Treatment Resistant Depression with Loss of Antidepressant Response: Rapid-Acting Antidepressant Action of Dextromethorphan, A Possible Treatment Bridging Molecule.

Dextromethorphan (DM) can produce a rapid-acting antidepressant effect in treatment-resistant unipolar major depressive disorder (MDD), similar to ketamine. In a patient who had failed adequate trials of citalopram and vortioxetine and lost response to fluoxetine and bupropion, a 300 mg oral loading dose of DM followed by 60 mg twice daily led to improvement within 48 hours that lasted 7 days and was sustained up to 20 days with daily administration, after which the response gradually waned over 7 days. The effect is thought to involve mTOR activation, NMDA receptor antagonism, sigma-1 and beta adrenergic receptor stimulation, and serotonin transporter inhibition.

Study at a glance

Abstract

Dextromethorphan (DM) may have ketamine-like rapid-acting, treatment-resistant, and conventional antidepressant effects.1,2 This reports our initial experience with DM in unipolar Major Depressive Disorder (MDD). A patient with treatment-resistant MDD (failing adequate trials of citalopram and vortioxetine) with loss of antidepressant response (to fluoxetine and bupropion) twice experienced a rapid-acting antidepressant effect within 48 hours of DM administration and lasting 7 days, sustained up to 20 days with daily administration, then gradually developing labile loss of antidepressant response over the ensuing 7 days. Upon full relapse in DSM-5 MDD while taking 600 mg/day of the strong CYP2D6 inhibitor bupropion XL, a 300 mg oral loading dose of DM was given, followed by 60 mg po bid after an additional dose-finding period, without side effects. DM exhibited a ketamine-like rapid-acting antidepressant effect, thought to be mediated by mTOR activation (related to NMDA PCP site antagonism, sigma-1 and beta adrenergic receptor stimulation) and 5HTT inhibition, resulting in AMPA receptor trafficking, and dendritogenesis, spinogenesis, synaptogenesis, and increased neuronal survival (related to NMDA antagonism and sigma-1 and mTOR signaling). This report appears to be the first report of a rapid-acting effect in unipolar MDD and adds to antidepressant effects observed in the retrospective chart review of 77 patients with Bipolar II Disorder (Kelly and Lieberman 2014). If replicated, there is some reason to think that the administration of other agents with DM, such as lithium or D-cycloserine, might prolong the duration of the rapid-antidepressant effect.