The New and EmergIng PharmacologIC Treatments For MDD

Aslihan Uyar¹Ali Saffet Gonul^2*

• ¹Mugla Sitki Kocman University Research Hospital, Mugla, Türkiye
• ²Ege University, Bornova, Türkiye

Major depressive disorder (MDD) presents a significant global health challenge, characterized by a high prevalence and significantly impact on quality of life. Traditional antidepressants fall short in efficacy and onset speed, up to 60% of patients. This review delves into the new and emerging pharmacologic treatments for MDD, focusing on their mechanisms of action, clinical effectiveness, and potential to fill the gaps left by conventional therapies. New and emerging treatments in MDD have centered on different neurobiological pathways than the traditional monoaminergic systems. Ketamine and its enantiomer, S-ketamine, have been highlighted for their rapid antidepressant effects, acting through non-competitive NMDA receptor antagonism and other pathways involving synaptic plasticity. Clinical trials have demonstrated ketamine's ability to quickly reduce symptoms, particularly in treatment-resistant cases, with effects noticeable within hours and lasting several days post-administration. Furthermore, the combination of dextromethorphan and bupropion has shown promise. This formulation leverages dextromethorphan's NMDA receptor antagonism and sigma-1 receptor agonism, complemented by bupropion's inhibition of monoamine uptake and metabolism, resulting in quicker and more durable antidepressant effects compared to monotherapy. Neurosteroids such as brexanolone and zuranolone, targeting γaminobutyric acid (GABA)-A receptors, have emerged as effective treatments for postpartum depression. Brexanolone, administered via infusion, and zuranolone, available as an oral formulation, both have demonstrated efficacy in clinical settings. Novel treatments targeting opioid pathways, like esmethadone, and selective kappareceptor antagonists offer new hope for addressing symptoms of MDD through mechanisms not traditionally associated with antidepressant action.