Expert opinion on therapeutic targets
April 1, 2024
Carlos Arrabal-Gómez, Pedro Serrano-Castro, Jose Andrés Sánchez-Pérez et al.
7 citations
A combination of an NPY1R agonist and Ketamine, given together to rodents, produced stronger antidepressant-like effects than either drug alone. The animals showed less immobility in a forced swimming test, a standard measure of antidepressant activity. This behavioral change was linked to increased formation of NPY1R/TrkB receptor complexes and higher levels of brain-derived neurotrophic factor (BDNF) in the ventral dentate gyrus of the hippocampus, along with increased neurogenesis. The results suggest that co-activating NPY1R and TrkB pathways may represent a novel therapeutic strategy for major depressive disorder that warrants further clinical investigation.
Expert opinion on therapeutic targets
June 1, 2025
Naomi Xiao, Liyang Yin, Kayla M Teopiz et al.
5 citations
Sigma-1 receptors (S1Rs) may be a target and mediator of antidepressant activity. They regulate neurotransmitter release (including monoamines and glutamate), influence intracellular calcium levels, and affect immune inflammatory responses. In August 2022, the FDA approved dextromethorphan-bupropion, the first antidepressant whose hypothesized mechanism includes activity at S1Rs. The review synthesizes preclinical and clinical data on S1R physiology, pathophysiology, and function. Modulating sigma-1 systems is relevant to current FDA-approved treatments for major depressive disorder and may inform future therapeutic development. Whether sigma-1 modulation uniquely targets difficult-to-treat symptoms like anhedonia remains unknown.
Expert opinion on therapeutic targets
January 28, 2026
Gia Han Le, Roger S. McIntyre
1 citation
Up to half of adults with major depressive disorder who do not respond to two or more standard antidepressants may have treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan are the first glutamatergic treatments to work rapidly and robustly for TRD, but their exact mechanisms are unclear. This review integrates evidence that elevated tonic NMDA receptor currents, mainly through NR2C/D subunits, underlie TRD. Ketamine, esketamine, and dextromethorphan selectively dampen these currents to produce rapid and sustained antidepressant effects. Ketamine and esketamine's affinity for NR2A/B subunits likely drives dissociative effects not seen with dextromethorphan. Future drug development should focus on subunit-biased ligands.