New and emerging pharmacologic treatments for MDD.
Frontiers in psychiatry January 1, 2025 Aslihan Uyar, Ali Saffet Gonul
Major depressive disorder (MDD) remains a major global health problem, and traditional antidepressants often work slowly or not at all—up to 60% of patients do not respond adequately. This review describes emerging pharmacologic treatments that target neurobiological pathways beyond the usual monoamine systems. Ketamine and S-ketamine produce rapid antidepressant effects, often within hours, by blocking NMDA receptors and enhancing synaptic plasticity; these effects can last several days after a single dose, especially in treatment-resistant cases. A combination of dextromethorphan and bupropion also shows quicker and more durable benefits than either drug alone. Neurosteroids like brexanolone (given intravenously) and zuranolone (oral) effectively treat postpartum depression by modulating GABA-A receptors. New agents acting on opioid pathways, such as esmethadone and selective kappa receptor antagonists, offer additional novel approaches.