New research: Ketamine activates opioid system to treat depression

August 29, 2018

Washington, D.C., -- A new study appearing online today from the American Journal of Psychiatry finds that ketamine's acute antidepressant effect requires opioid system activation, the first time that a receptor site has been shown in humans to be necessary for any antidepressant's mechanism of action. While opioids have been used historically to treat depression, they are known to carry a high risk of dependence. Alan F. Schatzberg, M.D., who led this research at Stanford, cautions against widespread and repeated use of ketamine for depression treatment until more research can be done on both the mechanism of action and the risk of tolerance, abuse and dependence.

Previous research has found ketamine to have rapid-onset antidepressant effects. While the specific mechanism of action for these effects was unknown, it had been generally thought to be due to NMDA receptor antagonism. Since many efforts to develop NMDA antagonists as antidepressants have been unsuccessful, this new study aimed at determining the role of the opioid system in ketamine's antidepressant and dissociative effects in adults with treatment-resistant depression.

Nolan R. Williams, M.D., and Boris D. Heifets, M.D., Ph.D., from Stanford University, co-first authors of the article, hypothesized that ketamine's antidepressant effects may be related to intrinsic opioid receptor properties of ketamine. The study looked at whether use of naltrexone, an opioid blocker, prior to ketamine treatment would reduce the acute antidepressant effects of the ketamine or its dissociative effects. The researchers conducted a randomized double-blind crossover trial involving individuals with treatment resistant depression. Participants received the opioid blocker or a placebo prior to ketamine infusion treatment. Twelve participants completed both conditions in randomized order.

Use of naltrexone dramatically blocked the antidepressant effects of the ketamine but not the dissociative effects, so the trial was halted at the interim analysis. Participants receiving the ketamine plus naltrexone experienced much less reduction in depression symptoms than participants receiving ketamine plus placebo. There were no differences in ketamine-induced dissociation between those receiving naltrexone or a placebo.

In an accompanying editorial in the American Journal of Psychiatry, Mark S. George, M.D., with the Medical University of South Carolina and the VA Medical Center in Charleston, S.C., notes, "We would hate to treat the depression and suicide epidemics by overusing ketamine, which might perhaps unintentionally grow the third head of opioid dependence." George cautions 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."

George also suggests more attention to other underused treatments for depression and suicidality, including electroconvulsive therapy, transcranial magnetic stimulation and cervical vagus nerve stimulation.
American Psychiatric Association

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