RESISTance Exercise for Depression Trial

Official title

Resistance Exercise to Treat Major Depression Via Cerebrovascular Mechanisms: Confirming Efficacy and Informing Precision Medicine

Overview

Depression is a leading cause of disability worldwide and current treatments are ineffective for many people. This trial will investigate the efficacy of a 16-week high vs low dose resistance exercise training program for the treatment of Major Depressive Disorder (MDD) in 200 adults.

Detailed description

Frontline treatments for major depressive disorder (MDD), including psycho- and pharmacotherapy, have limited effectiveness, and there is a critical need to develop and test novel, efficacious treatments for MDD and simultaneously work to optimize its benefits. Resistance exercise training (RET) is a promising but understudied treatment approach. This trial will investigate the efficacy of RET for treatment of MDD in a 1:1 randomized controlled trial (n=200) of 16 weeks of high vs low progressive RET in adults with DSM-5 diagnosed MDD. Further, this project will explore potential mechanisms leading to symptom improvement, including changes in cerebrovascular function (i.e., cerebral blood velocity and pulsatility) and self-efficacy, while also using supervised machine learning tools to predict depression changes, cerebrovascular changes, and participant adherence. Upon completion, this study will build towards identifying and translating mechanistically driven behavioral treatments to reduce the global burden of mental illness.

Interventions

• Behavioral High Dose Resistance Exercise Training
  Progressive resistance exercise training
• Behavioral Low Dose Resistance Exercise Training Group
  Progressive resistance exercise training

Primary outcome measures

• Change in depressive symptom severity measured by GRID Hamilton Depression Rating Scale (GRID-HAM-D) [Time frame: Weeks 0, 8, 16, 26, 52]
• Change in self-reported depression symptom severity measured by Quick Inventory of Depressive Symptoms (QIDS) [Time frame: Weeks 0, 1-16 (once per week across the intervention), 26, 52]
• Cerebral mean blood velocity [Time frame: Weeks 0, 8, 16, 26, 52]
• Cerebral blood velocity pulsatility [Time frame: Weeks 0, 8, 16, 26, 52]

Secondary outcome measures (12)

• Changes in general self efficacy measured by New General Self-Efficacy Scale [Time frame: Weeks 0, 8, 16, 26, 52]
• Changes in RET-specific self efficacy measured by a modified version of the New General Self-Efficacy Scale [Time frame: Weeks 0, 1-16 (once per week across the intervention), 26, 52]
• Change in suicidal thoughts measured by Columbia-Suicide Severity Rating Scale (CSSRS) [Time frame: Weeks 0, 8, 16, 26, 52]
• Change in muscular strength measured by Estimated 1 Repetition Maximum (RM) Strength Test [Time frame: Weeks 0, 8, 16, 26, 52]
• Change in grip strength [Time frame: Weeks 0, 8, 16, 26, 52]
• Global cerebral blood flow [Time frame: Weeks 0, 8, 16, 26, 52]
• Brachial blood pressure [Time frame: Weeks 0, 8, 16, 26, 52]
• Carotid blood pressure [Time frame: Weeks 0, 8, 16, 26, 52]
• Aortic stiffness [Time frame: Weeks 0, 8, 16, 26, 52]
• Carotid stiffness [Time frame: Weeks 0, 8, 16, 26, 52]
• End-tidal Carbon Dioxide (CO2) [Time frame: Weeks 0, 8, 16, 26, 52]
• Cerebrovascular reactivity to breath holds [Time frame: Weeks 0, 8, 16, 26, 52]

Eligibility criteria

Inclusion criteria

• Be diagnosed with DSM-5 MDD, confirmed via Structured Clinical Interview for DSM-5 (SCID).
• Have current depressive symptoms of at least mild severity defined by the Hamilton Rating Scale of Depression 17 greater than or equal to 8 (HAMD; using the GRID-HAMD evaluated by trained, masked raters)
• Be ages 18-65
• EITHER not taking any mental health medications or seeking other mental health treatment (e.g., behavioral, psychological) OR be on a stable mental health medication and/or treatment regimen for the past 8 weeks, and intend to maintain that regimen for the duration of the study
• Safe to exercise based on physical activity screening questions or physician clearance
• Willing to be randomized to either condition
• have a Smartphone

Exclusion criteria

• Currently pregnant, nursing, or planning to become pregnant during the trial
• Class III+ obesity
• Diagnosed with lifetime or current Psychosis, Mania, or Bipolar Disorder, via the SCID
• Diagnosed with current Substance Use Disorder, via the SCID
• Active suicidal ideation with specific plan and intent ('5' score on Suicidal Ideation from Columbia Suicide Severity Rating Scale), which would necessitate immediate emergent care
• Exhibit behavioral disturbance (e.g., aggression, mild-moderate cognitive impairment) that would significantly interfere with study participation, as assessed by clinical research personnel
• Currently meets resistance exercise recommendations (2 days per week) for the last 8 weeks
• Self-reporting a concussion/traumatic brain injury within the last 3 months
• Having cardiovascular disease, uncontrolled hypertension, or uncontrolled diabetes

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• Iowa State University — Ames
• University of Wisconsin - Madison — Madison

Publications

• Meyer JD, Smith SL, Gidley JM, Molina A, Churchill SL, Kelly SJE, Lansing JE, Wade NG, Phillips AL, Liu P, Herring MP, Murray TA, Barnes JN, Goldberg SB, Lefferts WK. Protocol for a randomized controlled trial of a resistance exercise training to treat major depression via cerebrovascular mechanisms (RESIST Trial). Trials. 2025 Aug 26;26(1):306. doi: 10.1186/s13063-025-09025-z. PMID 40859378

Identifiers

NCT: NCT06110897 · 2025-0295 · 1R01MH130566-01A1 · Protocol Version 9/15/2025 · A176000 · EDUC/KINESIOLOGY

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗