Emerging Pharmacological Treatments for Major Depressive Disorder: A Narrative Review of Clinical Trials from 2023 to 2025
Keywords:
depression, antidepressants, esketamine, psilocybin, zuranolone, treatment-resistant, NMDA, clinical trials, pharmacotherapyAbstract
Major depressive disorder (MDD) remains a leading cause of global disability, affecting approximately 332 million individuals worldwide. Despite decades of monoaminergic antidepressant use, up to 60% of patients fail to achieve adequate remission with first-line therapies. This narrative review examines clinical trial evidence published between 2023 and 2025 for novel and emerging pharmacological treatments targeting non-monoaminergic pathways, including NMDA receptor antagonists (esketamine, dextromethorphan–bupropion, esmethadone), GABA-A receptor modulators (zuranolone), serotonergic psychedelics (psilocybin/COMP360), and kappa-opioid receptor antagonists (aticaprant). Efficacy outcomes are compared across drug classes using MADRS and HAM-D scales. The ESCAPE-TRD trial demonstrated esketamine's superiority over quetiapine in treatment-resistant depression (TRD), while psilocybin showed clinically meaningful sustained effects in phase 2 and phase 3 studies. Zuranolone received FDA approval for postpartum depression. Kappa-opioid antagonists showed promise in phase 2 but failed phase 3 endpoints. A tabular comparison of efficacy by drug class is provided. These findings illustrate a paradigm shift from serotonin-centric models toward rapid-acting, mechanism-driven interventions for depression.
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