¹St John of God Hospital, Pharmacy Department, Dublin, Ireland, ²RCSI University of Medicine and Health Sciences, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland, ³University College Dublin, Department of Psychiatry, Dublin, Ireland, ⁴St Vincent's University Hospital, Department of Psychiatry, Dublin, Ireland, ⁵University Medical Center Groningen, Center for Clinical Neuroscience and Cognition, Groningen, Netherlands, ⁶WHO Youth Advisory Group, Quality of Child and Adolescent Mental Healthcare, Athens, Greece, ⁷SpunOut, National Action Panel, Dublin, Ireland, ⁸University of Edinburgh, Centre for Clinical Brain Sciences, Division of Psychiatry, Edinburgh, United Kingdom

Background: Early intervention in first-episode psychosis (FEP) is critical for long-term outcomes with antipsychotic medicines among the primary treatment options. However, existing clinical practice guidelines (CPGs) do not provide sex-specific recommendations, despite females experiencing distinct vulnerabilities to antipsychotic side-effects. In particular, hyperprolactinaemia and cardiometabolic side-effects are associated with substantial subjective distress and potential long-term physical health risks for females across the reproductive lifespan.

Aims & Objectives: We aimed to develop a CPG on the preferred antipsychotic medicines for females experiencing FEP.

Method: An international multidisciplinary panel, including experts-by-experience, used the GRADE-ADOLOPMENT process and AGREE II framework to adapt existing FEP guidelines for adults and adolescents. Key health questions were developed through stakeholder consultation and literature review. Critically important patient outcomes were prioritised, and evidence was synthesised on side-effect profiles, with recommendations agreed by consensus. The guideline algorithm was field-tested and externally reviewed by experts.

Results: Prolactin-elevation and cardiometabolic side-effects were prioritised in antipsychotic medicine selection for females. Medicines with higher risks—first-generation antipsychotics, olanzapine, quetiapine, risperidone, paliperidone, and amisulpride—are not recommended first-line. Aripiprazole is recommended as the preferred first-choice due to its consistently favourable prolactin and cardiometabolic profile. Alternative options with low or low-to-moderate risk profiles are recommended for adults and adolescents, supported by shared decision-making tools.

Discussion & Conclusions: This is the first CPG addressing antipsychotic choice for females with FEP. By prioritising critically important patient outcomes and lived experience, the guideline supports safer, sex-sensitive prescribing for females that may improve treatment acceptability, adherence, and equity in psychosis care.