Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder.
Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes
Journal of Medicinal Chemistry January 23, 2025 DOI: 10.1021/acs.jmedchem.4c02467 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Keywords | Depression treatment Ketamine therapy Mental health research Antidepressant medication |
| Citations | 2 |
| Key points | Argues that the (R)-enantiomer of ketamine is the most effective and least abuseable antidepressant, and that its metabolite (2R,6R)-HNK inhibits mGlu2, increasing BDNF release and synaptogenesis. |
Abstract
Treatment-resistant depression responds quickly to ketamine. As an N-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (R)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (S)-enantiomer for medical usage. (2R,6R)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers.
Comparable studies
Other theoretical and historical papers on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper | |
| The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression | 2023 | Theoretical or philosophical paper | |
| Ketamine in Bipolar Disorder: A Review | 2020 | Theoretical or philosophical paper | |
| Rethinking the role of TRKB in the action of antidepressants and psychedelics. | 2024 | Theoretical or philosophical paper |