Predicting Social Cognitive Outcomes in Adolescent-Onset Schizophrenia: A Hierarchical Analysis of Pharmacogenetic, Clinical, and Environmental Factors

Background: Socio-cognitive deficits constitute a core and persistent feature of adolescent-onset schizophrenia, significantly impairing functional outcomes. However, the interplay between genetic metabolic markers such as CYP2D6 and specific socio-cognitive phenotypes remains poorly understood. Methods: This cross-sectional study included 73 adolescents with schizophrenia and 58 matched healthy controls. Theory of Mind (ToM) was evaluated using the Reading the Mind in the Eyes Test (RMET), while empathy was assessed with the Cambridge Empathy Quotient. Symptom severity was measured via the Positive and Negative Syndrome Scale (PANSS). CYP2D6 polymorphisms were genotyped using RT-PCR, classifying participants as Normal or Reduced (Intermediate) metabolizers. Hierarchical multiple regression analyses were performed, controlling for sex, IQ, and psychosocial factors. Results: Patients demonstrated significantly lower RMET and empathy scores compared to controls. Reduced CYP2D6 metabolizers exhibited poorer ToM performance and more severe negative symptoms. The final RMET model accounted for 88.8% of variance (p < 0.001), with CYP2D6 status emerging as a significant independent predictor (β = 0.178, p = 0.005), alongside IQ and negative symptoms. In contrast, the empathy model explained 49.0% of variance, with CYP2D6 effects fully mediated by negative symptom severity. Conclusion: Adolescents with reduced CYP2D6 metabolic activity exhibit greater negative symptom burden and impaired social-cognitive functioning. Our findings reveal a double dissociation: ToM functions as a stable, biologically anchored trait, while empathy serves as a state-dependent construct primarily driven by the negative syndrome. These insights advocate for the integration of pharmacogenetic stratification in the treatment of early-onset schizophrenia.