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Background: Major depressive disorder (MDD) is the leading cause of disability worldwide and one of the most heterogeneous mental health disorders. Although there are effective treatments for MDD, about 50% of patients do not respond to treatment. One of the greatest challenges in improving current treatments is identifying the mechanisms responsible for therapeutic change in MDD. The proposed study aims to identify patient-specific mechanisms of change in two treatments for MDD by investigating whether subpopulations of patients differ in the mechanisms of change that operate when receiving a given treatment. Based on theories of targeting weakness and building on strength, we will examine whether the mechanism of change operating when a treatment is provided depends on whether the treatment targets the patient's strength or weakness. Method: To test our hypothesis that two treatments, supportive-expressive treatment (SET) and emotion-focused treatment (EFT), differ in their mechanisms of change and to explore whether focusing on the patient's strength or weakness will result in better treatment outcome, we conduct a mechanistic randomized controlled trial. One hundred and twenty-four individuals diagnosed with MDD are randomized to 16 sessions of either SET or EFT. The two treatments are theorized to differ in their main mechanism of change: SET places emphasis on insight as its main mechanism of change, and EFT places emphasis on emotional processing. Both can serve as strength- or weakness-focused treatments, based on the patient's baseline levels of insight and emotional processing. The primary outcome is the Hamilton Rating Scale for Depression. Additional measures include self-report measures and clinical interviews, hormonal, motion, acoustic, physiological, and neuroimaging assessments, performance on cognitive tasks, and narrative material (collected from the sessions and interviews). Discussion: The RCT will expand our understanding of mechanisms of change in psychotherapy, from one-size-fits-all to patient-specific mechanisms of change. By informing therapists about which of the two approaches is most effective with patients based on their baseline characteristics, the RCT will contribute to progress toward personalized treatment. Trial registration: clinicaltrials.gov Identifier: NCT04576182 submitted on October 1st 2020. Funding: The Israel Science Foundation. Trial status: Recruitment is ongoing. [ABSTRACT FROM AUTHOR]