Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized

•What is the primary question addressed by this study? OPTIMUM is a pragmatic clinical trial evaluating the safety and effectiveness of augmentation versus switch antidepressant strategies in older adults with treatment resistant depression.•What is the main finding of this study? In this submission, we present the study design, methodology and processes for stakeholder engagement of this pragmatic trial. We reflect on early challenges and creative solutions in the conduction the study involving 1) recruitment, 2) Increasing use of polypharmacy by depressed older adults, resulting in potentially hazardous scenarios, 3) reporting of adverse events and standardization of procedures and 4) dissemination of study results.•What is the meaning of the finding? The methods presented and rationale for study design, including early involvement of stake holders; as well as the challenges and solutions implemented in the early stages of the trial, contribute to inform on methodological and procedural choices for future pragmatic studies in older adults with depression. Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalenc