REVIEW OF: Lii TR et al, Nat Mental Health 2023;1:876–886 [Epub ahead of print]

STUDY TYPE: Randomized triple-blind placebo-controlled trial

Ketamine has rapid and robust antidepressant effects. However, critics have pointed out that ketamine’s dissociative effects may make subjects in clinical trials aware that they have received the active drug, breaking the blind and inflating the treatment’s efficacy. Supporting that is the fact that ketamine’s efficacy has been higher in trials that compared it to an inert placebo than those that compared it to a psychoactive substance like a benzodiazepine (Wilkinson ST et al, Neuropsychopharmacology 2019;44(7):1233–1238). This new study sought to eliminate those expectancy effects by administering ketamine under general anesthesia.

The authors randomized 40 patients with moderate to severe major depressive disorder who were undergoing elective surgery to receive either a single infusion of ketamine (0.5 mg/kg, the usual dose for treatment-resistant depression) or saline placebo. Both were given while patients were under anesthesia for routine surgeries. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at one, two, and three days post-infusion. Clinical response, defined as a 50% or greater reduction in MADRS scores from screening baseline, was a secondary outcome. Subjects were followed for 14 days after infusion. The study was funded by a grant from the Society for Neuroscience in Anesthesiology and Critical Care.

Surprisingly, no significant difference emerged between ketamine and placebo groups in the three-day follow-up. Sixty percent of patients in the ketamine group, vs 50% in the placebo group, had a clinical response on day one, and 45% vs 50% had a clinical response on day three. 

In this study, ketamine’s antidepressant effect was similar to previous reports, but the placebo effect was unexpectedly high, leading to no significant difference between the two. Group assignment didn’t influence depression outcomes. Two subjects in the ketamine group and one in the placebo group received nitrous oxide, while standard general anesthesia was maintained with propofol and isoflurane. Less than half of the subjects correctly identified their treatment, with similar distribution in both groups. Interestingly, those who believed they received ketamine improved more, regardless of their actual treatment, hinting at the influence of expectancy. It’s possible that conscious experience of ketamine’s psychoactive effects plays a role in improving depression, and that if the subjects had been awake, the ketamine group would have shown a higher response than placebo.

CARLAT TAKE

This study does not negate ketamine’s antidepressant effects but reminds us how potent the placebo is in psychiatry. It’s something to keep in mind as other psychoactive substances like cannabidiol and psilocybin test the limits of our blinds.