2025/01/06 by Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes · 1 voice
Medicine · Neuroscience · #Treatment of Major Depression #Tryptophan and brain disorders #Neuroscience and Neuropharmacology Research
paper · doi:10.1021/acs.jmedchem.4c02467
openalex publication_date 2025/01/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/15
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. (2 R,6 R )-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.