Abstract
It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD).We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project:a.)the monocyte expression levels of 5 key pro-inflammatory cytokine/chemokine genes (ICCGs), 5 type I interferon stimulated genes (ISGs), and 4 kynurenine pathway (KP) enzyme genes (i.e. IDO-1, KMO, CCBL1/KAT II and CCBL2/KAT III) by standard q-PCR,b.)serum levels of TRP, 5-HTrp, 5-HIAA, KYN, KYNA, 3-HK, XA, PIC, and QUIN by LC-MS/MS and/or HPLC, and calculated various TRP/KP metabolism ratios.We then correlated outcomes to each other, and to the clinical characteristics of patients.Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231).An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts).TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD.Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated.
Highlights
With a lifetime prevalence of up to 8–12% (Smith, 2014), major depressive disorder (MDD) is considered as a leading cause of disability worldwide (WHO, 2020)
The IDS-C score was recorded in the 231 Muenster patients with MDD; we calculated a HAM-D 17 correlate score from this IDS-C score as described in the literature (Rush et al, 1986; Trivedi et al, 2004)
The TRP catabolic pathway in patients with MDD shows various activation and deactivation steps which are linked to their proinflammatory state
Summary
With a lifetime prevalence of up to 8–12% (Smith, 2014), major depressive disorder (MDD) is considered as a leading cause of disability worldwide (WHO, 2020). It is associated with numerous somatic diseases (e.g. rheumatoid arthritis, obesity) (Clarke and Currie, 2009; Preiss et al, 2013), increasing mortality rates. These patients were characterized by elevated serum levels of proinflammatory cytokines/chemokines, such as IL-6, IL-8 and/or CCL2 (Weigelt et al, 2011; Carvalho et al, 2014; Grosse et al, 2015)
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