Steroidomic Differences Among Clozapine, Olanzapine, and Risperidone in Male Patients with First-Episode Psychosis, Including a Treatment-Resistant Schizophrenia Subgroup.

Clozapine (Clo) is the most effective antipsychotic for treatment-resistant schizophrenia (TRS), yet the mechanisms underlying its unique clinical profile remain insufficiently understood. Neuroactive steroids (NASs) influence neuronal excitability, neuroplasticity, inflammation, and stress responses-domains disrupted in schizophrenia-and may contribute to antipsychotic pharmacodynamics. This pilot study examined whether Clo exhibits a distinctive steroidomic pattern compared with olanzapine (Ola) and risperidone (Ris) in male patients with first-episode psychosis, including a clinically defined TRS subgroup receiving Clo. Serum collected after group-specific treatment durations (Clo: 17.7 ± 12.4; Ola: 13.9 ± 1.9; Ris: 12.9 ± 1.3 months) was analyzed by GC-MS/MS, with steroidogenic enzyme activities inferred from precursor-product molar ratios as proxies of metabolic balance. Statistical evaluation included age-adjusted ANCOVA, OPLS, multiple regression, and trend-based analysis of coordinated pathway-level shifts. Although Ola increased several steroid concentrations, its overall and unconjugated trends did not differ significantly from Clo (p = 0.515 and p = 0.409). At the multivariate level, however, the two profiles were significantly discriminated (OPLS: R2Y = 50.8%, CV-ANOVA p = 0.011), indicating that the difference lies in the coordinated pattern rather than the global magnitude of change. Clo showed a distinctive exploratory pattern: lower DHEA, higher 5α-reduced pregnane NAS, altered androgen turnover, reduced CYP17A1 lyase proxy activity, and a mild but statistically significant increase in the cortisol-to-cortisone ratio, and was clearly distinguished from Ris by broad steroid increases. This may indicate a shift toward a profile with potential GABAergic and neuroprotective features, although interpretations remain exploratory given the small, cross-sectional, male-only sample and the non-independence of steroid pathways. Neurosteroidogenesis may thus contribute to antipsychotic response variability and offer candidate biomarkers, warranting validation in larger longitudinal studies.