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

T. Masuda
F. Misawa
M. Takase
J. M. Kane, Zucker School of Medicine at Hofstra/Northwell
C. U. Correll, Zucker School of Medicine at Hofstra/Northwell


© 2019 American Medical Association. All rights reserved. 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.