Esketamine for treatment resistant depression

ABSTRACT

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants.

Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2–3 trials are reviewed.

Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine’s approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.

KEYWORDS:

• Esketamine
• treatment resistant depression
• ketamine
• glutamate
• nmda receptor

Article highlights

• TRD carries a large burden of illness.

• Currently available treatments have limited efficacy and/or a lengthy time to response.

• The addition of esketamine intranasally to a new antidepressant increases rates of response and remission in TRD.

• IN esketamine will offer a new adjunctive treatment option for patients who fail to respond to trials of two or more antidepressants, but due to its requirement of a risk evaluation and mitigation strategy (REMS) for distribution and use, as well as potential limitations in third party coverage, access to this treatment may prove limited for patients.

• IN esketamine appears to be safe, and well tolerated in the short term, but longer-term studies are required, particularly to look at urinary and cognitive side effects, and to evaluate addictive potential.

• IN esketamine may offer patients relief from an otherwise burdensome illness.

• Other agents targeting the glutamate system may prove novel antidepressants/adjuncts and offer promise within the field of psychiatry.

• Given the strong data from animal studies suggesting that R-ketamine is a good antidepressant with a better adverse effect profile than esketamine, clinical studies on R-ketamine as an antidepressant are warranted.

• Future head-to-head clinical comparisons of racemic ketamine, esketamine and R-ketamine will be important.

Declaration of interest

J Swainson has received speaking honoraria from Otsuka and Lundbeck and has acted on advisory boards for Otsuka, Lundbeck, and Janssen. R Thomas, S Dursun and M Demas have acted on advisory boards for Janssen. C Chrenek has received speaking honoraria from Otsuka and has acted on advisory boards for Otsuka, Lundbeck, and Janssen. LJ Klassen has received research grants and speaker’s honoraria from and has acted on an advisory board for Shire. They have also received speaker’s honoraria from and acted on advisory boards for Janssen, Lundbeck, Otsuka, Pfizer, Purdue, and Sunovion. They have also acted on an advisory board for Allergan and received speaker’s honoraria from CPA and The Canadian ADHD Resource Alliance. P Chokka received speaker’s honoraria and acted on advisory boards for Allergan, Lundbeck, Janssen, Purdue, Sunovion, and Shire. They have also received research grants from Lundbeck, Janssen, and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript in an inventor holding a patent of R-ketamine in the treatment of depression. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.