Abstract
BACKGROUND: Bipolar disorder (BD) is a chronic condition marked by mood dysregulation, with many patients not achieving full remission despite available treatments. Inflammation, indicated by elevated C-reactive protein (CRP) levels, has been implicated in BD pathophysiology. Dextromethorphan, with neuroprotective and anti-inflammatory properties, shows promise as an add-on therapy. This study investigates whether baseline CRP levels predict response to dextromethorphan in a placebo-controlled trial for bipolar disorder. AIMS & OBJECTIVES: This study investigates the lasting impact of VPA, both alone and with dextromethorphan (DM), using CRP as an indicator for the classification to evaluate the therapeutic effect. METHOD: Patients aged 20–65, diagnosed with BD and referred by senior psychiatrists, underwent Structured Clinical Interview for DSM-IV-TR (SCID-IV) to confirm their diagnoses. Following a one-week open-label treatment with valproic acid (500–1,000 mg daily), participants were randomly assigned to one of three groups: valproic acid alone, valproic acid plus placebo, or valproic acid plus extended-release dextromethorphan (30/60 mg/day). Participants completed neuropsychological assessments, including the Continuous Performance Test (CPT) and the Wechsler Memory Scale-Third Edition (WMS-III). CRP was analyzed as a log-transformed continuous variable due to its skewed distribution, consistent with previous studies. Additionally, CRP was stratified into two groups based on chronic low-grade inflammation criteria: levels >3 mg/L and at least two measurements above this cutoff. The chi-square test assessed sex differences and other categorical variables. A Generalized Estimation Equation (GEE) mixed model analyzed medication effects, baseline symptom severity, visit interactions, and LogCRP-by-medication interaction. ANCOVA assessed the impact of valproic acid add-on dextromethorphan on changes in LogCRP from baseline to week 12 (IBM SPSS 24.0). RESULTS: A total of 98 BD with a mean age of 30.81±10.77 years in the VPA+DM group completed the pre- and post-tests. The results showed significant interaction between LogCRP and time on several indices of WMS-III, including visual memory, general memory, attention/concentration, and WCST, including the total errors, conceptual level response, and perseverative error. DISCUSSION & CONCLUSIONS: The significant interaction between LogCRP and time on cognitive indices in this study highlights the potential role of inflammation in cognitive dysfunction in bipolar disorder. Elevated CRP levels, indicative of chronic low-grade inflammation, may contribute to deficits in key cognitive domains, including memory, attention, and executive function. These findings are consistent with previous research suggesting a link between inflammation and cognitive impairment in mood disorders. Moreover, the impact of valproic acid combined with dextromethorphan (VPA+DM) on these cognitive outcomes warrants further exploration. The results suggest that inflammatory markers such as CRP could potentially serve as biomarkers for cognitive dysfunction in BD and might help tailor treatments based on inflammatory profiles. Future studies are needed to confirm these findings and explore the mechanisms by which inflammation affects cognitive function in BD, as well as the potential therapeutic benefits of targeting inflammation in this population. This study suggests that baseline CRP levels interact with treatment time to influence cognitive performance in bipolar disorder. Elevated CRP was associated with poorer outcomes in visual memory, attention, and executive function, as measured by the WMS-III and WCST.