Clinical pharmacology and therapeutics
November 1, 2024
Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al.
34 citations
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.
Translational psychiatry
November 17, 2025
Noah Stapper, Lindsay L Benster, Sahit Menon et al.
1 citation
A systematic review of 24 clinical trials examined neurophysiological biomarkers linked to treatment-induced changes in suicidal ideation. Most studies were published within the past five years but showed methodological heterogeneity, including non-randomized designs and concurrent interventions. Despite limitations, findings suggest that the anterior cingulate cortex is involved in the anti-suicidal effects of intravenous ketamine, an effect absent with oral ketamine, possibly explaining intravenous ketamine's superior clinical effects. Improvements in suicidal ideation following electroconvulsive therapy and magnetic seizure therapy were associated with activity in the prefrontal cortex. These patterns may indicate that acute effects of intravenous ketamine and sustained effects of seizure therapies involve differential modulation of these brain regions.
Journal of affective disorders
November 1, 2026
Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.
In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.