Serotonin – Kynurenine Hypothesis of Depression: Historical Overview and Recent Developments

Abstract

In the late 60th - early 70th of the last century Prof. IP Lapin (June 26, 1930 – August 23, 2012) suggested that “intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component” while “activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect”. He suggested that in depression cortisol-inducible activation of liver enzyme, tryptophan 2,3-dioxygenase (TDO), shunted “metabolism of tryptophan away from serotonin production towards kynurenine production” leading to serotonin deficiency. He was the first to suggest and discover that kynurenine and its metabolites affect brain functions, and propose the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect. Further major developments of serotonin-kynurenine hypothesis include the discovery of antidepressant and cognition-enhancing effects of post-serotonin metabolite, N-acetylserotonin, an agonist to tyrosine kinase B(TrkB) receptors of brain derived neurotrophic factor. The discovery of indoleamine 2,3–dioxygenase (IDO), another rate-limiting enzyme of TRY – KYN metabolism, located in brain and inducible by pro-inflammatory cytokines, suggested the link between depression and aging/aging-associated medical (e.g., insulin resistance, obesity, cardiovascular), psychiatric (e.g., vascular cognitive impairment) and other disorders associated with chronic inflammation (e.g., hepatitis virus C, psoriasis) disorders.

Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

“…Findings of less circulating TRY and more KYN have been proposed as evidence of the decreased production of serotonin in association with depression [2,7,21,23]. This hypothesized greater efficiency of converting TRY to KYN might, in turn, reflect increased activity of the KYN-synthesizing enzyme indoleamine-2,3-dioxygenase, perhaps through the influence of increased production of glucocorticoids, cytokines, and other inflammatory peptides that can occur with major depression [34].…”

“…In general, the preceding findings have been proposed to support a relationship of the increased production of KYN and related metabolites with major depression, possibly via impairment of neuroprotective mechanisms, enhancement of neurotoxic mechanisms, or shifting TRY away from the production of the mood-influencing neurotransmitter, 5-hydroxytryptamine (serotonin) [2,7,21].…”

“…For example, inflammatory cytokines may increase enzymatic conversion of L-tryptophan (TRY) to KYN by indoleamine-2,3-dioxygenase [1,2]. KYN and its metabolism have been linked to several neuropsychiatric conditions, including major depressive disorder (MDD) and bipolar disorder (BD).…”

“…KYN and its metabolism have been linked to several neuropsychiatric conditions, including major depressive disorder (MDD) and bipolar disorder (BD). These proposed associations are supported by observations of altered concentrations of TRY (decreased) or KYN (increased), with an increased ratio of KYN/TRY (or a lower TRY/KYN ratio), sometimes with reduced kynurenic (KA), and increased quinolinic acid (QA) and xanthurenic acid (XA), as well as reduced concentrations of serotonin (5-hydroytryptamine) and its main metabolic product 5-hydroxyindolacetic acid (5-HIAA) in serum, plasma, or cerebrospinal fluid (CSF) [2][3][4][5][6][7][8][9][10][11][12]. However, such associations have not been reported in all studies [13,14].…”

Vaccinating against depression or anxiety: is it plausible?

“…A biological preparation ('vaccine') could be prepared with the microbial candidates suggested by current (Table 1) and future studies, and then tested in patients with elevated C-reactive protein levels (a marker of inflammatory forms of MDD). Gut pathobionts may only account for one inflammatory upstream path for immune activation leading to MDD (see also the complex interaction of pro-inflammatory cytokines with kynurenine metabolism in depression [16]). Technological advances in sequencing the human microbiome, and reductions in costs, could make it possible in the near future to use a personalized medicine approach, targeting known pathobionts identified in individuals with MDD.…”