A randomized controlled trial of intranasal ketamine in major depressive disorder

Abstract

Background: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial.

Methods: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured.

Results: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters.

Conclusions: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

Trial registration: ClinicalTrials.gov NCT01304147.

Keywords: Antidepressant; depression; glutamate; intranasal; ketamine; treatment resistant.

Figure 1. Change in depression severity in patients with treatment-resistant depression following intranasal ketamine or placebo

Change in MADRS depression severity 24 hours following administration was the primary outcome measure and was significantly greater following intranasal ketamine than placebo in the modified intention-to-treat group (n=18; p<0.001). MADRS, Montgomery-Asberg Depression Rating Scale; range is 0–60 with higher scores indicating greater severity of depressive symptoms. *p<0.05, **p<0.01.

Figure 2. Response rates in patients with treatment-resistant depression following intranasal ketamine or placebo

Response was defined as a decrease from baseline of at least 50% on MADRS. Modified intention-to-treat group (n=18).