From bias to signal: the prognostic meaning of baseline pharmacotherapy in clinical high-risk for psychosis

Observational evidence is increasingly central to prognostic precision in early intervention in mental health, particularly in Clinical High-Risk for Psychosis (CHR-P) populations where trajectories are heterogeneous and clinical decisions unfold sequentially. In this context, baseline pharmacological exposure should not be treated merely as a nuisance variable or dismissed because it may reflect confounding by indication, confounding by severity, or protopathic bias. These mechanisms limit causal interpretation, but they may also explain why treatment exposure carries prognostic information. Antipsychotic, antidepressant, benzodiazepine, or combined exposure at CHR-P inception may encode prior clinical deterioration, symptom burden, comorbidity, treatment-seeking pathways, clinician concern, partial treatment response, or pharmacologically attenuated expression of emerging psychosis. Current prognostic models often prioritize demographic, symptomatic, cognitive, and functional predictors while giving insufficient attention to baseline pharmacotherapy, despite its availability, clinical interpretability, and temporal relevance. Incorporating medication exposure, dose, duration, indication, adherence, severity, and longitudinal treatment changes may improve risk stratification, reduce hidden heterogeneity, and support more precise evaluation of preventive interventions. The key implication is methodological and clinical: treatment exposure should be interpreted with causal humility but prognostic pragmatism. In CHR-P research, medication history is not simply a source of bias; it is part of the longitudinal clinical record and may help identify prognostically non-equivalent subgroups.