Depression is linked to an altered stress response, as measured by elevated levels of cortisol and systemic inflammation. Many individuals become resistant to pharmacological treatments; however, non-pharmacological treatments, such as increased physical activity and exercise training, can reduce symptoms of depression in some patients. A decade ago, a key paper helped to define the mechanisms that underlie the effect of non-pharmacological treatments.

In a study published in 2014, Agudelo and colleagues sought to elucidate how stress, inflammation and depression were linked to the therapeutic benefits of exercise on symptoms of depression. The authors focused on tryptophan degradation via the kynurenine pathway, given the sensitivity of the first rate-limiting enzymes (tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase) to cortisol and inflammatory cytokines. At the time, kynurenine (a neurotoxic metabolite) and kynurenic acid (a neuroprotective metabolite) were the only kynurenine-pathway metabolites that had been implicated in mental health disorders, including depression. Kynurenine, but not kynurenic acid, can readily cross the blood–brain barrier. Thus, most kynurenine found in the brain comes from the peripheral circulation.