Assessing the Clinical & Neural Outcomes in Depressed Youth Randomized to One of Two Intensities of Aerobic Exercise

Rationale: Major depressive disorder (MDD) is a debilitating disorder characterized by persistent negative mood and a broad range of cognitive, and functional impairments. MDD is estimated to affect 4.4% of the global population, or over 300 million individuals, representing the single largest contributor to non-fatal health loss worldwide. Current treatment options are associated with sub-optimal rates of remission, with only 30-35% of MDD sufferers attaining remission with antidepressant drug monotherapy. One group for whom treatment selection is a particular challenge is transitional aged youth (TAY), encompassing the late teenage years into the early twenties. Although MDD onset typically occurs during this period - as high as 8.2% in Canadian TAY - the psychiatric community has only recently begun to recognize TAY as a unique psychiatric cohort in need of directed treatment. For example, although the use selective serotonin reuptake inhibitors (SSRIs) is the first-line treatment for MDD in adults, their utility in TAY is hampered by the possibility of increased suicidal ideation within this cohort. The need for alternative and tailored treatment options for TAY with MDD is therefore of paramount importance. Aerobic exercise (AE) has recently been recognized as one such intervention, with some reports showing outcomes comparable to pharmacological and psychotherapeutic approaches in adult populations. Few studies however, have investigated to what extent these findings extend to TAY. Further, there is little consensus as to which intensity level, or "dose", of AE offers the most benefit, which neural features underlie the putative benefits of AE in depressed TAY, and the impact on both psychosocial and cognitive processes.

Objectives: The primary objectives of this study are: 1) to determine the effects of moderate vs. high intensity AE on clinically-rated and subjective symptoms of MDD in TAY; and 2) to examine the psychosocial, cognitive, and neuromodulatory effects of these interventions.

Methods: This two-arm, randomized trial will recruit 40 TAY (16-24 yrs) with MDD/persistent depressive disorder (PDD) into one of two AE intensity groups: medium or high. Intensity is defined as a percentage of heart rate reserve (HRR) achieved during exercise, as outlined in the American College of Sports Medicine (ACSM) guidelines (moderate: 50-55% of HRR; N=20; high: 80-85% HRR; N=20). All participants will undergo supervised and guided AE intervention sessions (~30min), three times per week, for twelve consecutive weeks. Pertinent clinical and psychosocial scores, as well as cardiac function (as assessed by maximal oxygen consumption [VO2max]), will be recorded pre-intervention (Week 0), mid-intervention (Week 6), and post-intervention (Week 12). Additionally, participants will undergo electroencephalographic (EEG) and functional magnetic resonance neuroimaging (fMRI) before and after the completion of AE intervention. Specifically, neural dynamics will be recorded at rest and during cognitive tasks engaging working memory (N-Back task) and response inhibition (Flanker task) - cognitive abilities, which have been shown to be impaired in MDD in TAY. Both clinical/psychosocial and neuroimaging outcomes will be compared using time as the within-group, and intervention type as between-group factors.

Hypotheses: The investigators expect a significant reduction in depression symptoms post (vs. pre) intervention and, based on preliminary evidence in adults, a greater reduction may emerge in those participating in the high (vs. moderate) intensity AE. Further, the investigators expect changes in fMRI profiles from pre- to post-intervention (showing normalization of brain activity and connectivity profiles); the same is true of EEG/event-related potential (ERP) features. They also expect a positive relation between VO2max and brain-based changes.

Significance: Findings from this project will help guide future large-scale investigations of AE as a potential treatment for TAY by clarifying the relation between changes to physical indices, depressive symptoms and neural profiles. Importantly, identifying the brain features modulated by AE will broaden our understanding of the neurobiological markers underlying depressive states, allowing for targeted therapeutic approaches and better outcomes for TAY suffering from MDD.