New and emerging pharmacologic treatments for MDD.
Aslihan Uyar, Ali Saffet Gonul
Frontiers in Psychiatry 2025 DOI: 10.3389/fpsyt.2025.1621887 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine S-ketamine brexanolone zuranolone esmethadone selective kappa receptor antagonists |
| Topics | Neuroplasticity Depression |
| Keywords | Pharmacologic innovations Psychopharmacology Rapid-acting therapies Treatment resistant depression |
| Key findings | Newer antidepressants targeting NMDA receptors, GABA-A receptors, and opioid pathways can produce faster and more effective relief than traditional treatments, particularly for treatment-resistant depression and postpartum depression. |
Abstract
Major depressive disorder (MDD) presents a significant global health challenge, characterized by a high prevalence and significant impact on quality of life. Traditional antidepressants fall short in terms of 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, which act through non-competitive N-methyl-d-aspartate (NMDA) receptor antagonism and other pathways involving synaptic plasticity. Clinical trials have demonstrated the ability of ketamine 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 the NMDA receptor antagonism and sigma-1 receptor agonism of dextromethorphan, complemented by the inhibition of monoamine uptake and metabolism by bupropion, resulting in quicker and more durable antidepressant effects compared with monotherapy. Neurosteroids such as brexanolone and zuranolone, which target γ-aminobutyric 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, such as esmethadone, and selective kappa receptor antagonists offer new hope for addressing the symptoms of MDD through mechanisms not traditionally associated with antidepressant action.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 3
- Neuroscientific Basis of Ketamine as an Analgesic and Emerging Role in the Management of Depression. Current Pain and Headache Reports April 21, 2026
- Next-Generation Pharmacotherapy for Depressive Disorders: From Novel Compounds to Optimized Use of Available Drugs. Drug Design, Development and Therapy 2026
- Bupropion-Memantine Combination in the Treatment of Major Depressive Disorder and Treatment-Resistant Depression. Human psychopharmacology May 2026
Cites 20
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- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
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and 15 more in the library