[Skip to Content]
[Skip to Content Landing]
Original Investigation
July 31, 2019

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

Author Affiliations
  • 1Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York
  • 2Sumitomo Dainippon Pharma Co, Ltd, Medical Affairs, Tokyo, Japan
  • 3Yamanashi Prefectural KITA Hospital, Yamanashi, Japan
  • 4Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
  • 5Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York
  • 6Feinstein Institute for Medical Research, Manhasset, New York
  • 7Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
JAMA Psychiatry. 2019;76(10):1052-1062. doi:10.1001/jamapsychiatry.2019.1702
Key Points

Question  Meta-analyzing nonrandomized cohort studies, how does clozapine compare with other second-generation antipsychotics (SGAs)?

Findings  In this systematic review and meta-analysis of 63 cohort studies comprising 109 341 participants, although more severely ill patients received clozapine, use of clozapine was associated with better effectiveness outcomes regarding hospitalization, all-cause discontinuation, and overall symptoms but with a higher risk of cardiometabolic-related outcomes vs other SGAs.

Meaning  In a more generalizable sample of patients with schizophrenia than in randomized trials, clozapine was statistically and clinically associated with better effectiveness outcomes compared with other SGAs, but some concerns about safety require careful monitoring and clinical attention.


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 = 109 341) (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 = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; 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.