Oral Ketamine for the Treatment of Depression: A randomized controlled trial and meta-analysis
Abstract
Background
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 easy to administer with established safety and efficacy for patients with chronic and severe pain at home.
Aims
With this trial we further investigated the evidence on the efficacy and tolerability of oral ketamine as an antidepressant treatment.
Method
41 patients diagnosed with a moderate to severe depressive episode were randomized to receive either 1mg/kg peroral ketamine or 0.03mg/kg midazolam solution as an active comparator, administered six times over two weeks in a double-blind trial (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02992496">NCT02992496</ext-link>).
Results
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 4.0 (95%-CI: [2.1, 36.2]) 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 507 patients, meta-analysis of randomized controlled trials on oral ketamine treatment demonstrated its antidepressant efficacy with a NNT = 4.89 (95%-CI: [3.18, 10.54]) for response and a NNT = 6.88 (95%-CI: [4.18, 19.27]) for remission.
Conclusions
Despite that the current trial did not meet its primary endpoint, possibly due to the presence of an active comparator and low immediate side effects, 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 high-income areas.
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