Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis

Ketamine represents a significant advancement in antidepressant therapy, but the commonly used intravenous and intranasal application routes currently limit its availability beyond specialized centers. By contrast, oral ketamine treatment might constitute an alternative that is widely available, easy to administer, and has potential advantages with regard to tolerability. Forty-five patients diagnosed with a moderate to severe depressive episode received either 1 mg/kg peroral ketamine or 0.03 mg/kg midazolam solution as an active comparator, administered six times over two weeks in a double-blind trial. While statistical significance for the primary endpoint of MADRS score reduction after one week was not achieved, response rates favored ketamine with a number needed to treat (NNT) of 4.6 (95 %-CI: [2.4, 62.6]) at this timepoint. Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its metabolite norketamine measured in plasma. In a total of 592 patients, meta-analysis of randomized controlled trials on oral ketamine treatment demonstrated its antidepressant efficacy with a NNT = 4.89 (95 %-CI: [3.41, 8.66]) for response and a NNT = 9.16 (95 %-CI: [5.49, 27.59]) for remission. Despite that the current trial did not meet its primary endpoint, the cumulative evidence up-to-date suggests that oral ketamine treatment leads to relevant improvements in the outcomes of patients with depression. In light of the ease of administration and high tolerability with oral application, this evidence may contribute to removing some of the obstacles that currently restrict the availability of antidepressant treatment with ketamine to specialized centers.