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

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BackgroundAlthough the validity and safety of antipsychotic polypharmacy remains unclear, it is commonplace in the treatment of schizophrenia. This study aimed to investigate the degree that antipsychotic polypharmacy contributed to metabolic syndrome in outpatients with schizophrenia, after adjustment for the effects of lifestyle.MethodsA cross-sectional survey was carried out between April 2007 and October 2007 at Yamanashi Prefectural KITA hospital in Japan. 334 patients consented to this cross-sectional study. We measured the components consisting metabolic syndrome, and interviewed the participants about their lifestyle. We classified metabolic syndrome into four groups according to the severity of metabolic disturbance: the metabolic syndrome; the pre-metabolic syndrome; the visceral fat obesity; and the normal group. We used multinomial logistic regression models to assess the association of metabolic syndrome with antipsychotic polypharmacy, adjusting for lifestyle.ResultsSeventy-four (22.2%) patients were in the metabolic syndrome group, 61 (18.3%) patients were in the pre-metabolic syndrome group, and 41 (12.3%) patients were in visceral fat obesity group. Antipsychotic polypharmacy was present in 167 (50.0%) patients. In multinomial logistic regression analyses, antipsychotic polypharmacy was significantly associated with the pre-metabolic syndrome group (adjusted odds ratio [AOR], 2.348; 95% confidence interval [CI], 1.181-4.668), but not with the metabolic syndrome group (AOR, 1.269; 95%CI, 0.679-2.371).ConclusionsThese results suggest that antipsychotic polypharmacy, compared with monotherapy, may be independently associated with an increased risk of having pre-metabolic syndrome, even after adjusting for patients' lifestyle characteristics. As metabolic syndrome is associated with an increased risk of cardiovascular mortality, further studies are needed to clarify the validity and safety of antipsychotic polypharmacy.

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Objective Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. Methods Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author‐defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis‐Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. Results 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14–8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71–7.32; p = 0.0004), severity of hyperthermia (Unit‐OR = 1.30, 95%CI = 1.16–1.46; p < 0.0001), and older age (Unit‐OR = 1.05, 95%CI = 1.02–1.07; p = 0.0014). Even in univariate, patient‐level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long‐acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first‐generation antipsychotic: n = 38/433 (8.8%) vs. second‐generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non‐antipsychotic co‐treatments were not associated with NMS mortality. Conclusion Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs.

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No studies have compared clinical outcomes after discontinuation of clozapine between patients who responded to clozapine and those who did not. Therefore, we examined 1-year clinical outcomes after clozapine discontinuation in responders and nonresponders. We reviewed data on patients who discontinued clozapine and retrospectively followed them for 1 year. Clinical information was collected from medical records starting at the initiation of clozapine administration, at discontinuation and at 1 year after discontinuation. In addition, clinical status was assessed using the Clinical Global Impression -Severity (CGI-S) and Clinical Global Impression -Improvement (CGI-I) scales. We classified the patients into clozapine responder and nonresponder groups according to the CGI-I score. Thirty-nine patients were enrolled in this study. Olanzapine was the most common antipsychotic prescribed after clozapine discontinuation in both the responder and nonresponder groups. The mean CGI-S score significantly increased 1 year after clozapine discontinuation in the responder group and significantly decreased in the nonresponder group; there was a significant difference in changes in the CGI-S scores between the groups. The difference remained significant after controlling for clozapine dose and duration of treatment. The findings suggest that clinicians may consider continuing and discontinuing clozapine treatment for patients who responded to clozapine and those who did not, respectively.