Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations.

Between 2014 and 2024, 363 clinical trials on ketamine were registered. Most trials addressed FDA-approved uses: anesthesia (22%), pain management (28%), and esketamine for treatment-resistant depression (29%). Trials for treatment-resistant depression have reached phase III and IV. Combinations with electroconvulsive therapy, psychotherapy, virtual reality, or transcranial magnetic stimulation are common. Sub-anesthetic doses may offer new treatments for neuropsychiatric conditions involving glutamate excitotoxicity and oxidative stress, such as major depression, schizophrenia, and bipolar disorder. The number of ketamine studies is expected to grow, and new variants may be approved for additional indications.

Study at a glance

Abstract

Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)-ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment-resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014-2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term "Ketamine." The highest number of trials were found for the FDA-approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non-psychiatric conditions with pharmacological and non-pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub-anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.