Javier Ortiz‐Orendain, Santiago Castiello‐de Obeso, Luis Enrique Colunga‐Lozano, Yue Hu, Nicola Maayan, Clive E Adams

Many people with schizophrenia do not achieve a satisfactory treatment response with their initial antipsychotic drug treatment. Sometimes a second antipsychotic, in combination with the first, is used in these situations. To examine whether:1. treatment with antipsychotic combinations is effective for schizophrenia; and2. treatment with antipsychotic combinations is safe for the same illness. We searched the Cochrane Schizophrenia Group's register which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran searches in September 2010, August 2012 and January 2016. We checked for additional trials in the reference lists of included trials. We included all randomised and quasi-randomised controlled trials comparing antipsychotic combinations with antipsychotic monotherapy for the treatment of schizophrenia and/or schizophrenia-like psychoses. We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CIs. For the meta-analysis we used a random-effects model. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for included studies. Sixty-two studies are included in the review, 31 of these compared clozapine monotherapy with clozapine combination. We considered the risk of bias in the included studies to be moderate to high. The majority of trials had unclear allocation concealment, method of randomisation and blinding, and were not free of selective reporting.There is some limited evidence that combination therapy is superior to monotherapy in improving clinical response (RR 0.73, 95% CI 0.63 to 0.85; participants = 2364; studies = 29, very low-quality evidence), although subgroup analyses show that the positive result was due to the studies with clozapine in both the monotherapy and combination groups (RR 0.66, 95% CI 0.53 to 0.83; participants = 1127; studies = 17). Few studies reported on rate of relapse, most likely due to the short length of the studies. Overall, a combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in preventing relapse (RR 0.63, 95% CI 0.31 to 1.29; participants = 512; studies = 3, very low-quality evidence), but the pooled data showed high heterogeneity (I² = 82%). A combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in reducing the number of participants discontinuing treatment early (RR 0.89, 95% CI 0.73 to 1.07; participants = 3103; studies = 43, low-quality evidence). No difference was found between treatment groups in the number of participants hospitalised (RR 0.96, 95% CI 0.36 to 2.55; participants = 202; studies = 3, low-quality evidence) . We did not find evidence of a difference between treatment groups in serious adverse events or those requiring discontinuation (RR 1.05, 95% CI 0.65 to 1.69; participants = 2398; studies = 30, very low-quality evidence). There is as lack of evidence on clinically important change in quality of life, with only four studies reporting average endpoint or change data for this outcome on three different scales, none of which showed a difference between treatment groups. Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials, limiting the assessment of long-term efficacy and safety. We found very low-quality evidence that a combination of antipsychotics may improve the clinical response. We also found low-quality evidence that a combination of antipsychotics is may make no difference at preventing participants from leaving the study early, preventing relapse and/or causing more serious adverse events than monotherapy.