Ketamine may produce antidepressant effects through opioid receptors

Originally an anesthetic, ketamine has emerged as a fast-acting antidepressant treatment for people who don’t respond to standard therapies. Ketamine works through glutamate receptors in the brain to induce anesthesia, but the complex process underlying its antidepressant effects remains unclear and few researchers have studied the mechanism in humans. Now, a team led by Alan Schatzberg and Nolan Williams of Stanford University report that ketamine’s antidepressant effects in people may require signaling through opioid receptors (Am. J. Psychiatry 2018, DOI: 10.1176/appi.ajp.2018.18020138).

Given this mechanism, the researchers think that clinicians should use ketamine sparingly to avoid potential consequences such as tolerance and dependence. The drug already has known side effects, including triggering hallucinations and other dissociative effects. But others who study ketamine think the mechanism requires further study before concluding that using ketamine in depression treatment could have opiatelike dependency issues.

Previous research in animals suggested that ketamine interacts with opioid receptors. But no one had determined whether that activity was required for the drug’s antidepressant effects.

To test that connection, the team designed a small clinical trial in which 12 people who are resistant to conventional depression treatments received an intravenous infusion of ketamine. The researchers then determined the treatment’s effectiveness using standard depression surveys. Seven of the 12 participants responded to ketamine, which is on par with response rates for the general population. The people in the study got the ketamine treatment twice: once after taking a placebo pill and another time after taking naltrexone, an opioid receptor blocker.

For those who responded to ketamine, their depression symptoms were significantly lower for three days when they took the placebo, compared with when they took naltrexone. Naltrexone didn’t affect the level of ketamine-induced dissociative effects in the participants.

David Feifel, a professor emeritus of psychiatry at University of California, San Diego, who has used ketamine to treat people with depression, says the findings don’t necessarily mean that ketamine produces its antidepressant effects by acting as a type of opiate. The opioid system plays an important role in regulating mood, Feifel says, and it’s possible that many antidepressant treatments require these pathways to be fully functional.

Carlos A. Zarate Jr. of the National Institute of Mental Health, says the work is intriguing and exciting, but preliminary. He hopes others test this mechanism in larger studies.

“Even if the opioid system is part of the mechanism of ketamine’s antidepressant effect,” he adds, “many investigators are moving beyond ketamine to try to create drugs that don’t have its negative consequences.” For example, Zarate and colleagues at University of Maryland School of Medicine and National Institutes of Health are planning a Phase I clinical trial early next year to test the antidepressant effects of a ketamine metabolite called (2R-6R)-hydroxynorketamine (HNK). The HNK metabolite has shown efficacy in mice without the dissociative side effects or abuse potential seen with ketamine. Zarate and colleagues also showed that HNK has negligible effects on opioid receptors.

Schatzberg calls for more studies to determine if patients develop tolerance or dependency issues with the long-term use of ketamine. He and coworkers are studying different strategies to extend the antidepressant effects of ketamine, so that clinicians can reduce repeated use of the drug.