Ketamine for depression: where do we go from here?

Abstract

Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.

Figure 1

Antidepressant responses to ketamine at 3 to 4 hours, 24 hours, and 72 hours postinfusion across all open-label investigations and controlled trials to date (N = 101). The 2010 study by aan het Rot et al. (33) involved six ketamine infusions; the data visualized here represent antidepressant responses after the last infusion. Studies in which more patients classified as sustained (>72 hours) responders are listed higher in the figure legend. BD, bipolar disorder (dashed lines); IV, intravenous; MDD, major depressive disorder (continuous lines).