Table 3.

Randomized double-blind placebo-controlled or active-controlled studies evaluating the efficacy of ketamine in patients with TRD.

Author(s), Year	Design	Sample Characteristics	Main Results	Response and Remission Rates	Limitations	Conclusions
Murrough et al. 2013a [38]	Two-site, parallel-arm, randomized controlled placebo- control study	Seventy-three patients were randomized to a single infusion of ketamine or to midazolam assessed by the MADRS.	The ketamine group had greater improvement on the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). At 24 hours, the likelihood of response was greater with ketamine than midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.	Response rate is 64%.	The rigid recruitment criteria are a major limitation. Patients with histories of psychotic symptoms or substance abuse were excluded. Also, a significant percentage (17.2%) of screened patients refused or were unable to tolerate psychotropic medication washout prior to randomization. Finally, only the efficacy of a single infusion of ketamine over a brief follow-up period has been investigated.	Ketamine showed rapid antidepressant effects after a single infusion in TRD patients.
Niciu et al. 2013 [37]	Randomized, controlled, crossover study	Twenty-two patients with TRD who received placebo or 40-minute ketamine infusion were evaluated with the YMRS.	Overall, 4 of 22 patients scored greater than 12 on the YMRS. These patients who were randomized to ketamine peaked at the end of the 40-minute infusion and returned to baseline by the following day.	Response and remission rates are not reported.	The unipolar subjects were unmedicated for at least 2 weeks before and during the whole study. The small sample size did not allow the generalization of the findings.	This transient mood elevation is inconsistent with a persistent substance-induced syndrome. The study did not support mania induction with a single dose of ketamine in TRD patients.
Zarate et al. 2006 [36]	Randomized placebo-controlled, double-blind crossover study	Eighteen subjects with DSM-IV TRD were randomized in a placebo-controlled, double-blind crossover study.	A significant improvement was observed in depressed subjects treated with ketamine (110 minutes after administration) compared with subjects treated with placebo. The effect size for the drug difference was 1.46 [0.91-2.01] after 24 hours, and 0.68 [0.13-1.23] after 1 week. 71% of those treated with ketamine met response and 29% met remission criteria the next day after the administration of ketamine. 35% of these subjects continued to respond for at least 1 week.	Response rate is 71% and remission rate is 29% the day following ketamine infusion.	The sample size was relatively small to allow the generalization of the present findings. Limitations in preserving study blind may have biased patient reporting by reducing placebo effects, potentially confounding results.	Ketamine was associated with robust and fast antidepressant effects when administered within 2 hours post-infusion. Also, a significant improvement was observed for at least 1 week.