Ketamine and esketamine produce rapid antidepressant effects in major depressive disorder and treatment-resistant depression, but their impact on patient-reported quality of life has been unclear. A systematic review of five studies found that both agents improve quality of life measures on scales such as the WHOQOL-BREF, Assessment of Quality of Life 8D, and EuroQol-5 Dimension-5 Layers, with statistically significant results. However, the studies had an overall moderate risk of bias and varied in the quality-of-life scales used and study duration. Further research should examine effects on specific quality-of-life domains.
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.