Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
2 papers in the library · 36 citations · publishing 2024-2025
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (RR-HNK), was tested in a Phase 1 study in healthy volunteers for safety and tolerability. RR-HNK lacks anesthetic and dissociative effects but retains antidepressant and analgesic activity in preclinical models. In single doses from 0.1 to 4 mg/kg and multiple doses of 1 and 2 mg/kg given intravenously over 40 minutes, RR-HNK showed minimal adverse events and no serious adverse events. It did not cause dissociation or sedation. Drug levels in the body increased proportionally with dose, and cerebrospinal fluid analysis confirmed it reached the central nervous system. Some participants showed increases in gamma brain wave activity at lower to mid doses. These results support moving to Phase 2 trials.
Ketamine rapidly reduces depressive symptoms in treatment-resistant depression but does not improve working memory, attention, or concentration. In a crossover trial, 21 individuals with treatment-resistant depression (14 with bipolar disorder, 7 with major depressive disorder) received ketamine or placebo infusions. Brain activity measured by magnetoencephalography during a working memory task showed increased gamma power in the parieto-occipital junction and decreased gamma power in the posterior superior temporal sulcus and inferior frontal gyrus after ketamine compared to placebo. These distinct gamma power changes in brain regions linked to attention and working memory suggest that ketamine alters neural activity without improving cognitive performance, highlighting the need for further research into its neurobiological mechanisms.