Why Severe COVID-19 Patients Are at Greater Risk of Developing Depression: A Molecular Perspective

The prevailing evidence suggests that patients with severe COVID-19 seem to have an overreaction of the immune system demonstrating exacerbated levels of inflammation caused by a "cytokine storm." At this early stage, the mechanisms underpinning COVID-19 are still subject to intense scrutiny and the long-term mental health consequences as a result of the disease are unknown. Here we discuss the hypothesis that patients who survive severe COVID-19 and who experience significant activation of the immune system, are at greater risk of developing depression. We posit that a phenomenon known as cytokine storm dramatically activates the enzyme indoleamine 2,3-dioxygenase (IDO-1), resulting in the increase in kynurenine metabolites. Kynurenine is metabolized by IDO-1 in the brain, producing chemokines, in which a prolonged exposure may result long-term brain impairment. In this article, we also propose the possibility that a SARS-CoV-2 neuroinvasion increases the local levels of angiotensin II by angiotensin-converting enzyme 2 down-regulation. Thereby, angiotensin II could increase kynurenine metabolites producing pro-oxidative and pro-inflammatory effects, resulting in impairment of cognitive function, enhanced oxidative stress and decreased brain-derived neurotrophic factor. It is our premise that patients who experience such a cytokine storm may be at increased risk of long-term mental illness, such as depression.