Rapid-acting antidepressants

Jeffrey M. Witkin, Anna E. Martin, Lalit K. Golani, Nina Z. Xu, Jodi Smith

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABA A (α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.

Original languageEnglish (US)
Title of host publicationAdvances in Pharmacology
PublisherAcademic Press Inc.
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Publication series

NameAdvances in Pharmacology
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925

Fingerprint

Antidepressive Agents
Ketamine
AMPA Receptors
N-Methyl-D-Aspartate Receptors
Hallucinogens
Scopolamine Hydrobromide
Psilocybin
Banisteriopsis
Pharmaceutical Preparations
Anhedonia
Lysergic Acid Diethylamide
Biogenic Amines
GABA-A Receptors
Therapeutics
Medicine
Pharmacology

Keywords

  • GABAA α5
  • Ketamine
  • mGlu2/3 receptor antagonists
  • Psychedelic drugs
  • Rapid-acting antidepressants
  • Scopolamine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Witkin, J. M., Martin, A. E., Golani, L. K., Xu, N. Z., & Smith, J. (2019). Rapid-acting antidepressants. In Advances in Pharmacology (Advances in Pharmacology). Academic Press Inc.. https://doi.org/10.1016/bs.apha.2019.03.002

Rapid-acting antidepressants. / Witkin, Jeffrey M.; Martin, Anna E.; Golani, Lalit K.; Xu, Nina Z.; Smith, Jodi.

Advances in Pharmacology. Academic Press Inc., 2019. (Advances in Pharmacology).

Research output: Chapter in Book/Report/Conference proceedingChapter

Witkin, JM, Martin, AE, Golani, LK, Xu, NZ & Smith, J 2019, Rapid-acting antidepressants. in Advances in Pharmacology. Advances in Pharmacology, Academic Press Inc. https://doi.org/10.1016/bs.apha.2019.03.002
Witkin JM, Martin AE, Golani LK, Xu NZ, Smith J. Rapid-acting antidepressants. In Advances in Pharmacology. Academic Press Inc. 2019. (Advances in Pharmacology). https://doi.org/10.1016/bs.apha.2019.03.002
Witkin, Jeffrey M. ; Martin, Anna E. ; Golani, Lalit K. ; Xu, Nina Z. ; Smith, Jodi. / Rapid-acting antidepressants. Advances in Pharmacology. Academic Press Inc., 2019. (Advances in Pharmacology).
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