Review of: Williams NR et al, Am J Psychiatry 2018;175:1–11

Type of study: Double-blind, placebo-controlled, crossover study

Ketamine’s rapid antidepressant effects have now been demonstrated in over two dozen double-blind, placebo-controlled trials, but how it works is less clear. For many years, NMDA receptor antagonism was thought responsible, but other NMDA antagonists have not worked well in depression. Another possibility is the endogenous opioid system, which is responsible for ketamine’s analgesic effects. If that system is also involved in ketamine’s antidepressant effects, then the opioid antagonist naltrexone ought to interfere with those benefits. This study sought to determine whether naltrexone would in fact dampen ketamine’s benefits in depression.

Thirty subjects with chronic, highly refractory depression were enrolled (with a mean of 9.8 unsuccessful antidepressant trials). Each participant received, in random order, 2 separate IV infusions of ketamine 0.5 mg/kg—one preceded by naltrexone 50 mg and the other preceded by placebo. The primary outcome was reduction in depressive symptoms at postinfusion day 1. The dissociative effects of ketamine were examined as well.

When ketamine was given with a placebo, the response (58%) and remission (42%) rates for depression were high, but coadministration with naltrexone brought those rates to zero. In contrast, naltrexone did not have any discernible impact on ketamine’s dissociative effects. Data collected on blinding suggested that participants were unable to discern when they were receiving naltrexone vs placebo.

The results were dramatic enough that the study was halted midway through for ethical reasons, so only 12 of the 30 subjects completed both arms.

TCPR’s Take
Could ketamine be nothing more than an opiate masquerading as an NMDA receptor antagonist? While the opioid system appears critical to ketamine’s antidepressant effects, that doesn’t mean ketamine directly affects opioid receptors in the way that morphine or codeine does. Endogenous opioids have well-known mood elevating properties, and exercise and even placebo stimulate endogenous opioids. Given the public health crises stemming from both treatment-refractory depression and opioid abuse, this study will no doubt stimulate a flurry of research into the exact role that the opioid system plays. Perhaps ketamine will unlock some of the mysteries behind the mechanisms of ­antidepressants.