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Cochrane Database of Systematic Reviews

Clozapine dose for schizophrenia (Review)

Subramanian S, Völlm BA, Huband N

Subramanian S, Völlm BA, Huband N.

Clozapine dose for schizophrenia.
Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD009555.
DOI: 10.1002/14651858.CD009555.pub2.

www.cochranelibrary.com

Clozapine dose for schizophrenia (Review)

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 25
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Analysis 1.1. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 1 Mental state: Average endpoint score (BPRS-A, high = poor) - medium term. . . . . 53
Analysis 1.2. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 2 Adverse effects: 1a. Weight - BMI - short term. . . . . . . . . . . . . . . . 54
Analysis 1.3. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 3 Adverse effects: 1b. Weight - weight gain. . . . . . . . . . . . . . . . . . 55
Analysis 1.4. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 4 Adverse effects: 1c. Weight - body weight at endpoint - short term. . . . . . . . . 56
Analysis 1.5. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 5 Adverse effects: 2a. Metabolic - blood glucose - short term. . . . . . . . . . . . 57
Analysis 1.6. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 6 Adverse effects: 2b. Metabolic - lipid profile - short term. . . . . . . . . . . . 58
Analysis 1.7. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300
mg/day), Outcome 7 Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 2.1. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 1 Mental state: 1a. Average endpoint score (BPRS-A, high = poor) - medium term. . . . 60
Analysis 2.2. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 2 Adverse effects: 1a. Weight - BMI - short term. . . . . . . . . . . . . . . . 60
Analysis 2.3. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 3 Adverse effects: 1b. Weight - weight gain. . . . . . . . . . . . . . . . . . 61
Analysis 2.4. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 4 Adverse effects: 1c. Weight - body weight at endpoint - short term. . . . . . . . . 62
Analysis 2.5. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 5 Adverse effects: 2a. Metabolic - blood glucose - short term. . . . . . . . . . . . 63
Analysis 2.6. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 6 Adverse effects: 2b. Metabolic - lipid profile - short term. . . . . . . . . . . . 64
Analysis 2.7. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day), Outcome 7 Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 3.1. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 1 Mental state: 1a. Clinically important response as (BPRS score > 30% change). . . . . 66
Analysis 3.2. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 2 Mental state: 1b. Average endpoint score (BPRS-A total, high = poor). . . . . . . . 67
Clozapine dose for schizophrenia (Review) i
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.3. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 3 Mental state: 1c. Average endpoint score (BPRS-A subscores, high = poor) - short term. . 68
Analysis 3.4. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 4 Mental state: 1e. Clinical improvement, clinician assessed. . . . . . . . . . . . 69
Analysis 3.5. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 5 Adverse effects: 1a. Weight - BMI - short term. . . . . . . . . . . . . . . . 69
Analysis 3.6. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 6 Adverse effects: 1b. Weight - weight gain. . . . . . . . . . . . . . . . . . 70
Analysis 3.7. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 7 Adverse effects: 1c. Weight - body weight at endpoint - short term. . . . . . . . . 71
Analysis 3.8. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 8 Adverse effects: 2a. Metabolic - blood glucose - short term. . . . . . . . . . . . 72
Analysis 3.9. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 9 Adverse effects: 2b. Metabolic - lipid profile - short term. . . . . . . . . . . . 73
Analysis 3.10. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 10 Adverse effects: 3. Various effects - short term. . . . . . . . . . . . . . . 74
Analysis 3.11. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 11 Adverse effects: 4. Average endpoint scores (TESS, high = poor) - short term. . . . . 75
Analysis 3.12. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600
mg/day), Outcome 12 Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . 76
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 78

Clozapine dose for schizophrenia (Review) ii

Clozapine dose for schizophrenia

Selvizhi Subramanian1 , Birgit A Völlm2 , Nick Huband2

1 Department of Psychiatry, Morecambe Community Mental Health Team, Morecambe, UK. 2 Division of Psychiatry & Applied
Psychology, University of Nottingham Innovation Park, Nottingham, UK

Contact address: Nick Huband, Division of Psychiatry & Applied Psychology, University of Nottingham Innovation Park, Institute of
Mental Health, Triumph Road, Nottingham, NG7 2TU, UK. [email protected].

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: New, published in Issue 6, 2017.

Citation: Subramanian S, Völlm BA, Huband N. Clozapine dose for schizophrenia. Cochrane Database of Systematic Reviews 2017,
Issue 6. Art. No.: CD009555. DOI: 10.1002/14651858.CD009555.pub2.

ABSTRACT
Background
Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by
profound disruptions in thinking and speech, emotional processes, behaviour and sense of self. Clozapine is useful in the treatment
of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms
(such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what
dose of clozapine is most effective with the least side effects.
Objectives
To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment
of schizophrenia, schizophreniform and schizoaffective disorders.
Search methods
We searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials (August 2011 and 8 December 2016).
Selection criteria
All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at
different doses in people with schizophrenia and related disorders, diagnosed by any criteria.
Data collection and analysis
We independently inspected citations from the searches, identified relevant abstracts, obtained full articles of relevant abstracts, and
classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous
data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention-to-treat basis based on a random-effects
model. For continuous data, we calculated mean differences (MD) again based on a random-effects model. We assessed risk of bias for
included studies and created ’Summary of findings’ tables using GRADE.
Main results
We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low
dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a
small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data
were available for the main outcomes of global state, service use or quality of life.
Clozapine dose for schizophrenia (Review) 1
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Very low dose compared to low dose
We found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating
Scale-Anchored (BPRS-A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI −4.50 to 11.60, very low quality evidence). One study
found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD −0.10, 95% CI −0.95 to 0.75,
low-quality evidence).
Very low dose compared to standard dose
We found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS-A
endpoint score (1 RCT, n = 31, MD 6.67, 95% CI −2.09 to 15.43, very low quality evidence). One study found no difference between
groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI −0.76 to 0.96, low-quality evidence)
Low dose compared to standard dose
We found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician-assessed
clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium-quality evidence) and clinically important response as
more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium-quality evidence). One study found
no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI −0.84 to 1.24, low-quality evidence).
We found some evidence of effect for other adverse effect outcomes; however, the data were again limited.
Very low dose compared to low dose
There was limited evidence that serum triglycerides were lower at low-dose clozapine compared to very low dose in the short term (1
RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49).
Low dose compared to standard dose
Weight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD −2.70, 95% CI −5.38 to −0.02). Glucose
level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD −1.60, 95% CI −2.90 to −0.30). Total cholesterol
levels were higher at very low compared to standard dose (1 RCT, n = 58, n = 58, MD 1.00, 95% CI 0.20 to 1.80).
Low dose compared to standard dose
There was evidence of fewer adverse effects, measured as lower TESS scores, in the low-dose group in the short term (2 RCTs, n = 266,
MD −3.99, 95% CI −5.75 to −2.24); and in one study there was evidence that the incidence of lethargy (RR 0.77, 95% CI 0.60 to
0.97), hypersalivation (RR 0.70, 95% CI 0.57 to 0.84), dizziness (RR 0.56, 95% CI 0.39 to 0.81) and tachycardia (RR 0.57, 95% CI
0.45 to 0.71) was less at low dose compared to standard dose.
Authors’ conclusions
We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials
on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was
less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects
was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally
of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social
functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium- or
long-term outcome data, and on dose regimes above the standard rate.

PLAIN LANGUAGE SUMMARY

Clozapine dose in schizophrenia
Background: Schizophrenia is a severe mental illness that affects thinking and perception. People with schizophrenia often experience
profound disruptions in their speech, emotional processes, behaviour and sense of self. Antipsychotic medication can be a helpful
treatment for schizophrenia; however, taking antipsychotic medication can have unpleasant effects. Clozapine is an antipsychotic drug
that can be useful in treating schizophrenia, particularly when other antipsychotic medications have not worked. It is unclear, however,
what dose of clozapine is most effective with the least side effects. This review investigates the effects of receiving clozapine at four
different dose levels (high dose, standard dose, low dose, very low dose).
Clozapine dose for schizophrenia (Review) 2
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Searching: An electronic search for studies that randomised people with schizophrenia to receive different doses of clozapine was run in
August 2011 and again on 8 December 2016.
Results: We found five studies with 452 participants which met our inclusion criteria. Each compared the effects of clozapine at very
low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). None of the
studies examined the effects of clozapine at higher than the standard dose. There was nothing to choose between standard, low and
very low doses in terms of body mass index (BMI) measurements in the short term. However, weight gain was greater in those receiving
the standard dose compared to those receiving the low dose. The incidence of unpleasant side effects (which included feeling lethargic,
producing too much saliva, and feeling dizzy) was less at low dose compared to standard dose.
Quality of evidence: For main outcomes the quality was low or very low.
Conclusions: We found no evidence that might indicate the best dose of clozapine for patients with schizophrenia. Careful consideration
has to be given to balancing the advantages and disadvantages of different doses in relation to weight gain and other side effects. Overall
measurements of BMI were similar between groups; however, some side effects appear to be lower at lower doses. Overall, this review
highlights the lack of evidence-based information available for addressing the question of what dose of clozapine is most effective with
the least side effects. There is a need for large, well-designed and well-reported randomised clinical trials to address this question. There
is a particular need for such trials to look at longer-term outcomes, and to examine the effects of clozapine when given at greater than
the standard dose.

Clozapine dose for schizophrenia (Review) 3

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

CLOZAPINE: VERY LOW DOSE (up to 149 mg/ day) versus LOW DOSE (150- 300 mg/ day) for schizophrenia

Patient or population: patients with schizophrenia

Settings:
Intervention: Clozapine: very low dose (up to 149 m g/ day) versus low dose (150 m g/ day to 300 m g/ day)

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Control Clozapine: very low

dose (up to 149 mg/
day) versus low dose
(150 mg/ day to 300
mg/ day)

Global state: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important response, as (0) outcom e.
defined by individual
studies

M ental state: clinically The m ean clinical re- 31 ⊕ * Pre-def ined outcom e
important response, as sponse: m ental state (1 study) very low1,2,3 not reported: M ental
defined by individual - average scores - state m easured as av-
studies * m edium term end- erage endpoint scores
Follow-up: 16 weeks point (BPRS-A, high = (BPRS-A, high = worse)
worse) in the interven-
tion group was
3.55 higher
(4.50 to 11.60 higher)
4
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review)

Functioning: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important change in (0) outcom e.
general functioning, as
defined by individual
studies

Adverse effect: clin- The m ean adverse ef - 59 ⊕⊕

ically important ad- f ect - any clinically (1 study) low2,3
verse effect (weight - im portant specif ic ad-
BM I) verse ef f ects - BM I in
Follow-up: 6 weeks the intervention group
was
0.1 lower
(0.95 lower to 0.75
higher)

Service use: number of See com m ent See com m ent Not estim able 0 See com m ent No study reported this
days hospitalised (0) outcom e.

Service use: time to See com m ent See com m ent Not estim able 0 See com m ent No study reported this
hospitalisation (0) outcom e.

Quality of life: clini- See com m ent See com m ent Not estim able 0 See com m ent No study reported this
cally important change (0) outcom e.
in general quality of life

* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% CI) is based on the assum ed
risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: Conf idence interval

GRADE Working Group grades of evidence

200)
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6
BACKGROUND who suffer from schizophrenia at a specific point in time) as 4.6
per 1000; the median lifetime prevalence for persons (the number
Schizophrenia is a serious mental illness characterised by pro-
of people in the population who have ever manifested the disease)
found disruptions in thinking and speech, emotional processes,
was 4.0 per 1000; and the lifetime morbid risk (the likelihood of
behaviour and sense of self (WHO 2013). It can have great impact
a particular individual developing schizophrenia in their lifetime)
in terms of both human suffering and societal expenditure (van
as 7.2 per 1000. Acute schizophrenia predominantly manifests it-
Os 2009). It is among the world’s top ten causes of long-term dis-
self with positive symptoms such as abnormal experiences; these
ability, leading to problems in social and occupational functioning
include abnormal perceptions in the absence of a stimulus (hal-
and self-care (Meuser 2004). Before the introduction of clozapine,
lucinations), false fixed beliefs (delusions), and disordered think-
doctors largely relied on first generation (typical) antipsychotics,
ing. Chronic schizophrenia typically manifests itself with nega-
such as chlorpromazine, to control persisting symptoms and to
tive symptoms. Though there is no complete agreement as to the
prevent further exacerbations or relapse of illness (Kane 1990).
specification of negative symptoms, it is generally agreed that they
Clozapine is the first second generation (atypical) antipsychotic
include poverty of speech, blunting of affect, lack of volition and
drug introduced to the market. Arnt suggested that second gen-
social withdrawal (Gelder 2001). More than 50% of people with
eration antipsychotics are those that do not cause movement dis-
schizophrenia are not receiving appropriate care and about 90% of
orders (catalepsy) in rats at clinically effective doses (Arnt 1998).
people with untreated schizophrenia live in developing countries
When clozapine was introduced it proved to be superior in con-
(WHO 2013). Most cases of schizophrenia can be treated and
trolling treatment-resistant illness, with fewer extrapyramidal side
those affected can lead a productive life and be integrated in soci-
effects (EPSEs) than typical antipsychotics such as chlorpromazine
ety. The incidence of treatment resistance in schizophrenia is about
(Kane 1988). However, clozapine was largely withdrawn from use
20% (Kerwin 2005). Clozapine reduces psychotic symptoms in
in 1975 following the death of some patients due to the develop-
30% to 60% of such schizophrenia patients who have failed to re-
ment of agranulocytosis. This withdrawal, however, was not fol-
spond to adequate trials of other antipsychotics (Buchanan 1995).
lowed worldwide. For example, Scandinavia, Germany and China
continued to use clozapine. Subsequent studies demonstrated that
clozapine could be administered safely when patients are carefully
monitored for side effects such as agranulocytosis (Kane 1988; 2. Schizophreniform disorder
Naheed 2001). Following this, clozapine was reintroduced in the According to the Diagnostic and Statistical Manual of Mental Dis-
USA in 1990 with hopes that it would improve quality of life, cog- orders, Fourth Edition, schizophreniform disorder is a condition
nitive functioning and movement disorders, and also reduce nega- with symptoms similar to schizophrenia but lasting less than six
tive symptoms such as poverty of speech, blunting of affect, lack of months (DSM-IV). In 1937 and 1939, follow-up studies were
volition and social withdrawal in the management of treatment-re- undertaken on patients who initially presented with symptoms
sistant schizophrenia. During this reintroduction, some safeguards similar to schizophrenia. Two different outcomes were identified
were put in place; for example, clozapine is recommended to be in those patients. One group, whose symptoms were typical of
used only in treatment-resistant schizophrenia along with regular schizophrenia, were identified as having a poor prognosis. The
monitoring for side effects such as agranulocytosis. other group, whose symptoms were similar to those of schizophre-
nia but who had prominent affective symptoms, had a better
outcome; Langfeldt introduced the concept of schizophreniform
Description of the condition psychoses to describe this latter group (Noreik 1967; Guldberg
1991). Langfeldt’s original schizophreniform cases were reviewed
by other researchers using DSM-III and International Statistical
1. Schizophrenia Classification of Diseases and Related Health Problems, Ninth Re-
WHO 2013 estimates that about 24 million people worldwide vision (ICD-9) criteria. They concluded that most of the original
are affected by schizophrenia. The symptoms typically emerge in schizophreniform cases described by Langfeldt possibly appeared
late adolescence or early adulthood. It is unclear as to what exactly to more closely resemble affective disorders with psychoses, rather
causes schizophrenia, but both genetic and environmental factors than schizophrenia-like illness (Bergem 1990; Guldberg 1991).
are thought to play a role. WHO 2013 identified a low incidence DSM-IV uses schizophreniform disorder to define a disorder that
of 3 per 100,000, whereas McGrath 2008 identified the median would otherwise meet the diagnostic criteria for schizophrenia
incidence of schizophrenia as 15.2 per 100,000 people. Saha 2005 but lasts less than six months (Gelder 2001). There are currently
found no significant difference in prevalence between urban, rural, no reliable data on prevalence rates of schizophreniform disorder
and mixed sites. The prevalence of schizophrenia in migrants is (Kaplan 2005). Treatment is similar to that of schizophrenia. Good
higher compared to native-born individuals and is lower in poorer prognostic factors for schizophreniform illness include episodic
countries than in richer countries. Saha 2005 identified the me- illness, recurrent course and a family history of mood disorders
dian point prevalence of schizophrenia (the proportion of people (Benazzi 2003).

Clozapine dose for schizophrenia (Review) 7

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3. Schizoaffective disorder tremor, seizures, fatigue, impaired temperature regulation, urinary
In 1933 Jacob Kasanin coined the term schizoaffective psychosis incontinence, urinary retention, leukopenia, eosinophilia, leuco-
(Kasanin 1933). Schizoaffective psychosis can be considered as a cytosis, and, less commonly, agranulocytosis, and other cardiovas-
syndrome on the continuum between schizophrenia and mood cular and respiratory side effects (BNF 2012).
disorders (such as depression and bipolar affective disorder) and
presents with symptoms of both these illnesses (Danilevici te Accessibility of clozapine
2002). ICD-10 considers schizoaffective disorder as an episodic
disorder in which both affective and schizophrenic symptoms Upon reintroduction of clozapine in the USA in 1990, cloza-
are prominent but which does not justify a diagnosis of ei- pine was recommended to be used only in treatment-resistant
ther schizophrenia or a depressive or manic episode. Studies on schizophrenia, along with regular monitoring for side effects such
schizoaffective disorder suggest that it is relatively common in clin- as agranulocytosis. The British National Formulary currently rec-
ical settings. Among admissions to inpatient mental health facil- ommends clozapine be used only in “schizophrenia (including psy-
ities for functional psychosis, 10% to 30% comprise schizoaffec- chosis in Parkinson’s disease) in patients unresponsive to, or in-
tive disorder. The lifetime prevalence of schizoaffective disorder is tolerant of, conventional antipsychotic drugs” (BNF 2012). The
estimated to be between 0.5% and 0.8% and the illness typically National Institute for Health and Care Excellence recommends
presents with an episodic course (Azorin 2005). Psychotic features clozapine in people suffering from schizophrenia who did not re-
may include both positive and negative symptoms along with af- spond adequately to sequential use of adequate doses of at least
fective symptoms. Outcome is predicted by premorbid function- two different antipsychotic drugs, at least one of which should be
ing, number of past episodes, persistence of psychotic features and a non-clozapine second-generation antipsychotic (NICE). Cloza-
degree of cognitive impairment. Vieta 2010 suggests that bipo- pine is made available only through the manufacturer’s propri-
lar-type schizoaffective illness can be treated with second genera- etary monitoring system, and all the UK manufacturers of clozap-
tion antipsychotics, either alone or in conjunction with a mood ine such as Novartis (Clozaril), Merz (Denzapine), and Teva (Za-
stabiliser. The depressive type of schizoaffective disorder can be ponex) require that the patients, prescribers and supplying phar-
treated with a second generation antipsychotic in conjunction with macists be registered with their relevant patient monitoring ser-
either an antidepressant or a mood stabiliser. Electroconvulsive vice. Through shared care arrangements with local community
therapy (ECT) can be considered in refractory cases. Prognosis pharmacies dispensing clozapine, it is possible in the UK to initiate
appears to be better than for schizophrenia, but worse than for clozapine treatment in the community after registration with the
affective disorder (Azorin 2005). patient monitoring services is completed (CMHP). However, gen-
eral practitioners generally do not prescribe clozapine in the UK.
Aitchison 1997 suggested that the costs of prescribing clozapine
Description of the intervention could be recouped on savings in future inpatient care. Wang 2004
indicated that if clozapine was made available as a first-line an-
Prescribing of clozapine requires a number of preparatory steps. tipsychotic, it might possibly lead to small gains in life expectancy,
For example, before initiation of clozapine a base line physical ex- at moderate but acceptable costs. Kane 2011 opined that clozapine
amination should be performed with an ECG and base line blood still remains strikingly under-utilised and that many practitioners
tests, including full blood count. Patients must be registered with across the world and across different clinical settings do not use
the clozapine patient monitoring services, and full blood count clozapine even when indicated.
must be monitored once a week for the first 18 weeks, thereafter
fortnightly for 34 weeks and then once in every four weeks for
the period of time clozapine is taken. For adults over 16 years
of age, clozapine should be started at a very low dose, e.g. 12.5
How the intervention might work
mg once or twice a day. On the second day, 25 mg to 50 mg is Clozapine (Figure 1) was the first atypical antipsychotic to show
given, and, if well tolerated, the dose can be gradually increased definite benefit in treatment of patients where symptoms failed to
in steps of 25 mg to 50 mg daily over 14 to 21 days up to 300 respond to typical agents. Clozapine has the highest affinity for
mg daily in divided doses. If necessary, the dose can be increased dopamine D4, 5-HT1C, 5-HT2, alpha 1, muscarinic and his-
further. Elderly people may need slower titration. During initia- tamine H1 receptors, but moderate affinity is also seen for many
tion and titration, pulse and blood pressure (in standing and ly- other receptor subtypes (Coward 1992). Clozapine causes fewer
ing position) should be monitored regularly to identify persistent extrapyramidal side effects (EPSEs) than typical antipsychotics
tachycardia and postural hypotension. If clozapine, for whatever (Kane 1988). Clozapine appears to be more active at the limbic site
reason, was omitted for a period of 48 hours, it should be restarted than the striatal site and this might explain its low extrapyramidal
from lowest dose and titrated upwards. Adverse effects of clozap- side effect profile. It is metabolized mainly in the liver. Norcloza-
ine include constipation, troublesome hypersalivation, tachycar- pine is an active metabolite of clozapine. Monitoring the plasma
dia, ECG changes, hypertension, drowsiness, dizziness, headache, levels of clozapine and norclozapine helps to assess compliance. It

Clozapine dose for schizophrenia (Review) 8

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
is suggested that the therapeutic response is associated with clozap-
ine blood levels between 200 ng/ml and 400 ng/ml (Kronig 1995).
Chemicals that affect cytochrome enzymes can reduce or increase
plasma clozapine concentration.

Figure 1. Clozapine structure

Why it is important to do this review However, it is important to note that the relationship between the
Different guidelines suggest different dosing for clozapine. For ex- dose of clozapine and the resulting serum level is weak (Taylor
ample, BNF 2012 recommends a usual dose of 200 mg/day to 1995). This could be a reason why there is wide variation of the
450 mg/day and the maximum daily dose of 900 mg. Merz, the clinically effective dose in different individuals. It is still unclear as
UK manufacturer of Denzapine, also advises the prescription of to what dose of clozapine is most effective with the least side effects.
clozapine at a dose between 200 mg/day and 450 mg/day, with It must be borne in mind as well that patient non-compliance can
maximum doses up to 900 mg/day. Novartis, the UK manufac- be as high as 50% under outpatient conditions and this could be
turer of Clozaril, suggests that while many patients may respond due to drug-related side effects (Gaebel 1997), and lead to relapse.
adequately at doses between 300 mg/day and 600 mg/day, it may Clozapine produces severe adverse effects. Hence we will review
be necessary to raise the dose to the 600 mg/day to 900 mg/day the evidence for doses of clozapine that are both tolerable and
range to obtain an acceptable response. Kaplan 2005 suggests that effective in the management of schizophrenia, schizophreniform
daily doses between 250 mg/day and 450 mg/day are usually con- and schizoaffective disorders. This is one of a series of reviews on
sidered adequate and daily dosage above 600 mg/day is seldom the effects of clozapine (Table 1).
indicated. Semple 2007 advises that usual doses of 200 mg to 450
mg daily can be used, and that an increase in frequency of seizures
occurs at doses greater than 600 mg/day. Stahl 2006 suggests us-
ing 300 mg/day to 450 mg/day with a maximum of 900 mg/day, OBJECTIVES
and that doses of more than 550 mg/day may require concomitant To compare the efficacy and tolerability of clozapine at different
anticonvulsant medications to reduce the risk of seizures. Plasma doses and to identify the optimal dose of clozapine in the treatment
levels may help guide dosing, with studies suggesting that maximal of schizophrenia, schizophreniform and schizoaffective disorders.
clinical efficacy may be achieved when plasma levels of clozapine
are between 200 ng/ml and 400 ng/ml (typically associated with a
dose of 300 mg/day to 400 mg/day (Kronig 1995; Simpson 1999). METHODS
Clozapine dose for schizophrenia (Review) 9
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Criteria for considering studies for this review Secondary outcomes

Types of studies
We included all relevant randomised controlled trials, reporting 1. Global state
useable data, that compared different doses of clozapine, irrespec-
1.1 Relapse (as defined by the individual studies).
tive of blinding status and published language. Where people were
1.2 Average endpoint global state score.
given additional treatments along with clozapine, we included the
1.3 Average change in global state scores.
trial only if the adjunct treatment was equal in both groups and
1.4 Needing additional medication.
only the clozapine doses were randomised. We included studies on
treatment-resistant illnesses and took the opportunity to examine
clozapine’s effect on the course of the illness (for example acute, 2. Mental state
partial remission, remission, first episode). We excluded case series
and non-randomised trials, and quasi-randomised trials where, for 2.1 Clinically important change in general mental state score.
example, allocation is undertaken on alternate days of the week or 2.2 Average endpoint general mental state score.
by alphabetical order. 2.3 Average change in general mental state scores.
2.4 Clinically important change in specific symptoms (e.g. positive
symptoms of schizophrenia, negative symptoms of schizophrenia).
Types of participants 2.5 Average endpoint specific symptom score.
We included studies on people with schizophrenia, schizophreni- 2.6 Average change in specific symptom scores.
form disorder and schizoaffective disorder diagnosed by any crite- 2.7 Healthy days.
ria. We decided to include schizophreniform and schizoaffective
disorders as these conditions may be caused by similar disease pro-
cesses and may require similar treatment approaches (Carpenter 3. Death
1994). 3.1 Suicide.
3.2 Natural causes.

Types of interventions
We compared the efficacy of different doses of clozapine in differ- 4. Leaving the studies early
ent arms in the same trial. We did not compare efficacy of clozap- 4.1 Any reason.
ine to any other antipsychotic or to placebo or to any other medi- 4.2 Specific reason (as described by individual studies; for example:
cations. The intervention of interest was clozapine: oral formula- adverse events, treatment inefficacy).
tion, any dose, comparison of different doses. We predefined the
dosage categories as follows.
5. Behaviour
1. Very low dose clozapine: up to 149 mg/day.
5.1 Clinically important change in general behaviour.
2. Low-dose clozapine: 150 mg/day to 300 mg/day.
5.2 Average endpoint general behaviour score.
3. Standard-dose clozapine: 301 mg/day to 600 mg/day.
5.3 Average change in general behaviour scores.
4. High-dose clozapine: 601 mg/day to 900 mg/day.
5.4 Clinically important change in specific aspects of behaviour.
5. Very high dose clozapine: 901 mg/day and above.
5.5 Average endpoint specific aspects of behaviour.
5.6 Average change in specific aspects of behaviour.
Types of outcome measures
We grouped outcomes into short term (up to 12 weeks), medium
term (13 to 26 weeks) and long term (more than 26 weeks). 6. Functioning
6.1 Clinically important change in general functioning.
6.2 Average endpoint general functioning score.
Primary outcomes 6.3 Average change in general functioning scores.
6.4 No clinically important change in specific aspects of function-
ing, such as social or life skills.
1. Global state
6.5 Average endpoint specific aspects of functioning, such as social
Clinically important response as defined by the individual studies or life skills.
(e.g. global impression “much improved” or 50% reduction on a 6.6 Average change in specific aspects of functioning, such as social
rating scale). or life skills.

Clozapine dose for schizophrenia (Review) 10

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7. Cognitive functioning 12. Economic outcomes
7.1 Clinically important change in overall cognitive functioning. 12.1 Direct costs.
7.2 Average endpoint overall cognitive functioning score. 12.2 Indirect costs.
7.3 Average change in overall cognitive functioning score.
7.4 Clinically important change in specific aspects of cognitive
functioning. 13. ’Summary of findings’ table
7.5 Average endpoint specific aspects of cognitive functioning. We used the GRADE approach to interpret findings (Schünemann
7.6 Average change in specific aspects of cognitive functioning. 2011); and GRADE Profiler (GRADEpro GDT) to import data
from Review Manager 5 (RevMan 5) to create ’Summary of find-
ings’ tables. These tables provide outcome-specific information
8. Quality of life concerning the overall quality of evidence from each included
study in the comparison, the magnitude of effect of the inter-
8.1 Clinically important change in general quality of life. ventions examined and the sum of available data on all outcomes
8.2 Average endpoint general quality of life score. we rated as important to patient care and decision making. We
8.3 Average change in general quality of life score. selected the following outcomes for inclusion in the Summary
8.4 Clinically important change in specific aspects of quality of of findings for the main comparison; Summary of findings 2;
life. Summary of findings 3.
8.5 Average endpoint specific aspects of quality of life. 1. Global state: clinically important response, as defined by
8.6 Average change in specific aspects of quality of life. individual studies.
2. Mental state: clinically important response, as defined by
individual studies.
9. Adverse effects 3. Functioning: clinically important change in general
functioning, including social or life skills, as defined by
9.1 Number of participants with at least one adverse effect.
individual studies.
9.2 Clinically important specific adverse effects (such as effects
4. Adverse effect: clinically important adverse effect.
on white blood cell count, cardiac effects, movement disorders,
5. Service use: number of days hospitalised.
hypersalivation, seizures, prolactin increase and metabolic side ef-
6. Service use: time to hospitalisation.
fects (such as weight gain, hyperlipidaemia and hyperglycaemia)).
7. Quality of life: clinically important change in general
9.3 Clinically important general adverse effects.
quality of life.
9.4 Average endpoint general adverse effect score.
9.5 Average change in general adverse effect score.
9.6 Average endpoint specific adverse effect score.
9.7 Average change in specific adverse effect score. Search methods for identification of studies
9.8 Use of any drugs for adverse effects.

Electronic searches
10. Satisfaction with treatment
10.1 Recipient of care not satisfied with treatment.
Cochrane Schizophrenia Group’s Study-Based Register of
10.2 Recipient of care average satisfaction score.
Trials
10.3 Recipient of care average change in satisfaction score.
10.4 Carer not satisfied with treatment. On 8 December 2016, the information specialist searched the
10.5 Carer average satisfaction score. register using the following search strategy:
10.6 Carer average change in satisfaction score. Dosage - Clozapine in Intervention Field of STUDY
In a study-based register such as this, searching the major con-
cept retrieves all the synonyms and relevant studies because all the
studies have already been organised based on their interventions
11. Service use
and linked to the relevant topics.
11.1 Number of patients hospitalised. This register is compiled by systematic searches of major re-
11.2 Number of days hospitalised. sources (including AMED, BIOSIS, CINAHL, Embase, MED-
11.3 Time to hospitalisation. LINE, PsycINFO, PubMed, and registries of clinical trials) and
11.4 Number of patients discharged or readmitted (as defined in their monthly updates, handsearches, grey literature, and confer-
individual trial). ence proceedings (see Group’s Module). There is no language,

Clozapine dose for schizophrenia (Review) 11

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
date, document type, or publication status limitations for inclu- 1.2 Forms
sion of records in the register. We extracted data onto standard forms.
For previous searches, please see Appendix 1.

2. Data management
Searching other resources

2.1 Scale-derived data

1. Reference searching We included continuous data from rating scales only if (a) the
We searched the reference lists of each included paper, but failed psychometric properties of the measuring instrument had been
to find any new studies. described in a peer-reviewed journal (Marshall 2000), and (b)
the measuring instrument had not been written or modified by
one of the trialists for that particular trial. Ideally the measuring
2. Personal contact instrument should either be:
(a) a self-report;
Where possible, we contacted the first author of trials or citations
(b) an instrument completed by an independent rater or relative
for missing information on unpublished data or trials. Where con-
(not the therapist);
tact with the first author was not possible through the Cochrane
(c) a global assessment of an area of functioning and not sub-
Schizophrenia Group, we attempted to contact the other authors.
scores which are not, in themselves, validated or shown to be reli-
At the time of writing, we have not received any of the missing
able. However there are exceptions: we included sub-scores from
data we requested, though one author indicated he will send the
mental state scales measuring positive and negative symptoms of
requested information at a future date. We have discussed this in
schizophrenia.
detail under relevant Results sections.
We realise that this is not often reported clearly and we note in
Description of studies if this was the case or not.

Data collection and analysis

2.2 Endpoint versus change data
There are advantages of both endpoint and change data. Change
Selection of studies data can remove a component of between-person variability from
the analysis. On the other hand, calculation of change needs two
One review author (SS) inspected citations from the searches,
assessments (baseline and endpoint) which can be difficult in un-
identified relevant abstracts, obtained full articles of all relevant
stable and difficult-to-measure conditions such as schizophrenia.
abstracts, and classified studies as ’included’, ’excluded’, or ’with
We primarily used endpoint data, and only used change data if
information missing’. We placed the last under ’pending classifica-
the former were not available. We combined endpoint and change
tion’ and contacted the authors for further clarification. A second
data in the analysis by the use throughout of mean differences
review author (BV) independently inspected a random 20% of
(MD) rather than standardised mean differences (Deeks 2011).
citations to ensure reliability.

2.3 Skewed data

Data extraction and management
Continuous data on clinical and social outcomes are often not
normally distributed. To avoid the pitfall of applying paramet-
ric tests to non-parametric data, we aimed to apply the following
1.1 Data extraction standards to all data before inclusion: a) standard deviations and
One review author (SS) extracted data from all included reports. means are reported in the paper or obtainable from the authors;
To ensure reliability, a second review author (BV) independently b) when a scale starts from the finite number zero, the standard
extracted data from a random 25% sample of these reports. There deviation, when multiplied by two, is less than the mean (as oth-
was no disagreement. Had there been disagreement, we would have erwise the mean is unlikely to be an appropriate measure of the
documented decisions and contacted authors of studies for clarifi- centre of the distribution (Altman 1996); c) if a scale started from
cation where necessary. We extracted data presented in graphs and a positive value (such as the PANSS which can have values from
figures only, whenever possible. We attempted to contact authors 30 to 210), the calculation described above was modified to take
in order to obtain missing information or clarification whenever the scale starting point into account. In these cases skew is present
necessary. if 2SD > (S −S min), where S is the mean score and S min is

Clozapine dose for schizophrenia (Review) 12

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the minimum score. Endpoint scores on scales often have a finite outcome data and selective reporting. There was no disagreement.
start and end point and the above rules can be applied. We did If there had been disagreement, we would have resolved it by fur-
not come across skewed endpoint data in our review, but if we had ther discussion. The level of risk of bias is noted in both the text
then we would have entered skewed endpoint data from studies of the review and in the ’Summary of findings’ table.
of fewer than 200 participants as other data within the Data and
analyses section rather than into a statistical analysis. Skewed end-
point data would pose fewer problems when looking at means if Measures of treatment effect
the sample size is large, and we would have then entered these into
syntheses.
1. Binary data
When continuous data are presented on a scale that includes a
possibility of negative values (such as change data), it is difficult For binary outcomes we calculated a standard estimation of the
to tell whether data are skewed or not, and we would have entered risk ratio (RR) and its 95% confidence interval (CI). It has been
skewed change data into statistical analysis. shown that RR is more intuitive than odds ratios (Boissel 1999);
and that odds ratios tend to be interpreted as RR by clinicians
(Deeks 2000). The number needed to treat for an additional ben-
2.4 Common measure eficial outcome/harmful outcome (NNTB/NNTH) statistic with
To facilitate comparison between trials, where possible we tried its confidence intervals is intuitively attractive to clinicians but is
to convert variables reported in different metrics (e.g. days spent problematic both in its accurate calculation in meta-analyses and
in hospital as mean days per year or per week or per month) to a interpretation (Hutton 2009). For binary data presented in the
common metric (e.g. mean days per month). ’Summary of findings’ table/s, where possible we calculated illus-
trative comparative risks.

2.5 Conversion of continuous to binary

Where possible, we would have converted outcome measures to 2. Continuous data
dichotomous data. This would have been done by identifying cut- We estimated mean difference (MD) between groups for contin-
off points on rating scales and dividing participants accordingly uous outcomes. We preferred not to calculate effect size measures
into ’clinically improved’ or ’not clinically improved’. It is generally (standardised mean difference (SMD)). However, if very similar
assumed that if there is a 50% reduction in a scale-derived score scales had been used, we would have presumed there was a small
such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962) difference in measurement and would have calculated effect size
or the Positive and Negative Syndrome Scale (PANSS, Kay 1986), and transformed the effect back to the units of one or more of the
this could be considered as a clinically significant response (Leucht specific instruments.
2005a; Leucht 2005b). If data based on these thresholds had not
been available, we would have used the primary cut-off presented
by the original authors. Where data on clinical improvement was Unit of analysis issues
presented as ’very effective’, ’effective’ and ’no improvement’, we
grouped these to form the dichotomous outcome of ’effective’/’no
1. Cluster trials
improvement’.
Studies increasingly employ ’cluster randomisation’ (such as ran-
domisation by clinician or practice) but analysis and pooling of
2.6 Direction of graphs clustered data poses problems. Firstly, authors often fail to account
Where possible, we entered data in such a way that the area to for intra-class correlation in clustered studies, leading to a ’unit
the left of the line of no effect indicates a favourable outcome for of analysis’ error (Divine 1992), whereby P values are spuriously
lower dose of clozapine. low, confidence intervals unduly narrow and statistical significance
overestimated. This causes type I errors (Bland 1997; Gulliford
1999).
Assessment of risk of bias in included studies There were no cluster trials included in our review. If there had
One review author (SS) independently assessed risk of bias by using been cluster studies, then where clustering was not accounted for
criteria described in the Cochrane Handbook for Systematic Reviews in primary studies we would have presented data in a table, with a
of Interventions to assess trial quality (Higgins 2011b). A second (*) symbol to indicate the presence of a probable unit of analysis
review author (BV) randomly checked 25% to ensure reliability. error. In subsequent versions of this review we will contact first
This set of criteria is based on evidence of associations between authors of studies to obtain intra-class correlation coefficients for
overestimate of effect and high risk of bias of the article such as se- their clustered data and adjust for this by using accepted methods
quence generation, allocation concealment, blinding, incomplete (Gulliford 1999).

Clozapine dose for schizophrenia (Review) 13

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
If clustering had been incorporated into the analysis of primary 1. Overall loss of credibility
studies, we would have presented these data as if from a non-clus-
At some degree of loss of follow-up, data must lose credibility (Xia
ter randomised study, but would have adjusted for the clustering
2009). If more than 50% of data had been unaccounted for in any
effect. Statistical advice has been sought in the past: it was advised
particular outcome, we had decided neither to reproduce these
that binary data should be presented in a report and divided by a
data nor to use them within our analyses. In this review, however,
’design effect’. This is calculated using the mean number of par-
loss of data was never more than 50% for any outcome or in any
ticipants per cluster (m) and the intra-class correlation coefficient
arm. If the loss of data had been more than 50% but the total loss
(ICC): [Design effect = 1 + (m − 1) * ICC] (Donner 2002). If
had been less than 50%, we would have marked such data with
the ICC had not been reported we would have assumed it to be
(*) to indicate that the result might have been prone to bias.
0.1 (Ukoumunne 1999). If cluster studies had been appropriately
analysed taking into account intra-class correlation coefficients
and relevant data documented in the report, synthesis with other
studies might have been possible using the generic inverse variance 2. Binary
technique.
Those who left the study early were all assumed to have the same
outcome as those who completed, with the exception of the out-
2. Cross-over trials
comes of death and adverse effects.

We only used data from the first phase of cross-over studies. A

major concern of cross-over trials is the carry-over effect. It occurs
if an effect (e.g. pharmacological, physiological or psychological) 3. Continuous
of the treatment in the first phase is carried over to the second
phase. As a consequence, on entry to the second phase participants
can differ systematically from their initial state despite a wash-out
phase. For the same reason cross-over trials are not appropriate 3.1 Attrition
if the condition of interest is unstable (Elbourne 2002). Because
Had attrition for a continuous outcome been between 0% and
both these effects are very likely in severe mental illness, we decided
50% and completer-only data had been reported, we would have
to use data from the first phase of cross-over studies only. In our
reproduced these data.
review, the Simpson 1999 trial was conducted in three phases of
16 weeks each, lasting for a total of 48 weeks with the last two
phases being crossed over. For this trial we included the data from
the first 16 weeks only (i.e. before cross-over occurred). 3.2 Standard deviations
In our review, there were few data whose standard deviations (SDs)
were missing. We tried to obtain the missing values from the au-
3. Studies with multiple treatment groups
thors, but were unsuccessful. Where there are missing measures of
There was no relevant additional treatment in any of the included variance for continuous data, but an exact standard error (SE) and
trials. If a study had involved additional treatment arms, we would confidence intervals available for group means, and either P value
have presented the additional arms in comparisons only if rele- or t value available for differences in mean, we can calculate them
vant and would not have reproduced data from irrelevant arms. according to the rules described in the Cochrane Handbook for Sys-
For binary data, we would simply have added these and combined tematic reviews of Interventions (Higgins 2011a): When only the
within a two-by-two table. For continuous data, we would have standard error (SE) is reported, SDs are calculated by the formula
combined the data following the formula in the Cochrane Hand- SD = SE * square root (n). The Cochrane Handbook for Systematic
book for Systematic Reviews of Interventions (Higgins 2011a). In reviews of Interventions (Higgins 2011a) present detailed formulae
cases where a study had two intervention arms which both fell for estimating SDs from P values, t or F values, confidence in-
within a single-dosage category defined in Types of interventions tervals, ranges or other statistics. If these formulae do not apply,
(for example, in Chen 2013 where both the 301 mg/day to 400 we could calculate the SDs according to a validated imputation
mg/day intervention and the 401 mg/day to 500 mg/day interven- method which is based on the SDs of the other included studies
tion fell within the ‘standard’ dose category), means and standard (Furukawa 2006). Although some of these imputation strategies
deviations were combined for continuous outcomes using meth- can introduce error, the alternative would be to exclude a given
ods described in section 7.7.3.8 of Higgins 2011a. study’s outcome and thus to lose information. We examined the
validity of the imputations in a sensitivity analysis excluding im-
puted values. In our review we needed to exclude some outcome
Dealing with missing data
data as suggested by this last option.

Clozapine dose for schizophrenia (Review) 14

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3.3 Last observation carried forward Assessment of reporting biases
We anticipated that in some studies the method of last observa-
tion carried forward (LOCF) would have been reported. As with
all methods of imputation to deal with missing data, LOCF in- 1. Protocol versus full study
troduces uncertainty about the reliability of the results (Leucht We attempted to locate protocols of the included randomised tri-
2007). We found no cases where less than 50% of the LOCF data als but were unsuccessful. We therefore compared the outcomes
were available; if we had, we would have reproduced these data listed in the Methods section of the trial report with those actually
and indicated that they were based on LOCF assumptions. reported in the results.

Assessment of heterogeneity 2. Funnel plot

Reporting biases arise when the dissemination of research findings
is influenced by the nature and direction of results (Egger 1997).
1. Clinical heterogeneity These are described in Chapter 10 of the Cochrane Handbook for
Systematic Reviews of Interventions (Sterne 2011). We are aware
We considered all included studies initially, without seeing com- that funnel plots may be useful in investigating reporting biases
parison data to judge clinical heterogeneity. We inspected all stud- but have limited power to detect small-study effects. We did not
ies for clearly outlying people or situations which we had not pre- use funnel plots as there were only three randomised controlled
dicted would arise, but we did not come across any such outlying studies included in this review.
conditions.

Data synthesis
2. Methodological heterogeneity
We understand that there is no closed argument in favour of ei-
We considered all included studies initially without seeing com- ther a fixed-effect or a random-effects model. The random-effects
parison data to judge methodological heterogeneity. We simply method incorporates an assumption that the different studies are
inspected all studies for clearly outlying methods which we had estimating different, yet related, intervention effects. This often
not predicted would arise, but we did not come across any such seems to be true to us and the random-effects model takes into
outlying methods. account differences between studies even if there is no statistically
significant heterogeneity. There is, however, a disadvantage to the
random-effects model: it adds weight to small studies, which often
3. Statistical heterogeneity are the most biased ones. Depending on the direction of effect,
these studies can either inflate or deflate the effect size. We chose
a random-effects model for all analyses. The reader is, however,
3.1 Visual inspection able to choose to inspect the data using the fixed-effect model by
opening this review in RevMan 5 format and selecting to view by
We visually inspected the graphs to investigate the possibility of
“fixed effect” model under the properties section of each graph.
statistical heterogeneity.

Subgroup analysis and investigation of heterogeneity

3.2 Employing the I² statistic
We investigated heterogeneity between studies by considering the
I² method alongside the Chi² P value. The I² provides an estimate 1. Subgroup analyses
of the percentage of inconsistency thought to be due to chance We had planned to report data on subgroups of participants (for
(Higgins 2003). The importance of the observed value of I² de- example, those who received additional medications or had addi-
pends on (i) magnitude and direction of effects, and (ii) strength tional diagnoses), but we did not encounter such subgroups.
of evidence for heterogeneity (e.g. P value from Chi² test, or a
confidence interval for I²). I² estimates greater than or equal to
50% and accompanied by a statistically significant Chi² statistic 1.1 Clinical state, stage or problem
are interpreted as evidence of substantial levels of heterogeneity This review provides an overview of the effects of clozapine for
(Deeks 2011). If substantial levels of heterogeneity had been found people with schizophrenia, schizophreniform and schizoaffective
in the primary outcome, we would have explored reasons for het- disorder. Our aim was also to report data on subgroups of people
erogeneity (Subgroup analysis and investigation of heterogeneity). in the same clinical state, stage and with similar problems (for

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
example patients in agitated state, partial remission, remission or but would have continued to employ our assumption. We did not
first episode), but we did not come across any such subgroups. have to make such assumptions in our review.

2. Investigation of heterogeneity 3. Risk of bias

We report if inconsistency was high. First, we investigated whether We analysed the effects of excluding trials that were judged to be
data were entered correctly. Secondly, if the data were correct, we at high risk of bias across one or more of the domains - randomi-
visually inspected the graphs and successively removed outlying sation, allocation concealment, blinding and outcome reporting
studies to see if heterogeneity was restored. For this review we and other bias - for the meta-analyses of the primary outcome. If
decided that we would present the data if this occurred in no the exclusion of trials at high risk of bias did not substantially alter
more than 10% of the total weighting of the summary findings. If the direction of effect or the precision of the effect estimates, then
not, we would not pool data but would only discuss the issues. If we included data from these trials in the analysis.
unanticipated clinical or methodological heterogeneity had been
obvious, we would have stated the hypotheses regarding these for
4. Imputed values
future reviews or versions of this review and would not have un-
dertaken analyses relating to these. We did not include any cluster trials. If any had been included, we
would have undertaken sensitivity analysis to assess the effects of
including data from trials where we had used imputed values for
Sensitivity analysis ICCs in calculating the design effect. If substantial differences in
the direction or precision of effect estimates in any of the sensitivity
analyses had been noted, we would not have pooled data, but
1. Implication of randomisation
would have presented them separately.

We would have included in a sensitivity analysis primary outcomes

data from studies where randomisation was implied but was not 5. Fixed-effect and random-effects
clearly described, but we did not come across such studies. If there We synthesised all data using a random-effects model.
had been no substantive difference when the implied randomised
studies were added to those with better description of randomisa-
tion, then we would have employed all data from these studies.

RESULTS
2. Assumptions for lost binary data
Where assumptions were made regarding participants lost to fol-
low-up (see Dealing with missing data) we would have compared Description of studies
the findings of the primary outcomes when we used our assump- For substantive description of studies please also see Characteristics
tion compared with completer data only. If there had been a sub- of included studies, Characteristics of excluded studies and Char-
stantial difference, we would have reported the results and dis- acteristics of ongoing studies.
cussed them but would have continued to employ our assumption.
Where assumptions were made regarding missing SDs data (see
Dealing with missing data), we would have compared the findings Results of the search
on primary outcomes when we used our assumption compared The search strategy yielded 122 citations. One was a duplicate.
with completer data only. We would have undertaken a sensitivity We closely inspected 23 full-text reports; and after excluding 18
analysis testing as to how prone results would have been to change full-text reports, we included five studies in the review. A random
with completer data only compared to the imputed data using the 20% of the citations were independently reviewed by one review
above assumption. If there would have been a substantial differ- author (BV) to increase reliability. Details of the search results are
ence, we would have reported these results and discussed them illustrated in the PRISMA table (Figure 2).

Clozapine dose for schizophrenia (Review) 16

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(range 35 to 54) suffering from schizophrenia, treatment refrac-
Included studies
tory or schizoaffective disorder, diagnosed by DSM-III-R criteria.
We included five studies with a total of 452 participants. Mean illness duration was 25.1 years (range 1 to 38 years) and the
median number of psychiatric hospitalisations was five (range 1
to 25). Patients had not shown a satisfactory clinical response to
1. Study length
treatment with at least three neuroleptic drugs (each given for at
Chen 1998 and Chen 2013 were short-term trials lasting six weeks. least six weeks in doses equivalent to 1000 mg/day of chlorpro-
Sheng 1990 and Liu 2005 were also short term (12 weeks). The mazine).
Simpson 1999 trial was originally conducted in three phases of
16 weeks each, lasting for a total of 48 weeks. However, after the
first 16 weeks, the non-responders in the trial were crossed over 4. Settings
to other arms and hence they were not randomised anymore after Simpson 1999 used a research ward inpatient setting in a State
the initial 16 weeks. So, as per protocol, we included the results hospital in the USA. Liu 2005 was conducted in an inpatient
of only the first 16 weeks (medium term: 13 to 26 weeks) from setting in a medical college. The settings for Chen 1998, Chen
these citations. There were no long-term studies (> 26 weeks). 2013 and Sheng 1990 were unclear.

2. Design
5. Interventions
All included studies were randomised controlled trials. Chen 1998
We classified interventions into five groups according to clozapine
is a randomised controlled trial comparing the efficacy of cloza-
dosage. Liu 2005 administered clozapine at less than 150 mg/day
pine at doses of 200 mg and 500 mg; details of blinding status
(very low dose), at 150 mg/day to 300 mg/day (low dose) and at
and of any sponsorship are unclear. Liu 2005 is a randomised con-
more than 300 mg/day (standard dose). Simpson 1999 adminis-
trolled trial comparing clozapine at doses of less than 150 mg/day,
tered clozapine at 100 mg/day (very low dose), 300 mg/day (low
150 mg/day to 300 mg/day and more than 300 mg/day, in which
dose) and 600 mg/day (standard dose). Chen 1998 administered
participants were allocated using a random number table; details
clozapine at 200 mg/day (low dose) and at 500 mg/day (standard
of blinding status and of any sponsorship are unclear. Chen 2013
dose). Chen 2013 administered doses of 200 mg/day to 300 mg/
is a randomised trial comparing doses of 200 mg/day to 300 mg/
day, 301 mg/day to 400 mg/day and 401 mg/day to 500 mg/day.
day, 301 mg/day to 400 mg/day and 401 mg/day to 500 mg/day.
Sheng 1990 administered doses of 300 mg/day and 600 mg/day.
Sheng 1990 is a randomised trial comparing doses of 300 mg/day
No trial administered clozapine at more than 601 mg/day (high
and 600 mg/day. Simpson 1999 is an implied randomised con-
dose) or more than 901 mg/day (very high dose).
trolled trial comparing the efficacy of clozapine at different doses
of 100 mg/day, 300 mg/day and 600 mg/day in 50 patients. The
trial was sponsored by Novartis Pharmaceuticals and conducted 6. Outcomes
between 1992 and 1995; the participants stayed in the research
centre for four weeks for adaptation (naturalistic baseline with no
modification in their treatment regimen) and underwent a four- 6.1 Rating scales
week haloperidol treatment followed by a one-week wash out be-
Details of the scales that provided usable data are shown below.
fore the first phase of clozapine treatment.
Reasons for exclusions of data and/or scales are given under ‘Out-
comes’ in the Characteristics of included studies table.
3. Participants
A total of 452 participants were included in the five trials. Chen
1998 conducted their study on a total of 176 male and female pa- 6.1.1 Mental state
tients, aged between 17 and 55 years, suffering from schizophre-
nia and with illness duration of 8 (± 11 months) on average. Liu 6.1.1.1 Brief Psychiatric Rating Scale BPRS (Overall 1962)
2005 included 87 male patients aged between 18 and 45 years and The BPRS is an 18-item scale measuring positive symptoms, gen-
used CCMD-3 to diagnose patients suffering from schizophre- eral psychopathology and affective symptoms. High scores indi-
nia. Chen 2013 and Sheng 1990 randomised 90 and 51 patients cate more severe symptoms. The original scale has 16 items that
with schizophrenia, respectively. Simpson 1999 was conducted on are rated in interview format using Likert scale ratings from 1
a total of 22 males and 28 females with a mean age of 44.8 years (‘absent’) to 7 (‘very severe’) with scores ranging from 0 to 112. A

Clozapine dose for schizophrenia (Review) 18

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
revised 18-item scale is commonly used with scores ranging from excluded Han 2001 as different doses of sulpiride were prescribed
0 to 126. The BPRS-A is an anchored version of the BPRS. It in the clozapine arms. VanderZwaag 1996 and VanderZwaag 1997
describes expected symptoms and problems for each of the seven compared the effectiveness of different serum clozapine levels, but
rating options for each item. As such, it is thought that the BPRS- not the effects of different doses of clozapine. Nair 1998 and
A anchor points provide an increased level of standardisation, lead- Nair 1999 were excluded because the authors compared those
ing to an improvement in rater reliability (Woerner 1988). The with and without probable tardive dyskinesia in subgroups of 23
BPRS-A and its subscales have been validated (Lachar 2001). Chen and 33 participants respectively from the Simpson 1999 trial, but
1998 and Simpson 1999 reported data on the BPRS-A. provided no additional data relevant to this review.

Studies awaiting classification

6.1.2 Adverse events
Abraham 1997 is a report of a trial conducted from 1992 to 1995,
6.1.2.1 Treatment-Emergent Signs and Symptoms - TESS ( reported in detail in Simpson 1999 where it is mentioned that
NIMH 1985) global state was measured using the Clinical Global Impression
This checklist assesses a variety of characteristics for each adverse (CGI) and these data would be discussed in Abraham 1997. How-
event, including severity, relationship to the drug, temporal char- ever, Abraham 1997 only retrospectively analysed the data on re-
acteristics (timing after a dose, duration and pattern during the sponders and non-responders; four participants responded, but it
day), contributing factors, course, and action taken to counteract was unclear from the report which groups they belonged to and the
the effect. Symptoms can be listed a priori or can be recorded as CGI data for the dosage groups were also missing. We contacted
observed by the investigator. A low score indicates low levels of the main trialist who indicated he would provide the missing data,
adverse effects. Chen 1998 and Chen 2013 reported data on this but this has not been received at the time of writing. If we receive
outcome. this subsequently, we will include it in an update of this review.

Excluded studies Ongoing studies

Of the 122 references identified using the search strategy, one was We did not identify any ongoing studies.
a duplicate. We closely inspected 28 reports and excluded 23. Liu
2005a and Tang 2000 were not randomised trials. All data were
missing in de Leon 1995a and de Leon 2004 and we contacted the
Risk of bias in included studies
author who confirmed that no further data were available. de Leon None of the studies explicitly described the allocation process fully.
2003 was excluded as the data on serum antimuscarinic activity Some of the studies were selective in presenting their data on
was missing at 16 weeks before the cross-over point. Potkin 1993 outcomes. Some of the outcomes in the trials could not be used and
and Potkin 1994 also had all data missing from the reports and no we have not received missing data we requested from the authors
data were useable; we contacted the author regarding the missing of the trials. Simpson 1999 was a trial sponsored by a clozapine
data but no response has been received at the time of writing. We drug company. See Figure 3, Figure 4.

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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 4. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation
of findings 3 Clozapine: low dose (150 mg/day to 300 mg/
All five studies were described as randomised. Allocation in Liu day) versus standard dose (301 mg/day to 600 mg/day) for
2005 was via a random number generator. Simpson 1999, Sheng schizophrenia
1990, Chen 2013 and Chen 1998 did not describe the methods In the text below, data from Simpson 1999 have been adjusted
used to generate the allocation sequence. None of the studies re- in accordance with the published corrections (Simpson 2001).
ported on how the results of allocation were concealed. Specifically, the standard errors for BPRS-A endpoint scores which
were originally reported by the authors as if they were standard
deviations have been converted to standard deviations.
Blinding
Simpson 1999 was described as a double-blind trial with assessors
blinded and all patients receiving the same number of identical Comparison 1: clozapine: very low dose (up to 149
capsules every time, although the authors appear not to have tested mg/day) versus low dose (150 mg/day to 300 mg/day)
the success of blinding for participants or evaluators. This may
increase the risk of observer bias with potential for overestimation
of positive effects and underestimation of negative ones. Chen 1.1 Mental state: average endpoint scores (BPRS-A, high =
1998 and Liu 2005 did not report if their trials were blinded. poor) - medium term
Chen 2013 and Sheng 1990 did not report how blinding took Simpson 1999 found no significant difference in endpoint mental
place. Blinding may be less important for objective outcomes such state scores at 16 weeks measured using the BPRS-A (n = 31, MD
as death, but the studies included here reported only subjective 3.55, 95% CI −4.50 to 11.60; Analysis 1.1).
outcomes.

1.2 Adverse effects: 1a. weight - BMI (kg/m²) - short term

Incomplete outcome data Liu 2005 found no significant difference in BMI at the end of six
Chen 1998, Chen 2013 and Sheng 1990 appear to have had no weeks in the very low dose group compared to the low dose group
loss to follow up. Liu 2005 reported on three participants who left (n = 59, MD −0.10, 95% CI −0.95 to 0.75; Analysis 1.2).
the study early with clear reasons for doing so. Simpson 1999 re-
ported the number leaving the study early and explicitly described
1.3 Adverse effects: 1b. weight gain (kg; average)
that their last observations were carried forward; however, data on
the scale for the Assessment of Negative Symptoms (SANS) were Simpson 1999 (reported in de Leon 2007) found no significant
not reported. de Leon 2007 reported data on patients who com- difference between the groups in weight gain at week 12 (n =
pleted the Simpson 1999 trial. However the number of patients 27, 1 RCT, MD −1.10, 95% CI −3.93 to 1.73; Analysis 1.3).
on whom measures were reported differed slightly from week to There was similarly no significant difference between the groups
week, and it is unclear why the number of patients on whom mea- in weight gain at 16 weeks (n = 28, 1 RCT, MD −1.30, 95% CI
surements were reported at each week differed, who had missed −4.86 to 2.26; Analysis 1.3).
their measurements and why the measurements were not taken.
1.4 Adverse effects: 1c. weight - body weight at endpoint (kg;
Selective reporting average) - short term

Simpson 1999 did not report on SANS. Sheng 1990 did not report Liu 2005 found no significant difference in body weight between
BPRS or TESS scores. Simpson 1999 reported responders’ and the groups at the end of six weeks (n = 59, 1 RCT, MD 0.00, 95%
non-responders’ data only at 48 weeks, which is after the cross- CI −3.92 to 3.92; Analysis 1.4).
over point at 16 weeks. No data is reported before the cross-over. One study, Liu 2005, reported on two other adverse effects.

Effects of interventions 1.5 Adverse effects: 2a. metabolic - blood glucose - before
See: Summary of findings for the main comparison Clozapine: and after meal
very low dose (up to 149 mg/day) versus low dose (150 mg/day No difference between the groups were found before a meal (n =
to 300 mg/day) for schizophrenia; Summary of findings 2 59, 1 RCT, MD −0.40, 95% CI −1.06 to 0.26), one hour after
Clozapine: very low dose (up to 149 mg/day) versus standard meal (n = 59, 1 RCT, MD −0.70, 95% CI −2.01 to 0.61), two
dose (301 mg/day to 600 mg/day) for schizophrenia; Summary hours after meal (n = 59, 1 RCT, MD 0.30, 95% CI −0.98 to

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1.58) and three hours after meal (n = 59, 1 RCT, MD −0.70, 2.2 Adverse effects: 1a. weight - BMI (in kg/m²) - short term
95% CI −1.59 to 0.19). There was no significant difference in Liu 2005 found no significant difference in body mass index (BMI)
the overall analysis (n = 59, 1 RCT, MD −0.43, 95% CI −0.89 at the end of six weeks in the very low dose group compared to the
to 0.03; Analysis 1.5). standard-dose group (n = 58, 1 RCT, MD 0.10, 95% CI −0.76
to 0.96; Analysis 2.2).

1.6 Adverse effects: 2b. metabolic - lipid profile - short term

2.3 Adverse effects: 1b. weight - weight gain (kg; average)
Participants on low-dose clozapine had significantly lower serum
Simpson 1999 (reported by de Leon 2007) found significantly
triglycerides than those on a very low dose (n = 59, 1 RCT, MD
lower weight gain in the very low dose group at 12 weeks (n =
1.00, 95% CI 0.51 to 1.49). Otherwise there was no significant
27, 1 RCT, MD −2.70, 95% CI −5.38 to −0.02), although no
difference between the groups in terms of serum total cholesterol
significant difference between the groups at 16 weeks (n = 28, 1
(n = 59, 1 RCT, MD 0.50, 95% CI −0.12 to 1.12), high density
RCT, MD −3.10, 95% CI −6.73 to 0.53; Analysis 2.3).
lipoprotein (HDL) (n = 59, 1 RCT, MD 0.04, 95% CI −0.14 to
0.22), low density lipoprotein (LDL) (n = 59, 1 RCT, MD 0.10,
95% CI −0.36 to 0.56), Apo-A1 (n = 59, 1 RCT, MD 0.05, 95% 2.4 Adverse effects: 1c. body weight at endpoint - short term
CI −0.10 to 0.20) and Apo-B (n = 59, 1 RCT, MD 0.13, 95% (kg; average)
CI −0.16 to 0.42). All Analysis 1.6.
Liu 2005 found no significant difference in body weight between
the groups at six weeks (n = 58, 1 RCT, MD 1.00, 95% CI −2.66
to 4.66; Analysis 2.4).
1.7 Leaving the study early

Simpson 1999 found no significant difference in numbers leav- 2.5 Adverse effects: 2a. metabolic - blood glucose - short
ing the study early between the groups in the medium term for term
any reason (n = 31, 1 RCT, RR 6.00, 95% CI 0.31 to 115.56;
Analysis 1.7). Liu 2005 reported no significant difference between Liu 2005 found that glucose level one hour after a meal was sig-
the groups in the short term due to specific side effects (n = 60, 1 nificantly less in the very low dose group (n = 58, 1 RCT, MD
RCT, RR 0.33, 95% CI 0.01 to 7.87; Analysis 1.7). The overall −1.60, 95% CI −2.90 to −0.30). There was no significant differ-
analysis showed no significant difference in the numbers leaving ence between the groups before meal (n = 58, 1 RCT, MD −0.10,
the study early between the very low dose and the low-dose groups 95% CI −0.68 to 0.48), two hours after meal (n = 58, 1 RCT,
in the short and medium term (n = 91, 2 RCTs, RR 1.50, 95% MD −0.60, 95% CI −1.89 to 0.69) or three hours after meal (n
CI 0.09 to 25.41; Analysis 1.7). = 58, 1 RCT, MD −0.30, 95% CI −1.55 to 0.95). There was no
significant difference in the overall analysis between the groups (n
= 58, 1 RCT, MD −0.49, 95% CI −1.12 to 0.13). All Analysis
2.5.
Missing outcomes

For this comparison, no studies reported on global state, death,

2.6 Adverse effects: 2b. lipid profile - short term
behaviour, functioning, quality of life, satisfaction with treatment,
service use and economic costs. Liu 2005 found that standard dose was associated with signifi-
cantly lower serum levels of total cholesterol (n = 58, 1 RCT, MD
1.00, 95% CI 0.20 to 1.80), triglycerides (n = 58, 1 RCT, MD
1.30, 95% CI 0.81 to 1.79) and Apo-B (n = 58, 1 RCT, MD
Comparison 2: clozapine: very low dose (up to 149 0.23, 95% CI 0.01 to 0.45). No significant difference was found
mg/day) versus standard dose (301 mg/day to 600 between the groups in high density lipoprotein (HDL) (n = 58, 1
mg/day) RCT, MD 0.10, 95% CI −0.13 to 0.33), low density lipoprotein
(LDL) (n = 58, 1 RCT, MD 0.00, 95% CI −0.39 to 0.39) or Apo-
A1 levels (n = 58, 1 RCT, MD 0.04, 95% CI −0.10 to 0.18). All
Analysis 2.6.
2.1 Mental state: average endpoint scores (BPRS-A, high =
poor) - medium term

Simpson 1999 found no significant difference in mean endpoint 2.7 Leaving the study early
BPRS-A scores at 16 weeks (n = 31, 1 RCT, MD 6.67, 95% CI Simpson 1999 found no significant difference in numbers leaving
−2.09 to 15.43; Analysis 2.1). the study early for any reason between the groups in the medium

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
term (n = 31, 1 RCT, RR 1.21, 95% CI 0.20 to 7.55). Liu 2005 3.3.3 Conceptual Disorganisation
reported no significant difference between the groups in numbers Chen 1998 found no significant difference between the groups
leaving the study early due to specific physical side effects in the at week 6 (n = 176, 1 RCT, MD 0.20, 95% CI −0.02 to 0.42,
short term (n = 60, 1 RCT, RR 0.20, 95% CI 0.01 to 4.00). Analysis 3.2.5).
The overall analysis showed no significant difference between the
groups (n = 91, 2 RCTs, RR 0.73, 95% CI 0.14 to 3.72; Analysis
2.7). 3.3.4 Excitement
Chen 1998 found no significant difference between the groups
at week 6 (n = 176, 1 RCT, MD 0.00, 95% CI −0.10 to 0.10;
Missing outcomes Analysis 3.3).
For this comparison, no studies reported on global state, death,
behaviour, functioning, quality of life, satisfaction with treatment,
3.3.5 Uncooperativeness
service use and economic costs.
Chen 1998 found no significant difference between the groups
at week 6 (n = 176, 1 RCT, MD 0.00, 95% CI −0.21 to 0.21;
Comparison 3: clopazine: low dose (150 mg/day to Analysis 3.3).
300 mg/day) versus standard dose (301 mg/day to 600
mg/day) 3.4 Mental state: 1d. clinical improvement (clinician
assessed)
There was no significant difference between groups at 12 weeks
3.1 Mental state: 1a. clinically important response (BPRS (Chen 1998; Chen 2013) (n = 141, 2 RCTs, RR 0.76, 95% CI
score > 30% change) 0.36 to 1.61; Analysis 3.4).
Chen 1998 found no significant difference in curative rate between
the groups (n = 176, 1 RCT, RR 0.93, 95% CI 0.78 to 1.10;
3.5 Adverse effects: 1a. weight - BMI (in kg/m²) - short term
Analysis 3.1).
Liu 2005 found no significant difference in body mass index at the
end of six weeks in the low dose group compared to the standard
3.2 Mental state: 1b. average endpoint score (BPRS-A total, dose group (n = 57, 1 RCT, MD 0.20, 95% CI −0.84 to 1.24;
high = poor) Analysis 3.5)

Chen 1998 reported no significant difference between the groups

for total scores at week 6 (n = 176, 1 RCT, MD 1.70, 95% CI 3.6 Adverse effects: 1b. weight - weight gain (kg; average)
−1.26 to 4.66; Analysis 3.2). Simpson 1999 reported no signifi- Simpson 1999 (reported in de Leon 2007) found no significant
cant difference between the groups for total scores at 16 weeks (n difference in weight gain between the groups at week 12 (n = 30,
= 34, 1 RCT, MD 3.12, 95% CI −4.20 to 10.44; Analysis 3.2). 1 RCT, MD −1.60, 95% CI −4.47 to 1.27) or week 16 (n = 30,
MD −1.80, 95% CI −5.38 to 1.78; Analysis 3.6).

3.3 Mental state: 1c. average endpoint score (BPRS-A,

subscores, high = poor) 3.7 Adverse effects: 1c. body weight at endpoint (kg;
average) - short term
Liu 2005 found no significant difference in body weight between
3.3.1 Anxiety the groups in the short term (n = 57, 1 RCT, MD 1.00, 95% CI
−3.42 to 5.42; Analysis 3.5.4).
Chen 1998 found no significant difference between the groups
at week 6 (n = 176, 1 RCT, MD 0.00, 95% CI −0.09 to 0.09;
Analysis 3.3). 3.8 Adverse effects: 2a. metabolic - blood glucose - short
term
Liu 2005 found no significant difference in glucose levels between
3.3.2 Blunted Affect the groups before meal (n = 57, 1 RCT, MD 0.30, 95% CI −0.23
Chen 1998 found no significant difference between the groups to 0.83; Analysis 3.8), one hour after meal (n = 57, 1 RCT, MD
at week 6 (n = 176, 1 RCT, MD 0.00, 95% CI −0.18 to 0.18; −0.90, 95% CI −2.33 to 0.53; Analysis 3.8), two hours after meal
Analysis 3.3). (n = 57, 1 RCT, MD −0.90, 95% CI −2.14 to 0.34; Analysis

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3.8), three hours after meal (n = 57, 1 RCT, MD 0.40, 95% CI Meta-analysis of two studies, Chen 1998 and Chen 2013, found
−0.84 to 1.64; Analysis 3.8). There was no difference between total TESS scores were significantly lower in the low-dose group
the groups in the overall analysis (1 RCT, MD −0.12, 95% CI compared to standard dose (n = 124, 2 RCTs, MD −3.99, 95%
−0.79 to 0.56; Analysis 3.8). CI −5.75 to −2.24; Analysis 3.11). Chen 1998 found that TESS
scores were significantly lower in the low-dose group compared
to standard dose on sub scores for behavioural toxicity (n = 176,
3.9 Adverse effects: 2b. metabolic - lipid profile - short term 1 RCT, MD −1.00, 95% CI −1.51 to −0.49; Analysis 3.11),
Liu 2005 found no significant difference between the groups in vegetative nervous system (n = 176, 1 RCT, MD −0.90, 95%
serum total cholesterol (n = 57, 1 RCT, MD 0.50, 95% CI −0.29 CI −1.61 to −0.19; Analysis 3.11) and cardiovascular system (n
to 1.29; Analysis 3.9), triglycerides (n = 57, 1 RCT, MD 0.30, 95% = 176, 1 RCT, MD −0.60, 95% CI −0.98 to −0.22; Analysis
CI −0.12 to 0.72; Analysis 3.9), high density lipoprotein (HDL) 3.11).
(n = 57, 1 RCT, MD 0.06, 95% CI −0.16 to 0.28; Analysis 3.9),
low density lipoprotein (LDL) (n = 57, 1 RCT, MD −0.10, 95%
3.12 Leaving the study early
CI −0.50 to 0.30; Analysis 3.9), Apo A-1 (n = 57, 1 RCT, MD
−0.01, 95% C −0.14 to 0.12; Analysis 3.9) and Apo-B levels (n For this comparison, no participant left the study early in Chen
= 57, 1 RCT, MD 0.10, 95% CI −0.14 to 0.34; Analysis 3.9). 1998. Simpson 1999 found no significant difference in numbers
leaving the study early for any reason between the groups in the
medium term (n = 34, 1 RCT, RR 0.20, 95% CI 0.01 to 3.88;
3.10 Adverse effects: 3. various effects - short term Analysis 3.12). Liu 2005 found no significant difference in num-
bers leaving the study early between the groups in the short term
Chen 1998 found a significantly greater incidence in the standard
due to specific side effects (n = 60, 1 RCT, RR 0.50, 95% CI
compared to the low dose group for lethargy (n = 176, RR 0.77,
0.05 to 5.22; Analysis 3.12). There was no difference between the
95% CI 0.60 to 0.97; Analysis 3.10), hypersalivation (n = 176,
groups in the overall analysis (n = 47, 2 RCTs, RR 0.35, 95% CI
RR 0.70, 95% CI 0.57 to 0.84; Analysis 3.10), dizziness (n = 176,
0.06 to 2.21; Analysis 3.12).
RR 0.56, 95% CI 0.39 to 0.81; Analysis 3.10) and tachycardia (n
= 176, RR 0.57, 95% CI 0.45 to 0.71; Analysis 3.10).
Missing outcomes
For this comparison, no studies reported on global state, death,
3.11 Adverse effects: 4. average endpoint score (TESS, high
behaviour, functioning, quality of life, satisfaction with treatment,
= poor) - short term
service use and economic costs.

Clozapine dose for schizophrenia (Review) 25

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

CLOZAPINE: VERY LOW DOSE (up to 149 mg/ day) versus STANDARD DOSE (301- 600 mg/ day) for schizophrenia

Patient or population: patients with schizophrenia

Settings:
Intervention: Clozapine: very low dose (up to 149 m g/ day) versus standard dose (301 m g/ day to 600 m g/ day)

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Control Clozapine: very low

dose (up to 149 mg/
day) versus standard
dose (301 mg/ day to
600 mg/ day)

Global state: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important response, as (0) outcom e.
defined by individual
studies

M ental state: clinically The m ean clinical re- 31 ⊕ * Pre-def ined outcom e
important response, as sponse: m ental state (1 study) very low1,2,3 not reported: M ental
defined by individual - average scores - state m easured as av-
studies * m edium term end- erage endpoint scores
Follow-up: 16 weeks point (BPRS-A, high = (BPRS-A, high = worse)
worse) in the interven-
tion group was
6.67 higher
(2.09 to 15.43 higher)
26
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review)

Functioning: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important change in (0) outcom e.
general functioning, as
defined by individual
studies

Adverse effect: clin- The m ean adverse ef - 58 ⊕⊕

Service use: number of See com m ent See com m ent Not estim able 0 See com m ent No study reported this
days hospitalised (0) outcom e.

Service use: time to See com m ent See com m ent Not estim able 0 See com m ent No study reported this
hospitalisation (0) outcom e.

Quality of life: clini- See com m ent See com m ent Not estim able 0 See com m ent No study reported this
cally important change (0) outcom e.
in general quality of life

* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is
based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: Conf idence interval;

GRADE Working Group grades of evidence

200)
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28
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review)

Clozapine: low dose (150 mg/ day to 300 mg/ day) versus standard dose (301 mg/ day to 600 mg/ day) for schizophrenia

Patient or population: patients with schizophrenia

Settings:
Intervention: Clozapine: low dose (150 m g/ day to 300 m g/ day) versus standard dose (301 m g/ day to 600 m g/ day)

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Control Clozapine: low dose

(150 mg/ day to 300
mg/ day) versus stan-
dard dose (301 mg/ day
to 600 mg/ day)

Global state: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important response, as (0) outcom e.
defined by individual
studies

M ental state: clinically Low1 RR 0.93 176 ⊕⊕

important response in (0.78 to 1.1) (1 study) low 1,3
mental state 200 per 1000 186 per 1000
BPRS score >30% (156 to 220)
change
Follow-up: 6 weeks M oderate 1

500 per 1000 465 per 1000

(390 to 550)

High1

800 per 1000 744 per 1000

(624 to 880)
29
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review)

Functioning: clinically See com m ent See com m ent Not estim able 0 See com m ent No study reported this
important change in (0) outcom e.
general functioning, as
defined by individual
studies

Adverse effect: clin- The m ean adverse ef - 57 ⊕⊕

ically important ad- f ect - any clinically (1 study) low2,3
verse effect ( weight - im portant specif ic ad-
BM I) verse ef f ects - BM I in
Follow-up: 6 weeks the intervention group
was
0.2 higher
(0.84 lower to 1.24
higher)

Service use: number of See com m ent See com m ent Not estim able 0 See com m ent No study reported this
days hospitalised (0) outcom e.

Service use: time to See com m ent See com m ent Not estim able 0 See com m ent No study reported this
hospitalisation (0) outcom e.

Quality of life: clini- See com m ent See com m ent Not estim able 0 See com m ent No study reported this
cally important change (0) outcom e.
in general quality of life

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low quality: We are very uncertain about the estim ate.
1 Risk of bias rated as ’serious’ (downgraded by 1) as allocation concealm ent, blinding status and trial sponsorship unclear
30
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Clozapine dose for schizophrenia (Review)
2Indirectness: rated ’serious’ (downgraded by 1) as proxy m easure of pre-def ined outcom e
3Im precision: rated as ’serious’ (downgraded by 1) as only one study providing data, sm all num ber of participants (less than
200)
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31
DISCUSSION on which arm the four responders belonged to but we have not
received the data at the time of writing.
There were no studies comparing high dose or very high dose of
clozapine and none of the reports identified presented outcomes
Summary of main results in the longer term.

We included five studies with data from 452 participants suffering

from schizophrenia and schizoaffective disorders diagnosed by any 1 Comparison: clozapine: very low dose (up to 149
criteria. We categorised doses of clozapine into five categories: very mg/day) versus low dose (150 mg/day to 300 mg/day)
low dose clozapine: up to 149 mg/day; low-dose clozapine: 150
mg/day to 300 mg/day; standard-dose clozapine: 301 mg/day to
600 mg/day; high-dose clozapine: 601 mg/day to 900 mg/day; Short term
and very high dose clozapine: 901 mg/day and above. Simpson We found no evidence relating to clinical response. In terms of ad-
1999 compared the effects of clozapine at doses of 100 mg/day verse effects, in one RCT of 59 participants there was no difference
(very low), 300 mg/day (low dose) and 600 mg/day (standard between the groups in BMI at endpoint with the very low dose
dose) over both short term (up to 12 weeks) and medium term (16 group only 0.1 lower (0.95 lower to 0.75 higher) (Liu 2005). On
weeks). Chen 2013 compared doses of 200 mg/day to 300 mg/ other outcomes, the same study found low-dose clozapine asso-
day, 301 mg/day to 400 mg/day, and 401 mg/day to 500 mg/day ciated with lower serum triglycerides compared to very low dose,
over 12 weeks. Sheng 1990 compared doses of 300 mg/day and but no differences between the groups in other elements of the
600 mg/day over 12 weeks. Liu 2005 compared effects of three lipid profile, in blood glucose levels, in body weight at endpoint
different doses of clozapine: less than 150 mg/day (very low dose); or in leaving the study early.
150 mg/day to 300 mg/day (low dose); and more than 300 mg/
day (standard) over short term.
Liu 2005 reported over six weeks on outcomes including leaving Medium term
the study early, body weight, body mass index (BMI), lipid profile We found no evidence relating to clinical response. In one small
and blood glucose levels measured before meals, and one hour, two RCT of 31 participants (Simpson 1999), there was no difference
hours and three hours after meals. Chen 2013 reported on mental between the groups in average BPRS-A scores and no difference
state as clinical improvement (clinician assessed), and on TESS on change in mental state score. On other outcomes, no difference
scale scores. Outcomes reported by Sheng 1990 were mental state was found between the groups in terms of weight gain or number
as clinical improvement (clinician assessed), but the authors did leaving the study early (Simpson 1999).
not report BPRS scores or TESS scale scores.
Chen 1998 compared clozapine at doses of 200 mg/day (low dose)
and 500 mg/day (standard dose) in short-term and reported data 2 Comparison: clozapine: very low (up to 149 mg/day)
over six weeks on outcomes including global state on clinically versus standard dose (301 mg/day to 600 mg/day)
important response as defined by individual studies (curative rate:
BPRS score < 30% change = no improvement), mental state on the
Brief Psychiatric Rating scale-Anchored (BPRS-A) and subscores Short term
of this scale, and adverse reaction using the TESS scale and the We found no evidence relating to clinical response in the short
incidence of lethargy, hypersalivation, dizziness, and tachycardia. term. In terms of adverse effects, in one RCT of 58 participants
Simpson 1999 reported on leaving the study early, BPRS-A total there was no difference between the groups in BMI at endpoint
scores. Though their report stated that they measured CGI and with the very low dose group only 0.1 higher (0.76 lower to 0.96
SANS, these data were not reported in the paper. Data on end body higher) (Liu 2005). There was no difference in body weight at
weight, weight gain and BMI over shorter term and medium term endpoint in the same study, although the very low dose group had
were reported in de Leon 2007. Data on BMI could not be used as less weight gain than the standard-dose group at six and 12 weeks.
it was not presented according to doses. We also could not use data On other outcomes, we found evidence in one study that the
on “clinically important response as defined by individual studies” very low dose group had lower glucose levels one hour post meal
as the details of responders were presented only at 48 weeks and compared to the standard-dose group, but otherwise there was no
not at 16 weeks (before cross-over). In addition, it is reported that difference between the groups in blood glucose measurements (Liu
four people responded at end of 16 weeks, but it is unclear which 2005); and no difference between the groups in numbers leaving
dosage group these four patients belonged to. Simpson 1999 stated the study early. In the same study, at six weeks standard dose was
that data on CGI would be discussed in Abraham 1997, but we associated with lower serum triglycerides, serum total cholesterol
found this was not the case. We contacted the author for data and Apo-B, but otherwise there was no difference between the
on CGI, SANS, data on responders at 16 weeks and the details groups in terms of lipid profile (Liu 2005). These results should

Clozapine dose for schizophrenia (Review) 32

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
be interpreted with caution as this trial was conducted only for six a number of outcomes could not be extracted. Four of the five
weeks with a small number of participants. included studies were based on a small number of participants.
The quality of the evidence available was judged very low to low,
and the following findings should be interpreted cautiously. We
Medium term
found no evidence relating to clinical response in the short or
We found no evidence relating to clinical response in the medium medium term. At the end of six weeks, incidence of lethargy, hy-
term. On other outcomes, no differences between the groups were persalivation, dizziness and tachycardia was lower at low- com-
found in the medium term for weight gain or numbers leaving the pared to standard-dose regimes; also side effects as measured by
study early (Simpson 1999). the Treatment Emergent Side Effect Scale (TESS) were less at low
compared to standard dose. At six weeks, very low dose was as-
3. Comparison: clozapine: low dose (150 mg/day to sociated with lower levels of blood glucose one hour post meal
300 mg/day) versus standard dose (301 mg/day to 600 than standard dose and weight gain was the least in this group. At
mg/day) six weeks, standard dose was associated with lower serum triglyc-
erides, serum total cholesterol and Apo-B than very low dose, and
low-dose recipients had lower serum triglycerides than those on
Short term very low dose. This might suggest that the lipid variation may not
We found no evidence relating to clinical response or to clinically be associated with doses of clozapine in the short term, such as
significant response in global state in the short term. In one RCT six weeks’ duration, but more trials are needed to validate the side
of 57 participants there was no difference between the groups in effects of clozapine long term
BMI at endpoint with the low-dose group only 0.2 higher (0.84
lower to 1.24 higher) (Liu 2005). On other outcomes, there was
no difference between the groups on body weight at endpoint, Overall completeness and applicability of
lipid profile or blood glucose measurements. Side effects measured evidence
by TESS were less in the low-dose group in two studies (Chen
1998; Chen 2013), and the incidence of lethargy, hypersalivation,
dizziness and tachycardia were also less in the low-dose group in Completeness
one study (Chen 1998). We suggest that the studies identified are insufficient to clearly
identify what dose of clozapine is optimal for people suffering
from schizophrenia and schizophreniform psychosis to gain a de-
Medium term
sired response to illness, attain remission and experience an im-
We found no evidence from one RCT of 34 participants that proved quality of life. Important information on outcomes rele-
mental state at endpoint, numbers leaving the study early or weight vant to clinicians, consumers and policy makers (such as relapse,
gain differed between the groups (Simpson 1999). remission, social functioning and quality of life, service utilisation,
cost-effectiveness, satisfaction with care, and quality of life) is not
4. Missing outcomes currently available.
There was no information available on other important outcomes
such as clinically significant response in social or life skills, relapse, Applicability
prolactin increase, service use, satisfaction with care or quality of The five studies in our review reported on 14 outcomes and only
life. on short-term and medium-term durations. We could not identify
any studies which compared high and very high doses of clozapine
5. Summary
or which considered outcomes long term. This can lead to diffi-
culties in generalising our findings in the management of chronic
We identified just three randomised controlled trials that met our
illness such as schizophrenia. The evidence appears to be incom-
inclusion criteria. We looked at a range of different doses includ- plete and there are various limitations in the applicability of the
ing very low (up to 149 mg/day), low (150 mg/day to 300 mg/
results from our review.
day), standard (301 mg/day to 600 mg/day), high (601 mg/day
to 900 mg/day) and very high (901 mg/day and above). All trials
identified compared very low dose, low dose and standard dose
only. No trials were identified comparing high dose or very high
Quality of the evidence
dose to standard dose. Two studies were only of six weeks’ and two The quality of the evidence was poor. Only one of the included
were of 12 weeks’ duration; one study relates to a trial of 48 weeks, studies was clearly described as a double blind trial; the other
but only for a 16-week period before crossing over. The data for studies were not clear about blinding status. In addition, data were

Clozapine dose for schizophrenia (Review) 33

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
selectively reported in some papers, which raises the possibility of 2. For clinicians
bias. The quality of the evidence was also limited by the small Based on effects on mental state, we found no evidence on the
number of participants reported on by Simpson 1999 (n = 31), optimal dosing of clozapine. Careful consideration has to be given
Chen 2013 (n = 90), Sheng 1990 (n = 51) and Liu 2005 (n = to balancing the advantages and disadvantages of different dosing
59). It is also of concern that two trials were conducted only for schemes, in particular in relation to side effects which seem to be
six weeks. Schizophrenia is a chronic illness and medications such lower at lower doses. We were unable to identify any trials on high
as clozapine would need to be prescribed for a longer period of and very high doses of clozapine.
time so that these results may not generalise in the longer term.
More good-quality trials are therefore needed to allow findings to
be substantiated and firm conclusions to be drawn. 3. For managers or policy makers
More studies are needed to replicate and validate findings so far,
and to ascertain effects on outcomes such as relapse, remission,
social functioning, quality of life, service utilisation, cost-effective-
Potential biases in the review process ness, satisfaction with care, quality of life. There is a particular lack
of medium- or long-term outcome data and on above-standard
We are not aware of any flaws in our review process. The search
dosing regimes.
for trials was thorough and the review authors followed the criteria
prespecified in the protocol. It is always possible, however, that we Implications for research
could have failed to identify relevant studies.

1. General

Much more data would have been available if the recommenda-

Agreements and disagreements with other tions of the CONSORT statement had been anticipated by the
studies or reviews trialists (Moher 2001). Allocation concealment is essential for the
To our knowledge there has been no other systematic review or result of a trial to be considered valid and gives the assurance that
meta-analysis comparing different doses of clozapine. selection bias is kept to the minimum. Well-described and tested
blinding could have encouraged confidence in the control of per-
formance and detection bias. It is also important to know how
many, and from which groups, people were withdrawn in order to
evaluate exclusion bias. It would also have been helpful if authors
had presented data in a useful manner which reflects association
AUTHORS’ CONCLUSIONS between intervention and outcome, for example relative risk, odds
ratio, risk or mean differences, as well as raw numbers. Binary out-
Implications for practice comes should be calculated in preference to continuous results, as
they are easier to interpret. If P values are used, the exact value
should be reported.
1. For people with schizophrenia
2. Specific
We found no evidence relating dose to clinical response in the short
or medium term. A standard dose (301 mg/day to 600 mg/day)
helps in improvement of illness but causes more adverse effects 2.1 Reviews
than lower doses. Evidence from our review indicates that the Inspection of the table of excluded studies does not suggest any
very low dose of clozapine (< 150 mg/day) is associated with least particular need for additional review topics in relation to clozapine
side effects. Evidence supports that the low dose (150 mg/day to dose since data from any new eligible report will be included in
300 mg/day) could be the optimal dose to see a clinical response updates of this review.
with fewest side effects. Standard dose appears to be associated A number of the excluded studies examined adverse effects of
with more side effects than the other two groups which might clozapine at differing dose regimes, but could not be included
necessitate close monitoring of weight, lipid profile and glucose. because they reported results by serum clozapine level and not
We could not reach a conclusion on high dose and very high dose by clozapine dose. There may therefore be value in additionally
of clozapine. Hence, in practice, every patient needs to be titrated reviewing those studies that focus on serum clozapine levels under
on the most appropriate dose of clozapine necessary to gain a a separate or modified protocol.
response, guided by close monitoring for emergence of side effects. Excluded studies in relation to other Cochrane Reviews

Clozapine dose for schizophrenia (Review) 34

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Excluded study Comparison Existing Cochrane review

de Leon 1995a Akathisia at three clozapine dose levels None currently

de Leon 2003 Muscarinic side effects at three clozapine dose levels None currently

de Leon 2004 Serum prolactin level at three clozapine dose levels None currently

Han 2001 Two different dose levels of clozapine with an adjunc- Wang 2010
tive medication (sulpiride)

Liu 2005 BPRS and TESS scores at three clozapine dose levels None currently

Nair 1998 Those with and without probable tardive dyskinesia at None currently
three clozapine dose levels

Nair 1999 Those with and without probable tardive dyskinesia at None currently
three clozapine dose levels

Potkin 1993 BPRS, CGI & EPS scores at two clozapine dose levels None currently

Potkin 1994 BPRS scores at two clozapine dose levels None currently

Tang 2000 Clinical response at three plasma clozapine concentra- None currently
tion levels

VanderZwaag 1996 BPRS scores at three different serum clozapine levels. None currently

VanderZwaag 1997 BPRS scores at three different serum clozapine levels. None currently

• Blinding: participants, clinical staff and researchers blinded

2.2 Trials
to allocation status.
• Outcomes: functioning (clinically significant response in
Clozapine is usually reserved for people suffering from treatment- social or life skills), clinical response (e.g. clinically significant
resistant illnesses. In spite of clozapine being in use for a very long response in mental state), service utilisation (e.g. time to
time, there are still insufficient trials to clearly evidence which dose hospitalisation, number of days hospitalised), quality of life,
of clozapine is optimal for people suffering from schizophrenia relapse, satisfaction with care, and any clinically important
and schizophreniform psychosis, to gain response to illness, attain adverse effects (e.g. weight gain, prolactin increase).
remission and improve quality of life.
We consider an ‘ideal’ study might have the following character-
istics.
• Participants: adults diagnosed with schizophrenia or
ACKNOWLEDGEMENTS
schizoaffective disorder. Random allocation with 150
participants per arm and 100% follow-up. The Cochrane Schizophrenia Group Editorial Base in Notting-
• Intervention: three contrasting levels of clozapine dose - ham produces and maintains standard text for use in the Methods
high (601 mg/day to 900 mg/day), standard (301 mg/day to 600 section of their reviews. We have used this text as the basis of what
mg/day) and low (150 mg/day to 300 mg/day). appears here and adapted it as required.

Clozapine dose for schizophrenia (Review) 35

References to studies included in this review de Leon 1995b {published data only}
Diaz FJ, De Leon J, Josiassen RC, Cooper TB, Simpson
Chen 1998 {published data only} GM. Plasma clozapine concentration coefficients of
Chen YG, Zhao JP, Xie GR, Chen JD, Zhu RH, Liao JD, et variation in a long-term study. Schizophrenia Research 2005;
al. A study on serum concentration and clinical response of 72(2-3):131–5.
clozapine with different dose administration for treatment Nair C, Abraham G, Stanilla JK, Simpson GM, Josiassen
of schizophrenia. Chinese Journal of Psychiatry 1998;31(2): RC. Tardive dyskinesia and extrapyramidal symptoms in
104–7. treatment-resistant schizophrenics treated with clozapine.
Chen 2013 {published data only} Schizophrenia Research 1997;24(1-2):272.
Chen YH, Cao Q, Chen WQ. The effect of clozapine Simpson GM, Josiassen RC, Stanilla JK, de Leon J, Chand
for patients with schizophrenia: a clinical trial N, Abraham G, et al. “Double-blind study of clozapine dose
response in chronic schizophrenia”: correction. American
[ ]. Modern Journal of Psychiatry 2001;158(5):834.
Diagnosis and Treatment [ ] 2013, issue de Leon J, Diaz FJ, Josiassen RC, Cooper TB, Simpson
15:3460–1. GM. Does clozapine decrease smoking?. Progress in Neuro-
Psychopharmacology and Biological Psychiatry 2005;29(5):
Liu 2005 {published data only}
757–62.
Liu SF, Wang Y, Wang DP, Wei P, Wang SG, Ma HJ, et al.
de Leon J, Diaz FJ, Wedlund P, Josiassen RC, Cooper TB,
Effects of different doses clozapine on glucose metabolism
Simpson GM. Haloperidol half-life after chronic dosing.
in male schizophrenics. Chinese Journal of New Drugs and
Journal of Clinical Psychopharmacology 2004;24(6):656–60.
Clinical Remedies 2005;24(2):98–101.
Liu SF, Wei P, Wang SG, Wang DP, Wang Y, Ma HJ, et de Leon 2003 {published data only}
al. Effects of varied dosage of clozapine on blood lipid de Leon J, Odom-White A, Josiassen RC, Diaz FJ, Cooper
and glucometabolism in schizophrenia. Chinese Journal of TB, Simpson GM. Serum antimuscarinic activity during
Psychiatry 2005;38(2):82–5. clozapine treatment. Journal of Clinical Psychopharmacology
2003;23(4):336–41.
Sheng 1990 {published data only}
Sheng XQ, Hua K, Yan H, Luo LH. Clozapine therapy in de Leon 2004 {published data only}
schizophrenia. Chinese Journal of Nervous and Mental de Leon J, Diaz FJ, Josiassen RC, Simpson GM. Possible
individual and gender differences in the small increases in
Disorders [ ] 1990; Vol. 16, issue plasma prolactin levels seen during clozapine treatment.
2:90–2. European Archives of Psychiatry and Clinical Neuroscience
Simpson 1999 {published data only} 2004;254(5):318–25. MEDLINE: 15365707
Simpson GM. Correction. American Journal of Psychiatry Guo 2003 {published data only}
2001;158(5):834. Guo JY, Du QX. A study of beam changes after taking the
∗
Simpson GM, Josiassen RC, Stanilla JK, de Leon J, Nair different dosages of clozapine in patients with schizophrenic.
C, Abraham G, et al. Double blind study of clozapine dose
response in chronic schizophrenia. American Journal of Medical Journal of Chinese People’s Health [ ]
Psychiatry 1999;156(11):1744–50. MEDLINE: 10553738 2003;15(11):655–6.
de Leon J, Diaz FJ, Josiassen RC, Cooper TB, Simpson GM. Han 2001 {published data only}
Weight gain during a double-blind multidosage clozapine Han YC, Shi SS, Xu RJ, Shang FZ. Controlled clinical
study. Journal of Clinical Psychopharmacology 2007;27(1): trial of high versus low dose clozapine combined with
22–7. MEDLINE: 17224708 sulpiride for schizophrenia. Shandong Archives of Psychiatry
References to studies excluded from this review [ ] 2001;14(2):138–9.
Borges 2010 {published data only} Liu 2005a {published data only}
Borges N, Sverdloff CE, Moreira R, Domingues C, Borges Liu SF, Mu JL, Zhang YJ, Wang SG, Wei P, Wang DP, et
B, Lacerda A, et al. Evaluation by ancova of comparative al. Effect of clozapine of different dosages on the cognitive
bioavailability of two oral formulations of clozapine in function in patients with schizophrenia assessed by the
steady state in schizophrenic volunteers under a different changes of p300 potentials. Chinese Journal of Clinical
doses regime. Clinical Pharmacology and Therapeutics 2010; Rehabilitation 2005;9(8):56–7.
87(Suppl 1):S94. Matz 1974 {published data only}
de Leon 1995a {published data only} Matz R, Rick W, Thompson H, Gershon S. Clozapine -
de Leon J, Odom-White A, Stanilla J, Joiassen R, Simpson a potential antipsychotic agent without extrapyramidal
GM. Does clozapine induce akathisia?. Schizophrenia manifestations. Current Therapeutic Research, Clinical and
Research 1995;15(1-2):207. Experimental 1974;16(7):687–95.
Clozapine dose for schizophrenia (Review) 36
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
McEvoy 1995 {published data only} patients. Journal of Clinical Psychopharmacology 1997;17(1):
McEvoy J, Freudenreich O, McGee M, VanderZwaag C, 49–53. MEDLINE: 9004057
Levin E, Rose J. Clozapine decreases smoking in patients
with chronic schizophrenia. Biological Psychiatry 1995;37
Additional references
(8):550–2. Aitchison 1997
McEvoy JP, VanderZwaag C, McGee M, Freudenreich O, Aitchison K, Kerwin R. Cost-effectiveness of clozapine. A
Wilson WH, Cooper TB. A double blind, randomized UK clinic-based study. British Journal of Psychiatry 1997;
trial comparing clozapine treatment within three distinct 171:125–30.
serum level ranges in patients with refractory chronic Altman 1996
schizophrenia. Schizophrenia Research 1996;22(18):127. Altman DG, Bland JM. Detecing skewness from summary
McEvoy 1996 {published data only} information. BMJ 1996;313(7066):1200. [OLZ020600]
McEvoy JP, Freudenreich O, Weiner RD. Clozapine- Arnt 1998
induced EEG changes as a function of clozapine serum Arnt J, Skarsfeldt T. Do novel antipsychotics have similar
levels. Schizophrenia Research 1996;18(2-3):233. pharmacological characteristics? A review of the evidence.
Nair 1998 {published data only} Neuropsychopharmacology 199;8(18):63-101.
Nair CJ, de Leon J, Simpson GM, Josiassen RC. Therapeutic Asenjo 2010
effects of clozapine on tardive dyskinesia. Cognitive and Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H,
Behavioral Practice 1998;5:119-27. Schmid F, Schwarz S, et al. Clozapine versus other atypical
Nair 1999 {published data only} antipsychotics for schizophrenia. Cochrane Database
Nair CJ, Josiassen RC, Abraham G, Stanilla JK, Tracy JI, of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/
Simpson GM. Does akathisia influence psychopathology 14651858.CD006633.pub2; PUBMED: 21069690]
in psychotic patients treated with clozapine?. Biological Azorin 2005
Psychiatry 1999;45:1376-83. Azorin JM, Kaladjian A, Fakra E. Current issues on
Potkin 1993 {published data only} schizoaffective disorder. Encephale 2005;31(3):359–65.
Potkin SG, Bera R, Gulasekaram B. High and low dose of Benazzi 2003
clozapine compared in a double-blind study. Schizophrenia Benazzi F. Outcome of schizophreniform disorder. Current
Research 1993;9:246–7. Psychiatry Reports 2003;5(3):192–6.
Potkin 1994 {published data only} Bergem 1990
Potkin SG, Bera R, Gulasekaram B, Costa J, Hayes S, Jin
Bergem AL, Dahl AA, Guldberg C, Hansen H. Langfeldt’s
Y, et al. Plasma clozapine concentrations predict clinical schizophreniform psychoses fifty years later. British Journal
response in treatment-resistant schizophrenia. Journal of
of Psychiatry 1990;157:351–4.
Clinical Psychiatry 1994;55(Suppl B):133–6. MEDLINE:
7961557 Bland 1997
Bland JM. Statistics notes. Trials randomised in clusters.
Tang 2000 {published data only}
BMJ 1997;315:600.
Tang Y, Peng C, Xiao H. Research for clozapine in
schizophrenia and the relationship between plasma BNF 2012
clozapine concentration and clinical response. Journal of British National Formulary. Royal Pharmaceutical Society.
London: BMJ Group, Pharmaceutical Press, Sep 2012:
Clinical Psychological Medicine [ ] 2000; 229–230.
10(6):335–7. Boissel 1999
VanderZwaag 1996 {published data only} Boissel JP, Cucherat M, Li W, Chatellier G, Gueyffier F,
VanderZwaag C, McGee M, McEvoy JP, Freudenreich Buyse M, et al. The problem of therapeutic efficacy indices.
O, Wilson WH, Cooper TB. Response of patients with 3. Comparison of the indices and their use [Apercu sur
treatment-refractory schizophrenia to clozapine within three la problematique des indices d’efficacite therapeutique, 3:
serum level ranges. American Journal of Psychiatry 1996;153 comparaison des indices et utilisation. Groupe d’etude
(12):1579–84. MEDLINE: 8942454 des Indices d’efficacite]. Therapie 1999;54(4):405–11.
VanderZwaag 1997 {published and unpublished data} [PUBMED: 10667106]
Freudenreich O, Weiner RD, McEvoy JP. Clozapine- Buchanan 1995
induced electroencephalogram changes as a function of Buchanan RW. Clozapine: efficacy and Safety. Schizophrenia
clozapine serum levels. Biological Psychiatry 1997;42(2): Bulletin 1995;21(4):579–91.
132–7. Carpenter 1994
Carpenter WT Jr, Buchanan RW. Schizophrenia. New
References to studies awaiting assessment
England Journal of Medicine 1994;330:681-90.
Abraham 1997 {published data only} Cipriani 2009
Abraham G, Nair C, Tracy JI, Simpson GM. The effects Cipriani A, Boso M, Barbui C. Clozapine combined
of clozapine on symptom clusters in treatment-refractory with different antipsychotic drugs for treatment resistant
Clozapine dose for schizophrenia (Review) 37
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
schizophrenia. Cochrane Database of Systematic Reviews can provide accurate results. Journal of Clinical Epidemiology
2009, Issue 3. [DOI: 10.1002/14651858.CD006324.pub2; 2006;59(1):7–10.
PUBMED: 19588385] Gaebel 1997
CMHP Gaebel W. Towards the improvement of compliance: the
The College of Mental Health Pharmacy. www.cmhp.org.uk significance of psycho-education and new antipsychotic
(accessed 5 August 2011). drugs. International Clinical Psychopharmacology 1997;12
Coward 1992 (Suppl 1):S37-42.
Coward DM. General pharmacology of clozapine. British Gelder 2001
Journal of Psychiatry Supplement 1992;17:5–11. Gelder MJ, Mayou R, Cowen P. Oxford Shorter Textbook of
Danilevici te 2002 Psychiatry. 4th Edition. New York, USA: Oxford University
Danilevici te V. Schizoaffective disorder: clinical symptoms Press, 2001.
and present-day approach to treatment. Medicina (Kaunas) Guldberg 1991
2002;38(11):1057–65. Guldberg CA, Dahl AA, Hansen H, Bergem AL. Were
Deeks 2000 Langfeldt’s schizophreniform psychoses really affective?.
Deeks J. Issues in the selection for meta-analyses of binary Psychopathology 1991;24(5):270–6.
data. 8th International Cochrane Colloquium; 2000 Gulliford 1999
Oct 25-28; Cape Town. Cape Town: The Cochrane Gulliford MC. Components of variance and intraclass
Collaboration, 2000. correlations for the design of community-based surveys
Deeks 2011 and intervention studies: data from the Health Survey for
Deeks JJ, Higgins JPT, Altman DG editor(s). Chapter 9: England 1994. American Journal of Epidemiology 1999;149
Analysing data and undertaking meta-analyses. In: Higgins (9):876–83.
JPT, Green S editor(s). Cochrane Handbook for Systematic
Higgins 2003
Reviews of Interventions Version 5.1.0 (updated March
Higgins JPT, Thompson SG, Deeks JJ, Altman DG.
2011). The Cochrane Collaboration, 2011. Available from
Measuring inconsistency in meta-analyses. BMJ 2003;327
www.handbook.cochrane.org.
(7414):557–60.
Divine 1992
Higgins 2011a
Divine GW, Brown JT, Frazier LM. The unit of analysis
Higgins JPT, Green S editor(s). Chapter 7: Selecting
error in studies about physicians’ patient care behavior.
studies and collecting data. In: Higgins JPT, Green S
Journal of General Internal Medicine 1992;7(6):623–9.
editor(s), Cochrane Handbook for Systematic Reviews
Donner 2002 of Interventions Version 5.1.0 (updated March 2011).
Donner A, Klar N. Issues in the meta-analysis of cluster The Cochrane Collaboration, 2011. Available from
randomized trials. Statistics in Medicine 2002;21(19): www.handbook.cochrane.org.
2971–80.
DSM-IV Higgins 2011b
American Psychiatric Association. Diagnostic and Statistical Higgins JPT, Altman DG, Sterne JAC editor(s). Chapter
Manual of Mental Disorders: DSM-IV-TR. American 8: Assessing risk of bias in included studies. In: Higgins
Psychiatric Association, 2000. JPT, Green S editor(s). Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March
Egger 1997
2011). The Cochrane Collaboration, 2011. Available from
Egger M, Davey-Smith G, Schneider M, Minder C. Bias
www.handbook.cochrane.org.
in meta-analysis detected by a simple, graphical test. BMJ
1997;315(7109):629–34. Hutton 2009
Elbourne 2002 Hutton JL. Number needed to treat and number needed to
Elbourne D, Altman DG, Higgins JPT, Curtina F, harm are not the best way to report and assess the results
Worthingtond HV, Vaile A. Meta-analyses involving cross- of randomised clinical trials. British Journal of Haematology
over trials: methodological issues. International Journal of 2009;146(1):27–30.
Epidemiology 2002;31(1):140–9. ICD-10
Essali 2009 World Health Organization. The ICD-10 Classification of
Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine Mental and Behavioural Disorders: Clinical Descriptions
versus typical neuroleptic medication for schizophrenia. and Diagnostic Guidelines. 10th Edition. World Health
Cochrane Database of Systematic Reviews 2009, Issue 1. Organization, 2004.
[DOI: 10.1002/14651858.CD000059.pub2; PUBMED: Kane 1988
19160174] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for
Furukawa 2006 the treatment resistant schizophrenic: a double-blind
Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe comparison with chlorpromazine. Archives of General
N. Imputing missing standard deviations in meta-analyses Psychiatry 1988;45(9):789-96.
Clozapine dose for schizophrenia (Review) 38
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kane 1990 McGrath 2008
Kane JM. Treatment programme and long term outcome McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a
in chronic schizophrenia. Acta Psychiatrica Scandinavica concise overview of incidence, prevalence, and mortality.
Supplementum 1990;358:151-7. Epidemiologic Reviews 2008;30:67–76. [DOI: 10.1093/
epirev/mxn001]
Kane 2011
Kane JM. A user guide to clozapine. Acta Psychiatrica Meuser 2004
Scandinavica 2011; Vol. 123, issue 6:407–8. Mueser KT, McGurk SR. Schizophrenia. Lancet 2004;363
(9426):2063-72. [PUBMED: 15207959]
Kaplan 2005
Sadock BJ, Sadock VA (editors). Kaplan & Sadock’s Moher 2001
Comprehensive Text Book of Psychiatry. 8th Edition. Moher D, Schulz KF, Altman D. The CONSORT
Philadelphia: Lippincott Williams & Wilkins, 2005. statement: revised recommendations for improving the
quality of reports of parallel-group randomized trials. JAMA
Kasanin 1933
2001;285(15):1987–91.
Kasanin J. The acute schizoaffective psychoses. American
Journal of Psychiatry 1933;90:97–126. Naheed 2001
Naheed M, Green B. Focus on clozapine. Current Medical
Kay 1986 Research and Opinion 2001;17(3):223-9.
Kay SR, Opler LA, Fiszbein A. Positive and Negative
Syndrome Scale (PANSS) Manual. North Tonawanda, NY: NICE
Multi-Health Systems, 1986. National Institute for Health and Clinical Excellence
(NICE). NICE clinical guideline 82: Schizophrenia
Kerwin 2005 core interventions in the treatment and management of
Kerwin R, Bolonna A. Management of clozapine-resistant schizophrenia in adults in primary and secondary care.
schizophrenia. Advances in Psychiatric Treatment 2005;11: www.nice.org.uk/guidance/CG82 (accessed 24 February
101–106. [DOI: 10.1192/apt.11.2.101] 2017).
Kronig 1995 NIMH 1985
Kronig MH, Munne RA, Szymanski S, Safferman AZ, National Institute of Mental Health (NIMH). TESS
Pollack S, Cooper T, et al. Plasma clozapine levels and (treatment emergent symptoms scale). Psychopharmacology
clinical response for treatment-refractory schizophrenic Bulletin 1985;22:1069–72.
patients. American Journal of Psychiatry 1995;152:179–82.
Noreik 1967
Lachar 2001 Noreik K, Astrup C, Dalgard OS, Holmboe R. A prolonged
Lachar D, Bailley SE, Rhoades HM, Espadas A, Aponte M, follow-up of acute schizophrenic and schizophreniform
Cowan KA, et al. New subscales for an anchored version of psychoses. Acta Psychiatrica Scandinavica 1967;43(4):432-
the Brief Psychiatric Rating Scale: construction, reliability, 43.
and validity in acute psychiatric admissions. Psychological Overall 1962
Assessment 2001;13(3):384–95. Overall JE, Gorham DR. The brief psychiatric rating scale.
Leucht 2005a Psychological Reports 1962;10:799–812.
Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Saha 2005
Engel R. Clinical implications of brief psychiatric rating Saha S, Chant D, Welham J, McGrath J. A systematic
scale scores. British Journal of Psychiatry 2005;187:366–71. review of the prevalence of schizophrenia. PLoS Medicine
[PUBMED: 16199797] 2005;2(5):e141.
Leucht 2005b Schünemann 2011
Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Schünemann HJ, Oxman AD, Vist GE, Higgins JPT,
Engel RR. What does the PANSS mean?. Schizophrenia Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting
Research 2005;79(2-3):231–8. [PUBMED: 15982856] results and drawing conclusions. In Higgins JPT, Green
Leucht 2007 S editor(s), Cochrane Handbook for Systematic Reviews
Leucht S, Engel RR, Bauml J, Davis JM. Is the superior of Interventions Version 5.1.0 (updated March 2011).
efficacy of new generation antipsychotics an artifact of The Cochrane Collaboration, 2011. Available from
LOCF?. Schizophrenia Bulletin 2007;33(1):183–91. www.cochrane-handbook.org.
[PUBMED: 16905632] Semple 2007
Marshall 2000 Smyth R, Burns J, Darjee R, McIntosh A. Oxford Handbook
Marshall M, Lockwood A, Bradley C, Adams CE, Joy of Psychiatry. New York: Oxford University Press Inc.,
C, Fenton M. Unpublished rating scales: a major source 2007.
of bias in randomised controlled trials of treatments for Simpson 2001
schizophrenia. British Journal of Psychiatry 2000;176: Simpson GM. Correction. American Journal of Psychiatry
249–52. 2001;158(5):834.
Clozapine dose for schizophrenia (Review) 39
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Stahl 2006 Vieta 2010
Stahl SM. Essential Psychopharmacology. Cambridge, New Vieta E. Developing an individualized treatment
York, USA: Cambridge University Press, 2006. plan for patients with schizoaffective disorder: from
Sterne 2011 pharmacotherapy to psychoeducation. Journal of Clinical
Sterne JAC, Egger M, Moher D editor(s). Chapter 10: Psychiatry 2010;71(Suppl 2):14–9.
Addressing reporting biases. In: Higgins JPT, Green S Wang 2004
editor(s). Cochrane Handbook for Systematic Reviews Wang PS, Ganz DA, Benner JS, Glynn RJ, Avorn J. Should
of Intervention. Version 5.1.0 (updated March 2011). clozapine continue to be restricted to third-line status for
The Cochrane Collaboration, 2011. Available from schizophrenia?: A decision-analytic model. Journal of
www.handbook.cochrane.org. Mental Health Policy and Economics 2004;7(2):77–85.
Syed 2008 Wang 2010
Syed R, Au K, Cahill C, Duggan L, He Y, Udu V, et Wang J, Omori IM, Fenton M, Soares BGO. Sulpiride
al. Pharmacological interventions for clozapine-induced augmentation for schizophrenia. Cochrane Database
hypersalivation. Cochrane Database of Systematic Reviews of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/
2008, Issue 3. [DOI: 10.1002/14651858.CD005579.pub2; 14651858.CD008125.pub2]
PUBMED: 18646130] WHO 2013
Taylor 1995 World Health Organisation. Health topics, mental health,
Taylor D, Duncan D. The use of clozapine plasma levels in schizophrenia. www.who.int/mental˙health/management/
optimising therapy. Psychiatric Bulletin 1995;19:753–55. schizophrenia/en/ (accessed 9 March 2013).
Ukoumunne 1999 Woerner 1988
Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Woerner MG, Mannuzza S, Kane JM. Anchoring the
Burney PGJ. Methods for evaluating area-wide and BPRS: an aid to improved reliability. Psychopharmacology
organisation-based intervention in health and health care: a Bulletin 1988;24(1):112–7.
systematic review. Health Technology Assessment 1999;3(5): Xia 2009
1–75. Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, El-
van Os 2009 Sayeh H, et al. Loss to outcomes stakeholder survey: the
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690): LOSS study. Psychiatric Bulletin 2009;33(7):254–7.
∗
635-45. [PUBMED: 19700006] Indicates the major publication for the study

Clozapine dose for schizophrenia (Review) 40

Characteristics of included studies [ordered by study ID]

Chen 1998

Methods Allocation: randomly assigned (no further details).

Blinding: not stated.
Duration: six weeks.
Setting: unclear.

Participants Diagnosis: schizophrenia.

N = 176.
Age: 17 to 55 years.
Sex: male and female (numbers not given)
Racial origin: unclear.
Consent: unclear.
History: Average length of illness: 8 ± 11months.

Interventions 1. Clozapine: dose 200 mg/day. N = 94.

2. Clozapine: dose 500 mg/day. N = 82.

Outcomes Global state: Clinically important response as defined by individual studies (BPRS score
> 30% change).
Mental state: average endpoint score and average change score B (BPRS-A).
Adverse effects: TESS scores, lethargy, hypersalivation, dizziness, tachycardia
Leaving the study early.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Randomly assigned, no further details.
bias)

Allocation concealment (selection bias) Unclear risk No details.

Blinding of participants and personnel High risk Not stated.

(performance bias)
All outcomes

Blinding of outcome assessment (detection High risk Not stated.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk All data reported; no loss to follow up.
All outcomes

Selective reporting (reporting bias) Low risk No indication of selective reporting.

Clozapine dose for schizophrenia (Review) 41

Other bias Unclear risk Sponsor unclear.

Chen 2013

Methods Allocation: randomised, method not stated

Blinding: double blind, no further details
Duration: twelve weeks.
Setting: not stated

Participants Patients with schizophrenia (inpatients; male & female)

Interventions 1. Clozapine: dose 200-300 mg/day. N = 30

2. Clozapine: dose 301-400 mg/day. N = 30
3. Clozapine: dose 401-500 mg/day. N = 30
Initial dose 25 mg/day in all cases: doses above achieved at 2-3 weeks

Outcomes Mental state: Clinical improvement, clinician assessed

Adverse effects: TESS scale score

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Randomly assigned, no further details.
bias)

Allocation concealment (selection bias) Unclear risk No details.

Blinding of participants and personnel High risk Not stated.

(performance bias)
All outcomes

Blinding of outcome assessment (detection High risk Not stated.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk All data reported; no loss to follow up.
All outcomes

Selective reporting (reporting bias) Low risk No indication of selective reporting.

Other bias Unclear risk Sponsor unclear.

Clozapine dose for schizophrenia (Review) 42

Methods Allocation: randomised using random number table

Blinding: not stated.
Duration: six weeks.
Setting: inpatient setting at a medical College.

Participants Diagnosis: schizophrenia (CCMD-3)

N = 87.
Age: 18 to 45 years.
Sex: 87 M.
Racial origin: unclear.
Consent: unclear.
History: information not available.

Interventions 1. Clozapine: dose < 150 mg/day. N = 30.

2. Clozapine: dose 150 to 300 mg/day. N = 29.
3. Clozapine: dose > 300 mg/day. N = 28.

Outcomes Adverse effects: serum lipid level before and after treatment, body weight, BMI.
Leaving the study early*.

Notes * Standard dose group: two participants left the study early (due to neutropenia and
tachycardia). Low dose group: one participant left the study early (due to increased level
of Alanine aminotransferase)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Allocation by random number table.
bias)

Allocation concealment (selection bias) Unclear risk Not stated

Blinding of participants and personnel High risk Not stated.

(performance bias)
All outcomes

Blinding of outcome assessment (detection High risk Not stated.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Three participants left the study early, rea-
All outcomes sons given.

Selective reporting (reporting bias) Low risk No indication of selective reporting.

Other bias Low risk No indication of other bias.

Clozapine dose for schizophrenia (Review) 43

Methods Allocation: randomised, method not stated.

Blinding: double blind, no further details.
Duration: twelve weeks.
Setting: not stated.

Participants Patients with schizophrenia (inpatients; male & female).

Interventions 1.Clozapine (capsule): dose 300 mg/day. N = 25.

2.Clozapine (capsule): dose 600 mg/day. N = 26.

Outcomes Mental state: Clinical improvement, clinician assessed.

Mental state: BPRS score (data not available).
Adverse effects: TESS scale score (data not available).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Randomly assigned, no further details.
bias)

Allocation concealment (selection bias) Unclear risk No details.

Blinding of participants and personnel Unclear risk ‘Double blind’, no further details.
(performance bias)
All outcomes

Blinding of outcome assessment (detection Unclear risk ‘Double blind’, no further details.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk All data reported; no loss to follow-up.
All outcomes

Selective reporting (reporting bias) High risk BPRS and TESS score data not available.

Other bias Unclear risk Sponsor unclear.

Clozapine dose for schizophrenia (Review) 44

Methods Allocation: implied randomisation trial, no details on method of allocation.

Blindness: double-blind, assessors blind to clozapine doses.
Duration: 16 weeks (first phase before cross over lasted 16 weeks; total of three phases
lasting 48 weeks).
Setting: Research ward, State Hospital Clinical Research Centre, USA

Participants Diagnosis: treatment refractory schizophrenia or schizoaffective disorder (DSM-III-R).

N = 48 (number who completed first 16 weeks before any cross-over).
Age: 35 to 54 years.
Sex: M 22, F 28.
Racial origin: Caucasian 43, African American 7.
Consent: signed informed consent.
History: average length of illness: mean 25.1 years (range 1 to 38 years), median of five
psychiatric hospitalizations (range 1 to 25); patients had not shown satisfactory clinical
response to treatment with at least three antipsychotic drugs (each given for at least six
weeks in doses equivalent to 1000 mg/day of chlorpromazine)

Interventions 1. Clozapine: dose 100 mg/day. N = 14.

2. Clozapine: dose 300 mg/day. N = 17.
3. Clozapine: dose 600 mg/day. N = 17.

Outcomes Mental state: (BPRS-A) total score.

Leaving the study early.

Notes 1. Patients stayed in research centre for four weeks for adaptation (naturalistic baseline
with no modification in their treatment regimen). Before first phase of clozapine treat-
ment, patients underwent a four-week haloperidol treatment and then a one-week wash
out. We contacted the main trialist to obtain missing data on CGI, SANS, responders
at 16 weeks, and on which dosage group the four responders belonged to but we have
not received results at the time of writing
2. data from Simpson 1999 have been adjusted in accordance with the published cor-
rections (Simpson 2001). Specifically, the standard errors for BPRS-A endpoint scores
which were originally reported by the authors as if they were standard deviations have
been converted to standard deviations

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection High risk Implied randomisation trial, no details on
bias) method of allocation

Allocation concealment (selection bias) Unclear risk No details.

Blinding of participants and personnel Unclear risk Participants were blinded to doses of cloza-
(performance bias) pine; no details on personnel giving the
All outcomes treatment

Clozapine dose for schizophrenia (Review) 45

Blinding of outcome assessment (detection Low risk Assessors were blinded to doses of clozap-
bias) ine.
All outcomes

Incomplete outcome data (attrition bias) High risk 44 out of 48 patients completed the first 16
All outcomes weeks of the trial; four patients had their
last observation carried forward. If a patient
had attained the maximum assigned dose
for two weeks, his or her data were carried
forward for end-point analysis. However,
as clozapine can take more time to exert its
effect, if the patient leaves the study soon
after two weeks, the last observation carried
forward might underestimate the efficiency
of that particular dose of clozapine

Selective reporting (reporting bias) High risk Responders’ data reported at 48 weeks, but
not at end of 16 weeks and 32 weeks by
dose; CGI, SANS not reported

Other bias High risk Sponsored by Novartis Pharmaceuticals.

BPRS: Brief Psychiatric Rating Scale

BPRS-A: Brief Psychiatric Rating Scale - Anchored

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Borges 2010 Allocation: random allocation.

Participants: all had schizophrenia.
Intervention: examined bioavailability at a clozapine dose regime of between 200 mg/day and 800 mg/day
Outcome: no additional data for this review; study examined only the bioavailability of clozapine

de Leon 1995a Allocation: method of allocation unclear.

Participants: all had schizophrenia or schizoaffective disorder
Intervention: compared akathisia at three clozapine doses of 100mg/day, 300mg/day & 600mg/day
Outcomes: Barnes akathisia scale endpoint and change scores unavailable

de Leon 1995b Allocation: random allocation.

Participants: all had treatment refractory schizophrenia or schizoaffective disorder
Intervention: three clozapine doses of 100 mg/day, 300 mg/day and 600 mg/day
Outcome: no additional data for this review; these 4 studies examined (a) relationship between tardive dyski-
nesia and extrapyramidal symptoms, (b) coefficients of variation in the relationship between dose and plasma

Clozapine dose for schizophrenia (Review) 46

concentration levels, (c) plasma cotinine levels, and (d) effects of haloperidol

de Leon 2003 Allocation: method of allocation unclear.

Participants: all had schizophrenia or schizoaffective disorder
Intervention: compared muscarinic side effects at three clozapine doses of 100mg/day, 300mg/day & 600mg/
day
Outcomes: no usable data before the first cross-over.

de Leon 2004 Allocation: method of allocation unclear.

Participants: all had schizophrenia or schizoaffective disorder
Intervention: compared serum prolactin level at three clozapine doses of 100mg/day, 300mg/day & 600mg/
day
Outcomes: no usable data before the first cross-over.

Guo 2003 Allocation: non-randomized controlled trial.

Participants: all had schizophrenia.
Intervention: studied BEAM changes after taking three different dosages of clozapine: < 150 mg/day vs 150
mg/day to 400 mg/day vs > 400 mg/day
Outcomes: BEAM changes.

Han 2001 Allocation: random allocation.

Participants: all had schizophrenia.
Intervention: two clozapine doses of < 300mg/day & > 300mg/day, but adjunctive medication (sulpiride) not
held constant between different clozapine dosage groups
Outcomes: compared BPRS and TESS scores between groups.

Liu 2005a Allocation: not allocated at random.

Participants: all had schizophrenia.
Intervention: three different clozapine doses.
Outcomes: compared PANSS scores and p300 test results.

Matz 1974 Allocation: not randomised; allocation at discretion of psychiatrists in charge

Participation: all had schizophrenia.
Intervention: examined effects of clozapine at two doses (up to 100 mg t.i.d. and up to 400 mg t.i.d.)
Outcome: BPRS and NOSIE, plus TES for adverse effects.

McEvoy 1995 Allocation: random allocation.

Participants: all had schizophrenia.
Intervention: examined BPRS, CGI, smoking measures & EEG changes at three clozapine serum level ranges
(50 ng/mL to 150 ng/mL, 200 ng/mL to 300 ng/mL & 350 ng/mL to 450ng/mL)
Outcome: no additional data for this review; comparison was by serum clozapine level, and not by clozapine
dose

McEvoy 1996 Allocation: random allocation.

Participants: all had chronic schizophrenia.
Intervention: examined smoking measures at three clozapine serum level ranges (50 ng/mL to 150ng/mL, 200
ng/mL to 300ng/mL & 350 ng/mL to 450ng/mL)
Outcome: no additional data for this review; comparison was by serum clozapine level, and not by clozapine
dose

Clozapine dose for schizophrenia (Review) 47

Nair 1998 Allocation: random allocation.

Participants: all had treatment refractory schizophrenia or schizoaffective disorder
Intervention: three clozapine doses of 100 mg/day, 300 mg/day and 600 mg/day
Outcome: no additional data; study compared those with and without probable tardive dyskinesia in a subgroup
of 23 participants from the Simpson 1999 trial.

Nair 1999 Allocation: random allocation.

Participants: all had treatment refractory schizophrenia or schizoaffective disorder
Intervention: three clozapine doses of 100 mg/day, 300 mg/day and 600 mg/day
Outcome: no additional data; study compared those with and without probable tardive dyskinesia in a subgroup
of 33 participants from the Simpson 1999 trial.

Potkin 1993 Allocation: random allocation.

Participants: all had chronic schizophrenia.
Intervention: compared BPRS, CGI & EPS scores at two clozapine doses of 400mg/day & 800mg/day
Outcomes: data limited to the ’first 25’ patients with no information on which dosage group they belonged
to; attempts to contact first author unsuccessful

Potkin 1994 Allocation: random allocation.

Participants: all had schizophrenia.
Intervention: clozapine commenced at 400 mg/day with participants randomised at end of week four to 400mg/
day or 800mg/day. Study compared dosage groups on BPRS scores and numbers discontinuing in the first
three weeks
Outcomes: compared BPRS scores by serum clozapine level, and not by clozapine dose; attempts to contact
first author unsuccessful

Tang 2000 Allocation: not randomly allocated.

Participants: all had schizophrenia.
Intervention: examined the relationship between plasma clozapine concentration and clinical response

VanderZwaag 1996 Allocation: random allocation.

Participants: all had chronic schizophrenia.
Intervention: examined the change in BPRS and SANS scores at three different serum clozapine levels
Outcomes: compared BPRS scores by serum clozapine level, and not by clozapine dose

VanderZwaag 1997 Allocation: random allocation.

Participants: all had chronic schizophrenia.
Intervention: examined the change in EEG at three different serum clozapine levels
Outcomes: compared BPRS scores by serum clozapine level, and not by clozapine dose

Clozapine dose for schizophrenia (Review) 48

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of studies awaiting assessment [ordered by study ID]

Abraham 1997

Methods Allocation: unclear, no details.

Blindness: double-blind, rated independently.
Duration: 16 weeks.
Setting: inpatient.

Participants Diagnosis: treatment resistant schizophrenia or schizoaffective disorder (DSM-III-R).

N = 30.
Age: 35 to 53 years.
Sex: M 17, F 13.
Racial origin: not stated.
Consent: signed informed consent.
History: Average length of illness: 24.9 years (range 16.1 to 33.7 years)

Interventions 1. Clozapine: dose 100 mg/day.

2. Clozapine: dose 300 mg/day.
3. Clozapine: dose 600 mg/day.

Outcomes None.

Notes This report presents additional results from the Simpson 1999 trial. Patients were allowed to adapt to new clinical
environment for minimum of four weeks, followed by four weeks of haloperidol treatment and a one-week wash-out
period. Participants who were randomised to 300 mg/day or 600 mg/day of clozapine were subsequently categorised
as “improvers” or “non-improvers” based on change in CGI scores, and these groups were compared on demographics,
baseline characteristics and BPRS scores. No information was given, however, on the dosage group to which the
improvers and non-improvers belonged. We contacted the lead author who agreed to send the missing data, but
at the time of writing this had not been received. If we subsequently receive this data, we will include it in future
versions of this review

Clozapine dose for schizophrenia (Review) 49

Comparison 1. CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mental state: Average endpoint 1 31 Mean Difference (IV, Random, 95% CI) 3.55 [-4.50, 11.60]
score (BPRS-A, high = poor) -
medium term
2 Adverse effects: 1a. Weight - 1 59 Mean Difference (IV, Random, 95% CI) -0.10 [-0.95, 0.75]
BMI - short term
3 Adverse effects: 1b. Weight - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
weight gain
3.1 short term 1 27 Mean Difference (IV, Random, 95% CI) -1.1 [-3.93, 1.73]
3.2 medium term 1 28 Mean Difference (IV, Random, 95% CI) -1.3 [-4.86, 2.26]
4 Adverse effects: 1c. Weight - 1 59 Mean Difference (IV, Random, 95% CI) 0.0 [-3.92, 3.92]
body weight at endpoint - short
term
5 Adverse effects: 2a. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
blood glucose - short term
5.1 Before meal 1 59 Mean Difference (IV, Random, 95% CI) -0.40 [-1.06, 0.26]
5.2 1 hour after meal 1 59 Mean Difference (IV, Random, 95% CI) -0.70 [-2.01, 0.61]
5.3 2 hours after meal 1 59 Mean Difference (IV, Random, 95% CI) 0.30 [-0.98, 1.58]
5.4 3 hours after meal 1 59 Mean Difference (IV, Random, 95% CI) -0.70 [-1.59, 0.19]
6 Adverse effects: 2b. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
lipid profile - short term
6.1 triglycerides 1 59 Mean Difference (IV, Random, 95% CI) 1.00 [0.51, 1.49]
6.2 cholesterol - total 1 59 Mean Difference (IV, Random, 95% CI) 0.50 [-0.12, 1.12]
6.3 lipoprotein - high density 1 59 Mean Difference (IV, Random, 95% CI) 0.04 [-0.14, 0.22]
(HDL)
6.4 lipoprotein - low density 1 59 Mean Difference (IV, Random, 95% CI) 0.10 [-0.36, 0.56]
(LDL)
6.5 Apo A-1 1 59 Mean Difference (IV, Random, 95% CI) 0.05 [-0.10, 0.20]
6.6 Apo-B 1 59 Mean Difference (IV, Random, 95% CI) 0.13 [-0.16, 0.42]
7 Leaving the study early 2 91 Risk Ratio (M-H, Random, 95% CI) 1.50 [0.09, 25.41]
7.1 any reason - medium term 1 31 Risk Ratio (M-H, Random, 95% CI) 6.0 [0.31, 115.56]
7.2 specific reason (alanine 1 60 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.87]
aminotransferase level) - short
term

Clozapine dose for schizophrenia (Review) 50

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 2. CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600
mg/day)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mental state: 1a. Average 1 31 Mean Difference (IV, Random, 95% CI) 6.67 [-2.09, 15.43]
endpoint score (BPRS-A, high
= poor) - medium term
2 Adverse effects: 1a. Weight - 1 58 Mean Difference (IV, Random, 95% CI) 0.10 [-0.76, 0.96]
BMI - short term
3 Adverse effects: 1b. Weight - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
weight gain
3.1 short term 1 27 Mean Difference (IV, Random, 95% CI) -2.70 [-5.38, -0.02]
3.2 medium term 1 28 Mean Difference (IV, Random, 95% CI) -3.10 [-6.73, 0.53]
4 Adverse effects: 1c. Weight - 1 58 Mean Difference (IV, Random, 95% CI) 1.0 [-2.66, 4.66]
body weight at endpoint - short
term
5 Adverse effects: 2a. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
blood glucose - short term
5.1 one hour after meal 1 58 Mean Difference (IV, Random, 95% CI) -1.60 [-2.90, -0.30]
5.2 before meal 1 58 Mean Difference (IV, Random, 95% CI) -0.10 [-0.68, 0.48]
5.3 two hours after meal 1 58 Mean Difference (IV, Random, 95% CI) -0.60 [-1.89, 0.69]
5.4 three hours after meal 1 58 Mean Difference (IV, Random, 95% CI) -0.30 [-1.55, 0.95]
6 Adverse effects: 2b. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
lipid profile - short term
6.1 cholesterol - total 1 58 Mean Difference (IV, Random, 95% CI) 1.00 [0.20, 1.80]
6.2 triglycerides 1 58 Mean Difference (IV, Random, 95% CI) 1.30 [0.81, 1.79]
6.3 Apo - B 1 58 Mean Difference (IV, Random, 95% CI) 0.23 [0.01, 0.45]
6.4 lipoprotein - high density 1 58 Mean Difference (IV, Random, 95% CI) 0.10 [-0.13, 0.33]
(HDL)
6.5 lipoprotein - low density 1 58 Mean Difference (IV, Random, 95% CI) 0.0 [-0.39, 0.39]
(LDL)
6.6 Apo A -1 1 58 Mean Difference (IV, Random, 95% CI) 0.04 [-0.10, 0.18]
7 Leaving the study early 2 91 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.14, 3.72]
7.1 any reason - medium term 1 31 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.20, 7.55]
7.2 specific reason 1 60 Risk Ratio (M-H, Random, 95% CI) 0.2 [0.01, 4.00]
(neutropenia and tachycardia) -
short term

Clozapine dose for schizophrenia (Review) 51

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 3. CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mental state: 1a. Clinically 1 176 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.78, 1.10]
important response as (BPRS
score > 30% change)
2 Mental state: 1b. Average 2 Mean Difference (IV, Random, 95% CI) Subtotals only
endpoint score (BPRS-A total,
high = poor)
2.1 short term 1 176 Mean Difference (IV, Random, 95% CI) 1.70 [-1.26, 4.66]
2.2 medium term 1 34 Mean Difference (IV, Random, 95% CI) 3.12 [-4.20, 10.44]
3 Mental state: 1c. Average 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
endpoint score (BPRS-A
subscores, high = poor) - short
term
3.1 anxiety 1 176 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.09, 0.09]
3.2 blunted affect 1 176 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.18, 0.18]
3.3 conceptual disorganisation 1 176 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.02, 0.42]
3.4 excitement 1 176 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.10, 0.10]
3.5 uncooperativeness 1 176 Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.21, 0.21]
4 Mental state: 1e. Clinical 2 141 Risk Ratio (M-H, Random, 95% CI) 0.76 [0.36, 1.61]
improvement, clinician assessed
5 Adverse effects: 1a. Weight - 1 57 Mean Difference (IV, Random, 95% CI) 0.20 [-0.84, 1.24]
BMI - short term
6 Adverse effects: 1b. Weight - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
weight gain
6.1 short term 1 165 Mean Difference (IV, Random, 95% CI) -1.60 [-3.81, 0.61]
6.2 medium term 1 30 Mean Difference (IV, Random, 95% CI) -1.80 [-5.38, 1.78]
7 Adverse effects: 1c. Weight - 1 57 Mean Difference (IV, Random, 95% CI) 1.0 [-3.42, 5.42]
body weight at endpoint - short
term
8 Adverse effects: 2a. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
blood glucose - short term
8.1 before meal 1 57 Mean Difference (IV, Random, 95% CI) 0.30 [-0.23, 0.83]
8.2 one hour after meal 1 57 Mean Difference (IV, Random, 95% CI) -0.90 [-2.33, 0.53]
8.3 two hours after meal 1 58 Mean Difference (IV, Random, 95% CI) -0.90 [-2.14, 0.34]
8.4 three hours after meal 1 57 Mean Difference (IV, Random, 95% CI) 0.40 [-0.84, 1.64]
9 Adverse effects: 2b. Metabolic - 1 Mean Difference (IV, Random, 95% CI) Subtotals only
lipid profile - short term
9.1 cholesterol - total 1 57 Mean Difference (IV, Random, 95% CI) 0.5 [-0.29, 1.29]
9.2 triglycerides 1 57 Mean Difference (IV, Random, 95% CI) 0.30 [-0.12, 0.72]
9.3 lipoprotein - high density 1 57 Mean Difference (IV, Random, 95% CI) 0.06 [-0.16, 0.28]
(HDL)
9.4 lipoprotein - low density 1 57 Mean Difference (IV, Random, 95% CI) -0.10 [-0.50, 0.30]
(LDL)
9.5 Apo A -1 1 57 Mean Difference (IV, Random, 95% CI) -0.01 [-0.14, 0.12]
9.6 Apo - B 1 57 Mean Difference (IV, Random, 95% CI) 0.10 [-0.14, 0.34]
10 Adverse effects: 3. Various 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
effects - short term
Clozapine dose for schizophrenia (Review) 52
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10.1 lethargy 1 176 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.60, 0.97]
10.2 hypersalivation 1 176 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.57, 0.84]
10.3 dizziness 1 176 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.39, 0.81]
10.4 tachycardia 1 176 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.45, 0.71]
11 Adverse effects: 4. Average 2 Mean Difference (IV, Random, 95% CI) Subtotals only
endpoint scores (TESS, high =
poor) - short term
11.1 total 2 266 Mean Difference (IV, Random, 95% CI) -3.99 [-5.75, -2.24]
11.2 subscore - behavioural 1 176 Mean Difference (IV, Random, 95% CI) 1.00 [-1.51, -0.49]
toxicity
11.3 subscore - vegetative 1 176 Mean Difference (IV, Random, 95% CI) -0.90 [-1.61, -0.19]
nervous system
11.4 subscore - cardiovascular 1 176 Mean Difference (IV, Random, 95% CI) -0.60 [-0.98, -0.22]
system
12 Leaving the study early 3 270 Risk Ratio (M-H, Random, 95% CI) 0.35 [0.06, 2.21]
12.1 any reason: short term 1 176 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
12.2 any reason: medium 1 34 Risk Ratio (M-H, Random, 95% CI) 0.20 [0.01, 3.88]
term
12.3 specific reason: short 1 60 Risk Ratio (M-H, Random, 95% CI) 0.5 [0.05, 5.22]
term

Analysis 1.1. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 1 Mental state: Average endpoint score (BPRS-A, high = poor) - medium term.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 1 Mental state: Average endpoint score (BPRS-A, high = poor) - medium term

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Simpson 1999 14 49.43 (12.65) 17 45.88 (9.61) 100.0 % 3.55 [ -4.50, 11.60 ]

Total (95% CI) 14 17 100.0 % 3.55 [ -4.50, 11.60 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.86 (P = 0.39)
Test for subgroup differences: Not applicable

-20 -10 0 10 20
Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 53

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.2. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 2 Adverse effects: 1a. Weight - BMI - short term.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 2 Adverse effects: 1a. Weight - BMI - short term

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 30 23.1 (1.2) 29 23.2 (2) 100.0 % -0.10 [ -0.95, 0.75 ]

Total (95% CI) 30 29 100.0 % -0.10 [ -0.95, 0.75 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.23 (P = 0.82)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 54

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.3. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 3 Adverse effects: 1b. Weight - weight gain.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 3 Adverse effects: 1b. Weight - weight gain

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 short term
Simpson 1999 12 1.1 (3.3) 15 2.2 (4.2) 100.0 % -1.10 [ -3.93, 1.73 ]

Subtotal (95% CI) 12 15 100.0 % -1.10 [ -3.93, 1.73 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.76 (P = 0.45)
2 medium term
Simpson 1999 13 1.3 (4.7) 15 2.6 (4.9) 100.0 % -1.30 [ -4.86, 2.26 ]

Subtotal (95% CI) 13 15 100.0 % -1.30 [ -4.86, 2.26 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.72 (P = 0.47)
Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.93), I2 =0.0%

-100 -50 0 50 100

Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 55

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.4. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 4 Adverse effects: 1c. Weight - body weight at endpoint - short term.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 4 Adverse effects: 1c. Weight - body weight at endpoint - short term

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 30 69 (6) 29 69 (9) 100.0 % 0.0 [ -3.92, 3.92 ]

Total (95% CI) 30 29 100.0 % 0.0 [ -3.92, 3.92 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 56

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.5. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 5 Adverse effects: 2a. Metabolic - blood glucose - short term.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 5 Adverse effects: 2a. Metabolic - blood glucose - short term

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Before meal
Liu 2005 30 4.7 (1.4) 29 5.1 (1.2) 100.0 % -0.40 [ -1.06, 0.26 ]

Subtotal (95% CI) 30 29 100.0 % -0.40 [ -1.06, 0.26 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.18 (P = 0.24)
2 1 hour after meal
Liu 2005 30 8.1 (2.3) 29 8.8 (2.8) 100.0 % -0.70 [ -2.01, 0.61 ]

Subtotal (95% CI) 30 29 100.0 % -0.70 [ -2.01, 0.61 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.05 (P = 0.29)
3 2 hours after meal
Liu 2005 30 7.3 (2.6) 29 7 (2.4) 100.0 % 0.30 [ -0.98, 1.58 ]

Subtotal (95% CI) 30 29 100.0 % 0.30 [ -0.98, 1.58 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.46 (P = 0.64)
4 3 hours after meal
Liu 2005 30 5.5 (1.8) 29 6.2 (1.7) 100.0 % -0.70 [ -1.59, 0.19 ]

Subtotal (95% CI) 30 29 100.0 % -0.70 [ -1.59, 0.19 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.54 (P = 0.12)
Test for subgroup differences: Chi2 = 1.78, df = 3 (P = 0.62), I2 =0.0%

-2 -1 0 1 2
Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 57

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.6. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 6 Adverse effects: 2b. Metabolic - lipid profile - short term.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 6 Adverse effects: 2b. Metabolic - lipid profile - short term

Mean Mean
Study or subgroup very low dose low dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 triglycerides
Liu 2005 30 2.7 (1.1) 29 1.7 (0.8) 100.0 % 1.00 [ 0.51, 1.49 ]

Subtotal (95% CI) 30 29 100.0 % 1.00 [ 0.51, 1.49 ]

Heterogeneity: not applicable
Test for overall effect: Z = 4.00 (P = 0.000063)
2 cholesterol - total
Liu 2005 30 4.4 (1.1) 29 3.9 (1.3) 100.0 % 0.50 [ -0.12, 1.12 ]

Subtotal (95% CI) 30 29 100.0 % 0.50 [ -0.12, 1.12 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.59 (P = 0.11)
3 lipoprotein - high density (HDL)
Liu 2005 30 1.03 (0.37) 29 0.99 (0.34) 100.0 % 0.04 [ -0.14, 0.22 ]

Subtotal (95% CI) 30 29 100.0 % 0.04 [ -0.14, 0.22 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.43 (P = 0.67)
4 lipoprotein - low density (LDL)
Liu 2005 30 2.2 (0.9) 29 2.1 (0.9) 100.0 % 0.10 [ -0.36, 0.56 ]

Subtotal (95% CI) 30 29 100.0 % 0.10 [ -0.36, 0.56 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.43 (P = 0.67)
5 Apo A-1
Liu 2005 30 0.94 (0.31) 29 0.89 (0.29) 100.0 % 0.05 [ -0.10, 0.20 ]

Subtotal (95% CI) 30 29 100.0 % 0.05 [ -0.10, 0.20 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.64 (P = 0.52)
6 Apo-B
Liu 2005 30 1.03 (0.56) 29 0.9 (0.59) 100.0 % 0.13 [ -0.16, 0.42 ]

Subtotal (95% CI) 30 29 100.0 % 0.13 [ -0.16, 0.42 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.87 (P = 0.39)
Test for subgroup differences: Chi2 = 15.42, df = 5 (P = 0.01), I2 =68%

-100 -50 0 50 100

Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 58

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.7. Comparison 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150
to 300 mg/day), Outcome 7 Leaving the study early.

Review: Clozapine dose for schizophrenia

Comparison: 1 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus LOW DOSE (150 to 300 mg/day)

Outcome: 7 Leaving the study early

Study or subgroup very low dose low dose Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 any reason - medium term

Simpson 1999 2/14 0/17 51.9 % 6.00 [ 0.31, 115.56 ]

Subtotal (95% CI) 14 17 51.9 % 6.00 [ 0.31, 115.56 ]

Total events: 2 (very low dose), 0 (low dose)
Heterogeneity: not applicable
Test for overall effect: Z = 1.19 (P = 0.24)
2 specific reason (alanine aminotransferase level) - short term
Liu 2005 0/30 1/30 48.1 % 0.33 [ 0.01, 7.87 ]

Subtotal (95% CI) 30 30 48.1 % 0.33 [ 0.01, 7.87 ]

Total events: 0 (very low dose), 1 (low dose)
Heterogeneity: not applicable
Test for overall effect: Z = 0.68 (P = 0.50)
Total (95% CI) 44 47 100.0 % 1.50 [ 0.09, 25.41 ]
Total events: 2 (very low dose), 1 (low dose)
Heterogeneity: Tau2 = 1.74; Chi2 = 1.71, df = 1 (P = 0.19); I2 =42%
Test for overall effect: Z = 0.28 (P = 0.78)
Test for subgroup differences: Chi2 = 1.71, df = 1 (P = 0.19), I2 =42%

0.001 0.01 0.1 1 10 100 1000

Favours very low dose Favours low dose

Clozapine dose for schizophrenia (Review) 59

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 1 Mental state: 1a. Average endpoint score (BPRS-A, high = poor) - medium term.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 1 Mental state: 1a. Average endpoint score (BPRS-A, high = poor) - medium term

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Simpson 1999 14 49.43 (12.65) 17 42.76 (12.04) 100.0 % 6.67 [ -2.09, 15.43 ]

Total (95% CI) 14 17 100.0 % 6.67 [ -2.09, 15.43 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.49 (P = 0.14)
Test for subgroup differences: Not applicable

-20 -10 0 10 20
Favours very low dose Favours standard dose

Analysis 2.2. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 2 Adverse effects: 1a. Weight - BMI - short term.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 2 Adverse effects: 1a. Weight - BMI - short term

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 30 23.1 (1.2) 28 23 (2) 100.0 % 0.10 [ -0.76, 0.96 ]

Total (95% CI) 30 28 100.0 % 0.10 [ -0.76, 0.96 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.23 (P = 0.82)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours very low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 60

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.3. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 3 Adverse effects: 1b. Weight - weight gain.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 3 Adverse effects: 1b. Weight - weight gain

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 short term
Simpson 1999 12 1.1 (3.3) 15 3.8 (3.8) 100.0 % -2.70 [ -5.38, -0.02 ]

Subtotal (95% CI) 12 15 100.0 % -2.70 [ -5.38, -0.02 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.97 (P = 0.048)
2 medium term
Simpson 1999 13 1.3 (4.7) 15 4.4 (5.1) 100.0 % -3.10 [ -6.73, 0.53 ]

Subtotal (95% CI) 13 15 100.0 % -3.10 [ -6.73, 0.53 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.67 (P = 0.094)
Test for subgroup differences: Chi2 = 0.03, df = 1 (P = 0.86), I2 =0.0%

-100 -50 0 50 100

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Analysis 2.4. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 4 Adverse effects: 1c. Weight - body weight at endpoint - short term.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 4 Adverse effects: 1c. Weight - body weight at endpoint - short term

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 30 69 (6) 28 68 (8) 100.0 % 1.00 [ -2.66, 4.66 ]

Total (95% CI) 30 28 100.0 % 1.00 [ -2.66, 4.66 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.54 (P = 0.59)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

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Clozapine dose for schizophrenia (Review) 62

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Analysis 2.5. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 5 Adverse effects: 2a. Metabolic - blood glucose - short term.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 5 Adverse effects: 2a. Metabolic - blood glucose - short term

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 one hour after meal

Liu 2005 30 8.1 (2.3) 28 9.7 (2.7) 100.0 % -1.60 [ -2.90, -0.30 ]

Subtotal (95% CI) 30 28 100.0 % -1.60 [ -2.90, -0.30 ]

Heterogeneity: not applicable
Test for overall effect: Z = 2.42 (P = 0.015)
2 before meal
Liu 2005 30 4.7 (1.4) 28 4.8 (0.8) 100.0 % -0.10 [ -0.68, 0.48 ]

Subtotal (95% CI) 30 28 100.0 % -0.10 [ -0.68, 0.48 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.34 (P = 0.74)
3 two hours after meal
Liu 2005 30 7.3 (2.6) 28 7.9 (2.4) 100.0 % -0.60 [ -1.89, 0.69 ]

Subtotal (95% CI) 30 28 100.0 % -0.60 [ -1.89, 0.69 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.91 (P = 0.36)
4 three hours after meal
Liu 2005 30 5.5 (1.8) 28 5.8 (2.9) 100.0 % -0.30 [ -1.55, 0.95 ]

Subtotal (95% CI) 30 28 100.0 % -0.30 [ -1.55, 0.95 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.47 (P = 0.64)
Test for subgroup differences: Chi2 = 4.43, df = 3 (P = 0.22), I2 =32%

-2 -1 0 1 2
Favours very low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 63

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.6. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 6 Adverse effects: 2b. Metabolic - lipid profile - short term.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 6 Adverse effects: 2b. Metabolic - lipid profile - short term

Mean Mean
Study or subgroup very low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 cholesterol - total
Liu 2005 30 4.4 (1.4) 28 3.4 (1.7) 100.0 % 1.00 [ 0.20, 1.80 ]

Subtotal (95% CI) 30 28 100.0 % 1.00 [ 0.20, 1.80 ]

Heterogeneity: not applicable
Test for overall effect: Z = 2.44 (P = 0.015)
2 triglycerides
Liu 2005 30 2.7 (1.1) 28 1.4 (0.8) 100.0 % 1.30 [ 0.81, 1.79 ]

Subtotal (95% CI) 30 28 100.0 % 1.30 [ 0.81, 1.79 ]

Heterogeneity: not applicable
Test for overall effect: Z = 5.17 (P < 0.00001)
3 Apo - B
Liu 2005 30 1.03 (0.56) 28 0.8 (0.26) 100.0 % 0.23 [ 0.01, 0.45 ]

Subtotal (95% CI) 30 28 100.0 % 0.23 [ 0.01, 0.45 ]

Heterogeneity: not applicable
Test for overall effect: Z = 2.03 (P = 0.043)
4 lipoprotein - high density (HDL)
Liu 2005 30 1.03 (0.37) 28 0.93 (0.5) 100.0 % 0.10 [ -0.13, 0.33 ]

Subtotal (95% CI) 30 28 100.0 % 0.10 [ -0.13, 0.33 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.86 (P = 0.39)
5 lipoprotein - low density (LDL)
Liu 2005 30 2.2 (0.9) 28 2.2 (0.6) 100.0 % 0.0 [ -0.39, 0.39 ]

Subtotal (95% CI) 30 28 100.0 % 0.0 [ -0.39, 0.39 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
6 Apo A -1
Liu 2005 30 0.94 (0.31) 28 0.9 (0.22) 100.0 % 0.04 [ -0.10, 0.18 ]

Subtotal (95% CI) 30 28 100.0 % 0.04 [ -0.10, 0.18 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.57 (P = 0.57)
Test for subgroup differences: Chi2 = 28.92, df = 5 (P = 0.00), I2 =83%

-1 -0.5 0 0.5 1
Favours very low dose Favours standard dose

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.7. Comparison 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE
(301-600 mg/day), Outcome 7 Leaving the study early.

Review: Clozapine dose for schizophrenia

Comparison: 2 CLOZAPINE: VERY LOW DOSE (up to 149 mg/day) versus STANDARD DOSE (301-600 mg/day)

Outcome: 7 Leaving the study early

Study or subgroup very low dose standard dose Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 any reason - medium term

Simpson 1999 2/14 2/17 71.5 % 1.21 [ 0.20, 7.55 ]

Subtotal (95% CI) 14 17 71.5 % 1.21 [ 0.20, 7.55 ]

Total events: 2 (very low dose), 2 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 0.21 (P = 0.84)
2 specific reason (neutropenia and tachycardia) - short term
Liu 2005 0/30 2/30 28.5 % 0.20 [ 0.01, 4.00 ]

Subtotal (95% CI) 30 30 28.5 % 0.20 [ 0.01, 4.00 ]

Total events: 0 (very low dose), 2 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 1.05 (P = 0.29)
Total (95% CI) 44 47 100.0 % 0.73 [ 0.14, 3.72 ]
Total events: 2 (very low dose), 4 (standard dose)
Heterogeneity: Tau2 = 0.10; Chi2 = 1.06, df = 1 (P = 0.30); I2 =6%
Test for overall effect: Z = 0.38 (P = 0.70)
Test for subgroup differences: Chi2 = 1.01, df = 1 (P = 0.31), I2 =1%

0.002 0.1 1 10 500

Favours very low dose Favours standard dose

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Analysis 3.1. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 1 Mental state: 1a. Clinically important response as (BPRS score > 30% change).

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 1 Mental state: 1a. Clinically important response as (BPRS score > 30% change)

Study or subgroup low dose standard dose Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chen 1998 68/94 64/82 100.0 % 0.93 [ 0.78, 1.10 ]

Total (95% CI) 94 82 100.0 % 0.93 [ 0.78, 1.10 ]

Total events: 68 (low dose), 64 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 0.88 (P = 0.38)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 66

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.2. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 2 Mental state: 1b. Average endpoint score (BPRS-A total, high = poor).

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 2 Mental state: 1b. Average endpoint score (BPRS-A total, high = poor)

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 short term
Chen 1998 94 30.9 (11.7) 82 29.2 (8.2) 100.0 % 1.70 [ -1.26, 4.66 ]

Subtotal (95% CI) 94 82 100.0 % 1.70 [ -1.26, 4.66 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.13 (P = 0.26)
2 medium term
Simpson 1999 17 45.88 (9.61) 17 42.76 (12.04) 100.0 % 3.12 [ -4.20, 10.44 ]

Subtotal (95% CI) 17 17 100.0 % 3.12 [ -4.20, 10.44 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.84 (P = 0.40)
Test for subgroup differences: Chi2 = 0.12, df = 1 (P = 0.72), I2 =0.0%

-4 -2 0 2 4
Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 67

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.3. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 3 Mental state: 1c. Average endpoint score (BPRS-A subscores, high = poor) - short
term.
Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 3 Mental state: 1c. Average endpoint score (BPRS-A subscores, high = poor) - short term

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 anxiety
Chen 1998 94 1.2 (0.3) 82 1.2 (0.3) 100.0 % 0.0 [ -0.09, 0.09 ]

Subtotal (95% CI) 94 82 100.0 % 0.0 [ -0.09, 0.09 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
2 blunted affect
Chen 1998 94 1.6 (0.6) 82 1.6 (0.6) 100.0 % 0.0 [ -0.18, 0.18 ]

Subtotal (95% CI) 94 82 100.0 % 0.0 [ -0.18, 0.18 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
3 conceptual disorganisation
Chen 1998 94 1.9 (0.8) 82 1.7 (0.7) 100.0 % 0.20 [ -0.02, 0.42 ]

Subtotal (95% CI) 94 82 100.0 % 0.20 [ -0.02, 0.42 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.77 (P = 0.077)
4 excitement
Chen 1998 94 1.1 (0.4) 82 1.1 (0.3) 100.0 % 0.0 [ -0.10, 0.10 ]

Subtotal (95% CI) 94 82 100.0 % 0.0 [ -0.10, 0.10 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
5 uncooperativeness
Chen 1998 94 1.5 (0.7) 82 1.5 (0.7) 100.0 % 0.0 [ -0.21, 0.21 ]

Subtotal (95% CI) 94 82 100.0 % 0.0 [ -0.21, 0.21 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Chi2 = 2.91, df = 4 (P = 0.57), I2 =0.0%

-100 -50 0 50 100

Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 68

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.4. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 4 Mental state: 1e. Clinical improvement, clinician assessed.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 4 Mental state: 1e. Clinical improvement, clinician assessed

Study or subgroup Low dose Standard dose Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Chen 2013 15/30 51/60 47.4 % 0.59 [ 0.40, 0.85 ]

Sheng 1990 23/25 25/26 52.6 % 0.96 [ 0.83, 1.10 ]

Total (95% CI) 55 86 100.0 % 0.76 [ 0.36, 1.61 ]

Total events: 38 (Low dose), 76 (Standard dose)
Heterogeneity: Tau2 = 0.27; Chi2 = 14.30, df = 1 (P = 0.00016); I2 =93%
Test for overall effect: Z = 0.72 (P = 0.47)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours standard dose Favours low dose

Analysis 3.5. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 5 Adverse effects: 1a. Weight - BMI - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 5 Adverse effects: 1a. Weight - BMI - short term

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 29 23.2 (2) 28 23 (2) 100.0 % 0.20 [ -0.84, 1.24 ]

Total (95% CI) 29 28 100.0 % 0.20 [ -0.84, 1.24 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.38 (P = 0.71)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 69

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.6. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 6 Adverse effects: 1b. Weight - weight gain.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 6 Adverse effects: 1b. Weight - weight gain

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 short term
Simpson 1999 15 2.2 (4.2) 150 3.8 (3.8) 100.0 % -1.60 [ -3.81, 0.61 ]

Subtotal (95% CI) 15 150 100.0 % -1.60 [ -3.81, 0.61 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.42 (P = 0.16)
2 medium term
Simpson 1999 15 2.6 (4.9) 15 4.4 (5.1) 100.0 % -1.80 [ -5.38, 1.78 ]

Subtotal (95% CI) 15 15 100.0 % -1.80 [ -5.38, 1.78 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.99 (P = 0.32)
Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.93), I2 =0.0%

-100 -50 0 50 100

Favours low dose Favours standard dose

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.7. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 7 Adverse effects: 1c. Weight - body weight at endpoint - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 7 Adverse effects: 1c. Weight - body weight at endpoint - short term

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Liu 2005 29 69 (9) 28 68 (8) 100.0 % 1.00 [ -3.42, 5.42 ]

Total (95% CI) 29 28 100.0 % 1.00 [ -3.42, 5.42 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.44 (P = 0.66)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 71

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.8. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 8 Adverse effects: 2a. Metabolic - blood glucose - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 8 Adverse effects: 2a. Metabolic - blood glucose - short term

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 before meal
Liu 2005 29 5.1 (1.2) 28 4.8 (0.8) 100.0 % 0.30 [ -0.23, 0.83 ]

Subtotal (95% CI) 29 28 100.0 % 0.30 [ -0.23, 0.83 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.11 (P = 0.27)
2 one hour after meal
Liu 2005 29 8.8 (2.8) 28 9.7 (2.7) 100.0 % -0.90 [ -2.33, 0.53 ]

Subtotal (95% CI) 29 28 100.0 % -0.90 [ -2.33, 0.53 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.24 (P = 0.22)
3 two hours after meal
Liu 2005 29 7 (2.4) 29 7.9 (2.4) 100.0 % -0.90 [ -2.14, 0.34 ]

Subtotal (95% CI) 29 29 100.0 % -0.90 [ -2.14, 0.34 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.43 (P = 0.15)
4 three hours after meal
Liu 2005 29 6.2 (1.7) 28 5.8 (2.9) 100.0 % 0.40 [ -0.84, 1.64 ]

Subtotal (95% CI) 29 28 100.0 % 0.40 [ -0.84, 1.64 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.63 (P = 0.53)
Test for subgroup differences: Chi2 = 5.14, df = 3 (P = 0.16), I2 =42%

-4 -2 0 2 4
Favours low dose Favours standard dose

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.9. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 9 Adverse effects: 2b. Metabolic - lipid profile - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 9 Adverse effects: 2b. Metabolic - lipid profile - short term

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 cholesterol - total
Liu 2005 29 3.9 (1.3) 28 3.4 (1.7) 100.0 % 0.50 [ -0.29, 1.29 ]

Subtotal (95% CI) 29 28 100.0 % 0.50 [ -0.29, 1.29 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.24 (P = 0.21)
2 triglycerides
Liu 2005 29 1.7 (0.8) 28 1.4 (0.8) 100.0 % 0.30 [ -0.12, 0.72 ]

Subtotal (95% CI) 29 28 100.0 % 0.30 [ -0.12, 0.72 ]

Heterogeneity: not applicable
Test for overall effect: Z = 1.42 (P = 0.16)
3 lipoprotein - high density (HDL)
Liu 2005 29 0.99 (0.34) 28 0.93 (0.5) 100.0 % 0.06 [ -0.16, 0.28 ]

Subtotal (95% CI) 29 28 100.0 % 0.06 [ -0.16, 0.28 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.53 (P = 0.60)
4 lipoprotein - low density (LDL)
Liu 2005 29 2.1 (0.9) 28 2.2 (0.6) 100.0 % -0.10 [ -0.50, 0.30 ]

Subtotal (95% CI) 29 28 100.0 % -0.10 [ -0.50, 0.30 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.50 (P = 0.62)
5 Apo A -1
Liu 2005 29 0.89 (0.29) 28 0.9 (0.22) 100.0 % -0.01 [ -0.14, 0.12 ]

Subtotal (95% CI) 29 28 100.0 % -0.01 [ -0.14, 0.12 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.15 (P = 0.88)
6 Apo - B
Liu 2005 29 0.9 (0.59) 28 0.8 (0.26) 100.0 % 0.10 [ -0.14, 0.34 ]

Subtotal (95% CI) 29 28 100.0 % 0.10 [ -0.14, 0.34 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.83 (P = 0.40)
Test for subgroup differences: Chi2 = 4.12, df = 5 (P = 0.53), I2 =0.0%

-1 -0.5 0 0.5 1
Favours low dose Favours standard dose

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.10. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE
(301 to 600 mg/day), Outcome 10 Adverse effects: 3. Various effects - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 10 Adverse effects: 3. Various effects - short term

Study or subgroup low dose standard dose Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 lethargy
Chen 1998 50/94 57/82 100.0 % 0.77 [ 0.60, 0.97 ]

Subtotal (95% CI) 94 82 100.0 % 0.77 [ 0.60, 0.97 ]

Total events: 50 (low dose), 57 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 2.21 (P = 0.027)
2 hypersalivation
Chen 1998 55/94 69/82 100.0 % 0.70 [ 0.57, 0.84 ]

Subtotal (95% CI) 94 82 100.0 % 0.70 [ 0.57, 0.84 ]

Total events: 55 (low dose), 69 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 3.66 (P = 0.00025)
3 dizziness
Chen 1998 29/94 45/82 100.0 % 0.56 [ 0.39, 0.81 ]

Subtotal (95% CI) 94 82 100.0 % 0.56 [ 0.39, 0.81 ]

Total events: 29 (low dose), 45 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 3.13 (P = 0.0018)
4 tachycardia
Chen 1998 46/94 71/82 100.0 % 0.57 [ 0.45, 0.71 ]

Subtotal (95% CI) 94 82 100.0 % 0.57 [ 0.45, 0.71 ]

Total events: 46 (low dose), 71 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 5.01 (P < 0.00001)
Test for subgroup differences: Chi2 = 4.37, df = 3 (P = 0.22), I2 =31%

0.01 0.1 1 10 100

Favours low dose Favours standard dose

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Analysis 3.11. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301
to 600 mg/day), Outcome 11 Adverse effects: 4. Average endpoint scores (TESS, high = poor) - short term.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 11 Adverse effects: 4. Average endpoint scores (TESS, high = poor) - short term

Mean Mean
Study or subgroup low dose standard dose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 total
Chen 1998 94 7.5 (8.8) 82 10.5 (8.8) 45.0 % -3.00 [ -5.61, -0.39 ]

Chen 2013 30 8.5 (4.9) 60 13.3 (6.2) 55.0 % -4.80 [ -7.15, -2.45 ]

Subtotal (95% CI) 124 142 100.0 % -3.99 [ -5.75, -2.24 ]

Heterogeneity: Tau2 = 0.02; Chi2 = 1.01, df = 1 (P = 0.32); I2 =1%
Test for overall effect: Z = 4.46 (P < 0.00001)
2 subscore - behavioural toxicity
Chen 1998 94 0.9 (1.1) 82 1.9 (2.1) 100.0 % -1.00 [ -1.51, -0.49 ]

Subtotal (95% CI) 94 82 100.0 % -1.00 [ -1.51, -0.49 ]

Heterogeneity: not applicable
Test for overall effect: Z = 3.87 (P = 0.00011)
3 subscore - vegetative nervous system
Chen 1998 94 3.6 (2.7) 82 4.5 (2.1) 100.0 % -0.90 [ -1.61, -0.19 ]

Subtotal (95% CI) 94 82 100.0 % -0.90 [ -1.61, -0.19 ]

Heterogeneity: not applicable
Test for overall effect: Z = 2.48 (P = 0.013)
4 subscore - cardiovascular system
Chen 1998 94 1.5 (1.1) 82 2.1 (1.4) 100.0 % -0.60 [ -0.98, -0.22 ]

Subtotal (95% CI) 94 82 100.0 % -0.60 [ -0.98, -0.22 ]

Heterogeneity: not applicable
Test for overall effect: Z = 3.13 (P = 0.0018)
Test for subgroup differences: Chi2 = 14.36, df = 3 (P = 0.00), I2 =79%

-1 -0.5 0 0.5 1
Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 75

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.12. Comparison 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE
(301 to 600 mg/day), Outcome 12 Leaving the study early.

Review: Clozapine dose for schizophrenia

Comparison: 3 CLOZAPINE: LOW DOSE (150 to 300 mg/day) versus STANDARD DOSE (301 to 600 mg/day)

Outcome: 12 Leaving the study early

Study or subgroup low dose standard dose Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI

1 any reason: short term

Chen 1998 0/94 0/82 Not estimable

Subtotal (95% CI) 94 82 Not estimable

Total events: 0 (low dose), 0 (standard dose)
Heterogeneity: not applicable
Test for overall effect: not applicable
2 any reason: medium term
Simpson 1999 0/17 2/17 38.5 % 0.20 [ 0.01, 3.88 ]

Subtotal (95% CI) 17 17 38.5 % 0.20 [ 0.01, 3.88 ]

Total events: 0 (low dose), 2 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 1.06 (P = 0.29)
3 specific reason: short term
Liu 2005 1/30 2/30 61.5 % 0.50 [ 0.05, 5.22 ]

Subtotal (95% CI) 30 30 61.5 % 0.50 [ 0.05, 5.22 ]

Total events: 1 (low dose), 2 (standard dose)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
Total (95% CI) 141 129 100.0 % 0.35 [ 0.06, 2.21 ]
Total events: 1 (low dose), 4 (standard dose)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.23, df = 1 (P = 0.63); I2 =0.0%
Test for overall effect: Z = 1.11 (P = 0.27)
Test for subgroup differences: Chi2 = 0.23, df = 1 (P = 0.63), I2 =0.0%

0.005 0.1 1 10 200

Favours low dose Favours standard dose

Clozapine dose for schizophrenia (Review) 76

Title Reference

Clozapine versus other atypical antipsychotics for schizophrenia Asenjo 2010

Clozapine combined with different antipsychotic drugs for treat- Cipriani 2009
ment resistant schizophrenia

Clozapine versus typical neuroleptic medication for schizophrenia Essali 2009

Pharmacological interventions for clozapine-induced hypersaliva- Syed 2008

tion

APPENDICES

Appendix 1. Previous searches

Search in 2011

Electronic searches

Cochrane Schizophrenia Group Trials Register

We searched the register (August 2011) using the following phrase:
[(*clozapin* or *clozaril* or *leponex* or *denzapin* or *zaponex* in intervention of STUDY) AND (*dose* or *dosage* or *dosage?
effect* or *dose?activity* or *dose?dependence* or *dose?effect* or *dose?rate* or *dose?response* or *dosage?scheme* or *drug?response*
or *effective?dose* or *dose?finding* or *dose?calculation* or *therapeutic?equiv* or *blood?level* or *blood?drug* or *serum?level* or
*serum?drug* or *plasma-level* or *plasma-drug* or *high?dos* or *low?dos* or *medium?dos* or *standard?dos* or *middle?dos* or
*maximum?dos* or *minimum?dos* or *threshold?dos* in title abstract and index terms of reference)]
This register is compiled by systematic searches of major databases, hand searches and conference proceedings (see group module).

Searching other resources

1. Reference searching
We searched the reference lists of each included paper, but failed find any new studies.

2. Personal contact
Where possible, we contacted the first author of trials or citations for missing information on unpublished data or trials.Where the
first author’s contact was not possible through the Cochrane Schizophrenia group, we attempted to contact the other authors. At the
time of writing, we have not received any of the missing data we requested, though one author indicated he will send the requested
information in future. We have discussed this in detail under relevant sections of results.
Clozapine dose for schizophrenia (Review) 77
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HISTORY
Protocol first published: Issue 1, 2012
Review first published: Issue 6, 2017

Date Event Description

8 December 2016 Amended Search was undertaken and 8 studies (13 references) added to ’Studies awaiting classification’ section
of the review. One study (Abraham 1997) already was in this section from last update.

CONTRIBUTIONS OF AUTHORS
Selvizhi Subramanian - protocol development, study selection, data collection and synthesis, report writing.

Birgit A V llm - protocol development, study selection, data collection and synthesis, report writing.
Nick Huband - data synthesis, report writing.

DECLARATIONS OF INTEREST
Selvizhi Subramanian - none known.

Birgit A V llm - none known.

Nick Huband - none known.

SOURCES OF SUPPORT

Internal sources
• none, Other.

External sources
• none, Other.

Clozapine dose for schizophrenia (Review) 78

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
The original categorisation of doses of clozapine was slightly changed to enable us to accommodate the doses compared in the trials of
the four included papers.

Clozapine dose for schizophrenia (Review) 79

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