Melanin-concentrating hormone: A promising target for antidepressant treatment

Depression represents a complex neuropsychiatric disorder with an escalating global health burden, characterized by heterogeneous pathophysiology and profound impairments in cognitive-emotional functioning. Current treatment methods have limited efficacy in some individuals and may induce undesirable side effects, necessitating the exploration of novel therapeutic targets and techniques. Emerging research has identified neuropeptide systems as pivotal regulators of mood-related circuits, with melanin-concentrating hormone (MCH) signaling emerging as a particularly promising candidate for antidepressant development. The potential involvement of MCH in the pathophysiology of depression was first proposed over two decades ago. Since then, accumulating evidence from recent studies has progressively illuminated its multifaceted roles in modulating depressive behaviors and underlying neurobiological mechanisms. This review systematically analyzes the mechanistic interplay between MCH signaling and depression pathophenotypes, including its relationship with the hypothalamic-pituitary-adrenal (HPA) axis, neurotransmitter systems, synaptic plasticity, and the regulation of sleep-wakefulness. Particular emphasis is placed on advancing the therapeutic rationale for MCH receptor 1 (MCHR1) antagonists, which demonstrate rapid-onset antidepressant efficacy in preclinical studies compared to traditional agents. Nonetheless, the antidepressant mechanism of the MCH system still requires further elucidation to confirm its therapeutic potential.