Lithium versus lamotrigine in bipolar disorder type II: protocol for a single-blinded, pragmatic, randomised controlled trial (the LiLa-Bipolar RCT)

INTRODUCTION: Bipolar II disorder (BDII) accounts for the majority of patients with bipolar disorder (BD), yet evidence supporting first-line mood stabilising treatment with lithium and lamotrigine is scarce, and the certainty of the evidence is very low. This highlights a critical evidence gap within psychiatric care. The lithium versus lamotrigine-bipolar randomised controlled trial (RCT) aims to compare lithium and lamotrigine on self-rated day-to-day mood instability (MI) and other patient-centred outcomes in BDII, hypothesising the superiority of lithium. METHODS AND ANALYSIS: A two-arm, single-blind, parallel-group, superiority RCT with a target sample size of 200 patients (accounting for attrition), recruiting patients with newly diagnosed BDII from specialised outpatient mood disorder clinics in the capital region of Copenhagen, Denmark. Participants are randomised in a 1:1 ratio to receive either lithium or lamotrigine for 6 months. The primary outcome is MI, assessed via daily smartphone-based mood ratings. MI is chosen as the primary outcome measure due to its internal validity as a real-life measure for patients and external validity as it reflects both illness severity and functional impairment. Secondary outcomes include the proportion of participants showing a non-response to treatment and observer-rated changes in depressive symptoms over 6 months, measured using the six-item version of the Hamilton Depression Rating Scale. Primary analyses will follow the intention-to-treat principle using linear mixed models. The trial is monitored by the good clinical practice.Recruitment commenced on 8 May 2024, and the final participant follow-up (last patient last visit) is expected on 1 December 2027. ETHICS AND DISSEMINATION: The trial has received approvals from the Danish Research Ethics Committee, the Danish Medicines Agency (EU CT No. 2023-5 09 607-32-00) and the Capital Region Data Agency (P-2023-307). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov/NCT06184581.