Background Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side eCects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are oOen used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-eCect burden without increasing the risk of relapse. Objectives To assess the eCicacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia. Search methods We conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews. Selection criteria We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment. Data collection and analysis At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life, rehospitalisations and dropouts due to adverse eCects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse eCect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse eCects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach. Main results We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk. No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no diCerence between dose reduction and continuation on scales measuring quality of life (standardised mean diCerence (SMD) -0.01, 95% confidence interval (CI) -0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI -0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence). Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable eCect sizes; however, the 95% CI does not exclude the possibility of no diCerence (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence). More participants in the dose reduction group in comparison to the continuation group leO the study early due to adverse eCects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable eCect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence). Lastly, there was no diCerence between the dose reduction and continuation groups in the number of participants with at least one adverse eCect based on data from four studies with estimable eCect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable eCect sizes), I2 = 0%, moderate certainty evidence).
