Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder.
Journal of medicinal chemistry January 23, 2025 Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes 2 citations
Ketamine provides rapid relief for treatment-resistant depression. As an NMDAR antagonist, it may affect prefrontal cortex neurons. The (R)-enantiomer is the most effective and least abuseable antidepressant, though only the (S)-enantiomer is FDA-approved. The metabolite (2R,6R)-Hydroxynorketamine inhibits mGlu2 in presynaptic glutamatergic neurons, increasing BDNF release, which activates TrkB and promotes synaptogenesis. This Perspective explores ketamine's synthesis, pharmacology, metabolism, and effects in animal and human studies to explain differences in biological activity between its enantiomers.