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.

Keywords: Trp metabolism; brain-derived neurotrophic factor; depression; inflammation; kynurenine pathway; microbiota; serotonin pathway; stress.

Figure 1

Schematic abstract of the information presented in this review. Briefly, the Trp metabolism is important in several processes connected with depression, particularly neuroinflammation, stress response, gut microbiota dysregulation, and brain-derived neurotrophic factor activity. Illustration created with BioRender [8]. TPH2: tryptophan hydroxylase 2; 5-HT1A: serotonin 1A receptor; IDO: indoleamine 2-3-dioxygenase 1; TDO: tryptophan 2,3-dioxygenase; SERT: serotonin transporter.

Figure 2

Depression is a complex disease. Hypothalamic–pituitary–adrenal (HPA) axis dysfunction, low levels of neurotransmitters (such as 5-HT, noradrenaline, and dopamine) and neurotrophic factors (such as BDNF), brain atrophy of regions such as the hippocampus, increased levels of inflammation and oxidative stress, and decreased levels of neurogenesis are some underlying features of depression. Illustration created with BioRender [8].

Figure 3

Summary of the two major metabolic pathways of the amino acid Trp: 5-HT and Kyn pathways. All of the abbreviations are described in text. Illustration created with BioRender [8].