Treating patients who have bipolar II disorder (BD-II) with a combination of add-on dextromethorphan 30 mg/day and memantine 5 mg/day (DM30+MM5) is significantly more effective than placebo for improving clinical symptoms and plasma brain-derived neurotrophic factor (BDNF), according to a study published in International Journal of Bipolar Disorders.

In this double-blind, randomized, controlled clinical trial, patients with a diagnosis of BD-II (N=270) were randomly assigned to the add-on DM30 group (n=69), the MM5 group (n=66), the DM30+MM5 group (n=66), or to placebo (n=69) for 12 weeks, during which they continued receiving 500 mg and 1000 mg of daily valproate (VPA) treatment. The severity of mood symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). Researchers assessed symptom severity and immunological parameters (plasma tumor necrosis factor [TNF]-α, C-reactive protein [CRP], and plasma BDNF).

After 12 weeks of treatment, the mean within-group changes in HDRS and YMRS scores were significant in all treatment groups. In the DM30+MM5 group, depression scores were significantly decreased (P =.03), BDNF scores were significantly higher (P =.04), and CRP levels were significantly lower, which correlated significantly with changes in YMRS scores (P =.03). There was no significant finding related to response or remission rates.

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Limitations of this study included evaluating only peripheral BDNF and cytokines samples instead of central nervous system samples. Researchers also did not explore other factors (smoking, diet, health supplements, or weight) that could affect the correlation between metabolic profiles and proinflammatory factors. In addition, the sample size was small. It is possible that other medications permitted during the study obscured the mood-stabilizing effect of the add-on therapy.

The researchers demonstrated that compared with placebo, treating patients with BD-II using add-on combination therapy of DM30+MM5 may attenuate depressive symptoms and raise plasma BDNF levels. However, this therapy had little effect on other cytokines and metabolic profiles, and BDNF levels were not directly related to depressive symptoms. The researchers concluded, “We also found significant associations between changes in plasma BDNF and cytokine levels and changes in certain metabolic parameters, which suggested that inflammation might be the common pathogenesis between metabolic disturbance and [BD-II].”


Lee SY, Wang TY, Chen SL, et al. Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial. Int J Bipolar Disord. 2020;8(1):11