Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants
This review (2020) review looks at the common mechanisms that underly the effects of ketamine and classical psychedelics. Although the research is in its infancy, the authors identify neuroplasticity via glutamatergic common downstream mechanisms.
Authors
- Carlos Zarate
- Lawrence Park
Published
Abstract
Background
The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.
Methods
This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.
Results
Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.
Conclusions
Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
Research Summary of 'Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants'
Introduction
Kadriu and colleagues situate their review in the context of a paradigm shift in antidepressant pharmacotherapy triggered by subanesthetic ketamine, which produces rapid and relatively sustained antidepressant effects contrary to the long lag time typical of conventional monoaminergic treatments. They note that ketamine has provided a clinical and methodological blueprint for evaluating other compounds with abuse liability and that recent clinical studies suggest classic serotonergic psychedelics (SPs) such as psilocybin, LSD, ayahuasca (DMT), and 5-MeO-DMT may also produce rapid, durable reductions in depressive symptoms following a transient psychoactive period. This paper aims to summarise areas of overlap between ketamine and SP research rather than provide an exhaustive clinical review. Specifically, the authors review converging cellular and molecular mechanisms, electrophysiological and neuroimaging observations, and the therapeutic relevance of the psychoactive state, and they consider whether a common downstream, glutamate-dependent mechanism could underlie rapid-acting antidepressant (RAAD) effects across these pharmacologically distinct agents. They emphasise that modern SP research remains preliminary and that rigorous investigation is required to clarify safety, efficacy, and mechanisms.
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Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021). Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. International Journal of Neuropsychopharmacology, 24(1), 8-21. https://doi.org/10.1093/ijnp/pyaa087
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