Major depressive disorder (MDD) is a debilitating condition with frequent relapses. Augmentation strategies may improve psychotherapy outcomes, particularly if they enhance mechanisms of change. Using an experimental therapeutics approach, this pilot trial evaluated whether 30 min of individual moderate exercise immediately before individual cognitive behavioral therapy (ActiveCBT) engages two mechanistic targets (behavioral activation and therapeutic alliance) compared to a time- and attention-matched control (CalmCBT). Forty adults with DSM-5 MDD were severity-stratified and randomized to 8 weeks of ActiveCBT ( n = 19) or CalmCBT ( n = 21). Primary outcomes were the Working Alliance Inventory–Short Revised (WAI; Bond, Task, Goals subscales) and Behavioral Activation for Depression Scale (BADS). Depression outcomes included Hamilton Rating Scale for Depression (HAMD) response (≥50% reduction) and remission (HAMD<8) from a masked assessor. Generalized estimating equations estimated group effects across time, standardized as Cohen's d, with a priori success defined as d ≥ 0.35 for both or d ≥ 0.55 for either WAI or BADS. The average standardized effect for WAI-Bond favoring ActiveCBT was d = 0.36 (95% CI: −0.19, 0.90, p = 0.20) and BADS was d = 0.43 (−0.07, 0.94; p = 0.09). Secondary exploratory analyses found a significant remission benefit for ActiveCBT over CalmCBT (69% vs 33%, p < 0.05), with similar response rates. Exercise priming demonstrated directional mechanistic signals in both specific (behavioral activation) and nonspecific (therapeutic bond) targets, with potential remission benefits from exploratory analyses. These findings preliminarily suggest that exercising before therapy could augment CBT and offer a safe, accessible way to potentially boost its antidepressant effects. This study was prospectively registered at ClinicalTrials.gov ( NCT06001346 ). • We report a pilot/target engagement trial of exercise vs calm priming of CBT in MDD • Exercising right before therapy enhanced working alliance and behavioral activation • Directional effects met pre-specified thresholds for both alliance and activation • A large remission benefit was found for ActiveCBT in exploratory analyses • Effective group blinding in treatment and assessments led to high internal validity
Meyer et al. (Sun,) studied this question.