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Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA. One hundred and sixty-six participants in the Tulsa 1000 study with a DSM-V diagnosis of MDD completed diffusion tensor imaging and provided a serum sample for the quantification of CRP, KynA, and QA. Correlational tractography was performed using DSI Studio to map the specific white matter pathways that correlated with CRP and KynA/QA. CRP was negatively related to KynA/QA (standardized beta coefficient, SBC = -0.35 with standard error, Std.E = 0.13, p < 0.01) after controlling for nine possible confounders, i.e., age, sex, body mass index (BMI), medication status, lifetime alcohol use, severity of depression, severity of anxiety, length of illness, and smoking status. Higher concentrations of CRP were associated with decreased white matter integrity (fractional anisotropy, FA) of the bilateral cingulum and fornix after controlling for the nine potential confounders (SBC = -0.43, Std.E = 0.13, p = 0.002). Greater serum KynA/QA was associated with increased white matter integrity of the bilateral fornix, bilateral superior thalamic radiations, corpus callosum, and bilateral cingulum bundles after controlling for the same possible confounders (SBC = 0.26, Std.E = 0.09, p = 0.005). The relationship between CRP and FA was not mediated by KynA/QA. Exploratory analyses also showed that KynA/QA but not CRP was associated with self-reported positive affect, attentiveness, and fatigue measured with the PANASX (SBCs = 0.17-0.23). Taken together, these results are consistent with the hypothesis that within a subgroup of MDD patients, a higher level of systemic inflammation alters the balance of KP metabolism but also raise the possibility that CRP and neuroactive KP metabolites represent independent molecular mechanisms underlying white matter alterations in MDD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Substance use disorders (SUD) with comorbid depression and anxiety are linked to poor treatment outcome and relapse. Although some depressed individuals exhibit elevated blood-based inflammation (interleukin-6 [IL-6] and C reactive protein [CRP]), few studies have examined whether the presence of SUD exacerbates inflammation., Methods: Treatment-seeking individuals with major depressive disorder (MDD), anxiety disorders, and/or SUD (N = 160; 80 % with MDD) recruited into the Tulsa 1000 study provided blood samples, participated in clinical interviews, and completed a questionnaire battery querying symptoms of current psychopathology and emotional processing. Analyses followed a multistep process. First, groups were created on the presence versus absence of 1+ lifetime SUD diagnoses: SUD+ (37 F, 43 M) and SUD- (60 F, 20 M). Second, a principal component analysis (PCA) of questionnaire data resulted in two factors, one indexing negative emotionality/withdrawal motivation and one measuring positive emotionality/approach motivation. Third, SUD groups, extracted PCA factors, and nuisance covariates (age, body mass index [BMI], nicotine use, psychotropic medication [and hormone/contraception use in females]) were entered as simultaneous predictors of blood-based inflammation (IL-6, IL-8, IL-10, tumor necrosis factor-α, and CRP)., Results: Within females, SUD + exhibited higher IL-8 and IL-10 but lower CRP levels than SUD-. In contrast, SUD was not associated with biomarker levels in males. Across sexes, higher BMI was linked to higher IL-6 and CRP levels, and within the five biomarkers, IL-6 and CRP shared the most variance., Conclusion: These findings point to sex-specific inflammatory profiles as a function of SUD that may provide new targets for intervention., (Copyright © 2021 Elsevier B.V. All rights reserved.)