Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder

ABSTRACT

Introduction: In March 2019, intranasal esketamine was approved by the Food and Drug Administration (FDA) for the treatment of treatment-resistant depression (TRD) in adults. This review presents the results of clinical trials underlying the FDA approval of intranasal esketamine.

Areas covered: Esketamine’s efficacy and safety in TRD were assessed in 5 phase III studies: three 4-week, placebo-controlled studies, and two long-term trials. One short-term trial showed statistically significant antidepressant effects of esketamine vs placebo, while a long-term withdrawal study showed that esketamine is significantly beneficial in terms of extending time to relapse, compared to placebo. Two other short-term trials did not meet the prespecified statistical tests for showing efficacy, although improvement in depressive symptoms from baseline to the end of week 4 favors esketamine over placebo.

Expert opinion: Intranasal esketamine is a new treatment option for people with TRD. The main benefit of esketamine is rapid onset of antidepressant activity, but the effects of prolonged treatment are still preliminary. The main concerns relate to the safety aspects of prolonged esketamine therapy, when considering its abuse potential. While data for esketamine use over a long period of time is lacking, its use should be carefully monitored.

KEYWORDS:

• Antidepressants
• esketamine
• intranasal
• ketamine
• major depressive disorder
• treatment-resistant depression

Article highlights

• Esketamine is an S-enantiomer of ketamine and a potent noncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist.

• Intranasal esketamine is a new treatment option for patients with a treatment-resistant depression (TRD).

• In 2019 intranasal esketamine in conjunction with an oral antidepressant has been approved by the Food and Drug Administration (FDA) for treating TRD in adults.

• The FDA approval was based on positive results of phase III clinical trials. TRANSFORM-2 study showed a significant improvement in patients’ depressive symptoms for esketamine vs placebo, while withdrawal SUSTAIN-1 study showed delayed time to relapse of symptoms of depression during maintained esketamine treatment.

• The SUSTAIN-2 study showed that long-term esketamine treatment is generally well tolerated. However due to concerns about sedation and dissociation as well as abuse potential of esketamine it should be administered in healthcare settings under direct supervision of patients.

• In conclusion, although the rapid effect of therapeutic onset (as early as 24 hours post-dose) of intranasal esketamine is a great advantage over conventional antidepressants, data regarding its use in depressed patients should still be considered as preliminary and therapy should be closely monitored.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One referee reports having served as a clinical consultant for MedAvante-ProPhase and has received lecture honoraria from and/or consultancy fees from Scienta, AB-Biotics, Novumed, and Janssen Pharmaceuticals. Another referee declares having served as a consultant for Janssen and was a co-investigator for some of the studies mentioned within this manuscript. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Box 1. Drug Summary Box

Table

Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Additional information

Funding

This paper was not funded.