Long-term safety of ketamine and esketamine in treatment of depression

ABSTRACT

Introduction

Ketamine can produce rapid-acting antidepressant effects. Esketamine (Spravato), the S-enantiomer of racemic ketamine, was approved by the FDA for treatment-resistant depression in 2019. Here we review what is known about the long-term safety of both racemic ketamine and esketamine as therapies for psychiatric disorders.

Areas Covered

In this article, we conducted a safety review of ketamine and esketamine. In looking at ketamine and esketamine long-term safety effects, we considered data available from experimental studies and several phase-three clinical trials.

Expert Opinion

Based on available data, the most common side effects of ketamine/esketamine are generally transient, mild, and self-limited. These include dissociation, nausea, headache, elevated heart rate, and blood pressure. Treatment with esketamine may lead to an increased risk of lower urinary tract symptoms, such as dysuria or urgency. However, severe bladder pathology has not been reported among patients receiving doses of esketamine/ketamine in line with prescribing guidelines for depression. There is considerable data that ketamine at high doses can lead to long-term impairments in cognition. However, the esketamine clinical trials found that cognition generally remains stable or improves over time, suggesting that when used appropriately, there is no increased risk of cognitive impairment.

KEYWORDS:

• Ketamine
• esketamine
• depression
• safety

Article highlights

• Racemic ketamine has shown evidence of efficacy for the treatment of mood disorders but is not approved by any regulatory body as a therapy for any psychiatric illness.

• Esketamine has received regulatory approval (US) for treatment-resistant depression and major depression with suicidal ideation.

• The most common side effects of ketamine/esketamine include dissociation, headache, and nausea. These are generally transient, mild, and self-limited

• Recent long-term safety data of esketamine in mood disorders suggest a favorable side effect profile; there is concern for increased incidence of lower urinary tract symptoms, though severe bladder pathology (seen in those who use high-dose ketamine illicitly) has not been seen in clinical settings.

Declaration of interests

S Wilkinson has received contract funding from Janssen, Sage Therapeutics, and Oui Therapeutics for the conduct of clinical trials administered through Yale University; he has received consulting fees from Biohaven Pharmaceuticals, Sage Therapeutics, Janssen, and Oui Therapeutics. J Krystal has received consulting fees from Aptinyx, Inc., Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cadent Therapeutics, Inc., Clexio Bioscience, Ltd., COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Greenwich Biosciences, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd, is on the board of directors at Freedom Biosciences, Inc.; he is a member of the scientific advisory board at Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cadent Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., EpiVario, Inc., Eisai, Inc., Jazz Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., RBNC Therapeutics, Inc., Tempero Bio, Inc., Terran Biosciences, Inc.; he owns stock at Biohaven Pharmaceuticals, Sage Pharmaceuticals, and Spring Care, Inc. and owns stock options at Biohaven Pharmaceuticals Medical Sciences, EpiVario, Inc., Neumora Therapeutics, Inc., Terran Biosciences, and Inc., Tempero Bio, Inc. J Krystal has also received free drug for research studies from Astra Zeneca (Saracatinib), Novartis (Mavoglurant) and Cerevel (CVL-751). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notes

1. Data for these tabulations are taken from the Clinical Trials Registry (www.clinicaltrials.gov).

2. Data for these tabulations come from the published literature of the FDA-registered clinical trials and from the Clinical Trials Registry (www.clinicaltrials.gov).

Additional information

Funding

This paper was not funded.