ECT augmentation of clozapine for clozapine-resistant schizophrenia: A meta-analysis of randomized controlled trials

Treatment-resistant schizophrenia (TRS) is common and debilitating. A subgroup of patients even has clozapine-resistant schizophrenia (CRS). We aimed to evaluate the efficacy and safety of electroconvulsive therapy (ECT) augmentation of clozapine for CRS. Systematic literature search of randomized controlled trials (RCTs) reporting on ECT augmentation of clozapine in CRS. Co-primary outcomes included symptomatic improvement at post-ECT assessment and study endpoint. Eighteen RCTs (n = 1769) with 20 active treatment arms were identified and meta-analyzed. Adjunctive ECT was superior to clozapine regarding symptomatic improvement at post-ECT assessment (Standardized Mean Difference (SMD) = -0.88, 95% Confidence Interval (CI): -1.33 to -0.44; I-2 = 86%, P = 0.0001) and endpoint assessment (SMD: -1.44, 95%CI: -2.05 to -0.84; I-2 = 95%, P < 0.00001), separating as early as week 1-2 (SMD = -0.54, 95%CI: -0.88 to 0.20; I-2 = 77%, P = 0.002). Adjunctive ECT was also superior regarding study-defined response at post-ECT assessment (53.6% vs. 25.4%, Risk Ratio (RR) = 1.94, 95%CI: 1.59-2.36; I-2 = 0%, P < 0.00001, number-needed-to-treat (NNT) = 3, 95%CI: 3-5) and endpoint assessment (67.7% vs. 41.4%, RR = 1.66, 95%CI: 1.38-1.99; I-2 = 47%, P < 0.00001, NNT = 4, 95%CI: 3-8), and remission at post-ECT assessment (13.3% vs. 3.7%, RR = 3.28, 95%CI: 1.80-5.99; I-2 = 0%, P = 0.0001, NNT = 13, 95%CI: 6-100) and endpoint assessment (23.6% vs. 13.3%, RR = 1.80, 95%CI: 1.39 to 2.35; I-2 = 5%, P < 0.0001, NNT = 14, 95%CI: 6-50). Patient-reported memory impairment (24.2% vs. 0%; RR = 16.10 (95%CI: 4.53-57.26); I-2 = 0%, P < 0.0001, number-needed-to-harm (NNH) = 4, 95%CI: 2-14) and headache (14.5% vs 1.6%; RR = 4.03 (95%CI: 1.54-10.56); I-2 = 0%, P = 0.005, NNH = 8, 95%CI: 4-50) occurred more frequently with adjunctive ECT. No significant group differences were found regarding discontinuation and other adverse effects. Despite increased frequency of self-reported memory impairment and headache, ECT augmentation of clozapine is a highly effective and relatively safe treatment for CRS. Registration number: CRD42018089959