Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial

James W. Murrough, Elizabeth Wade, Sehrish Sayed, Gabriella Ahle, Drew D. Kiraly, Alison Welch, Katherine A. Collins, Laili Soleimani, Dan V. Iosifescu, Dennis S. Charney

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. Methods The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10 mg by mouth administered every 12 h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. Results There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: −13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: −5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. Limitations Open-label, proof-of-concept design. Conclusions Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10 mg administered every 12 h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

Original languageEnglish (US)
Pages (from-to)277-283
Number of pages7
JournalJournal of Affective Disorders
Volume218
DOIs
StatePublished - Aug 15 2017
Externally publishedYes

Keywords

  • Antidepressant
  • Depression
  • Dextromethorphan
  • Glutamate
  • N-methyl-d-aspartate (NMDA) receptor
  • Treatment resistant

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health

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