The Tryptophan Catabolite or Kynurenine Pathway in a Major Depressive Episode with Melancholia, Psychotic Features and Suicidal Behaviors: A Systematic Review and Meta-Analysis

Abstract

Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower (p < 0.0001) TRP (standardized mean difference, SMD = −0.517, 95% confidence interval, CI: −0.735; −0.299) and TRP/CAAs (SMD= −0.617, CI: −0.957; −0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD= 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD= 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD= −0.260, CI: −0.487; −0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in Long COVID

“…In recent meta-analyses, no notable changes in TRYCAT production have been observed in depression and schizophrenia, even though low tryptophan levels are a characteristic of both diseases (Almulla, Thipakorn et al 2022. Increased production of TRYCATs appears to be a characteristic of acute inflammatory conditions, such as critical acute COVID-19 infection (Almulla, Al-Hakeim et al 2023) and interferon-induced depression (Bonaccorso, Marino et al 2002), as opposed to mild chronic inflammatory conditions, such as depression, schizophrenia, and Alzheimer's disease , Almulla, Thipakorn et al 2022.…”

“…The copyright holder for this this version posted March 16, 2023. ; https://doi.org/10. 1101/2023.03.11.23287152 doi: medRxiv preprint oxidative stress toxicity (OSTOX) and decreased antioxidant defenses (ANTIOX) , Maes, Rachayon et al 2022 According to a recent meta-analysis, the acute infectious phase is characterized by a considerable activation of indoleamine-2,3-dioxygenase (IDO), which leads to tryptophan depletion and an increase in the synthesis of tryptophan catabolites (TRYCATs) (Almulla, Thipakorn et al 2022). Moreover, activation of the TRYCAT pathway is related to critical illness and higher mortality .…”

“…TRYCATs such as 3HK and QA, for instance, generate neurooxidative toxicity, resulting in oxidative cell damage and lipid peroxidation (Goldstein, Leopold et al 2000, Smith, Smith et al 2009, Reyes Ocampo, Lugo Huitrón et al 2014. Tryptophan deficiency is also characteristic of major depression, somatization disorder, schizophrenia, cognitive deficits, and physiosomatic symptoms (Maes, Minner et al 1991, Maes and Rief 2012, Almulla, Thipakorn et al 2022. It is thought that increased production of neurotoxic TRYCATs may contribute to the neuropsychiatric symptoms of major depression, bipolar disorder, schizophrenia, anxiety, somatization disorder, and chronic fatigue syndrome, as well as neurocognitive impairments (Maes, Galecki et al 2011, Cordeiro, Guimaraes et al 2014, Morris, F Carvalho et al 2016, Ormstad, Simonsen et al 2020, Milaneschi, Allers et al 2021.…”

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV)

“…Two recent large-scale meta-analyses by Almulla et al have provided evidence that infection-induced depression can be a distinct type of depression based on its pathomechanism [ 14 , 15 ]. The first analysis showed that patients with MDD and BP were connected, with a decrease in TRP concentration without overactivity of the kynurenine pathway [ 9 ].…”

“…Pierrucci-Lagha et al found that, in a non-Hispanic Caucasian sample, L A /L A homozygotes showed greater depressive symptoms, whereas among a Hispanic sample, the S/S, L G /L G , and S/L G groups reported the highest rates of depression symptoms during IFN treatment. Analysis of the above-mentioned studies leads to an interesting observation: in studies that simultaneously investigated the impact of HTR1A and 5-HTTLPR polymorphisms on depressive symptoms, only HTR1A significantly influenced the increase in depressive symptoms or the diagnosis of depression [ 12 , 14 , 15 ].…”