Expert Opinion on Therapeutic Targets
October 14, 2008
Francis Rodriguez Bambico, Gabriella Gobbi
80 citations
Major depression is the most common mental disorder, but current antidepressants have limited effectiveness. Recent research suggests that drugs activating cannabinoid CB(1) receptors or enhancing endocannabinoid levels have antidepressant-like effects, while the CB(1) antagonist rimonabant increases depression and suicide risk. CB(1) agonists and fatty acid amide hydrolase (FAAH) inhibitors work similarly to existing antidepressants by boosting serotonin and norepinephrine transmission and promoting new neuron growth in the hippocampus. FAAH inhibitors cause fewer adverse cannabinoid effects and have a wider therapeutic window than direct CB(1) agonists. However, because the endocannabinoid system also affects peripheral body functions, side effects require attention.
Expert Opinion on Therapeutic Targets
September 20, 2016
Kenji Hashimoto
68 citations
The NMDA receptor antagonist ketamine produces rapid and lasting antidepressant effects in people with treatment-resistant depression, but how it does so is not fully understood. A key metabolite of (R)-ketamine, called (2R,6R)-hydroxynorketamine (HNK), shows antidepressant effects in rodent models of depression. This suggests that the conversion of (R)-ketamine into (2R,6R)-HNK is crucial for its antidepressant action. The article discusses these findings and their broader significance.
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.