Clozapine dose for schizophrenia

Selvizhi Subramanian; Birgit A Völlm; Nick Huband

doi:10.1002/14651858.CD009555.pub2

Dos clozapine untuk skizofrenia

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Referencias

References to studies included in this review

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References to studies excluded from this review

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References to studies awaiting assessment

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Additional references

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios a la espera de clasificación

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 bias)	Unclear risk	Randomly assigned, no further details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not stated.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported; no loss to follow up.
Selective reporting (reporting bias)	Low risk	No indication of selective reporting.
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 bias)	Unclear risk	Randomly assigned, no further details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not stated.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported; no loss to follow up.
Selective reporting (reporting bias)	Low risk	No indication of selective reporting.
Other bias	Unclear risk	Sponsor unclear.

Liu 2005

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 bias)	Low risk	Allocation by random number table.
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not stated.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Three participants left the study early, reasons given.
Selective reporting (reporting bias)	Low risk	No indication of selective reporting.
Other bias	Low risk	No indication of other bias.

Sheng 1990

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 bias)	Unclear risk	Randomly assigned, no further details.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	‘Double blind’, no further details.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	‘Double blind’, no further details.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All data reported; no loss to follow‐up.
Selective reporting (reporting bias)	High risk	BPRS and TESS score data not available.
Other bias	Unclear risk	Sponsor unclear.

Simpson 1999

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 treatment, 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 corrections (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 bias)	High risk	Implied randomisation trial, no details on method of allocation.
Allocation concealment (selection bias)	Unclear risk	No details.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants were blinded to doses of clozapine; no details on personnel giving the treatment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assessors were blinded to doses of clozapine.
Incomplete outcome data (attrition bias) All outcomes	High risk	44 out of 48 patients completed the first 16 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]

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estudios incluidos
estudios a la espera de clasificación

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 dyskinesia and extrapyramidal symptoms, (b) coefficients of variation in the relationship between dose and plasma 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.
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.

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

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.

Data and analyses

Open in table viewer

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: Average endpoint score (BPRS‐A, high = poor) ‐ medium term Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	3.55 [‐4.50, 11.60]
Open in figure viewer 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.
2 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	59	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.95, 0.75]
Open in figure viewer 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.
3 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ body weight at endpoint ‐ short term Show forest plot	1	59	Mean Difference (IV, Random, 95% CI)	0.0 [‐3.92, 3.92]
Open in figure viewer 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.
5 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 (HDL)	1	59	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.14, 0.22]
6.4 lipoprotein ‐ low density (LDL)	1	59	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.36, 0.56]
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 Show forest plot	2	91	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.09, 25.41]
Open in figure viewer 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.
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 aminotransferase level) ‐ short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]

Open in table viewer

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. Average endpoint score (BPRS‐A, high = poor) ‐ medium term Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	6.67 [‐2.09, 15.43]
Open in figure viewer 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.
2 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	58	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.76, 0.96]
Open in figure viewer 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.
3 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ body weight at endpoint ‐ short term Show forest plot	1	58	Mean Difference (IV, Random, 95% CI)	1.0 [‐2.66, 4.66]
Open in figure viewer 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.
5 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 (HDL)	1	58	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.13, 0.33]
6.5 lipoprotein ‐ low density (LDL)	1	58	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.39, 0.39]
6.6 Apo A ‐1	1	58	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.10, 0.18]
7 Leaving the study early Show forest plot	2	91	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.14, 3.72]
Open in figure viewer 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.
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 (neutropenia and tachycardia) ‐ short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 4.00]

Open in table viewer

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. Clinically important response as (BPRS score > 30% change) Show forest plot	1	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.78, 1.10]
Open in figure viewer 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).
2 Mental state: 1b. Average endpoint score (BPRS‐A total, high = poor) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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).
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 endpoint score (BPRS‐A subscores, high = poor) ‐ short term Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer 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.
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 improvement, clinician assessed Show forest plot	2	141	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.36, 1.61]
Open in figure viewer 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.
5 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	57	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.84, 1.24]
Open in figure viewer 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.
6 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ body weight at endpoint ‐ short term Show forest plot	1	57	Mean Difference (IV, Random, 95% CI)	1.0 [‐3.42, 5.42]
Open in figure viewer 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.
8 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
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 (HDL)	1	57	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.16, 0.28]
9.4 lipoprotein ‐ low density (LDL)	1	57	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.50, 0.30]
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 effects ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer 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.
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 endpoint scores (TESS, high = poor) ‐ short term Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
Open in figure viewer 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.
11.1 total	2	266	Mean Difference (IV, Random, 95% CI)	‐3.99 [‐5.75, ‐2.24]
11.2 subscore ‐ behavioural toxicity	1	176	Mean Difference (IV, Random, 95% CI)	1.00 [‐1.51, ‐0.49]
11.3 subscore ‐ vegetative nervous system	1	176	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.61, ‐0.19]
11.4 subscore ‐ cardiovascular system	1	176	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.98, ‐0.22]
12 Leaving the study early Show forest plot	3	270	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.06, 2.21]
Open in figure viewer 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.
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 term	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 3.88]
12.3 specific reason: short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.22]

Figure 1

Clozapine structure

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Figure 2

Study flow diagram.

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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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Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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).

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Summary of findings for the main comparison. Clozapine: very low dose (up to 149 mg/day) versus low dose (150 mg/day to 300 mg/day) for schizophrenia

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 mg/day) versus low dose (150 mg/day to 300 mg/day)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	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 important response, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Mental state: clinically important response, as defined by individual studies * Follow‐up: 16 weeks		The mean clinical response: mental state ‐ average scores ‐ medium term endpoint (BPRS‐A, high = worse) in the intervention group was 3.55 higher (4.50 to 11.60 higher)		31 (1 study)	⊕⊝⊝⊝ very low^1,2,3	* Pre‐defined outcome not reported: Mental state measured as average endpoint scores (BPRS‐A, high = worse).
Functioning: clinically important change in general functioning, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Adverse effect: clinically important adverse effect (weight ‐ BMI) Follow‐up: 6 weeks		The mean adverse effect ‐ any clinically important specific adverse effects ‐ BMI in the intervention group was 0.1 lower (0.95 lower to 0.75 higher)		59 (1 study)	⊕⊕⊝⊝ low^2,3
Service use: number of days hospitalised	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Service use: time to hospitalisation	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Quality of life: clinically important change in general quality of life	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias: rated as 'serious' (downgraded by 1) due to attrition bias, reporting bias, and sponsorship by Novartis Pharmaceuticals. ² Indirectness: rated 'serious' (downgraded by 1) as proxy measure of pre‐defined outcome ³ Imprecision: rated 'serious' (downgraded by 1) as only one study providing data, small number of participants (less than 200)

Summary of findings for the main comparison. Clozapine: very low dose (up to 149 mg/day) versus low dose (150 mg/day to 300 mg/day) for schizophrenia

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Summary of findings 2. Clozapine: very low dose (up to 149 mg/day) versus standard dose (301 mg/day to 600 mg/day) for schizophrenia

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 mg/day) versus standard dose (301 mg/day to 600 mg/day)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	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 important response, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Mental state: clinically important response, as defined by individual studies * Follow‐up: 16 weeks		The mean clinical response: mental state ‐ average scores ‐ medium term endpoint (BPRS‐A, high = worse) in the intervention group was 6.67 higher (2.09 to 15.43 higher)		31 (1 study)	⊕⊝⊝⊝ very low^1,2,3	* Pre‐defined outcome not reported: Mental state measured as average endpoint scores (BPRS‐A, high = worse).
Functioning: clinically important change in general functioning, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Adverse effect: clinically important adverse effect (weight ‐ BMI) Follow‐up: 6 weeks		The mean adverse effect ‐ any clinically important specific adverse effects ‐ BMI in the intervention group was 0.1 higher (0.76 lower to 0.96 higher)		58 (1 study)	⊕⊕⊝⊝ low^2,3
Service use: number of days hospitalised	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Service use: time to hospitalisation	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Quality of life: clinically important change in general quality of life	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias: rated as 'serious' (downgraded by 1) due to attrition bias, reporting bias, and sponsorship by Novartis Pharmaceuticals. ² Indirectness: rated 'serious' (downgraded by 1) as proxy measure of pre‐defined outcome ³ Imprecision: rated 'serious' (downgraded by 1) as only one study providing data, small number of participants (less than 200)

Summary of findings 2. Clozapine: very low dose (up to 149 mg/day) versus standard dose (301 mg/day to 600 mg/day) for schizophrenia

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Summary of findings 3. Clozapine: low dose (150 mg/day to 300 mg/day) versus standard dose (301 mg/day to 600 mg/day) for schizophrenia

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 mg/day to 300 mg/day) versus standard dose (301 mg/day to 600 mg/day)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Clozapine: low dose (150 mg/day to 300 mg/day) versus standard dose (301 mg/day to 600 mg/day)
Global state: clinically important response, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Mental state: clinically important response in mental state BPRS score >30% change Follow‐up: 6 weeks	Low¹		RR 0.93 (0.78 to 1.1)	176 (1 study)	⊕⊕⊝⊝ low ^1,3
	200 per 1000	186 per 1000 (156 to 220)
	Moderate¹
	500 per 1000	465 per 1000 (390 to 550)
	High¹
	800 per 1000	744 per 1000 (624 to 880)
Functioning: clinically important change in general functioning, as defined by individual studies	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Adverse effect: clinically important adverse effect ( weight ‐ BMI) Follow‐up: 6 weeks		The mean adverse effect ‐ any clinically important specific adverse effects ‐ BMI in the intervention group was 0.2 higher (0.84 lower to 1.24 higher)		57 (1 study)	⊕⊕⊝⊝ low^2,3
Service use: number of days hospitalised	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Service use: time to hospitalisation	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Quality of life: clinically important change in general quality of life	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias rated as 'serious' (downgraded by 1) as allocation concealment, blinding status and trial sponsorship unclear ² Indirectness: rated 'serious' (downgraded by 1) as proxy measure of pre‐defined outcome ³ Imprecision: rated as 'serious' (downgraded by 1) as only one study providing data, small number of participants (less than 200)

Summary of findings 3. Clozapine: low dose (150 mg/day to 300 mg/day) versus standard dose (301 mg/day to 600 mg/day) for schizophrenia

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Table 1. Other reviews in the clozapine series

Title	Reference
Clozapine versus other atypical antipsychotics for schizophrenia	Asenjo 2010
Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia	Cipriani 2009
Clozapine versus typical neuroleptic medication for schizophrenia	Essali 2009
Pharmacological interventions for clozapine‐induced hypersalivation	Syed 2008

Table 1. Other reviews in the clozapine series

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: Average endpoint score (BPRS‐A, high = poor) ‐ medium term Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	3.55 [‐4.50, 11.60]

2 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	59	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.95, 0.75]

3 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ body weight at endpoint ‐ short term Show forest plot	1	59	Mean Difference (IV, Random, 95% CI)	0.0 [‐3.92, 3.92]

5 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 (HDL)	1	59	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.14, 0.22]
6.4 lipoprotein ‐ low density (LDL)	1	59	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.36, 0.56]
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 Show forest plot	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 aminotransferase level) ‐ short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. Average endpoint score (BPRS‐A, high = poor) ‐ medium term Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	6.67 [‐2.09, 15.43]

2 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	58	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.76, 0.96]

3 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ body weight at endpoint ‐ short term Show forest plot	1	58	Mean Difference (IV, Random, 95% CI)	1.0 [‐2.66, 4.66]

5 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 (HDL)	1	58	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.13, 0.33]
6.5 lipoprotein ‐ low density (LDL)	1	58	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.39, 0.39]
6.6 Apo A ‐1	1	58	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.10, 0.18]
7 Leaving the study early Show forest plot	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 (neutropenia and tachycardia) ‐ short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 4.00]

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. Clinically important response as (BPRS score > 30% change) Show forest plot	1	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.78, 1.10]

2 Mental state: 1b. Average endpoint score (BPRS‐A total, high = poor) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 endpoint score (BPRS‐A subscores, high = poor) ‐ short term Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

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 improvement, clinician assessed Show forest plot	2	141	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.36, 1.61]

5 Adverse effects: 1a. Weight ‐ BMI ‐ short term Show forest plot	1	57	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.84, 1.24]

6 Adverse effects: 1b. Weight ‐ weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ body weight at endpoint ‐ short term Show forest plot	1	57	Mean Difference (IV, Random, 95% CI)	1.0 [‐3.42, 5.42]

8 Adverse effects: 2a. Metabolic ‐ blood glucose ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 ‐ lipid profile ‐ short term Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

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 (HDL)	1	57	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.16, 0.28]
9.4 lipoprotein ‐ low density (LDL)	1	57	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.50, 0.30]
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 effects ‐ short term Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

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 endpoint scores (TESS, high = poor) ‐ short term Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 total	2	266	Mean Difference (IV, Random, 95% CI)	‐3.99 [‐5.75, ‐2.24]
11.2 subscore ‐ behavioural toxicity	1	176	Mean Difference (IV, Random, 95% CI)	1.00 [‐1.51, ‐0.49]
11.3 subscore ‐ vegetative nervous system	1	176	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.61, ‐0.19]
11.4 subscore ‐ cardiovascular system	1	176	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.98, ‐0.22]
12 Leaving the study early Show forest plot	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 term	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 3.88]
12.3 specific reason: short term	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.22]

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

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Referencias

References to studies included in this review

Chen 1998 {published data only}

Chen 2013 {published data only}

Liu 2005 {published data only}

Sheng 1990 {published data only}

Simpson 1999 {published data only}

References to studies excluded from this review

Borges 2010 {published data only}

de Leon 1995a {published data only}

de Leon 1995b {published data only}

de Leon 2003 {published data only}

de Leon 2004 {published data only}

Guo 2003 {published data only}

Han 2001 {published data only}

Liu 2005a {published data only}

Matz 1974 {published data only}

McEvoy 1995 {published data only}

McEvoy 1996 {published data only}

Nair 1998 {published data only}

Nair 1999 {published data only}

Potkin 1993 {published data only}

Potkin 1994 {published data only}

Tang 2000 {published data only}

VanderZwaag 1996 {published data only}

VanderZwaag 1997 {published and unpublished data}

References to studies awaiting assessment

Abraham 1997 {published data only}

Additional references

Aitchison 1997

Altman 1996

Arnt 1998

Asenjo 2010

Azorin 2005

Benazzi 2003

Bergem 1990

Bland 1997

BNF 2012

Boissel 1999

Buchanan 1995

Carpenter 1994

Cipriani 2009

CMHP

Coward 1992

Danileviciūte 2002

Deeks 2000

Deeks 2011

Divine 1992

Donner 2002

DSM‐IV

Egger 1997

Elbourne 2002

Essali 2009

Furukawa 2006

Gaebel 1997

Gelder 2001

Guldberg 1991

Gulliford 1999

Higgins 2003

Higgins 2011a

Higgins 2011b

Hutton 2009

ICD‐10

Kane 1988

Kane 1990

Kane 2011

Kaplan 2005

Kasanin 1933

Kay 1986

Kerwin 2005

Kronig 1995

Lachar 2001

Leucht 2005a

Leucht 2005b

Leucht 2007

Marshall 2000

McGrath 2008

Meuser 2004