Electroconvulsive Therapy as an Adjunctive Treatment for Clozapine-Resistant Schizophrenia

Clozapine-resistant schizophrenia (CRS) is a severe condition with limited therapeutic options. Electroconvulsive therapy (ECT) has been proposed as augmentation, but its efficacy remains uncertain due to methodological limitations and inconsistent findings. This meta-analysis assessed the efficacy and safety of ECT as an adjunctive treatment in CRS. A systematic review and meta-analysis of RCTs was conducted following PRISMA guidelines. Databases were searched up to March 2025. The primary outcome was clinical response, defined in each RCT as a ≥40% to 50% reduction in positive psychotic symptoms. Secondary outcomes included response at ≥20% reduction, changes in negative/general symptoms, adverse effects, and dropouts. Three RCTs (102 participants) were included, two with sham-ECT controls. ECT significantly increased response compared with control for the primary outcome (RR = 5.63; 95% CI: 1.00 to 31.57; P = 0.04; I² = 0%), but showed no difference at the ≥20% threshold (RR = 1.96; 95% CI: 0.45 to 8.44; P = 0.36; I² = 55%). Other secondary outcomes were not pooled due to heterogeneity. ECT was generally well tolerated, with a low dropout rate. The primary outcome was driven by one large-effect study without sham-ECT and using clozapine monotherapy as control, while sham-controlled studies showed no significant benefit. The absence of differences at the ≥20% response threshold likely reflects the sham-ECT effects. Although underpowered, this outcome was reported to discuss active placebo effects. Given CRS severity and limited options, ECT may still be considered in selected cases, but further high-quality sham-controlled RCTs with standardized protocols are required.