Next-step treatment for schizophrenia non-responsive to antipsychotics: a systematic review and network meta-analysis

Summary Background Antipsychotics are often insufficient for schizophrenia, but the optimal next-step strategies for non-response remain uncertain. Guidelines recommend some pharmacological, psychological, and non-invasive brain stimulation (NIBS) approaches, but we do not know which one works best. We summarized current evidence for schizophrenia non-responsive to antipsychotics. Methods We searched the Cochrane Schizophrenia Group registry (up till January 13, 2025), and PubMed up till January 8, 2026 for randomized controlled trials (RCTs) of patients non-responsive to prior antipsychotic treatment, with persistent symptoms after at least one adequate 4-week antipsychotic trial. Raters needed to be masked. The primary outcome was change in overall symptoms analyzed using random-effects network meta-analyses of standardized mean differences (SMDs) with 95% confidence intervals (CIs). The protocol was pre-registered (https://osf.io/wcs5d/). Findings Fifty-nine RCTs (5409 participants; mean age 39.8 years; 3416 men, 1441 women) were included; 5013 contributed to the primary analysis. Antipsychotic combination therapy (k = 18; n=575; SMD −0.25, 95% CI −0.46 to −0.04; CINeMA: very low) and electroconvulsive therapy (ECT; k=5; n=97; SMD −0.51, −0.96 to −0.06; very low) might be more efficacious than continuing the same antipsychotic. Cognitive behavioral therapy for psychosis (CBTp) showed weak evidence of benefit over continuing the same antipsychotic (k = 5; n=340; SMD −0.23, −0.58 to 0.11; very low). Other strategies—xanomeline–trospium augmentation, dose escalation, transcranial magnetic stimulation, and switching to clozapine or other antipsychotics—were inconclusive. Combination therapy increased adverse events (OR 1.93, 1.26–3.00). We found no evidence of subgroup difference among non-clozapine- and clozapine-non-response. Interpretation The results were very uncertain. More head-to-head trials are needed. We found no evidence supporting dose-escalation nor switching to clozapine. Very weak evidence suggested efficacy of antipsychotic combination and ECT augmentation and they might be considered, but with substantial caution. Funding This study was funded by the German Research Foundation (DFG, #468853597) and the Federal Ministry of Research, Technology, and Space (BMTR, #01EE2303B), and partly by a grant from SENSHIN Medical Research Foundation given to YF, DAAD fellowship to NHS and CSC scholarship to YHW.