Major depressive disorder is a leading cause of disability worldwide, and conventional therapies fail many patients, especially those with treatment-resistant depression (TRD). This review examines novel drug targets and candidates in Phase I–III clinical trials. The most promising approaches include blocking glutamatergic neurotransmission with NMDA and mGlu5 receptor antagonists, modulating the opioidergic system with κ receptor antagonists, and using hallucinogenic tryptamine derivatives. The only registered drug for TRD is the NMDA receptor antagonist S-ketamine, but add-on therapies with second-generation antipsychotics, nutritive, anti-inflammatory, and neuroprotective agents also appear effective. Ongoing large-scale omics and neuroimaging studies may reveal new molecular mechanisms and therapeutic strategies.
A systematic review of Phase 1-3 clinical trials from 2014 to 2024 found no breakthrough in pharmacotherapy for chronic primary pain conditions including fibromyalgia, complex regional pain syndrome, and chronic low back pain. The lack of progress may stem from unsuccessful approaches to reveal pathophysiological mechanisms, lack of translational preclinical animal models, and patient population heterogeneity with comorbidities. Most trials focused on repurposing antidepressants, antiepileptics, psychedelics, and immune modulators. Promising candidates targeted cannabinoid, glutamate, GABAergic, neuroinflammatory, and immune mechanisms. Only cannabidiol (CBD) and (es)ketamine were tested for all three conditions despite similar etiological factors.