Meta-Analysis Finds No Clear Sex Differences in Antipsychotic Efficacy
Key Clinical Summary
- An individual participant data meta-analysis of 18 fixed-dose trials involving 7062 adults with acute schizophrenia found no evidence of sex differences in antipsychotic efficacy for overall symptom improvement.
- Antipsychotics reduced all-cause treatment dropout more among female participants than males, although the credibility of this finding was moderate.
- Antipsychotic-associated prolactin increases were greater among females, while other tolerability outcomes and dose–response relationships showed no clear sex differences.
Antipsychotics demonstrated similar efficacy for reducing overall schizophrenia symptoms in males and females, according to findings published in The Lancet Psychiatry. However, sex differences emerged in treatment acceptability and prolactin elevation, as antipsychotic use was associated with a greater reduction in all-cause dropout and larger prolactin increases in females compared with males.
Study Findings
Researchers performed pairwise, dose-response, and network meta-analyses using individual participant data from 18 fixed-dose trials. The 7062 participants had a mean age of 40.9 years and received either haloperidol, olanzapine, paliperidone, risperidone, or placebo. Overall symptom severity, measured by the Positive and Negative Syndrome Scale (PANSS) or the closest available assessment at week 6, was evaluated as the primary outcome.
The investigators reported no evidence of sex differences in drug effects on overall symptoms (difference of standardized mean differences [DoSMD] 0·04, 95% CI −0·09 to 0·18).
Similar dose-response curves were observed in both males and females, with plateaus at 3-5 mg risperidone equivalents. The network meta-analysis additionally showed no clear sex-specific treatment effects.
Sex differences emerged in 2 outcomes; antipsychotics were associated with a greater reduction of all-cause dropout in females than in males (ratio of odds ratios 0·74, 95% CI 0·56–0·98; moderate credibility), and prolactin increase was greater in females than males (DoSMD 0·83, 0·67–0·99; high credibility). No other tolerability outcomes displayed clear differences.
Clinical Implications
The findings suggest that antipsychotic efficacy estimates from previous meta-analyses may be applicable to both women and men with acute schizophrenia. While these results challenge earlier suggestions of sex differences in treatment response, the observed differences in all-cause dropout and prolactin elevation also highlight the importance of considering treatment acceptability and specific adverse effects when evaluating antipsychotic therapy.
“But we should be careful when we talk about any potential subgroup differences,” first author Yuki Furukawa, MD, Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Germany, told Psych Congress Network via email.
“False-positive differences could lead to under- or overtreatment in some subgroups. Even when a subgroup difference is true, when the difference is trivial, it should not affect daily clinical decisions.”
Expert Commentary
Furukawa also explained that differences in the handling of missing data may account for discrepancies between the current findings and earlier research on sex-specific antipsychotic efficacy.
“We used multiple imputation, whereas previous studies used last-observation-carried-forward,” he said. “It should also be noted that the potential sex difference previously reported was very small. All in all, sex difference in antipsychotics seems to be non-existent, or trivial at most.”
Furukawa emphasized that future research should include sex-stratified outcome reporting “to elucidate any potential sex differences.”
The investigators further concluded that female participation in clinical trials remains important for improving sex and gender equity in schizophrenia research.
