Intranasal Ketamine Delivers Rapid Antidepressant Effect

Caroline Cassels

April 09, 2014

Intranasal ketamine delivers a rapid antidepressant effect in patients with treatment-resistant major depressive disorder (MDD), new research shows.

Investigators report that the N-methyl-D-asparate (NMDA) glutamate receptor, administered via intranasal spray, had a significant antidepressant effect within 24 hours of administration. If confirmed in larger studies, the researchers say these findings may herald a new antidepressant drug class.

"What we have here is a proof-of-concept study, and we consider the results very promising. We hope to see this line of research further developed so that we have more treatments to offer patients with severe, difficult-to-treat major depressive disorder," study investigator Dennis S. Charney, MD, Icahn School of Medicine at Mount Sinai in New York City, said in a release.

The study was published online April 2 in Biological Psychiatry.

Common Anesthetic

A US Food and Drug Administration (FDA)–approved anesthetic that has been in common use for years, ketamine has also been subverted as a drug of abuse and can lead to serious psychiatric or cognitive problems when misused.

Previous research conducted by the same group of investigators and reported by Medscape Medical News has shown that low-dose intravenous ketamine has a rapid effect on patients with resistant depression.

To determine the safety and efficacy of an intranasal formulation of the drug, the investigators conducted a small, double-blind, crossover study. A total of 20 patients with MDD who had failed to respond to at least 1 trial of antidepressants were randomly assigned to receive a single 50-mg dose of ketamine or saline 7 days apart.

In each treatment period, study participants were assessed at 40 minutes, 120 minutes, 240 minutes, 24 hours, 48 hours, 72 hours, and 7 days following treatment intervention.

The study's primary outcome was change in depression severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included durability of response, changes in self-reports of depression, anxiety, and the proportion of responders.

The investigators also measured potential psychotomimetic, dissociative, hemodynamic, and general adverse effects.

Novel Mechanism

Study results based on 18 participants revealed greater improvement in depressive symptoms at 24 hours following ketamine administration compared with placebo [t = 4.39, P < .001; estimated mean MADRS score difference of 7.6 ± 3.7 (95% confidence interval, 3.9 - 11.3).

The researchers also found that 8 of 18 patients (44%) met response criteria 24 hours following ketamine administration vs 1 of 18 (6%) following placebo (P = .033).

The investigators also found that intranasal ketamine was "well tolerated with minimal psycotomimetic or dissociative effects and was not associated with clinically significant hemodynamic parameters."

Dr. James Murrough

"One of the primary effects of ketamine in the brain is to block the NMDA. There is an urgent clinical need for new treatments for depression with novel mechanisms of action. With further research and development, this could lay the groundwork for using NMDA-targeted treatments for major depressive disorder," principal investigator James Murrough, MD, said in a release.

"To our knowledge, this study represents the first controlled investigation of intranasal administration for an NMDA antagonist in depression. While these findings are suggestive of efficacy and of a favorable tolerability profile, much more research is required before the true efficacy and safety of this intervention can be assessed.

"Future studies designed to optimize dosing while identifying relapse prevention strategies and biomarkers of treatment response will provide additional needed data to maximize benefit for patients and minimize side effects," the investigators conclude.

Author disclosures can be found in the original article.

Biol Psychiatry. Published online April 2, 2014. Abstract


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