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1 Content of the Supplement Supplementary Appendix 1: Study protocol... 2 Supplementary Table 1: Included studies characteristics and risk of bias... 8 Supplementary Table 2: Excluded studies with reasons Supplementary Table 3: Additional details of the search and search terms Supplementary Table 4: Data items and changes from the protocol Supplementary Figure 1 and 2: Risk of bias assessment Forests plots with individual studies (Supplementary Figures 3-60) Subgroup analyses (Supplementary Figures 61-83) Sensitivity analyses (Supplementary Figures 84-96) Meta-regression analyses (Supplementary Tables 5-19) Analyses of publication bias (Supplementary Tables 20-23) Supplementary Table 24: Summary of findings table Outline and discussion of related systematic reviews and meta-analyses (Supplementary Tables 25-33)

2 Supplementary Appendix 1: Study protocol This protocol was originally published online at PROSPERO International prospective register of systematic reviews (see Citation below). Antidepressants added to antipsychotic drugs for schizophrenia Bartosz Helfer, Stefan Leucht, Rolf Engel, Markus Dold, Maximilian Huhn, Myrto Samara Citation Bartosz Helfer, Stefan Leucht, Rolf Engel, Markus Dold, Maximilian Huhn, Myrto Samara. Antidepressants added to antipsychotic drugs for schizophrenia. PROSPERO 2014:CRD Available from Review question(s) What are the effects of adding antidepressants to antipsychotic drugs in schizophrenia? Searches We will search the register of controlled therapy studies of the Cochrane Schizophrenia Group (CSG), for which a number of electronic databases are regularly searched: Biological Abstracts, CINAHL, Cochrane Library, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, System for the Information on Grey Literature in Europe, Sociofile etc. The CSG also regularly hand searches abstract books of major conferences, and various trial registers such as clinicaltrials.gov. First authors of included studies will be contacted for missing data, and we will also contact pharmaceutical companies manufacturing antidepressants. There will be no restrictions in language apart from articles from mainland China, and no restriction in publication period. The search strategy has not yet been fully developed, but the terms will be broad and combine terms for schizophrenia and antidepressants. Types of study to be included We will only include studies that randomly assigned participants with schizophrenia or related disorders to antidepressants or placebo/no treatment. Quasi-randomized studies (e.g. allocation by day of the week) will be excluded. In cross-over trials only data up to the point of the first cross-over will be used. Cluster-randomized trials will be generally excluded. Condition or domain being studied Schizophrenia is a chronic and disabling psychiatric disorder. It afflicts approximately one per cent of the population world-wide with little gender differences. Typical manifestations are 'positive' symptoms such as fixed, false beliefs (delusions) and perceptions without cause 2

3 (hallucinations), 'negative' symptoms such as apathy and lack of drive, disorganization of behavior and thought, and catatonic symptoms such as mannerisms and bizarre posturing. Schizophrenic patients and their families suffer severely from their illness, 70% of the schizophrenic patients have no jobs and up to 10% commit suicide. Participants/ population We will include people with schizophrenia and schizophrenia (-like) psychosis (e.g. schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used. Intervention(s), exposure(s) The intervention will be antidepressants (SSRIs, TCAs, MAOs) that are marketed in at least one country, administered by any mode (oral tablets, oral liquid) and at any effective dose. Antidepressants will be added to antipsychotics (any drug, dose or mode of administration). Comparator(s)/ control The control interventions will be placebo or no intervention added to antipsychotics. Since we will also include randomized, but unblinded studies, trials simply giving no pharmacological treatment in the control group will be accepted as well. Context We will include studies irrespective of setting and participant age, gender or illness history. Outcome(s) Primary outcomes The primary outcome will be depressive symptoms at endpoint/mean reduction of depressive symptoms from baseline to endpoint as measured by the Calgary Depression Scale, the Hamilton Depression Scale or the Montgomery-Asberg Depression Scale. Secondary outcomes Clinically important response in terms of depressive symptoms. Overall symptoms of schizophrenia as measured by mean scores of rating scales (e.g. PANSS; BPRS) Positive symptoms - as measured by relevant scales such as the subscale of the PANSS or the SAPS Negative symptoms - as measured by relevant scales such as the subscale of the PANSS or the SANS Premature discontinuation ( dropout ) due to any reason as a measure of overall acceptability Premature discontinuation due to inefficacy of treatment as a measure of overall efficacy Premature discontinuation due to side-effects as a measure of overall tolerability Exacerbation of psychosis 3

4 Quality of life Adverse effects: at least one adverse effect Adverse effects: specific Data extraction, (selection and coding) Two reviewers will independently inspect all abstracts identified by the searches. Disagreement will be resolved by discussion and if necessary a third reviewer will be involved. Where doubt still remains, we will acquire the full article for further inspection. Once the full articles are obtained, at least two reviewers will independently decide whether the studies meet the review criteria. If disagreement cannot be resolved by discussion and a third reviewer, we will seek further information from the study authors. Two reviewers will independently extract data from all selected trials. When there is disagreement it will be resolved by discussion with a third reviewer. When this is impossible we will contact the study authors to resolve the dilemma. Data will be extracted on standard simple forms that will be piloted based on a random sample of 10 studies. Risk of bias (quality) assessment Working independently, two authors will assess the risk of bias using the tool described in the Cochrane Handbook for Systematic Reviews of Interventions.This tool encourages consideration of how the sequence was generated, how allocation was concealed, the integrity of blinding at outcome, the completeness of outcome data, selective reporting and other biases. We will not include studies were sequence generation was at high risk of bias or where allocation was clearly not concealed. For example, we will exclude quasi-randomised studies such as those using allocation by day of the week, date of birth, alternate allocation. In addition, we will describe cross-over studies to be at risk of bias and we will exclude cross-over studies in a sensitivity analysis. Strategy for data synthesis For dichotomous outcomes we will carry out an intention-to-treat analysis (ITT). If the authors applied such a strategy, we will use their results. If the original authors presented only the results of the per-protocol or completer population, we will assume that those participants lost to follow-up would not have had a change in their outcome (i.e. they would not have improved). As an effect size measure we will calculate the relative risk (RR) and its 95% confidence interval (CI). For continuous outcomes an ITT analysis will be used when available. The effect size measure for continuous outcomes will be the standardized mean difference (SMD), calculated as Hedges s g. When standard errors instead of standard deviations (SD) are presented, the former will be converted to standard deviations. If both are missing and cannot be obtained from the authors we will estimate SDs from confidence intervals, or t-values, or p-values or will derive SDs from those of the other studies using a validated imputation technique. 4

5 We primarily chose the random effects model by Der-Simonian and Laird for all analyses. We will, however, examine in a sensitivity analysis of the primary outcome whether the use of a fixed effects model leads to a substantial difference. We will examine potential publication bias by funnel-plots. Heterogeneity/homogeneity will be investigated by visual inspection of the forest plots, by applying the chi-square test to assess homogeneity (significance level a priori set at p<0.1) and by the I-squared value. Analysis of subgroups or subsets Preplanned subgroup analysis will include the comparison of different classes of antidepressants against each other (e.g. TCA vs. SSRI vs. MAO) and also different phases of occurrence of depressive symptoms (acute episode vs. post-psychotic depression) and different patient populations (e.g. predominant negative symptoms, treatment resistant symptoms, first episode). The following potential effect modifiers will be addressed by meta-regression: schizophrenia severity at baseline (BPRS or PANSS total score at baseline), depressive symptoms severity at baseline (HAM-D, Calgary Depression Scale) antidepressant dose and study duration. The following sensitivity analyses are planned for the primary outcome: exclusion of nondouble-blind studies, fixed effects instead of random effects model, exclusion of schizoaffective participants, and exclusion of imputed statistics. Dissemination plans We plan to publish our results in a major medical journal and hope they will be quickly implemented in treatment guidelines. Contact details for further information Bartosz Helfer Klinik fur Psychiatrie und Psychotherapie der TU-Munchen Klinikum rechts der Isar Ismaningerstr Munchen Germany bartosz.helfer@gmail.com Organisational affiliation of the review Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Review team 5

6 Mr Bartosz Helfer, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Professor Stefan Leucht, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Professor Rolf Engel, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany Dr Markus Dold, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Dr Maximilian Huhn, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Dr Myrto Samara, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Technische Universtität München, Klinikum rechts der Isar, Germany Collaborators Dr Georgia Salanti, Department of Hygiene and Epidemiology, University of Ioannina, Greece Anticipated or actual start date 01 January 2014 Anticipated completion date 01 January 2015 Funding sources/sponsors Bundesministerium für Bildung und Forschung (German Federal Ministry of Education and Research), grant number: 01KG1213 Conflicts of interest In the last three years Stefan Leucht has received honoraria for lectures from Abbvie, Astra Zeneca, BristolMyersSquibb, ICON, EliLilly, Janssen, Johnson & Johnson, Roche, SanofiAventis, Lundbeck and Pfizer; for consulting/advisory boards from Roche, EliLilly, Medavante, BristolMyersSquibb, Alkermes, Janssen, Johnson & Johnson and Lundbeck. EliLilly has provided medication for a study with SL as primary investigator. Language English Country Germany Subject index terms status Subject indexing assigned by CRD Subject index terms 6

7 Antidepressive Agents; Antipsychotic Agents; Drug Therapy, Combination; Humans; Schizophrenia Stage of review Ongoing Date of registration in PROSPERO 02 January 2014 Date of publication of this revision 02 January 2014 Stage of review at time of this submission Started Preliminary searches No Piloting of the study selection process No Formal screening of search results against eligibility criteria No Data extraction No Risk of bias (quality) assessment No Data analysis No 7

8 Supplementary Table 1: Included studies characteristics and risk of bias Abbasi 2010 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 14 Number of Females: 6 Age (Mean, SD): 34.50±7.51 Duration of Illness (years): 7.42±3.21 Number of Hospitalizations: 4.65±2.45 Number of Males: 13 Number of Females: 7 Age (Mean, SD): 33.35±6.42 Duration of Illness (years): 7.84±3.4 Number of Hospitalizations: 4.50±2.18 Inclusion criteria: chronic schizophrenia, active phase of illness DSM-IV-TR min PANSS: 60 Exclusion criteria: a clinically significant organic and neurological disorder, serious psychotic disorders other than schizophrenia, use of any medications identified as contradicted with mirtazapine, treatment with antidepressant medication within 1 month of screening; and a current diagnosis of major mood or substance abuse disorder. The PANSS depression item score (exclusion level 4) was used to exclude patients with significant level of depression. Pregnant or lactating women and those of reproductive age without adequate contraception were also excluded Interventions Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: 6 mg/day Dose Antidepressant: 30 mg/day Duration of Trial (weeks): 8 Number Randomized: 20 Dose Antipsychotic: 6 mg/day Dose Antidepressant: Duration of Trial (weeks): 8 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) Responders (at least 50% PANSS improvement) Adverse events Identification Sponsorship source: independent (university) Country: Iran Setting: inpatients 8

9 Authors name: Seyed-Hesameddin Abbasi Institution: Research Unit, Tehran Heart Center (S. Akhondzadeh). Address: Tehran University of Medical Sciences, Tehran, Iran Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) judgement Low risk Low risk Low risk Low risk Low risk Comment: Patients were randomized to receive mirtazapine or placebo in a 1:1 ratio using a computergenerated code Comment: The assignments were kept in sealed, opaque envelopes until data analysis. Comment: "Throughout the study, the person who administered the medications, the rater and the patients were blind to assignments" Comment: "Throughout the study, the person who administered the medications, the rater and the patients were blind to assignments" Comment: Dropout rate was low and evenly distributed between groups (1/20 and 1/20). Reasons for dropout in both group were the same (consent withdrawal). Comment: Results (mean & SD) of the Extrapyramidal Symptoms Rating Scale are not described. Selective reporting High risk (reporting bias) Other bias Low risk Comment: No other source of bias. Addington 2002 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 6 Number of Females: 15 Age (Mean, SD): 36.7 (20-67) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 12 Number of Females: 15 Age (Mean, SD): 38.8 (21-57) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: meeting DSM-IV criteria for both SCZ in remission and for a major depressive episode; receiving a stable dose of antipsychotic medication and to be clinically stable (within at least 1 month maintaining a score of at least 4 or less on all positive symptoms of PANSS Excluded criteria: at risk of suicide or attempted suicide 9

10 Pretreatment: The mean baseline CDSS score was slightly higher in sertralinetreated group. Also, a higher proportion of sertraline-treated subjects were nonwhite. Interventions Intervention Characteristics Number Randomized: 21 Dose Antipsychotic: CPZ equivalents 441 mg/day Dose Antidepressant: Sertraline 50mg/day Duration of Trial (weeks): 6 Number Randomized: 27 Dose Antipsychotic: Various antipsychotics, mean dose could be averaged from table Dose Antidepressant: placebo Duration of Trial (weeks): 6 Outcomes CDRS HAM-D Dropouts (any reason) Responders (at least 50% HAM-D improvement; at least 50% CDRS improvement Identification Sponsorship source: no information of sponsorship and resources of capsules Country: Canada Setting: outpatients Authors name: Donald Addinton Institution: Department of Psychiatry and Community Health Sciences, University of Calgary addington@calgary.ca Address: Street, NW, Calgary, Alberta T2N, 2T9 Notes Continuous outcomes: Yikang Zhu the baseline score were extracted from Figures Adverse outcomes: Yikang Zhu not reported Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) judgement Low risk Unclear risk Low risk Low risk Quote: "Randomization was per- formed with a computer-generated random list." Comment: No description Quote: "double-blind randomized trial." Comment: double blind Unclear risk Quote: "Of the 27 subjects randomized to placebo, 26 (96.3%) had completed ratings at visit 6. Of 21 subjects random- ized to placebo, 20 (95.2%) had completed ratings at visit 6." Comment: Reasons for drop-out NOT provided 10

11 Selective reporting (reporting bias) High risk Quote: "PANSS and ESRS scores at base- line were nearly identical in the two study groups." Comment: No means and SDs of PANSS and ESRS scores for each group at baseline reported Other bias Low risk Quote: "a higher proportion of sertraline-treated subjects were nonwhite (23.8%) than were placebotreated sub- jects (14.8%)." Amiri 2008 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 14 Number of Females: 6 Age (Mean, SD): 32.70±6.10 Duration of Illness (years): 7.15±3.52 Number of Hospitalizations: 4.35±1.87 Number of Males: 15 Number of Females: 5 Age (Mean, SD): 33.65±7.27 Duration of Illness (years): 7.67±3.79 Number of Hospitalizations: 4.15±1.49 Inclusion criteria: The minimum score of 60 on Positive and Negative Syndrome Scale and min. of 15 on negative sub-scale Excluded criteria: clinically significant organic and neurological disorder, serious psychotic disorders other than schizophrenia, use of any medications identified as contradicted with selegiline, treatment with antidepressant medication within 1 month of screening, and a current diagnosis of major mood or substance abuse disorder. The PANSS depression item score (exclusion level more or equal to 4) was used to exclude patients with significant level of depression. Pregnant or lactating women and those of reproductive age without adequate contraception were also excluded. Pretreatment: Interventions Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: Risperidone 6mg/day Dose Antidepressant: Selegiline 10mg/day Duration of Trial (weeks): 8 Number Randomized: 20 Dose Antipsychotic: Risperidone 6mg/day Duration of Trial (weeks): 8 Outcomes CDRS HAM-D Dropouts (any reason) Responders (at least 50% HAM-D; at least 50% CDRS) 11

12 Identification Sponsorship source: This study was supported by a grant from Tehran University of Medical Sciences to Dr Shahin Akhondzadeh (grant number: 2453). Country: Iran Setting: Inpatients Authors name: Afshar Amiri Institution: Tehran University of Medical Sciences s.akhond@neda.net Address: Prof. S. Akhondzadeh, Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran 13337, Iran. Tel: Fax: Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) judgement Low risk Quote: "Patients were randomized to receive selegiline or placebo in a 1: 1 ratio using a computer-generated code." Comment: no details Allocation concealment Unclear risk (selection bias) Blinding of participants and Low risk Comment: Throughout the study, the person who personnel (performance administered the medications, the rater and the bias) patients were blind to assignments. Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data Low risk Comment: Dropout rate was low and evenly (attrition bias) distributed. Selective reporting High risk Comment: ESRS data not given (reporting bias) Other bias Low risk Comment: no other bias Arango 2000 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 12 Number of Females: 5 Age (Mean, SD): 35.8 (10) Duration of Illness (years): 7.2 (1.7) Number of Hospitalizations: not reported Number of Males: 11 Number of Females: 4 Age (Mean, SD): 37.4 (6) Duration of Illness (years): 7.1 (1.9) Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: Patients were free of significant drug abuse or any neurological problem such as serious head injury that might cause or seriously exacerbate their psychotic symptoms. 12

13 Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 16 Dose Antipsychotic: not reported Dose Antidepressant: 36.2 mg (SD 20.9) Duration of Trial (weeks): 8 Number Randomized: 16 Dose Antipsychotic: not reported Duration of Trial (weeks): 8 Outcomes HAM-D SANS BPRS Positive BPRS Negative Dropouts (any reason) Exacerbation of psychosis Adverse events Identification Risk of bias table Bias Sponsorship source: This work was supported in part by a grant from Eli Lilly and Company, and PHS grant MH40279 Country: USA Setting: outpatient Authors name: Celso Arango Institution: University of Maryland not reported Address: Maryland Psychiatric Research Center, P.O. Box 21247, University of Maryland, Baltimore, Maryland Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Becker 1970 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported 13

14 Age (Mean, SD): (9.74) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): (8.95) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 29 Dose Antipsychotic: 8-16 mg/day Dose Antidepressant: 75 mg/day Duration of Trial (weeks): 39 Number Randomized: 29 Dose Antipsychotic: 8-16 mg/day Duration of Trial (weeks): 39 Outcomes BPRS Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Sponsorship source: The medication and the grant-in-aid for data analyses were supplied by Merck Sharp & Dohme Research Lab-oratories, West Point, Pa. Country: USA Setting: inpatients Authors name: Robert E. Becker Institution: University of Connecticut Health Center, Address: 2 Holcomb St.. Hartford, Conn Authors' judgement Unclear risk Unclear risk Low risk Low risk High risk Support for judgement Comment: randomized, no further details Comment: no details Comment: double blind Comment: double blind Comment: unclear how the dropouts are distributed into the groups, no reasons for dropout Comment: Number of patients in the individual groups not reported Selective reporting (reporting High risk bias) Other bias Low risk Comment: no other bias Becker

15 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 27 Dose Antipsychotic: not reported Dose Antidepressant: not reported Duration of Trial (weeks): 4 Number Randomized: 28 Dose Antipsychotic: not reported Duration of Trial (weeks): 4 Outcomes Dropouts (any reason) Identification Risk of bias table Bias Sponsorship source: not reported Country: USA Setting: inpatients or outpatients Authors name: Robert E. Becker Institution: University of Connecticut School of Medicine, Farmington, Conn. Authors' judgement Low risk 15 Support for judgement Random sequence generation (selection bias) Comment: computer-generated randomized code Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: no dropouts bias) Selective reporting (reporting bias) High risk Comment: no BPRS or Hamilton data from clinical scales reported

16 Other bias High risk Comment: not entirely clear how many patients got which drug Becker 1983 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 21 Number of Females: 7 Age (Mean, SD): 37.6 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 14 Number of Females: 10 Age (Mean, SD): 39.8 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: newly admitted and chronically hospitalized patients who matched the DSM-II description of schizophrenic syndrome and met the Research Diagnostic Criteria (RDC) for SCZ; also met the RDC for major depressive syndrome on the basis of the presence of depressed mood or clearly stated pervasive loss of interest, even though they denied having depressive feelings; those who had ratings of moderate to severe depression (scores of 3 or 4) on the Hamilton depression item; those who had ratings of 2 or less on the Hamilton depression item but had ratings of moderate to severe impairment (scores of 3 or 4) on the work and activities item. Exclusion criteria: no information Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 28 Dose Antipsychotic: 640 mg/ day Dose Antidepressant: 156 mg/ day Duration of Trial (weeks): 4 Number Randomized: 24 Dose Antipsychotic: 640 mg/ day Duration of Trial (weeks): 4 Outcomes HAM-D BPRS BPRS Depression Dropouts (any reason) Responders (CGI-I) Identification Sponsorship source: no information Country: USA Setting: Inpatients 16

17 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Authors name: Robert E. Becker Institution: the Rhode Island Psychiatric Research and Training Center; the Department of Psychiatry, Brown University no information Address: Rhode Island Psychiatric Research and Training Center, P.O. Box 8269, Cranston, RI Authors' judgement Low risk Unclear risk Low risk Low risk Low risk Support for judgement Selective reporting Low risk (reporting bias) Other bias Low risk Comment: no other bias Quote: "On the basis of a computer-generated code, patients were randomly assigned to a double-blind 4- week trial comparing thiothixene and placebo against chlorpromazine and imipramine." Comment: On the basis of a computer-generated code, patients were randomly assigned to Comment: no details provided Quote: "Chlorpromazine and thiothixene were supplied in identical oval capsules containing either 100 mg of chlorpromazine or S mg of thiothixene. Placebo and 25 mg of imipramine were supplied in matched capsules." Comment: double blind Comment: double blind Quote: "One patient, without consulting the clinician, discontinued chlorpromazine plus imipramine because of drowsiness." Comment: low dropout rate Comment: no selective reporting Berk 2001 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 29.5 SD Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 29.5 SD Duration of Illness (years): not reported 17

18 Number of Hospitalizations: not reported Inclusion criteria: treated with haloperidol 5 mg daily were selected Exclusion criteria: Patients with significant medical illnesses and those with abnormal routine lab results were excluded, as were patients on concomitant medication for medical indications. Patients on any other psychotropic Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: 5 mg/day Dose Antidepressant: 30 mg/day Duration of Trial (weeks): 6 Number Randomized: 15 Dose Antipsychotic: 5 mg/day Duration of Trial (weeks): 6 Outcomes HAM-D PANSS total PANSS positive PANSS negative CGI-I, CGI-S Dropouts (any reason) Dropouts (side effects) Adverse events Identification Sponsorship source: not reported Country: South Africa Setting: inpatients Authors name: Berk Institution: Witwatersrand University Medical School berk@chiron.wits.ac.za Address: Department of Psychiatry, Witwatersrand University Medical School,7 York Road, Parktown, 2193, South Africa Notes Continuous outcomes: SE converted to SD Risk of bias table Bias Authors' Support for judgement judgement Random sequence Unclear risk Comment: randomized, no further details generation (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data Low risk Comment: low dropout rate (attrition bias) Selective reporting (reporting bias) High risk Comment: Clinical Global Impression CGI. Severity and Improvement Scales and the Simpson Angus Scale are not reported 18

19 Other bias Low risk Comment: no other bias Berk 2009 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 14 Number of Females: 4 Age (Mean, SD): 37.80, Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 18 Number of Females: 2 Age (Mean, SD): 35.90, 9.20 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: 18 to 65 years Exclusion criteria: any significant medical illness, were on any other psychotropic agent except benzodiazepines, met criteria for substance abuse or were pregnant or not on contraceptives if female and in the reproductive age. Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: 7.10 SD 3.29 (risperidone equivalents) Dose Antidepressant: 30mg/day Duration of Trial (weeks): 6 Number Randomized: 20 Dose Antipsychotic: 6.33 SD 3.54 (risperidone equivalents) Duration of Trial (weeks): 6 Outcomes CDRS HAM-D PANSS total PANSS positive PANSS negative Dropouts (any reason) Dropouts (side effects) Adverse events Identification Sponsorship source: Company Country: Australia Setting: Inpatients Authors name: Berk Institution: The University of Melbourne seetald@barwonhealth.org.au 19

20 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Address: Dr S. Dodd, Department of Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, PO Box 281,Geelong 3220, Australia. Tel: þ Fax: þ Authors' judgement Unclear risk Unclear risk Low risk Low risk Unclear risk Support for judgement Selective reporting (reporting High risk bias) Other bias Low risk No other bias Comment: randomized. No further details. Comment: No details presented. Comment: double blind. No further description. Comment: double blind Comment: Low drop-out, equally distributed (17.5%). Reasons for drop-out not clearly described. Comment: Not all predefined results are described. SAS not described. Berman 1995 Methods Participants Study design: Randomized controlled trial Study grouping: Crossover Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 42.5 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 42.5 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: DSM-III-R diagnosis of schizophrenia with OC symptoms. Each patient had to have at least two obsessions and/or compulsions, as defined by the Yale-Brown Obsessive-Compulsive Symptom Scale(YBOCS), [20] that were not related to an acute schizophrenic exacerbation and had persisted for more than 6 months. In addition, the patients had to be stabilized on their medications (i.e., had not had worsening of their psychotic symptoms or change in their psychiatric medication for at least 2 weeks before entering the study). All subjects had to be receiving a dose of neuroleptic medication equivalent to at least 300 mg of chlorpromazine per day. Patients who were treated with low-potency neuroleptics (such as chlorpromazine or thioridazine) were excluded because. 20

21 Exclusion criteria: Subjects with affective disorders or significant affective component (i.e., symptoms of depression such as hopelessness, helplessness, and change in appetite or sleeping patterns, suicidality) were not included in the study. Also, patients with a history of mania were excluded from entering the protocol. Subjects with a history of coronary artery disease, hepatic disease, dementia, seizure disorder, or brain tumors were excluded. Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 3 Dose Antipsychotic: not reported Dose Antidepressant: 250 mg/day Duration of Trial (weeks): 6 Number Randomized: 3 Dose Antipsychotic: not reported Duration of Trial (weeks): 6 Outcomes Dropouts (any reason) CGI-S Identification Sponsorship source: not reported Country: USA Setting: outpatient Authors name: Ileana Berman Institution: Commonwealth Research Center, Massachusetts Mental Health Center, Harvard Medical School, Department of Psychiatry, Boston, Massachusetts Address: FDR Veterans Affairs Hospital, Montrose, NY Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Bodkin 2005 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 27 21

22 Number of Females: 5 Age (Mean, SD): 38.0 SD 9.0 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 28 Number of Females: 6 Age (Mean, SD): 39.9 SD 8.7 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Inclusion criteria included a Scale for the Assessment of Negative Symptoms (SANS) total summary score 12, with at least two global subscale scores 3; antipsychotic medication treatment 1 year, at the current dose 1 month, with any other psychotropic medications at a constant dose for 1month. Exclusion criteria: Exclusion criteria included a score 5 on any Brief Psychiatric Rating Scale (BPRS) thinking disturbance item; treatment within 1 month of screening with antidepressant medication; and a current diagnosis of major mood or substance abuse disorder. Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 33 Dose Antipsychotic: 727 mg/day SD 737 (CPZ equiv) Dose Antidepressant: 10 mg/day Duration of Trial (weeks): 12 Number Randomized: 34 Dose Antipsychotic: 570 mg/day SD 476 (CPZ equiv) Duration of Trial (weeks): 12 Outcomes HAM-D BPRS SANS SAS Dropouts (any reason) CGI (improv) CGI (severity) Identification Sponsorship source: Company Country: USA Setting: outpatients Authors name: Bodkin Institution: Harvard Medical School abodkin@mclean.harvard.edu Address: Dr. Bodkin, McLean Hospital, 115 Mill, St., Belmont, MA Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation Low risk Comment: "1:1 random assignment" (selection bias) Allocation concealment (selection bias) Unclear risk Comment: No further description 22

23 Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Low risk Low risk Unclear risk Comment: double blind Comment: double blind Comment: Low drop-out (10%), equally distributed. Reasons for drop-out are not provided. Comment: no selective reporting Selective reporting (reporting Low risk bias) Other bias Low risk Comment: No other source of bias. Brockington 1978 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 13 Dose Antipsychotic: 450 mg/day Dose Antidepressant: 150 mg/day Duration of Trial (weeks): 4 Number Randomized: 14 Dose Antipsychotic: 600 mg/day Duration of Trial (weeks): 4 Outcomes Dropouts (any reason) Responders (recovery or partial recovery) Identification Sponsorship source: amitriptyline by Camden Pharma, Hospital grant Country: UK Setting: inpatients Authors name: Brockington Institution: Maudsley, Bethlem and St Francis Hospitals, London not available 23

24 Address: University Hospital of South Manchester, West Didsbury, Manchester 20 Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Unclear risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: low dropout rate (14%), but no reasons for dropout Selective reporting (reporting bias) High risk Comment: adverse events, BPRS and depression scores reported, only significant difference reported Other bias Low risk Comment: no other bias Buchanan 1996 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 15 Number of Females: 3 Age (Mean, SD): 36.8 SD 6.4 Duration of Illness (years): 16.2 SD 4.3 Number of Hospitalizations: not reported Number of Males: 8 Number of Females: 7 Age (Mean, SD): 32.8 SD 6.0 Duration of Illness (years): 15.6 SD 6.4 Number of Hospitalizations: not reported Inclusion criteria: outpatients who had received at least 6 months of clozapine treatment (with doses of at least 300 mg/day) and met criteria for a minimum level of residual positive or negative symptoms were entered into the study. Exclusion criteria: Patients with concurrent alcohol or substance abuse, organic brain disorder, mental retardation or a medical condition that contraindicated clozapine or fluoxetine treatment were excluded. Intervention Characteristics Number Randomized: 18 Dose Antipsychotic: SD 89.0 mg/ day Dose Antidepressant: m=48.9 (SD=14.1) mg/day Duration of Trial (weeks): 8 24

25 Number Randomized: 16 Dose Antipsychotic: SD mg/ day Duration of Trial (weeks): 8 Outcomes HAM-D SANS Dropouts (any reason) BPRS Positive Identification Risk of bias table Bias Sponsorship source: University Country: USA Setting: outpatients Authors name: Buchanan Institution: University of Maryland School of Medicine not available Address: Dr. Buchanan, Niarvland Psychiatric Research Center, P.O. Box 21247, Baltimore. MD Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: Low drop-out. Reasons for drop-out described. Selective reporting (reporting bias) High risk Comment: side effects not reported from the predefined results, side-effects are not described. Other bias Low risk Comment: No other bias. Bustillo 2003 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 12 Number of Females: 3 Age (Mean, SD): 33 (12) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 12 Number of Females: 3 Age (Mean, SD): 36 (11) Duration of Illness (years): not reported 25

26 Number of Hospitalizations: not reported Inclusion criteria: (1) DSM-IV schizophrenia or schizoaffective disorder confirmed with the SCID DSM-IV; (2) history of partial response or intolerability to atypical antipsychotic medication; (3) years old Exclusion criteria: Exclusion criteria were: (1) neurological disorder or active substance abuse; (2) prior treatment with olanzapine or treatment with any atypical antipsychotic within the previous 4 weeks; (3) significant medical problems; (4)use of antidepressant or mood stabilizing agents within the previous 6 weeks; (5) history of manic episode. Pretreatment: not reported Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: 5-20mg/day (m=15, SD=4.8) Dose Antidepressant: 20-60mg/day (m=56, SD=11) Duration of Trial (weeks): 16 (m=14.4, SD=11.8) Number Randomized: 15 Dose Antipsychotic: 5-20mg/day (m=15, SD=4.2) Duration of Trial (weeks): 16 (m=14.4, SD=11.8) Outcomes HAM-D PANSS positive PANSS negative BAS SAS AIMS Dropouts (any reason) Identification Sponsorship source: Lilly Pharmaceutical Corporation Country: USA Setting: outpatients Authors name: Juan R Bustillo Institution: University of New Mexico jbustillo@salud.unm.edu Address: Department of Psychiatry, University of New Mexico, Albuquerque, NM, USA Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment (selection Unclear risk Comment: No details presented. bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) High risk Comment: High drop-out (n=11). Reasons for drop-out are not provided. Selective reporting (reporting bias) Low risk Comment: no selective reporting, all predefined outcomes are presented. Other bias Low risk Comment: no other bias 26

27 Caforio 2013 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 12 Number of Females: 2 Age (Mean, SD): 30.7 (7.7) Duration of Illness (years): 7.5 (7.9) Number of Hospitalizations: not reported Number of Males: 9 Number of Females: 5 Age (Mean, SD): 27.8 (7.06) Duration of Illness (years): 6.61 (5.67) Number of Hospitalizations: not reported Inclusion criteria: Inclusion criteria were diagnosis of schizophrenia with recent exacerbation of psychotic symptoms requiring hospitalization. Exclusion criteria: Exclusion criteria were history of alcohol or drug abuse in the last12 months and any diagnosable systemic or neurological condition. Interventions Intervention Characteristics Number Randomized: 14 Dose Antipsychotic: 15.7 SD 7.7 mg/day Dose Antidepressant: 30mg/day Duration of Trial (weeks): 8 Number Randomized: 14 Dose Antipsychotic: 18.8 SD 7.2 mg/day Dose Antidepressant: Duration of Trial (weeks): 8 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) Adverse events Identification Sponsorship source: University, Company Country: Italy Setting: inpatients Authors name: Caforio Institution: University of Bari, Italy a.bertolino@psichiat.uniba.it Address: Alessandro Bertolino, MD, PhD, Group of Psychiatric Neuroscience Department of Neuroscience and Sense Organs, University of Bari, Bari, Italy Risk of bias table 27

28 Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Authors' judgement Low risk Unclear risk Low risk Low risk High risk Support for judgement Comment: Randomized in a 1:1 ratio. Comment: No details presented. Comment: double blind Comment: double blind Comment: High drop-out (36%). Reasons for drop-out are not provided in detail ("reasons unrelated to treatment"). Comment: results from Calgary Depression Scale not reported Selective reporting (reporting High risk bias) Other bias Low risk Comment: No other source of bias. Chaichan 2004 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 5 Number of Females: 5 Age (Mean, SD): ± Duration of Illness (years): 8.75 ± 8.77 Number of Hospitalizations: not reported Number of Males: 6 Number of Females: 3 Age (Mean, SD): ± Duration of Illness (years): ± Number of Hospitalizations: not reported Inclusion criteria: The inclusion criteria were as follows: aged between 15 and 70 years and a Brief Psychiatric Rating Scale (BPRS) total score15of at least 24 (based on a 0 6-point scale) at the time of screening. Exclusion criteria: Patients were excluded if they had a current diagnosis of substance use disorder, substance-induced psychotic disorder, or serious medical illness. Also excluded from the study were patients who were pregnan tor lactating, had clinically abnormal laboratory data, reported a history of severe allergies or multiple adverse drug reactions, or had received treatment with a depot antipsychotic agent within the preceding 6weeks. Intervention Characteristics Number Randomized: 10 Dose Antipsychotic: 15mg/day Dose Antidepressant: 50mg/day 28

29 Duration of Trial (weeks): 6 Number Randomized: 10 Dose Antipsychotic: 15mg/day Duration of Trial (weeks): 6 Outcomes BPRS Dropouts (any reason) BPRS Positive BPRS Negative Identification Risk of bias table Bias Responders (50% or more reduction of BPRS scores) Sponsorship source: Olanzapine provided by Eli Lilly Co. Ltd. (Thailand), fluvoxamine by Berli Jucker Public Co. Ltd. (Thailand). Country: Thailand Setting: inpatients or outpatients Authors name: Chaichan Institution: Nakhonsawan Psychiatric Hospital psychi@mozart.inet.co.th Address: Dr Warawat Chaichan, Nakhonsawan Psychiatric Hospital, Phayuhakiri, Nakhonsawan 60130, Thailand Authors' Support for judgement judgement Random sequence generation (selection bias) Low risk Comment: Block randomization was used to generate the random allocation sequence Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and High risk Comment: Only patients were blinded. personnel (performance bias) Blinding of outcome High risk Comment: Only patients were blinded. assessment (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: Low drop-out (n=1). Reasons for dropout not described. Selective reporting (reporting bias) High risk Comment: Not all predefined results are presented. Results of the side-effect scale are not presented in detail. Other bias Low risk Comment: no other bias Cho 2011 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 6 Number of Females: 5 Age (Mean, SD): SD Duration of Illness (years): 9.94 SD 8.16 Number of Hospitalizations: not reported Number of Males: 5 29

30 Number of Females: 4 Age (Mean, SD): SD 9.57 Duration of Illness (years): 5.96 SD 7.48 Number of Hospitalizations: not reported Inclusion criteria: Inclusion criteria were as follows: 1) age between 21 and 70 years; 2) diagnosis of schizophrenia based on the Structured Clinical Interview for DSM-IV (SCID), after receiving a physical (neurological) exam, electroencephalography, and magnetic resonance imaging; and 3) score of at least 4 on the Clinical Global Impressions scale (CGI) and stable, with no changes in CGI (as determined by two investigators, SH Lee and TK Choi) or medication dosage, for 8 weeks. Exclusion criteria: Exclusion criteria were as follows: 1) evidence of organic mental disorder; 2) drug or alcohol dependence that required inpatient treatment and/or detoxification; 3) presence of a depressive episode based on the SCID or patients highly rated in HAMD [the Hamilton Depression Rating Scale 17]; and 4) other conditions, such as a serious medical condition, history of bipolar or schizoaffective disorder, suicidality, possibility of pregnancy, and lactation. None was taking any psychotropic agent except benztropine, alprazolam, and propranolol Interventions Intervention Characteristics Number Randomized: 12 Dose Antipsychotic: 3.00 (1.94) mg/day Dose Antidepressant: 15-30mg/day Duration of Trial (weeks): 8 Number Randomized: 9 Dose Antipsychotic: 4.22 (1.83) mg/day Duration of Trial (weeks): 8 Outcomes HAM-D PANSS total PANSS positive PANSS negative SANS BAS SAS Dropouts (any reason) Adverse events Responders (20% SANS score reduction at Endpoint vs Baseline) Identification Sponsorship source: University Country: South Korea Setting: outpatients Authors name: Cho Institution: CHA University School of Medicine leesanghyuk@yahoo.com Address: Sang-Hyuk Lee Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, 351 Yatap-Dong, Bundang-Gu, Seongnam-Si, Kyounggi-Do , South Korea Tel.: ; fax: Risk of bias table 30

31 Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: Randomized. No further description. Allocation concealment (selection Unclear risk Comment: No details presented. bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: Low drop-out (n=1). Reason for drop-out not described. Selective reporting (reporting bias) Low risk Comment: no selective reporting; All predefined results were presented. Other bias Low risk Comment: no other bias Chouinard 1975 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: 12 Number of Females: 12 Age (Mean, SD): Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 12 Number of Females: 12 Age (Mean, SD): 45.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 24 Dose Antipsychotic: 20 mg/ day Dose Antidepressant: 125 mg/ day Duration of Trial (weeks): 12 Number Randomized: 24 Dose Antipsychotic: 20 mg/ day Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes BPRS Dropouts (inefficacy) Exacerbation of psychosis Adverse events 31

32 Identification CGI (improv) CGI (severity) BPRS Depression BPRS Negative Sponsorship source: no information Country: Canada Setting: outpatient Authors name: Chouinard Institution: Hospital St-Jean-de-Dieu not available Address: Dr. Chouinard, Department of Research, INRS-SANTE, Hospital St-Jean-de-Dieu, Montreal-Gamelin, Quebec Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: insufficient information; it is unclear whether all do have been reported Selective reporting (reporting bias) High risk Comment: Dropout probably not fully reported but this is debatable; SDs not reported Other bias Low risk Comment: no other bias Collins 1967 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported 32

33 Interventions Intervention Characteristics Number Randomized: 29 Dose Antipsychotic: 24 mg/day Dose Antidepressant: 150 mg/day Duration of Trial (weeks): 12 Number Randomized: 29 Dose Antipsychotic: 24 mg/day Duration of Trial (weeks): 12 Outcomes Adverse events Identification Risk of bias table Bias Sponsorship source: Medication from industry Country: UK Setting: inpatients Comments: Authors name: A.D. Collins Institution: High Royds Hospital not available Address: A.D. Collins, High Royds Hospital, Menston, Yorkshire, UK Authors' judgement Unclear risk Support for judgement Random sequence generation (selection bias) Comment: randomized, no further details Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition High risk Comment: completer Analysis, Dropouts bias) and reasons not reported Selective reporting (reporting bias) High risk Comment: some SDs not reported; Dropouts not reported Other bias Low risk Comment: no other bias Decina 1994 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Baseline Characteristics Number of Males: 23/2 Number of Females: 24/2 Age (Mean, SD): 55.9 ±6.3 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 23/2 Number of Females: 24/2 Age (Mean, SD): 55.9 ±6.3 Duration of Illness (years): not reported Number of Hospitalizations: not reported 33

34 Inclusion criteria: Inpatients of either sex who were between ages 18 and 65 years, had resided in long-term treatment wards, and had an established clinical diagnosis of chronic schizophrenia with stable symptomatology, absence of florid psychotic symptoms, and an unchanged medication regimen of neuroleptics over at least the previous three months. Exclusion criteria: Patients were excluded from the study if they had a suspected on definite organic psychiatric disorder, nontrivial systemic or neurological diseases (inducing seizure disorders), on any previous primary diagnosis of a major afflictive disorder. Patients were also exuded if they were currently being treated with antidepressants on lithium salts. Interventions Intervention Characteristics Number Randomized: 26 Dose Antipsychotic: antipsychotics, stable dose, n.i. (it seems that there were no SGAs, clozapine, pimozide and sulpiride excluded) Dose Antidepressant: trazodone 300mg/day Duration of Trial (weeks): 6 Number Randomized: 21 Dose Antipsychotic: antipsychotics, stable dose, n.i. (it seems that there were no SGAs, clozapine, pimozide and sulpiride excluded) Dose Antidepressant: placebo Duration of Trial (weeks): 6 Outcomes Exacerbation of psychosis Identification Sponsorship source: no indication of sponsor Country: Italy Setting: inpatients Authors name: Decina Institution: research- oriented tertiary care psychiatric hospital in Guidonia (Rome), Italy. not available Address: Dr. Decina, Ospedale, Santa Maria Immacolata, Via Tiburtina 188, Guidonia, Rome, Italy. Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) judgement Unclear risk Unclear risk Low risk Low risk Low risk Comment: randomized, no further detail Comment: no details Comment: double blind Comment: double blind Comment: the authors do not Report the Groups of the Dropouts and they did a completer Analysis, but as 34

35 there were only two Dropouts this is unlikely to have affected the results Selective reporting Low risk Comment: no selective reporting (reporting bias) Other bias Low risk Comment: no other bias Dufresne 1988 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 41.4 (13.8) Duration of Illness (years): 0.33 Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 41.8 (12.2) Duration of Illness (years): 0.33 Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: Patients were excluded from the study if they suffered from organic mental and neurological disorders, were incapable of conversation, had a history or evidence of a seizure disorder, had a history of alcoholism in the past 2 years, had a myocardial infarction within the last 2 months, were pregnant or lactating, or had a history of intolerance to phenothiazine or thioxanthine antipsychotics Interventions Intervention Characteristics Number Randomized: 19 Dose Antipsychotic: mg per day (SD = 16.23) Dose Antidepressant: mg per day (SD = ) Duration of Trial (weeks): 10 Number Randomized: 19 Dose Antipsychotic: mg per day (SD = 16.23) Duration of Trial (weeks): 10 Outcomes HAM-D BPRS Dropouts (any reason) Identification Sponsorship source: not indicated Country: USA Setting: inpatients Authors name: Dufresne Institution: University of Rhode Island not available 35

36 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Address: Rhode Island Psychiatric Research and Training Center, Rhode Island, Department of Mental Health, Retardation, and Hospitals, Cranston, and the University of Rhode Island Department of Pharmacology and Toxicology, Kingston Authors' judgement Unclear risk Unclear risk Low risk Low risk High risk High risk Support for judgement Comment: randomized, no further details Comment: no details Comment: double blind Comment: double blind Other bias Low risk Comment: no other bias Evins 2001 Comment: high dropout rate; reasons not indicated Comment: last endpoint data not reported, CGI data not reported, reasons of do not indicated, sideeffects numbers not given, only statistical test Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 6 Number of Females: 3 Age (Mean, SD): 45.5 ± 7.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 5 Number of Females: 4 Age (Mean, SD): 42.7 ± 7.9 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Outpatients at an urban community mental health center with a diagnosis of schizophrenia who had been on a stable dose of antipsychotic medications for at least 4weeks, and who reported cigarette use greater than half a pack per day and a desire to quit smoking, were eligible for the study. A clinical diagnosis of schizophrenia was confirmed by unstructured interview and chart review(aee) using DSM-IV criteria Exclusion criteria: Subjects were excluded if they were experiencing acute exacerbation of psychosis, active co-morbid substance abuse, or bulimia, or if they had history of seizure disorder. Subjects with current 36

37 but not past major depressive episode were excluded. Concurrent treatment with other antidepressant medications was not exclusionary. Pretreatment: considerable difference in SANS at baseline! Interventions Intervention Characteristics Number Randomized: 9 Dose Antipsychotic: 14.5 mg/day haloperidol equiv Dose Antidepressant: 150 mg/day Duration of Trial (weeks): 12 Number Randomized: 9 Dose Antipsychotic: 13.5 mg/day haloperidol equiv Duration of Trial (weeks): 12 Outcomes HAM-D BPRS SANS Dropouts (any reason) Adverse events BPRS Positive Identification Sponsorship source: not industry, Company only provided medication Country: USA Setting: outpatients Authors name: Evins Institution: Massachusetts General Hospital a_eden_evins@hms.harvard.edu Address: Dr. A. Eden Evins, MD, Schizophrenia Research Program, Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114, USA. Tel: +1 (617) ; Fax: +1 (617) Risk of bias table Bias Authors' Support for judgement judgement Random sequence Unclear risk Comment: randomized, no further details generation (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind, identical capsules personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: one Dropout not reported, but this is only 5%, so unlikely that it would have impacted the results, but this is debatable Comment: side-effect scales not reported, one do not reported Selective reporting High risk (reporting bias) Other bias Low risk Comment: no other bias Evins 2005 Methods Study design: Randomized controlled trial Study grouping: Parallel group 37

38 Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 16 Number of Females: 9 Age (Mean, SD): 46.0 (9.4) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 20 Number of Females: 8 Age (Mean, SD): 45.5 (8.3) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Eligible participants were adults who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for schizophrenia or schizoaffective disorder depressed type, had stable symptoms and a stable dose of antipsychotic medication for 30 days, did not meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for current major depression, had baseline HAM-D score <20, smoked 10 or more cigarettes per day, and were willing to set a quit date within 4 weeks of the date of enrollment. Exclusion criteria: Subjects with seizure disorder, history of bulimia, and history of mania or substance abuse disorder other than nicotine or caffeine within 6 months of enrollment were not eligible. Subjects taking clozapine at a dose of >500 mg/d without an adequate dose of an anticonvulsant were also excluded. Although there is some evidence that bupropion may inhibit CYP2D6 activity, 18 subjects treated with medications dependent on CYP2D6 for their metabolism were not excluded. Interventions Intervention Characteristics Number Randomized: 26 Dose Antipsychotic: in CPZ equivalents: (164.7) Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 12 Number Randomized: 28 Dose Antipsychotic: in CPZ equivalents: (260.1) Duration of Trial (weeks): 12 Outcomes HAM-D PANSS total PANSS positive PANSS negative SANS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Adverse events Identification Sponsorship source: not industry, Company only provided medication Country: USA Setting: outpatients 38

39 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Authors name: Evins Institution: Massachusetts General Hospital Address: A. Eden Evins, MD, MPH, Massachusetts General Hospital Schizophrenia Program, 25 Stanford Authors' judgement Unclear risk Unclear risk Low risk Low risk Low risk Support for judgement Comment: randomized, no further details Comment: no details Comment: double blind Comment: double blind Selective reporting High risk (reporting bias) Other bias Low risk Comment: no other bias Comment: low dropout rate, evenly distributed; Dropouts reasons and Groups not reported, but low number, thus unlikely that they would have biased results Comment: EPS Rating scale results not reported Evins 2007 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 44.8 (9.2) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 43.6 (10.9) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Eligible participants were adults with schizophrenia by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria capacity to consent, stable psychiatric symptoms and antipsychotic dose for 30 days or more, smoked 10cigarettes or more per day for the past year, and were willing to set a smoking-quit date within 4 weeks of enrollment. 39

40 Exclusion criteria: Those with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for current major depressive disorder, Hamilton Rating Scale for Depression(HAM-D) score of greater than 19, or substance use disorder other than nicotine or caffeine within 6 months of screening were not eligible, nor were those taking bupropion or NRT in the prior month, those with seizure disorder and bulimia, or those on clozapine of more than500 mg/d without a therapeutic dose of an anticonvulsant Interventions Intervention Characteristics Number Randomized: 25 Dose Antipsychotic: not reported Dose Antidepressant: 300 mg/ day Duration of Trial (weeks): 12 Number Randomized: 26 Dose Antipsychotic: not reported Duration of Trial (weeks): 12 Outcomes HAM-D PANSS total SANS BAS SAS AIMS Dropouts (side effects) Dropouts (any reason) Adverse events Identification Sponsorship source: not industry sponsored, Company only provided pills Country: USA Setting: outpatients Authors name: Evins Institution: Massachusetts General Hospital a_eden_evins@hms.harvard.edu Address: A. Eden Evins, MD, MPH, Addiction Research Program, Massachusetts General Hospital, 25 Staniford Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate, evenly distributed Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias 40

41 Fatemi 2013 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: 7 Number of Females: 2 Age (Mean, SD): 41.4 ± 9.8 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 7 Number of Females: 2 Age (Mean, SD): 43 ± 8.44 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: all participants were regular smokers (at least 10 cigarettes per day), and expressed a motivation to either quit or reduce smoking. Subjects were also required to have no substance abuse within the previous three months, did not use other nicotine products (i.e., smokeless tobacco), and were not currently taking bupropion or varenicline. All participants received 20 min of anti-smoking counseling at each visit Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 9 Dose Antipsychotic: not reported Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 12 Number Randomized: 9 Dose Antipsychotic: not reported Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes BPRS SAPS SANS BAS SAS AIMS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis Adverse events Identification Sponsorship source: not industry sponsored, companies only provided medication Country: USA Setting: outpatients 41

42 Risk of bias table Bias Authors name: Fatemi Institution: Minnesota Medical School address: Address: Department of Psychiatry, Division of Neuroscience Research, Universityof Minnesota Medical School, 420 Delaware St. SE, MMC 392,Minneapolis, MN 55455, United States Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment (selection bias) Low risk Comment: Sugar pill created and masked by the pharmacy to be used as a control Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) High risk Comment: High dropout rate (one-third), not evenly distributed (one-third vs two-thirds) Selective reporting (reporting Unclear risk Comment: antipsychotic drugs not reported bias) Other bias Low risk Comment: no other bias Friedman 2005 Methods Participants Study design: Randomized controlled trial Study grouping: Crossover Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: To be eligible for this study, patients had to have been treated with a stable dose of an atypical antipsychotic for a minimum period of 4 weeks prior to entry. In addition, subjects were required to demonstrate a 4-week period of symptom stability (defined as no more than 20% change on consecutive ratings on the PANSS) 25 prior to baseline assessments. Exclusion criteria: Patients were excluded if they were actively abusing substances, had any medical diagnoses which may have affected cognitive performance, met criteria for a current episode of major depression or scored greater than 12on the Montgomery-Asberg 42

43 Depression Rating Scale26 or, were receiving treatment with anticholinergic or antidepressant medications. Interventions Intervention Characteristics Number Randomized: 10 Dose Antipsychotic: all SGAs, dose n.i Dose Antidepressant: 40 mg/day Duration of Trial (weeks): 12 Number Randomized: 9 Dose Antipsychotic: all SGAs, dose n.i Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) Dropouts (side effects) Adverse events Identification Sponsorship source: Industrial sponsor (Forest Lab.) Country: USA Setting: inpatients or outpatients Authors name: Joseph I. Friedman Institution: The Mount Sinai School of Medicine jfriedman1@ rcn.com Address: Department of Psychiatry, Mount Sinai School of Medicine, Box 1230,One Gustave L. Levy Place, New York, NY Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data Low risk Comment: low dropout rate (attrition bias) Selective reporting (reporting High risk bias) Other bias Low risk Comment: no other bias Comment: Montgomery-Asberg Depression Rating Scale not completely reported George 2002 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics 43

44 Number of Males: 10 Number of Females: 6 Age (Mean, SD): 45.4 (11.9) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 8 Number of Females: 8 Age (Mean, SD): 40.9 (9.4) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Subjects required an FTND score of 5 or higher, an expired CO level 10 parts per million (ppm) and plasma cotinine level 150 ng/ml at baseline evaluation for study inclusion. In addition, subjects needed to be clinically stable on psychotic and affective symptomatology before study entry. Schizophrenic subjects screened for this trial needed to express a strong desire to quit smoking at study baseline to participate, as assessed by clinical evaluation over three pre randomization assessment sessions and by a score of 3or higher on an assessment measure of self-reported motivation(a Likert scale rated 0 4) to stop smoking (George et al 2000a);available on request from Exclusion criteria: Schizophrenic subjects with a history of epilepsy or seizures were excluded from study participation, as were subjects with a history of alcohol/drug abuse or dependence (except nicotine and caffeine) in the 6 months before study entry Interventions Intervention Characteristics Number Randomized: 16 Dose Antipsychotic: 719 (500) CPZ equivalents (mg/day) Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 10 Number Randomized: 16 Dose Antipsychotic: 795 (576) CPZ equivalents (mg/day) Dose Antidepressant: placebo Duration of Trial (weeks): 10 Outcomes PANSS total PANSS positive PANSS negative AIMS Dropouts (any reason) Adverse events Identification Sponsorship source: grants, not industry, Company only provided medication Country: USA Setting: outpatients Authors name: Tony P. George Institution: Yale University School of Medicine not available Address: Tony P. George, M.D., Department of Psychiatry, YaleUniversity School of Medicine, Room S-109, Substance Abuse Center,Connecticut Mental Health Center, 34 Park Street, New Haven CT

45 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Authors' judgement Unclear risk Low risk Low risk Low risk Support for judgement Comment: randomized, no further details Comment: Study medications were prepared by research pharmacists at CMHC, using encapsulation of SR bupropion tablets with blue opaque capsules Comment: double blind Comment: double blind High risk Comment: dropouts not evenly distributed (12% vs 32%), no reasons for discontinuation provided High risk Comment: Endpoint data for PANSS Total not reported, dropout reasons not indicated Other bias Low risk Comment: no other bias George 2008 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 17 Number of Females: 12 Age (Mean, SD): 41.2 SD 9.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 18 Number of Females: 11 Age (Mean, SD): 39.3 SD 6.9 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Inclusion Criteria: DSM-IV diagnosis of schizophrenia or schizoaffective disorder and nicotine dependence Fagerstrom Test for Nicotine Dependence (FTND) score greater than 5 Smokes at least 20 cigarettes per day (1 pack per day) Expired breath CO level > 10 ppm and cotinine level > 210 ng/ml at the baseline measurement Currently taking a stable dose of antipsychotic Complete remission from positive symptoms of psychosis as judged by a psychiatric evaluation Exclusion criteria: Exclusion Criteria: Meets criteria for current abuse or dependence for any alcohol or illicit substance within the past month History of hypersensitivity to bupropion or the nicotine transdermal patch (NTP) Current diagnosis of a serious documented medical disorder that would make bupropion treatment risky OR results of 45

46 psychiatric/medical screening that suggest a reason for concern (e.g., a history of severe heart, liver, or kidney disease or diabetes mellitus) Currently taking monoamine oxidase inhibitors or bupropion (Zyban or Wellbutrin) Currently taking diabetes mellitus medications, St. John's Wort, appetite suppressants, ephedrine-containing medications, theophylline, clonidine, reserpine, methyldopa, or antianginal medications (e.g., beta-blockers, calcium channel blockers, nitroglycerin preparations) History of schizoaffective disorder and not stabilized on a mood stabilizer (e.g., lithium, valproate, carbamazepine) Interventions Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: CPZ equiv 472 mg/day SD 316 Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 10 Number Randomized: 29 Dose Antipsychotic: CPZ equiv 583 mg/day SD 440 Duration of Trial (weeks): 10 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) Exacerbation of psychosis Identification Sponsorship source: independent Country: Canada Setting: outpatients Authors name: Tony P. George Institution: Centre for Addiction and Mental Health (TPG), Faculty of Medicine, University of Toronto, Ontario, Canada Tony_George@camh.net. Address: Tony P. George, M.D., FRCPC, Professor and Chair in Addiction Psychiatry, University of Toronto, Faculty of Medicine, Centre for Addiction and Mental Health, 33 Russell Street, RS 4039, Toronto, Ontario Canada M5S 2S1 Risk of bias table Bias Authors' Support for judgement judgement Random sequence Unclear risk Comment: randomized, no further details generation (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) High risk High risk Comment: low overall dropout rate, but not evenly distributed between groups (16% versus 30%) with incomplete reasons Comment: no endpoint data for clinical scales provided no PANSS and BDI at endpoint reported 46

47 Other bias Low risk Comment: no other bias Goff 1995 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 18 Number of Females: 2 Age (Mean, SD): 42.2 SD 9.1 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 20 Number of Females: 1 Age (Mean, SD): 42.8 SD 9.4 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Patients had been treated with a stable dose of fluphenazine decanoate or haloperidol decanoate for at least 6months and had a total score on the Brief Psychiatric Rating Scale(BPRS) (Overall and Gorham 1962) of 30 or greater. Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: CPZ equiv 1132 SD 575 mg/day Dose Antidepressant: 20 mg/day Duration of Trial (weeks): 6 Number Randomized: 21 Dose Antipsychotic: CPZ equiv 922 SD 612 mg/day Duration of Trial (weeks): 6 Outcomes HAM-D BPRS SAS AIMS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis Adverse events BPRS Depression BPRS Positive BPRS Negative Identification Sponsorship source: independent (NIMH) and industry (Eli Lilly) Country: USA Setting: outpatients Authors name: Goff 47

48 Risk of bias table Bias Institution: Massachusetts General Hospital not available Address: D, C. Goff, Freedom Trail Clinic, 25 Staniford St., Boston MA 02114, USA Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: no incomplete data Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Han 2000 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 13 Number of Females: 5 Age (Mean, SD): 34.56(± 7.14) Duration of Illness (years): 11 SD 5 Number of Hospitalizations: not reported Number of Males: 10 Number of Females: 8 Age (Mean, SD): 35.00(± 6.33) Duration of Illness (years): 12 SD 6.5 Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria:, organic mental disorders, neurological diseases, a history of substance abuse, including alcohol, antidepressants and lithium or are taking within the last six months electroconvulsive therapy Intervention Characteristics Number Randomized: 24 Dose Antipsychotic: (±328.60) Dose Antidepressant: 20 mg/day Duration of Trial (weeks): 6 Number Randomized: 25 Dose Antipsychotic: (±596.61) Duration of Trial (weeks): 6 48

49 Outcomes BPRS HAM-D PANSS total PANSS positive PANSS negative Dropouts (any reason) CGI (severity) Identification Risk of bias table Bias Sponsorship source: not indicated Country: South Korea Setting: inpatients Authors name: Pyoung-Ju Han Institution: Wonkwang University School of Medicine not available Address: Department of Neuropsychiatry, Wonkwang University School of Medicine, Iksan Authors' judgement Low risk Support for judgement Random sequence generation (selection bias) Comment: randomized with a random number table Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: high dropout rate; only bias) completers were analyzed, no ITT Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Hanlon 1964 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 0 Number of Females: 28 Age (Mean, SD): 55 SD 9 Duration of Illness (years): 1.6 SD 0.75 Number of Hospitalizations: not reported Number of Males: 0 Number of Females: 29 Age (Mean, SD): 54 SD 8 Duration of Illness (years): 1.6 SD 0.92 Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported 49

50 Interventions Intervention Characteristics Number Randomized: 28 Dose Antipsychotic: 24mg/day Dose Antidepressant: 150mg/day Duration of Trial (weeks): 12 Number Randomized: 29 Dose Antipsychotic: 24mg/day Duration of Trial (weeks): 12 Outcomes Dropouts (any reason) Dropouts (side effects) Adverse events Identification Risk of bias table Bias Sponsorship source: Company (Merck Sharp) Country: USA Setting: inpatients Authors name: Hanlon Institution: Spring Grove State Hospital, Baltimore, Marlyland not available Address: Dr Hanlon, Spring Grove State Hospital, Baltimore, Marlyland Authors' judgement Unclear risk Support for judgement Random sequence generation Comment: randomized, no further details (selection bias) Allocation concealment (selection Low risk Comment: distributed by pharmacy in bias) identical containers Blinding of participants and High risk Comment: double blind, but ward personnel (performance bias) physicians aware of treatment Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Unclear risk Comment: Low drop-out (15%). Reasons bias) for dropout not all described. Selective reporting (reporting bias) Low risk Comment: no selective reporting; all predefined results are presented. Other bias Low risk Comment: no other bias Hayashi 1997 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 16 Number of Females: 10 Age (Mean, SD): 64.2 (7.0) Duration of Illness (years): 34.5 (12.2) Number of Hospitalizations: not reported 50

51 Number of Males: 7 Number of Females: 6 Age (Mean, SD): 59.9 (9.3) Duration of Illness (years): 33.1 (11.9) Number of Hospitalizations: not reported Inclusion criteria: met DSM-IV criteria for SCZ, according to a semistructured interview derived from the Structured Clinical Interview for DSM-III-R; ages over 50 years; duration of illness for at least 10 years; the present admission was for at least 1 year with patients demonstrating moderate-to-severe negative symptoms as assessed using PANSS; diagnosed with tardive dyskinesia using the criteria of Jeste and Wyatt. Exclusion criteria: if they had a suspected or definite organic psychiatric disorder (including dementia), neurological disorder (including seizures and Parkinson's disease) or a previous primary diagnosis of a major affective disorder; it they were currently receiving an antidepressant agent. Pretreatment: no significant difference in baseline characteristics Interventions Intervention Characteristics Number Randomized: 26 Dose Antipsychotic: 548 mg/d (SD: 354)chlorpromazine equivalent Dose Antidepressant: the mean dose of mianserin at week 5 was 58.5 mg/d (SD: 1.5) and that of trazodone was mg/d (SD: 7.7) Duration of Trial (weeks): 5 Number Randomized: 13 Dose Antipsychotic: 740 mg/d (SD: 531)chlorpromazine equivalent Dose Antidepressant: placebo Duration of Trial (weeks): 5 Outcomes BPRS SANS AIMS Dropouts (side effects) Dropouts (any reason) Adverse events BPRS Positive Identification Sponsorship source: no information Country: Japan Setting: inpatients Authors name: T. Hayashi, S. Yamawaki Institution: Hiroshima Seiyoin Hospital, Aki-gun no information Address: Kasumi, Minami-ku, Hiroshima 734, Japan Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) judgement Unclear risk 51 Comment: "randomly assigned" no further information

52 Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: low drop-out and reasons provided Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Hinkelmann 2013 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 25 Number of Females: 10 Age (Mean, SD): 40.5 (11.2) Duration of Illness (years): 12.4 (11.1) Number of Hospitalizations: not reported Number of Males: 9 Number of Females: 7 Age (Mean, SD): 38.3 (8.4) Duration of Illness (years): 9.7 (9.3) Number of Hospitalizations: not reported Inclusion criteria: diagnosed with SCZ according to DSM-IV, predominantly negative symptoms (scoring >=4 in at least 1 item of PANSS negative sub-sale, on stable antipsychotics for at least 2 weeks before inclusion Exclusion criteria: concurrent alcohol or substance abuse, other psychiatric or somatic disorders and abnormal laboratory findings Pretreatment: baseline imbalance in positive symptoms and depressive symptoms Interventions Intervention Characteristics Number Randomized: 35 Dose Antipsychotic: not reported Dose Antidepressant: Citalopram: 30mg (10.2); Reboxetine: 5.4mg (1.96) Duration of Trial (weeks): 4 Number Randomized: 16 Dose Antipsychotic: not reported Dose Antidepressant: placebo Duration of Trial (weeks): 4 Outcomes PANSS total PANSS positive 52

53 Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) PANSS negative HAM-D Dropouts (any reason) CGI (improv) Responders (25% reduction in the PANSS negative scale compared with baseline) Sponsorship source: independent Country: Germany Setting: no information Authors name: Kim Hinkelmann Institution: Department of Psychiatry and Psychotherapy, University of Hamburg; Department of Psychiatry and Psychotherapy, Charite Medical Center, Berlin Address: Department of Psychiatry and Psychotherapy, Charite Medical Center, Campus Benjamin Franklin, Eschenallee 3, Berlin Authors' judgement Low risk Low risk Low risk Low risk High risk Support for judgement Quote: "The randomization was organized using the PLAN procedure from the SAS/STAT software (SAS Institute Inc, Cary, NC)." Quote: "Allo- cation codes for each patient were provided in sealed envelopes through the pharmacy of the University of Hamburg," Comment: double blind Comment: double blind Comment: low drop-out (<25%), but NOT evenly distributed (see Table 1) and no reasons for drop out Comment: no UKU data Selective reporting High risk (reporting bias) Other bias High risk Comment: baseline imbalance in positive symptoms and depression Hogarty 1995 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported) Duration of Illness (years): not reported Number of Hospitalizations: not reported 53

54 Interventions Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Participants aged from 18 to 55 yrs, met Research Diagnostic Criteria for either schizophrenia or schizoaffective disorder at the time of their last psychotic episode, and had shown persistent distress or defect features for at least 3 months prior to the study. Exclusion criteria: not indicated Intervention Characteristics Number Randomized: 16 Dose Antipsychotic: not reported Dose Antidepressant: not indicated Duration of Trial (weeks): 12 Number Randomized: 17 Dose Antipsychotic: not reported Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes BPRS Dropouts Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Sponsorship source: NIMH grant, medication provided by Princeton Pharmaceuticals Country: USA Setting: inpatients and outpatients Authors name: G.E. Hogarty Institution: The Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine not indicated Address: not indicated Authors' judgement Unclear risk Unclear risk Low risk High risk 54 Support for judgement "randomly assigned" no further information no details Comment: double blind Incomplete outcome data Low risk (attrition bias) Selective reporting (reporting Low risk no selective reporting bias) Other bias Low risk no other bias "The same psychiatrist and nurse treated and assessed a patient throughout all relevant trials." no drop-outs

55 Iancu 2010 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 15 Number of Females: 5 Age (Mean, SD): 35.5 SD 8.7 Duration of Illness (years): 14.2 SD 9.5 Number of Hospitalizations: Number of Males: 14 Number of Females: 6 Age (Mean, SD): 38.8 SD 6.88 Duration of Illness (years): 13.8 SD 6.6 Number of Hospitalizations: Inclusion criteria: Eligibility criteria included the following: age of years, diagnosis of chronic schizophrenia, a total Positive and Negative Syndrome Scale (PANSS) score of 50 and stable treatment with antipsychotics. Exclusion criteria: Exclusion criteria included axis I comorbid disorders (Major Depressive Disorder (MDD) and mania), pregnancy, lactation, impaired renal or hepatic function and history of sensitivity to SSRIs. MDD was an exclusion criterion in order to ascertain that the improvement was not due to the abating of a depressive state. The diagnosis of depression was based on the presence of symptoms such as dysphoric mood and affect, morning evening variation and vegetative symptoms (characteristic of depression more than of negative symptoms).additional exclusion criteria included mental retardation, organic conditions (brain tumors and drug abuse) and recent exacerbation of the psychiatric condition (i.e. suicide attempt, severe psychotic exacerbation or hospitalization in high-security units). Patients were excluded from the study if they subsequently withdrew informed consent or if their state worsened according to the clinical judgment of the investigator or according to a Clinical Global Impression (CGI-I) score of condition much worsened. Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: Dose Antidepressant: 20 mg/day Duration of Trial (weeks): 10 Number Randomized: 20 Dose Antipsychotic: Dose Antidepressant: Duration of Trial (weeks): 10 55

56 Outcomes HAM-D PANSS total PANSS positive PANSS negative SANS AIMS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis CGI (severity) Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Sponsorship source: Lundbeck, industry sponsored Country: Israel Setting: inpatients or outpatients Authors name: Iancu Institution: Yavne Mental Health Center, 4 Dekel Street, Yavne, Israel iulian1@bezeqint.net Address: Corresponding author. Yavne Mental Health Center, 4 Dekel Street, Yavne, Israel. Tel.: ; fax: Authors' judgement Unclear risk Low risk Low risk Low risk Low risk Low risk Support for judgement Comment: randomized, no further details Comment: Patients were assigned their randomization number at the time of study initiation and the code was concealed in the pharmacy of our center in opaque sealed envelopes Comment: double blind Comment: double blind Comment: low dropout rate, evenly distributed between groups Comment: no selective reporting Other bias Low risk Comment: no other bias Izakova 2009 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Open Label: YES Intention-to-treat data: no Baseline Characteristics Number of Males: 1 56

57 Number of Females: 26 Age (Mean, SD): 44.92,10.40 Duration of Illness (years): 10.9 SD 9.48 Number of Hospitalizations: not reported Number of Males: 1 Number of Females: 26 Age (Mean, SD): 41.92, Duration of Illness (years): SD Number of Hospitalizations: not reported Inclusion criteria: men and women aged 18 to 65hospitalised for schizoaffective disorder, depressed type, diagnosed by ICD 10 and DSM-V first or recurrent episode, relapse or gradual decompensation. PANSS negative symptoms sub-score had to be higher than the positive subscore, CDSS had to be 5 at the initial assessment Exclusion criteria: current therapy with depot AP, women in childbearing age without reliable contraception, any other mental disorder (other than schizoaffective depressed type), ECT, history of inefficacy of the used study medication serious or unstable study medication Interventions Intervention Characteristics Number Randomized: 27 Dose Antipsychotic: 4.15 mg/day (SD 3.38) Dose Antidepressant: mg/day (SD 38.47) Duration of Trial (weeks): 12 Number Randomized: 27 Dose Antipsychotic: 3.29 mg/day (SD 1.51) Dose Antidepressant: no treatment Duration of Trial (weeks): 12 Outcomes Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis Identification Sponsorship source: no information Country: Slovakia Setting: inpatients or outpatients Authors name: Izakova Institution: Psychiatric Clinic Faculty of Medicine Comenius University and Faculty Hospital Bratislava ahalaris@lumc.edu Address: Angelos HalarisDepartment of Psychiatry and Behavioral Neursciences, LoyolaUniversity Medical Center2160 S.First Ave. Buildíng 105 Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) judgement Low risk Comment: The randomization codes were assigned using the method of random number selection 57

58 Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and High risk Comment: open label personnel (performance bias) Blinding of outcome High risk Comment: open label assessment (detection bias) Incomplete outcome data (attrition bias) High risk Comment: high dropout rate, not evenly distributed Selective reporting (reporting High risk Comment: means and SDs not reported bias) Other bias Low risk Comment: no other bias Jasovic Gasic 1997 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 37 Dose Antipsychotic: not reported Dose Antidepressant: 162,5 mg/day Duration of Trial (weeks): 4 Number Randomized: 15 Dose Antidepressant: not reported Duration of Trial (weeks): 4 Outcomes HAM-D Dropouts (any reason) Identification Sponsorship source: not indicated Country: Serbia Setting: inpatients Authors name: Jasovic-Gasic Institution: Wonkwang University School of Medicine not available 58

59 Risk of bias table Bias Address: not indicated Authors' judgement Unclear risk Support for judgement Random sequence generation Comment: randomized, no further details (selection bias) Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data Low risk Comment: no dropouts (attrition bias) Selective reporting (reporting High risk Comment: BPRS not reported, baseline data bias) not reported Other bias Unclear risk Comment: only Abstract is available, some additional information was obtained from the authors Jockers Scherubl 2005 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 4 Number of Females: 7 Age (Mean, SD): 40.0 SD 6.8 Duration of Illness (years): 9.9 SD 8.3 Number of Hospitalizations: not reported Number of Males: 8 Number of Females: 6 Age (Mean, SD): 40.8 SD 11.8 Duration of Illness (years): 9.9 SD 7.4 Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Intervention Characteristics Number Randomized: 14 Dose Antipsychotic: CPZ equiv 438.5± Dose Antidepressant: 30mg/day Duration of Trial (weeks): 12 Number Randomized: 15 Dose Antipsychotic: CPZ equiv ± Dose Antidepressant: not reported 59

60 Duration of Trial (weeks): 12 Outcomes HAM-D PANSS positive PANSS negative BAS SAS AIMS Dropouts (any reason) Dropouts (side effects) Adverse events Identification Risk of bias table Bias Sponsorship source: The study was supported as an investigator initiated trial by GlaxoSmithKline Country: Germany Setting: outpatients Authors name: Jockers-Scherübl Institution: Charite University Medicine Berlin Address: Dr Maria C. Jockers-Scheru bl, Klinik für Psychiatrie und Psychotherapie, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, D Berlin, Germany. Tel: ; fax: Authors' judgement Unclear risk Support for judgement Random sequence generation (selection bias) Comment: randomized, no further details Allocation concealment (selection Unclear risk Comment: No details presented. bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Unclear risk Comment: Low drop-out; distribution bias) unclear, reasons unclear. Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Joffe 2009 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 11 Number of Females: 9 Age (Mean, SD): (9.24) Duration of Illness (years): (9.08) Number of Hospitalizations: not reported 60

61 Number of Males: 9 Number of Females: 10 Age (Mean, SD): (9.68) Duration of Illness (years): (9.43) Number of Hospitalizations: not reported Inclusion criteria: The inclusion criteria were: in-/outpatients, aged 18 to 65 years, diagnosed with schizophrenia or schizoaffective disorder (depressive type) (DSM-IVTR;APA, 2000), presence of positive or negative symptoms or both, resulting in the illness of at least moderate severity ( 4on the Clinical Global Impression (CGI) severity scale) (Guy,1976); and the clinical condition which had remained unchanged during 6 previous weeks. The patients had to receive 1 FGAs at a daily dose of 400 mg chlorpromazine equivalents, which had remained unchanged for 6 previous weeks (8 weeks for depot FGAs). Exclusion criteria: Exclusion criteria were: a previous lack of response to an add-on antidepressant with affinity to 5HT2, current SGA, a history of non-response to any SGA, a serious medical condition, (in order to avoid a possible exacerbation of the illness provoked by the antidepressant) a history of bipolar or schizoaffective disorder, bipolar type; substance misuse, expected poor compliance, suicidality, treatment with any antidepressant, mood stabilizer, buspiron or triptan, any antipsychotics other than those currently in use within previous 6 weeks, regular use of benzodiazepines (unless necessary) or accidental use of benzodiazepines in daily doses of 30 mg of diazepam equivalents, and (for fertile females)pregnancy, lactation, or inability/unwillingness to use contraception. Interventions Intervention Characteristics Number Randomized: 20 Dose Antipsychotic: CPZ equiv (123.53) mg/ day Dose Antidepressant: 30mg/day Duration of Trial (weeks): 6 Number Randomized: 21 Dose Antipsychotic: CPZ equiv (164.87) mg/ day Dose Antidepressant: Duration of Trial (weeks): 6 Outcomes SAS PANSS total PANSS positive PANSS negative Dropouts (any reason) Adverse events CGI (improv) CGI (severity) Responders (those with 20% decrease on the total PANSS scores) Identification Sponsorship source: grant from the Stanley Medical Research Institute (SMRI), Bethesda, Maryland USA. Country: Russia Setting: inpatients or outpatients 61

62 Risk of bias table Bias Random sequence generation (selection bias) Authors name: Joffe Institution: Helsinki University Central Hospital Address: Department of Psychiatry, Helsinki University Central Hospital, Välskärinkatu 12, FI Helsinki, Finland. Tel.: , (mobile) Authors' judgement Low risk Support for judgement Comment: Randomized. "Blocked randomization was performed with a randomization table. Thick envelopes with randomization codes were open only when the database was closed." Comment: Thick envelopes with randomization codes were open only when the database was closed Comment: double blind Allocation concealment Low risk (selection bias) Blinding of participants Low risk and personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome Low risk Comment: Only one Drop-out. Reasons for Dropout data (attrition bias) described. Selective reporting High risk Comment: Not all predefined results are presented, (reporting bias) especially SD s (FU) are missing. Other bias Low risk Comment: no other bias Johnson 1981 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 30.6 SD 9.4 Duration of Illness (years): not reported Number of Hospitalizations: 3.6 Number of Males: not reported Number of Females: not reported Age (Mean, SD): 30.6 SD 9.4 Duration of Illness (years): not reported Number of Hospitalizations: 3.2 Inclusion criteria: chronic SCZ patients diagnosed on the basis of positive Feighner or Schneiderian symptoms, who met the criteria of depression (BDI score of 15 or more); in a steady mental state, free from EPS. Exclusion criteria: BPRS (total score >5, excluding depression) were excluded at onset or at the end of third and fifth week. 62

63 Interventions Intervention Characteristics Number Randomized: 25 Dose Antipsychotic: not reported Dose Antidepressant: mg/day Duration of Trial (weeks): 5 Number Randomized: 25 Dose Antipsychotic: not reported Duration of Trial (weeks): 5 Outcomes HAM-D Dropouts (any reason) Adverse events Responders (HAM-D score <5 (those with good improvement at Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) the endpoint)) Sponsorship source: the North Manchester General Hospital and University Hospital of South Manchester.all drugs and placebo were provided by Lundbeck Ltd. Country: UK Setting: inpatients Authors name: D. A. W. Johnson Institution: University Hospital of South Manchester no information Address: West Didsbury, Manchester M20 8LR Authors' judgement Unclear risk Unclear risk Low risk Low risk Support for judgement Comment: "randomly distributed" no further information Comment: No description Comment: double blind Comment: double blind Low risk Comment: "The study was continued until 25 patients in each group completed a five week period of assessment." High risk Comment: Hamilton Scale scores not reported. "The BPRS was completed at onset and was repeated at the end of the third and fifth weeks." NO DATA Other bias Low risk Comment: no other bias Jungerman 1999 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes 63

64 Participants Baseline Characteristics Number of Males: 4 Number of Females: 4 Age (Mean, SD): 37 (7.1) Duration of Illness (years): 15 (6) Number of Hospitalizations: 3.3 (2.2) Number of Males: 4 Number of Females: 4 Age (Mean, SD): 34.4 (6.5) Duration of Illness (years): 13 (5) Number of Hospitalizations: 3.5 (2.0) Inclusion criteria: Participants in this study were maintained on stable antipsychotic treatment with standard medications for the previous 3 months with relative clinical stability but still manifesting residual symptomatology (baseline Positive and Negative Syndrome Scale [PANSS] Negative Symptoms subscale score of at least 15, which is reasonable if taking into account a partial medication effect). Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 8 Dose Antipsychotic: CPZ equiv 390 (240) mg day Dose Antidepressant: 15 mg/day Duration of Trial (weeks): 8 Number Randomized: 8 Dose Antipsychotic: Z equiv 330 (120) mg day Duration of Trial (weeks): 8 Outcomes HAM-D PANSS total PANSS positive PANSS negative BPRS AIMS Dropouts (any reason) CGI (improv) Identification Sponsorship source: University, Company provided medication Country: Israel Setting: outpatient Authors name: Jungerman Institution: Technion-Israel Institute of Technology, Haifa, Israel not available Address: Ehud Klein, MD, Department of Psychiatry, Rambam Medical Center, Haifa 31096, Israel. Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details 64

65 Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: no dropouts Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Kasckow 2001 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 9 Number of Females: 0 Age (Mean, SD): 65.4 (12.7) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 10 Number of Females: 0 Age (Mean, SD): 59.2 (8.2) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: physically and psychologically stable Exclusion criteria: alcohol or drug abuse, head injury, co-morbid psychiatric disorder Interventions Intervention Characteristics Number Randomized: 9 Dose Antipsychotic: not reported Dose Antidepressant: 20-40mg/day Duration of Trial (weeks): 10 Number Randomized: 10 Dose Antipsychotic: not reported Duration of Trial (weeks): 10 Outcomes HAM-D PANSS total Dropouts (any reason) Dropouts (inefficacy) Adverse events CGI (improv) Identification Sponsorship source: NIH, VA Country: USA Setting: inpatients 65

66 Risk of bias table Bias Authors name: Kasckow Institution: University of Cincinati Address: Authors' judgement Unclear risk Support for judgement Random sequence generation (selection bias) Comment: randomized, no further details Allocation concealment (selection Unclear risk Comment: No description. bias) Blinding of participants and personnel High risk Comment: single blind (performance bias) Blinding of outcome assessment High risk Comment: single blind (detection bias) Incomplete outcome data (attrition Low risk Comment: Low drop-out. Reasons for bias) Drop-out described. Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Kim 1997 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 32 Number of Females: 13 Age (Mean, SD): 36.8 (10.7) Duration of Illness (years): 11.6 (6.5) Number of Hospitalizations: not reported Number of Males: 20 Number of Females: 12 Age (Mean, SD): 34.5 (6.9) Duration of Illness (years): 10.3 (6.6) Number of Hospitalizations: not reported Inclusion criteria: not available Exclusion criteria: not available Intervention Characteristics Number Randomized: 45 Dose Antipsychotic: 25.2 (14.2) Haloperidol equivalents Dose Antidepressant: 20-40mg/day Duration of Trial (weeks): 6 Number Randomized: 32 Dose Antipsychotic: 23.5 (10.7) Haloperidol equivalents Duration of Trial (weeks): 6 66

67 Outcomes HAM-D BPRS PANSS positive PANSS negative Identification Risk of bias table Bias Sponsorship source: not available Country: South Korea Setting: not available Authors name: Jin Mee Kim Institution: Seoul National Mental Health Hospital not available Address: not available Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned", no further information Allocation concealment (selection bias) Unclear risk Comment: No description. Blinding of participants and personnel High risk Comment: single blind (performance bias) Blinding of outcome assessment High risk Comment: single blind (detection bias) Incomplete outcome data (attrition Unclear risk Comment: insufficient information bias) Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Korsgaard 1986 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Crossover Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 56.8 Duration of Illness (years): 17.9 Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 56.8 Duration of Illness (years): 17.9 Number of Hospitalizations: not reported Inclusion criteria: Patients with a total score of at least 5 on a rating scale for parkinsonian symptoms(see evaluations) were included Exclusion criteria: not reported Intervention Characteristics Number Randomized: 8 67

68 Dose Antipsychotic: CPZ equiv: 653 mg/day Dose Antidepressant: 60 mg/day Duration of Trial (weeks): 3 Number Randomized: 8 Dose Antipsychotic: CPZ equiv: 653 mg/day Duration of Trial (weeks): 3 Outcomes Dropouts (any reason) Identification Sponsorship source: Country: Denmark Setting: inpatients Authors name: Soren Koorsgard Institution: Sct. Hans Hospital, Roskilde not available Address: not available Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection Unclear risk Comment: randomized, no details bias) Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: no dropouts bias) Selective reporting (reporting bias) High risk Comment: only data at the end of all phases is given Other bias Low risk Comment: no other bias Kramer 1989 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 37.6 (2.0) Duration of Illness (years): 14.9 (1.8) Number of Hospitalizations: 11.6 (4.0) Number of Males: not reported Number of Females: not reported Age (Mean, SD): 35.4 (2.1) Duration of Illness (years): 14.0 (1.6) Number of Hospitalizations: 9.7 (2.4) 68

69 Inclusion criteria: ages of 18 and 60 years; who initially met criteria for long-standing SCZ and subsequently met research diagnostic criteria for a current episode of schizoaffective disorder (mainly schizophrenic) with a depressive syndrome, and who scored at least 30 on BPRS and 17 on HRSD. Exclusion criteria: who had continuous drug or alcohol abuse, nontrivial systemic or neurologic diseases, or any prior primary diagnosis indicating a major affective disorder. Interventions Intervention Characteristics Number Randomized: 44 Dose Antipsychotic: Haloperidol: 30.4 mg/d (SD: 3.2) Dose Antidepressant: Tricyclic: mg/d (SD: 13.9) Duration of Trial (weeks): 4 Number Randomized: 22 Dose Antipsychotic: Haloperidol: 29.1 mg/d (SD: 3.3) Dose Antidepressant: Placebo: mg/d (SD: 9.8) Duration of Trial (weeks): 4 Outcomes HAM-D BPRS Dropouts (any reason) Dropouts (side effects) Identification Risk of bias table Bias Exacerbation of psychosis Sponsorship source: no information Country: USA Setting: inpatients Authors name: Mark S. Kramer Institution: Department of Psychiatry and Human Behavior, Jefferson Medical College, Thomas Jefferson University no information Address: Coatesville Veterans Administration Medical Center, Coatesville, PA 19320, USA Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned" no further information Allocation concealment Unclear risk Comment: no description (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: low drop-out and evenly distributed and reasons provided Selective reporting (reporting bias) High risk Comment: no number of participants per group reported, dropout for individual groups not reported Other bias Low risk Comment: no other bias 69

70 Kurland 1981 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 19 to 53 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 19 to 53 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: diagnosed as SCZ, free of physical complications and had a score of 18 or above on the HAMD, age ranged from 19 to 53 years; had been stabilized for a period of two weeks or longer on a constant dosage of either chlorpromazine or haloperidol. Exclusion criteria: pregnant females; patients demonstrating significant physical disease; patients with epilepsy, mental retardation, senility, organic brain disease, or a history of alcohol or drug abuse; patients who have received another investigational drug within 14 days; patients exhibiting sensitivity to any of the inhibitors within 14 days of starting this study; or patients who had been treated with an antiparkinsonian agent. Also, during the course of the study, if a patient required treatment with an antiparkinsonian medication, the patient was dropped from the study Interventions Intervention Characteristics Number Randomized: 13 Dose Antipsychotic: haloperidol: 6 to 15 mg; chlorpromazine: 75 to 300 mg Dose Antidepressant: 225 mg/day Duration of Trial (weeks): 4 Number Randomized: 15 Dose Antipsychotic: haloperidol: 6 to 15 mg; chlorpromazine: 75 to 300 mg Dose Antidepressant: placebo Duration of Trial (weeks): 4 Outcomes Dropouts (any reason) Responders (any degree of improvement) Identification Sponsorship source: no information Country: USA Setting: no information Authors name: Albert A. Kurland 70

71 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Institution: the Maryland Psychiatric Research Center, Institute of Psychiatry, School of Medicine, University of Maryland no information Address: Baltimore, Md Authors' judgement Unclear risk Unclear risk Low risk Low risk Support for judgement Comment: randomized, no further details Comment: no details Comment: double blind Comment: double blind Low risk Comment: low drop-out (less than 25%), evenly distributed between group, reasons provided High risk Comment: no BPRS, HAMD, CGI and Zung- SRDS data Selective reporting (reporting bias) Other bias Low risk Comment: no other bias Lee 1997 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Intervention Characteristics Number Randomized: 19 Dose Antipsychotic: not reported Dose Antidepressant: 20 mg/day Duration of Trial (weeks): 8 Number Randomized: 19 71

72 Dose Antipsychotic: not reported Duration of Trial (weeks): 8 Outcomes Dropouts (any reason) Identification Risk of bias table Bias Sponsorship source: unclear Country: South Korea Setting: unclear Authors name: Lee Institution: Korea University Address: Department of Psychiatry, College of Medicine, Korea University, Seoul Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Unclear risk Comment: dropouts not reported Selective reporting (reporting bias) High risk Comment: no outcomes reported Other bias Unclear risk Comment: insufficient information Lee 1998 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 10 Number of Females: 8 Age (Mean, SD): 40.1 (8.2) Duration of Illness (years): 10.1 (6.5) Number of Hospitalizations: not reported Number of Males: 10 Number of Females: 8 Age (Mean, SD): 49.7 (9.9) Duration of Illness (years): 10.8 (6.1) Number of Hospitalizations: not reported Inclusion criteria: Clinically significant positive or negative symptoms such as delusion, hallucination, or blunted affect, despite good compliance with their treatment regimens at least 2 years before the study, were prerequisites for inclusion in this study. Also, we selected 72

73 patients without depression according to the Hamilton Rating Scale for Depression (rating less than 10) and extrapyramidal symptoms as measured by the Simpson-Angus Extrapyramidal Effects (S-A) Scale(rating less than 5) to exclude secondary negative symptoms Exclusion criteria: Patients were excluded if they had known organic syndromes, mental retardation, mood disorder, or any active major medical problems. Subjects were included only after giving written informed consent, and they were free to withdraw from the study for any reason at any time. Interventions Intervention Characteristics Number Randomized: 18 Dose Antipsychotic: 19.2 (13.5) mg/day Dose Antidepressant: 50 mg/day Duration of Trial (weeks): 8 Number Randomized: 18 Dose Antipsychotic: 21.9 (15.4) mg/day Duration of Trial (weeks): 8 Outcomes PANSS total PANSS positive PANSS negative SAS Dropouts (inefficacy) Exacerbation of psychosis Identification Risk of bias table Bias CGI (improv) Sponsorship source: Country: South Korea Setting: inpatients Authors name: Lee Institution: Department of Psychiatry, College of Medicine, Korea University leeminso@unitel.co.kr. Address: Min Soo Lee, MD, Department of Psychiatry,College of Medicine, Korea University, 126-1, 5-Ka, Anam-Dong, Sungbuk-Ku, Seoul, , Korea Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no details (selection bias) Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) High risk Comment: no information about overall dropout rate Selective reporting (reporting bias) High risk Comment: no selective reporting Other bias Low risk Comment: no other bias 73

74 Lu 2004 Methods Study design: Randomized controlled trial Study grouping: Parallel group Open Label: YES Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 10 Number of Females: 24 Age (Mean, SD): 32.9 (8.5) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 10 Number of Females: 24 Age (Mean, SD): 35.1 (9.4) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: aged 18 to 60 years, meeting the DSM-IV diagnosis of SCZ, treatment-resistant to typical antipsychotics Exclusion criteria: receiving clozapine or other atypical antipsychotics prior to initiation of clozapine treatment; pretreated with depot antipsychotics for at least 6 months before study entry. Patients with an Axis I diagnosis other than SCZ or with a medical or neurologic illness Pretreatment: The co-administration group had significantly lower plasma levels of nor-clozapine and clozapine N-oxide. Interventions Intervention Characteristics Number Randomized: 34 Dose Antipsychotic: ± 56.3 mg/day Dose Antidepressant: 50 mg/day Duration of Trial (weeks): 12 Number Randomized: 34 Dose Antipsychotic: ± mg/day Dose Antidepressant: no treatment Duration of Trial (weeks): 12 Outcomes Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis Adverse events CGI (improv) Identification Sponsorship source: independent (grants) Country: Taiwan Setting: inpatients Authors name: Mong-Liang Lu, Hsien-Yuan Lane Institution: Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei hylane@pchome com tw 74

75 Address: No. 2 Yuh-Der Road, Taichung 404, Taiwan Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomized" no further information Allocation concealment (selection bias) Unclear risk Comment: no description Blinding of participants and personnel (performance bias) High risk Comment: single blind; "openlabel" Blinding of outcome assessment (detection bias) Unclear risk Comment: single blind, no further details Incomplete outcome data (attrition bias) Low risk Comment: no dropouts Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Mico 2011 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 13 Number of Females: 7 Age (Mean, SD): 35.9 ± 7.1 Duration of Illness (years): 6.8± 3.1 Number of Hospitalizations: not reported Number of Males: 11 Number of Females: 9 Age (Mean, SD): 34± 6.8 Duration of Illness (years): 6.1± 3.2 Number of Hospitalizations: not reported Inclusion criteria: demonstrated persistent positive and negative symptoms despite an adequate trial of clozapine were included in this study. Patients scoring 25 or more on the brief psychiatric rating scale (Overall and Gorham, 1962) at both the screening and baseline evaluation were classified as partial responders or non-responders Exclusion criteria: The criteria for exclusion were primary or secondary diagnosis of bipolar disorder, either manic or mixed episode, as defined by Diagnostic and Statistical Manual and Mental Disorder-IV Text Revision; active suicide intent, or a suicide attempt in the preceding 6 months; significant concurrent medical illnesses, organic brain disease, dementia, or a traumatic brain injury; history of substance and alcohol dependence (excluding nicotine),mental retardation, and pregnant or lactating women were excluded. Women of childbearing potential were required to have a negative pregnancy test at the screening, and to practice a medically acceptable method of contraception. Intervention Characteristics 75

76 Number Randomized: 20 Dose Antipsychotic: ± 66.7 mg/day Dose Antidepressant: 60mg/day Duration of Trial (weeks): 16 Number Randomized: 20 Dose Antipsychotic: ± 67.2 mg/day Duration of Trial (weeks): 16 Outcomes CDRS PANSS total PANSS positive PANSS negative BPRS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Adverse events Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Sponsorship source: University Country: Italy Setting: outpatients Authors name: Mico Institution: Universitario Via Consolare Valeria, Messina Italy Address: Department of Neurosciences, Psychiatric and Anesthesiological Sciences, Policlinico Universitario Via Consolare Valeria, Messina Italy Authors' judgement Low risk Low risk Low risk Low risk Support for judgement Comment: Randomized: "Randomization automated system on a 1:1 basis. The randomization list was held securely throughout the study, and released only after study completion." Comment: The randomization list was held securely throughout the study, and released only after study completion. Comment: double blind Comment: double blind Low risk Comment: Low drop out (15% vs. 20%). Reasons for drop-out are provided. Low risk Comment: no selective reporting; All predefined results are presented. Other bias Low risk Comment: no other bias Mulholland 1998 Methods Study design: Randomized controlled trial 76

77 Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 7 Number of Females: 6 Age (Mean, SD): 39.3 (12.0) Duration of Illness (years): 16.7 (10.3) Number of Hospitalizations: 7.7 (12.9) Number of Males: 9 Number of Females: 4 Age (Mean, SD): 37.0 (10.4) Duration of Illness (years): 14.7 (10.4) Number of Hospitalizations: 4.9 (5.4) Inclusion criteria: meeting the DSM-III-R criteria for chronic SCZ, no changes to their antipsychotic or anticholinergic medication in the previous 2 months, currently outpatients, had no admissions to hospital in the previous 6 months, with a score of three or greater on the depression item of BPRS and a score of 15 or greater on BDI Exclusion criteria: if they had received antidepressant therapy or ECT in the previous 2 months or were currently receiving an antidepressant, lithium, clozapine or a benzodiazepine, other than as an hypnotic. Patients with a history of an adverse reaction to an SSRI, organic brain disorder, alcohol or drug abuse or an acute or poorly controlled systemic illness were also excluded. Patients with a score of 10 or greater on ESRS and a score of three or greater on the global item of BAS were excluded. Pretreatment: The placebo group and the sertraline group did NOT differ significantly with respect to any demographic or treatment variables (Table 1) Interventions Intervention Characteristics Number Randomized: 13 Dose Antipsychotic: CPZ equiv 400 (395) mg/day Dose Antidepressant: 75 mg/day Duration of Trial (weeks): 8 Number Randomized: 13 Dose Antipsychotic: CPZ equiv 290 (179) mg/day Dose Antidepressant: placebo Duration of Trial (weeks): 8 Outcomes HAM-D BPRS SANS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Adverse events BPRS Depression Responders (Patients with CGI-Improvement scores of minimally, much or very much improved were categorized as responders) 77

78 Identification Risk of bias table Bias Random sequence generation (selection bias) Sponsorship source: Company (Pfizer and Invicta) Country: UK Setting: outpatients Authors name: Ciaran Mulholland, Stephen J. Cooper Institution: Department of Mental Health, Queen's University Belfast Address: Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK Authors' judgement Low risk Support for judgement Quote: "Patients who met entry criteria on both occasions were randomized to double-blind treatment with sertraline or placebo using a computer generated list of" Comment: randomized to double-blind treatment with sertraline or placebo using a computer generated list of numbers Comment: no description Allocation concealment Unclear risk (selection bias) Blinding of participants Low risk Comment: double blind and personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data High risk Comment: high dropout rate, not evenly distributed (attrition bias) Selective reporting High risk Comment: result from BAS not reported (reporting bias) Other bias Low risk Comment: no other bias Niitsu 2012 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 14 Number of Females: 9 Age (Mean, SD): 38.6 (9.5) Duration of Illness (years): 12.3 (9.3) Number of Hospitalizations: not reported Number of Males: 15 Number of Females: 9 Age (Mean, SD): 36.3 (9.4) Duration of Illness (years): 10.8 (7.5) Number of Hospitalizations: not reported 78

79 Inclusion criteria: The inclusion criteria were subjects who (1) were aged 20 to 59 years, eliminating the possibility of including patients with dementia; (2) were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia, confirmed by the Structured Clinical Interview for DSM-IV; and (3) had been receiving monotherapy with a stable dose of an atypical antipsychotic drug for at least 8 weeks before study entry. Enrolled patients were required to receive a fixed dose and type of an atypical antipsychotic drug throughout the trial. Exclusion criteria: Exclusion criteria were subjects who (1) had cognitive disorders besides schizophrenia (e.g., dementia), (2) were pregnant or breast feeding women, (3) had a history of manic state, (4) had other DSM-IV Axis I or II comorbidities, and (5) had unstable DSM IV Axis III comorbidities, for example, diabetes mellitus. Pretreatment: PANSS 78.0 (11.0) 71.1 (10.3) Interventions Intervention Characteristics Number Randomized: 24 Dose Antipsychotic: Risperidone equiv: 4.8 (2.9) mg/day Dose Antidepressant: 87.5 mg/d Duration of Trial (weeks): 8 Number Randomized: 24 Dose Antipsychotic: Risperidone equiv: 5.5 (3.6) mg/day Duration of Trial (weeks): 8 Outcomes MARDS PANSS total SANS QLS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Adverse events Identification Sponsorship source: University Country: Japan Setting: outpatients Authors name: Niitsu Institution: University Center for Forensic Mental Health, Inohana, Chiba hashimoto@faculty.chiba-u.jp Address: Kenji Hashimoto, PhD, Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Inohana, Chiba , Japan Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) judgement Low risk Comment: Randomized. "Randomization procedure established by UMIN. Participants who signed the informed consent form and who were eligible according to the inclusion/exclusion criteria were randomly assigned to the fluvoxamine or placebo groups in a 1:1 ratio."; "We used 79

80 Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Low risk Low risk Low risk Low risk Low risk Other bias Low risk Comment: no other bias computer-generated randomization sequences and a central registration system established by the biostatistician in UMIN. Randomization was performed with the minimization method, and the allocation factors were sex and type of atypical antipsychotic medication. Until the trial was concluded, the randomization sequence was available only to a dispensing doctor and a pharmacist at Chiba University Hospital, whose only role was to dispense medication." Comment: Until the trial was concluded, the randomization sequence was available only to a dispensing doctor and a pharmacist at Chiba University Hospital, whose only role was to dispense medication Comment: DB. In response to a randomization request, a dispensing doctor received a code number from UMIN and prescribed a blinded trial medication to a participant. Blinding to participants, care providers, and those assessing outcomes was successful." Comment: DB. "In response to a randomization request, a dispensing doctor received a code number from UMIN and prescribed a blinded trial medication to a participant. Blinding to participants, care providers, and those assessing outcomes was successful." Comment: Low drop-out (n=4). Reasons for drop-out presented Comment: no selective reporting all predefined results are presented. Omranifard 2012 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 13 Number of Females: 14 Age (Mean, SD): 33.4 ± 6.9 Duration of Illness (years): <1 year: 18, 1-5 years: 5, >5 years: 4 Number of Hospitalizations: None: 5, 1 time: 9, >=2 times: 13 Number of Males: 14 Number of Females: 13 Age (Mean, SD): 34.7 ± 10.2 Duration of Illness (years): <1 year: 6, 1-5 years: 9, >5 years: 12 Number of Hospitalizations: None: 8, 1 time: 8, >=2 times: 11 Inclusion criteria: diagnosed with post-psychotic depressive disorder of SCZ (DSM-IV-TR) or clinically significant sub-syndromal depressive symptoms with a diagnosis of SCZ before, aged years, receiving a 80

81 stable dose of atypical antipsychotics, clinically stable defined as a period of at least one month maintaining a score of at least 4 or less on all positive symptoms of PANSS. Exclusion criteria: any serious medical condition that interfere with safe study participation; any substance abuse or dependency except nicotine; pregnancy or nursing in women; using any psychotropic drugs except atypical antipsychotics. Pretreatment: The only significant difference was that subjects assigned to the placebo group were more likely to have a more prolonged illness (p = 0.004) Interventions Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: not reported Dose Antidepressant: started sertraline at 50 mg/d and the dose was raised to 100 mg/d after 4 weeks, and 200 mg/d after 8 weeks if partial response was not seen Duration of Trial (weeks): 12 Number Randomized: 30 Dose Antipsychotic: not reported Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes CDRS Dropouts (any reason) Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Dropouts (side effects) Sponsorship source: independent (university) Country: Iran Setting: inpatients or outpatients Authors name: Victoria Omranifard, Mohammad Reza Sharbafchi Institution: Department of Psychiatry, Behavioral Sciences Research Center and Student Research Committee, Isfahan University of Medical Sciences sharbafchi@yahoo.com Address: no information Authors' judgement Unclear risk Unclear risk Low risk Low risk Support for judgement Comment: "randomized" no further information Comment: no details Comment: double blind Comment: double blind 81

82 Incomplete outcome data (attrition bias) Low risk Selective reporting Low risk (reporting bias) Other bias Low risk Comment: no other bias Poyurovsky 2002 Quote: "taking a trip (1 patient) and drug side effects including sedation and gastrointestinal disturbances (2 patients) (Figure 1)." Comment: low dropout rate, evenly distributed Quote: "However, 3 patients were eliminated from the placebo group since one did not answer the phone, one s family refused to continue the treatment, and one had poor compliance. Similarly, 3 patients were eliminated from the sertraline group" Comment: no selective reporting Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Participants Baseline Characteristics Number of Males: 21/2 Number of Females: 9/2 Age (Mean, SD): 24.3 SD 4.4 Duration of Illness (years): SD 4.62 Number of Hospitalizations: not reported Number of Males: 21/2 Number of Females: 9/2 Age (Mean, SD): 26.1 SD 7.9 Duration of Illness (years): SD 2.35 Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: We excluded uncooperative, aggressive, and suicidal patients and subjects with medical illnesses that could affect body weight Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: 10 mg/day Dose Antidepressant: 20mg/day Duration of Trial (weeks): 8 Number Randomized: 15 Dose Antipsychotic: 10 mg/day Duration of Trial (weeks): 8 Outcomes HAM-D SAPS SANS Dropouts (any reason) Dropouts (inefficacy) Exacerbation of psychosis Adverse events 82

83 Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) CGI Sponsorship source: Supported by the Sarah and Moshe Mayer Foundation Country: Israel Setting: inpatients Authors name: Poyurovsky Institution: Tirat Carmel Mental Health Center, Tirat Carmel, Israel. tau.ac.il ( ) Address: Dr. Weizman, Research Unit, Geha Psychiatric Hospital, Rabin Medical Center, Petah Tiqva 49100, Israel Authors' judgement Unclear risk Unclear risk Low risk Low risk Unclear risk Support for judgement Comment: Randomized. No further description. Comment: No details presented. Comment: double blind Comment: double blind Comment: Drop-out not evenly distributed (27% vs. 13%). Reasons for drop-outs are provided. Comment: no selective reporting; Predefined results are described. Selective reporting (reporting Low risk bias) Other bias Low risk Comment: no other bias Poyurovsky 2003 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 9 Number of Females: 4 Age (Mean, SD): 31.5 (12.9) Duration of Illness (years): 3.1 (3.0) Number of Hospitalizations: 1.2 (0.3) Number of Males: 8 Number of Females: 5 Age (Mean, SD): 30 (10.2) Duration of Illness (years): 2.8 (3.0) Number of Hospitalizations: 1.1 (0.2) Inclusion criteria: Other inclusion criteria for the study were <4 weeks of antipsychotic drug exposure in the preceding 6 months, no previous olanzapine treatment, and a recommendation for olanzapine treatment by the treating physician during the current hospitalization 83

84 Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 13 Dose Antipsychotic: 10 mg/day Dose Antidepressant: 4mg/day Duration of Trial (weeks): 6 Number Randomized: 13 Dose Antipsychotic: 10 mg/day Duration of Trial (weeks): 6 Outcomes HAM-D SAPS SANS Dropouts (any reason) Dropouts (side effects) Adverse events CGI (improv) CGI Identification Risk of bias table Bias Random sequence generation (selection bias) Sponsorship source: Company Country: Israel Setting: Inpatients Authors name: Poyurovsky Institution: Tirat Carmel Mental Health Center (Israel) poyurovs@tx.technion.ac.il Address: Dr. Poyurovsky, Research Unit, Tirat Carmel Mental Health Center, 9 Eshkol St., Tirat Carmel 30200, Israel; tyrmichael@matat.health.gov.il ( ). Authors' judgement Low risk Support for judgement Comment: Randomized. "The participants were allocated according to entries of a table of random numbers." Comment: No details presented. Allocation concealment Unclear risk (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data Unclear risk Comment: Low drop-out, equally distributed (attrition bias) (23%). reasons for drop-out not described. Selective reporting (reporting High risk Comment: Not all predefined results are bias) presented, e.g. BAS, SAS. Other bias Low risk Comment: no other bias Poyurovsky 2003a Methods Study design: Randomized controlled trial Study grouping: Parallel group 84

85 Intention-to-treat data: no Participants Baseline Characteristics Number of Males: 8 Number of Females: 3 Age (Mean, SD): 42.5 (12.9) Duration of Illness (years): 15.4 (11.9) Number of Hospitalizations: 6.5 (3.8) Number of Males: 9 Number of Females: 4 Age (Mean, SD): 45.5 (7.5) Duration of Illness (years): 18.7 (11.7) Number of Hospitalizations: 8.2 (5.0) Inclusion criteria: Only patients maintained on conventional antipsychotic agents for at least 4 6 months and who were able to cooperate with clinical and neurocognitive evaluation participated in the study. Exclusion criteria: Patients with organic brain damage, alcohol /drug abuse or other DSM-IV Axis-I psychiatric disorders were excluded. Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: WHO DDD (defined daily dosage): 5.2 (3.0) Dose Antidepressant: 15mg/day Duration of Trial (weeks): 4 Number Randomized: 15 Dose Antipsychotic: WHO DDD (defined daily dosage): 2.9 (3.0) Duration of Trial (weeks): 4 Outcomes SAPS SANS BAS SAS AIMS HAM-D Dropouts (any reason) Dropouts (side effects) CGI (improv) CGI Identification Sponsorship source: University Country: Israel Setting: inpatients Authors name: Poyurovsky Institution: Tirat Carmel Mental Health Center (Israel) tyrmichael@matat.health.gov.il Address: Tirat Carmel Mental Health Center, 9 Eshkol Street, Tirat Carmel 30200, Israel Risk of bias table Bias Authors' judgement 85 Support for judgement

86 Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Unclear risk Unclear risk Low risk Low risk Unclear risk Comment: Randomized. No further description. Comment: No details presented. Comment: double blind Comment: double blind Comment: Drop-out not evenly distributed (27% vs. 13%). Reasons for drop-out are provided. Comment: no selective reporting; All predefined results are presented. Selective reporting (reporting Low risk bias) Other bias Low risk Comment: no other bias Poyurovsky 2006 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 20 Number of Females: 10 Age (Mean, SD): 34.9 (11.5) Duration of Illness (years): not reported Number of Hospitalizations: 1.9 (1.0) Number of Males: 16 Number of Females: 14 Age (Mean, SD): 34.4 (11.1) Duration of Illness (years): not reported Number of Hospitalizations: 2.0 (1.8) Inclusion criteria: Eligible antipsychotic-treated inpatients (57 men, 33 women; age , range years) with primary diagnoses of schizophrenic disorder (n 80), delusional disorder (n 7), or major depressive disorder with psychotic features (n 3) met DSM-IV research criteria for acute akathisia (American Psychiatric Association 2000). A score of 2 on the global scale (range 0 5) of the Barnes Akathisia Scale (BAS) (Barnes 1989) was required. Exclusion criteria: Exclusion criteria included treatment with betablockers, anticholinergics, or benzodiazepines for emergent akathisia prior to screening; diagnoses of non-acute akathisia (withdrawal, chronic); change in antipsychotic regimen within 3 days prior to onset of akathisia; treatment with long-acting antipsychotic agents; or contraindications to beta-blockers Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: not reported 86

87 Dose Antidepressant: 15mg/day Duration of Trial (weeks): 1 Number Randomized: 30 Dose Antipsychotic: not reported Duration of Trial (weeks): 1 Outcomes HAM-D BPRS BAS SAS Dropouts (any reason) Adverse events Responders (responders (reduction of 2 points on BAS)) Identification Sponsorship source: University Country: Israel Setting: inpatients Authors name: Poyurovsky Institution: Tirat Carmel Mental Health Center (Israel) poyurovs@tx.technion.ac.il Address: Michael Poyurovsky, M.D., Tirat Carmel Mental Health Center, Research Unit, 9 Eshkol Street, Tirat Carmel 30200, Israel; Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Allocation concealment Low risk Comment: Patients were randomly assigned to treatment according to a table of random numbers Low risk Comment: Capsules were dispensed by the non-blind (selection bias) study pharmacist using patient-coded containers. Blinding of participants and personnel (performance bias) Low risk Comment: "Clinical and research staff and patients were unaware of and could not determine the study drug assignment by appearance or otherwise; "double blind Blinding of outcome assessment (detection bias) Low risk Comment: "Clinical and research staff and patients were unaware of and could not determine the study drug assignment by appearance or otherwise; "double blind Incomplete outcome data (attrition bias) High risk Comment: not evenly distributed dropout rate, higher in one group (20% vs 33%). Reasons for dropout not described. Selective reporting (reporting bias) High risk Comment: Not all predefined results are presented (SAS, BPRS, HAM-D) Other bias Low risk Comment: no other bias Poyurovsky 2007 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics 87

88 Number of Males: 23 Number of Females: 8 Age (Mean, SD): 30.3 (8.5) Duration of Illness (years): 4.0 (5.6) Number of Hospitalizations: 1.7 (1.3) Number of Males: 15 Number of Females: 13 Age (Mean, SD): 29.5 (7.2) Duration of Illness (years): 3.0 (4.0) Number of Hospitalizations: 1.3 (0.5) Inclusion criteria: inclusion criteria in the present study were none or less than 4 weeks of antipsychotic drug exposure and a recommendation for olanzapine treatment by the treating physician Exclusion criteria: Exclusion criteria included major mood disorders, aggressive or suicidal behavior, medical illnesses that could affect bodyweight (e.g., diabetes mellitus and hypothyroidism), and obesity (body mass index [BMI] 30 kg/m2) Interventions Intervention Characteristics Number Randomized: 31 Dose Antipsychotic: 10mg/day Dose Antidepressant: 4mg/day Duration of Trial (weeks): 6 Number Randomized: 29 Dose Antipsychotic: 10mg/day Dose Antidepressant: Duration of Trial (weeks): 6 Outcomes SAPS SANS BAS SAS HAM-D Dropouts (any reason) Dropouts (inefficacy) Adverse events Identification Risk of bias table Bias CGI (improv) Sponsorship source: The study was supported in part by grant no.03t- 294 from the Stanley Medical Research Institute. Country: Israel Setting: inpatients Authors name: Poyurovsky Institution: Tirat Carmel Mental Health Center (Tirat Carmel, Israel) poyurovs@tx.technion.ac.il Address: Rappaport Faculty of Medicine, Israel Institute of Technology Technion, Haifa, Israel Authors' judgement Support for judgement 88

89 Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Low risk Unclear risk Low risk Comment: Randomized; "The participants were allocated according to entries on a table of random numbers to receive olanzapine (fixed dose of 10 mg at 8:00 P.M.) with either reboxetine (4 mg/day, administered in 2-mg doses twice daily) or placebo (twice daily) for 6 weeks." Comment: no details Comment: "Clinical and research staff and patients were unaware of and could not determine the study drug assignment by appearance or otherwise." Low risk Comment: double blind; "Clinical and research staff and patients were unaware of and could not determine the study drug assignment by appearance or otherwise." High risk Comment: high drop-out in both groups (n=18, 30%). Reasons for drop-out are provided. Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Prusoff 1979 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: ages of 18 and 65 years; an unequivocal diagnosis of SCZ according to the American Psychiatric Association DSM-II and the New Haven Schizophrenia Index (NHSI) and depressive symptoms reach a score of at least 7 on the Raskin Depression Scale (range 3 to 15) Exclusion criteria: serious physical illness, alcoholism, drug addiction or organic brain syndrome, pregnancy or lactation, and patients receiving psychotropic medication other than perphenazine in the previous four weeks Pretreatment: no significant differences Intervention Characteristics 89

90 Number Randomized: 20 Dose Antipsychotic: 30.8 mg/day Dose Antidepressant: mg/day Duration of Trial (weeks): 26 Number Randomized: 20 Dose Antipsychotic: 32 mg/day Dose Antidepressant: Duration of Trial (weeks): 26 Outcomes HAM-D BPRS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Responders (at least minimally improved) Identification Risk of bias table Bias Sponsorship source: Supported by a grant from Merck Sharp. & Dohme. no information of medication resources Country: USA Setting: outpatients Authors name: Brigitte A. Prusoff Institution: Department of Psychiatry and the Connecticut Mental Health Center, Yale University School of Medicine no information Address: 904 Howard Ave, Suite 2A, New Haven, CT 06519, USA Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) High risk Comment: high dropout rate Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Reznik 2000 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Open Label: YES Intention-to-treat data: yes Baseline Characteristics Number of Males: 10 Number of Females: 4 Age (Mean, SD): 38.8 (9.2) 90

91 Duration of Illness (years): 4.1 (2.3) Number of Hospitalizations: not reported Number of Males: 12 Number of Females: 4 Age (Mean, SD): 35.5 (7.7) Duration of Illness (years): 3.8 (1.7) Number of Hospitalizations: not reported Inclusion criteria: aged 18 years or older, with a DSM-IV diagnosis of SCZ, scoring at least 26 points of Y-BOCS at baseline, physically healthy and had normal findings for the laboratory tests (hematology, blood chemistry, and urinalysis) Exclusion criteria: all residual noncompliant, chronically institutionalized patients and those with SCZ who had concomitant, marked depressive symptoms, comorbid alcohol or drug abuse Pretreatment: The demographic characteristics and psychiatric histories of the patients did NOT differ between the two groups at baseline. Interventions Intervention Characteristics Number Randomized: 14 Dose Antipsychotic: perphenazine 32 to 48 mg/day or haloperidol 10 to 15 mg/day Dose Antidepressant: mg/day Duration of Trial (weeks): 8 Number Randomized: 16 Dose Antipsychotic: perphenazine 32 to 48 mg/day or haloperidol 10 to 15 mg/day Duration of Trial (weeks): 8 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) CGI (improv) Identification Sponsorship source: no information Country: Israel Setting: inpatients Authors name: Reznik Ilya, Sirota Pinkhas Institution: Abarbanel Mental Health Center Bat-Yam and Sackler Faculty of Medicine, Tel-Aviv University psrt1a@netvision.net.il Address: 15 Keren Kayemet Street, Bat-Yam, 59110, Israel Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) judgement Unclear risk Unclear risk Comment: randomized, no further details Comment: no details 91

92 Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) High risk Low risk Low risk Comment: open study Quote: "The evaluation was repeated after 8 weeks of the combined therapy in both groups by the same well-trained rater who was not aware what kind of treatment each patient received." Comment: well-trained rater who was not aware what kind of treatment each patient received Quote: "A total of 30 patients were enrolled in the study. Two patients from the combined treatment group were studied twice (see above), so equal groups of 16 patients were included in the efficacy analysis. All patients completed the 8-week trial." Comment: no dropouts Comment: no selective reporting Selective reporting Low risk (reporting bias) Other bias High risk Comment: A total of 30 patients were enrolled in the study. Two patients from the combined treatment group were studied twice (see above), so equal groups of 16 patients were included in the efficacy analysis Salokangas 1996 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: aged years; had SCZ diagnosis according to DSM- III-R, with a stable psychic condition and stable antipsychotic medication during the previous 3 months; PANSS total score of 50 or higher and score 4 or higher on at least one of the following PANSS items P7, N4, G2 and G6. Exclusion criteria: clinically relevant somatic disorder; SSRI or clomipramine treatment during the previous 6 months; concomitant use of clozapine, lithium, carbamazepine, buspirone or any antidepressant; pregnancy or lack of contraception in a woman of childbearing age; 92

93 known hypersensitivity to citalopram; and known history of drug noncompliance Interventions Intervention Characteristics Number Randomized: 45 Dose Antipsychotic: CPZ eqiuv: 475 mg/ day (SD 456)) Dose Antidepressant: 40 mg/ day Duration of Trial (weeks): 12 Number Randomized: 45 Dose Antipsychotic: CPZ eqiuv: 464 mg/ day (SD 341) Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes HAM-D PANSS total PANSS negative PANSS positive Dropouts (any reason) CGI (severity) Responders (PANSS total score improvement) Identification Sponsorship source: no information Country: Finland Setting: mixed Authors name: R.K.R. Salokangas Institution: Department of Psychiatry, University of Turku no information Address: FIN Turku, Finland Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned" no further information Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: low drop-out and evenly distributed, but no reasons provided Selective reporting (reporting bias) High risk Comment: specific adverse events, SAS data, baseline characteristic data not reported Other bias Low risk Comment: no other bias Schiele 1963 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics 93

94 Number of Males: not reported Number of Females: not reported Age (Mean, SD): 36 Duration of Illness (years): 5.9 Number of Hospitalizations: 2.4 Number of Males: not reported Number of Females: not reported Age (Mean, SD): 36 Duration of Illness (years): 5.9 Number of Hospitalizations: 2.4 Inclusion criteria: Patients were selected for this study if, on admission, they had a primary diagnosis of schizophrenia and also had evidence of depression, anergia or withdrawal. Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: 5-50 mg/day, adjusted individually Dose Antidepressant: 60 mg/day Duration of Trial (weeks): 8 Number Randomized: 30 Dose Antipsychotic: 5-50 mg/day, adjusted individually Duration of Trial (weeks): 8 Outcomes Dropouts (any reason) Responders (were greatly improved or ready for discharge at Endpoint) Identification Sponsorship source: National Institute of Mental Health Country: USA Setting: inpatients Authors name: Schiele Institution: From the Veterans -Administration Hospital, St. Cloud, Minnesota no information Address: no information Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate, evenly distributed between groups 94

95 Selective reporting (reporting bias) High risk Comment: no adverse events reported, no SDs provided Other bias Low risk Comment: no other bias Schutz 2001 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 14 Number of Females: 1 Age (Mean, SD): 32.8 SD 6.2 Duration of Illness (years): 8.75 SD 7.05 Number of Hospitalizations: not reported Number of Males: 14 Number of Females: 1 Age (Mean, SD): 32.2 SD 7.9 Duration of Illness (years): 7.46 SD Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: Patients with significant medical illnesses and/or those on concomitant medication for medical indications were excluded. Patients on any other psychotropic medication other than benzodiazepines were also excluded. Patients with a history of any other major psychiatric illness were excluded, as were those meeting the criteria for substance abuse or who had a history of regularly consuming more than three alcoholic beverages daily. Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: 5 mg/ day Dose Antidepressant: 8 mg/day Duration of Trial (weeks): 6 Number Randomized: 15 Dose Antipsychotic: 5 mg/ day Dose Antidepressant: Duration of Trial (weeks): 6 Outcomes HAM-D PANSS total PANSS positive PANSS negative SAS Dropouts (any reason) Dropouts (side effects) Adverse events CGI (improv) 95

96 CGI (severity) Responders (20% reduction in symptoms on the PANSS) Identification Sponsorship source: University Country: South Africa Setting: inpatients Authors name: Schutz Institution: Sterkfontein Hospital Address: Michael Berk, Department of Psychiatry, University of Melbourne, Swanston Centre, PO Box 281, Geelong, Victoria, 3220, Australia Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: Randomized. No further description. Allocation concealment Unclear risk Comment: No details presented. (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) High risk Comment: high dropout rate, not evenly distributed between groups Selective reporting (reporting bias) High risk Comment: no data for baseline HAM-D and SAS, no SDs for other reported baseline data Other bias Low risk Comment: no other bias Shafti 2007 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 25 Number of Females: 0 Age (Mean, SD): 39(±4) Duration of Illness (years): 8.3 (2) Number of Hospitalizations: not reported Number of Males: 25 Number of Females: 0 Age (Mean, SD): 41(±4) Duration of Illness (years): 7 (2) Number of Hospitalizations: not reported Inclusion criteria: The inclusion criteria consisted of the diagnosis of schizophrenia according to the DSM-IV, the presence of negative symptoms of schizophrenia, and the duration of schizophrenia for more than two years. High negative symptom scores (more than 20% of total 96

97 SANS), low positive symptom scores (less than 20% of total SAPS), low extrapyramidal symptom scores (less than 25% of total SAS), and, finally, low depressive symptom scores (HDS less than l0) were the foundation of our inclusion criteria. Exclusion criteria: An HDS greater than 10 and an MMSE less than 25 were diagnosed as depression and cognitive disturbance, and led to patient exclusion. Interventions Intervention Characteristics Number Randomized: 25 Dose Antipsychotic: 5 mg/day Dose Antidepressant: 10mg/day Duration of Trial (weeks): 8 Number Randomized: 25 Dose Antipsychotic: 5 mg/day Dose Antidepressant: Duration of Trial (weeks): 8 Outcomes HAM-D SANS Dropouts (any reason) Adverse events Responders (reduction of 20% or more in the severity of SANS Identification Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) scores) Sponsorship source: University Country: Iran Setting: inpatients Authors name: Shafti Institution: Department of Psychiatry, Razi Psychiatric Hospital, Tehran,lran ssshafti@yahoo.com Address: Saeed Shoja Shafti, MD, Department ofpsychiatry, Razi Psychiatric Hospital, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran; Phone: ; Fax: ; Authors' judgement Unclear risk Unclear risk Low risk Low risk Low risk High risk Support for judgement Comment: Randomized. No further description. Comment: No details presented. Comment: double blind; "The patients and the researchers were blind about which group was taking escitalopram or placebo." Comment: double blind; "The patients and the researchers were blind about which group was taking escitalopram or placebo." Comment: No drop-outs. Comment: Some predefined results are not presented, e.g. SAPS, SAS, HAM-D. 97

98 Other bias Low risk Comment: no other bias Shiloh 2002 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 5 Number of Females: 4 Age (Mean, SD): 32.8 (9.0) Duration of Illness (years): 12.6 (7.5) Number of Hospitalizations: 7.2 (3.9) Number of Males: 6 Number of Females: 3 Age (Mean, SD): 42.6 (7.3) Duration of Illness (years): 11.4 (7.2) Number of Hospitalizations: 13.4 (12.0) Inclusion criteria: treatment-resistant inpatients meeting the DSM-IV criteria for schizophrenia were included in this study. All were hospitalized following an acute psychotic exacerbation of the disorder and all previously failed to respond to at least three types of typical antipsychotics (fluphenazine, thioridazine, trifluoperazineor zuclopenthixol) administered at adequate therapeutic doses for a period of not less than6 weeks each. None of the participants had received prior treatment with an atypical APD, including clozapine. Treatment resistance was defined as a less than 15% decrease in the BPRS score compared with values on admission. Exclusion criteria: Exclusion criteria were a known history of alcohol or substance abuse, past record of non-compliance to medical treatment or prior use of the antipsychotics used in this study (either perphenazine or haloperidol). Pretreatment: The typical APD/ mianserin group was characterized by an earlier age of onset of schizophrenia ( versus years; P=0.02) Interventions Intervention Characteristics Number Randomized: 9 Dose Antipsychotic: CPZ equiv: (170.4) Dose Antidepressant: 30mg/day Duration of Trial (weeks): 6 Number Randomized: 9 Dose Antipsychotic: CPZ equiv: (229.6) Duration of Trial (weeks): 6 Outcomes HAM-D BPRS SAPS 98

99 Identification Risk of bias table Bias SANS Dropouts (any reason) Adverse events Sponsorship source: University Country: Israel Setting: inpatients Authors name: Shiloh Institution: Geha Psychiatric Hospital and Felsenstein Medical Research Center Tel: /9; fax: ; shiloh r@netvision.net.il Address: ProfessorAbrahamWeizman, Geha Psychiatric Hospital,POBox 102, PetahT qva 49100, Israel Authors' Support for judgement judgement Random sequence generation (selection bias) Low risk Comment: Randomized. "according to a table of random numbers" Allocation concealment (selection Unclear risk Comment: No details presented. bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data Low risk Comment: no dropouts (attrition bias) Selective reporting (reporting bias) High risk Comment: Not all predefined results are presented; especially FU-data are missing Other bias Low risk Comment: no other bias Shoja Shafti 2006 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 42±4 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 44±4 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: The inclusion criteria consisted of diagnosis of Schizophrenia according to Diagnostic and Statistical Manual of Mental 99

100 Disorders(DSM-IV),11 the presence of negative symptoms of schizophrenia, and duration of schizophrenia of more than two years Exclusion criteria: 1 Major depressive disorder2 Schizoaffective disorder3 Mental retardation4 Bipolar disorder5 Neurological disorders6 Using atypical antipsychotic7 Using antidepressants or lithium8 Medical complications9 Unstable, irritable, aggressive patients10 Duration less than one year11 Parkinsonism12 Medical deafness or muteness Interventions Intervention Characteristics Number Randomized: 25 Dose Antipsychotic: 5 mg/ day Dose Antidepressant: 50 mg/day Duration of Trial (weeks): 6 Number Randomized: 25 Dose Antipsychotic: 5 mg/ day Duration of Trial (weeks): 6 Outcomes HAM-D Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Responders (reduction of 20% or more in the severity of SANS scores) Identification Sponsorship source: university Country: Iran Setting: inpatients Authors name: Saeed shoja-shafti Institution: Razi Psychiatric Hospital, Tehran, ssshafti@yahoo.com Address: Department of PsychiatryRazi Psychiatric Hospital,University of SocialWelfare andrehabilitation Sciences,Tehran, Iran.Tel: Fax: Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate Selective reporting (reporting bias) High risk Comment: no Endpoint data reported Other bias Low risk Comment: no other bias Silver 1992 Methods Study design: Randomized controlled trial 100

101 Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 9 Number of Females: 6 Age (Mean, SD): 41 Duration of Illness (years): 11 Number of Hospitalizations: not reported Number of Males: 10 Number of Females: 5 Age (Mean, SD): 42 Duration of Illness (years): 12.5 Number of Hospitalizations: not reported Inclusion criteria: physically well and fulfilled DSM-III-R criteria for chronic SCZ; a history of at least 5 years of illness, at least 1 year of hospitalization, and a score of at least "moderate" on one of the five global scales of the SANS; the dose of antipsychotic and anticholinergic medications were constant for at least 4 weeks prior to the start of the trial and were kept so during the study period Exclusion criteria: no information Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: CPZ equiv: 488 mg/day Dose Antidepressant: mg/day Duration of Trial (weeks): 7 Number Randomized: 15 Dose Antipsychotic: CPZ equiv: 461 mg/day Dose Antidepressant: placebo Duration of Trial (weeks): 7 Outcomes HAM-D BPRS SAPS SANS SAS Dropouts (any reason) Identification Sponsorship source: Medication from industry (Agis) Country: Israel Setting: inpatients Authors name: Henry Silver Institution: Flugelman (Mazra) Psychiatric Hospital no information Address: Doar Na Ashrat, Israel Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) judgement Unclear risk 101 Comment: "randomly allocated" no further information

102 Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Low risk Quote: "All patients completed the trial." Comment: no dropouts Selective reporting (reporting Low risk Comment: no selective reporting bias) Other bias Unclear risk Comment: Mistake in main outcome Table (Endpoint data identical to Baseline data for BPRS) Silver 2000 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 8 Number of Females: 22 Age (Mean, SD): 43 (10.3) Duration of Illness (years): 19.7 (9.7) Number of Hospitalizations: not reported Number of Males: 11 Number of Females: 12 Age (Mean, SD): 43 (10.3) Duration of Illness (years): 19.7 (9.7) Number of Hospitalizations: not reported Inclusion criteria: Diagnosis of SCZ (DSM-III-R) with a history of at least 2 years of illness; current state sufficiently severe to require inpatient treatment with a continuous current hospitalization of at least 2 months; scores of at least 'moderate' on at least one of the global items of SANS and SAPS after not less than 2 months of antipsychotic treatment in doses equivalent to not less than 1000 mg of chlorpromazine Exclusion criteria: meeting DSM-III-R criteria for depression, those with a history of organic brain damage, alcohol or drug abuse or with current significant physical illness Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: CPZ equiv: 1603 (990) mg Dose Antidepressant: mg/day Duration of Trial (weeks): 6 Number Randomized: 23 Dose Antipsychotic: CPZ equiv: 1603 (990) mg Dose Antidepressant: placebo 102

103 Duration of Trial (weeks): 6 Outcomes BPRS SAPS SANS SAS Dropouts (any reason) BPRS Depression Identification Risk of bias table Bias Sponsorship source: Company (Solvay and Agis) Country: Israel Setting: inpatients Authors name: H. Silver Institution: Clinical Research Unit, Flugelman (Mazra) Psychiatric Hospital, Doar Na Ashrat (Acco) mdsilver@tx.technion.ac.il Address: Sha'ar Menashe Mental Health Center, Mobile Post Hefer 38814, Israel Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned" no further information Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: dropout rate low, but unevenly distributed between groups (23% to 0%) Selective reporting (reporting bias) High risk Comment: SAS Endpoint/ Change not reported Other bias Low risk Comment: no other bias Singh 1978 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 17 Number of Females: 13 Age (Mean, SD): 41 Duration of Illness (years): 17.4 Number of Hospitalizations: 4.8 Number of Males: 17 Number of Females: 13 Age (Mean, SD): 44.4 Duration of Illness (years):

104 Number of Hospitalizations: 5 Inclusion criteria: no other psychiatric condition or major somatic illness, HAM-D at least 18 Exclusion criteria: pregnancy, hypersensitivity to any drugs used in the trail Interventions Intervention Characteristics Number Randomized: 30 Dose Antipsychotic: not reported Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 6 Number Randomized: 30 Dose Antipsychotic: not reported Duration of Trial (weeks): 6 Outcomes HAM-D BPRS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis Identification Risk of bias table Bias Adverse events Sponsorship source: pharmaceutical company (Inter Canada Pharmaceuticals Ltd.) Country: Canada Setting: inpatients Authors name: A.N. Singh Institution: The Hamilton Psychiatric Hospital, Hamilton, Ontario, Canada not available Address: Dr. A.N. Singh, P.O. Box 585, Hamilton, Ontario, Canada Authors' judgement Unclear risk Support for judgement Random sequence generation Comment: randomized, no further details (selection bias) Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: there were no dropouts bias) Selective reporting (reporting bias) High risk Comment: results of side-effect scales were not completely reported Other bias Low risk Comment: no other bias Siris 1993 Methods Study design: Randomized controlled trial 104

105 Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 30.7 (4.1) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 30.7 (4.1) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 7 Dose Antipsychotic: not reported Dose Antidepressant: 200 mg/day Duration of Trial (weeks): 9 Number Randomized: 3 Dose Antipsychotic: not reported Duration of Trial (weeks): 9 Outcomes Exacerbation of psychosis Responders (CGI very much improved rating at Endpoint) Identification Sponsorship source: Grant from National Institute of Drug Abuse Country: USA Setting: outpatient Authors name: Samuel Siris Institution: Hillside Hospital, New York not available Address: Dr. Samuel G. Siris, Hillside Hospital, rd Street, Glen Oaks, NY Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: no dropout reported 105

106 Selective reporting (reporting bias) High risk Comment: no CGI scores given only responder, no other scale given Other bias Low risk Comment: no other bias Siris 2000 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 19 Number of Females: 19 Age (Mean, SD): 35.3±11.3 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 20 Number of Females: 12 Age (Mean, SD): 31.5±8.7 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: met Research Diagnostic Criteria (RDC) for SCZ or schizoaffective disorder for their most recent episode of flagrant psychosis; were currently either non-psychotic or only residually psychotic according to the RDC; concomitantly manifest a depressive syndrome consistent with the definition of post-psychotic depression (PPD) in the Appendix of DSM-IV; also prior to study entry, patients were required to have a Hamilton Depression Rating Scale score of at least 12, and were required to maintain that score for at least three consecutive weekly ratings; the last HDRS rating could not be the lowest of the three for the patient to be allowed to be randomized at baseline. Exclusion criteria: no information Pretreatment: no information Interventions Intervention Characteristics Number Randomized: 38 Dose Antipsychotic: not reported Dose Antidepressant: 200 mg/day Duration of Trial (weeks): 6 Number Randomized: 34 Dose Antipsychotic: not reported Duration of Trial (weeks): 6 Outcomes HAM-D Dropouts (any reason) Dropouts (inefficacy) CGI (improv) Responders (rating of much improved or very much improved ) on the CGI Global Improvement Scale at the Endpoint) 106

107 Identification Risk of bias table Bias Sponsorship source: no information Country: USA Setting: inpatients or outpatients Authors name: Samuel Siris Institution: Hillside Hospital / Long Island Jewish Medical Center siris@lij.edu Address: rd Street, Glen Oaks, NY 11004, USA Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no description Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment (detection Low risk Comment: double blind bias) Incomplete outcome data (attrition bias) Low risk Comment: low dropout rate Selective reporting (reporting bias) High risk Comment: adverse events not reported Other bias Low risk Comment: no other bias Spina 1994 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 12 Number of Females: 5 Age (Mean, SD): 46.3 (10.6) Duration of Illness (years): at least 5 years Number of Hospitalizations: not reported Number of Males: 11 Number of Females: 6 Age (Mean, SD): 45.4 (10.5) Duration of Illness (years): at least 5 years Number of Hospitalizations: not reported Inclusion criteria: age years; psychiatric diagnosis of chronic SCZ according to DSM-III-R with a history of at least 5 years of illness; a score of at least "moderate" on one of the five global subscales of the SANS at baseline; a baseline total score lower than 20 on HAMD; the dose of antipsychotics had been stable for at least 4 weeks prior to the study and was left unchanged throughout the study. Exclusion criteria: presence of any other primary psychiatric diagnosis, significant concurrent physical illness, alcoholism or other drug addiction, pregnancy or lactation. Intervention Characteristics 107

108 Number Randomized: 17 Dose Antipsychotic: CPZ equiv: 247 (78) mg/day Dose Antidepressant: 20 mg/ day Duration of Trial (weeks): 12 Number Randomized: 17 Dose Antipsychotic: CPZ equiv: 233 (87) mg/day Duration of Trial (weeks): 12 Outcomes HAM-D BPRS SAPS SANS Dropouts (any reason) Dropouts (side effects) Exacerbation of psychosis CGI (improv) CGI (severity) Responders (20% SANS score reduction at Endpoint vs Baseline) Identification Sponsorship source: independent (no conflict of interest) Country: Italy Setting: inpatients Authors name: E. Spina Institution: Institute of Pharmacology, University of Messina no information Address: Piazza XX Settembre, 4, Messina, Italy Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned" no further information Allocation concealment Unclear risk Comment: no details (selection bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome Low risk Comment: double blind assessment (detection bias) Incomplete outcome data Low risk Comment: low drop-out (less than 25%) and (attrition bias) Selective reporting (reporting bias) High risk reasons provided Comment: results for all adverse events not reported, no SAS data, no ECG and laboratory tests data Other bias Low risk Comment: no other bias Sumiyoshi 2001 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics 108

109 Number of Males: 9 Number of Females: 6 Age (Mean, SD): 27.8 (6.3) Duration of Illness (years): 6.3 (4.3) Number of Hospitalizations: not reported Number of Males: 6 Number of Females: 5 Age (Mean, SD): 31.8 (9.4) Duration of Illness (years): 7.5 (5.4) Number of Hospitalizations: not reported Inclusion criteria: outpatients meeting DSM-IV criteria for schizophrenia Exclusion criteria: Patients with an axis I diagnosis, a history of any alcohol or substance abuse, epilepsy, brain damage, or neurological disorders and the presence of cardiovascular or metabolic disease. Interventions Intervention Characteristics Number Randomized: 15 Dose Antipsychotic: CPZ equiv: 250 mg/day Dose Antidepressant: 30 mg/ day Duration of Trial (weeks): 6 Number Randomized: 11 Dose Antipsychotic: CPZ equiv: 215 mg/day Duration of Trial (weeks): 6 Outcomes BPRS (total, positive sub-score, negative sub-score) Dropouts SAS Identification Sponsorship source: independent (grant from the Japan Research Foundation for Clincal Pharmacology) Country: Japan Setting: outpatients Authors name: Tomiki Sumiyoshi Institution: Toyama Medical and Pharmaceutical University School of Medicine tomiki.sumiyoshi@mcmail.vanderbilt.edu Address: not indicated Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "randomly assigned" no further information Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Unclear risk Comment: no information (performance bias) Blinding of outcome assessment Low risk Comment: blind raters (detection bias) Incomplete outcome data (attrition Low risk Comment: no drop-outs bias) Selective reporting (reporting bias) Low risk Comment: no selective reporting 109

110 Other bias Low risk Comment: no other bias Teja 1975 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Physically healthy chronic schizophrenics of either sex between the ages of 20 to 60 years who had been in the hospital for a minimum of 2 years were selected for the study Exclusion criteria: Patients with a known previous history of epileptic seizures, leucotomy, or mental sub-normality were excluded from the study. Patients with schizoaffective illness were excluded in view of the study s aim to investigate the role of antidepressant medications in the treatment of process chronic schizophrenics. Interventions Intervention Characteristics Number Randomized: 28 Dose Antipsychotic: not reported Dose Antidepressant: 150 mg/day Duration of Trial (weeks): 16 Number Randomized: 28 Dose Antipsychotic: not reported Duration of Trial (weeks): 16 Outcomes Responders (markedly improved at Endpoint) Identification Sponsorship source: University, Company provided medication Country: USA Setting: inpatients Authors name: Jagdish S. Teja Institution: University of Virginia School of Medicine not available Address: University of Virginia School of Medicine, Charlottesville, Virginia 22901, USA Risk of bias table Bias Authors' judgement Support for judgement 110

111 Random sequence generation Unclear risk Comment: randomized, no details (selection bias) Allocation concealment (selection bias) Unclear risk Comment: no description Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) High risk Comment: Not mentioned whether there were dropouts Selective reporting (reporting bias) High risk Comment: BPRS not reported Other bias Low risk Comment: no other bias Tidey 2011 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: 19 Number of Females: 8 Age (Mean, SD): 45.1±8.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 22 Number of Females: 8 Age (Mean, SD): 45.1±8.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Participants were eligible if they had a diagnosis of schizophrenia or schizoaffective disorder as confirmed by the Structured Clinical Interview for DSMIV-TR Axis I Disorders, were at least18 years of age, smoked at least 20 cigarettes per day, had scores of 6 or more on the Fagerström Test of Nicotine Dependence (Heatherton et al. 1991), had been clinically stable on psychoactive medications for at least 2 months prior to enrollment, and had scores of 4 or more on the Contemplation Ladder, indicating some interest in quitting smoking. Exclusion criteria: Exclusionary criteria included pregnancy, positive breath alcohol level or urine drug toxicity test, medication or medical condition contraindicating the use of bupropion, and very high psychiatric symptom severity that would preclude the completion of study procedures (ratings of six or higher on the excitement, uncooperativeness, conceptual disorganization, tension, posturing, disorientation, or emotional withdrawal items from the Brief Psychiatric Rating Scale). Pretreatment: There were some statistically significant baseline differences Intervention Characteristics 111

112 Number Randomized: 27 Dose Antipsychotic: First and second-generation antipsychotics Dose Antidepressant: 300 mg/day Duration of Trial (weeks): 3 Number Randomized: 30 Dose Antipsychotic: not reported Duration of Trial (weeks): 3 Outcomes PANSS total PANSS positive PANSS negative Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Adverse events Identification Sponsorship source: NIH grant Country: USA Setting: outpatient Comments: the patients also received other antidepressants in an uncontrolled fashion Authors name: Jennifer W. Tidey Institution: Brown University Jennifer_Tidey@brown.edu Address: Center for Alcohol and Addiction Studies, Brown University,Box S-121-5, Providence, RI 02912, USA Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) judgement Low risk Unclear risk Low risk Low risk Unclear risk Comment: randomized, coin toss Comment: it is not entirely clear, they only speak about an independent investigator who filled the capsules Comment: double blind Comment: double blind Comment: 5 dropouts were not used in the analysis, no strict ITT, and there is imbalance between groups 1 versus 4, but these are only 10% of the patients Selective reporting (reporting bias) High risk Comment: no Endpoint data for clinical scales reported Other bias High risk Comment: many patients received other antidepressants in an uncontrolled manner Usall

113 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 45 Number of Females: 12 Age (Mean, SD): (12.45) Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 22 Number of Females: 11 Age (Mean, SD): (12.36) Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: diagnosis of SCZ (DSM-IV), age between 18 and 65 years; treatment with a stable dose of either olanzapine or risperidone for at least 60 days prior to inclusion in the study; presence of significant negative symptoms defined as 1 or more negative symptom with a severity score greater than 4 on the PANSS negative scale. Exclusion criteria: substance use/dependence disorders in the previous 6 months; mental retardation; antidepressant or mood stabilizer use in the previous 4 months; and use of more than 1 antipsychotic or use of antipsychotics other than olanzapine or risperidone; patients with scores greater than 20 on the HDRS; pregnant and lactating women; and subjects with severe renal failure (serum Cr >5 mg/dl), history of hemorrhagic disorders, or intolerance or allergy to reboxetine or citalopram. Interventions Intervention Characteristics Number Randomized: 57 Dose Antipsychotic: Risperidone equiv: 5.25 mg/day (median) Dose Antidepressant: 19 mg/day Duration of Trial (weeks): 26 Number Randomized: 33 Dose Antipsychotic: Risperidone equiv: 6 mg/day (median) Dose Antidepressant: placebo Duration of Trial (weeks): 26 Outcomes HAM-D PANSS total PANSS positive PANSS negative SANS Dropouts (any reason) Exacerbation of psychosis Identification Sponsorship source: independent (grant) Country: Spain Setting: inpatients or outpatients Authors name: Judith Usall 113

114 Risk of bias table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Institution: Parc Sanitari Sant Joan de Deu C/Antoni Pujadas Address: 42 Sant Boi de Liobregat 08830, Barcelona, Spain Authors' judgement Low risk Low risk Low risk Low risk Unclear risk Support for judgement Selective reporting High risk (reporting bias) Other bias Low risk Comment: no other bias Comment: randomized according to random numbers table Comment: randomly assigned by the Parc Sanitari Sant Joan de Déu trial pharmacy to 1 of the 3 treatment groups in a 1:1:1 proportion on the basis of a random number list. Quote: "Placebo, reboxetine, and citalopram tablets were prepared so that they were identical in appearance. All study personnel and participants remained blind to treatment assignment for the duration of the study." Comment: double blind Comment: double blind Comment: dropout rate higher than 25% (citalopram 26%, reboxetine 29%, placebo 30%), but evenly distributed between groups and justified by a long duration of follow up (6 months) Comment: SAS and UKS Baseline and Endpoint not reported Vestre 1969 Methods Participants Interventions Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): 39.1 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): 39.1 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Intervention Characteristics 114

115 Number Randomized: 24 Dose Antipsychotic: 16-32mg/day Dose Antidepressant: mg/day Duration of Trial (weeks): 4 Number Randomized: 24 Dose Antipsychotic: mg/day Duration of Trial (weeks): 4 Outcomes Dropouts (side effects) Adverse events Identification Risk of bias table Bias Sponsorship source: independent (research grant and NIMH support) Country: USA Setting: inpatient Authors name: Norris D. Vestre Institution: Veterans Administration Hospital, St. Cloud, Minnesota, USA not available Address: Dr. Vestre, Department of Psychology, Indiana State University, Terre Haute, Indiana Authors' Support for judgement judgement Random sequence generation Unclear risk Comment: randomized, no further details (selection bias) Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition bias) Unclear risk Comment: low overall dropout rate, but unclear how many patients in each group Selective reporting (reporting High risk Comment: BPRS not fully reported bias) Other bias Low risk Comment: no other bias Waehrens 1980 Methods Participants Study design: Randomized controlled trial Study grouping: Crossover Intention-to-treat data: no Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported 115

116 Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: not reported Exclusion criteria: not reported Interventions Intervention Characteristics Number Randomized: 10 Dose Antipsychotic: not reported Dose Antidepressant: 138 mg/day Duration of Trial (weeks): 8 Number Randomized: 10 Dose Antipsychotic: not reported Dose Antidepressant: Placebo Duration of Trial (weeks): 8 Outcomes Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Identification Risk of bias table Bias Sponsorship source: not indicated Country: Denmark Setting: inpatients Authors name: J. Waehrens Institution: Sct. Hans Hospital, Roskilde, Denmark not available Address: J. Gerlach, Sct. Hans Hospital, Dept. H., DK-4000 Roskilde, Denmark Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: randomized, no further details Allocation concealment (selection bias) Unclear risk Comment: no details Blinding of participants and personnel Low risk Comment: double blind (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: low dropout rate bias) Selective reporting (reporting bias) High risk Comment: no data for the first crossover phase reported Other bias Low risk Comment: no other bias Weiner 2012 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics 116

117 Number of Males: 19 Number of Females: 5 Age (Mean, SD): 49.5 ± 7.8 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 18 Number of Females: 4 Age (Mean, SD): 47.8 ± 8.2 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: clinically stable outpatients with a DSM-IV diagnosis of SCZ or schizoaffective disorder who smoked at least 10 cigarettes per day and who were interested in quitting smoking or cutting down; had a total score of at least 4 (moderate) out of a possible 10 (severe) on FTND. Exclusion criteria: Participants were excluded if they had a neurologic diagnosis, current major depressive episode, substance dependence (other than nicotine) in the last 6 months or substance abuse (excluding nicotine) in the last 3 months, if they were not medically stable, or if they were currently taking bupropion. Pretreatment: no group differences on any demographic characteristics. Interventions Intervention Characteristics Number Randomized: 24 Dose Antipsychotic: not reported Dose Antidepressant: subjects started study medication (bupropion SR 150 mg), with dosing once daily for 3 days and then twice daily for the remainder of the study Duration of Trial (weeks): 12 Number Randomized: 22 Dose Antipsychotic: not reported Dose Antidepressant: placebo Duration of Trial (weeks): 12 Outcomes SANS Dropouts (any reason) Dropouts (side effects) Exacerbation of psychosis Adverse events Identification Sponsorship source: funded in part by the Veterans Affairs Capitol Network (VISN 5) Mental Illness Research, Education, and Clinical Center and National Institute of Mental Health Grant MH , Advance Center for Intervention Services Research. bupropion (Zyban), clozapine (Clozaril, FazaClo, and others), olanzapine (Zyprexa). Country: USA Setting: outpatients Authors name: Elaine Weiner Institution: The Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore eweiner@mprc.umaryland.edu 117

118 Address: Elaine Weiner, MD, Maryland Psychiatric Research Center, PO Box 21247, Baltimore, MD Risk of bias table Bias Authors' Support for judgement judgement Random sequence generation (selection bias) Unclear risk Comment: "Random assignments made by the statistician"; no further information Allocation concealment (selection Unclear risk Comment: no details bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data High risk Comment: high drop-out (>25%) (attrition bias) Selective reporting (reporting bias) High risk Comment: no endpoint data for clinical scales; reported no BPRS, SANS, SAS data Other bias Low risk Comment: no other bias Wynchank 2003 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Baseline Characteristics Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: not reported Number of Females: not reported Age (Mean, SD): not reported Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: diagnosis of SCZ, schizophreniform psychosis or cannabis-induced psychotic disorder according to DSM-IV; no anticholinergic medications were prescribed for at least 2 weeks prior to the start of the trial or permitted during it; had both acute and chronic EPS, particularly parkinsonian EPS. Exclusion criteria: development of severe EPS requiring intramuscular anticholinergic treatment, the administration of a depot antipsychotic in the previous month, administration of anticholinergic medication in the last 2 weeks and patients whose clinical condition required antipsychotic medication in addition to haloperidol 10 mg daily; patients who had not developed drug-induced parkinsonism within 2 weeks of starting treatment with haloperidol; patients with clinically significant medical disorders and those with abnormal routine laboratory results. 118

119 Pretreatment: no significant difference between two groups in the scores for the SAS, BAS, AIMS, CGI. Interventions Intervention Characteristics Number Randomized: 25 Dose Antipsychotic: 10 mg/d Dose Antidepressant: 200mg/d Duration of Trial (weeks): 1 Number Randomized: 24 Dose Antipsychotic: 10 mg/d Duration of Trial (weeks): 1 Outcomes BAS SAS AIMS CGI (severity) Identification Sponsorship source: no information Country: South Africa and Australia Setting: inpatients Authors name: Dora Wynchank, Michael Berk Institution: Department of Psychiatry, Witwatersrand University Medical School; Department of Psychiatry, University of Melbourne mikebe@barwonhealth.org.au Address: Swanston Centre, PO Box 281, Geelong, Victoria 3220, Australia Risk of bias table Bias Authors' Support for judgement Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) judgement Low risk Unclear risk Low risk Low risk Unclear risk Quote: "Patients selected for participation in the trial were assigned a number (between 1 and 49) in the order of their selection. These numbers had randomly been assigned to either placebo or active treatment groups using a computer generated program." Comment: no description Comment: double blind Comment: double blind Comment: no description High risk Comment: no Chouinard scale data, no SD data at visit 1 and visit 2 Other bias Low risk Comment: no other bias Zisook

120 Methods Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: yes Participants Baseline Characteristics Number of Males: 81 Number of Females: 23 Age (Mean, SD): SD 7.68 Duration of Illness (years): not reported Number of Hospitalizations: not reported Number of Males: 74 Number of Females: 20 Age (Mean, SD): SD 6.33 Duration of Illness (years): not reported Number of Hospitalizations: not reported Inclusion criteria: Consenting outpatients 40 years of age or older were eligible for the study if they met DSM-IV criteria for schizophrenia or schizoaffective disorder; met study criteria for sub-syndromal depression, defined as having 2 to4 of the 9 DSM-IV symptoms of MDE present most of the time for at least 2 weeks; had a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score 823; and were on a stable dose of an antipsychotic medication. Exclusion criteria: Potential participants were excluded if they met clinical diagnosis of a dementing disorder (such as vascular dementia); had a recent (within 2 months) diagnosis of major depression or mania; had active substance abuse or dependence that, in the research physician s opinion, would impact on diagnostic decisions, safety, or anticipated adherence; were judged (clinically) to be a serious suicide risk, for whom the possibility of being treated with placebo rather than citalopram augmentation was considered unsafe; had previously experienced allergic reaction or significant adverse events while taking citalopram; or were advised (on the basis of the treating or study physicians judgment) not to take selective serotonin reuptake inhibitors (SSRIs). Interventions Intervention Characteristics Number Randomized: 109 Dose Antipsychotic: not reported Dose Antidepressant: 10-40mg/day Duration of Trial (weeks): 12 Number Randomized: 103 Dose Antipsychotic: not reported Duration of Trial (weeks): 12 Outcomes CDRS HAM-D PANSS positive PANSS negative QLS BAS 120

121 Identification Risk of bias table Bias SAS AIMS Dropouts (any reason) Dropouts (inefficacy) Dropouts (side effects) Responders (at least 50% HAM-D, at least 50% CDRS) Adverse events CGI (severity) BPRS Negative Responders (global impression score of at least two) Sponsorship source: This work was supported by National Institute of Mental Health(NIMH) grant RO-1 MH Citalopram Augmentation of Older Patients with Schizophrenia (S. Zisook, principal investigator), and NIMH grants MH66248, MH19934, and P30 MH and the Department of Veterans Affairs. Dr. Kasckow was supported by NIMH grant R01 MH6398, the VISN 4 MIRECC, and a VISN 4 Competitive Pilot Project Fund award Country: USA Setting: outpatients Authors name: Zisook Institution: University of California San Diego, Veterans Affairs szisook@ucsd.edu Address: Sidney Zisook, M.D., University of California, San Diego, Department of Psychiatry, 3350 La Jolla Village Dr., San Diego, CA Authors' judgement Unclear risk Support for judgement Random sequence generation (selection bias) Comment: Randomized. No further description. Allocation concealment (selection Unclear risk Comment: No details presented. bias) Blinding of participants and Low risk Comment: double blind personnel (performance bias) Blinding of outcome assessment Low risk Comment: double blind (detection bias) Incomplete outcome data (attrition Low risk Comment: Low drop-out (24.7%). bias) Reasons for drop-out described. Selective reporting (reporting bias) Low risk Comment: no selective reporting Other bias Low risk Comment: no other bias Zoccali 2004 Methods Participants Study design: Randomized controlled trial Study grouping: Parallel group Intention-to-treat data: no Baseline Characteristics Number of Males: 6 Number of Females: 4 Age (Mean, SD): 30.7±

122 Duration of Illness (years): 9.6± 4.9 Number of Hospitalizations: not reported Number of Males: 7 Number of Females: 3 Age (Mean, SD): 33.4 ±9.0 Duration of Illness (years): 13.6 ±7.2 Number of Hospitalizations: not reported Inclusion criteria: Exclusion criteria: Patients with any other major psychiatric disorder, significant concurrent medical illnesses, organic brain disorder, history of substance and alcohol abuse, mental retardation, and pregnant or lactating women were excluded. To exclude the presence of a depressive episode, subjects who scored more than 20 on the Hamilton Rating Scale for Depression (Hamilton, 1967) were excluded from the study. Interventions Intervention Characteristics Number Randomized: 12 Dose Antipsychotic: 320mg/day (SD=151.2) Dose Antidepressant: 30mg/day Duration of Trial (weeks): 8 Number Randomized: 12 Dose Antipsychotic: 325mg/day (SD=131.7) Duration of Trial (weeks): 8 Outcomes HAM-D BPRS SAPS SANS Dropouts (any reason) Adverse events BPRS Depression Responders (reduction of over 20% from baseline on SANS total score) Identification Sponsorship source: University Country: Italy Setting: outpatients Authors name: Zoccali Institution: rocco.zoccali@unime.it Address: Professor Rocco Zoccali,Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche,Policlinico Universitario Via Consolare Valeria, Messina Italy.Tel: ; fax: Risk of bias table Bias Authors' Support for judgement judgement Random sequence Unclear risk Comment: Randomized. No further description. generation (selection bias) Allocation concealment (selection bias) Unclear risk Comment: No details presented. 122

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132 Teja, J. S.; Grey, W. H.; Clums, J. M.; Warren, C.. Tranquilizers or anti-depressants for chronic schizophrenics: a long term study. Australian & New Zealand Journal of Psychiatry 1975;9(4): [DOI: ] Tidey 2011 Tidey, J. W.; Rohsenow, D. J.; Kaplan, G. B.; Swift, R. M.; Reid, N.. Effects of contingency management and bupropion on cigarette smoking in smokers with schizophrenia. Psychopharmacology 2011;217(2): [DOI: /s ] Usall 2014 NCT Reboxetine and Citalopram as an Adjunct Treatment to Second Generation Antipsychotics in the Treatment of Negative Symptoms of Schizophrenia. [DOI: ] Usall, J.; López-Carrilero, R.; Iniesta, R.; Roca, M.; Caballero, M.; Rodriguez-Jimenez, R.; Oliveira, C.; Bernardo, M.; Corripio, I.; Sindreu, S.D.; Piqueras, J.C.G.; Felipe, A.E.; De Corres, B.F.; Ibáñez, A.; Huerta, R.. Double-blind, placebo-controlled study of the efficacy of reboxetine and citalopram as adjuncts to atypical antipsychotics for negative symptoms of schizophrenia. Journal of Clinical Psychiatry 2014;75(6): [DOI: ] Vestre 1969 Vestre, N. D.; Dehnel, L. L.; Schiele, B. C.. A sequential comparison of amitriptyline, perphenazine and the amitriptyline-perphenazine combination in recently admitted anergic schizophrenics. Psychosomatics 1969;10(5): [DOI: ] Waehrens 1980 Waehrens, J.; Gerlach, J.. Antidepressant drugs in anergic schizophrenia. A double-blind cross-over study with maprotiline and placebo. Acta Psychiatrica Scandinavica 1980;61(5): [DOI: ] Weiner 2012 Weiner, E.; Ball, M. P.; Buchholz, A. S.; Gold, J. M.; Evins, A. E.; McMahon, R. P.; Buchanan, R. W.. Bupropion sustained release added to group support for smoking cessation in schizophrenia: A new randomized trial and a meta-analysis. Journal of Clinical Psychiatry 2012;73(1): [DOI: /JCP.10m06143gre] Wynchank 2003 Wynchank, D.; Berk, M.. Nefazodone reduces antipsychotic-induced extrapyramidal side effects. XXIst Collegium Internationale Neuro-psychopharmacologicum, Glasgow, Scotland. 12th-16th July, [DOI: ] Wynchank, Dora; Berk, Michael. Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double-blind randomised parallel group placebo-controlled trial. Human Psychopharmacology 2003;18(4): [DOI: ] Zisook 2009 Dawes, S. E.; Palmer, B. W.; Meeks, T.; Golshan, S.; Kasckow, J.; Mohamed, S.; Zisook, S.. Does antidepressant treatment improve cognition in older people with schizophrenia or schizoaffective disorder and comorbid subsyndromal depression? Neuropsychobiology 2012;65(3): [DOI: ] Kasckow, John; Fellows, Ian; Golshan, Shahrokh; Solorzano, Ellen; Meeks, Thomas; Zisook, Sidney. Treatment of subsyndromal depressive symptoms in middle-age and older patients with schizophrenia: effect of age on response.. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2010;18: [DOI: /JGP.0b013e3181dba12f] Kasckow, John; Lanouette, Nicole; Patterson, Thomas; Fellows, Ian; Golshan, Shahrokh; Solorzano, Ellen; Zisook, Sidney. Treatment of subsyndromal depressive symptoms in middle-aged and older adults with schizophrenia: effect on functioning. International Journal of Geriatric Psychiatry 2010;25(2): [DOI: ] Lanouette, N. M.; Kaskow, J. W.; Fellows, I.; Patterson, T. L.; Golshan, S.; Zisook, S.. Subsyndromal depressive symptoms in schizophrenia: Effect of treatment response on functional outcomes. American Journal of Geriatric Psychiatry 2009;17:A128-A129. [DOI: ] 132

133 NCT Antidepressant Treatment in Older Adults With Schizophrenia. [DOI: ] Vahia, I. V.; Lanouette, N. M.; Golshan, S.; Fellows, I.; Mohamed, S.; Kasckow, J. W.; Zisook, S.. Adding antidepressants to antipsychotics for treatment of subsyndromal depressive symptoms in schizophrenia: Impact on positive and negative symptoms. Indian Journal of Psychiatry 2013;55(2): [DOI: ] Zisook, Sidney; Kasckow, John W.; Golshan, Shahrokh; Fellows, Ian; Solorzano, Ellen; Lehman, David; Mohamed, Somaia; Jeste, Dilip V.. Citalopram augmentation for subsyndromal symptoms of depression in middle-aged and older outpatients with schizophrenia and schizoaffective disorder: a randomized controlled trial. Journal of Clinical Psychiatry 2009;70(4): [DOI: ] Zisook, Sidney; Kasckow, John W.; Lanouette, Nicole M.; Golshan, Shahrokh; Fellows, Ian; Vahia, Ipsit; Mohamed, Somaia; Rao, Sanjai. Augmentation with citalopram for suicidal ideation in middle-aged and older outpatients with schizophrenia and schizoaffective disorder who have subthreshold depressive symptoms: a randomized controlled trial. Journal of Clinical Psychiatry 2010;71(7): [DOI: ] Zoccali 2004 Zoccali, Rocco; Muscatello, Maria Rosaria; Cedro, Clemente; Neri, Pietro; La Torre, Diletta; Spina, Edoardo; Di Rosa, Antonio Enrico; Meduri, Mario. The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebocontrolled study.. International clinical psychopharmacology 2004;19:71-6. [DOI: ] 133

134 Supplementary Table 2: Excluded studies with reasons Abdollahian 2009 Reason for exclusion Akhondzadeh 2008 Reason for exclusion Akhondzadeh 2009 Reason for exclusion Amrami Weizman 2013 Reason for exclusion Arango 2000 Reason for exclusion Arbitman 1970 Reason for exclusion Avenoso 1997 Reason for exclusion Bacher 1991 Reason for exclusion Baldini 1970 Reason for exclusion Benkert 1996 Reason for exclusion Biondi 1999 Reason for exclusion Bodkin 1996 Reason for exclusion Bogetto 1995 Reason for exclusion Boyer 1990 Reason for exclusion Brancato 1994 Reason for exclusion Bucci 1987 Reason for exclusion Canuso 2010 Reason for exclusion No usable data Drug never marketed Drug never marketed Duplicate Study No usable data No usable data Not randomized Wrong study design Wrong comparator No usable data Study type Not randomized Wrong comparator Wrong intervention Not randomized Not randomized Wrong study design 134

135 Carman 1981 Reason for exclusion Centorrino 1994 Reason for exclusion Collins 1991 Reason for exclusion Cooper 1979 Reason for exclusion Cooper 1989 Reason for exclusion D'Arrigo 2005 Reason for exclusion D'Souza 1994 Reason for exclusion Daniel 1994 Reason for exclusion DelleChiaie 2007 Reason for exclusion Deutsch 1977 Reason for exclusion Dim 1968 Reason for exclusion Dwivedi 2002 Reason for exclusion Fatemi 2005 Reason for exclusion Faucher 2005 Reason for exclusion Fitzgerald 2004 Reason for exclusion Friedman 2008 Reason for exclusion Gallant 1967 Reason for exclusion Wrong intervention Not randomized Wrong intervention No usable data Wrong patient population Study type Study type Study type Not randomized Wrong comparator Drug never marketed Study type No usable data Not randomized Wrong intervention Wrong intervention Wrong intervention Goff

136 Reason for exclusion Goff 1995 Reason for exclusion Goncalves 1976 Reason for exclusion Goode 1983 Reason for exclusion Grinshpoon 2000 Reason for exclusion Hanlon 1970 Reason for exclusion Haskell 1974 Reason for exclusion Heller 1966 Reason for exclusion Hiemke 2002 Reason for exclusion Hinze Selch 2000 Reason for exclusion Hirschowitz 1983 Reason for exclusion Hwang 1993 Reason for exclusion Janecek 1963 Reason for exclusion Jockers Scherubl 2001 Reason for exclusion Joffe 1998 Reason for exclusion Johnson 1981 Reason for exclusion Not randomized Duplicate Study Wrong intervention Wrong intervention Study type Wrong patient population Wrong patient population Study type Not randomized No usable data Wrong patient population Study type Wrong patient population Not randomized Not randomized Duplicate Study JPRN UMIN Reason for exclusion No usable data Kane 1989 Reason for exclusion Study type 136

137 Kasckow 2008 Reason for exclusion Khan 1987 Reason for exclusion Kirli 1998 Reason for exclusion Kishi 2013 Reason for exclusion Kodesh 2003 Reason for exclusion Kontaxakis 2004 Reason for exclusion Kornhuber 1985 Reason for exclusion Lan 2006 Reason for exclusion Lapolla 1967 Reason for exclusion Lee 1996 Reason for exclusion Legare 2013 Reason for exclusion Levy 1983 Reason for exclusion Levy 2003 Reason for exclusion Li 2008 Reason for exclusion Liang 2003 Reason for exclusion Lindenmayer 1990 Reason for exclusion Litman 1993 Reason for exclusion Study type Not randomized Wrong comparator Study type No usable data Study type No usable data Mainland China Not randomized Not randomized Study type Wrong comparator Study type Mainland China Mainland China Study type Drug never marketed Lund 2001 Reason for exclusion Study type 137

138 Mazeh 2004 Reason for exclusion McClelland 1987 Reason for exclusion Melamed 1996 Reason for exclusion Mena 1964 Reason for exclusion Mercer 1988 Reason for exclusion Mercer 1988a Reason for exclusion Michaux 1969 Reason for exclusion Miodownik 2006 Reason for exclusion Not randomized Wrong patient population Study type Wrong comparator Wrong patient population Duplicate Study Not randomized Follow up < 1 week Muller Siecheneder 1998 Reason for exclusion Wrong patient population Nakanishi 2004 Reason for exclusion Ogata 1981 Reason for exclusion Oltman 1966 Reason for exclusion Overall 1964 Reason for exclusion Patch 1967 Reason for exclusion Patel 1997 Reason for exclusion Pishkin 1972 Reason for exclusion Potkin 2002 Reason for exclusion Not randomized Wrong comparator Wrong study design Wrong comparator Wrong patient population Study type Wrong intervention Wrong comparator 138

139 Poyurovsky 1996 Reason for exclusion Poyurovsky 1998 Reason for exclusion Poyurovsky 1999 Reason for exclusion Poyurovsky 2002 Reason for exclusion Poyurovsky 2003 Reason for exclusion Poyurovsky 2003a Reason for exclusion Poyurovsky 2003b Reason for exclusion Poyurovsky 2007 Reason for exclusion Poyurovsky 2013 Reason for exclusion Purdon 1998 Reason for exclusion Ranjbar 2011 Reason for exclusion Reznik 2000 Reason for exclusion Sabbatini 1984 Reason for exclusion Santoro 2010 Reason for exclusion Sharpley 1964 Reason for exclusion Shaskan 1975 Reason for exclusion Sheremata 2004 Reason for exclusion Not randomized No usable data Follow up < 1 week Duplicate Study Follow up < 1 week No usable data Study type Duplicate Study Wrong intervention Study type No usable data Not randomized Wrong patient population Not randomized Wrong intervention Duplicate Study Study type Shim 2003 Reason for exclusion Not randomized 139

140 Silver 1995 Reason for exclusion Silver 1996 Reason for exclusion Silver 1996a Reason for exclusion Silver 1996b Reason for exclusion Silver 1998 Reason for exclusion Silver 2003 Reason for exclusion Silver 2003a Reason for exclusion Siris 1989 Reason for exclusion Siris 1989a Reason for exclusion Siris 1990 Reason for exclusion Siris 1994 Reason for exclusion Sofronov 2011 Reason for exclusion Sofronov 2013 Reason for exclusion St Jean 1966 Reason for exclusion Sterlin 1971 Reason for exclusion Strous 1999 Reason for exclusion Stryjer 2010 Reason for exclusion Study type Not randomized Not randomized Not randomized Wrong comparator Study type Study type Wrong study design Study type Study type Study type No usable data No usable data Not randomized Wrong comparator Study type Follow up < 1 week Tong

141 Reason for exclusion Ungvari 1997 Reason for exclusion Ungvari 2010 Reason for exclusion Mainland China cross over Drug not marketed VanAlphen 1996 Reason for exclusion Vartiainen 1995 Reason for exclusion Volterra 1990 Reason for exclusion Yasui Furukori 2004 Reason for exclusion Yi 2000 Reason for exclusion Zhang 2002 Reason for exclusion Ziedonis 1992 Reason for exclusion Study type cross over Drug not marketed Study type Mainland China Mainland China Not randomized References Abdollahian 2009 Abdollahian, E.. Effects of selegiline on negative symptoms in schizophrenia: A double-blind, placebo-controlled, study. European Archives of Psychiatry and Clinical Neuroscience 2009;259:S82. [DOI: ] Akhondzadeh 2008 Akhondzadeh, Shahin; Malek-Hosseini, Mojgan; Ghoreishi, Aboulfazl; Raznahan, Maedeh; Rezazadeh, Shams-Ali. Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Progress in Neuro- Psychopharmacology & Biological Psychiatry 2008;32(8): [DOI: ] Akhondzadeh 2009 Akhondzadeh, Shahin; Malek-Hosseini, Mojgan. Effect of ritanserin on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. British Journal of Clinical Pharmacology 2009;68(2):304. [DOI: ] Amrami Weizman 2013 Amrami-Weizman, A.; Maayan, R.; Gil-Ad, I.; Pashinian, A.; Fuchs, C.; Kotler, M.; Poyurovsky, M.. The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients. Psychopharmacology 2013;230(1): [DOI: ] Arango 2000 Arango, C.; Kirkpatrick, B.; Buchanan, R. W.. Fluoxetine as an add-on medication to typical antipsychotics in chronic schizophrenia. Schizophrenia Research (Xth Biennial Winter Workshop on Schizophrenia. Davos, Switzerland. February 5-11, 2000) [DOI: ] Arbitman

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152 Supplementary Table 3: Additional details of the search and search terms Databases searched No of results retrieved Medline (Ovid SP) 1117 Cochrane Central register of Controlled Trials (CENTRAL) Embase (Ovid SP) 2890 Biosis 523 Psycinfo 415 Pubmed 3050 Clinicaltrials.gov 352 WHO International Trial Registry 114 Total before duplication Total after duplication 7159 BIOSIS search strategy # #30 AND #29 Indexes=BIOSIS Previews Timespan=All years # 30 6,013,203 TAXONOMIC DATA: (Human) Indexes=BIOSIS Previews Timespan=All years # #28 AND #25 AND #21 AND #20 Indexes=BIOSIS Previews Timespan=All years # ,553 #27 OR #26 Indexes=BIOSIS Previews Timespan=All years # 27 69,148 TOPIC: (amisulpride or asenapine or benperidol or chlorpromazine or chlorprothixene or clopenthixol or clozapine or cyamemazine or droperidol or flupehenazine or flupenthixol or fluphenazine or haloperidol or iloperidone or levomepromazine or loxapine or lurasidone or mesoridazine or molindone or olanzapine or paliperidone or pericyazine or perphenazine or pimozide or pipothiazine or prochlorperazine or promazine or promethazine or quetiapine or risperidone or sertindole or stelazine or sulpiride or thioridazine or thiothixene or trifluoperazine or triflupromazine or ziprasidone or zotepine or zuclopenthixol) Indexes=BIOSIS Previews Timespan=All years # 26 71,330 TOPIC: (antipsychoti* or neurolept*) Indexes=BIOSIS Previews Timespan=All years # ,363 #24 OR #23 OR #22 Indexes=BIOSIS Previews Timespan=All years # ,764 TOPIC: (agomelatine or ameser* or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine* or danitracen* or dapiprazole* or demexiptilin* or desipramine or desvenlafaxine or dexamisole* or deximafen* or dibenzepin* or dimenthazan* or dimetacrine or dioxadrol* or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin* or fenmetazol* or fezolamin* or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin* or heterocyclic* or Hypericum or ifoxetin* or impiramine or iofepramine or ipramin* or iprindole or iproniazid or izocarboxazid* or lazabemide or levoprotiline* or lithium or litracen* or lofepramine or maleate or maprotiline or medifoxamin* or melitracen or metapramin* or mianserin or milnacipram or milnacipran or minaprin* or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin* or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan* 152

153 or oxamine* or oxaprotilin* or oxetin* or oxitriptan* or paroxetine or phenelzine or piberbalin* or pipofezin* or pirlindol* or pramin* or prazepin* or praziton* or pridefin* or propizepin* or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram* or rubidium* or sertraline or setiptilin* or sibutramine or teniloxazin* or tetracyclic* or tianeptine or tofenacin* or toloxatone or trametralin* or tranylcipromine or trazodone or trebenzomin* or tricyclic* or trimipramine or triptylin* or trocimine* or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or "sodium hexacyclonate*" or "monoamine oxidase inhibitor*" or "trazium esilate*" or "selegiline transdermal" or "serotonin reuptake inhibitor*" or "St John's Wort") Indexes=BIOSIS Previews Timespan=All years # 23 11,044 TOPIC: ((NARI or "noradrenaline reuptake inhibitor*" or NDRI or "norepinephrinedopamine reuptake inhibitor*" or SNRI or "serotonin-norepinephrine reuptake inhibitor*" or NASSA or "noradrenergic serotonergic antidepressant*" or SARI or TCA)) Indexes=BIOSIS Previews Timespan=All years # 22 67,490 TOPIC: (Antidepress* or Thymoleptic* or Thymoanaleptic*) Indexes=BIOSIS Previews Timespan=All years # ,926 TOPIC: (schizo*) Indexes=BIOSIS Previews Timespan=All years # 20 2,530,878 #19 OR #14 OR #13 OR #12 OR #5 OR #2 OR #1 Indexes=BIOSIS Previews Timespan=All years # 19 77,703 #18 AND #17 Indexes=BIOSIS Previews Timespan=All years # ,013 #16 OR #15 Indexes=BIOSIS Previews Timespan=All years # ,101 DS=random* OR TS=random* OR TI=random* Indexes=BIOSIS Previews Timespan=All years # ,460 DS=assign* OR TS=assign* OR TI=assign* Indexes=BIOSIS Previews Timespan=All years # 15 35,070 DS=allocate* OR TS=allocate* OR TI=allocate* Indexes=BIOSIS Previews Timespan=All years # 14 35,422 DS=crossover* OR TS=crossover* OR TI=crossover* Indexes=BIOSIS Previews Timespan=All years # 13 2,001,033 #9 OR #8 OR #7 OR #6 Indexes=BIOSIS Previews Timespan=All years # ,328 #11 OR #10 Indexes=BIOSIS Previews Timespan=All years # ,416 DS=blind* OR TS=blind* OR TI=blind* Indexes=BIOSIS Previews Timespan=All years # 10 47,022 DS=mask* OR TS=mask* OR TI=mask* Indexes=BIOSIS Previews Timespan=All years # DS=trebl* OR TS=trebl* OR TI=trebl* Indexes=BIOSIS Previews Timespan=All years # 8 79,963 DS=tripl* OR TS=tripl* OR TI=tripl* Indexes=BIOSIS Previews Timespan=All years # 7 661,242 DS=doubl* OR TS=doubl* OR TI=doubl* Indexes=BIOSIS Previews Timespan=All years # 6 1,392,721 DS=singl* OR TS=singl* OR TI=singl* Indexes=BIOSIS Previews Timespan=All years # 5 414,751 #4 AND #3 Indexes=BIOSIS Previews Timespan=All years 153

154 # 4 556,223 DS=trial* OR TI=trial* OR TS=trial* Indexes=BIOSIS Previews Timespan=All years # 3 7,142,037 DS=Clin* OR TI=Clin* OR TS=Clin* Indexes=BIOSIS Previews Timespan=All years # 2 267,963 DS=randomi* OR TS=randomi* OR TI=randomi* Indexes=BIOSIS Previews Timespan=All years # MQ=randomized clinical trial* Indexes=BIOSIS Previews Timespan=All years ClinicalTrials.gov Library search strategy antidepressants and antipsychotic and schizophrenia and randomised = 49 "noradrenaline reuptake inhibitor" and antipsychotic and schizophrenia and randomised = 1 "serotonin reuptake inhibitor" and antipsychotic and schizophrenia and randomised = 172 "monoamine oxidase inhibitor" and antipsychotic and schizophrenia and randomised = 1 "noradrenergic serotonergic" and antipsychotic and schizophrenia and randomised = 0 "serotonin-norepinephrine reuptake inhibitor" and antipsychotic and schizophrenia and randomised = 0 "norepinephrine-dopamine reuptake inhibitor" and antipsychotic and schizophrenia and randomised = 0 schizophrenia and randomised and agomelatine = 0 schizophrenia and randomised and ameser* = 0 schizophrenia and randomised and amineptine = 0 schizophrenia and randomised and amitriptyline = 0 schizophrenia and randomised and amoxapine = 0 schizophrenia and randomised and atomoxetine = 11 schizophrenia and randomised and benactyzine = 0 schizophrenia and randomised and brofaramine = 0 schizophrenia and randomised and brofaromine = 0 schizophrenia and randomised and buproprion = 0 schizophrenia and randomised and butriptyline = 0 schizophrenia and randomised and caroxazone = 0 schizophrenia and randomised and cianopramine = 0 schizophrenia and randomised and citalopram = 20 schizophrenia and randomised and clomipramine = 0 schizophrenia and randomised and clorgyline = 0 schizophrenia and randomised and clovoxamine* = 0 schizophrenia and randomised and danitracen* = 0 schizophrenia and randomised and dapiprazole* = 0 schizophrenia and randomised and demexiptilin* = 0 schizophrenia and randomised and desipramine = 1 schizophrenia and randomised and desvenlafaxine = 0 schizophrenia and randomised and dexamisole* = 0 schizophrenia and randomised and deximafen* = 0 schizophrenia and randomised and dibenzepin* = 0 schizophrenia and randomised and dimenthazan* = 0 schizophrenia and randomised and dimetacrine = 0 schizophrenia and randomised and dioxadrol* = 0 schizophrenia and randomised and dosulepin = 0 schizophrenia and randomised and dothiepin = 0 schizophrenia and randomised and doxepin = 0 schizophrenia and randomised and duloxetine = 2 schizophrenia and randomised and escitalopram = 20 schizophrenia and randomised and etoperidone = 0 schizophrenia and randomised and femoxetin* = 0 schizophrenia and randomised and fenmetazol* = 0 schizophrenia and randomised and fezolamin* = 0 schizophrenia and randomised and fluoxetine = 6 schizophrenia and randomised and flupenthixol = 2 schizophrenia and randomised and fluphenazine = 5 schizophrenia and randomised and fluvoxamine = 2 154

155 schizophrenia and randomised and gamfexin* = 0 schizophrenia and randomised and heterocyclic* = 0 schizophrenia and randomised and Hypericum = 0 schizophrenia and randomised and ifoxetin* = 0 schizophrenia and randomised and imipramine = 1 schizophrenia and randomised and iofepramine = 0 schizophrenia and randomised and ipramin* = 0 schizophrenia and randomised and iprindole = 0 schizophrenia and randomised and iproniazid = 0 schizophrenia and randomised and izocarboxazid* = 1 schizophrenia and randomised and lazabemide = 1 schizophrenia and randomised and levoprotiline* = 1 schizophrenia and randomised and lithium = 10 schizophrenia and randomised and litracen* = 0 schizophrenia and randomised and lofepramine = 0 schizophrenia and randomised and maleate = 0 schizophrenia and randomised and maprotiline = 0 schizophrenia and randomised and medifoxamin* = 0 schizophrenia and randomised and melitracen = 0 schizophrenia and randomised and metapramin* = 0 schizophrenia and randomised and mianserin = 0 schizophrenia and randomised and milnacipram = 0 schizophrenia and randomised and milnacipran = 0 schizophrenia and randomised and minaprin* = 0 schizophrenia and randomised and mipramine = 0 schizophrenia and randomised and mirtazapine = 0 schizophrenia and randomised and mirtzapine = 0 schizophrenia and randomised and moclobemide = 0 schizophrenia and randomised and nefazodone = 0 schizophrenia and randomised and nialamide = 0 schizophrenia and randomised and nomeldin* = 0 schizophrenia and randomised and nomifensine = 0 schizophrenia and randomised and norpramin = 1 schizophrenia and randomised and nortriptyline = 0 schizophrenia and randomised and noxiptiline = 0 schizophrenia and randomised and omeprazole = 0 schizophrenia and randomised and opipramol = 0 schizophrenia and randomised and oxaflozan* = 0 schizophrenia and randomised and oxamine* = 0 schizophrenia and randomised and oxaprotilin* = 0 schizophrenia and randomised and oxetin* = 0 schizophrenia and randomised and oxitriptan* = 0 schizophrenia and randomised and paroxetine = 5 schizophrenia and randomised and phenelzine = 0 schizophrenia and randomised and piberbalin* = 0 schizophrenia and randomised and pipofezin* = 0 schizophrenia and randomised and pirlindol* = 0 schizophrenia and randomised and pramin* = 0 schizophrenia and randomised and prazepin* = 0 schizophrenia and randomised and praziton* = 0 schizophrenia and randomised and pridefin* = 0 schizophrenia and randomised and propizepin* = 0 schizophrenia and randomised and proptriptyline = 0 schizophrenia and randomised and protriptyline = 0 schizophrenia and randomised and quinupramine = 0 schizophrenia and randomised and reboxetine = 2 schizophrenia and randomised and rolipram* = 1 schizophrenia and randomised and rubidium* = 0 schizophrenia and randomised and sertraline = 11 schizophrenia and randomised and setiptilin* = 0 155

156 schizophrenia and randomised and sibutramine = 1 schizophrenia and randomised and teniloxazin* = 0 schizophrenia and randomised and tetracyclic* = 0 schizophrenia and randomised and tianeptine = 0 schizophrenia and randomised and tofenacin* = 0 schizophrenia and randomised and toloxatone = 0 schizophrenia and randomised and trametralin* = 0 schizophrenia and randomised and tranylcypromine = 0 schizophrenia and randomised and trazodone = 1 schizophrenia and randomised and trebenzomin* = 1 schizophrenia and randomised and tricyclic* = 4 schizophrenia and randomised and trimipramine = 0 schizophrenia and randomised and triptylin* = 0 schizophrenia and randomised and trocimine* = 0 schizophrenia and randomised and tryptophan = 1 schizophrenia and randomised and tyrima = 0 schizophrenia and randomised and venlafaxine = 2 schizophrenia and randomised and vilazodone = 0 schizophrenia and randomised and viloxazine = 0 schizophrenia and randomised and viqualine = 0 schizophrenia and randomised and vortioxetine = 0 schizophrenia and randomised and zimelidine = 0 schizophrenia and randomised and Zyban = 15 schizophrenia and randomised and "sodium hexacyclonate" = 0 schizophrenia and randomised and "trazium esilate" = 0 schizophrenia and randomised and "selegiline transdermal" = 0 schizophrenia and randomised and "St John's Wort" = 0 Cochrane Central Register of Controlled Trials search strategy ID Search #1 MeSH descriptor: [Antidepressive Agents] explode all trees #2 (Antidepress* or Thymoleptic* or Thymoanaleptic*):ti,ab,kw (Word variations have been searched) #3 (NARI or "noradrenaline reuptake inhibitor*" or NDRI or "norepinephrine-dopamine reuptake inhibitor*" or SNRI or "serotonin-norepinephrine reuptake inhibitor*" or NASSA or "noradrenergic serotonergic antidepressant*" or SARI or TCA):ti,ab,kw (Word variations have been searched) #4 (agomelatine or ameser* or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine* or danitracen* or dapiprazole* or demexiptilin* or desipramine or desvenlafaxine or dexamisole* or deximafen* or dibenzepin* or dimenthazan* or dimetacrine or dioxadrol* or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin* or fenmetazol* or fezolamin* or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin* or heterocyclic* or Hypericum or ifoxetin* or impiramine or iofepramine or ipramin* or iprindole or iproniazid or izocarboxazid* or lazabemide or levoprotiline* or lithium or litracen* or lofepramine or maleate or maprotiline or medifoxamin* or melitracen or metapramin* or mianserin or milnacipram or milnacipran or minaprin* or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin* or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan* or oxamine* or oxaprotilin* or oxetin* or oxitriptan* or paroxetine or phenelzine or piberbalin* or pipofezin* or pirlindol* or pramin* or prazepin* or praziton* or pridefin* or propizepin* or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram* or rubidium* or sertraline or setiptilin* or sibutramine or teniloxazin* or tetracyclic* or tianeptine or tofenacin* or toloxatone or trametralin* or tranylcipromine or trazodone or trebenzomin* or tricyclic* or trimipramine or triptylin* or trocimine* or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or "sodium hexacyclonate*" or "monoamine oxidase inhibitor*" or "trazium esilate*" or "selegiline transdermal" or "serotonin reuptake inhibitor*" or "St John's Wort"):ti,ab #5 #1 or #2 or #3 or #4 #6 MeSH descriptor: [Antipsychotic Agents] explode all trees #7 (antipsychoti* or neurolept*):ti,ab,kw (Word variations have been searched) 156

157 #8 (amisulpride or asenapine or benperidol or chlorpromazine or chlorprothixene or clopenthixol or clozapine or cyamemazine or droperidol or flupehenazine or flupenthixol or fluphenazine or haloperidol or iloperidone or levomepromazine or loxapine or lurasidone or mesoridazine or molindone or olanzapine or paliperidone or pericyazine or perphenazine or pimozide or pipothiazine or prochlorperazine or promazine or promethazine or quetiapine or risperidone or sertindole or stelazine or sulpiride or thioridazine or thiothixene or trifluoperazine or triflupromazine or ziprasidone or zotepine or zuclopenthixol):ti,ab #9 #6 or #7 or #8 #10 #5 and #9 in Trials = 1858 Embase search strategy exp antidepressant agent/ (316375) 2 (Antidepress$ or Thymoleptic$ or Thymoanaleptic$).tw. (68942) 3 (NARI or "noradrenaline reuptake inhibitor$" or NDRI or "norepinephrine-dopamine reuptake inhibitor$" or SNRI or "serotonin-norepinephrine reuptake inhibitor$" or NASSA or "noradrenergic serotonergic antidepressant$" or SARI or TCA).tw. (12538) 4 (agomelatine or ameser$ or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine$ or danitracen$ or dapiprazole$ or demexiptilin$ or desipramine or desvenlafaxine or dexamisole$ or deximafen$ or dibenzepin$ or dimenthazan$ or dimetacrine or dioxadrol$ or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin$ or fenmetazol$ or fezolamin$ or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin$ or heterocyclic$ or Hypericum or ifoxetin$ or impiramine or iofepramine or ipramin$ or iprindole or iproniazid or izocarboxazid$ or lazabemide or levoprotiline$ or lithium or litracen$ or lofepramine or maleate or maprotiline or medifoxamin$ or melitracen or metapramin$ or mianserin or milnacipram or milnacipran or minaprin$ or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin$ or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan$ or oxamine$ or oxaprotilin$ or oxetin$ or oxitriptan$ or paroxetine or phenelzine or piberbalin$ or pipofezin$ or pirlindol$ or pramin$ or prazepin$ or praziton$ or pridefin$ or propizepin$ or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram$ or rubidium$ or sertraline or setiptilin$ or sibutramine or teniloxazin$ or tetracyclic$ or tianeptine or tofenacin$ or toloxatone or trametralin$ or tranylcipromine or trazodone or trebenzomin$ or tricyclic$ or trimipramine or triptylin$ or trocimine$ or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or "sodium hexacyclonate$" or "monoamine oxidase inhibitor$" or "trazium esilate$" or "selegiline transdermal" or "serotonin reuptake inhibitor$" or "St John's Wort").ti,ab. (196089) 5 or/1-4 (443577) 6 Antipsychotic Agents/ (61894) 7 (antipsychoti$ or neurolept$).tw. (61609) 8 chlorpromazine/ or risperidone/ or olanzapine/ or quetiapine/ or haloperidol/ or clozapine/ (111265) 9 (amisulpride or asenapine or benperidol or chlorpromazine or chlorprothixene or clopenthixol or clozapine or cyamemazine or droperidol or flupehenazine or flupenthixol or fluphenazine or haloperidol or iloperidone or levomepromazine or loxapine or lurasidone or mesoridazine or molindone or olanzapine or paliperidone or pericyazine or perphenazine or pimozide or pipothiazine or prochlorperazine or promazine or promethazine or quetiapine or risperidone or sertindole or stelazine or sulpiride or thioridazine or thiothixene or trifluoperazine or triflupromazine or ziprasidone or zotepine or zuclopenthixol).ti,ab. (69379) 10 or/6-9 (178414) 11 exp Schizophrenia/ (146026) 12 schiz$.tw. (139240) 13 or/11-12 (176423) 14 (clin$ adj2 trial).mp. ( ) 15 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. (216411) 16 (random$ adj5 (assign$ or allocat$)).mp. (126081) 17 randomi$.mp. (778188) 18 crossover.mp. (69660) 19 exp randomized-controlled-trial/ (374656) 157

158 20 exp double-blind-procedure/ (121249) 21 exp crossover-procedure/ (43275) 22 exp single-blind-procedure/ (20436) 23 exp randomization/ (66855) 24 or/14-23 ( ) 25 5 and 10 and 13 and 24 (2890) Ovid MEDLINE(R) search strategy exp Antidepressive Agents/ (123888) 2 (Antidepress$ or Thymoleptic$ or Thymoanaleptic$).tw. (47492) 3 (NARI or "noradrenaline reuptake inhibitor$" or NDRI or "norepinephrine-dopamine reuptake inhibitor$" or SNRI or "serotonin-norepinephrine reuptake inhibitor$" or NASSA or "noradrenergic serotonergic antidepressant$" or SARI or TCA).tw. (8732) 4 (agomelatine or ameser$ or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine$ or danitracen$ or dapiprazole$ or demexiptilin$ or desipramine or desvenlafaxine or dexamisole$ or deximafen$ or dibenzepin$ or dimenthazan$ or dimetacrine or dioxadrol$ or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin$ or fenmetazol$ or fezolamin$ or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin$ or heterocyclic$ or Hypericum or ifoxetin$ or impiramine or iofepramine or ipramin$ or iprindole or iproniazid or izocarboxazid$ or lazabemide or levoprotiline$ or lithium or litracen$ or lofepramine or maleate or maprotiline or medifoxamin$ or melitracen or metapramin$ or mianserin or milnacipram or milnacipran or minaprin$ or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin$ or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan$ or oxamine$ or oxaprotilin$ or oxetin$ or oxitriptan$ or paroxetine or phenelzine or piberbalin$ or pipofezin$ or pirlindol$ or pramin$ or prazepin$ or praziton$ or pridefin$ or propizepin$ or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram$ or rubidium$ or sertraline or setiptilin$ or sibutramine or teniloxazin$ or tetracyclic$ or tianeptine or tofenacin$ or toloxatone or trametralin$ or tranylcipromine or trazodone or trebenzomin$ or tricyclic$ or trimipramine or triptylin$ or trocimine$ or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or "sodium hexacyclonate$" or "monoamine oxidase inhibitor$" or "trazium esilate$" or "selegiline transdermal" or "serotonin reuptake inhibitor$" or "St John's Wort").ti,ab. (149657) 5 or/1-4 (225645) 6 Antipsychotic Agents/ (43502) 7 (antipsychoti$ or neurolept$).tw. (42780) 8 chlorpromazine/ or risperidone/ or olanzapine/ or quetiapine/ or haloperidol/ or clozapine/ (38945) 9 (amisulpride or asenapine or benperidol or chlorpromazine or chlorprothixene or clopenthixol or clozapine or cyamemazine or droperidol or flupehenazine or flupenthixol or fluphenazine or haloperidol or iloperidone or levomepromazine or loxapine or lurasidone or mesoridazine or molindone or olanzapine or paliperidone or pericyazine or perphenazine or pimozide or pipothiazine or prochlorperazine or promazine or promethazine or quetiapine or risperidone or sertindole or stelazine or sulpiride or thioridazine or thiothixene or trifluoperazine or triflupromazine or ziprasidone or zotepine or zuclopenthixol).ti,ab. (57014) 10 or/6-9 (104025) 11 exp Schizophrenia/ (88226) 12 schiz$.tw. (104582) 13 or/11-12 (124632) 14 5 and 10 and 13 (3816) 15 exp clinical trial/ (816681) 16 exp randomized controlled trials/ (99686) 17 exp double-blind method/ (130918) 18 exp single-blind method/ (20630) 19 exp cross-over studies/ (36242) 20 randomized controlled trial.pt. (397216) 21 clinical trial.pt. (495266) 22 controlled clinical trial.pt. (89680) 23 (clinic$ adj2 trial).mp. (598043) 158

159 24 (random$ adj5 control$ adj5 trial$).mp. (518595) 25 (crossover or cross-over).mp. (66347) 26 ((singl$ or double$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. (180327) 27 randomi$.mp. (597230) 28 (random$ adj5 (assign$ or allocat$ or assort$ or reciev$)).mp. (171391) 29 or/15-28 ( ) and 29 (1117) PsycINFO search strategy exp antidepressant drugs/ (33280) 2 (Antidepress$ or Thymoleptic$ or Thymoanaleptic$).tw. (32700) 3 (NARI or "noradrenaline reuptake inhibitor$" or NDRI or "norepinephrine-dopamine reuptake inhibitor$" or SNRI or "serotonin-norepinephrine reuptake inhibitor$" or NASSA or "noradrenergic serotonergic antidepressant$" or SARI or TCA).tw. (1667) 4 (agomelatine or ameser$ or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine$ or danitracen$ or dapiprazole$ or demexiptilin$ or desipramine or desvenlafaxine or dexamisole$ or deximafen$ or dibenzepin$ or dimenthazan$ or dimetacrine or dioxadrol$ or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin$ or fenmetazol$ or fezolamin$ or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin$ or heterocyclic$ or Hypericum or ifoxetin$ or impiramine or iofepramine or ipramin$ or iprindole or iproniazid or izocarboxazid$ or lazabemide or levoprotiline$ or lithium or litracen$ or lofepramine or maleate or maprotiline or medifoxamin$ or melitracen or metapramin$ or mianserin or milnacipram or milnacipran or minaprin$ or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin$ or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan$ or oxamine$ or oxaprotilin$ or oxetin$ or oxitriptan$ or paroxetine or phenelzine or piberbalin$ or pipofezin$ or pirlindol$ or pramin$ or prazepin$ or praziton$ or pridefin$ or propizepin$ or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram$ or rubidium$ or sertraline or setiptilin$ or sibutramine or teniloxazin$ or tetracyclic$ or tianeptine or tofenacin$ or toloxatone or trametralin$ or tranylcipromine or trazodone or trebenzomin$ or tricyclic$ or trimipramine or triptylin$ or trocimine$ or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or "sodium hexacyclonate$" or "monoamine oxidase inhibitor$" or "trazium esilate$" or "selegiline transdermal" or "serotonin reuptake inhibitor$" or "St John's Wort").ti,ab. (42185) 5 or/1-4 (65392) 6 exp Neuroleptic Drugs/ (26416) 7 (antipsychoti$ or neurolept$).tw. (32883) 8 chlorpromazine/ or risperidone/ or olanzapine/ or quetiapine/ or haloperidol/ or clozapine/ (15119) 9 (amisulpride or asenapine or benperidol or chlorpromazine or chlorprothixene or clopenthixol or clozapine or cyamemazine or droperidol or flupehenazine or flupenthixol or fluphenazine or haloperidol or iloperidone or levomepromazine or loxapine or lurasidone or mesoridazine or molindone or olanzapine or paliperidone or pericyazine or perphenazine or pimozide or pipothiazine or prochlorperazine or promazine or promethazine or quetiapine or risperidone or sertindole or stelazine or sulpiride or thioridazine or thiothixene or trifluoperazine or triflupromazine or ziprasidone or zotepine or zuclopenthixol).ti,ab. (27135) 10 or/6-9 (48216) 11 exp Schizophrenia/ (75710) 12 schiz$.tw. (109183) 13 or/11-12 (109889) 14 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. (20952) 15 (random$ adj5 (assign$ or allocat$)).mp. (32873) 16 randomi$.mp. (55086) 17 crossover.mp. (5644) 18 or/14-17 (92482) 19 5 and 10 and 13 and 18 (415) PubMed search strategy

160 #15 Search (#5 and #10 and #13 and #14) 3050 #14 Search (((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh])) #13 Search (#11 or #12) #12 Search psychotic[title/abstract] #11 Search schizo*[title/abstract] #10 Search (#6 or #7 or #8 or #9) #9 Search ((chlorpromazine or risperidone or olanzapine or quetiapine or haloperidol or clozapine[mesh Terms])) #8 Search ((amisulpride OR asenapine OR benperidol OR chlorpromazine OR chlorprothixene OR clopenthixol OR clozapine OR cyamemazine OR droperidol OR fluphenazine OR flupenthixol OR fluphenazine OR haloperidol OR iloperidone OR levomepromazine OR loxapine OR lurasidone OR mesoridazine OR molindone OR olanzapine OR paliperidone OR pericyazine OR perphenazine OR pimozide OR pipothiazine OR prochlorperazine OR promazine OR promethazine OR quetiapine OR risperidone OR sertindole OR stelazine OR sulpiride OR thioridazine OR thiothixene OR trifluoperazine OR triflupromazine OR ziprasidone OR zotepine OR zuclopenthixol[title/abstract])) #7 Search ((antipsychoti* or neurolept*[title/abstract])) #6 Search "Antipsychotic Agents"[Mesh] #5 Search (#1 or #2 or #3 or #4) #4 Search ((agomelatine or ameser* or amineptine or amitriptyline or amoxapine or atomoxetine or benactyzine or brofaramine or brofaromine or buproprion or butriptyline or caroxazone or cianopramine or citalopram or clomipramine or clorgyline or clovoxamine* or danitracen* or dapiprazole* or demexiptilin* or desipramine or desvenlafaxine or dexamisole* or deximafen* or dibenzepin* or dimenthazan* or dimetacrine or dioxadrol* or dosulepin or dothiepin or doxepin or duloxetine or escitalopram or etoperidone or femoxetin* or fenmetazol* or fezolamin* or fluoxetine or flupenthixol or fluphenazine or fluvoxamine or gamfexin* or heterocyclic* or Hypericum or ifoxetin* or impiramine or iofepramine or ipramin* or iprindole or iproniazid or izocarboxazid* or lazabemide or levoprotiline* or lithium or litracen* or lofepramine or maleate or maprotiline or medifoxamin* or melitracen or metapramin* or mianserin or milnacipram or milnacipran or minaprin* or mipramine or mirtazepine or mirtzapine or moclobemide or moclobemide or nefazodone or nialamide or nomeldin* or nomifensine or norpramin or nortriptyline or noxiptiline or omeprazole or opipramol or oxaflozan* or oxamine* or oxaprotilin* or oxetin* or oxitriptan* or paroxetine or phenelzine or piberbalin* or pipofezin* or pirlindol* or pramin* or prazepin* or praziton* or pridefin* or propizepin* or proptriptyline or protriptyline or quinupramine or reboxetine or rolipram* or rubidium* or sertraline or setiptilin* or sibutramine or teniloxazin* or tetracyclic* or tianeptine or tofenacin* or toloxatone or trametralin* or tranylcipromine or trazodone or trebenzomin* or tricyclic* or trimipramine or triptylin* or trocimine* or tryptophan or tyrima or venlafaxine or vilazodone or viloxazine or viqualine or vortioxetine or zimelidine or Zyban or sodium hexacyclonate* or monoamine oxidase inhibitor* or trazium esilate* or selegiline transdermal or serotonin reuptake inhibitor* or St John's Wort[Title/Abstract])) #3 Search (NARI or noradrenaline reuptake inhibitor* or NDRI or norepinephrine-dopamine reuptake inhibitor* or SNRI or serotonin-norepinephrine reuptake inhibitor* or NASSA or noradrenergic serotonergic antidepressant* or SARI or TCA[Title/Abstract]) #2 Search ((Antidepress* or Thymoleptic* or Thymoanaleptic*[Title/Abstract])) #1 Search "Antidepressive Agents"[Mesh] WHO search strategy antidepress* and antipsychotic* and schizophrenia = 3 antidepress* and schizophrenia = 7 schizophrenia and random* and noradrenaline reuptake inhibitors = 0 schizophrenia and reuptake = 1 antidepress* and schizophrenia = 7 monoamine oxidase inhibitor and schizophrenia = 0 noradrenergic serotonergic and schizophrenia = 0 schizophrenia and agomelatine = 3 schizophrenia and ameser* = 0 schizophrenia and amineptine = 0 160

161 schizophrenia and amitriptyline = 1 schizophrenia and amoxapine = 0 schizophrenia and atomoxetine = 9 schizophrenia and benactyzine = 0 schizophrenia and brofaramine = 0 schizophrenia and brofaromine = 0 schizophrenia and buproprion = 0 schizophrenia and butriptyline = 0 schizophrenia and caroxazone = 0 schizophrenia and cianopramine = 0 schizophrenia and citalopram = 10 schizophrenia and clomipramine = 1 schizophrenia and clorgyline = 0 schizophrenia and clovoxamine* = 0 schizophrenia and danitracen* = 0 schizophrenia and dapiprazole* = 0 schizophrenia and demexiptilin* = 0 schizophrenia and desipramine = 1 schizophrenia and desvenlafaxine = 1 schizophrenia and dexamisole* = 0 schizophrenia and deximafen* = 0 schizophrenia and dibenzepin* = 0 schizophrenia and dimenthazan* = 0 schizophrenia and dimetacrine = 0 schizophrenia and dioxadrol* = 0 schizophrenia and dosulepin = 0 schizophrenia and dothiepin = 0 schizophrenia and doxepin = 1 schizophrenia and duloxetine = 2 schizophrenia and escitalopram = 6 schizophrenia and etoperidone = 0 schizophrenia and femoxetin* = 0 schizophrenia and fenmetazol* = 0 schizophrenia and fezolamin* = 0 schizophrenia and fluoxetine = 2 schizophrenia and flupenthixol = 4 schizophrenia and fluphenazine = 4 schizophrenia and fluvoxamine = 5 schizophrenia and gamfexin* = 0 schizophrenia and heterocyclic* = 0 schizophrenia and Hypericum = 1 schizophrenia and ifoxetin* = 0 schizophrenia and imipramine = 1 schizophrenia and iofepramine = 0 schizophrenia and ipramin* = 0 schizophrenia and iprindole = 0 schizophrenia and iproniazid = 0 schizophrenia and izocarboxazid* = 0 schizophrenia and lazabemide = 0 schizophrenia and levoprotiline* = 0 schizophrenia and lithium = 9 schizophrenia and litracen* = 0 schizophrenia and lofepramine = 0 schizophrenia and maleate = 2 schizophrenia and maprotiline = 1 schizophrenia and medifoxamin* = 0 schizophrenia and melitracen = 0 schizophrenia and metapramin* = 0 schizophrenia and mianserin = 1 schizophrenia and milnacipram = 0 161

162 schizophrenia and milnacipran = 0 schizophrenia and minaprin* = 0 schizophrenia and mipramine = 0 schizophrenia and mirtazapine = 6 schizophrenia and mirtzapine = 0 schizophrenia and moclobemide = 1 schizophrenia and nefazodone = 0 schizophrenia and nialamide = 0 schizophrenia and nomeldin* = 0 schizophrenia and nomifensine = 0 schizophrenia and norpramin = 0 schizophrenia and nortriptyline = 1 schizophrenia and noxiptiline = 0 schizophrenia and omeprazole = 0 schizophrenia and opipramol = 1 schizophrenia and oxaflozan* = 0 schizophrenia and oxamine* = 0 schizophrenia and oxaprotilin* = 0 schizophrenia and oxetin* = 0 schizophrenia and oxitriptan* = 0 schizophrenia and paroxetine = 2 schizophrenia and phenelzine = 0 schizophrenia and piberbalin* = 0 schizophrenia and pipofezin* = 0 schizophrenia and pirlindol* = 0 schizophrenia and pramin* = 0 schizophrenia and prazepin* = 0 schizophrenia and praziton* = 0 schizophrenia and pridefin* = 0 schizophrenia and propizepin* = 0 schizophrenia and proptriptyline = 0 schizophrenia and protriptyline = 0 schizophrenia and quinupramine = 0 schizophrenia and reboxetine = 4 schizophrenia and rolipram* = 0 schizophrenia and rubidium* = 0 schizophrenia and sertraline = 6 schizophrenia and setiptilin* = 0 schizophrenia and sibutramine = 1 schizophrenia and teniloxazin* = 0 schizophrenia and tetracyclic* = 0 schizophrenia and tianeptine = 0 schizophrenia and tofenacin* = 0 schizophrenia and toloxatone = 0 schizophrenia and trametralin* = 0 schizophrenia and tranylcypromine = 1 schizophrenia and trazodone = 2 schizophrenia and trebenzomin* = 0 schizophrenia and tricyclic* = 0 schizophrenia and trimipramine = 1 schizophrenia and triptylin* = 0 schizophrenia and trocimine* = 0 schizophrenia and tryptophan = 1 schizophrenia and tyrima = 0 schizophrenia and venlafaxine = 2 schizophrenia and vilazodone = 0 schizophrenia and viloxazine = 0 schizophrenia and viqualine = 0 schizophrenia and vortioxetine = 1 schizophrenia and zimelidine = 0 162

163 schizophrenia and Zyban = 0 schizophrenia and sodium hexacyclonate = 0 schizophrenia and trazium esilate = 0 schizophrenia and selegiline transdermal = 0 schizophrenia and St John's Wort = 1 163

164 Supplementary Table 4: Data items and changes from the protocol Background information Sponsorship source Country Setting (inpatients or outpatients) Author's name Institution Address Group (parallel group or crossover) Baseline characteristics Inclusion Criteria Exclusion Criteria Number of Males Number of Females Age (Mean, SD) Duration of Illness (years) Number of Hospitalizations Intervention characteristics Antidepressant Antipsychotic Number Randomized Dose Antipsychotic Dose Antidepressant Duration of Trial (weeks) Outcomes: Continuous Primary: 1) Depressive symptoms Calgary Depression Scale for Schizophrenia (CDSS) Baseline and Endpoint The Hamilton Rating Scale for Depression (HRSD) Baseline and Endpoint The Montgomery Åsberg Depression Rating Scale (MADRS) Baseline and Endpoint The Brief Psychiatric Rating Scale (BPRS) Depression Score [post-hoc] 2) Negative symptoms [set post-hoc as primary due to its importance] The Positive and Negative Syndrome Scale (PANSS) Negative Score Baseline and Endpoint The Scale for the Assessment of Negative Symptoms (SANS) Baseline and Endpoint The Brief Psychiatric Rating Scale (BPRS) Negative Score [post-hoc] Secondary: Positive symptoms The Positive and Negative Syndrome Scale (PANSS) - Positive Score Baseline and Endpoint The Scale for the Assessment of Positive Symptoms (SAPS) Baseline and Endpoint The Brief Psychiatric Rating Scale (BPRS) Positive Score [post-hoc] Overall symptoms The Positive and Negative Syndrome Scale (PANSS) Total score Baseline and Endpoint The Brief Psychiatric Rating Scale (BPRS) Total score Baseline and Endpoint The Clinical Global Impression - Severity scale (CGI-S) [post-hoc] The Clinical Global Impression - Improvement scale (CGI-I) [post-hoc] The Quality of Life Scale (QLS) The Barnes Akathisia Scale (BARS) The Simpson Angus Scale (SAS) The Abnormal Involuntary Movement Scale (AIMS) Outcomes: Dichotomous Dropouts (any reason) 164

165 Dropouts (inefficacy) Dropouts (side effects) Exacerbation of psychosis At least 50% HRSD improvement At least 50% CDSS improvement At least 50% MADRS improvement [no data available] At least 50% PANSS Total Score improvement At least 50% PANSS Negative Score improvement [no data available] At least 50% PANSS Positive Score improvement [no data available] Responders as defined by the authors [post-hoc] Adverse events At least one Abdominal Pain Agitation Akathisia Anxiety Appetite decrease Appetite increase Blurred vision Chest pain Constipation Cramps Diarrhea Dizziness Drowsiness Dry mouth Ejaculatory disorder Erectile disorder Fatigue Flatulence Flu Headache Heartbeat (rapid) Hypertension Insomnia Irritability Libido decrease Nausea Pain muscle/joint, etc. Parkinsonism Pharyngitis Rash Respiratory infection Shortness of breath Sleep difficulties Tinnitus Tremor Urination, difficulty Urination, increased Vomiting Weight gain 165

166 Supplementary Figure 1 and 2: Risk of bias assessment Supplementary Figure 1: Risk of bias summary Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. 166

167 Supplementary Figure 2: Risk of bias summary Risk of bias summary: review authors' judgements about each risk of bias item for each included study ( + : low risk of bias;? : unclear risk of bias; - : high risk of bias) 167

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