Quality of Life in Adolescents with Schizophrenia: The Importance of Social Cognition and Residual Psychopathology in the Context of CYP2D6 Polymorphism

Background and Objectives: Schizophrenia in adolescence severely impairs quality of life (QoL) and disrupts critical social, academic, and neurodevelopmental periods. Beyond symptom remission, functional recovery and subjective well-being have become central therapeutic goals; however, the specific contributions of pharmacogenetic, social–cognitive, and residual clinical factors to QoL in early-onset schizophrenia remain largely unexplored. This study investigated the contribution of CYP2D6 metabolizer status, social cognition (theory of mind and empathy), residual psychopathology, and family factors to subjective QoL in adolescents with schizophrenia. Materials and Methods: A cross-sectional study of 52 adolescents with DSM-5 schizophrenia (PAT-SCZ) and 51 matched healthy controls. QoL was measured with the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). Social cognition was assessed using the revised Reading the Mind in the Eyes Test (RMET). Residual symptoms were rated with the Positive and Negative Syndrome Scale (PANSS). CYP2D6 genotyping classified patients as normal metabolizers (NMs) or reduced-function metabolizers (RM: intermediate/poor). Two multivariable OLS regression models examined predictors of QoL. Results: Patients showed markedly lower QoL, impaired theory of mind, lower empathy, and higher residual symptoms than controls (all p < 0.0001). Within patients, reduced-function metabolizer (RM) status was associated with poorer QoL, weaker social cognition, higher negative/general psychopathology, and lower IQ. Two multivariable regression models explained 84.2–84.3% of the variance in QoL (adjusted R2). Social cognition (RMET scores) and CYP2D6 reduced-function metabolizer status emerged as the strongest predictors (β = 0.363 and β = −0.362, respectively, both p < 0.0001), followed by negative symptom severity and dysfunctional family relationships (all p < 0.05). Conclusions: Pharmacogenetic (CYP2D6), social–cognitive, and clinical factors strongly determine QoL in adolescent schizophrenia. Routine CYP2D6 genotyping, social-cognition remediation, and family interventions should be integrated into early treatment to improve long-term well-being.