Université Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR 1018, CESP-Inserm, Team Moods, Faculté de Pharmacie, Bâtiment Henri MOISSAN, Orsay, FRA, France.
2 papers in the library · 5 citations · publishing 2024-2025
Ketamine produces rapid and lasting antidepressant effects in depressed patients. A metabolite called (2R,6R)-hydroxynorketamine (HNK) may contribute to these effects. In anxious male mice, blocking the liver enzyme cytochrome P450 with fluconazole before ketamine or HNK altered drug metabolism: it raised ketamine and norketamine levels in blood and brain but sharply reduced HNK levels. Fluconazole also prevented ketamine's sustained antidepressant-like actions in behavioral tests and its enhancement of cortical GABA levels 24 hours after injection. Giving (2R,6R)-HNK alone reversed fluconazole's blockade of ketamine's antidepressant-like activity. The findings suggest that HNK is essential for ketamine's sustained antidepressant effects and that drug interactions with cytochrome P450 inhibitors may affect ketamine treatment in patients.
A combination of two FDA-approved drugs—(R,S)-ketamine, an anesthetic and NMDAR antagonist, and prucalopride, a 5-HT4 receptor agonist used for constipation—reduced stress-induced behavioral changes in male and female rodents after various stressors (fear conditioning, learned helplessness, stress-enhanced fear learning, and chronic corticosterone exposure). The combined treatment was more effective than either drug alone, and intranasal delivery also worked. Chronic administration of the combination broadly alleviated stress-related behaviors, suggesting potential for treating stress-induced psychiatric disorders in humans.