The hypothalamus as a therapeutic target: Towards novel approaches for managing antipsychotic-induced weight gain

Antipsychotic drugs (APDs) represent the cornerstone of pharmacological treatment for psychotic disorders, primarily exerting their therapeutic effects through dopamine D2 receptor antagonism or partial agonism. Their interaction with additional neurotransmitter systems - particularly serotonergic, histaminergic, cholinergic, and adrenergic receptors - has been implicated in the development of metabolic side effects, including weight gain and increased cardiovascular risk. Notably, APDs with the highest therapeutic efficacy, such as clozapine and olanzapine, are also associated with the greatest risk of metabolic disturbances, indicating a complex relationship between symptom improvement and adverse metabolic outcomes. In this review, we explore current evidence on the role of the hypothalamus in APD-induced obesity, with a focus on region-specific neurobiological mechanisms and pathophysiological pathways. The review also evaluates the effectiveness of existing anti-obesity interventions and discusses how these strategies may mitigate metabolic side effects without compromising antipsychotic efficacy. Furthermore, the review presents emerging therapeutic approaches, including clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing, adenoviral interventions, nano therapies, and small extracellular vesicles targeting hypothalamic function.