Considerations on Esketamine for Depression
by Ivar Rambags, Marco Aqil, and Jennifer Them
Back in 1956, ketamine was originally derived from phencyclidine as a shorter acting analogue with less delirious side effects . By then still known as CI-581, ketamine’s first clinical results were published by Corssen and Domino in 1966 and revealed itself to be a compound that could rapidly produce a profound state of analgesia with a very promising safety profile . A few years later, ketamine got approved by the US Food and Drug Administration (FDA) in 1970  under the name Ketalar as an anesthetic. Interestingly, ketamine is actually a compound consisting of two mirror-molecules known as (S)- and (R)-ketamine that have slightly different pharmacological profiles. The specific qualities of both chiral molecules have, therefore, been applied for specific research goals. Particularly the (S)- variant, which is commonly written down as ‘esketamine’, has shown promise in the treatment of patients suffering from treatment resistant depression and suicidality. It is, therefore, great to see that the FDA recognised the potential of esketamine by approving it for these conditions on the 5th of March 2019.
An important component of the approval, which you can read in full detail here, is to only provide treatment via a restricted distribution system, and under supervision of a healthcare professional. The hope is that these restrictions should minimize the risk of abuse and addiction, which is non-trivial for esketamine (in comparison, for example, with classical psychedelics), and the potential development of illegal markets outside the clinic, as has happened previously with unrestricted prescription of opioids (e.g. Codeine) or stimulants (e.g. Ritalin). Moreover, off-label prescription of ketamine in so called ‘ketamine clinics’ has sparked some worrisome concerns. It remains to be seen how the situation will evolve in the coming years, and whether people suffering from treatment resistant depression and suicidality will be allowed to access a medication that they might urgently need.
Innovative treatments such as esketamine, MDMA or classical psychedelics in combination with psychotherapy may be crucial and even lifesaving in some cases, but they are still far from being extensively understood and tested. In line with APRA standpoints, this move by the FDA highlights the need for more research on understudied substances and practices, as well as the importance of remaining mindful of known and potentially unpredicted downsides, while waiting for the results of ever larger and placebo-controlled clinical trials to roll in. For a more in-depth analysis of the results and limitations of current studies on ketamine, we highlight this very interesting post by Dr. Eiko Fried and Dr. Lucy Robinson.
- Li, L., & Vlisides, P. E. (2016). Ketamine: 50 years of modulating the mind. Frontiers in human neuroscience, 10, 612. doi: 10.3389/fnhum.2016.00612
- Corssen, G., & Domino, E. F. (1966). Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative Cl-581. Anesthesia & Analgesia, 45(1), 29-40.
- Ketalar (1970). “U.S. food and drug administration, center for drug evaluation and research,” in Label and Approval History. Available online at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist [Ref list]
- “Only two of Janssen’s five phase III trials had shown a benefit greater than taking a placebo. Still, in February an independent panel recommended FDA approval.”
Canuso, Carla M., et al. “Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study.” American journal of psychiatry 175.7 (2018): 620-630.