Optimizing Outcomes of Treatment - Resistant Depression in Older Adults (OPTIMUM): Study Design and Sample

Introduction Late-life treatment resistant depression (LLTRD) is common in older adults as many fail to respond to first-line pharmacotherapies such as SSRIs and SNRIs. LLTRD is associated with deleterious effects as it leads to worsening of medical outcomes, increased disability, and worsening of cognitive dysfunction. Thus, there remains a need to determine more effective and safer treatments for LLTRD. Next line treatments, including augmentation strategies (e.g., with aripiprazole, bupropion, or lithium) or switching to a tricyclic antidepressant have not been studied systematically in older adults. OPTIMUM is a pragmatic randomized clinical trial (RCT) in which we compared strategies of augmentation vs switching in older adults (60 years and older) with TRD in a five- center collaborative study funded by the Patient-Centered Outcomes Research Institute (PCORI). OPTIMUM compared the effectiveness and risks of several strategies using a two-step protocol. Methods Participants were recruited and randomized if they were 60 years and older, met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for Major Depressive Disorder and had a score of 10 or higher on the Patient Health Questionnaire (PHQ-9), despite having been treated with at least two antidepressants with an adequate dosage and for at least four weeks (with previous antidepressants being different from the medications being tested in OPTIMUM). Upon study entry, participants either continued their index antidepressant, if assigned to augmentation, or tapered it off, if assigned to switching. Randomization occurred in two steps, with each step lasting 10 weeks. In Step 1, participants were randomized to one of three strategies: augmentation with aripiprazole, augmentation with bupropion, or switch to bupropion. Treatment effectiveness was assessed using the Montgomery Asberg Depression Rating Scale (MADRS) after ten weeks of treatment. Those who do not remit (defined as a MADRS score Results Step 1 involved 621 participants, of which 212 were randomized to augmentation with aripiprazole, 206 to augmentation with bupropion, and 203 to a switch to bupropion. Of these 621 Step-1 participants, 269 (43%) were >70 years, 415 (67%) were female, and 98 (16%) were non-Caucasian. Step 2 involved 251 participants of which 127 were randomized to augmentation to augmentation with lithium and 124 to a switch to nortriptyline. Of these 251 Step-2 participants, 104 (41%) were >70 years, 176 (70%) were female, and 26 (10%) were non-Caucasian. Conclusions OPTIMUM is a pragmatic RCT comparing the effectiveness, tolerability, and safety of several augmentation and switch strategies in a large and diverse group of patients with LLTRD. The study responds to the need of clinicians and patients to make treatment decisions and improve the quality of life of their patients with LLTRD based on evidence on the benefits and risks of commonly used treatment options. Funding This research was funded through a Patient-Centered Outcomes Research Institute (PCORI) award TRD-1511- 33321.