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.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.