Protocol for a randomized controlled trial of a resistance exercise training to treat major depression via cerebrovascular mechanisms (RESIST Trial).

Background: Many adults with major depressive disorder (MDD) do not engage in treatment and may also not respond when current frontline treatments are completed. Resistance exercise training (RET) is an understudied behavioral treatment option, which may help with MDD management through improving cerebral blood flow that is commonly impaired in adults with MDD. The purpose of this study is to use gold-standard research methods to determine the validity (clinical efficacy) of RET for treating MDD and to determine potential cerebrovascular pathways through which RET might improve MDD symptoms.

Methods: This study will be a randomized controlled trial of 200 adults with DSM-5-diagnosed MDD of at least mild severity. Participants will be randomized to 16 weeks of twice-weekly RET at either guidelines-based high dose (60% one-repetition maximum initial load; n = 100) or a low-dose/SHAM (30% one-repetition maximum initial load; n = 100) progressive, upper- and lower-body program using resistance machines. The primary clinical outcomes of this trial are depressive symptom severity, assessed via clinician-rated GRID-Hamilton Depression Rating Scale and self-reported Quick Inventory of Depressive Symptomatology. Secondary outcomes that will examine potential mediators are cerebral blood flow (via cerebral blood velocity and pulsatility) and self-efficacy (via New General Self-Efficacy Scale and RET Task Self-Efficacy). Group differences will be evaluated during assessment visits at weeks 0 (Baseline), 8, 16 (Post-Intervention), 26, and 52. Additional analyses will explore predictors of treatment success and participants' maintenance of the RET past the active intervention.

Discussion: RET is an understudied behavioral treatment for MDD. This randomized controlled trial will critically build on previous studies by using a large sample size, rigorously examining potential (provocative, plausible) biological and psychological mechanisms of RET's hypothesized antidepressant effects, and determining potential persistent effects with short- and long-term follow-up assessments. If clinical efficacy is confirmed, RET would be added as a highly translatable, accessible, low-cost alternative treatment option for individuals with MDD. Further effectiveness and implementation research would be required if efficacy is confirmed in this trial.

Trial Registration: This trial is registered on ClinicaTrials.gov (ID: NCT06110897; October 20th, 2023; https://clinicaltrials.gov/study/NCT06110897 ).