In the Journals

Ketamine’s antidepressant effect may require opioid system activation

Findings from a double-blind crossover study indicated that ketamine’s acute antidepressant effect involves the activation of the brain’s opioid system.

“For nearly 2 decades, ketamine's antidepressant mechanism of action was thought to be through its N-methyl-D-aspartate (NMDA) receptor antagonism properties,” Nolan R. Williams, MD, clinical assistant professor of psychiatry and behavioral sciences at Stanford University, told Healio Psychiatry.

“While there is a body of basic science literature supporting this notion, there has never been a direct assessment of this effect in humans,” he continued. “We have known for some time that ketamine also acts on the opioid receptor system, yet no one to date has assessed the role of the opioid system in ketamine's antidepressant mechanism of action.”

The investigators examined whether opioid receptor antagonism before administration of IV ketamine weakened its acute antidepressant or dissociative effects in a mechanistic double-blind crossover study of adults with treatment-resistant depression. Response was defined as a score reduction of 50% or more on the 17-item Hamilton Depression Rating Scale (HAM-D) on the first post-infusion day.

IV ketamine was infused once each across two conditions — the ketamine plus naltrexone condition and the ketamine plus placebo condition. In a counterbalanced manner, participants received pretreatment with naltrexone (50 mg) prior to IV ketamine infusion (0.5 mg/kg) and placebo prior to the other ketamine infusion.

Overall, 12 participants completed both conditions in randomized order. On the first and third post-infusion days, the researchers observed that the reductions in six-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition. Results from secondary analysis showed similar results, regardless of the robustness of ketamine response.

“By pre-administering naltrexone, this study allowed for selective blockade of one of ketamine's effects (action on opioid system) while preserving ketamine's other effects (glutamate, etc.). If ketamine did not exert its antidepressant effects through the opioid system, the effect of ketamine on depression would have been the same after both infusions,” Williams explained. “That was not the case and we were able to block the antidepressant effect with naltrexone, demonstrating the central role of the opioid system in ketamine's antidepressant effects.”

Williams and colleagues also found no differences in ketamine-induced dissociation between conditions. The trial was halted at the interim analysis because naltrexone blocked the antidepressant effects of ketamine. The study was ended early to prevent exposing additional patients to the ineffective combination treatment, Williams said in a press release.

“Ketamine is not working as an NMDA receptor antagonist to produce its antidepressant effects and requires the opioid system to exert its effects,” Williams said. “Clinicians should take the same precautions with ketamine as they do with classic opioids.”

“That ketamine's therapeutic mechanism and rewarding properties are linked should give some pause to practitioners who may be giving repeated ketamine infusions,” study author Boris D. Heifets, MD, PhD, clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford, told Healio Psychiatry. “Pain, depression and opioid use are all at epidemic proportions in the U.S., and this study adds to the growing awareness that these processes are tightly linked in the brain. Addressing one of these medical issues will likely involve a multi-pronged approach that addresses the other issues as well.”

More research is needed to understand ketamine’s antidepressant effects and its mechanisms, Mark S. George, MD, of the psychiatry and behavioral sciences department at Medical University of South Carolina, wrote in a related editorial.

“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 wrote. “If ketamine does indirectly activate opioid receptors, it could even have positive effects in approaching the opioid as well as the other epidemics.” – by Savannah Demko

Disclosures: Williams reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. George reports consulting for Brainsway, Magstim, Mecta, Neuronetics, NeoSync, and PureTech Ventures; grants from Brainsway, Mecta, and Neuronetics; receiving donated equipment for research trials from Brainsway, Magstim, Mecta, and Neuronetics; and serving on data safety monitoring boards for Microtransponder and NeoSync. He is editor-in-chief for Brain Stimulation (published by Elsevier).

Findings from a double-blind crossover study indicated that ketamine’s acute antidepressant effect involves the activation of the brain’s opioid system.

“For nearly 2 decades, ketamine's antidepressant mechanism of action was thought to be through its N-methyl-D-aspartate (NMDA) receptor antagonism properties,” Nolan R. Williams, MD, clinical assistant professor of psychiatry and behavioral sciences at Stanford University, told Healio Psychiatry.

“While there is a body of basic science literature supporting this notion, there has never been a direct assessment of this effect in humans,” he continued. “We have known for some time that ketamine also acts on the opioid receptor system, yet no one to date has assessed the role of the opioid system in ketamine's antidepressant mechanism of action.”

The investigators examined whether opioid receptor antagonism before administration of IV ketamine weakened its acute antidepressant or dissociative effects in a mechanistic double-blind crossover study of adults with treatment-resistant depression. Response was defined as a score reduction of 50% or more on the 17-item Hamilton Depression Rating Scale (HAM-D) on the first post-infusion day.

IV ketamine was infused once each across two conditions — the ketamine plus naltrexone condition and the ketamine plus placebo condition. In a counterbalanced manner, participants received pretreatment with naltrexone (50 mg) prior to IV ketamine infusion (0.5 mg/kg) and placebo prior to the other ketamine infusion.

Overall, 12 participants completed both conditions in randomized order. On the first and third post-infusion days, the researchers observed that the reductions in six-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition. Results from secondary analysis showed similar results, regardless of the robustness of ketamine response.

“By pre-administering naltrexone, this study allowed for selective blockade of one of ketamine's effects (action on opioid system) while preserving ketamine's other effects (glutamate, etc.). If ketamine did not exert its antidepressant effects through the opioid system, the effect of ketamine on depression would have been the same after both infusions,” Williams explained. “That was not the case and we were able to block the antidepressant effect with naltrexone, demonstrating the central role of the opioid system in ketamine's antidepressant effects.”

Williams and colleagues also found no differences in ketamine-induced dissociation between conditions. The trial was halted at the interim analysis because naltrexone blocked the antidepressant effects of ketamine. The study was ended early to prevent exposing additional patients to the ineffective combination treatment, Williams said in a press release.

“Ketamine is not working as an NMDA receptor antagonist to produce its antidepressant effects and requires the opioid system to exert its effects,” Williams said. “Clinicians should take the same precautions with ketamine as they do with classic opioids.”

“That ketamine's therapeutic mechanism and rewarding properties are linked should give some pause to practitioners who may be giving repeated ketamine infusions,” study author Boris D. Heifets, MD, PhD, clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford, told Healio Psychiatry. “Pain, depression and opioid use are all at epidemic proportions in the U.S., and this study adds to the growing awareness that these processes are tightly linked in the brain. Addressing one of these medical issues will likely involve a multi-pronged approach that addresses the other issues as well.”

More research is needed to understand ketamine’s antidepressant effects and its mechanisms, Mark S. George, MD, of the psychiatry and behavioral sciences department at Medical University of South Carolina, wrote in a related editorial.

“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 wrote. “If ketamine does indirectly activate opioid receptors, it could even have positive effects in approaching the opioid as well as the other epidemics.” – by Savannah Demko

Disclosures: Williams reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. George reports consulting for Brainsway, Magstim, Mecta, Neuronetics, NeoSync, and PureTech Ventures; grants from Brainsway, Mecta, and Neuronetics; receiving donated equipment for research trials from Brainsway, Magstim, Mecta, and Neuronetics; and serving on data safety monitoring boards for Microtransponder and NeoSync. He is editor-in-chief for Brain Stimulation (published by Elsevier).