PROJECT SUMMARY/ABSTRACT Frontline treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT), have limited effectiveness, with ~½ of patients not responding to CBT and ½ relapsing within 2 years. Strategies that could increase the potency of MDD treatments are needed. We have previously shown large psychological and neuroplasticity improvements for 75 minutes post-exercise in adults with MDD. This creates a neurologically fertile post-exercise window with the potential to maximize the effects of CBT performed immediately after exercise. We have developed a novel treatment strategy using aerobic exercise to prime a subsequent CBT session (‘ActiveCBT’). Exercise priming is hypothesized to lead to greater engagement of CBT mechanisms of action through both common (e.g., working alliance) and specific (e.g., behavioral activation) factors linked to depression outcomes; this CBT augmentation approach has yet to be empirically tested. Our published and preliminary work show exercise acutely improves psychological (eg, state anhedonia) and neuroplastic (eg, BDNF) markers in MDD, and our n=10 pilot feasibility trial of this project indicates high likelihood for logistical success and plausible effects of exercise priming on target mechanisms. The R61 will consist of an 8-week randomized controlled trial in 40 adults with MDD performing 30-minutes of moderate exercise or quiet rest (ActiveCBT vs. CalmCBT) prior to weekly CBT sessions. Using a time- and attention-matched control, all participants will view a standardized documentary series for these 30 pre-therapy minutes with the only difference between groups being exercise. This project will also employ cutting-edge, machine learning and natural language processing via the Lyssn platform to objectively evaluate therapy. The overall R61 goals are to: 1) demonstrate exercise priming effects on target CBT mechanisms (working alliance and behavioral activation), 2) link psychological and neuroplastic exercise priming to CBT mechanisms, and 3) explore sensitivity of objective machine learning-based markers from Lyssn to ActiveCBT-induced therapy differences. Upon identification of a moderate between-group difference in working alliance and/or behavioral activation favoring ActiveCBT, the R33 will proceed with a 2:1 randomized, controlled trial (n=100), comparing ActiveCBT to CalmCBT. The overall R33 goals are to: 1) confirm effects of exercise priming on target CBT mechanisms, and 2) determine the preliminary efficacy signal of exercise priming, and determine the strength of the efficacy link with CBT mechanisms. Our working hypotheses are that we will confirm higher working alliance and/or behavioral activation in ActiveCBT, with greater depression effects at 8 weeks and 12 weeks later linked to greater working alliance and/or behavioral activation. These trials will establish the potential for a subsequent confirmatory efficacy trial to rigorously test the potential of exercise priming to enhance treatment. If this innovative, biologically-informed approach successfully ‘primes’ subsequent therapy, this could be used to augment other treatments and in other disorders, significantly improving mental health treatment.

PROJECT NARRATIVE Current treatments for depression, including cognitive behavior therapy (CBT) and medication, are not effective for many people, leading to a high global burden of depression. We propose to investigate the effects of a novel intervention approach, intentionally sequencing aerobic exercise immediately prior to CBT sessions to take advantage of the powerful short-term biological and psychological effects of exercise to increase the potency of the psychotherapy (termed ‘ActiveCBT’) using established and cutting-edge techniques to measure both specific and common factors underlying the antidepressant effect of CBT (ie, mechanisms of CBT). This series of studies will determine the potential of this elegant exercise priming approach to enhance key mechanisms of CBT (R61 project) prior to a larger replication of the trial that establishes the effects of ActiveCBT on overall depression outcomes while linking augmented mechanisms in ActiveCBT to better treatment effects (R33 project).