Combinations of dextromethorphan for the treatment of mood disorders - a review of the evidence

ABSTRACT

Introduction

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. However, many patients do not achieve an adequate clinical improvement with pharmacotherapies targeting monoamine receptors, and the onset of therapeutic benefit typically lags by 4–6 weeks. There is a significant need for mechanistically novel treatments with more rapid efficacy. Combinations of dextromethorphan, an oral N-methyl-D-aspartate (NMDA) receptor antagonist, can potentially fill this gap.

Areas covered

US Clinical Trials registration was systematically searched for studies examining the effects of dextromethorphan in mood disorders. Results were gathered via a PubMed search, adding also press releases, and poster presentations. Two case reports and eight clinical trials were identified for the treatment of MDD or treatment resistant depression (TRD); we also reviewed additional studies in bipolar disorder.

Expert opinion

Clinical studies show that the combinations of dextromethorphan with quinidine or bupropion have been effective in decreasing depressive symptomatology in MDD. However, dextromethorphan studies in adults with TRD or with bipolar depression have shown mixed results. The combination of dextromethorphan and bupropion is a well-tolerated, safe, and efficacious treatment option for adults with MDD. Additional studies analyzing the effects of dextromethorphan and bupropion for TRD and bipolar depression are needed.

KEYWORDS:

• Major depressive disorder (MDD)
• depression
• treatment resistant depression (TRD)
• bipolar disorder
• dextromethorphan
• bupropion
• glutamate

Article highlights

• The mechanisms of most currently approved antidepressants involve modulation of monoamine pathways; the compounds have limited efficacy and the onset of their therapeutic action is typically delayed by weeks. Novel treatments with more rapid efficacy are needed.

• The use of ketamine and esketamine, glutamate NMDA receptor antagonists with a more rapid onset of antidepressant efficacy, is limited due to logistical difficulties (e.g. in office administration, need for post-administration monitoring).

• Dextromethorphan has similar pharmacological properties to ketamine. However, dextromethorphan is administered orally and does not require monitoring.

• The combination of dextromethorphan and the antidepressant bupropion represents the first oral NMDA receptor antagonist FDA-approved for treatment of MDD.

• This novel treatment is safe, well-tolerated, and has rapid and significant antidepressant efficacy in MDD. However, additional studies are required to fully support its efficacy in treatment resistant depression or in bipolar disorder.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

DV Iosifescu has, in the last five years, received consulting honoraria from Alkermes, Allergan, Angelini, Axsome, Biogen, Boehringer Ingelheim, Centers for Psychiatric Excellence, Clexio, Global Medical Education, Jazz Pharmaceuticals, Lundbeck, Neumora Therapeutics, Otsuka, Precision Neuroscience, Relmada, Sage, and Sunovion and research support (through his academic institution) from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Otsuka, Roche, and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was not funded.