Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions

Ketamine, administered in subanesthetic doses, is gaining recognition as an off-label treatment for severe and even treatment-refractory depression. This article explores potential pharmacokinetic and pharmacodynamic drug interactions of relevance to the use of ketamine in depression. Sparse evidence suggests that ketamine will not induce clinically significant drug interactions except to the extent that these are predictable by its clinical actions. A small body of literature indicates that drugs that induce cytochrome P450 (CYP) 2B6 and CYP3A4 will reduce exposure to ketamine and that drugs that inhibit these enzymes will increase exposure to ketamine. Common genetic polymorphisms of the CYP2B6 gene may also be associated with variations in the exposure to ketamine. However, the clinical implications of such variations in exposure have not been sufficiently studied. A very small number of reports and studies suggest that concurrent benzodiazepine medication may diminish the antidepressant benefits of ketamine. Likewise, a small body of literature suggests that drugs (such as lamotrigine) that inhibit glutamatergic signaling may reduce the adverse effects of ketamine; however, it is unknown whether these drugs also diminish the antidepressant effect. Data from clinical trials indicate that most conventional antidepressants can probably be combined with ketamine without compromising efficacy or increasing the adverse effect burden.