(218) Safety and Effectiveness of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists for Depression: A Narrative Review

Sunday, August 28, 2022

8:00 AM – 1:45 PM CEST

Location: Hall C

Publication Number: 1263

Presenting Author(s)

G. Caleb Alexander, MD
– Professor of Epidemiology and Medicine, JHSPH Center for Drug Safety & Effectiveness, Baltimore, Maryland, United States

Co-Author(s)

Thomas J. Moore
– Johns Hopkins University Bloomberg School of Public Health, Center for Drug Safety and Effectiveness, Johns Hopkins University Bloomberg School of Public Health, Santa Fe, New Mexico, United States
Abdallah Alami
– (3) McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Canada
Donald Mattison, MD
– University of Ottawa, Canada

Background: There has been a recent rise in the use of NMDA antagonists ketamine and esketamine for treatment of depression.

Objectives: To examine evidence regarding the safety and effectiveness of NMDA receptor antagonists for the treatment of depression.

Methods: We conducted a narrative, multidisciplinary review to assess the risks and benefits and to identify answered and unanswered questions about NMDA antagonists. We searched PubMed from inception through April 2021 and identified 21,298 studies indexed to ketamine and 309 studies indexed to esketamine. In addition to the peer-reviewed literature we also searched the U.S. Food and Drug Administration (FDA) website for relevant summary, medical, statistical and pharmacology/toxicology reviews.

Results: Decades of evidence indicate that NMDA receptor blockade produces anesthesia and loss of consciousness at higher doses and an altered state of consciousness at lower doses or as the drug is metabolized and eliminated. In animal studies, the administration of NMDA antagonists is associated with vacuolization in neurons, and then as exposure increases, apoptotic cell death. The most prevalent adverse effect of sub-anesthetic doses or illicit use of NMDA antagonists is the rapid induction of an altered mental state, which can be managed with medical supervision and monitoring and is typically characterized as lasting two hours or less. However, an altered mental state persists beyond this duration in some individuals, and evidence from animal and human studies indicates that frequent use may result in neurotoxicity and cognitive decline. The U.S. FDA approved esketamine for treatment-resistant depression despite several deviations from typical evidentiary thresholds for market access, and clinical studies in humans for the treatment of depression with ketamine or treatment-resistant depression with esketamine have not been adequately designed to characterize toxicity risks or to establish acceptable thresholds for repeat-dose exposures.

Conclusions: Despite a recent increase in the use of NMDA antagonists for the treatment of depression, evidence of efficacy is inconclusive and little is known regarding the risks of repeat exposures.