Dextromethorphan Studied for Use In Bipolar Disorder

Dextromethorphan neuroprotective characteristics may play a role in patients with bipolar disorder.

Changes in inflammatory cytokines, and dysfunction of the neurotrophic system are thought to be involved in the pathology of bipolar disorder.1 Dextromethorphan (DM) has been reported to have neuroprotection on dopaminergic neurons, and protective effect against inflammation-related neuron damage.2

The mechanism of the neuroprotective effects of DM is associated with the inhibition of microglia activation.3 Inflammatory responses are mediated by activated microglia within the central nervous system in response to neuronal damage. A study published in the Journal of Psychiatry & Neuroscience suggests both neuroinflammatory, and systemic inflammatory processes are involved in the pathophysiology of bipolar disorder.4

A study published in the journal European Neuropsychopharmacology investigated whether treating bipolar with valproic acid (VPA) plus low-dose (30 or 60 mg/day) DM is more effective than treating with VPA only. In a 12-week, randomized, double-blind study, patients were randomly assigned to the VPA+DM 30mg, VPA+DM 60mg, or VPA + placebo groups. 1

The study also looked into whether DM affects plasma cytokines, and brain derived neurotrophic factor (BDNF) levels.1 BDNF is highly expressed in areas of the brain that regulate brain functions, such as memory, and emotions (cerebral cortex and hippocampus).5 BDNF, and other neurotrophic factors are believed to neutralize the negative impact of stress hormones. Before treatment, it was found that patients with bipolar had higher plasma cytokine, and lower plasma BDNF levels compared to control patients. 1 BDNF changes in plasma were significantly greater in the VPA+DM 60mg group than in the VPA + placebo group.1 It was concluded that patients with bipolar have a certain degree of systemic inflammation and BDNF dysfunction. Treatment with VPA + DM 60 mg provided patients with bipolar significantly more neurotrophic benefit than did VPA treatment alone.

A retrospective chart review was performed of depressed patients with treatment resistant bipolar II or bipolar not otherwise specified (NOS) disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg.6 The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment. Seventy-seven participants were included, and all had been experiencing depressive symptoms for at least 2 years. The mean number of failed medication trials was 21.2.6 The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1-2 days of starting dextromethorphan and quinidine.

The quality of evidence available for use of DM for treatment of bipolar disorder is limited. Addition of DM may provide neuroprotective benefits in patients who have bipolar disorder, as the European Neuropsychopharmacology study performed has suggested. The adverse effect profile of dextromethorphan is minimal with appropriate use. Further safety, and efficacy data will be needed to correlate use of DM for treatment of bipolar disorder. A phase 3 trial randomized clinical trial is currently in progress looking at treatment response, and adverse effects. It aims to clarify the curative effect of DM, and memantine add-on therapy to valproate in the treatment of bipolar disorders.


  • Chen SL, Lee SY, Chang YH et al. Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder. Eur Neuropsychopharmacol. 2014 Nov;24(11):1753-9. doi: 10.1016/j.euroneuro.2014.09.001. Epub 2014 Sep 16.
  • Add-on Dextromethorphan in Bipolar Disorders (DM). Accessed May 8, 2018.
  • Lu RB, Li CL, Chung YL (2016) New Concept of Bipolar Disorders. J Pharmacogenomics Pharmacoproteomics 7:e152. doi:10.4172/2153-0645.1000e152
  • Grande I, Fries GR, Kunz M, Kapczinski F. The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder. Psychiatry Investigation. 2010;7(4):243-250. doi:10.4306/pi.2010.7.4.243.
  • Kelly TF, Lieberman DZ. The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. J Affect Disord. 2014;167:333-5. doi: 10.1016/j.jad.2014.05.050. Epub 2014 Jun 2.
  • Jakobsson J, Bjerke M, Sahebi S, et al. Monocyte and microglial activation in patients with mood-stabilized bipolar disorder. Journal of Psychiatry & Neuroscience: JPN. 2015;40(4):250-258. doi:10.1503/jpn.140183.