Clozapine Not Superior to Second-Generation Antipsychotics for Treatment-Resistant Schizophrenia, Study Finds
When compared to second-generation antipsychotics, clozapine did not establish superior efficacy as an intervention for treatment-resistant schizophrenia, according to a systematic review and independent participant data (IPD) meta-analysis published in The Lancet Psychiatry.
“Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia,” wrote lead author Johannes Schneider-Thoma, MD, Department of Psychiatry and Psychotherapy, School of Medicine and Health, Technical University of Munich, Munich, Germany, and study coauthors. “However, available meta-analyses of randomized controlled trials (RCTs) have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies.”
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To further investigate, the authors conducted a systematic review and IPD meta-analysis of available studies comparing the efficacy of clozapine to other second-generation antipsychotics in treatment-resistant schizophrenia. The review included 19 double-blind and single-blind RCTs (N =1599). Of those trials, 12 provided IPD (n = 1052; mean [SD] age 37.67 [11.24] years [range, 10-66 years]; 348 [33.08%] women and 704 [66.92%] men). The primary outcome was the change in overall schizophrenia symptoms at 6 to 8 weeks, measured by the Positive and Negative Syndrome Scale (PANSS). Researchers fitted a Bayesian random-effects IPD meta-regression model that utilized several prognostic factors or treatment effect modifiers, including baseline severity scores, duration of illness, and sex. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) scale was used to assess the confidence of the evidence. Several sensitivity analyses were also conducted at the participant level to harmonize the outcomes of the different studies.
The review found that the estimated mean difference in change from baseline PANSS was –0.64 points (95% CrI –3.97 to 2.63; τ=2.68), which indicated a small benefit of other second-generation antipsychotics over clozapine. However, the confidence of this evidence was graded as low.
“Overall, we found no indication for superior efficacy of clozapine, since the point estimate of the primary analysis yielded an estimate close to 0,” the authors wrote. “Moreover, none of the multiple sensitivity analyses, the secondary outcomes, or the comparisons between clozapine and specific second-generation antipsychotics indicated a substantial difference between clozapine and other second-generation antipsychotics.”
The study was limited by several factors, including the lack of IPD from 7 of the included trials and the inability to investigate all prognostic factors and treatment effects due to the unavailable data. Furthermore, 4 of the IPD studies included participants who had previously not tolerated antipsychotics along with treatment-resistant patients, but did not code for this difference, impacting the researchers’ ability to only assess data of treatment-resistant participants. “However, sensitivity analyses excluding studies admitting participants who were intolerant to previous antipsychotics and studies with comparably relaxed definitions of treatment resistance showed no evidence of superior efficacy of clozapine,” researchers wrote.
The authors emphasized the need for future research to focus on strictly defined treatment-resistant schizophrenia and explore individual differences in response to clozapine to better support clinical guideline recommendations.
