Augmented esketamine nasal spray therapy effective for major depressive disorder

Antidepressants augmented with intranasal esketamine appeared effective among patients with major depressive disorder who were treatment-resistant or acutely suicidal, according to study results published in Journal of Clinical Psychiatry.

“Randomized controlled trials have demonstrated intravenous ketamine’s robust and consistent antidepressant effects,” George I. Papakostas, MD, of Massachusetts General Hospital Clinical Trials Network and Institute in Boston, and colleagues wrote. “With ketamine’s very poor oral bioavailability due to extensive first-pass metabolism, the IV route has been the preferred and most studied mode of administration, although not without its logistical pitfalls; the requirement of twice- or thrice-weekly infusion visits, along with the repeated insertion of IV lines, represent significant patient burden and inconvenience. This has led to the consideration of more convenient routes, such as the intranasal formulation.”

Prior studies have shown intranasal ketamine administration had a bioavailability of between 45% to 50% across different age and racial groups, which surpassed the bioavailability of rectal, sublingual and oral formulations. The FDA has approved esketamine — the S-enantiomer of ketamine racemate and an N-methyl-d-aspartate receptor antagonist — as a rapid-acting intranasal therapy for treatment-resistant depression and is currently under development for suicidality.

In the current study, Papakostas and colleagues aimed to evaluate the efficacy of adjunctive intranasal esketamine among patients with MDD. They searched the PubMed/MEDLINE database up to January 2019, as well abstracts of major psychiatric meetings held since 2010, and they cross-referenced the term intranasal with the term esketamine in the searches. The investigators initially identified and reviewed 241 study abstracts and included randomized, double-blind clinical trials that compared adjunctive placebo with adjunctive intranasal esketamine for MDD. They used a random-effects model to calculate the standardized mean difference between placebo, which was intranasal saline, and esketamine in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, and this served as the study’s primary outcome.

Papakostas and colleagues pooled five trials with 774 patients. Results showed greater efficacy for adjunctive esketamine compared with placebo for MADRS score change, response and remission (SMD = 0.36; 95% CI, 0.24-0.49; response risk ratio [RR] = 1.4; 95% CI, 1.22-1.61; remission RR = 1.45; 95% CI, 1.2-1.75). Regardless of differences in the study sample and fixed vs. new/optimized baseline antidepressants, results remained statistically significant, according to the investigators.

“Given that the majority of studies involved either introducing a new antidepressant or actively optimizing one during the double-blind phase of the study (as opposed to the more traditional augmentation study design involving pre-established antidepressant therapy that remains constant during the study), these results indicate a larger effect size with intranasal esketamine than traditional approved antidepressants or antipsychotics in MDD,” they wrote.