Body Composition-Mediated and Drug-Related Metabolic Dysregulation During Long-Term Antipsychotic Treatment in Youth

Second-generation antipsychotics (SGAs) are widely used in youths with severe mental illness but are frequently associated with cardiometabolic adverse effects. It remains unclear how much metabolic dysregulation results from body composition (BC) changes versus direct SGA effects. We followed 510 mostly antipsychotic-naive youths (male sex 55.7%, age of 4–17 years) initiating/reinitiating/switching to SGAs, with plasma concentration-verified adherence. BC and glucose/lipid metabolism changes were repeatedly assessed over 12 months. Metabolic changes were (1) controlled for and (2) correlated with body weight and fat mass, distinguishing BC-independent and BC-dependent metabolic dysregulation. BC-independent increases in total cholesterol, fasting glucose and triglycerides occurred especially with olanzapine and partially with risperidone but less with quetiapine and aripiprazole. Conversely, insulin resistance increased most in association with BC. SGAs dysregulate metabolism through distinct BC-independent and BC-dependent pathways, previously unexplored in large, well-characterized clinical samples. These findings highlight a need for cardiometabolic monitoring beyond weight in SGA-treated youths and for safer treatment alternatives. This study investigates cardiometabolic effects of second-generation antipsychotics in youth, distinguishing body composition-related changes from direct drug impacts. Findings reveal distinct metabolic dysregulation pathways, emphasizing the necessity for comprehensive monitoring and safer treatment options in clinical practice.