Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics A Systematic Review and Meta-analysis of Cohort Studies

IMPORTANCE Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice. OBJECTIVE To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies. DATA SOURCES Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018. STUDY SELECTION Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder. DATA EXTRACTION AND SYNTHESIS Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data. MAIN OUTCOMES AND MEASURES Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies. RESULTS Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90). CONCLUSIONS AND RELEVANCE In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.