Antidepressant Mechanism of Ketamine Revealed?

Megan Brooks

August 29, 2018

The antidepressant effects from ketamine hinge on activating the brain's opioid system, new research suggests.

A small study showed that pretreatment with naltrexone (multiple brands), an opioid blocker, dramatically blocked the antidepressant effect of ketamine, suggesting that ketamine's acute antidepressant effects require activation of the opioid system.

"The most straightforward clinical implication is that ketamine should not be given to someone taking naltrexone if the infusion is for depression and potentially pain," lead author Nolan Williams, MD, clinical assistant professor of psychiatry and behavioral science at Stanford University School of Medicine in California, told Medscape Medical News.

The findings were published online August 29 in the American Journal of Psychiatry.

Mechanisms of Action

Although the specific mechanisms of action responsible for the acute antidepressant effects of ketamine have yet to be determined, it has generally been thought that they are caused by the drug's effect on the brain's glutamate system. But the current findings place opioid receptor activation in the mix — and suggest that regular use of ketamine for depression could potentially lead to abuse or addiction.

"One needs to be careful with repeated use as to development of tolerance and dependence. While not studied to date, frequent dosing over time may lead to less effect," co–senior author Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford, told Medscape Medical News.

The researchers designed a double-blind crossover study of 30 adults with treatment-resistant depression who received placebo or 50 mg of naltrexone before intravenous infusion of 0.5 mg/kg of ketamine. The study was halted after a preplanned interim analysis of data from 12 patients who completed both conditions.

When ketamine was given with placebo, 7 of the 12 patients showed a decrease in depressive symptom score of at least 50% on the 17-item Hamilton Depression Rating Scale on postinfusion day 1.

However, ketamine had virtually no effect on depressive symptoms when it was preceded by the opioid blocker. Naltrexone had no effect on ketamine's dissociative effects.

"This was purely a mechanistic study, not a treatment trial. And the results were so clear that we ended the study early to avoid exposing additional patients to the ineffective combination treatment," Nolan said in a news release.

Just Another Opioid?

The "succinct and logical conclusion" from this research is that opioid receptors are necessary for ketamine's acute antidepressant effect, Mark George, MD, Institute of Psychiatry, Medical University of South Carolina in Charleston, writes in an accompanying editorial.

The study was small and needs to be replicated, he writes. "And, based on this single study, we cannot conclude that ketamine as an antidepressant is just another opioid, although the results would not be inconsistent with this conclusion," George adds.

It may be that ketamine's effects require combined activation of opioid and N-methyl-D-aspartate receptors, or that other actions of ketamine lead to opioid receptor activation, or that those opioid receptors modulate a different system, George notes.

"Clearly, this study opens up several next steps and studies to address questions that are crucial to answer, particularly given the size, cost, importance, and urgency" of the three ongoing epidemics: opioid dependence, depression, and suicide, he writes.

"Should emergency departments that are considering using intravenous ketamine as an antisuicide measure pause, as they may now be making depressed patients opioid addicts?" he asks.

"Many ketamine clinics are popping up around the country, sometimes without input from psychiatrists and without plans for transitioning depressed patients back to other therapies. Are they nothing more than modern opium dens?" he writes.

George agrees with the authors that with these new findings, "we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form."

The study was funded by the National Institutes of Health, the Brain and Behavior Research Foundation, the Avy L. and Roberta L. Miller Foundation, the Pritzker Family Fund, and Stanford's Department of Psychiatry and Behavioral Sciences. Dr Schatzberg has consulted for Alkermes and Avanir, has equity in various companies, including Corcept, Gilead, Incyte Genetics and Merck, and has received a grant from Janssen Pharmaceuticals. The original article contains a complete list of authors' relevant financial relationships. Dr George has served as a consultant for PureTech Ventures and as an unpaid consultant for Brainsway, Magstim, Mecta, Neuronetics, and NeoSync; has received research grants from Brainsway, Mecta, and Neuronetics; has served on data safety monitoring boards for Microtransponder and NeoSync; and serves as editor-in-chief for Brain Stimulation, published by Elsevier.

Am J Psychiatry. Published online August 29, 2018. Abstract, Editorial

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