Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective
Psychiatry and Clinical Neurosciences June 19, 2019 DOI: 10.1111/pcn.12902 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Esketamine |
| Keywords | Antidepressant Pharmacology Nmda receptor Anesthesia Hippocampus Cognition |
| Citations | 325 |
| Key findings | Ketamine and its enantiomers produce rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD, with preclinical data suggesting (R)-ketamine may be more potent and have fewer side effects than (S)-ketamine. |
Abstract
Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N ‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of ( R )‐ketamine (or arketamine) and ( S )‐ketamine (or esketamine). Because ( S )‐ketamine has higher affinity for NMDAR than ( R )‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that ( R )‐ketamine exerts greater potency and longer‐lasting antidepressant effects than ( S )‐ketamine in animal models of depression and that ( R )‐ketamine has less detrimental side‐effects than ( R,S )‐ketamine or ( S )‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABA A ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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: a paradigm shift for depression research and treatment | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review | |
| NEUROBIOLOGY OF STRESS, DEPRESSION, AND RAPID ACTING ANTIDEPRESSANTS: REMODELING SYNAPTIC CONNECTIONS | 2014 | Review |