No Effect of Low-Dose Aspirin Versus Placebo as Add-On Treatment in Bipolar Disorder-Results From a Randomised Controlled Trial (the A-Bipolar RCT).

introductionRobust evidence associates immunoinflammatory dysfunction and bipolar disorder (BD), with immune dysregulation present in patients newly diagnosed with BD. This suggests that anti-inflammatory agents, like low-dose aspirin (LDA), might be repurposed in the treatment of early-stage BD. Building on pharmacoepidemiologic and meta-analytic evidence, we conducted the first randomised controlled trial (RCT) testing the effects of add-on LDA in patients with newly diagnosed BD. We hypothesised that add-on treatment with LDA would reduce mood instability (MI), activity instability (AI), and depression severity.

methodsIn this parallel group, triple-blind, superiority RCT, patients newly diagnosed with BD, recruited from a public outpatient mood disorder clinic in the Capital Region of Denmark, were randomised 1:1 to 150 mg acetylsalicylic acid or placebo by an independent third party. The primary outcome was average MI at 6-month follow-up, assessed by the Root Mean Square of Successive Differences (RMSSDs) method. Secondary outcomes included average AI, assessed by the RMSSD method, and change in depressive symptoms, assessed with the 6-item Hamilton Depression Rating Scale, at 6 months. Tertiary outcomes included sleep variability, cognition, manic symptoms and questionnaires at 6 months.

resultsTwo hundred fifty patients were randomised from January 20, 2022, to May 30, 2024, with the last follow-up on November 18, 2024. Analyses included data from 240 patients (120 received placebo; 120 LDA), with a mean of 108 (SD = 57) daily mood registrations. The estimated treatment difference for MI was 0.022 (95% CI: -0.056 to 0.1, p = 0.58) for LDA compared to placebo, indicating no clinically relevant difference. No beneficial effects of LDA were found across secondary or tertiary outcomes. Methodologically, randomisation and blinding were successful, and serum-thromboxane B2 levels confirmed high adherence to LDA.

conclusionsLow-dose aspirin did not demonstrate any benefit on MI or on secondary or tertiary outcomes in patients with newly diagnosed BD. CLINICAL REGISTRATION: Clinicaltrials.gov registration number: NCT05035316.