Abstract
The approval of ketamine for treatment-resistant depression has created a model for a novel class of rapid-acting glutamatergic antidepressants. Recent research into other novel rapid-acting antidepressants – most notably serotonergic psychedelics (SPs) – has also proven promising. Presently, the mechanisms of action of these substances are under investigation to improve these novel treatments, which also exhibit considerable side effects such as dissociation. This chapter lays out the historical development of ketamine as an antidepressant, outlines its efficacy and safety profile, reviews the evidence for ketamine’s molecular mechanism of action, and compares it to the proposed mechanism of SPs. The evidence suggests that although ketamine and SPs act on distinct primary targets, both may lead to rapid restoration of synaptic deficits and downstream network reconfiguration. In both classes of drugs, a glutamate surge activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) throughput and increases in brain-derived neurotrophic factor (BDNF) levels. Taken together, these novel antidepressant mechanisms may serve as a framework to explain the rapid and sustained antidepressant effects of ketamine and may be crucial for developing new rapid-acting antidepressants with an improved side effect profile.
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Notes
- 1.
Unless otherwise specified, the term ketamine refers to racemic (R,S)-ketamine.
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Acknowledgements
Ioline Henter (NIMH) provided invaluable editorial assistance.
Disclosures
Funding for this work was provided in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857). Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. C. Kraus has received honoraria from Janssen, LivaNova, AOP Orphan, and Roche Austria. Dr. Kadriu is full-time employee at Janssen Research & Development, LLC and owns stock and stock options in Johnson & Johnson.
All other authors have no conflict of interest to disclose, financial or otherwise.
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Kojic, M., Saelens, J., Kadriu, B., Zarate, C.A., Kraus, C. (2022). Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics. In: Barrett, F.S., Preller, K.H. (eds) Disruptive Psychopharmacology . Current Topics in Behavioral Neurosciences, vol 56. Springer, Cham. https://doi.org/10.1007/7854_2022_313
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