Background Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP. Methods This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls. Results The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = − 1.002, 95%CI: − 1.738; − 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = − 0.909, 95% CI: − 1.569; − 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls. Conclusions Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.

Background: There is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs). Aims: To systematically review and meta-analyze TRP, its competing amino-acids (CAAs) and TRYCAT data in MDD and BD. Methods: This review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls. Results: TRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p<0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD=-0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD=-0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p<0.0001, SMD= -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p<0.0001, SMD=-0.304, 95%CI: -0.415, -0.194) but not in serum (p=0.054) or the central nervous system (CNS, p=0.771). The KYN/TRP ratio, frequently used as an index of indoleamine-dioxygenase (IDO) activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD. Conclusions: Our findings revealed that MDD/BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.

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Background: Immune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD). Methods: This study examines 48 cytokines/chemokines/growth factors, and classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles in the acute phase of FE-MDMD (n=71) versus healthy controls (40). Results: FE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-β. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56-60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6 and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naive FE-MDMD patients. Conclusions: FE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling.

Background: Adverse Childhood Experiences (ACEs) and Negative Life Events (NLEs) may activate immune-inflammatory pathways, which play a role in the onset of Major Depressive Disorder and its severe phenotype Major Dysmood disorder (MDMD). Objectives: To assess if elevated ACEs and NLEs in first episode (FE)-MDMD predict activation of the immune-inflammatory response system (IRS), chemokines, and growth factors that participate in the pathophysiology of MDMD. Methods: This research assessed the effects of ACEs and NLEs on forty-eight cytokines/chemokines/growth factors, in 71 FE-MDMD patients and forty heathy controls. Results: ACEs are highly significantly associated with the classical M1 macrophage, T helper (Th)-1, Th-1 polarization, IRS, and neurotoxicity immune profiles, and not with the alternative M2, and Th-2 immune profiles. There are highly significant correlations between ACEs and NLEs and different cytokines/chemokines/growth factors, especially with interleukin (IL)-16, CCL27, stem cell growth factor, and platelet-derived growth factor. Partial Least Squares analysis showed that 62.3% of the variance in the depression phenome (based on severity of depression, anxiety and suicidal behaviors) was explained by the regression on IL-4 (p=0.001, inversely), the sum of ACEs + NLEs (p<0.0001), and a vector extracted from 10 cytokines/chemokines/growth factors (p<0.0001; both positively associated). The latter partially mediated (p<0.0001) the effects of ACE + NLEs on the depression phenome. Conclusions: Part of the effects of ACEs and NLEs on the depression phenome is mediated via activation of immune and growth factor networks. These pathways have a stronger impact in subjects with lowered activities of the compensatory immune-regulatory system.