Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Todd D. Gould, Carlos A. Zarate, Scott M. Thompson
The Annual Review of Pharmacology and Toxicology October 9, 2018 DOI: 10.1146/annurev-pharmtox-010617-052811 via OpenAlex
Summary
Depression has long been treated with drugs that target monoamine brain systems, but these take weeks to work. Low doses of ketamine can improve core depressive symptoms—including mood, anhedonia, and suicidal ideation—within hours after a single dose, with effects lasting up to a week. This discovery has shifted thinking about how depression might be treated more effectively. This review covers clinical data on ketamine and other rapid-acting antidepressants and what is known about their mechanisms. It also discusses brain circuits engaged by these drugs and future medication targets such as hydroxynorketamine, metabotropic glutamate receptor 2/3 antagonists, and modulators of NMDA, AMPA, and GABA receptors.
Study at a glance
| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine Serotonin |
| Keywords | Anhedonia Monoaminergic Antidepressant Pharmacology |
| Citations | 132 |
| Key finding | Low subanesthetic doses of ketamine rapidly improve depressive symptoms including mood, anhedonia, and suicidal ideation within hours after a single administration, with relief lasting up to a week. |
Abstract
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.