Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.


This two-site randomized controlled trial, comparing single infusion of low-dose ketamine with psychoactive placebo control (midazolam), found that ketamine was associated with rapid-onset antidepressant effect in patients with treatment-resistant major depression. Ketamine was associated with a 64% response rate at 24 hours, compared with 28% in the control group. Effects were maintained for several days after infusion, but were no longer significant at 7 days. Ketamine was associated with transient hemodynamic and psychoactive effects in the hours after infusion, but not with psychotic or manic symptoms.


  • Randomized controlled trial.
  • N=73 patients with treatment-resistant major depression, currently having a major depressive episode, randomly assigned (2:1 ratio) to receive a single 40-minute IV infusion of:
    • Ketamine 0.5 mg/kg (n=47)
    • Midazolam 0.045 mg/kg (n=25)
  • Midazolam (short-acting benzodiazepine) was used as the control condition due to similarities with ketamine (fast onset of action, short half-life, sedation, and disorientation), to enhance study blinding.
  • Patients were free of concomitant antidepressants or psychotropic medications (except for zolpidem) prior to infusion.
  • Setting: two academic sites: Baylor College of Medicine and Icahn School of Medicine at Mount Sinai, from 2010-2012.
  • Primary outcome: reduction in depression severity 24 hours after infusion, assessed by Montgomery-Asberg Depression Rating Scale (MADRS). Scores range 0-60, higher scores indicate greater symptom severity. The 24-hour time frame was consistent with peak antidepressant effect noted in prior studies, and was long enough that acute drug effects would have passed.
  • Secondary outcomes:
    • MADRS response rate (reduction in baseline score by ≥50%)
    • Quick Inventory of Depressive Symptomatology-Self Report score change.
    • Clinical Global Impression (CGI) scores.
    • Durability of benefit up to 7 days after infusion.


  • At 24 hours, MADRS score was significantly more improved in ketamine group compared with midazolam group, a difference of 7.95 points (95% CI, 3.20-12.71). MADRS scores:
    • Ketamine, baseline: 32.6
    • Ketamine, 24 hours: 14.77
    • Midazolam, baseline: 31.1
    • Midazolam, 24 hours: 22.72
  • MADRS response rates at 24 hours:
    • Ketamine: 64%
    • Midazolam: 28%
  • CGI rating of improved or much improved:
    • Ketamine: 62%
    • Midazolam: 24%
  • Both groups showed slight worsening in MADRS scores from day 1 to day 7, with no identified difference in trajectories as a function of treatment. After adjusting for site and baseline scores, MADRS and QIDS-SR at day 7 were not significantly different.
  • Dissociative symptoms were experienced by 17% of patients in the ketamine group after infusion, resolving within 2 hours. No patient experienced severe psychotic symptoms.
  • Changes in blood pressure were observed after infusion, leading to discontinuation of infusion in two patients in the ketamine group (one with hypertension, the other with hypotension).


Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. doi:10.1176/appi.ajp.2013.13030392.

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