Ketamine’s Antidepressant Effect May Depend on Opioid System

The antidepressant effects of ketamine appear to depend on activation of the brain’s opioid receptors, underscoring the drug’s addictive potential, according to a report published this week in AJP in Advance.

When 12 patients with treatment-resistant depression were treated with the opioid antagonist naltrexone before receiving an infusion of ketamine, the antidepressant effects of ketamine were dramatically diminished.

“The implications for future research and clinical use of ketamine are potentially profound,” senior author Alan Schatzberg, M.D., the Kenneth T. Norris, Jr., Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, told Psychiatric News. Schatzberg is a past president of APA. Dr. Schatzberg shares senior authorship of the paper with Carolyn Rodriguez, M.D., Ph.D., assistant professor of psychiatry at Stanford. Lead authors of the study were Nolan R. Williams, M.D., an assistant clinical professor of psychiatry at Stanford, and Boris Heifets, M.D., Ph.D., an assistant clinical professor of anesthesiology at Stanford.

Ketamine, which was approved as an anesthetic in 1970, has been the object of enormous interest in the last several years for its ability to rapidly reduce symptoms of depression and acute suicidality. Hundreds of ketamine infusion centers have sprung up around the country offering off-label treatment for mood disorders.

Even as interest in ketamine has grown, many experts have remained cautious. Ketamine—which can produce distortions of sight and sound along with a sense of dissociation (feeling detached from self and the environment)—is used as a recreational drug.

Schatzberg said the AJP study provides a neurobiological basis for concerns about the safety of using ketamine, especially on a continual basis. “Repeated use could lead to tachyphylaxis [diminishing response to successive doses], and some health centers have indeed stopped offering treatment with ketamine,” he said. “Tolerance and abuse issues related to ketamine in humans need to be studied much more rigorously before we can truly consider this a safe treatment for depression.”

Schatzberg and colleagues originally planned a crossover trial of 30 adults with treatment-resistant depression comparing a 0.5 mg/kg intravenous infusion of ketamine preceded by either oral placebo or oral naltrexone (50 mg). All participants were required to have a score of at least 20 on the 17-item Hamilton Depression Rating Scale (HAM-D). Each participant was also required not to have benefited sufficiently from trials of at least four different antidepressant medications or other somatic treatments (such as electroconvulsive therapy, vagus nerve stimulation, or deep brain stimulation).

An initial 12 patients completed both arms of the crossover trial. The interval between ending the first condition and starting the second ranged from 14 to 63 days, with an average of 33 days.

Patients were administered the HAM-D at baseline and again on post-infusion days 1, 3, 5, 7, and 14. There were no significant differences in mean baseline 17-item HAM-D scores for the ketamine plus placebo condition and the ketamine plus naltrexone condition. In the ketamine plus placebo condition, seven of the 12 patients met the criterion for response (defined as a 50 percent reduction from baseline to post-infusion day 1 in 17-item HAM-D score); five of the seven responders met criteria for remission (defined as a score of 7 or less on HAM-D). In contrast, none of the seven patients who responded to ketamine plus placebo met the criteria for response on post-infusion day 1 of ketamine plus naltrexone.

On post-infusion day 1, patients receiving ketamine plus placebo experienced a dramatic reduction in mean 17-item HAM-D, with an average reduction of 22.3. There was also a statistically significant reduction from baseline in the ketamine plus naltrexone condition, but that improvement was significantly lower with an average reduction of 5.6.

Because patients who took naltrexone before ketamine continued to experience the dissociative effects of ketamine without the robust antidepressant response seen in the placebo group, the investigators halted the trial without recruiting more patients.

Schatzberg and colleagues noted that most studies of ketamine have focused on the drug’s effects on glutamate NMDA receptors but have not examined the drug’s effect on opioid receptors. “The public health significance of ketamine’s opioid properties needs to be studied,” they wrote. “While opioids have a history of use as antidepressants, they pose a significant risk if used chronically. … Thus, the abuse and dependence potential of frequent ketamine treatment in major depression needs further study, and our results provide strong justification for further caution against widespread and repeated use of ketamine before further mechanistic testing has been performed.”

In comments to Psychiatric News, Schatzberg said ketamine may still prove to be potentially useful as a one-time treatment in acutely suicidal patients. “The problem is the follow up,” he explained. “Do you keep giving the drug? And at what cost in consequences? I believe the field needs to step back. Proponents of the NMDA mechanism have underplayed the role of the opioid system and this has misled the field. Many companies may be spending a lot of money pursuing the wrong mode of action.”

In an editorial accompanying the study, Mark George, M.D., a professor of psychiatry, radiology, and neuroscience and director of the Brain Stimulation Laboratory at the Medical University of South Carolina, said the study should give pause to those wanting to rush use of ketamine. “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,” he wrote. “If ketamine does indirectly activate opioid receptors, it could even have positive effects in approaching the opioid epidemic as well as the other epidemics. In any case, we need to better understand ketamine’s mode of action and how it should best be used and administered.”

The study was supported by the Stanford Clinical and Translational Science Award, the 2016 NARSAD Young Investigator Grant program, the Brain and Behavior Research Foundation, the Avy L. and Robert L. Miller Foundation, and the Pritzker Family Fund. ■