Antipsychotics-induced Metabolic Alterations: Recounting the Mechanistic Insights, Therapeutic Targets and Pharmacological Alternatives

Atypical antipsychotics (AAPs) are the drug of choice in the management of mental illnesses by virtue of their advantage over typical antipsychotics i.e. least tendency of producing extrapyramidal motor symptoms (EPS) or pseudoparkinsonism. Despite the clinical efficacy, AAPs produces troublesome adverse effects, particularly hyperphagia, hyperglycemia, dyslipidemia weight gain, diabetes mellitus, insulin resistance and QT prolongation which further develops metabolic and cardiac complications with subsequent reduction in life expectancy, poor patient compliance, and sudden death. AAPs-induced weight gain and metabolic alterations are increasing at an alarming rate and became an utmost matter of concern for psychopharmacotherapy. Diverse underlying mechanisms have been explored such as the interaction of AAPs with neurotransmitter receptors, alteration in food reward anticipation behavior, altered expressions of hypothalamic orexigenic and anorexigenic neuropeptides, histamine H receptor-mediated hypothalamic AMP-activated protein kinase (AMPK) activation, increased blood leptin, ghrelin, pro-inflammatory cytokines. Antipsychotics induced imbalance in energy homeostasis, reduction in energy expenditure which is linked to altered expression of uncoupling proteins (UCP-1) in brown adipose tissue and reduced hypothalamic orexin expressions are emerging insights. In addition, alteration in gut-microbiota and subsequent inflammation, dyslipidemia, obesity, and diabetes after AAPs treatment are also associated with weight gain and metabolic alterations. Oral hypoglycemics and lipid-lowering drugs are mainly prescribed in the clinical management of weight gain associated with AAPs while many other pharmacological and nonpharmacological interventions also have been explored in different clinical and preclinical studies. In this review, we critically discuss the current scenario, mechanistic insights, biomarkers, and therapeutic alternatives for metabolic alterations associated with antipsychotics.