Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder

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.