Ketamine/esketamine: Putative mechanisms of action

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Details of how these agents produce rapid antidepressant effects have been misrepresented.



Since the FDA approved intranasal esketamine, there has understandably been significant dialogue, debate, and discussion about the possible mechanisms of action of its antidepressant effects. Ketamine, the racemate of esketamine and arketamine, has been used off-label since the late 1990s. The first study of IV ketamine’s rapid antidepressant activity was published in 2000.1 In that study, 7 patients with major depressive disorder (MDD) were treated in a double-blind/placebo-controlled manner with IV ketamine or placebo. Researchers found a significant antidepressant effect within 72 hours with the administration of IV ketamine.

There is a tremendous number of publications related to ketamine, which creates a large reservoir of information to review in an attempt to piece together what we currently know about the mechanisms of action of ketamine/esketamine (K/ESK). A search of PubMed using the search word “ketamine” (October 8, 2019; produced a list of 4,869 articles just in the last 5 years; and the search words “ketamine and depression” produced a list of 1,221 publications over the same time period.

The FDA approval of intranasal esketamine in March 2019 was based on 5 phase III clinical studies (albeit not all were positive studies) and >9 years of intensive preclinical and clinical research on the efficacy and safety of intranasal esketamine in treatment-resistant depression (TRD). At the time the FDA approved it, esketamine had been studied in 1,700 patients with TRD, with 1-year safety data on approximately 800 patients. Despite this established data portfolio, critics of K/ESK continue to opine that we do not have enough long-term experience with these drugs, and some key opinion leaders continue to voice caution about the clinical use of K/ESK until we obtain more information and experience.

An article in the September 2019 issue Currrent Psychiatryby Epstein and Farrell2 exemplifies my concern regarding the misrepresentation of significant details about what we know about the mechanism of action of K/ESK. Both K/ESK are certainly not “miracle cures,” and although I understand the use of this term in the article’s title, the continued use of this term to describe K/ESK in the article is detrimental. The authors caution about “miracle cures” ultimately proving to be harmful, and suggest that K/ESK could end up in the trash heap with Freud’s 1884 positive description of cocaine for depression and inducing insulin comas to treat patients with schizophrenia, a treatment used until 1960. These rogue treatments were used in the infancy of psychiatry, at a time when there was a paucity of treatments available in psychiatry, and only a primitive understanding of the brain.

Of greater concern to me is the authors’ simplistic and flawed description of the mechanism of action of ketamine. They state “based on available research, ketamine’s long-lasting effects seem to come from 2 mechanisms… activation of endogenous opioid receptors… [and] blockade of N-methyl-D-aspartate receptors.” In the spirit of scientific inquiry, I would like to explore the current evidence base of the putative mechanisms of action of K/ESK.

Ketamine: A plethora of studies

An impressive body of literature is attempting to piece together the complex and multidimensional neurophysiological mechanisms that result in ketamine’s rapid-acting antidepressant (RAAD) effect, which occurs as soon as 4 hours post-dose. A plethora of pre-clinical and clinical studies, including functional connectivity MRI scans in individuals with MDD, have provided a rough outline, albeit incomplete, of ketamine’s mechanisms of action. Ketamine was discovered in 1962 by chemist Calvin L. Stevens, who was experimenting with novel molecular structures to find a replacement for phencyclidine as a safer dissociative anesthetic. After successful experiments in human prisoners in 1964, ketamine was further studied and became FDA-approved in 1970 as a dissociative anesthetic. Lacking respiratory depression and hypotension, which were common adverse effects of other anesthetics, ketamine became commonly used on the battlefield in the Vietnam War, and continues to be used as a dissociative anesthetic.

Following the publication of the Berman article1 in 2000 that demonstrated apparent RAAD activity of IV ketamine, interest in ketamine’s use for TRD—a huge unmet need in psychiatry—skyrocketed. Since the FDA approval of iproniazid (a monoamine oxidase inhibitor) as the first medication approved to treat major depression in 1958, and the FDA approval of imipramine in 1959, all subsequent FDA-approved antidepressants have shared iproniazid/imipramine’s properties of modulating the monoamines serotonin, dopamine, and norepinephrine. The infamous Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial concluded that only 37% of patients with a major depressive episode achieve remission with their first antidepressant trial, and only 49% respond (50% improvement in symptoms).3 Ketamine/esketamine offered a novel mechanism of action, presumed to be related to the glutamate system, that demonstrated a clinical improvement in depressive symptoms in as few as 4 hours, with benefits that lasted up to 1 week after a single dose.

Continue to: A model of how ketamine works


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