Rapid-acting antidepressants.
Jeffrey M. Witkin, Anna E Martin, Lalit K Golani, Nina Z Xu, Jodi L Smith
Advances in pharmacology (San Diego, Calif.) 2019 DOI: 10.1016/bs.apha.2019.03.002 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Scopolamine Psilocybin Lysergic acid diethylamide Ayahuasca Esketamine (R)-ketamine Rapastinel TAK-653 |
| Topics | Ketamine |
| Keywords | Gabaa α5 Psychedelic drugs Rapid-acting antidepressants Scopolamine Mglu2/3 receptor antagonists |
| Citations | 71 |
| Key findings | Rapid-acting antidepressants, including ketamine and scopolamine, demonstrate rapid onset and large effect sizes in controlled clinical studies, with a general triggering mechanism involving AMPA receptor potentiation, but side effects and limited durability impede clinical translation. |
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 GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 24
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
- Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression CNS Drugs November 17, 2021
- Novel drug developmental strategies for treatment‐resistant depression British Journal of Pharmacology November 25, 2021
- Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. Brain Sciences January 25, 2025
- Discovering the Potential Mechanisms of Medicinal Mushrooms Antidepressant Activity: A Review Antioxidants March 2, 2023
and 19 more in the library
Cites 85
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 80 more in the library