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Introduction Depression is the dominant phase in bipolar disorder, but the available treatments are scarce. Lithium is a first-line option in several guidelines despite limited evidence, whereas cariprazine has a well-documented efficacy for depressive episodes. By comparing lithium and cariprazine in terms of efficacy and tolerability, we aim to contribute to an evidence-based positioning of lithium in future guidelines.Methods and analysis An open label, randomised, multicentre, investigator-sponsored comparison of lithium versus cariprazine with a treatment duration of 8 weeks. Participants are aged 18–65 years and are suffering from a depressive episode as part of bipolar disorder, type 1 or 2. The primary outcome is the difference between the two groups in change from baseline to endpoint on Hamilton depression scale, 6 item version, based on the modified intention-to-treat population. Continuous variables will be analysed by using two-sided t-tests and mixed effects models. For categorical measures, χ 2 tests and multivariable models will be applied. Secondary outcomes include AEs and measures of well-being, depressive, manic and suicidal symptoms, as well as cognitive function. The study is powered as a superiority trial, with a calculated study population of 122 participants.Ethics and dissemination Protocol has been approved by the regional ethical committee N-20220007 and European Medicines Agency. All participants provide written informed consent. The protocol was written according to Standard Protocol Items: Recommendations for Interventional Trials 2013 guidelines. Results will be disseminated in peer-reviewed international journals.Trial registration number EU-CTR, 2024-517170-20-01; NCT05913947.