient's behaviour, or
discussing him between themselves, or other types of hallucinatory voices coming
from some part of the body.
d. Persistent delusions of other kinds that are culturally inappropriate and completely
impossible (e.g. being able to control the weather or being in communication with
aliens from another world).
2. or at least two of the following:
e. Persistent hallucinations in any modality, when occurring every day for at least one
month, when accompanied by delusions (which may be fleeting or half-formed)
without clear affective content, or when accompanied by persistent over-valued
ideas.
f. Neologisms, breaks or interpolations in the train of thought, resulting in incoherence
or irrelevant speech.
g. Catatonic behaviour, such as excitement, posturing or waxy flexibility, negativism,
mutism and stupor.
h. "Negative" symptoms such as marked apathy, paucity of speech, and blunting or
incongruity of emotional responses (it must be clear that these are not due to
depression or to neuroleptic medication).
G2. Most commonly used exclusion criteria: If the patient also meets criteria for manic episode
(F30) or depressive episode (F32), the criteria listed under G1.1 and G1.2 above must
have been met before the disturbance of mood developed.
G3. The disorder is not attributable to organic brain disease (in the sense of F0), or to alcohol-
or drug-related intoxication, dependence or withdrawal.
Pattern of course
F20.x0 Continuous (no remission of psychotic symptoms throughout the period of
observation).
F20.x1 Episodic, with a progressive development of 'negative' symptoms in the intervals
between psychotic episodes;
F20.x2 Episodic, with persistent but non-progressive 'negative' symptoms in the intervals
between psychotic episodes;
F20.x3 Episodic (remittent) with complete or virtually complete remissions between psychotic
episodes;
F20.x4 Incomplete remission;
F20.x5 Complete or virtually complete remission;
F20.x8 Other pattern of course.
F20.x9 Course uncertain, period of observation too short.
47
Appendix 5
DOSING REGIMEN FOR DEPOT INJECTIONS OF ANTIPSYCHOTIC

Daily starting Minimum Pregnancy
Maximum daily Regimen Chlorpromazine Lactation
Antipsychotics dose Titration (mg) effective dose safety
dose (mg/day) frequency equivalent dose riskb
(mg/day) (mg/day) categorya
First-generation APs
100 mg/day
Chlorpromazine 50 - 100 50 - 200/day 200 1000 TDS C L3
(reference)
2 - 5 every
Haloperidol 2-5 2 20 OD/BD 2 mg/day C L2
1 - 7 days
24 (64 mg -
Perphenazine 4-8 4- 8/day 16 hospitalized TDS 10 mg/day C NA
patients)
200 every NA
Sulpiride 200 - 400 400 2400 BD 200 mg day NA
3 - 7 days
5 every C
Trifluoperazine 5 - 10 10 30 BD 5 mg/day NA
3 - 7 days
Second-generation APs
50 - 100 every
Amisulpride 50 300 1200 BD 400 mg/day NA NA
2 - 3 days
Aripiprazole 10 - 15 after L3
10 - 15 10 30 OD 15 mg/day C
2 weeks
Asenapine 5 - 10 after NA
10 10 20 BD 10 mg/day C
1 week
Clozapine Refer to
12.5 Appendix 3 300 - 900 900 OD/BD - B L3
and 4
Olanzapine 5/day for every
5 - 10 5 20 OD 10 mg/day C L2
1 week
Paliperidone 3 3 every 5 days 6 - 12 12 OD - C NA
Quetiapine IR: Refer to
IR: 50 footnote c IR: 300 - 450 IR: 750 IR: BD
400 mg/day C L4
ER: 300 ER: Refer to ER: 600 - 800 ER: 800 ER: OD
footnote d
Risperidone 1 every
1-2 2-4 16 OD/BD 4 mg/day C L3
2 - 3 days
48
Daily starting Minimum Pregnancy
Maximum daily Regimen Chlorpromazine Lactation
Antipsychotics dose Titration (mg) effective dose safety
dose (mg/day) frequency equivalent dose riskb
(mg/day) (mg/day) categorya
Sertindole 4 every -
4 12 24 OD NA NA
4 - 5 days
Ziprasidone 20 every
40 - 80 40 160 BD 80 mg/day C L4
2 - 3 days
IR: immediate release, ER: extended release, OD: once daily, BD: twice daily, TDS: thrice daily, NA: not available
aUnited States Food & Drug Administration (US FDA) categorisation of risk of drug use in pregnancy:
A=Controlled studies fail to demonstrate a risk to the foetus in the first trimester, and the possibility of foetal harm remains remote
B=Either animal-reproduction studies have not demonstrated a foetal risk but there is no controlled in human
C=Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in human
D=There is positive evidence of human foetal risk
X=Studies in animals or human beings have demonstrated foetal abnormalities
bAmerican College of Obstetricians and Gynecologists lactation risk categories: L1=Safest; L2=Safer; L3=Moderately safe; L4=Possibly hazardous;
L5=Contraindicated
cQuetiapine IR tablet: Day 1- 25 mg BD, Day 2- 50 mg BD, Day 3- 100 mg BD, Day 4- 150 mg BD. Then adjusted according to response.
dQuestiapine ER tablet: Day 1- 300 mg OD, Day 2- 600 mg OD. Then adjusted according to response.
Source:
1. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (14 th Edition). London: Wiley Blackwell; 2021
2. British National Formulary (BNF) 80. London: BMJ Group and Pharmaceutical Press; 2021
3. Monthly Index of Medical Specialities - MIMS Malaysia Online (Available at http://www.mims.com/malaysia)
4. ACOG Practice Bulletin. Clinical Practice Guidelines for Obstetrician-Gynaecologist - Use of Psychiatric Medications During Pregnancy and Lactation
49
Appendix 6
DOSING REGIMEN FOR DEPOT INJECTIONS OF ANTIPSYCHOTIC

Interval Pregnancy
Dose range Chlorpromazine Lactation
Antipsychotics Starting dose Titration (mg) Maximum dose between safety
(per injection) equivalent dose riskb
injections category a
300 mgc - 400 300 - 400 mg
Aripiprazole Not required 400 mg/month 4 weeks 400 mg/month C L3
mgd every month
Test dose 20
mg, then 20 -
40 mg after at
20 mg 50 mg every
least 7 days,
Flupenthixol (elderly - 4 weeks to
then 20 - 40 mg 400 mg/week 2 - 4 weeks 10 mg/week C NA
decanoate quarter to half 300 mg every
every 2 - 4
adult dose) 2 weeks
weeks, adjusted
according to
response
Test dose 12.5
mg, then 12.5 -
100 mg after 4 -
12.5 mg 7 days, then
Fluphenazine 14 - 35
(elderly - 6.25 12.5 - 100 mg 12.5 - 100 mg 100 mg/2 weeks 5 mg/week NA L3
decanoate days
mg) every 14 - 35
days, adjusted
according to
response
25 - 150
Paliperidone 150 mge Refer to every 1 month or 150 mg/month 1-3
100 mg/month NA NA
palmitate 175 mgf footnote d and e 175 - 525 every 525/3 months months
3 months
Test dose 100
100 mg mg, then 200 –
200 - 500 mg
Zuclopenthixol (elderly - 500 mg after at
every 1 to 600 mg/week 1 - 4 weeks 100 mg/week NA NA
decanoate quarter to half least 7 days,
4 weeks
adult dose) then 200 – 500
mg every 1 – 4
50
Interval Pregnancy
Dose range Chlorpromazine Lactation
Antipsychotics Starting dose Titration (mg) Maximum dose between safety
(per injection) equivalent dose riskb
injections category a
weeks, adjusted
according to
response
NA: Not available
aUnited States Food & Drug Administration (US FDA) categorisation of risk of drug use in pregnancy:
A=Controlled studies fail to demonstrate a risk to the foetus in the first trimester, and the possibility of foetal harm remains remote
B=Either animal-reproduction studies have not demonstrated a foetal risk but there is no controlled in human
C=Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in human
D=There is positive evidence of human foetal risk
X=Studies in animals or human beings have demonstrated foetal abnormalities
bAmerican College of Obstetricians and Gynecologists lactation risk categories: L1=Safest; L2=Safer; L3=Moderately safe; L4=Possibly hazardous;
L5=Contraindicated
cCPD2D6 poor metabolisers
dStarting dose can be administered following either one regimen (Abilify Maintena ®):
1) One injection start: Administer 1 injection 400 mg and continue treatment with 10 mg to 20 mg oral aripiprazole/day for 14 consecutive days to maintain
therapeutic aripiprazole concentrations during initiation of therapy
2) Two injection start: Administer two separate injections at separate injection sites, along with one 20 mg dose of oral aripiprazole. After the injection start, the
recommended dose range (300 - 400 mg) should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).
eMaintenance in patients previously responsive to paliperidone or risperidone (Xeplion®): 150 mg for 1 dose on day 1, then 100 mg for 1 dose on day 8. The
third dose subsequently adjusted at monthly intervals according to response.

fMaintenance in patients who are clinically stable on once-monthly IM paliperidone (Trivecta®): Initially 175 - 525 every 3 months using 3.5-fold higher dose of
the last once-monthly dose, adjusted according to response
Source:
4. British National Formulary (BNF) 80. London: BMJ Group and Pharmaceutical Press; 2021
5. Monthly Index of Medical Specialities - MIMS Malaysia Online (Available at http://www.mims.com/malaysia)
6. ACOG Practice Bulletin. Clinical Practice Guidelines for Obstetrician-Gynaecologist - Use of Psychiatric Medications During Pregnancy and Lactation
51
Appendix 7
CLOZAPINE INITIATION AND TITRATION REGIMEN FOR IN-PATIENT

Day Morning dose (mg) Evening dose (mg)
1 - 12.5
2 12.5 12.5
3 25 25
4 25 25
5 25 25
6 25 50
7 50 50
8 50 75
9 75 75
10 75 100
11 100 100
12 100 125
13 125 125a
14 125 150
15 150 150
18 150 200b
21 200 200
28 200 250c
Target dose for: a. female non-smokers (250 mg/day) b. male non-smokers (350 mg/day) c.
female smokers (450 mg/day)
Treatment breaks and blood monitoring:
1. If clozapine is omitted >48 hours, restart at 12.5 mg once or twice a day, gradually increased to
avoid the risk of serious AEs (e.g. hypotension, tachycardia, raised temperature). Continue with the
established monitoring frequency.
2. If clozapine is omitted >7 days, patient must have weekly blood test for 18 weeks following restarting
therapy.
3. Patients who have been on clozapine for >18 weeks and have had their treatment interrupted for >3
days, but <4 weeks, should have their blood monitored weekly for an additional 6 weeks. If no
haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed.
4. If clozapine treatment has been interrupted for ≥28 days, weekly monitoring is required for the next
18 weeks of treatment.
Discontinuation of treatment and blood monitoring:
1. If a patient discontinue treatment, blood monitoring is required at their current monitoring frequency
for a period of 4 weeks after stopping.
2. If clozapine is to be stopped for non-haematological reasons or is a planned discontinuation, then a
gradual reduction in dose over a 1 to 2-week period is recommended.
Source:
1. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (14 th
Edition). London: Wiley Blackwell; 2021
2. Northamptonshire Healthcare NHS. Foundation Trust. Clozapine Treatment Operational
Procedures; Oct 2017
52
SUGGESTED TITRATION REGIMEN FOR CLOZAPINE INITIATION IN THE COMMUNITY
Percentage dose
Day of the Morning Evening
Day Monitoring of previous
week dose (mg) dose (mg)
antipsychotics
1 Monday 6.25 6.25 A 100
2 Tuesday 6.25 6.25 A
3 Wednesday 6.25 6.25 A
4 Thursday A, B, full blood count
6.25 12.5
(FBC)
5 Friday A
Check results from day
4. Remind patient of
12.5 12.5
out-of-hours
arrangements for
weekend
6 Saturday No routine monitoring
12.5 12.5 unless clinically
indicated
7 Sunday No routine monitoring
12.5 12.5 unless clinically
indicated
8 Monday 12.5 25 A 75*
9 Tuesday 12.5 25 A
10 Wednesday 25 25 A
11 Thursday 25 37.5 A, B, FBC
12 Friday A
Check results from day
4. Remind patient of
25 37.5
out-of-hours
arrangements for
weekend
25 37.5 unless clinically
indicated
25 37.5 unless clinically
indicated
15 Monday 37.5 37.5 A 50*
16 Tuesday Not seen unless
37.5 37.5
problems
17 Wednesday 37.5 50 A
18 Thursday Not seen unless
37.5 50
problems
19 Friday 50 50 A, B, FBC
50 50 unless clinically
indicated
indicated
22 Monday 50 75 A 25*
23 Tuesday Not seen unless
50 75
problems
24 Wednesday 75 75 A
25 Thursday Not seen unless
75 75
problems
26 Friday 75 100 A, B, FBC
53
Percentage dose
Day of the Morning Evening
Day Monitoring of previous
week dose (mg) dose (mg)
antipsychotics
indicated
indicated
Note that much faster titrations can be undertaken in many patients where tolerability allows.
Further increments should be 25 - 50 mg/day (generally 25 mg/day) until target dose is reached.
A. Pulse, postural blood pressure, temperature should be taken before the dose and, ideally, between
30 minutes and 6 hours after the dose. Enquire about AEs.
B. Mental state, weight, review and actively manage AEs (e.g. behavioural advice, slow clozapine
titration or reduce dose of other AP, start adjunctive treatments). Consider troponin, C-Reactive Protein,
beta-natriuretic peptide.
*May need to be adjusted depending on AEs and mental state.
Source: Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (14 th
54
Appendix 8
MONITORING PARAMETERS FOR ANTIPSYCHOTICS
Parameter/Test Suggeste Action if results Drugs with Drugs for

d outside reference special which
frequenc range precautions monitoring
y is not
required
Urea and Baseline Investigate all Amisulpride and None
electrolytes and yearly abnormalities sulpirde renally
including as part of detected excreted -
creatinine or a routine consider reducing
estimated physical dose if eGFR
glomerular health reduced
filtration rate check
(GFR)]
Full blood count Baseline Stop suspect Clozapine - FBC None
and yearly medication if weekly for 18
as part of neutrophils weeks, then 2-
a routine <1.5x109/L weekly up to one
physical Refer to specialist year, then
health medical care if monthly
check and neutrophils
to detect <0.5x109/L
chronic Note high frequency
bone of benign ethnic
marrow neutropenia in
suppressi certain ethnic groups
on (small
risk
associate
d with
some
APs)
Blood lipids Baseline, Offer lifestyle advice Clozapine, Some APs
(cholesterol, three Consider changing olanzapine - 3- (e.g.
triglycerides) - months, AP and/or initiating monthly for first aripiprazole)
fasting sample if then statin therapy year, then yearly not clearly
possible yearly to associated
detect AP- with
induced dyslipidaemi
changes a, but
and prevalence
generally is high in
monitor this patient
physical group, so all
health patients
should be
monitored
Weight (include Baseline, Offer lifestyle advice Clozapine, Aripiprazole,
waist size and frequently Consider changing olanzapine - ziprasidone
BMI, if possible) for three AP and/or frequently for not clearly
months three months associated
55
y is not
required
then dietary/pharmacologi then 3-monthly with weight
yearly to cal intervention for first year, then gain but
detect AP- yearly monitoring
induced required
changes nonetheless
and - obesity
generally prevalence
monitor is high in
physical this patient
health group
Plasma glucose - Baseline, Offer lifestyle advice Clozapine, Some APs
fasting sample if at 4 - 6 Obtain fasting olanzapine, not clearly
possible months, sample or non- chlorpromazine - associated
then fasting HbA1c test at baseline, with
yearly to Refer to one month, then impaired
detect AP- endocrinologist 4 - 6 monthly fasting
induced glycemia,
changes but
and prevalence
generally is high in
monitor this patient
physical group, so all
health patients
should be
monitored
Electrocardiogram Baseline Discuss with/refer to Haloperidol, Risk of
me (ECG) and when cardiologist if sertindole - ECG sudden
target abnormality detected mandatory cardiac
dose is Ziprasidone - death
reached ECG mandatory increased
(ECG in some with most
changes situations APs
are rare in Ideally all
practice) patients
on should be
admission offered an
to hospital ECG at
and least yearly
before
discharge
if
medicatio
n regimen
changed
Blood pressure Baseline, If severe Clozapine, Amisulpride,
frequently hypotension or chlorpromazine aripiprazole,
during hypertension and quetiapine sulpride
dose (clozapine) most likely to be
titration associated with
56
y is not
required
and dose observed, slow rate postural
changes of titration hypotension
to detect Consider switching
AP- to another AP if
induced symptomatic
changes postural hypotension
and Treat hypertension
generally in line with Malaysia
monitor CPG on
physical Management of
health Hypertension (5th
Edition).
Prolactin Baseline, Switch drugs if Amisulpride, Asenapine,
then at six hyperprolactinaemia sulpride, aripirazole,
months, confirmed and risperidone and clozapine,
then symptomatic paliperidone quetiapine,
yearly to Consider tests of particularly olazapine
detect AP- bone mineral density associated with (<20 mg),
induced for those with hyperprolactinae ziprasidone
changes chronically raised mia usually does
prolactin not elevate
prolactin,
but worth
measuring if
symptoms
arise
Liver function tests Baseline, Stop suspect Clozapine and Amisulpride,
(LFT) then medication if LFT chlorpromazine sulpride
yearly as indicate hepatitis associated with
part of a (transaminases x3 hepatic failure
routine normal) or functional
physical damage
health (prothrombin
check and time/albumin
to detect change)
chronic
AP-
induced
changes
(rare)
Creatinine Baseline, In the psychiatric NMS more likely None
phosphokinase then if unit: with FGAs
NMS Stop suspect
suspected medication, monitor
temperature, pulse,
blood pressure
Consider
benzodiazepines if
not already
57
y is not
required
prescribed - IM
lorazepam
In the
medical/emergency
unit:
Rehydration,
bromocriptine +
dantrolene, sedation
with
benzodiazepines,
artificial ventilation if
required
Source: Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry (14 th
58
Appendix 9
CONSENSUS CRITERIA FOR ASSESSMENT AND DEFINITION OF

TREATMENT-RESISTANT SCHIZOPHRENIA
Domain and Minimum Requirement Optimum Requirement

Subdomain
Current symptoms
Assessment Interview using standardised Prospective evaluation of
rating scale (e.g., PANSS, treatment using a standardised
BPRS, SANS, SAPS) rating scale
Severity At least moderate severity At least moderate severity and
<20% symptom reduction during
a prospective trial or observation
of 6 weeks
Duration 12 weeks 12 weeks; specify duration of
treatment resistance
Subjective distress Not required Not required
Functioning At least moderate functional Same as for minimum criteria
impairment measured using a
validated scale (e.g., SOFAS)
Adequate treatment
Assessment of past Information to be gathered Same as for minimum criteria
response from patient/carer’s report,
staff and case notes, pill
counts and dispensing charts
Duration 6 weeks at a therapeutic Same as for minimum criteria
dosage; record minimum and
mean (SD) duration for each
treatment episode
Dosage Equivalent to >600 mg of Same as for minimum criteria
chlorpromazine per day
Number of APs 2 past adequate treatment 2 past treatment episodes with
episodes with different AP different AP and at least one
Specify median number of utilising a LAI AP (for at least
failed antipsychotic trials four months)
Specify median number of failed
AP trials
Current adherence 80% of prescribed doses Same as the minimum criteria,
taken; adherence should be with addition of trough AP serum
assessed using at least two levels measured on at least two
sources (pill counts,occasions separated by at least
dispensing chart reviews and two weeks (without prior
patient/carer’s report) notification to patient)
AP plasma levels monitored
on at least one occasion
Specify methods used to
establish adherence
Symptom domain Positive, negative, cognitive Same as for minimum criteria
Time course Early onset (within one year of Same as for minimum criteria
treatment onset), medium-
term onset (1 - 5 years after
treatment onset), late onset
59
Domain and Minimum Requirement Optimum Requirement
Subdomain
(>5 years after treatment
onset)
Ultra-treatment Meets the above criteria for Same as for minimum criteria
resistant: clozapine treatment resistance plus
failure to respond to adequate
clozapine treatment
Adapted: Howes OD, McCutcheon R, Agid O, et al. Treatment-Resistant Schizophrenia: Treatment
Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on
Diagnosis and Terminology. Am J Psychiatry. 2017;174(3):216-229
60
LIST OF ABBREVIATIONS
AAP(s) atypical antipsychotic(s)

ACT assertive community treatment
AE(s) adverse event(s)
AGREE II Appraisal of Guidelines for Research and Evaluation II
AP(s) antipsychotic(s)
APA American Psychiatric Association
AUC area under the curve
BPRS Brief Psychiatric Rating Scales
B-CATS Brief Cognitive Assessment Tool for Schizophrenia
CM case management
CBT cognitive behaviour therapy
CBT-p cognitive behaviour therapy for psychosis
CGI-S Clinical Global Impression Scale
CI confidence interval
CDSS Calgary Depression Rating Scale for Schizophrenia
CMHC community mental health centre
CPG clinical practice guidelines
CPZ chlorpromazine
CQ clinical questions
CrI credible interval
CT-R Recovery-Oriented Cognitive Therapy
CRT cognitive remediation therapy
DG development group
DSM-5 Diagnostic and Statistical Manual of Mental Disorders 5th
Edition
DUP duration of untreated psychosis
ECT electroconvulsive therapy
EPS extrapyramidal side effects
EWS early warning signs
FGA(s) first-generation antipsyhotic(s)
FSP full service partnerships
g gramme
GAF Global Assessment of Functioning
GRADE Grading Recommendations, Assessment, Development
and Evaluation
GHQ General Health Questionnaires
HAMD Hamilton Depression Rating Scale
HTA Health Technology Assessment
HR(s) hazard ratio(s)
ICD International Statistical Classification of Diseases and
Related Health Problems
ICM intensive case management
IM intramuscular
IQR interquartile range
IV intravenous
kg kilogramme
LAI long-acting injection
LBW low birth weight
MD mean difference
mg Milligram
MINI Mini International Neuropsychiatric Interview
61
ml millilitre
MoH Ministry of Health
ms millisecond
MSE mental state examination
ng nanogramme
NICE National Institute for Health and Care Excellence
NMS neuroleptic malignant syndrome
NNT(B) number needed to treat (to benefit)
NNTH number needed to treat to harm
NSA-4 4-item Negative Symptom Assessment
OR odds ratio
PANSS Positive and Negative Symptoms Scale for Schizophrenia
PPC pre-pregnancy care
PSP Personal and Social Performance
PQ-B Prodromal Questionnaire - Brief Version
QLS Quality of Life Scale
Q-LES-Q Quality of Life Enjoyment and Satisfaction Questionnaire
QoL quality of life
RCT(s) randomised controlled trial(s)
RC review committee
RR relative risk
SCID Structured Clinical Interview for DSM Disorders
SCID-5-CV Structured Clinical Interview for DSM-5 Disorders-
Clinician Version
SCL-90-R Symptom-Checklist-90-Revised
SEI specialised early intervention
SGA(s) second-generation antipsychotic(s)
SMD standardised mean difference
SPro Self-screen-Prodrome
SST social skills training
SUD substance use disorder
SQ Screening Questionnaire
TAU treatment as usual
tDCS transcranial direct current stimulation
TESS Treatment Emergent Side Effect Scale
TMS transcranial magnetic stimulation
TRRIP Treatment Response and Resistance in Psychosis
TRS treatment-resistant schizophrenia
USD United States Dollar
vs versus
62
ACKNOWLEDGEMENT
The CPG DG members would like to express their gratitude and appreciation to the following
for their contributions:
• Panel of external reviewers who reviewed the draft
• Technical Advisory Committee of CPG for their valuable input and feedback
• Health Technology Assessment and Clinical Practice Guidelines Council for approving the
CPG
• Dr Junainah Sabirin, Consultant Public Health Physician on the development of the CPG
• Ms. Rosnani Latip, Ms. Zamilah Mat Jusoh and Ms. Subhiyah Ariffin on retrieval of evidence
• All those who have contributed directly or indirectly to the development of the CPG
DISCLOSURE STATEMENT
The panel members of both DG and RC had completed disclosure forms. None held shares
in pharmaceutical firms or acts 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 Schizophrenia (Second Edition) was

supported financially in its entirety by the MoH Malaysia.
63

CPG 2021 Management of Schizophrenia (Second Edition) For Reviewers

Uploaded by

Copyright:

Available Formats

CPG 2021 Management of Schizophrenia (Second Edition) For Reviewers

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CPG 2021 Management of Schizophrenia (Second Edition) For Reviewers

Uploaded by

Copyright:

Available Formats

CLINICAL PRACTICE GUIDELINES

Ministry of Health Malaysian Psychiatric Academy of Medicine

Available on the following websites:

Also available as an app for Android and IOS platform: MyMaHTAS

UPDATING THE CPG

2. EARLY DETECTION AND REFERRAL 2

3. ASSESSMENT AND DIAGNOSIS 3

5. SERVICE LEVEL INTERVENTION 23

6. TRADITIONAL AND COMPLEMENTARY MEDICINE 27

8. IMPLEMENTING THE GUIDELINES 36

Level Study design

I Evidence from at least one properly randomised controlled trial

II-1 Evidence obtained from well-designed controlled trials without randomisation

II-2 Evidence obtained from well-designed cohort or case-control analytic studies,

III Opinions of respected authorities based on clinical experience; descriptive

SOURCE: US / CANADIAN PREVENTIVE SERVICES TASK FORCE 2001

ASSESSMENT AND DIAGNOSIS

• People with possible schizophrenia should be assessed thoroughly by history taking,

• Antipsychotics (APs) should be considered in the treatment of schizophrenia.

• Psychoeducation which includes early warning signs interventions should be given in

• Crisis intervention services should be offered in schizophrenia with acute psychiatric

• Clozapine should be offered in treatment-resistant schizophrenia.

References were also made to other CPGs on schizophrenia e.g.:

The objectives of the CPG are to provide recommendations on the management of

Primary, secondary and tertiary care settings

Members (in alphabetical order)

Dr. Ahmad Zabidin Zakaria Dr. Parveen Thanabalen

Dr. Hilwa Abdullah @ Mohd. Nor Dr. Ranimah Yahya

Dr. Izyan A. Wahab Associate Prof. Dr, Salina Mohamed

Ms. Norhameza Ahmad Badruddin

Members (in alphabetical order)

Datin Dr. Ang Kim Teng Ms. Noor Ratna Naharuddin

Ms. Anita Abu Bakar Dr. Noraini Darus

Dr. Baizury Bashah Dr. Norhayati Nordin

Dr. Izzuna Mudla Mohamed Ghazali Mr. Zulhan Ambi

The following external reviewers provided feedback on the draft:

Acute phase/exacerbation Stable phase/relapse prevention *Cases to be referred

Initial Phase Follow-Up Phase

PR/SE: Poor response or Yes

The holistic management of schizophrenia encompasses biological-psychosocial-spiritual

2. EARLY DETECTION AND REFERRAL

The risk factors of schizophrenia include:

• More evidence is warranted before screening tools for pre-psychosis in schizophrenia

*Refer to Subchapter 2.1

*Refer to the preceding yellow box

3. ASSESSMENT AND DIAGNOSIS

Bio-psychosocial assessment is essential in the diagnosis of schizophrenia. Established tools

In two cross-sectional studies, Structured Clinical Interview for DSM-5 Disorders-Clinician

Assessment of people with possible schizophrenia consists of thorough history taking,

Table 1. Initial Psychiatric Assessment

To date, there is no evidence found on biological assessment for schizophrenia.

3.2 Criteria of Diagnostic Classifications

• Disease severity is assessed based on presenting psychopathology and risk

The modalities of treatment in schizophrenia are:

• Current available guidelines for mental health services in primary care:

4.1 Pharmacological Intervention

4.1.1 Pharmacological agents

A network meta-analysis on schizophrenia showed that APs reduced overall symptoms

In a Cochrane systematic review, AP combination may improve clinical response compared