Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

Abstract

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.

Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders

“…In contrast, changes in the kynurenine pathway have been established as key players in inflammation-associated disorders, as well as for epilepsy, and neurodegenerative and autoimmune disorders [ 10 , 14 , 20 , 99 ]. Since neuroinflammation is a hallmark widely related to neurological and psychiatric diseases [ 11 ], many studies explored the possible role of the Tryp oxidation pathway [ 57 , 100 , 101 ]. Indeed, Tryp-kynurenine pathway activation seems relevant to the pathophysiology of neurological abnormalities by activating the neurotoxic branch and suppressing the neuroprotective one [ 53 , 102 , 103 , 104 , 105 , 106 , 107 ].…”

“…Moreover, nutritional physiologists recognised that dietary deficiency of Tryp could increase the neurotoxic metabolites in the kynurenine pathway [ 49 ] and result in CNS sequelae, such as ataxia, cognitive dysfunction, and dysphoria [ 55 , 56 ]. Clinical evidence suggests that depletion of this amino acid worsens depressive symptoms and mood states [ 57 ]. Additionally, a lack of Tryp increases cognitive dysfunction in people with AD [ 58 ].…”

Is SARS-CoV-2 a Risk Factor of Bipolar Disorder?—A Narrative Review

“…Changes in TRP metabolism and the accumulation of neurotoxic metabolites is discussed not only in MDD but also in BD [ 17 , 169 ]. In the group of bipolar patients who committed suicide, NAD—the end product of the kynurenine pathway, was significantly elevated in their anterior cingulate cortex (ACC) compared to BD patients who died of different reasons.…”

Women’s mood at high altitude. sexual dimorphism in hypoxic stress modulation by the tryptophan–melatonin axis

“…Pro-inflammatory cytokines seem to participate in causing depression. Patients treated with interferon alpha (IFN-α) show reduced levels of Trp, augmented levels of kynurenine (Kyn), and elevated Kyn/Trp ratio activity together with an increase in depressive symptoms ( Correia and Vale, 2022 ). An elevated Trp to kynurenine ratio, conversely, reflects endogenous adaptation to stress ( Poeggeler et al, 2022 ).…”