Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix, Indira Mendez-David, Isabelle Etting, Jean-Claude Alvarez, Josephine C McGowan, Jaclyn N. Highland, Panos Zanos, Jacqueline Lovett, Ruin Moaddel, Emmanuelle Corruble, Denis J. David, Todd D. Gould, Christine A. Denny, Alain M. Gardier
bioRxiv Preprint Server April 3, 2024 preprint DOI: 10.1101/2024.04.03.587904 via bioRxiv
Summary
AI-generated from the abstractKetamine'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.
Study at a glance
| Characteristics | Preclinical experimental study |
|---|---|
| Population | Male BALB/cJ mice with a highly anxious phenotype |
| Interventions | fluconazole ketamine (2R 6R)-hydroxynorketamine |
| Dose | fluconazole 10 and 20 mg/kg, i.p.; ketamine 10 mg/kg, i.p.; (2R,6R)-hydroxynorketamine single administration |
| Duration | 24 hours post-injection |
| Topics | Ketamine |
| Keywords | Ketamine treatment Ketamine therapy Ketamine research Ketamine effects Antidepressants |
| Key finding | Inhibiting ketamine metabolism with fluconazole prevented sustained antidepressant-like effects, which were rescued by (2R,6R)-HNK, indicating that this metabolite mediates ketamine's sustained antidepressant actions. |
Abstract
(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine’s metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration selectively rescued the antidepressant-like activity of ketamine in mice pretreated with fluconazole within 24 hours of treatment. Overall, these findings are consistent with an essential role of (6)-HNK in mediating the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.