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Ketamine No Better for Depression Than Placebo?


Ketamine was no more effective than placebo in reducing depressive symptoms in surgical patients with major depressive disorder (MDD), results of a new study, which contradict prior research, suggest. Although symptoms improved in both study groups, investigators say participants’ expectations of an improvement from ketamine may be driving that result.


  • The randomized, placebo-controlled trial included 40 patients who had previously been diagnosed with MDD and who were scheduled for elective noncardiac, nonintracranial surgery.

  • Participants completed pre- and post-surgery depression screenings with the Patient Health Questionnaire-8 (inclusion score was ≥ 12) and the Montgomery-Ǻsberg Depression Rating Scale (MADRS).

  • Patients received an infusion of 0.5 mg/kg of saline (placebo group; n = 20) or ketamine (n = 20) during surgery, along with general anesthesia.

  • At the end of a 14-day follow-up, patients were asked to guess whether they had received ketamine or placebo.


  • MADRS scores dropped by around half 1 day after treatment, indicating an improvement in depressive symptoms in both the group that received ketamine (mean decrease from 25 to 12.6 points) and the group that received placebo (mean decrease from 30 to 15.3 points). There was no significant difference between the two.

  • Participants in the ketamine and placebo groups also reported high rates of clinical response (60% and 50%, respectively) and remission (50% and 35%, respectively), again with no significant difference based on treatment with ketamine or placebo.

  • Only 36.8% of participants accurately guessed their treatment group. Those who guessed they had received ketamine had higher MADRS scores than those who guessed they had received placebo or said they didn’t know (10.1 vs 19.2 vs 23.0).

  • The ketamine group had a significantly shorter hospital stay (1.9 days) than the placebo group (4 days) (P = .02).


“Our primary findings differ from those of previous antidepressant trials with ketamine conducted without adequate masking, which find robust effects of ketamine,” the authors write, adding that “regardless of the intervention being tested, participant expectations of a positive outcome — also known as hope — may drive large decreases in depression symptoms seen in antidepressant trials.”


Heifets led the study, which was published online October 19 in Nature Mental Health. The study was funded by the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health, and the Stanford School of Medicine Research Office.


The investigators did not measure participants’ treatment expectations prior to randomization and could not determine what effect participant expectancy bias may have had on the results. In addition, there was no assessment of the blind for anesthesiologists who administered the ketamine or placebo to patients.


Heifets is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures. Other disclosures are noted in the original article.

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  • Posted on November 17, 2023