Service de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, Groupe Hospitalier Universitaires AP-HP, Université Paris-Saclay, Inserm U-1018, CESP, MOODS Team, 92380 Garches, France.
3 papers in the library · 6 citations · publishing 2022-2024
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 46-year-old man experienced a brief loss of consciousness and visual hallucinations after taking three tablets of the hallucinogenic tryptamine derivative 5-MeO-DALT, purchased online. Laboratory analysis quantified 32.5 mg of the drug per tablet (11% purity) and 7 ng/mL in the patient's plasma 8 hours after consumption. Poisonings from 5-MeO-DALT are rarely reported, but the broad availability of such products means emergency physicians and clinical toxicologists should consider recreational tryptamine ingestion, especially because most routine toxicological screenings do not detect them.
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.