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## Complete Summary

#### GUIDELINE TITLE

Schizophrenia.

#### BIBLIOGRAPHIC SOURCE(S)

Singapore Ministry of Health. Schizophrenia. Singapore: Singapore
Ministry of Health; 2003 Feb. 40 p. \[29 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [December 12, 2007,
    Carbamazepine](http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine):
    The U.S. Food and Drug Administration (FDA) has provided
    recommendations for screening that should be performed on specific
    patient populations before starting treatment with carbamazepine.

-   [September 17, 2007, Haloperidol
    (Haldol)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Haloperidol):
    Johnson and Johnson and the U.S. Food and Drug Administration (FDA)
    informed healthcare professionals that the WARNINGS section of the
    prescribing information for haloperidol has been revised to include
    a new Cardiovascular subsection.

-   [May 2, 2007, Antidepressant
    drugs](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Antidepressant):
    Update to the existing black box warning on the prescribing
    information on all antidepressant medications to include warnings
    about the increased risks of suicidal thinking and behavior in young
    adults ages 18 to 24 years old during the first one to two months of
    treatment.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Schizophrenia

#### GUIDELINE CATEGORY

Evaluation\
Management\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Psychiatry\
Psychology

#### INTENDED USERS

Allied Health Personnel\
Physicians\
Psychologists/Non-physician Behavioral Health Clinicians\
Social Workers

#### GUIDELINE OBJECTIVE(S)

-   To provide guidance to doctors on the many treatment options
    available for schizophrenia, based on the best available evidence
    from the medical literature

-   To provide patients with schizophrenia with the best possible care
    and outcome

-   To assist primary health care physicians in clinical decision-making

#### TARGET POPULATION

Adults with schizophrenia in Singapore

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis and Assessment**

1.  Assessment of patient for symptoms of schizophrenia, co-morbid
    psychiatric illness, co-morbid medical condition, or substance abuse

2.  Evaluation of patient\'s social supports, functioning, and relative
    risk of self-harm or harm to others

**Treatment**

1.  Pharmacotherapy

    -   First-line antipsychotic medications (trifluoperazine,
        chlorpromazine, thioridazine, haloperidol, sulpiride)

    -   Second-line antipsychotic medications (clozapine, risperidone,
        olanzapine, quetiapine, amisulpride)

    -   Depot antipsychotic medications

    -   Maintenance and discontinuation of antipsychotics

    -   Adjunctive medications, including anticholinergic agents,
        benzodiazepines, mood stabilizers (e.g., lithium, carbamazepine,
        valproate), and antidepressants

    -   Monitoring of response to medications and adjustments as
        necessary

2.  Electroconvulsive therapy (ECT)

3.  Psychosocial interventions

    -   Individual and group psychological therapy

    -   Psychoeducation/family intervention

    -   Social skills training

    -   Vocational training

4.  Referral to psychiatrist

#### MAJOR OUTCOMES CONSIDERED

-   Effectiveness and safety of medications

-   Side effects, adverse effects, and costs of treatment

-   Rates of relapse, coping skills, social and vocational functioning,
    and ability to function independently

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Levels of Evidence**

**Level Ia**: Evidence obtained from meta-analysis of randomised
controlled trials.

**Level Ib**: Evidence obtained from at least one randomised controlled
trial.

**Level IIa**: Evidence obtained from at least one well-designed
controlled study without randomisation.

**Level IIb**: Evidence obtained from at least one other type of
well-designed quasi-experimental study.

**Level III**: Evidence obtained from well-designed non-experimental
descriptive studies, such as comparative studies, correlation studies,
and case studies.

**Level IV**: Evidence obtained from expert committee reports or
opinions and/or clinical experiences of respected authorities.

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Grades of Recommendations**

**Grade A** (evidence levels Ia, Ib): Requires at least one randomised
controlled trial as part of the body of literature of overall good
quality and consistency addressing the specific recommendation.

**Grade B** (evidence levels IIa, IIb, III): Requires availability of
well conducted clinical studies but no randomised clinical trials on the
topic of recommendation.

**Grade C** (evidence level IV): Requires evidence obtained from expert
committee reports or opinions and/or clinical experiences of respected
authorities. Indicates absence of directly applicable clinical studies
of good quality.

**Good Practice Points**: Recommended best practice based on the
clinical experience of the guideline development group.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Not stated

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not applicable

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The recommendations that follow are those from the guideline\'s
executive summary; detailed recommendations can be found in the original
guideline document. Each recommendation is rated based on the level of
the evidence and the grades of recommendation. Definitions of the grades
of the recommendations (A, B, C, Good Practice Points) and level of the
evidence (Level I-Level IV) are presented at the end of the Major
Recommendations field.

**A** - Antipsychotic medications are the first-line treatment for
psychotic symptoms. (**Grade A, Level Ia**)

**A** - Clozapine is not used as a first-line antipsychotic because of
the risk of agranulocytosis. Its use is to be considered only after
other antipsychotic medications prove inadequate; it can only be
prescribed by a registered psychiatrist, and regular blood monitoring is
mandatory. (**Grade A, Level Ia**)

**A** - Most patients respond to a daily antipsychotic dose of 300 to
1,000 chlorpromazine (CPZ) equivalents administered for a minimum of 6
weeks (Dixon, Lehman, & Levine, 1995). Patients with a first episode
respond to lower doses than patients with recurrent episodes (McGorry,
1999; Remington, Kapur, & Zipursky, 1998; McEvoy, Hogarty, & Steingard,
1991). (**Grade A, Level Ia**)

**GPP** - Local Asian patients may respond to a lower daily
antipsychotic dose. (**GPP**)

**A** - Maintenance dose is generally lower than that used in acute
treatment, and the patient should continue with the lowest effective
dose of antipsychotic medication. Dosages in excess of 600 CPZ
equivalents/day should be avoided unless there are good clinical reasons
(e.g., symptom control) for a higher dose (Dixon, Lehman & Levine,
1995). (**Grade A, Level Ia**)

**B** - Patients who have not responded to recommended antipsychotic
medications should be considered for electroconvulsive therapy (ECT).
(**Grade B, Level III**)

**C** - The prophylactic use of anticholinergic agents should be
determined on a case-by-case basis, taking into account risk factors for
both extrapyramidal side effects (EPSE) and anticholinergic side effects
as well as the propensity of the antipsychotic medication to cause
extrapyramidal side effects. (**Grade C, Level IV**)

**B** - Patients who experience persistent and clinically significant
symptoms of anxiety and those with disruptive, dangerous, or assaultive
behaviour should receive a trial of adjunctive benzodiazepines (Johns &
Thompson, 1995). (**Grade B, Level III**)

**B** - Antidepressants should be considered for persistent depressive
symptoms and should be prescribed with an antipsychotic to prevent
worsening of psychosis (Black & Andresean, 1999). (**Grade B, Level
IIb**)

**B** - Supportive individual and group psychotherapy in combination
with medications can reduce relapses and enhance occupational and
vocational functioning (Scott & Dixon, 1995). (**Grade B, Level IIb**)

**A** - Cognitive Behavioural Therapy is beneficial in reducing the
symptoms (especially the positive symptoms) of schizophrenia (Garety,
Fowler, & Kuipers, 2000). (**Grade A, Level Ia**)

**A** - Psychoeducation and family intervention can help reduce relapse
rates. (**Grade A, Level Ib**)

**A** - Social skills training improves social adjustment and coping
skills, thereby reducing relapse rates (Benton & Schroeder, 1990;
Corrigan, 1991). (**Grade A, Level Ib**)

**A** - Vocational training is likely to benefit those who a) see
competitive employment as a personal goal, b) have a history of prior
competitive employment, c) have a minimal history of psychiatric
hospitalization, and d) have been assessed to have good work skills
(Lehman, 1995). (**Grade A, Level Ib**)

**Definitions**:

**Grades of Recommendations**

**Grade A** (evidence levels Ia, Ib): Requires at least one randomised
controlled trial as part of the body of literature of overall good
quality and consistency addressing the specific recommendation.

**Grade B** (evidence levels IIa, IIb, III): Requires availability of
well conducted clinical studies but no randomised clinical trials on the
topic of recommendation.

**Grade C** (evidence level IV): Requires evidence obtained from expert
committee reports or opinions and/or clinical experiences of respected
authorities. Indicates absence of directly applicable clinical studies
of good quality.

**Good Practice Points**: Recommended best practice based on the
clinical experience of the guideline development group.

**Levels of Evidence**

**Level Ia**: Evidence obtained from meta-analysis of randomised
controlled trials.

**Level Ib**: Evidence obtained from at least one randomised controlled
trial.

**Level IIa**: Evidence obtained from at least one well-designed
controlled study without randomisation.

**Level IIb**: Evidence obtained from at least one other type of
well-designed quasi-experimental study.

**Level III**: Evidence obtained from well-designed non-experimental
descriptive studies, such as comparative studies, correlation studies,
and case studies.

**Level IV**: Evidence obtained from expert committee reports or
opinions and/or clinical experiences of respected authorities.

#### CLINICAL ALGORITHM(S)

An algorithm is provided for pharmacological treatment of schizophrenia
in the acute phase.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### REFERENCES SUPPORTING THE RECOMMENDATIONS

[References open in a new
window](http://www.guideline.gov/summary/select_ref.aspx?doc_id=3750)

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

**Overall Benefits**

-   This guideline will provide guidance to doctors on the many
    treatment options available for schizophrenia and provide patients
    with the best possible care and outcome.

-   Psychosocial interventions can improve the course of schizophrenia
    when integrated with psychopharmacologic treatment by providing
    additional benefits for patients in such areas as relapse
    prevention, improved coping skills, better social and vocational
    functioning, and ability to function more independently.

**Specific Benefits**

-   Typical antipsychotic medications have been convincingly shown in
    well over 100 randomised double-blind studies to be more effective
    than placebo in the treatment of positive symptoms.

-   There is evidence that atypical antipsychotics are more or equally
    effective in controlling all four categories of symptoms in
    schizophrenia and are better tolerated than typical antipsychotics.

-   Controlled trials have shown that clozapine produces significant
    improvement in at least 30% of patients who show an inadequate
    response to two typical antipsychotics of different clinical
    classes.

-   Electroconvulsive therapy (ECT) is effective for schizophrenic
    patients with affective or catatonic symptoms.

-   Randomised trials have demonstrated that a combination of family
    intervention with antipsychotics reduce 1-year relapse rates from a
    40 to 53% range to a 2 to 23% range.

-   Studies have shown that, when combined with medications, individual
    and group psychological therapy reduces relapses and enhances
    occupational and vocational functioning.

-   Cognitive Behavioral Therapy (CBT) has been demonstrated to be
    beneficial in reducing the symptoms (especially positive symptoms)
    of schizophrenia.

-   Studies show that social skills training improves social adjustment
    and coping skills, thereby reducing relapse rates.

-   Controlled studies have shown that vocational interventions can be
    effective in helping patients find jobs and remain in competitive
    employment. Characteristics of patients who are more likely to
    benefit are those who a) see competitive employment as a personal
    goal, b) have a history of prior competitive employment, c) have a
    minimal history of psychiatric hospitalization, and d) have been
    assessed to have good work skills.

#### POTENTIAL HARMS

**Side Effects of Typical Antipsychotics**

-   Extrapyramidal side effects (e.g., acute dystonia, akathisia,
    parkinsonism)

-   Tardive dyskinesia (involuntary movement disorder) following
    prolonged use

-   Anticholinergic effects (e.g., dry mouth, blurred vision, urinary
    hesitancy or retention, constipation)

-   Anti-adrenergic effects (e.g., postural hypotension, inhibition of
    ejaculation)

-   Sedation

-   Lowered seizure threshold

-   Cardiovascular effects include electrocardiogram (ECG) changes
    (e.g., widening of QRS complex, prolonged QT interval), tachycardia,
    cardiac arrhythmias

-   Hyperprolactinaemia (amenorrhoea, galactorrhoea, and breast
    enlargement in women and impotence and/or gynaecomastia in men)

-   Skin and eye effects include allergic and phototoxic skin reactions;
    long-term use may cause pigmentary changes of skin, and corneal and
    lens deposits

-   Hepatic effects (e.g., minor abnormalities in liver function tests,
    cholestatic jaundice)

-   Neuroleptic malignant syndrome (a rare idiosyncratic and potentially
    fatal reaction characterized by hyperthermia, muscular rigidity,
    autonomic instability, alteration in consciousness level, and
    elevated serum creatinine phosphokinase)

-   Others (e.g., weight gain, nausea)

**Common Side Effects of Atypical Antipsychotics**

*Clozapine*

-   Sedation

-   Hypersalivation

-   Anticholinergic effects

-   Weight gain

-   Postural hypotension

-   Potentially serious agranulocytosis (about 0.34% per annum)

-   Potentially serious lowered seizure threshold in doses beyond 600 mg
    daily

*Olanzapine*

-   Weight gain

-   Sedation

-   Dizziness

-   Anticholinergic effects (dry mouth, constipation, retention of
    urine, blurring of vision)

*Quetiapine*

-   Somnolence

-   Dizziness

-   Postural hypotension

-   Anticholinergic effects (dry mouth, constipation, retention of
    urine, blurring of vision)

*Risperidone*

-   Insomnia

-   Anxiety

-   Agitation

-   Hyperprolactinaemia (amenorrhoea, galactorrhoea, sexual dysfunction)

*Amisulpride*

-   Insomnia

-   Anxiety

-   Agitation

-   Hyperprolactinaemia (amenorrhoea, galactorrhoea, sexual dysfunction)

**Cautions for Use of Benzodiazepines**

Patients with respiratory difficulties should be treated with caution.
All patients should be considered for gradual withdrawal at the earliest
opportunity to avoid an unnecessary risk of dependence, and all patients
should be observed for the paradoxical effect of disinhibition.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   These guidelines are not intended to serve as standards of medical
    care. Standards of medical care are determined on the basis of all
    clinical data available for an individual case and are subject to
    change as scientific knowledge advances and patterns of care evolve.

-   The contents of the guideline document are guidelines to clinical
    practice, based on the best available evidence at the time of
    development. Adherence to these guidelines may not ensure a
    successful outcome in every case, nor should they be construed as
    including all proper methods of care or excluding other acceptable
    methods of care. Each physician is ultimately responsible for the
    management of his/her unique patient in the light of the clinical
    data presented by the patient and the diagnostic and treatment
    options available.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

The following clinical audit parameters, based on recommendations in
these guidelines, are proposed:

1.  Percentage of schizophrenic patients prescribed antipsychotic
    medication

2.  Percentage of schizophrenic patients prescribed clozapine, who are
    intolerant or unresponsive to other antipsychotic medications

3.  Percentage of schizophrenic patients prescribed clozapine, whose
    full blood count is regularly monitored

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Foreign Language Translations\
Patient Resources

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Patient-centeredness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Singapore Ministry of Health. Schizophrenia. Singapore: Singapore
Ministry of Health; 2003 Feb. 40 p. \[29 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2003 Feb

#### GUIDELINE DEVELOPER(S)

Singapore Ministry of Health - National Government Agency \[Non-U.S.\]

#### SOURCE(S) OF FUNDING

Singapore Ministry of Health

#### GUIDELINE COMMITTEE

Workgroup on Schizophrenia

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Workgroup Members*: A/Prof Chong Siow Ann, Chief, Department of Early
Psychosis Intervention, Director of Research, Institute of Mental Health
and Woodbridge Hospital (Chairman); Dr Ang Ah Ling, Senior Consultant,
Institute of Mental Health and Woodbridge Hospital; Col(Dr) Ang Yong
Guan, Chairman of Chapter of Psychiatry, Academy of Medicine, Singapore;
Dr Chee Kuan Tsee, Senior Consultant, Institute of Mental Health and
Woodbridge Hospital; Dr Lyn Chua, Head, Department of Psychology,
Institute of Mental Health and Woodbridge Hospital; A/Prof Calvin Fones,
Head, Department of Psychological Medicine, National University
Hospital; Dr Leong Oil Ken, Senior Consultant, Institute of Mental
Health and Woodbridge Hospital; A/Prof Rathi Mahendran, Chief,
Department of General Psychiatry, Director of Training, Institute of
Mental Health and Woodbridge Hospital; Dr Francis Ngui, Consultant
Psychiatrist, President, Singapore Psychiatric Association, Medical
Director, Adam Road Hospital; A/Prof Ong Thiew Chye, Senior Consultant,
Department of Psychological Medicine, Tan Tock Seng Hospital; A/Prof Tan
Chay Hoon, Consultant Psychiatrist, National University Hospital; Dr Tan
Chue Tin, Consultant Psychiatrist, Mount Elizabeth Medical Centre; Dr
Tay Woo Kheng, Head, Division of Psychological Medicine, Changi General
Hospital; A/Prof Wong Kim Eng, Chairman Medical Board, Institute of
Mental Health and Woodbridge Hospital

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Singapore Ministry of Health Web
site](http://www.hpp.moh.gov.sg/HPP/1130910778681.html).

Print copies: Available from the Singapore Ministry of Health, College
of Medicine Building, Mezzanine Floor 16 College Rd, Singapore 169854.

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

The following is available:

-   Schizophrenia. Singapore: Singapore Ministry of Health; 2003. 28 p.

Electronic copies: Available in Portable Document Format (PDF) from the
[Singapore Ministry of Health Web
site](http://www.hpp.moh.gov.sg/HPP/MungoBlobs/764/780/2003 peb_schiz.pdf).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This summary was completed by ECRI on November 28, 2003. This summary
was updated by ECRI on January 18, 2006, following the U.S. Food and
Drug Administration advisory on Clozaril (clozapine). This summary was
updated by ECRI Institute on October 2, 2007, following the U.S. Food
and Drug Administration (FDA) advisory on Haloperidol. This summary was
updated by ECRI Institute on November 6, 2007, following the U.S. Food
and Drug Administration advisory on Antidepressant drugs. This summary
was updated by ECRI Institute on January 10, 2008, following the U.S.
Food and Drug Administration advisory on Carbamazepine.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions. Please contact the
Ministry of Health, Singapore by e-mail at <MOH_INFO@MOH.GOV.SG>.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/10/2008