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

Background: 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). Objective: 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 4,647 participants including 2,332 unipolar (MDD) and bipolar (BD) depressed patients and 2,315 healthy controls. Results: 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/CAA (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. Conclusion: Patients with affective disorders with melancholic and psychotic features and suicidal behaviors show 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

Adverse childhood experiences and recent negative events activate immune and growth factor pathways, which are associated with first episode major depression and suicidal behaviours

“…The fluorescence intensity (FI) of each protein was measured, and the blank subtracted values were used in the study (Rachayon, Jirakran et al 2022). We followed a procedure including several steps detailed in our previous study (Almulla, Ali Abbas Abo et al 2023). 1, itemizes all the analytes identified in our research and it also provides their corresponding gene IDs and alternate names.…”

“…When constructing our composite scores, we considered analytes that had measurable levels between 20% and 40% as prevalence rates (or dummy variables). As such, we calculated different immune profiles (as described in the introduction and ESF, Table 2), which included all analytes, unless their detectable concentrations were less than 20% (Rachayon, Jirakran et al 2022, Thisayakorn, Thipakorn et al 2022, Almulla, Ali Abbas Abo et al 2023. The primary outcome data in this study are the immunological profiles constructed using z-unit-weighted composite scores of several cytokines, chemokines, and growth factors.…”

“…have reported that the first episode (FE)-MDMD is concomitant with the activation of IRS and CIRS, as well as an elevation in immune-related neurotoxicity (Almulla, Ali Abbas Abo et al 2023). The study conducted by revealed that IL-16 was identified as the primary cytokine biomarker linked to FE-MDMD (Almulla, Ali Abbas Abo et al 2023).…”

Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 82 studies comprising 58 cytokines/chemokines/growth factors

“…Another key finding of our study is the observation of increased immuneassociated neurotoxicity in LC disease, calculated by aggregating neuro-immunotoxic mediators including IL-1β, IL-6, TNF-α, IL-2, IFN-γ, IL-12p70, IL-16, IL-17, CCL2, CCL3, CCL5, CCL11, CXCL1, CXCL8, CXCL10, GM-CSF, and M-CSF. This builds on our previous discovery that LC patients exhibit heightened immune-associated neurotoxicity, as measured by a composite based on the sum of inflammatory, insulin resistance, and oxidative stress biomarkers, which associates with a reduced quality of life in these patients (Al-Hakeim, Al-Naqeeb et al 2023, Almulla, Ali Abbas Abo et al 2023a). These studies have consistently found a significant association between chronic fatigue, affective symptoms (major LC symptoms), and immune-associated neurotoxicity.…”

Increased malondialdehyde and nitric oxide formation, lowered total radical trapping capacity coupled with psychological stressors largely predict the phenome of first-episode mild depression in undergraduate students

“…Maes et al (2018b) discovered in a previous investigation that ACEs can predict the phenome of MDD, with a part of these effects being mediated by compromised antioxidant defenses. Further potential mechanisms by which ACEs exert their effects on the manifestation of MDD include the microbiome, increased atherogenicity, T cell activation, and immune-associated neurotoxicity (Almulla et al, 2023;Maes et al, 2023b;Rachayon et al, 2023).…”