Increasing antipsychotic dose for non response in schizophrenia

Myrto T Samara; Elisabeth Klupp; Bartosz Helfer; Philipp H Rothe; Johannes Schneider‐Thoma; Stefan Leucht

doi:10.1002/14651858.CD011883.pub2

افزایش دوز داروی آنتی‌‌سایکوتیک برای عدم پاسخ به درمان در بیماری اسکیزوفرنی

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منابع دیگر نسخه‌های منتشرشده این مرور

Ir a:

منابع مطالعات واردشده در این مرور
منابع مطالعات خارج‌شده از این مرور
منابع اضافی

Helfer B, Leucht S, Rothe PH, Samara MT. Increasing antipsychotic dose for non response in schizophrenia. Cochrane Database of Systematic Reviews 2015, Issue 10. [DOI: 10.1002/14651858.CD011883]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Bjørndal 1980

Methods	Allocation: randomised, no further details Blinding: double, no further details Duration: 16 weeks; 4 weeks non‐randomised open‐label run‐in phase and 12 weeks randomised double‐blind phase Design: parallel Location: not indicated, probably single centre, Denmark Setting: inpatients
Participants	Diagnosis: chronic schizophrenia, severity of illness was 4 to 6 according to the disability scale used (0 indicated no symptoms, while a score of 7 indicated extremely severe degree of illness), no further details. N = 29, data only on 23 completers Gender: 29 men, 0 women Age: mean 34 years (range 19 to 60 years) for 23 completers History: duration of illness mean 9 years (range 2 to 20), length of stay in hospital mean 5 years (range 0.5 to 17), duration of antipsychotic treatment mean 8 years (range 1 to 18) for 23 completers; no further details.
Interventions	All participants firstly received open‐label 2 mg haloperidol tablets for 4 weeks (maximum dosage being 12 mg/day). Participants were then randomised to either: 1. dose increase: 20 mg haloperidol tablets; mean 103 mg/day at endpoint. N = 12; or 2. dose maintenance: 2 mg haloperidol tablets; mean 15 mg/day at endpoint. N = 11. The starting dose corresponded to the number of tablets reached during the open pretest period (mean 10 mg/day in both groups). During the first 6 weeks, the dose was adjusted according to effect and side effects, while during the following 6 weeks the dose was maintained constant as far as possible. Rescue medication: orphenadrine and chloralodol; no further details.
Outcomes	Clinically relevant response (defined as > 0% BPRS total score reduction) Global state: improved, possible improved, unchanged, or deteriorated (Global Assessment Scale) Adverse effects Unable to use: Leaving the study early (no separate numbers for the two groups) Mental state: general (BPRS total score, no mean, no SD), Nurses Observation Scale for Inpatient Evaluation (NOSIE total score, no SD) Plasma levels of haloperidol (no mean, no SD) and prolactin (no SD), and not protocol outcomes Other laboratory investigations (no mean, no SD), and not protocol outcomes
Notes	In this study, there was a 4‐week, open, pretest period during which participants received 2 mg haloperidol tablets (mean 10 mg/day). It is not clearly indicated whether all participants entering the double‐blind phase were non‐responders during the run‐in phase. Nevertheless, based on participant description and BPRS total scores at baseline, we assumed this is the case.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...patients were randomized..." (pg. 18); no further details
Allocation concealment (selection bias)	Unclear risk	No details were presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...12‐week double‐blind phase..." (pg. 18); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...12‐week double‐blind phase..." (pg. 18); no further details
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Twenty‐nine male, chronic schizophrenic patients ... consent to participate in the study. Six of the patients dropped out during the study, independent of the drug administered. The 23 patients completing the study ..." (pg. 18); no further details. Only completers were analysed.
Selective reporting (reporting bias)	High risk	BPRS total score, NOSIE, plasma levels and other laboratory values were assessed but no usable data were reported in the results.
Other bias	Low risk	No obvious risk for other bias

Goff 2013

Methods	Allocation: randomised, no further details Blinding: double, no further details Duration: 11 weeks; 3 weeks non‐randomised open‐label run‐in phase and 8 weeks randomised double‐blind phase. Design: parallel Location: multi‐centre (USA) Setting: inpatients (N = 30) and outpatients (N = 45)
Participants	Diagnosis: schizophrenia or schizoaffective disorder (DSM‐IV) N = 75 Gender: 52 men, 23 women Age: mean 40 years (SD = 11.9), range 16 to 65 years History: age at onset mean 25 years (SD = 9.1), no further details
Interventions	All participants firstly received open‐label ziprasidone treatment, titrated up to 160 mg/day, for a minimum of 3 weeks. Participants with persistent psychotic symptoms defined by a score of 4 (moderate) or greater on any item of PANSS despite ziprasidone treatment were then randomised to either: 1. dose increase: ziprasidone 320 mg/day; dose could be decreased to 240 mg/day. N = 38; or 2. dose maintenance: ziprasidone 160 mg/day. N = 37. Rescue medication: benztropine, propranolol, lorazepam, zolpidem; no further details.
Outcomes	Global state: clinically relevant response (defined as ≥20% PANSS total score reduction) Mental state: positive symptoms (PANSS positive subscore) Adverse effects: cardiac — QTc prolongation (number of participants with QTc longer than 500 msec) Unable to use: Leaving the study early (numbers not presented) Overall mental state (PANSS total score, no mean, no SD) Global state (change in CGI‐I, no SD; and CGI‐S, no mean, no SD) Negative symptoms (PANSS negative subscore, no mean, no SD) Depression (Calgary Depression Rating Scale (CDRS), no mean, no SD) Functioning (Global Assessment of Functioning, GAF, no mean, no SD) Adverse effects (EPS ‐ SAS (no mean, no SD), Akathisia ‐ BAS (no mean, no SD), tardive dyskinesia ‐ AIMS (no mean, no SD), Side Effect Checklist (no numbers), rate of adverse effects (no SD)) Vital signs (no numbers) Plasma levels (no SD) Cognition (Schizophrenia Cognition Rating Scale, no mean, no SD)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...eligible patients were randomly assigned to ziprasidone 40 mg capsules or matching placebo in a 1:1 ratio stratified according to the duration of prior ziprasidone treatment..." (pg. 486); no further details.
Allocation concealment (selection bias)	Unclear risk	No details were presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: " For the 8‐week double‐blind, placebo‐controlled trial..." (pg. 486); no further details.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: " For the 8‐week double‐blind, placebo‐controlled trial..." (pg. 486); no further details.
Incomplete outcome data (attrition bias) All outcomes	High risk	44% of the participants left the study early. Numbers per group as well as reasons for leaving the study early were not specified. For the primary outcome of clinically relevant response, only completers were analysed.
Selective reporting (reporting bias)	High risk	PANSS total score, PANSS negative sbscore, CGI, CDRS, SCoRS, SAS, BAS, AIMS, Side Effect Checklist, vital signs and plasma levels were assessed but no usable data were reported in the results.
Other bias	Low risk	No obvious risk for other bias

Honer 2011

Methods	Allocation: randomised, 2:1 with a computerised schedule Blinding: double, no further details Duration: 12 weeks; 4 weeks non‐randomised open‐label run in phase and 8 weeks randomised double‐blind phase. Design: parallel Location: multi‐centre (Canada) Setting: inpatients (N = 27) and outpatients (N = 104)
Participants	Diagnosis: schizophrenia or schizoaffective disorder (DSM IV) N = 131 Gender: 90 men, 41 women Age: mean 39.7 years (SD = 12.1), range 18 to 65 years History: not stated
Interventions	All participants firstly received open‐label quetiapine treatment 800 mg/day for 4 weeks. Participants with persistent positive and negative symptoms and CGI≥4 despite quetiapine treatment were then randomised to either: 1. dose increase: quetiapine 1200 mg/day; dose could be decreased. N = 88; or 2. dose maintenance: quetiapine 800 mg/day. N = 43. Rescue medication: flurazepam, zaleplon, lorazepam, anticholinergic medication. Antidepressant, mood‐stabilizing, or hypnotic medications were continued, if subjects were taking stable doses for a 30‐day period prior to trial entry.
Outcomes	Global state: clinically relevant response (defined as ≥ 20% PANSS total score reduction) Leaving the study early (due to side effects, any reason, inefficacy) Mental state: general mental state (PANSS total score), positive symptoms (PANSS positive subscore), negative symptoms (PANSS negative subscore) Global state (CGI‐Severity) Adverse effects: (at least one adverse effect, SAS (improved, no change, worsened), BAS (improved, no change, worsened), AIMS (improved, no change, worsened), death/suicide, BMI & weight increase, increase in heart rate, QTcF prolongation (≥450 ms), dizziness, headache, fatigue, somnolence, anxiety, dyskinesia, tremor). Functioning (SOFAS) Unable to use: Plasma levels, not a protocol outcome
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...randomised (2:1, with a computerized schedule) to supplementation with quetiapine or with placebo. The person who generated the randomization schedule was not involved in determining subject eligibility, administering treatment, or determining outcome." (pg. 14).
Allocation concealment (selection bias)	Low risk	Quote: "The person who generated the randomization schedule was not involved in determining subject eligibility, administering treatment, or determining outcome." (pg. 14).
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...double‐blind, placebo‐controlled trial..." (pg. 13); no further details.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...double‐blind, placebo‐controlled trial..." (pg. 13); no further details.
Incomplete outcome data (attrition bias) All outcomes	Low risk	21.3% of the participants left the study early. Reasons for leaving the study early were described. An ITT approach was used.
Selective reporting (reporting bias)	Low risk	Free from selective reporting
Other bias	Low risk	No obvious risk for other bias

Huang 1987

Methods	Randomisation: randomised, no further details Blinding: double, no further details Duration: 11 weeks; 2 weeks non‐randomised single‐blind run in phase and 9 weeks randomised double‐blind phase. Design: parallel Location: single‐centre (USA) Setting: inpatients
Participants	Diagnosis: schizophrenia (DSM III); treatment resistant. N = 50 Gender: not indicated Age: 21 to 55 years History: mentally ill for 2 years or more; treated with 2 or more antipsychotics at usual therapeutic doses (equivalent to thiothixene 60 mg/day) for 6 months or more without appreciable remission.
Interventions	All participants firstly received single‐blind thiothixene 60 mg/day for 2 weeks to confirm treatment resistance e.g. not showing moderate improvement during the first 3 weeks of treatment. Participants were then randomised to either: 1. dose increase: thiothixene up to 400 mg/day. N = 25; or 2. dose maintenance: thiothixene 60 mg/day. N = 25. Rescue medication: benztropine; no further details.
Outcomes	Global state: clinically relevant response (defined as moderate improvement in Roerig Global Scale (RGS) (Guy 1976)) Leaving the study early (due to adverse events, any reason and inefficacy) Mental state (BPRS total score, BPRS factors such as anxiety‐depression, anergia, thought disturbance, activity, hostility‐suspicion), Nurses Observation Scale for Inpatient Evaluation (NOSIE total score, NOSIE factors such as social competence, social interest, personal neatness, irritability, manifest psychosis, retardation, depression). Adverse effects (side effect check list, dystonia, dry mouth, blurred vision, drowsiness, orthostatic hypotension, tremor, dizziness, drooling, constipation, ataxia, akathisia, palpitations, headache, premature ventricular contractions). Unable to use: Vital signs (CBC, urinalysis, SMA‐12, ECG, blood pressure, pulse rate); no data were presented and not protocol outcomes.
Notes	50 participants were randomised. Eight of the 50 participants (4 in each group) showing moderate improvement on the RGS in the first 21 days were eliminated from the study as they were not considered to be treatment‐resistant.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...randomly assigned..." (pg. 70); no further details
Allocation concealment (selection bias)	Unclear risk	No details were presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...under double‐blind control to..." (pg. 70); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...under double‐blind control to..." (pg. 70); no further details
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear whether all those who left early were reported. It may be that 26% (13/50) left the study early.
Selective reporting (reporting bias)	High risk	No usable data on vital signs were reported in the results
Other bias	Low risk	No obvious risk for other bias

Kinon 1993

Methods	Randomisation: randomised, stratified based on week 3 serum fluphenazine levels Blinding: double, no further details Duration: 8 weeks; 4 weeks non‐randomised open‐label run in phase and 4 weeks randomised double‐blind phase. Design: parallel Location: single‐centre (USA) Setting: inpatients
Participants	Diagnosis: schizophrenia, schizoaffective disorder or schizophreniform disorder (DSM III‐R) N = 58 Gender: 64.1% males (of all participants entering the open label run in phase) (N = 156). Not indicated for randomised participants. Age: mean 29.4 years (SD = 7.0), range 18 to 50 years for all participants entering the open label run in phase (N = 156), not indicated for randomised participants. History: age at first hospitalisation ‒ mean 23.0 years (SD = 6.5); number of previous hospitalisations ‒ mean 2.6 (SD = 2.2); data for all participants entering the open label run in phase (N = 156), not indicated for randomised participants alone.
Interventions	All participants firstly received open label fluphenazine 20 mg/day for 4 weeks (N = 156). Participants who had a rating of worse than mild on each of the four BPRS psychotic items and a rating of less than much improved on the CGI‐I were considered non‐responders (N = 58) and were then randomised to: 1. dose increase: Fluphenazine 80 mg/day. N = 16; or 2. dose maintenance: Fluphenazine 20 mg/day. N = 18; or 3. additional intervention: haloperidol 20 mg/day. N = 13. Rescue medication: benztropine, no further details.
Outcomes	Global state: clinically relevant response (defined as CGI‐I ≤ 2, at least much improved) Mental state: general (BRPS total score), negative symptoms (modified SANS) Unable to use: Extrapyramidal symptoms (modified SAS, no mean)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Non responders were then randomly assigned to double‐blind treatment for...", "Subjects were stratified based on Week 3 serum fluphenazine levels..." (pg. 310); no further details.
Allocation concealment (selection bias)	Unclear risk	No details were presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...double‐blind treatment..." (pg.310); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...double‐blind treatment..." (pg.310); no further details
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Outcome not addressed. Data were presented for 81% (47/58) of all randomised participants
Selective reporting (reporting bias)	High risk	SAS was used but scores were available only for two items, not total
Other bias	Low risk	No obvious risk for other bias

Lindenmayer 2011

Methods	Randomisation: randomised, no further details Blinding: double, no further details Duration: 12 weeks; 4 weeks non‐randomised open‐label run in phase and 8 weeks randomised double‐blind phase. Design: parallel Location: multi‐centre (USA) Setting: inpatients
Participants	Diagnosis: schizophrenia or schizoaffective disorder (DSM‐IV‐R); suboptimal past treatment response N = 60 Gender: 55 men, 5 women Age: mean 40.15 years (SD = 10.2) History: age at onset ‒ mean 20.27 years (SD = 5.88); number of previous hospitalisations ‒ mean = 6.7 (SD = 5.88); suboptimal past treatment response, defined by (i) presence of persistent positive symptoms after at least 6 contiguous weeks of treatment with one or more typical or atypical antipsychotics at dosages ≥ 600 mg/d of chlorpromazine equivalents and (ii) poor level of functioning for the past 2 years defined as lack of competitive employment or enrolment in an academic or vocational program, and not having age‐expected interpersonal relations with someone outside the biological family of origin.
Interventions	All participants firstly received open label quetiapine 600 mg/day for 4 weeks. Participants who did not demonstrate an initial response to quetiapine treatment defined as ≤ 15% PANSS total score reduction were then randomised to either: 1. dose increase: quetiapine 1200 mg/day. N = 29; or 2. dose maintenance: quetiapine 600 mg/day. N = 31. Concomitant mood stabilisers on a stable dose for the past 2 months before trial initiation were allowed to continue.
Outcomes	Global state: clinically relevant response (defined as ≥ 20% PANSS total score reduction) Leaving the study early (due to side effects, any reason, inefficacy) Mental state: general (PANSS total score), positive symptoms (PANSS positive subscore), negative symptoms (PANSS negative subscore) Adverse effects: (SAS, AIMS, BAS, BMI/weight change, orthostatic hypotension, somnolence, agitation, constipation, weight gain) Functional changes (Social‐Adaptive Functioning Evaluation ‐ SAFE) Aggressive behaviour (BARS total score at endpoint) Unable to use: Global state (CGI no numbers presented) Vital signs and ECG; no data presented and not protocol outcomes Laboratory values (ALT, AST, GGT, glukose, lactate dehydrogenase, cholesterol, triglycerides), not protocol outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...patients were randomly assigned to...", "Stratification was done at the time of randomization to avoid imbalances secondary to the presence of concomitant mood stabilizer medications or the use of benztropine (or other antiparkinsonian agents) at baseline." (pg. 161); no further details.
Allocation concealment (selection bias)	Unclear risk	No details were presented
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "This was a prospective, randomised, double‐blind, parallel group, 8‐week trial of...", "All clinical and research stuff (subject, caregiver, investigator, outcomes assessor), except for the research pharmacists, were blinded to the randomization status." (pg. 161).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "This was a prospective, randomised, double‐blind, parallel group, 8‐week trial of...", "All clinical and research stuff (subject, caregiver, investigator, outcomes assessor), except for the research pharmacists, were blinded to the randomization status." (pg. 161).
Incomplete outcome data (attrition bias) All outcomes	High risk	53.3% of the participants left the study early. Numbers per group as well as reasons for leaving the study early were specified. Last observation carried forward (LOCF) methods were used.
Selective reporting (reporting bias)	High risk	Data on CGI, vital signs and ECG were not reported in the results.
Other bias	Low risk	No obvious risk for other bias

Loebel 2014

Methods	Randomisation: randomised, no further details Blinding: double, no further details Duration: 6 weeks; 2 weeks double‐blind run in phase and 4 weeks randomised double‐blind phase Design: parallel Location: multi‐centre Setting: inpatients
Participants	Diagnosis: acute schizophrenia, no further details N = 95 Gender: 60.1% males (of initially randomised participants to lurasidone 80 mg/day) (N = 198) Age: mean 40.5 years; range 18 to 75 years for all initially randomised participants to lurasidone 80 mg/day History: no details
Interventions	Participants were firstly randomised to double‐blind treatment with lurasidone 20 mg/day, lurasidone 80 mg/day, or placebo. After 2 weeks, only participants who were randomised to lurasidone 80 mg/day (N = 198) and showed < 20% PANSS total score reduction, were re‐randomised to either: 1. dose increase: lurasidone 160 mg/day. N = 43; or 2. dose maintenance: lurasidone 80 mg/day. N = 52. Rescue medication: no details
Outcomes	Leaving the study early: due to side effects Mental state: general (PANSS total score) Global state (CGI‐Severity change) Unable to use: Weight gain (not separately presented for the two groups)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Eligible patients were randomised to..." (pg. 476); no further details
Allocation concealment (selection bias)	Unclear risk	No details are presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...to double‐blind treatment with..." (pg. 476); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...to double‐blind treatment with..." (pg. 476); no further details
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Outcome not addressed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Low risk	No obvious risk for other bias

McEvoy 1991

Methods	Randomisation: randomised, no further details Blinding: double, no further details Duration: 6 weeks; 4 weeks non‐randomised open‐label run‐in phase and 2 weeks randomised double‐blind phase. Design: parallel Location: single‐centre (USA) Setting: inpatients
Participants	Diagnosis: schizophrenia or schizoaffective disorder (RDC). N = 48 Gender: 53.8% males (of all participants entering the open‐label run in phase) (N = 95). Not indicated for randomised participants. Age: mean 31.5 years (SD = 9.5) for all participants entering the open‐label run in phase, not indicated for randomised participants. History: no details
Interventions	All participants firstly received open label haloperidol at antipsychotic threshold (NT)* for at least 2 weeks. Non‐responding participants (not ready for discharge) were then randomised to either: 1. dose increase: haloperidol at a dosage two to ten times higher than NT dosage; mean 11.6 mg/day (SD = 4.7). N = 25; or 2. dose maintenance: haloperidol at NT dosage; mean 3.4 mg/day (SD = 2.3). N = 23. Rescue medication: biperiden, lorazepam, diphenhydramine, no further details
Outcomes	Global state: clinically relevant response (defined as BPRS total score ≤ 32 (16 items), with all psychosis items (conceptual disorganisation, hallucinatory behavior, hostility, suspiciousness. and unusual thought content) rated "mild" or less; their CGl global severity item was rated "mild" or less; and their CGI global change item was rated at least "moderately improved"). Leaving the study early: due to adverse events Mental sate: general (BRPS total score) Global state (CGI‐S) Unable to use: Negative symptoms: Wing negative symptoms scale (no mean, no SD) Mental state; self‐report of perceived medication effects: Medication Response Questionnaire (no mean, no SD) Adverse events: Extrapyramidal Side Effects Scale (no mean, no SD) and anticholonergic side effects (no numbers presented)
Notes	* Antipsychotic threshold (NT): the lowest antipsychotic dosage at which individual patients develop slight increase in rigidity is hypothesised to correspond to the lowest dosages at which these patients attain maximum antipsychotic benefit (Haase 1961). ** Response criterion: BPRS total score ≤ 32 (16 items), with all psychosis items (conceptual disorganisation, hallucinatory behaviour, hostility, suspiciousness. and unusual thought content) rated "mild" or less; their CGl global severity item was rated "mild" or less; and their CGI global change item was rated at least "moderately improved".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...patients were randomly assigned..." (pg. 740); no further details
Allocation concealment (selection bias)	Unclear risk	No details are presented
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "...on a double‐blind basis..." (pg. 740); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...on a double‐blind basis..." (pg. 740); no further details
Incomplete outcome data (attrition bias) All outcomes	Low risk	An ITT approach was used. 8.3% (4/48) of participants left the study early due to severe extrapyramidal side effects. This is probably the overall attrition rate.
Selective reporting (reporting bias)	High risk	Wing negative symptom scale, Medication Response Questionnaire, Extrapyramidal Side Effects Scale and anticholinergic side effects were not presented separately for the group of non‐responders
Other bias	Low risk	No obvious risk for other bias

McGorry 2011

Methods	Randomisation: randomised, no further details Blinding: single Duration: 8 weeks; 4 weeks non‐randomised open‐label run in phase and 4 weeks randomised single‐blind phase Design: parallel Location: single‐centre (Australia) Setting: inpatients
Participants	Diagnosis: schizophrenia, schizophreniform, schizoaffective, delusional disorder, psychotic disorder not otherwise specified, or brief psychosis (DSM‐IV); first psychotic episode N = 26 Gender: 18 men, 8 women Age: mean 21.62 years (SD = 3.98) History: age at onset ‒ mean 21 years (SD = 3.8); duration of untreated psychosis ‒ mean 267.1 days (SD = 416.5); a first episode of psychosis
Interventions	All participants firstly received open label risperidone 2 mg/day for 4 weeks. Participants who were considered 'slow responders' defined as a score of > 3 on each of the BPRS psychosis subscale items (i.e. mild), a CGI‐S > 3, and a CGI‐I > 3 were then randomised to: 1. dose increase: risperidone 3 or 4 mg/day (if required). N = 9; or 2. dose maintenance: risperidone 2 mg/day. N = 8; or 3. additional intervention: risperidone 2 mg/day with addition of lithium, titrated up to therapeutic levels (0.6 to 1.2 mmol). N = 9.
Outcomes	Global state: clinically relevant response (defined as ≥ 20% BPRS total score reduction) Leaving the study early (due to adverse events and any reason) Mental state: general (BPRS total score), positive symptoms (BPRS psychosis subscale), negative symptoms (BPRS negative subscale) Global state (CGI‐S) Quality of life: number of participants with at least 50% improvement inHQLS and mean endpoint score in HQLS Unable to use: Global state (CGI‐I, no numbers) Extrapyramidal adverse events (not separately presented for the group of 'slow responders') and weight gain (no SD).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...slow responders were randomised..." (pg. 3); no further details
Allocation concealment (selection bias)	Unclear risk	No details are presented
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "...randomised single blind to one of three open treatment groups" (pg. 3); no further details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "...randomised single blind to one of three open treatment groups" (pg. 3); no further details
Incomplete outcome data (attrition bias) All outcomes	Low risk	19.2% (5/26) participants left the study early. A LOCF approach was adopted for analysis of Phase II data
Selective reporting (reporting bias)	High risk	Original study author sent us data on most outcomes but data on CGI‐I, extrapyramidal side effects and weight gain were not reported.
Other bias	Low risk	No obvious risk for other bias

Sakurai 2016

Methods	Randomisation: randomised to 1 of the 2 treatment groups in a 1:1 ratio by simple randomisation stratified by their antipsychotic type and treatment setting; computer‐generated randomisation list. Blinding: double; identical powder form in amount and color; participants blinded to their allocated intervention; assessors blinded to the allocation. Duration: 4 weeks Design: parallel Location: single‐centre (Japan) Setting: inpatients and outpatients
Participants	Diagnosis: schizophrenia, schizoaffective or persistent delusional disorder (ICD‐10) N = 103 Gender: 38 men, 65 women Age: mean 50.7 years (SD = 15.81) History: duration of illness ‒ mean 16.05 years (SD = 14.4); total duration of antipsychotic treatment‐ mean 10.9 years (SD = 14).
Interventions	All participants had been receiving olanzapine 10 mg/day or risperidone 3 mg/day for at least 4 weeks. Participants who had a total score ≥ 60 on the PANSS, ≥ 3 on the CGI‐S, and ≤ 70 on the GAF were considered non‐responders and were randomised to either: 1. dose increase: olanzapine 20 mg/day or risperidone 6 mg/day (double antipsychotic dose). N = 52; or 2. dose maintenance: olanzapine 10 mg/day or risperidone 3 mg/day. N = 51.
Outcomes	Global state: clinically relevant response (defined as ≥ 25% PANSS total score reduction) Leaving the study early (due to adverse events, any reason and inefficacy) Mental state: general (PANSS total score), positive symptoms (PANSS positive subscore), negative symptoms (PANSS negative subscore) Global state (CGI‐I) Functioning: overall (GAF) Adverse effects (EPS ‐ SAS, Akathisia ‐ BAS, tardive dyskinesia ‐ AIMS) Unable to use: Global state: CGI‐S (no mean, no SD) Plasma concentrations, not a protocol outcome
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...randomly allocated to 1 of the 2 treatment groups in a 1:1 ratio by simple randomization stratified by their antipsychotic type (ie, olanzapine or risperidone) and treatment setting (ie, inpatient or outpatient)....according to a computer‐generated randomization list..." (pg. 1382).
Allocation concealment (selection bias)	Low risk	Quote: "The person who was independent of this study in the central office prepared a piece of paper on which 1 of the assigned groups was designated according to a computer‐generated randomization list, inserted it into an envelope on which a participant ID number was written, and sealed it. Upon registration of each participant, 1 of the investigators opened the envelope that corresponded to the participant's ID, and the person who prepared the envelopes confirmed that the envelopes were appropriately opened." (pg. 1382).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "During the 4‐week observation, all antipsychotic drugs were provided in identical powder form in amount and color with lactose added... Thus, the participants were blinded to their allocated intervention." (pg. 1382).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The following assessments were performed by assessors who were blinded to the allocation..." (pg. 1383).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Significantly more participants in the dose increase group (30.8%) than in the dose continuation group (13.7%) left the study early due to side effects. Reasons for leaving the study early were described. An ITT approach was used. Results between ITT analysis and only competers were similar.
Selective reporting (reporting bias)	High risk	CGI‐S was used but scores at endpoint were not available
Other bias	Low risk	No obvious risk for other bias

Scales

AIMS: Abnormal Involuntary Movement Score BAS: Barnes Akathisia Scale

BARS: Behavioral Activity Rating Scale

BAS: Barnes Akathisia Rating Scale

BPRS: Brief Psychiatric Rating Scale

CDRS: Calgary Depression Rating Scale

CGI‐I: Clinical Global impression‐Improvement

CGI‐S: Clinical Global impression‐Severity

CPRS: Comprehensive Psychopathological Rating Scale

GAF: Global Assessment of Functioning

HQLS: Heinrichs‐Carpenter‐Hanlon Quality of Life Scale

NOSIE: Nurse's Observation Scale for Inpatient Evaluation

PANSS: Positive and Negative Syndrome Scale for Schizophrenia

RGS: Roering Global Scale

SAFE: Social‐Adaptive Functioning Evaluation

SANS: Scale for the Assessment of Negative Symptoms

SAS: Simpson Angus Scale

SCoRS: Schizophrenia Cognition Rating Scale

SOFAS: Social and Occupational Functioning Scale

Diagnostic Tools

DSM: Diagnostic and Statistical Manual of Mental Disorders

ICD: International Classification of Diseases

RDC: Research Diagnostic Criteria for schizophrenia or schizoaffective disorders

Others

BMI: Body‐mass‐index

ECG: Electrocardiogram

EPS: Extrapyramidal Symptoms

ITT: Intention‐to‐treat

LOCF: Last observation carried forward

mg: Milligram

msec: Millisecond

N: Number

n.i.: Not indicated

SD: Standard deviation

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Agid 2013	Allocation: not randomised
Badgett 1996	Allocation: randomised Participants: schizophrenia (DSM‐III‐R) based on the CASH‐interview; at baseline, participants were stabilised on 20 mg/day of haloperidol, not non‐responders
Bai 2002	Allocation: not randomised
Baker 2003	Allocation: randomised Participants: schizophrenia, schizoaffective disorder, schizophreniform disorder, or bipolar I disorder, manic or mixed episode (DSM‐IV); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: rapid dose escalation or usual clinical practice
Bastecky 1982	Allocation: not indicated Participants: schizophrenia (chronic schizophrenics); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment
Bitter 1989	Allocation: randomised Participants: schizophrenia or schizoaffective disorder (acutely exacerbating) Interventions: initially 3 plasma levels of haloperidol; if no improvement after 6 weeks, randomly re‐assignment to one of the 3 plasma levels of haloperidol for another 6 weeks. Outcomes: no usable data.
Bondolfi 1995	Allocation: randomised Participants: schizophrenia (chronic according to DSM‐III), treatment‐resistant (defined by unresponsiveness or intolerance to appropriate doses of two different classes of conventional antipsychotics for at least 4 weeks each); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: no antipsychotic dose increase versus maintenance Comparison; either risperidone or clozapine; drug dosages could be changed after day 14 depending on each participant's response.
Branchey 1981	Allocation: randomised Participants: schizophrenia, chronic type (according to Research Diagnostic Criteria); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: loxapine continuation versus loxapine decrease; no dose increase group
Canuso 2010	Allocation: randomised Participants: acute exacerbation of schizoaffective disorder (DSM‐IV); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment.
Chen 1998	Allocation: not indicated Participants: no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment
Clerc 1989	Allocation: distributed by drawing of lots Participants: hospitalised participants all with negative symptoms (ICD‐9 and DSM‐III); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: 2 ranges of amisulpride doses (20 mg to 120 mg and 100 mg to 600 mg); no dose continuation group
CN138032	Allocation: randomised Participants: treatment‐resistant schizophrenia Interventions: 1. open‐label phase olanzapine or risperidone; 2. single‐blind placebo washout period; 3. double‐blind phase perphenazine vs. aripiprazole; 4. open‐label aripiprazole extended phase.
Cookson 1987	Allocation: randomised Participants: schizophrenia (hebephrenic or paranoid, ICD‐9); treatment‐resistant to low dosages of antipsychotics; improved with higher dosages. Interventions: 50% reduction of dosage or dosage continuation; no dose increase group
Coryell 1998	Allocation: randomised Participants: schizophrenia, acute exacerbation (DSM‐III) Interventions: 1st phase: low‐dose (< 18ng/ml), intermediate or high‐dose (> 25 ng/ml) range of haloperidol plasma levels for 3 weeks; 2nd phase: if no improvement, antipsychotic dose could randomly remain the same, be reduced or increased.
Daniel 1997	Allocation: not indicated Participants: schizophrenia or schizoaffective disorder; no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: ziprasidone 80 mg vs. ziprasidone 160 mg; no dose maintenance group
de Leon 2007	Allocation: randomised Participants: schizophrenia or schizoaffective disorder (DSM‐III); Kane et al criteria (Kane 1988) for defining treatment resistance. Interventions: 1st phase: 16 weeks in one of the following dose‐groups: 100, 300, 600 mg/day clozapine; if no improvement, randomization to one of the two other dosage groups; no dose maintenance group.
DeBuck 1972	Allocation: not randomised for non‐responders Participants: any psychoses with the exception of chronic organic psychosis with superimposed non‐psychotic symptomatology, and endogenous depression with retardation and apathy, and "acute organic psychosis".
Dencker 1978	Allocation: randomised Participants: schizophrenia; all participants firstly received open‐label 12.5 mg fluphenazine enanthate per week for 2 weeks and those who were proven "refractory to ordinary doses of neuroleptics" were then randomised. Interventions: 250 mg fluphenazine enanthate per week versus 12.5 mg fluphenazine enanthate per week. Outcomes: no usable data due to the cross‐over design of the trial.
Ericksen 1978	Allocation: randomised Participants: schizophrenia (acutely decompensated); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: haloperidol standard dose versus haloperidol high loading dose; no dose maintenance group.
Gardos 1971	Allocation: not indicated Participants: schizophrenia (treatment resistant, decompensated); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: thiothixene high dose versus thiothixene low dose Outcomes: no usable data
Gulliver 2010	Allocation: randomised Participants: schizophrenia, participants who maintained stability on open‐label oral olanzapine Interventions: randomised to low, medium or high doses of olanzapine long‐acting injection for 24 weeks
Harris 1997	Allocation: not indicated Participants: people with schizophrenia and related psychotic disorders over the age of 45 who met DSM‐IV criteria for "in remission''; not non‐responders.
Hirschowitz 1995	Allocation: not indicated Participants: participants with schizophrenia, stabilised on 20 mg/day; not non‐responders.
Hirschowitz 1997	Allocation: randomised Participants: schizophrenia (DSM‐III‐R) based on the CASH‐interview; participants free of medication at baseline or stabilised on 20 mg/day. Interventions: no dose continuation or increase group
Itil 1970	Allocation: not indicated. Participants: schizophrenia (chronic); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: fluphenazine 30 mg versus fluphenazine 800 mg; no dose maintenance or increase group.
Janicak 1997	Allocation: randomised. Participants: schizophrenia or schizoaffective disorder; acutely psychotic. Interventions: low, middle or high plasma level range of haloperidol; after 2 weeks, 50% of the non‐responders were randomly reassigned to the middle plasma level group.
Kane 1985	Allocation: not indicated. Participants: schizophrenia (remitted or stable); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: low‐dose fluphenazine decanoate versus standard‐dose fluphenazine decanoate; no dose increase group.
Lehmann 1980	Allocation: randomised. Participants: schizophrenia; no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: haloperidol 10 mg/day, 20 mg/day or individual dose of haloperidol; no dose increase or maintenance group.
McCreadie 1979	Allocation: randomised Participants: schizophrenia (female, drug‐resistant, chronic); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: flupentixol decanoate high‐dose (200 mg/2 weeks) versus standard dose (40 mg/2 weeks); no dose increase or maintenance group.
Mitchell 2004	Allocation: randomised Participants: schizophrenia, schizoaffective disorder, bipolar I disorder (DSM‐IV‐R); stable inpatients; the run‐in phase was not used to identify participants that have not responded to their current antipsychotic treatment. Interventions: run‐in phase of olanzapine 20 mg/day for 10 days; then, randomisation to olanzapine 20 mg/day, 30 mg/day or 40 mg/day for 10 days; finally, for an additional 10 days, 30 mg/day participants received olanzapine 40 mg/day; all other participants remained on the same dose. Outcomes: no usable data
NCT00539071	Allocation: randomised Participants: schizophrenia or schizoaffective disorder; eligible participants would be receiving or had received treatment with risperidone oral or long‐acting, or a combination that did not exceed 50 mg/2 weeks of long‐acting or oral risperidone 8 mg/day for at least 6 weeks within seven years of study entry without satisfactory response. Interventions: long‐acting risperidone 50 mg/week vs 75 mg to 100 mg/2 weeks. Outcomes: no usable data
NCT00862992	Allocation: randomised Participants: schizophrenia (DSM‐IV‐TR); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: low‐dose versus medium‐dose versus high‐dose of cariprazine; no dose increase or maintenance group.
NCT01457339	Allocation: randomised Participants: clinically stable participants with schizophrenia (on a stable dose of an antipsychotic drug); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: SPD489 multiple doses versus placebo; no dose increase or maintenance group.
NCT01569659	Allocation: randomised Participants: schizophrenia or schizoaffective disorder (DSM‐IV); Kane et al criteria (Kane 1988) for treatment‐resistance; no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment. Interventions: low dosage of lurasidone (80 mg/day) versus high dose of lurasidone (up to 240 mg/day); no dose increase or maintenance group.
Simpson 1999	Allocation: randomised Participants: any psychoses with the exception of chronic organic psychosis with superimposed non‐psychotic symptomatology, endogenous depression and acute organic psychosis. Interventions: clozapine 100, 300 or 600 mg/d; if no improvement was observed after 16 weeks, participants were randomised to one of the other two dosages, no maintenance group.
Suzuki 1992	Allocation: randomised Participants: schizophrenia (DSM‐III); not non‐responders
Volavka 1996	Allocation: not randomised for the group of non‐responders

Data and analyses

Open in table viewer

Comparison 1. Antipsychotic dose increase versus antipsychotic dose maintenance

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1a. Clinically relevant response as defined by trials Show forest plot	9	533	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.86, 1.40]
Open in figure viewer Analysis 1.1 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 1 Global state: 1a. Clinically relevant response as defined by trials.
2 Global state: 1b. Any change (improvement in Global Assesment scale) Show forest plot	1	23	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.32, 1.80]
Open in figure viewer Analysis 1.2 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 2 Global state: 1b. Any change (improvement in Global Assesment scale).
3 Global state: 2a. Average endpoint score (CGI‐Severity , high = poor) Show forest plot	3	196	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.40, 0.19]
Open in figure viewer Analysis 1.3 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 3 Global state: 2a. Average endpoint score (CGI‐Severity , high = poor).
4 Global state: 2b. Average change score ( CGI‐Severity, high = poor) Show forest plot	1	95	Mean Difference (IV, Random, 95% CI)	‐0.4 [‐0.80, ‐0.00]
Open in figure viewer Analysis 1.4 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 4 Global state: 2b. Average change score ( CGI‐Severity, high = poor).
5 Global state: 2c. Average endpoint score (CGI‐Improvement, high = poor) Show forest plot	1	103	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.35, 0.35]
Open in figure viewer Analysis 1.5 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 5 Global state: 2c. Average endpoint score (CGI‐Improvement, high = poor).
6 Leaving the study early: 1. Tolerability ‐ due to adverse events Show forest plot	7	496	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.52, 5.07]
Open in figure viewer Analysis 1.6 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 6 Leaving the study early: 1. Tolerability ‐ due to adverse events.
7 Leaving the study early: 2. Acceptability of treatment ‐ due to any reason Show forest plot	5	353	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.89, 1.90]
Open in figure viewer Analysis 1.7 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 7 Leaving the study early: 2. Acceptability of treatment ‐ due to any reason.
8 Leaving the study early: 3. Efficacy ‐ due to inefficacy Show forest plot	4	336	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.30, 2.28]
Open in figure viewer Analysis 1.8 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 8 Leaving the study early: 3. Efficacy ‐ due to inefficacy.
9 Mental state: 1a. General ‐ average endpoint score (PANSS total, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	‐1.81 [‐7.31, 3.69]
Open in figure viewer Analysis 1.9 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 9 Mental state: 1a. General ‐ average endpoint score (PANSS total, high = poor).
10 Mental state: 1b. General ‐ average change score (PANSS total, high = poor) Show forest plot	3	258	Mean Difference (IV, Random, 95% CI)	‐1.44 [‐6.85, 3.97]
Open in figure viewer Analysis 1.10 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 10 Mental state: 1b. General ‐ average change score (PANSS total, high = poor).
11 Mental state: 1c. General ‐ average endpoint and/or change score (PANSS total, high = poor) Show forest plot	4	389	Mean Difference (IV, Random, 95% CI)	‐2.13 [‐6.16, 1.90]
Open in figure viewer Analysis 1.11 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 11 Mental state: 1c. General ‐ average endpoint and/or change score (PANSS total, high = poor).
12 Mental state: 1d. General ‐ average endpoint score (BPRS total, high = poor) Show forest plot	3	99	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐4.60, 2.11]
Open in figure viewer Analysis 1.12 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 12 Mental state: 1d. General ‐ average endpoint score (BPRS total, high = poor).
13 Mental state: 1e. General ‐ average change score (BPRS total, high = poor) Show forest plot	1	42	Mean Difference (IV, Random, 95% CI)	‐2.38 [‐6.15, 1.39]
Open in figure viewer Analysis 1.13 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 13 Mental state: 1e. General ‐ average change score (BPRS total, high = poor).
14 Mental state: 1f. General ‐ average endpoint and/or change score (BPRS total, high = poor) Show forest plot	4	141	Mean Difference (IV, Random, 95% CI)	‐1.75 [‐4.25, 0.76]
Open in figure viewer Analysis 1.14 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 14 Mental state: 1f. General ‐ average endpoint and/or change score (BPRS total, high = poor).
15 Mental state: 1g. General ‐ average change score (NOSIE total, high = poor) Show forest plot	1	42	Mean Difference (IV, Random, 95% CI)	3.70 [‐5.38, 12.78]
Open in figure viewer Analysis 1.15 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 15 Mental state: 1g. General ‐ average change score (NOSIE total, high = poor).
16 Mental state: 2a. Positive symptoms ‐ Clinically important change Show forest plot	1	17	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.58, 3.07]
Open in figure viewer Analysis 1.16 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 16 Mental state: 2a. Positive symptoms ‐ Clinically important change.
17 Mental state: 2b. Positive symptoms ‐ average endpoint subscore (PANSS positive, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐2.79, 0.90]
Open in figure viewer Analysis 1.17 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 17 Mental state: 2b. Positive symptoms ‐ average endpoint subscore (PANSS positive, high = poor).
18 Mental state: 2c. Positive symptoms ‐ average change subscore (PANSS positive, high = poor) Show forest plot	3	238	Mean Difference (IV, Random, 95% CI)	0.04 [‐1.31, 1.40]
Open in figure viewer Analysis 1.18 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 18 Mental state: 2c. Positive symptoms ‐ average change subscore (PANSS positive, high = poor).
19 Mental state: 2d. Positive symptoms ‐ average endpoint subscore (BPRS positive,high = poor) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	0.40 [‐2.94, 3.74]
Open in figure viewer Analysis 1.19 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 19 Mental state: 2d. Positive symptoms ‐ average endpoint subscore (BPRS positive,high = poor).
20 Mental state: 3a. Negative symptoms ‐ average endpoint subscore (PANSS negative, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	0.32 [‐1.48, 2.11]
Open in figure viewer Analysis 1.20 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 20 Mental state: 3a. Negative symptoms ‐ average endpoint subscore (PANSS negative, high = poor).
21 Mental state: 3b. Negative symptoms ‐ average change subscore (PANSS negative, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.96, 0.67]
Open in figure viewer Analysis 1.21 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 21 Mental state: 3b. Negative symptoms ‐ average change subscore (PANSS negative, high = poor).
22 Mental state: 3c. Negative symptoms ‐ average endpoint subscore (BPRS negative, high = poor) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.97, 1.17]
Open in figure viewer Analysis 1.22 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 22 Mental state: 3c. Negative symptoms ‐ average endpoint subscore (BPRS negative, high = poor).
23 Mental state: 3d. Negative symptoms ‐ average endpoint score (SANS, high = poor) Show forest plot	1	34	Mean Difference (IV, Random, 95% CI)	1.5 [‐14.33, 17.33]
Open in figure viewer Analysis 1.23 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 23 Mental state: 3d. Negative symptoms ‐ average endpoint score (SANS, high = poor).
24 Adverse effects ‐ At least one adverse effect Show forest plot	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.55, 1.50]
Open in figure viewer Analysis 1.24 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 24 Adverse effects ‐ At least one adverse effect.
25 Adverse effects ‐ Cardiac: QTc prolongation Show forest plot	2	206	Risk Ratio (M‐H, Random, 95% CI)	2.47 [0.12, 50.39]
Open in figure viewer Analysis 1.25 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 25 Adverse effects ‐ Cardiac: QTc prolongation.
26 Adverse effects ‐ Cardiac: Orthostatic hypotension Show forest plot	2	102	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.25, 4.82]
Open in figure viewer Analysis 1.26 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 26 Adverse effects ‐ Cardiac: Orthostatic hypotension.
27 Adverse effects ‐ Cardiac: Palpitations Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]
Open in figure viewer Analysis 1.27 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 27 Adverse effects ‐ Cardiac: Palpitations.
28 Adverse effects ‐ Cardiac: Premature Ventricular Contractions Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]
Open in figure viewer Analysis 1.28 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 28 Adverse effects ‐ Cardiac: Premature Ventricular Contractions.
29 Adverse effects ‐ Constipation Show forest plot	2	102	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.44, 5.38]
Open in figure viewer Analysis 1.29 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 29 Adverse effects ‐ Constipation.
30 Adverse effects ‐ Dizziness Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.41, 1.44]
Open in figure viewer Analysis 1.30 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 30 Adverse effects ‐ Dizziness.
31 Adverse effects ‐ Drooling Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.20, 20.41]
Open in figure viewer Analysis 1.31 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 31 Adverse effects ‐ Drooling.
32 Adverse effects ‐ Death (suicide or naturalistic cause) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
Open in figure viewer Analysis 1.32 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 32 Adverse effects ‐ Death (suicide or naturalistic cause).
33 Adverse effects ‐ Extrapyramidal: Categorical deterioration (AIMS, high = poor) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.59, 3.26]
Open in figure viewer Analysis 1.33 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 33 Adverse effects ‐ Extrapyramidal: Categorical deterioration (AIMS, high = poor).
34 Adverse effects ‐ Extrapyramidal: average endpoint score (AIMS, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.7 [‐0.87, 2.27]
Open in figure viewer Analysis 1.34 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 34 Adverse effects ‐ Extrapyramidal: average endpoint score (AIMS, high = poor).
35 Adverse effects ‐ Extrapyramidal: average change score (AIMS, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	0.41 [‐1.15, 1.96]
Open in figure viewer Analysis 1.35 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 35 Adverse effects ‐ Extrapyramidal: average change score (AIMS, high = poor).
36 Adverse effects ‐ Extrapyramidal: akathisia Show forest plot	2	65	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.04, 14.02]
Open in figure viewer Analysis 1.36 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 36 Adverse effects ‐ Extrapyramidal: akathisia.
37 Adverse effects ‐ Extrapyramidal: categorical deterioration (BAS, high = poor) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.42, 5.14]
Open in figure viewer Analysis 1.37 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 37 Adverse effects ‐ Extrapyramidal: categorical deterioration (BAS, high = poor).
38 Adverse effects ‐ Extrapyramidal: average endpoint score (BAS, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.2 [‐0.74, 0.34]
Open in figure viewer Analysis 1.38 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 38 Adverse effects ‐ Extrapyramidal: average endpoint score (BAS, high = poor).
39 Adverse effects ‐ Extrapyramidal: average change score (BAS, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.59, 0.37]
Open in figure viewer Analysis 1.39 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 39 Adverse effects ‐ Extrapyramidal: average change score (BAS, high = poor).
40 Adverse effects ‐ Extrapyramidal: dystonia and/or dyskinesia Show forest plot	3	196	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.09, 2.73]
Open in figure viewer Analysis 1.40 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 40 Adverse effects ‐ Extrapyramidal: dystonia and/or dyskinesia.
41 Adverse effects ‐ Extrapyramidal: categorical deterioration in SAS Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.51, 2.93]
Open in figure viewer Analysis 1.41 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 41 Adverse effects ‐ Extrapyramidal: categorical deterioration in SAS.
42 Adverse effects ‐ Extrapyramidal: average endpoint score (SAS, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	0.93 [‐1.04, 2.91]
Open in figure viewer Analysis 1.42 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 42 Adverse effects ‐ Extrapyramidal: average endpoint score (SAS, high = poor).
43 Adverse effects ‐ Extrapyramidal: average change score (SA, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	0.21 [‐0.83, 1.26]
Open in figure viewer Analysis 1.43 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 43 Adverse effects ‐ Extrapyramidal: average change score (SA, high = poor).
44 Adverse effects ‐ Extrapyramidal: tremor Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.59, 4.26]
Open in figure viewer Analysis 1.44 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 44 Adverse effects ‐ Extrapyramidal: tremor.
45 Adverse effects ‐ Headache Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.52, 4.08]
Open in figure viewer Analysis 1.45 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 45 Adverse effects ‐ Headache.
46 Adverse effects ‐ Somnolence and/or drowsiness Show forest plot	4	256	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.81, 3.81]
Open in figure viewer Analysis 1.46 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 46 Adverse effects ‐ Somnolence and/or drowsiness.
47 Adverse effects ‐ Weight at endpoint (high = poor) Show forest plot	2	165	Mean Difference (IV, Random, 95% CI)	‐1.85 [‐7.09, 3.39]
Open in figure viewer Analysis 1.47 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 47 Adverse effects ‐ Weight at endpoint (high = poor).
48 Behaviour: average endpoint score (BARS, high = good) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.50, 0.30]
Open in figure viewer Analysis 1.48 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 48 Behaviour: average endpoint score (BARS, high = good).
49 Functioning ‐ Global Assessment of Functioning: average change score (GAF, high = good) Show forest plot	1	103	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.00, 1.80]
Open in figure viewer Analysis 1.49 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 49 Functioning ‐ Global Assessment of Functioning: average change score (GAF, high = good).
50 Functioning ‐ Social ‐ Adaptive Functioning Evaluation: average endpoint score (SAFE, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.16 [‐0.47, 0.79]
Open in figure viewer Analysis 1.50 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 50 Functioning ‐ Social ‐ Adaptive Functioning Evaluation: average endpoint score (SAFE, high = poor).
51 Functioning ‐ Social and Occupational Functioning Assessment: average endpoint score (SOFAS, high = good) Show forest plot	1	131	Mean Difference (IV, Random, 95% CI)	0.5 [‐3.80, 4.80]
Open in figure viewer Analysis 1.51 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 51 Functioning ‐ Social and Occupational Functioning Assessment: average endpoint score (SOFAS, high = good).
52 Quality of life: Clinically important change (at least 50% improvement HQLS, high = good) Show forest plot	1	17	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
Open in figure viewer Analysis 1.52 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 52 Quality of life: Clinically important change (at least 50% improvement HQLS, high = good).
53 Quality of life: Average endpoint score (HQLS, high = good) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	5.5 [‐13.66, 24.66]
Open in figure viewer Analysis 1.53 Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 53 Quality of life: Average endpoint score (HQLS, high = good).

Open in table viewer

Comparison 2. Subgroup analysis and investigation of heterogeneity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Single antipsychotic drugs Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 Subgroup analysis and investigation of heterogeneity, Outcome 1 Single antipsychotic drugs.
1.1 Fluphenazine	1	34	Risk Ratio (M‐H, Random, 95% CI)	2.25 [0.22, 22.53]
1.2 Haloperidol	2	71	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.80]
1.3 Quetiapine	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.86]
1.4 Risperidone	1	17	Risk Ratio (M‐H, Random, 95% CI)	9.9 [0.63, 155.08]
1.5 Thiothixene	1	42	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.94, 3.26]
1.6 Ziprasidone	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.45, 1.41]
2 Clinical state, stage or problem Show forest plot	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.2 Comparison 2 Subgroup analysis and investigation of heterogeneity, Outcome 2 Clinical state, stage or problem.
2.1 First episode patients	1	17	Risk Ratio (M‐H, Random, 95% CI)	9.9 [0.63, 155.08]
2.2 Not first episode patients	8	516	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.86, 1.34]

Open in table viewer

Comparison 3. Sensitivity analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Excluding studies with unclear randomisation methods Show forest plot	2	234	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.77, 1.44]
Open in figure viewer Analysis 3.1 Comparison 3 Sensitivity analysis, Outcome 1 Excluding studies with unclear randomisation methods.
2 Excluding studies with unclear allocation concealment methods Show forest plot	2	234	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.77, 1.44]
Open in figure viewer Analysis 3.2 Comparison 3 Sensitivity analysis, Outcome 2 Excluding studies with unclear allocation concealment methods.
3 Exclusion of studies with high risk of bias regarding blinding Show forest plot	8	516	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.86, 1.34]
Open in figure viewer Analysis 3.3 Comparison 3 Sensitivity analysis, Outcome 3 Exclusion of studies with high risk of bias regarding blinding.
4 Exclusion of studies with high risk of bias regarding incomplete outcome data Show forest plot	6	375	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.92, 1.54]
Open in figure viewer Analysis 3.4 Comparison 3 Sensitivity analysis, Outcome 4 Exclusion of studies with high risk of bias regarding incomplete outcome data.
5 Exclusion of studies with imputed values Show forest plot	8	458	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.90, 1.50]
Open in figure viewer Analysis 3.5 Comparison 3 Sensitivity analysis, Outcome 5 Exclusion of studies with imputed values.
6 Fixed effects Show forest plot	9	533	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.88, 1.38]
Open in figure viewer Analysis 3.6 Comparison 3 Sensitivity analysis, Outcome 6 Fixed effects.

Figure 1

Study flow diagram.

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Figure 2

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

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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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Analysis 1.1

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 1 Global state: 1a. Clinically relevant response as defined by trials.

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Analysis 1.2

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 2 Global state: 1b. Any change (improvement in Global Assesment scale).

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Analysis 1.3

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 3 Global state: 2a. Average endpoint score (CGI‐Severity , high = poor).

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Analysis 1.4

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 4 Global state: 2b. Average change score ( CGI‐Severity, high = poor).

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Analysis 1.5

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 5 Global state: 2c. Average endpoint score (CGI‐Improvement, high = poor).

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Analysis 1.6

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 6 Leaving the study early: 1. Tolerability ‐ due to adverse events.

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Analysis 1.7

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 7 Leaving the study early: 2. Acceptability of treatment ‐ due to any reason.

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Analysis 1.8

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 8 Leaving the study early: 3. Efficacy ‐ due to inefficacy.

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Analysis 1.9

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 9 Mental state: 1a. General ‐ average endpoint score (PANSS total, high = poor).

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Analysis 1.10

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 10 Mental state: 1b. General ‐ average change score (PANSS total, high = poor).

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Analysis 1.11

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 11 Mental state: 1c. General ‐ average endpoint and/or change score (PANSS total, high = poor).

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Analysis 1.12

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 12 Mental state: 1d. General ‐ average endpoint score (BPRS total, high = poor).

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Analysis 1.13

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 13 Mental state: 1e. General ‐ average change score (BPRS total, high = poor).

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Analysis 1.14

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 14 Mental state: 1f. General ‐ average endpoint and/or change score (BPRS total, high = poor).

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Analysis 1.15

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 15 Mental state: 1g. General ‐ average change score (NOSIE total, high = poor).

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Analysis 1.16

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 16 Mental state: 2a. Positive symptoms ‐ Clinically important change.

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Analysis 1.17

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 17 Mental state: 2b. Positive symptoms ‐ average endpoint subscore (PANSS positive, high = poor).

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Analysis 1.18

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 18 Mental state: 2c. Positive symptoms ‐ average change subscore (PANSS positive, high = poor).

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Analysis 1.19

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 19 Mental state: 2d. Positive symptoms ‐ average endpoint subscore (BPRS positive,high = poor).

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Analysis 1.20

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 20 Mental state: 3a. Negative symptoms ‐ average endpoint subscore (PANSS negative, high = poor).

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Analysis 1.21

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 21 Mental state: 3b. Negative symptoms ‐ average change subscore (PANSS negative, high = poor).

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Analysis 1.22

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 22 Mental state: 3c. Negative symptoms ‐ average endpoint subscore (BPRS negative, high = poor).

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Analysis 1.23

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 23 Mental state: 3d. Negative symptoms ‐ average endpoint score (SANS, high = poor).

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Analysis 1.24

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 24 Adverse effects ‐ At least one adverse effect.

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Analysis 1.25

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 25 Adverse effects ‐ Cardiac: QTc prolongation.

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Analysis 1.26

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 26 Adverse effects ‐ Cardiac: Orthostatic hypotension.

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Analysis 1.27

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 27 Adverse effects ‐ Cardiac: Palpitations.

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Analysis 1.28

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 28 Adverse effects ‐ Cardiac: Premature Ventricular Contractions.

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Analysis 1.29

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 29 Adverse effects ‐ Constipation.

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Analysis 1.30

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 30 Adverse effects ‐ Dizziness.

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Analysis 1.31

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 31 Adverse effects ‐ Drooling.

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Analysis 1.32

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 32 Adverse effects ‐ Death (suicide or naturalistic cause).

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Analysis 1.33

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 33 Adverse effects ‐ Extrapyramidal: Categorical deterioration (AIMS, high = poor).

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Analysis 1.34

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 34 Adverse effects ‐ Extrapyramidal: average endpoint score (AIMS, high = poor).

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Analysis 1.35

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 35 Adverse effects ‐ Extrapyramidal: average change score (AIMS, high = poor).

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Analysis 1.36

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 36 Adverse effects ‐ Extrapyramidal: akathisia.

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Analysis 1.37

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 37 Adverse effects ‐ Extrapyramidal: categorical deterioration (BAS, high = poor).

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Analysis 1.38

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 38 Adverse effects ‐ Extrapyramidal: average endpoint score (BAS, high = poor).

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Analysis 1.39

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 39 Adverse effects ‐ Extrapyramidal: average change score (BAS, high = poor).

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Analysis 1.40

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 40 Adverse effects ‐ Extrapyramidal: dystonia and/or dyskinesia.

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Analysis 1.41

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 41 Adverse effects ‐ Extrapyramidal: categorical deterioration in SAS.

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Analysis 1.42

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 42 Adverse effects ‐ Extrapyramidal: average endpoint score (SAS, high = poor).

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Analysis 1.43

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 43 Adverse effects ‐ Extrapyramidal: average change score (SA, high = poor).

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Analysis 1.44

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 44 Adverse effects ‐ Extrapyramidal: tremor.

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Analysis 1.45

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 45 Adverse effects ‐ Headache.

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Analysis 1.46

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 46 Adverse effects ‐ Somnolence and/or drowsiness.

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Analysis 1.47

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 47 Adverse effects ‐ Weight at endpoint (high = poor).

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Analysis 1.48

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 48 Behaviour: average endpoint score (BARS, high = good).

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Analysis 1.49

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 49 Functioning ‐ Global Assessment of Functioning: average change score (GAF, high = good).

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Analysis 1.50

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 50 Functioning ‐ Social ‐ Adaptive Functioning Evaluation: average endpoint score (SAFE, high = poor).

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Analysis 1.51

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 51 Functioning ‐ Social and Occupational Functioning Assessment: average endpoint score (SOFAS, high = good).

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Analysis 1.52

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 52 Quality of life: Clinically important change (at least 50% improvement HQLS, high = good).

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Analysis 1.53

Comparison 1 Antipsychotic dose increase versus antipsychotic dose maintenance, Outcome 53 Quality of life: Average endpoint score (HQLS, high = good).

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Analysis 2.1

Comparison 2 Subgroup analysis and investigation of heterogeneity, Outcome 1 Single antipsychotic drugs.

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Analysis 2.2

Comparison 2 Subgroup analysis and investigation of heterogeneity, Outcome 2 Clinical state, stage or problem.

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Analysis 3.1

Comparison 3 Sensitivity analysis, Outcome 1 Excluding studies with unclear randomisation methods.

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Analysis 3.2

Comparison 3 Sensitivity analysis, Outcome 2 Excluding studies with unclear allocation concealment methods.

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Analysis 3.3

Comparison 3 Sensitivity analysis, Outcome 3 Exclusion of studies with high risk of bias regarding blinding.

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Analysis 3.4

Comparison 3 Sensitivity analysis, Outcome 4 Exclusion of studies with high risk of bias regarding incomplete outcome data.

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Analysis 3.5

Comparison 3 Sensitivity analysis, Outcome 5 Exclusion of studies with imputed values.

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Analysis 3.6

Comparison 3 Sensitivity analysis, Outcome 6 Fixed effects.

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Table 1. Suggested design for future study

Methods	Randomisation: random. Allocation: concealed. Blinding: double blind. Duration: at least 2 weeks run‐in phase to confirm non response to initial treatment and at least 4 weeks randomised double‐blind phase. Setting: in‐ or out‐patients.
Participants	Diagnosis: patients with schizophrenia, schizoaffective disorder or schizophreniform disorder. N > 300 Gender: male and female patients. Age: mean 30 years (SD = 7.0), range 18 to 65 years.
Interventions	All patients firstly receive treatment with one antipsychotic drug for at least 2 weeks. Those patients who do not at least minimally improve after 2 weeks of treatment, are considered non‐responders and are randomised to: 1. Increasing the dose of the antipsychotic drug above the officially recommended dose range. 2. Continuing treatment with the antipsychotic drug at the same, initial dose (within the officially recommended dose range).
Outcomes	Response (e.g. defined as PANSS or BPRS decrease ≥ 50%).* Relapse. Leaving the study early due to any reason. Leaving the study early due to side effects. General mental state‐average change in general mental state scores. Adverse effects‐ at least one adverse effect; clinically important general adverse effects; sudden and unexpected death. Service use‐ time in hospital. Quality of life. All outcomes by time ‐ short term (up to 12 weeks), medium term (13 to 26 weeks) and long term (over 26 weeks).
Notes	*Primary outcome of interest.

Table 1. Suggested design for future study

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Summary of findings for the main comparison. Antipsychotic dose increase compared to antipsychotic dose continuation for non response in schizophrenia

Antipsychotic dose increase compared to antipsychotic dose continuation for non response in schizophrenia
Patient or population: non response in schizophrenia Setting: inpatients and outpatients Intervention: antipsychotic dose increase Comparison: antipsychotic dose continuation
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with antipsychotic dose continuation	Risk with antipsychotic dose increase
Global state: clinically relevant response: Assessed with response ratio follow‐up: range 2 weeks to 12 weeks	Study population		RR 1.09 (0.86 to 1.40)	533 (9 RCTs)	⊕⊕⊝⊝ LOW ¹
	309 per 1000	336 per 1000 (265 to 432)
Leaving the study early: tolerability ‐ leaving early due to adverse effects. Assessed with risk ratio follow‐up: range 2 weeks to 9 weeks	Study population		RR 1.63 (0.52 to 5.07)	496 (7 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	74 per 1000	121 per 1000 (39 to 376)
Leaving the study early: acceptability ‐ leaving early due to any reason. Assessed with: Risk ratio follow‐up: range 2 weeks to 9 weeks	Study population		RR 1.30 (0.89 to 1.90)	353 (5 RCTs)	⊕⊕⊝⊝ LOW ¹
	23 per 100	30 per 100 (20 to 43)
General mental state : PANSS total score change* assessed with: Weighted mean difference follow‐up: range 2 weeks to 9 weeks	The mean general mental state ‐ PANSS total score change ranged from −8.9 to 0.03 points	MD 1.44 points lower (6.85 lower to 3.97 higher)	‐	258 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^{3 4 5}	One other trial used the BPRS total score change and showed no clear difference between the two groups. Pre‐defined outcome: Clinically important change in general mental state not reported.
Adverse effects ‐ at least one adverse effect assessed with: Risk ratio follow‐up: range 2 weeks to 9 weeks	Study population		RR 0.91 (0.55 to 1.50)	191 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 6}
	716 per 1000	652 per 1000 (394 to 1000)
Service use: time in hospital	‐	see comment	‐	(0 studies)	‐	No studies reported this outcome.
Quality of life ‐ clinically important change in quality of life (defined as at least 50% improvement in HQLS)	Study population		not estimable	17 (1 RCT)	⊕⊕⊝⊝ LOW ¹
	0 per 1000	0 per 1000 (0 to 0)
*The risk in the intervention group (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; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Imprecision for dichotomous outcomes: a) sample size should be >800 and/or total number of events>300; in our review, both numbers are much smaller. b) the pooled estimate of effect includes both no effect and an appreciable benefit or appreciable harm. ² Inconsistency: Heterogeneity: Tau² = 1.03; Chi² = 11.24, df = 5 (P = 0.05); I² = 56% ³ Inconsistency: Heterogeneity: Tau² = 14.71; Chi² = 5.70, df = 2 (P = 0.06); I² = 65% ⁴ Imprecision for continuous outcomes: a) sample size is lower than 400, b) confidence interval includes no effect and the upper or lower confidence limit crosses the minimal important difference (MID), either for benefit of harm ⁵ Indirectness: The pre‐specified outcome (clinical important change in mental state) was not reported. ⁶ Inconsistency: Heterogeneity: Tau² = 0.10; Chi² = 3.62, df = 1 (P = 0.06); I² = 72%

Summary of findings for the main comparison. Antipsychotic dose increase compared to antipsychotic dose continuation for non response in schizophrenia

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Comparison 1. Antipsychotic dose increase versus antipsychotic dose maintenance

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global state: 1a. Clinically relevant response as defined by trials Show forest plot	9	533	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.86, 1.40]

2 Global state: 1b. Any change (improvement in Global Assesment scale) Show forest plot	1	23	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.32, 1.80]

3 Global state: 2a. Average endpoint score (CGI‐Severity , high = poor) Show forest plot	3	196	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.40, 0.19]

4 Global state: 2b. Average change score ( CGI‐Severity, high = poor) Show forest plot	1	95	Mean Difference (IV, Random, 95% CI)	‐0.4 [‐0.80, ‐0.00]

5 Global state: 2c. Average endpoint score (CGI‐Improvement, high = poor) Show forest plot	1	103	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.35, 0.35]

6 Leaving the study early: 1. Tolerability ‐ due to adverse events Show forest plot	7	496	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.52, 5.07]

7 Leaving the study early: 2. Acceptability of treatment ‐ due to any reason Show forest plot	5	353	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.89, 1.90]

8 Leaving the study early: 3. Efficacy ‐ due to inefficacy Show forest plot	4	336	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.30, 2.28]

9 Mental state: 1a. General ‐ average endpoint score (PANSS total, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	‐1.81 [‐7.31, 3.69]

10 Mental state: 1b. General ‐ average change score (PANSS total, high = poor) Show forest plot	3	258	Mean Difference (IV, Random, 95% CI)	‐1.44 [‐6.85, 3.97]

11 Mental state: 1c. General ‐ average endpoint and/or change score (PANSS total, high = poor) Show forest plot	4	389	Mean Difference (IV, Random, 95% CI)	‐2.13 [‐6.16, 1.90]

12 Mental state: 1d. General ‐ average endpoint score (BPRS total, high = poor) Show forest plot	3	99	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐4.60, 2.11]

13 Mental state: 1e. General ‐ average change score (BPRS total, high = poor) Show forest plot	1	42	Mean Difference (IV, Random, 95% CI)	‐2.38 [‐6.15, 1.39]

14 Mental state: 1f. General ‐ average endpoint and/or change score (BPRS total, high = poor) Show forest plot	4	141	Mean Difference (IV, Random, 95% CI)	‐1.75 [‐4.25, 0.76]

15 Mental state: 1g. General ‐ average change score (NOSIE total, high = poor) Show forest plot	1	42	Mean Difference (IV, Random, 95% CI)	3.70 [‐5.38, 12.78]

16 Mental state: 2a. Positive symptoms ‐ Clinically important change Show forest plot	1	17	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.58, 3.07]

17 Mental state: 2b. Positive symptoms ‐ average endpoint subscore (PANSS positive, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐2.79, 0.90]

18 Mental state: 2c. Positive symptoms ‐ average change subscore (PANSS positive, high = poor) Show forest plot	3	238	Mean Difference (IV, Random, 95% CI)	0.04 [‐1.31, 1.40]

19 Mental state: 2d. Positive symptoms ‐ average endpoint subscore (BPRS positive,high = poor) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	0.40 [‐2.94, 3.74]

20 Mental state: 3a. Negative symptoms ‐ average endpoint subscore (PANSS negative, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	0.32 [‐1.48, 2.11]

21 Mental state: 3b. Negative symptoms ‐ average change subscore (PANSS negative, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.96, 0.67]

22 Mental state: 3c. Negative symptoms ‐ average endpoint subscore (BPRS negative, high = poor) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.97, 1.17]

23 Mental state: 3d. Negative symptoms ‐ average endpoint score (SANS, high = poor) Show forest plot	1	34	Mean Difference (IV, Random, 95% CI)	1.5 [‐14.33, 17.33]

24 Adverse effects ‐ At least one adverse effect Show forest plot	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.55, 1.50]

25 Adverse effects ‐ Cardiac: QTc prolongation Show forest plot	2	206	Risk Ratio (M‐H, Random, 95% CI)	2.47 [0.12, 50.39]

26 Adverse effects ‐ Cardiac: Orthostatic hypotension Show forest plot	2	102	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.25, 4.82]

27 Adverse effects ‐ Cardiac: Palpitations Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]

28 Adverse effects ‐ Cardiac: Premature Ventricular Contractions Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]

29 Adverse effects ‐ Constipation Show forest plot	2	102	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.44, 5.38]

30 Adverse effects ‐ Dizziness Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.41, 1.44]

31 Adverse effects ‐ Drooling Show forest plot	1	42	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.20, 20.41]

32 Adverse effects ‐ Death (suicide or naturalistic cause) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

33 Adverse effects ‐ Extrapyramidal: Categorical deterioration (AIMS, high = poor) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.59, 3.26]

34 Adverse effects ‐ Extrapyramidal: average endpoint score (AIMS, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.7 [‐0.87, 2.27]

35 Adverse effects ‐ Extrapyramidal: average change score (AIMS, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	0.41 [‐1.15, 1.96]

36 Adverse effects ‐ Extrapyramidal: akathisia Show forest plot	2	65	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.04, 14.02]

37 Adverse effects ‐ Extrapyramidal: categorical deterioration (BAS, high = poor) Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.42, 5.14]

38 Adverse effects ‐ Extrapyramidal: average endpoint score (BAS, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.2 [‐0.74, 0.34]

39 Adverse effects ‐ Extrapyramidal: average change score (BAS, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.59, 0.37]

40 Adverse effects ‐ Extrapyramidal: dystonia and/or dyskinesia Show forest plot	3	196	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.09, 2.73]

41 Adverse effects ‐ Extrapyramidal: categorical deterioration in SAS Show forest plot	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.51, 2.93]

42 Adverse effects ‐ Extrapyramidal: average endpoint score (SAS, high = poor) Show forest plot	2	191	Mean Difference (IV, Random, 95% CI)	0.93 [‐1.04, 2.91]

43 Adverse effects ‐ Extrapyramidal: average change score (SA, high = poor) Show forest plot	2	163	Mean Difference (IV, Random, 95% CI)	0.21 [‐0.83, 1.26]

44 Adverse effects ‐ Extrapyramidal: tremor Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.59, 4.26]

45 Adverse effects ‐ Headache Show forest plot	2	173	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.52, 4.08]

46 Adverse effects ‐ Somnolence and/or drowsiness Show forest plot	4	256	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.81, 3.81]

47 Adverse effects ‐ Weight at endpoint (high = poor) Show forest plot	2	165	Mean Difference (IV, Random, 95% CI)	‐1.85 [‐7.09, 3.39]

48 Behaviour: average endpoint score (BARS, high = good) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.50, 0.30]

49 Functioning ‐ Global Assessment of Functioning: average change score (GAF, high = good) Show forest plot	1	103	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.00, 1.80]

50 Functioning ‐ Social ‐ Adaptive Functioning Evaluation: average endpoint score (SAFE, high = poor) Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	0.16 [‐0.47, 0.79]

51 Functioning ‐ Social and Occupational Functioning Assessment: average endpoint score (SOFAS, high = good) Show forest plot	1	131	Mean Difference (IV, Random, 95% CI)	0.5 [‐3.80, 4.80]

52 Quality of life: Clinically important change (at least 50% improvement HQLS, high = good) Show forest plot	1	17	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

53 Quality of life: Average endpoint score (HQLS, high = good) Show forest plot	1	17	Mean Difference (IV, Random, 95% CI)	5.5 [‐13.66, 24.66]

Comparison 1. Antipsychotic dose increase versus antipsychotic dose maintenance

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Comparison 2. Subgroup analysis and investigation of heterogeneity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Single antipsychotic drugs Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Fluphenazine	1	34	Risk Ratio (M‐H, Random, 95% CI)	2.25 [0.22, 22.53]
1.2 Haloperidol	2	71	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.67, 1.80]
1.3 Quetiapine	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.86]
1.4 Risperidone	1	17	Risk Ratio (M‐H, Random, 95% CI)	9.9 [0.63, 155.08]
1.5 Thiothixene	1	42	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.94, 3.26]
1.6 Ziprasidone	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.45, 1.41]
2 Clinical state, stage or problem Show forest plot	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 First episode patients	1	17	Risk Ratio (M‐H, Random, 95% CI)	9.9 [0.63, 155.08]
2.2 Not first episode patients	8	516	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.86, 1.34]

Comparison 2. Subgroup analysis and investigation of heterogeneity

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Comparison 3. Sensitivity analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Excluding studies with unclear randomisation methods Show forest plot	2	234	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.77, 1.44]

2 Excluding studies with unclear allocation concealment methods Show forest plot	2	234	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.77, 1.44]

3 Exclusion of studies with high risk of bias regarding blinding Show forest plot	8	516	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.86, 1.34]

4 Exclusion of studies with high risk of bias regarding incomplete outcome data Show forest plot	6	375	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.92, 1.54]

5 Exclusion of studies with imputed values Show forest plot	8	458	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.90, 1.50]

6 Fixed effects Show forest plot	9	533	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.88, 1.38]

Comparison 3. Sensitivity analysis

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Referencias

منابع مطالعات واردشده در این مرور

Bjørndal 1980 {published data only}

Goff 2013 {published data only}

Honer 2011 {published data only}

Huang 1987 {published data only}

Kinon 1993 {published data only}

Lindenmayer 2011 {published data only}

Loebel 2014 {published data only}

McEvoy 1991 {published data only}

McGorry 2011 {published data only}

Sakurai 2016 {published data only}

منابع مطالعات خارج‌شده از این مرور

Agid 2013 {published data only}

Badgett 1996 {published data only}

Bai 2002 {published data only}

Baker 2003 {published data only}

Bastecky 1982 {published data only}

Bitter 1989 {published data only}

Bondolfi 1995 {published data only}

Branchey 1981 {published data only}

Canuso 2010 {published data only}

Chen 1998 {published data only}

Clerc 1989 {published data only}

CN138032 {published data only}

Cookson 1987 {published data only}

Coryell 1998 {published data only}

Daniel 1997 {published data only}

DeBuck 1972 {published data only}

de Leon 2007 {published data only}

Dencker 1978 {published data only}

Ericksen 1978 {published data only}

Gardos 1971 {published data only}

Gulliver 2010 {published data only}

Harris 1997 {published data only}

Hirschowitz 1995 {published data only}

Hirschowitz 1997 {published data only}

Itil 1970 {published data only}

Janicak 1997 {published data only}

Kane 1985 {published data only}

Lehmann 1980 {published data only}

McCreadie 1979 {published data only}

Mitchell 2004 {published data only}

NCT00539071 {published data only}

NCT00862992 {published data only}

NCT01457339 {published data only}

NCT01569659 {published data only}

Simpson 1999 {published data only}

Suzuki 1992 {published data only}

Volavka 1996 {published data only}

منابع اضافی

Andreasen 1982

Baldessarini 1988

Barnes 1989

Barnes 2003

Bland 1997

Boissel 1999

Carpenter 1994

Clark 2011

Correll 2011

Davey Smith 1998

Davis 2004

Deeks 2000

Deeks 2011

DerSimonian 1986

Divine 1992

Dold 2015

Donner 2002

DSM‐IV‐TR 1994

Egger 1997

Elbourne 2002

Eum 2016

Friede 2017

Furukawa 2006

Furukawa 2011

Gardner 2010

Gulliford 1999

Guy 1976