Ketamine's antidepressant properties tied to the opioid system
In a recent study, researchers have found that the opioid system plays a significant role in mediating ketamine's antidepressant effects in adults with major depression.
The study, which involved 26 adults with moderate-to-severe depression, discovered that each participant received a standard low-dose ketamine infusion, either preceded by naltrexone (an opioid antagonist) or a placebo. The reduction in the antidepressant effect was estimated at about 28%, which was matched by a weaker improvement in mood the day after treatment.
Ketamine primarily acts as an NMDA receptor antagonist, promoting rapid synaptic plasticity. However, research suggests that it also indirectly activates the brain's opioid system, which may be essential for its antidepressant efficacy.
For instance, a clinical study using magnetic resonance spectroscopy demonstrated that when the opioid system was blocked, both the brain’s glutamatergic response and ketamine’s antidepressant effect diminished. This implies that opioid receptor engagement may facilitate ketamine’s modulation of glutamate neurotransmission and subsequent brain plasticity changes linked to mood improvement.
It's important to note that ketamine is not classified as an opioid. Its rapid antidepressant effect is likely a combination of NMDA receptor antagonism-induced synaptogenesis and opioid system facilitation, rather than opioid action alone.
The study also highlighted a potential difference between men and women, with the dampening effect of naltrexone on glutamate activity appearing more marked in male participants. Separate analysis by sex is likely to be important due to the differences observed in this study.
While the findings are promising, the small sample size means this finding needs to be explored further in larger research. Future studies should be larger, include a true placebo infusion, and use brain imaging to directly measure opioid receptor activity.
Dr. Jelen, who led the study, emphasized that the experiment was designed to explore how ketamine works, not to guide patient care. People taking naltrexone for other medical reasons are advised not to stop or alter their treatment based on these findings.
Understanding the pathways involved in ketamine's antidepressant effects could help guide more personalized treatment. If the opioid system is confirmed to be an important part of the process, it might one day influence who is most likely to benefit from ketamine and how it is used alongside other medications.
[1] Jelen, D., et al. (2022). Opioid receptor activity is essential for ketamine's antidepressant effect in major depression. Neuropsychopharmacology, 47(2), 200-210.
[2] Sanacora, G., et al. (2016). Mechanisms of ketamine's rapid antidepressant effects: A systematic review and meta-analysis of human neuroimaging studies. Molecular Psychiatry, 21(4), 458-469.
[3] Nestler, E. J. (2015). Molecular mechanisms of synaptic plasticity and depression. Nature Reviews Neuroscience, 16(1), 3-13.
[4] Carlson, P. J., et al. (2017). Ketamine and the opioid system: A review of the literature. Neuropharmacology, 128, 226-237.
[5] Carlson, P. J., et al. (2018). The opioid system and ketamine's antidepressant effects: A systematic review and meta-analysis. Journal of Affective Disorders, 242, 73-84.
Science indicates that the opioid system plays a crucial role in ketamine's antidepressant effects, as evidenced by studies showing that blocking the opioid system may reduce ketamine's antidepressant effect and lead to a weaker improvement in mood. In the realm of health and wellness, understanding the role of mental health, therapies, and treatments like ketamine could have significant implications for the treatment of medical-conditions such as major depression.
