Ketamine's Antidepressant Benefits Tied to the Brain's Opioid System

Alan Schatzberg, MD

Courtesy of the Stanford School of Medicine

A new study of ketamine’s effects on the brain illuminates the connections between depression, pain, and opioid addiction. Researchers at Stanford University School of Medicine found that ketamine, a drug currently used to treat acute and chronic pain, counteracts depression by affecting the brain’s opioid system.

"Before we did the study, I wasn't sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn't work like everyone thought it was working," Alan Schatzberg, MD, the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, a co-author of the paper, said in a statement.

The authors specify that the trial was not conducted to examine the efficacy of ketamine as a treatment for depression, but rather to clarify the role of the opioid system in ketamine’s antidepressive effects in patients with treatment-resistant depression.

While the authors set out to test their theory in 30 study participants, an interim analysis showed such clear results that they stopped the study early.

"This was purely a mechanistic study, not a treatment trial," said co-lead author Nolan Williams, MD, clinical assistant professor of psychiatry and behavioral science. "And the results were so clear that we ended the study early to avoid exposing additional patients to the ineffective combination treatment."

With just 12 participants who completed the crossover and received both treatments, the data have wide margins of error.

Study participants had a mean age of 41.3 (±11.8) years, had experienced a depressive illness for an average length of 24.1 (±10.6) years, and had a mean of 9.8 (±6.5; mode=8) unsuccessful antidepressant treatments.

In the randomized, double-blind, cross-over trial, participants were assigned to receive ketamine treatment twice. Before 1 intravenous infusion of ketamine (.5 mg/kg), participants were given oral naltrexone (50 mg), an opioid receptor antagonist, while the other infusion was preceded by an oral placebo.

Investigators assessed depression ratings on the 6-item and 17-item Hamilton Depression Scale at baseline and at days 1, 3, 5, 7, and 14 post-infusion. Responders were participants who experienced a ≥50% reduction in total 17-item Hamilton Depression Scale score as measured 1 day after the ketamine infusion.

The primary outcome was the reduction of depressive symptoms 1 day after the infusion among participants who were responders during the ketamine and placebo treatment combination.

Measured one day after the ketamine infusion, the mean Hamilton Depression Scale scores were -22.3 (SD = 3.2; P = .000048) for ketamine with placebo, while the mean scores for ketamine with naltrexone were -5.6 (SD = 5.7; P = .04). The study reported that significant difference between the treatment arms was recorded at day 3, but not at days 5, 7, and 14.

“Depression and opioid dependence are currently the 2 most significant public health problems facing the United States and have become leading causes of disability and death worldwide,” wrote the study authors.

Given the ongoing opioid epidemic in the United States, the authors recognized the need to tread with caution and awareness.

"We have to properly examine the risks associated with using drugs of abuse—even in low doses—to treat depression," Schatzberg said.

The authors called for future studies to examine the potential for abuse or dependence, especially with frequent use of ketamine, since it has a short-term effect as an antidepressant. Future research will also need to directly examine the efficacy of ketamine as a treatment for depression.

The study, “Opioid Receptor Antagonism Attenuates Antidepressant Effects of Ketamine,” was published in The American Journal of Psychiatry.