Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review
This review (2016) examines a number of preclinical reports which suggest that serotonergic neurotransmission could play an important role in ketamine's antidepressant-like activity. The authors hypothesize that ketamine may alleviate depression by increasing serotonin levels in the prefrontal cortex NMDA receptor inhibition and activation of AMPA glutamate receptors. Preclinical animal studies indicate that ketamine may also have an affinity towards serotonergic receptors, including the 5-HT2A receptor, in addition to glutamatergic neurotransmission.
Authors
- du Jardin, K. G.
- Müller, H. K.
- Elfving, B.
Published
Abstract
Review: A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine's antidepressant effects. The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine's antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine's antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine's antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.
Research Summary of 'Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review'
Introduction
Interest in the glutamatergic system in major depressive disorder (MDD) increased after reports that a single subanesthetic intravenous infusion of ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects within hours and remission in up to ~70% of treatment-resistant patients for periods lasting more than a week. Most mechanistic work has focussed on ketamine's effects on glutamate signalling and consequent synaptic plasticity, but ketamine has a complex pharmacological profile and may engage non-glutamatergic systems. Given longstanding evidence linking reduced central serotonergic tone to MDD and to responsiveness to conventional antidepressants, recent preclinical studies have explored whether serotonin (5-hydroxytryptamine; 5-HT) contributes to ketamine’s antidepressant-like actions. Gaarn Du Jardin and colleagues set out to critically review the available evidence for involvement of serotonergic signalling in ketamine’s antidepressant effects. They examine ketamine’s pharmacological targets and metabolites, summarise major mechanistic hypotheses for ketamine’s effects, outline points of interaction between glutamatergic and serotonergic systems at intracellular, synaptic and circuitry levels, and review preclinical and imaging data bearing on 5-HT tone, 5-HT release, and specific 5-HT receptor subtypes in relation to ketamine’s behavioural and neurochemical effects.
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Study Details
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- APA Citation
du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sanchez, C. (2016). Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 71, 27-38. https://doi.org/10.1016/j.pnpbp.2016.05.007
References (3)
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Roth, B. L., Gibbons, S., Arunotayanun, W. et al. · PLOS ONE (2013)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Cited By (1)
Papers in Blossom that reference this study
Keeler, J. L., Treasure, J., Juruena, M. F. et al. · Nutrients (2021)
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