EClinicalMedicine · 2026
Next-step treatment for schizophrenia non-responsive to antipsychotics: a systematic review and network meta-analysis.
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Furukawa Yuki, Salahuddin Nurul Husna, Wei Yaohui, Pinioti Elisavet, Kim David D, Milosavlijević Filip, Siafis Spyridon, Schneider-Thoma Johannes, Samara Myrto, Bighelli Irene, Leucht Stefan
Аннотация
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.
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.