Pharmacologic modulation of orexin signaling: Impact on glucose-insulin homeostasis and potential mechanism of antidepressant action.

In addition to their canonical role in sleep-wake regulation, endogenous orexin signaling is implicated in the homeostatic control of reward and motivation, stress and arousal, and glucose-insulin metabolism. Recent research has focused on the development of orexin antagonists, notably seltorexant, as adjunctive treatments in adults with major depressive disorder (MDD). Converging evidence implicates insulin resistance in MDD pathophysiology, highlighting the need to integrate preclinical, pharmacologic, and translational evidence examining the effects of orexin signaling on glucose-insulin homeostasis. A literature review was conducted using PubMed from database inception to June 2025 to identify preclinical and clinical studies examining the metabolic effects of orexin modulation. The search string included the terms related to: orexin, glucose, metabolism, and depression. Results were synthesized qualitatively across experimental models and clinical populations. Evidence indicates that orexin signaling affects multiple aspects of metabolic homeostasis. For example, orexins affect appetitive/consummatory behavior, exert incretin-like effects on insulin release and glucagon suppression, and increase energy expenditure via morphologically transitioning white-to-brown adipose tissue. These effects are mediated through both direct (eg, inhibition of gluconeogenic enzyme expression) and indirect pathways (eg, alterations in sleep architecture and attenuation of sympathoadrenal overactivity). Orexin antagonism, therefore, exerts multi-faceted physiological effects beyond sleep regulation. The antidepressant efficacy of seltorexant in MDD is greater in persons with moderate-to-severe insomnia, while remaining clinically meaningful in persons with less severe insomnia, implicating multiple mechanisms. Modulation of glucose-insulin homeostasis represents a putative, non-mutually exclusive mechanism through which orexin antagonism may contribute to antidepressant effects.