Low-dose aspirin versus placebo as adjunctive treatment in bipolar disorder (the Aspirin-Bipolar RCT): Results of exploratory biomarker analyses

Background: Low-dose aspirin (LDA) has anti-inflammatory and immune modulatory properties and has been proposed as an add-on treatment for bipolar disorder (BD). Whether its hypothesized biological targets are engaged in patients with BD remains unknown. Using biomarker data from the Aspirin-Bipolar RCT, we investigated inflammatory and hypothalamic-pituitary-adrenal (HPA) axis biomarkers as candidate mediators of the proposed effects of LDA. Methods: Secondary analysis of the Aspirin-Bipolar RCT including 250 patients (58% female) newly diagnosed with BD randomised to add-on LDA (n = 125) or placebo (n = 125). Biomarkers were measured at baseline (cytokines: n = 236; hair cortisol: n = 201) and 6-month follow-up (cytokines: n = 172; hair cortisol: n = 148). We examined whether baseline biomarkers predicted 6-month mood instability (MI, primary outcome), whether changes mediated the effects of LDA on MI, and whether patients with higher baseline inflammation responded differently to treatment. Higher inflammation was defined as baseline IL-6, IL-10, and TNF-α levels all above the median. Missing data was handled using multiple imputations. Results: Baseline biomarkers did not predict 6-month MI. Mediation analyses provided no evidence that the hypothesized biomarker pathways were engaged. Patients with higher baseline inflammation did not derive greater benefit from LDA than those with lower baseline inflammation. Effect estimates were consistently close to zero, with narrow confidence intervals. Conclusion: We found no evidence that the hypothesized biological pathways were engaged or that baseline inflammation modified treatment response. The findings argue against a major role for the proposed inflammatory and HPA-axis mechanisms and are consistent with the negative clinical findings of the primary Aspirin-Bipolar RCT. Clinicaltrials.gov registration number: NCT050353.