2026 ECNP Congress

EP02-2091

Sex differences in the effects of antipsychotic drugs in adults with acute schizophrenia: an individual-participant-data meta-analysis

Spyridon Siafis — Y. Furukawa, J. Schneider-Thoma, N. Nomura, N. Fares-Otero, S. Illing, B.W.C. Storosum, J.B. Zantvoord, G. Schoretsanitis, C. Schwarz, J. Schulz, H. Naiser, K.H. Möhrmann, J. Priller, J.M. Davis, O. Efthimiou, G. Salanti, S. Leucht · Technical University of Munich, TUM School of Medicine and Health- Department of Psychiatry and Psychotherapy, Munich, Germany

2026 ECNP Congress

Background

Antipsychotic drugs are the mainstay of treatment for schizophrenia, yet their efficacy and side-effect profiles may differ between sexes. It has been suggested that female individuals may have higher plasma concentrations at the same doses compared to males, potentially requiring lower doses to achieve equivalent efficacy and possibly being more susceptible to certain adverse events [1]. However, evidence to guide sex-specific prescribing is limited, and current treatment recommendations are largely based on pooled estimates from trials predominantly including male participants, which may obscure sex-specific effects and potentially risk over- or underdosing. A systematic evaluation of sex differences in antipsychotic effects is needed to inform sex-specific treatment recommendations for antipsychotic prescribing. Individual trials are typically underpowered to detect subgroup effects, and aggregate-data meta-analyses are constrained by incomplete sex-stratified reporting. Therefore, individual participant data are needed. Two previous individual participant data analyses of randomized trials have suggested somewhat greater efficacy in females; however, they were limited by methodological shortcomings and did not examine adverse events, dose-response relationships, or potential differences among individual compounds [2, 3]. Therefore, we aim to fill this gap with the current individual participant data meta-analysis.

Methods

We are conducting a systematic review and individual participant data meta-analysis of randomised controlled trials comparing antipsychotic drugs with each other or placebo in adults with acute schizophrenia. Studies with fixed dosing schedules are included in the main analysis to avoid potential dose titration based on sex. We search for eligible studies in the Vivli and the Yale University Open Data Access (YODA) Project’s trial data-sharing platforms (last search April 9, 2025). Individual participant data are harmonised into a common dataset, and risk of bias is assessed using the Risk of Bias 2 tool. The primary outcome is overall symptom severity measured with the Positive and Negative Syndrome Scale at six weeks or as close as possible. Secondary outcomes include treatment discontinuation, symptom domain severity, and adverse events commonly observed with antipsychotic drugs. We follow a stepwise approach for statistical analyses. One-stage mixed-effects regression models are used to assess sex as both a prognostic factor and an effect modifier through sex-by-treatment interaction terms. In addition, we conduct two-stage dose-response meta-analyses and network meta-analyses separately for male and female participants to evaluate dose-response relationships and differences between drugs. Missing data are handled using multiple imputation. The credibility of effect modification by sex is assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) framework [4]. The protocol has been registered in PROSPERO (CRD420251022957) and published in a peer-reviewed journal [5].

Results

We identified 34 trials, of which 18 fixed-dose trials are included in the main analysis. Data harmonisation and quality checks have been completed, and the statistical analyses are ongoing. Preliminary results will be presented at the conference.

Conclusions

This study may contribute to a more evidence-based understanding of potential sex-specific considerations in antipsychotic prescribing.

References

1 Brand BA, Willemse EJM, Hamers IMH, Sommer IE. Evidence-Based Recommendations for the Pharmacological Treatment of Women with Schizophrenia Spectrum Disorders. Curr Psychiatry Rep. 2023 Nov;25(11):723-733. 2. Rabinowitz J, Werbeloff N, Caers I, Mandel FS, Stauffer V, Ménard F, Kinon BJ, Kapur S. Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials. J Clin Psychiatry. 2014 Apr;75(4):e308-16. 3. Storosum BWC, Mattila T, Wohlfarth TD, Gispen-de Wied CC, Roes KCB, den Brink WV, de Haan L, Denys DAJP, Zantvoord JB. Gender differences in the response to antipsychotic medication in patients with schizophrenia: An individual patient data meta-analysis of placebo-controlled studies. Psychiatry Res. 2023 Feb;320:114997 4. Guyatt G, Zhao Y, Mayer M, Briel M, Mustafa R, Izcovich A, Hultcrantz M, Iorio A, Alba AC, Foroutan F, Sun X, Schunemann H, DeBeer H, Akl EA, Christensen R, Schandelmaier S. GRADE guidance 36: updates to GRADE’s approach to addressing inconsistency. J Clin Epidemiol. 2023 Jun;158:70-83. 5. Siafis S, Furukawa Y, Schneider-Thoma J, Nomura N, Fares-Otero NE, Storosum BWC, Zantvoord JB, Schwarz C, Schulz J, Naiser H, Möhrmann KH, Priller J, Davis JM, Efthimiou O, Salanti G, Leucht S. Sex differences in the efficacy and tolerability of antipsychotic drugs in people with an acute exacerbation of schizophrenia: protocol for an individual-participant-data, dose-response, network meta-analysis. F1000Res. 2025 Sep 23;14:967.