Neuroprotective, cognitive, and immunomodulatory effects of Valproic acid combined with dextromethorphan in bipolar disorder.

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BDVPA + DM, 30 BDVPA). Two groups showed no significant differences at baseline in cognition, cytokines, or BDNF. MANOVA showed significant time effects across groups in memory, attention, TNF-α, CRP, IL-8, and BDNF (p < .05), with no group-by-time interactions. Within-group analyses showed modest improvements in several WMS-R and CPT indices in both groups, and small-to-moderate cognitive effect sizes. Both groups showed reductions in selected inflammatory markers and increases in BDNF. Although exploratory within-group patterns suggested slightly larger numerical changes in the BDVPA + DM group, the absence of differential treatment effects limits interpretation. A fully blinded, placebo-controlled trial with long-term follow-up is needed to further clarify whether low-dose DM as an adjunct confers additive neuropsychological or immunomodulatory benefits in BD.