Neurobiological mechanisms of second-generation antipsychotic-induced obesity: Interactions between ghrelin signaling...

Second-generation (atypical) antipsychotics are central to the treatment of schizophrenia and related disorders but are frequently associated with significant metabolic adverse effects, particularly weight gain and obesity. These complications can impair treatment adherence and substantially increase the risk of cardiovascular and metabolic comorbidities. Accumulating evidence indicates that antipsychotic-induced metabolic dysregulation arises from complex interactions between central neurotransmitter systems and neuroendocrine regulators of appetite and energy balance. Among these, the orexigenic peptide ghrelin and its receptor, growth hormone secretagogue receptor 1a(GHSR1a), play a key role in linking peripheral metabolic signals with central reward pathways that govern feeding behavior. Ghrelin signaling also functionally interacts with multiple neurotransmitter systems and the hypothalamic-pituitary-adrenal (HPA) axis, all of which are targets of atypical antipsychotics. This narrative review examines the convergence of ghrelin signaling with serotonergic, dopaminergic, histaminergic, and cholinergic pathways involved in appetite regulation. We further consider how sex-dependent differences in ghrelin signaling, antipsychotic pharmacokinetics, and bidirectional interactions with the HPA axis contribute to metabolic vulnerability. In addition, we explore how the pharmacodynamic profiles of second-generation antipsychotics influence these neurochemical and neuroendocrine networks, highlighting shared receptor-level mechanisms that may promote increased food intake and metabolic dysfunction. Integrating insights from neuropharmacology, neuroendocrinology, and psychiatric neuroscience, this review outlines mechanisms underlying antipsychotic-associated obesity and identifies potential targets to mitigate metabolic side effects while preserving therapeutic efficacy.