Esketamine Nasal Spray for Treatment-Resistant Depression

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Depression is the leading cause of disability with a negative impact on function and quality of life, affecting about 300 million people worldwide [1]. Despite progress in treatment approach, one-third of individuals suffering from depression remain treatment-resistant [2]. Treatment resistant depression (TRD) is defined as non-response to two or more anti-depressants despite adequate dose and duration [3]. Esketamine nasal spray CIII has recently received a recommendation for approval from FDA for use in TRD in adults. In this article we will describe the mechanism of action of esketamine and the recent trial results (efficacy and safety) that lead to the approval for TRD management.

Ketamine is an N-methyl D-aspartate receptor antagonist, which can provide a rapid and sustained response in TRD as well as suicidal ideation at subanesthetic dose [4]. Esketamine is a glutamate receptor modulator and rapidly acting antidepressant that works by restoring connectivity between cells of the brain. Five phase 3 clinical trials (three short-term studies, one withdrawal maintenance of effect study, and one long-term safety study) observed the effects of esketamine nasal spray in TRD. Data from three of these studies resulted in a rapid decrease and sustained improvement in depressive symptoms with the use of esketamine plus an oral antidepressant as compared to placebo plus medication [3, 5, 6].

Two double-blind, active-controlled, multi-center short-term studies were carried out in two different age groups- adults and elderly (65 and older) with TRD. These individuals received esketamine or placebo nasal spray plus a newly initiated oral anti-depressant. The esketamine group resulted in significant improvement in depressive symptoms over 28 days among adults and clinically meaningful effects in all age groups as compared to placebo [3].

Two other studies demonstrated time-to-relapse and safety profile of esketamine nasal spray. Treatment-resistant individuals, who were either in remission or had a stable response to esketamine after 16 weeks, were divided into two groups, receiving esketamine nasal spray or placebo plus an oral anti-depressant. This was a randomized, double-blind, multi-center, active-controlled study. Among remitters, the relapse rate was 26.7% in the esketamine group as compared to 45.3% in the placebo group. In stable responders, the rates for relapse were 25.8% and 57.6% respectively for esketamine and placebo groups. The results further indicated that patients on esketamine had a 51% lower relapse risk as compared to placebo [5]. The other study was a long-term open-label study demonstrating esketamine tolerance and safety profile for up to 52 weeks as compared to short-term (4-week) studies. Side effects generally occurred in the first few weeks while still under supervision, were transient, subsided within the same day, and discontinuation rates were low. Observed side effects of esketamine during the dosing period were dizziness, dissociation, nausea, headache, drowsiness, metallic taste, reduced oral sensation, vertigo, and viral upper respiratory tract infection [6]. This study also concluded sustained improvement in depressive symptoms in the esketamine group for up to 52 weeks [6].

In September 2018, esketamine nasal spray was sought for approval from the FDA for TRD, which has recently been recommended to be approved. This approval will bring about a drug with a new mechanism of action as compared to other anti-depressants for refractory depression in fifty years. The esketamine nasal spray is a promising new intervention that can have a positive impact on the lives of people worldwide suffering from TRD.

Monitoring Editor: Rikinkumar S. Patel MD, MPH

Author: Saher Hoda Kamil MD

Author Affiliation: Austin State Hospital (Austin, TX)

Correspondence on Email: saherumair@gmail.com

References: are available on request

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