# 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)

## TL;DR

A clinical trial found that low-dose aspirin had no significant effect on mood instability or other outcomes in newly diagnosed bipolar disorder patients.

## Contribution

This is the first randomized controlled trial to test low-dose aspirin as an add-on treatment for early-stage bipolar disorder.

## Key findings

- Low-dose aspirin showed no benefit on mood instability compared to placebo.
- No improvements were observed in secondary outcomes like activity instability or depression severity.
- High adherence to aspirin was confirmed, and blinding was maintained, strengthening the study's validity.

## Abstract

Robust 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.

In 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.

Two 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.

Low‐dose aspirin did not demonstrate any benefit on MI or on secondary or tertiary outcomes in patients with newly diagnosed BD.

Clinicaltrials.gov registration number: NCT05035316

Significant Outcomes○In this methodologically stringent, well‐powered randomised controlled trial investigating the effects of add‐on treatment with low‐dose aspirin versus placebo in patients with newly diagnosed bipolar disorder, we found no beneficial effects on the primary outcome, patient‐reported daily mood instability.○No beneficial effects were observed across secondary outcomes and tertiary outcomes.○Blinding was maintained, adherence to low‐dose aspirin was high (as confirmed by serum‐thromboxane B2) and dropout and missing data were balanced, enhancing internal validity and reducing type 2 error risk.
Limitations○Our sample consisted of newly diagnosed (within 2 years) patients with few medical comorbidities and a relatively low baseline symptom burden, possibly limiting generalisability to patients with more symptomatic or progressed illness.

Significant Outcomes○In this methodologically stringent, well‐powered randomised controlled trial investigating the effects of add‐on treatment with low‐dose aspirin versus placebo in patients with newly diagnosed bipolar disorder, we found no beneficial effects on the primary outcome, patient‐reported daily mood instability.○No beneficial effects were observed across secondary outcomes and tertiary outcomes.○Blinding was maintained, adherence to low‐dose aspirin was high (as confirmed by serum‐thromboxane B2) and dropout and missing data were balanced, enhancing internal validity and reducing type 2 error risk.

In this methodologically stringent, well‐powered randomised controlled trial investigating the effects of add‐on treatment with low‐dose aspirin versus placebo in patients with newly diagnosed bipolar disorder, we found no beneficial effects on the primary outcome, patient‐reported daily mood instability.

No beneficial effects were observed across secondary outcomes and tertiary outcomes.

Blinding was maintained, adherence to low‐dose aspirin was high (as confirmed by serum‐thromboxane B2) and dropout and missing data were balanced, enhancing internal validity and reducing type 2 error risk.

Limitations○Our sample consisted of newly diagnosed (within 2 years) patients with few medical comorbidities and a relatively low baseline symptom burden, possibly limiting generalisability to patients with more symptomatic or progressed illness.

Our sample consisted of newly diagnosed (within 2 years) patients with few medical comorbidities and a relatively low baseline symptom burden, possibly limiting generalisability to patients with more symptomatic or progressed illness.