Next-Generation Pharmacotherapy for Depressive Disorders: From Novel Compounds to Optimized Use of Available Drugs.
Drug design, development and therapy January 1, 2026 Fan Bu, Lan Qin, Zhengchi Lou et al.
Depressive disorders remain a leading cause of disability, and many patients do not achieve lasting remission with current treatments, especially those with treatment-resistant depression (TRD) or bipolar depression. This narrative review examines next-generation pharmacotherapy from a drug-centered and mechanism-informed perspective. It covers NMDA receptor modulators, dextromethorphan-bupropion, multimodal antidepressants, neuroactive steroids like brexanolone and zuranolone, psychedelic-assisted therapy, kappa-opioid receptor antagonists, and bipolar-specific mood stabilizers. The review also discusses optimizing existing drugs through repurposing, augmentation, combination therapy, and precision approaches like pharmacogenomics. Progress depends on both developing new compounds and improving treatment selection, sequencing, and monitoring across unipolar depression, bipolar depression, and TRD.