The World Health Organisation predicts that major depression will be the second leading cause of global disability burden by the year 2020. Nevertheless, the pathophysiology remains poorly understood and treatment-resistance is commonplace. Improving the outcome of patient care strategies is thus essential to limit the substantial burden of this costly process at the personal and societal level as well to reduce the economic costs for the Irish healthcare system.
Exercise has shown some potential as an adjunct to the standard pharmacological options employed in depression. However, the mechanism underpinning this effect is poorly understood, a limiting factor in the uptake of this appealing option. Increased metabolism of tryptophan along the kynurenine pathway may be a biomarker of depression linked to mood and cognition. Recent preclinical studies suggest that exercise limits the adverse impact of this altered profile of tryptophan metabolism. In this innovative hypothesis-driven proposal, we will evaluate the ability of exercise to produce similar effects in human subjects and establish whether this is the mechanism underlying its beneficial effects in major depression.
Interrogation of this hypothesis will involve a number of integrated objectives. We will firstly optimise an exercise protocol towards the beneficial modulation of peripheral kynurenine pathway metabolism in healthy controls. Subsequently, we will apply this supervised schedule of exercise to a cohort of depressed subjects and track both the profile of peripheral kynurenine pathway metabolism and the associated symptomatic improvement. Finally, we will determine whether continued adherence to a prescribed program of unsupervised exercise is necessary and sufficient to maintain both the physiological and psychological benefits. The outcomes of this research will markedly increase our understanding of the benefits of exercise in depression and offer tangible economic and societal benefits in addition to the essential improvements in patient care which are so urgently required.
