Maintenance of antidepressant effect by dextromethorphan in patients with treatment-resistant depression who respond to ketamine intervention

Although conventional oral antidepressants are effective in patients with major depressive disorder (MDD), up to 30% of these patients do not achieve symptomatic remission, even after undergoing two trials of antidepressants. Such patients are classified as having treatment-resistant depression (TRD). The glutamate neurotransmitter system has attracted attention as a potential target for treatment that may serve as an alternative to antidepressant treatment. Ketamine is a prototypical N-methyl-D-aspartate receptor (NMDAR) antagonist that has demonstrated substantial promise as a rapid-acting antidepressant for patients with TRD. A single infusion of ketamine causes a noticeable antidepressant effect within 4 h, which peaks after 24 h and then gradually declines. Sustaining the initial clinical response to ketamine infusion in patients with TRD is a major clinical challenge. Dextromethorphan and ketamine share similar pharmacological properties, including their effects on NMDARs, mu-opioid receptors, and sigma-1 receptors. The pathogenesis of MDD, a complex and heterogeneous disorder, has been linked to multiple neurotransmitter systems. Patients with TRD who favorably respond to acute ketamine treatment are likely to respond well to subsequent dextromethorphan therapy. Therefore, we hypothesized that dextromethorphan could sustain the antidepressant effect of ketamine infusion. Because of the rapid and extensive metabolism of dextromethorphan by cytochrome P450 2D6 (CYP2D6), a high dose of dextromethorphan or a combination of dextromethorphan with CYP2D6 inhibitors is required to maintain the antidepressant effect of ketamine.