Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity

BACKGROUND: Reduced plasma tryptophan occurs in depression and somatization. Induction of indoleamine 2,3-dioxygenase (IDO) with consequent synthesis of tryptophan catabolites (TRYCATs) and lowered tryptophan are associated with the onset of depression in the puerperium and during interferon-alpha treatment. Depression is accompanied by lowered kynurenic acid, a neuroprotectant, or increased kynurenine, a neurotoxic TRYCAT.

AIMS AND METHODS: To examine plasma tryptophan; kynurenine; kynurenic acid; the kynurenine / tryptophan (KY/TRP) ratio, indicating IDO activity; and the kynurenine / kynurenic acid (KY/KA) ratio, indicating kynurenine aminotransferase (KAT) activity, in somatization; depression; somatization + depression; and controls. Illness severity is measured by the Somatic Symptom Index (SSI), the Screening for Somatoform Symptoms (SOMS), and the Beck Depression Inventory (BDI).

RESULTS: Tryptophan is significantly lower in patients than in controls and lower in somatization than in depression. KY/TRP is significantly increased in somatization. Kynurenic acid is significantly lower in patients than in controls, and lower in somatization than in depression. KY/KA is significantly higher in somatization and somatization + depression than in depression and controls. There are significant correlations between the severity of somatization, but not depression, and KY/TRP and KY/KA (positive) and tryptophan (negative). Kynurenine and kynurenic acid are significantly correlated in controls, somatization + depression, and depression, but not in somatization.

CONCLUSIONS: Somatization is characterized by increased IDO activity and disorders in KAT activity and an increased neurotoxic potential. The TRYCAT pathway may play a role in the pathophysiology of somatizing and “psychosomatic” symptoms through effects on pain, gut motility, the autonomic nervous system, peripheral NMDA receptors, etc. Even more, biological disorders, such as aberrations in the TRYCAT pathway, which are considered to be a hallmark for depression, are in fact attributable to somatization rather than to depression per se. Future research in depression on the TRYCAT pathway should always control for the possible effects of somatization.

Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmunue disease.

There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.