The effects of cytomegalovirus on brain structure following sport-related concussion.

The neurotrophic herpes virus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of traumatic brain injury, including sport-related concussion, are major physiological stressors that produce neuroinflammation. In theory, concussion could predispose to the reactivation of cytomegalovirus and amplify the effects of physical injury on brain structure. However, to our knowledge this hypothesis remains untested. This study evaluated the effect of cytomegalovirus serostatus on white and grey matter structure in a prospective study of athletes with concussion and matched contact-sport controls. Athletes who sustained concussion (n = 88) completed MRI at 1, 8, 15 and 45 days post-injury; matched uninjured athletes (n = 73) completed similar visits. Cytomegalovirus serostatus was determined by measuring serum IgG antibodies (n = 30 concussed athletes and n = 21 controls were seropositive). Inverse probability of treatment weighting was used to adjust for confounding factors between athletes with and without cytomegalovirus. White matter microstructure was assessed using diffusion kurtosis imaging metrics in regions previously shown to be sensitive to concussion. T1-weighted images were used to quantify mean cortical thickness and total surface area. Concussion-related symptoms, psychological distress, and serum concentration of C-reactive protein at 1 day post-injury were included as exploratory outcomes. Planned contrasts compared the effects of cytomegalovirus seropositivity in athletes with concussion and controls, separately. There was a significant effect of cytomegalovirus on axial and radial kurtosis in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion showed greater axial (P = 0.007, d = 0.44) and radial (P = 0.010, d = 0.41) kurtosis than cytomegalovirus negative athletes with concussion. Similarly, there was a significant association of cytomegalovirus with cortical thickness in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion had reduced mean cortical thickness of the right hemisphere (P = 0.009, d = 0.42) compared with cytomegalovirus negative athletes with concussion and showed a similar trend for the left hemisphere (P = 0.036, d = 0.33). There was no significant effect of cytomegalovirus on kurtosis fractional anisotropy, surface area, symptoms and C-reactive protein. The results raise the possibility that cytomegalovirus infection contributes to structural brain abnormalities in the aftermath of concussion perhaps via an amplification of concussion-associated neuroinflammation. More work is needed to identify the biological pathways underlying this process and to clarify the clinical relevance of this putative viral effect.

Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid.

BACKGROUND: An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown. METHODS: Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA). RESULTS: BA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). Neither the change in KynA/QA, nor baseline KynA/QA were associated with response to BA therapy. CONCLUSION: The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.

A hidden menace? Cytomegalovirus infection is associated with reduced cortical gray matter volume in major depressive disorder.

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (puncorrected < 0.05). The reductions in GMV of the right supramarginal gyrus (standardized beta coefficient (SBC) = -0.26) and left fusiform gyrus (SBC = -0.25) in sample 1 were replicated in sample 2: right supramarginal gyrus (puncorrected < 0.05, SBC = -0.32), left fusiform gyrus (PFDR < 0.01, SBC = -0.51). Posthoc tests revealed that the effect of HCMV was driven by differences between the HCMV+ and HCMV- MDD subgroups. HCMV IgG level, a surrogate marker of viral activity, was correlated with GMV in the left fusiform gyrus (r = -0.19, Puncorrected = 0.049) and right supramarginal gyrus (r = -0.19, puncorrected = 0.043) in the HCMV+ group of sample 1. Conceivably, HCMV infection may be a treatable source of neuropathology in vulnerable MDD patients.

Depression, aging, and immunity: implications for COVID-19 vaccine immunogenicity.

The aging process can have detrimental effects on the immune system rendering the elderly more susceptible to infectious disease and less responsive to vaccination. Major depressive disorder (MDD) has been hypothesized to show characteristics of accelerated biological aging. This raises the possibility that depressed individuals will show some overlap with elderly populations with respect to their immune response to infection and vaccination. Here we provide an umbrella review of this literature in the context of the SARS CoV-2 pandemic. On balance, the available data do indeed suggest that depression is a risk factor for both adverse outcomes following COVID-19 infection and for reduced COVID-19 vaccine immunogenicity. We conclude that MDD (and other major psychiatric disorders) should be recognized as vulnerable populations that receive priority for vaccination along with other at-risk groups.

Diagnosis-independent loss of T-cell costimulatory molecules in individuals with cytomegalovirus infection.

Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV+) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV+) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27-CD28-) cells within CD4+ and CD8+ T-cell subsets, i.e. naive (CCR7+CD45RA+), effector memory (EM, CCR7-CD45RA-), central memory (CM, CCR7+CD45RA-) and effector memory cells re-expressing CD45RA (EMRA, CCR7-CD45RA+). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27-CD28- cells within CD4+ and CD8+ memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV+ and depressed women were more likely to be CMV+ than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.

Reduced immunity to measles in adults with major depressive disorder.

BACKGROUND: Depression can impair the immunogenicity of vaccine administration in adults. Whereas many vaccinations are administered in childhood, it is not known whether adolescent or adult onset depression is associated with impairments in the maintenance of protection of childhood vaccines. This study tested the hypothesis that individuals with adolescent or adult onset mood disorders would display compromised immunity to measles, a target of childhood vaccination. METHODS: IgG antibodies to measles were quantified using a solid phase immunoassay in volunteers with bipolar disorder (BD, n = 64, mean age of onset = 16.6 ± 5.6), currently depressed individuals with major depressive disorder (cMDD, n = 85, mean age of onset = 17.9 ± 7.0), remitted individuals with a history of MDD (rMDD, n = 82, mean age of onset = 19.2 ± 8.6), and non-depressed comparison controls (HC, n = 202), all born after the introduction of the measles vaccine in the USA in 1963. RESULTS: Relative to HC, both the cMDD group (p = 0.021, adjusted odds ratios (OR) = 0.47, confidence interval (CI) = 0.24-0.90), and the rMDD group (p = 0.038, adjusted OR = 0.50, CI = 0.26-0.97) were less likely to test seropositive for measles. Compared with unmedicated MDD participants, currently medicated MDD participants had a longer lifetime duration of illness and were less likely to test seropositive for measles. CONCLUSIONS: Individuals with adolescent or adult onset MDD are less likely to test seropositive for measles. Because lower IgG titers are associated with increased risk of measles infection, MDD may increase the risk and severity of infection possibly because of impaired maintenance of vaccine-related protection from measles.

Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder.

Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0.05). Consistent with our previous findings in an overlapping sample, the KynA/3HK ratio and the log KynA/QA were reduced in the MDD group relative to the HC group (p's<0.05) and symptoms of anhedonia were negatively correlated with log KynA/QA in the MDD group (p<0.05). Both KynA/3HK and log KynA/QA at least partially mediated the relationship between diagnosis and cortical thickness of right BA32 (p's<0.05). CRP was inversely associated with BA32 thickness (p<0.01) and KynA/3HK partially mediated the relationship between CRP and the thickness of right BA32 (p<0.05). The results raise the possibility that the relative imbalance between KynA and neurotoxic kynurenine metabolites may partially explain the reductions in mPFC thickness observed in MDD, and further that these changes are more strongly linked to the putative effects of neuroactive kynurenine metabolites than those of inflammatory mediators.

Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder.

Low-grade inflammation is characteristic of a subgroup of currently depressed patients with major depressive disorder (dMDD). It may lead to the activation of the kynurenine-metabolic pathway and the increased synthesis of potentially neurotoxic metabolites such as 3-hydroxykynurenine (3HK) and quinolinic acid (QA), relative to kynurenic acid (KynA). Nevertheless, few studies have examined whether abnormalities in this pathway are present in remitted patients with MDD (rMDD). Here we compared the serum concentrations of kynurenine metabolites, measured using high performance liquid chromatography with tandem mass spectrometry, across 49 unmedicated subjects meeting DSM-IV-TR criteria for MDD, 21 unmedicated subjects meeting DSM-IV-TR criteria for rMDD, and 58 healthy controls (HCs). There was no significant group difference in the concentrations of the individual kynurenine metabolites, however both the dMDD group and the rMDD group showed a reduction in KynA/QA, compared with the HCs. Further, there was an inverse correlation between KynA/QA and anhedonia in the dMDD group, while in the rMDD group, there was a negative correlation between lifetime number of depressive episodes and KynA/QA as well as a positive correlation between the number of months in remission and KynA/QA. Our results raise the possibility that a persistent abnormality exists within the kynurenine metabolic pathway in MDD that conceivably may worsen with additional depressive episodes. The question of whether persistent abnormalities in kynurenine metabolism predispose to depression and/or relapse in remitted individuals remains unresolved.

Gene Age Gap Estimate (GAGE) for major depressive disorder: a penalized biological age model using gene expression.

Recent associations between Major Depressive Disorder (MDD) and measures of premature aging suggest accelerated biological aging as a potential biomarker for MDD susceptibility or MDD as a risk factor for age-related diseases. Statistical and machine learning regression models of biological age have been trained on various sources of high dimensional data to predict chronological age. Residuals or "gaps" between the predicted biological age and chronological age have been used for statistical inference, such as testing whether an increased age gap is associated with a given disease state. Recently, a gene expression-based model of biological age showed a higher age gap for individuals with MDD compared to healthy controls (HC). In the current study, we propose a machine learning approach that simplifies gene selection by using a least absolute shrinkage and selection operator (LASSO) penalty to construct an expression-based Gene Age Gap Estimate (GAGE) model. We construct the LASSO-GAGE (L-GAGE) model in an RNA-Seq study of 78 unmedicated individuals with MDD and 79 HC and then test for accelerated biological aging in MDD. When testing L-GAGE association with MDD, we account for factors such as sex and chronological age to mitigate regression to the mean effects. The L-GAGE shows higher biological aging in MDD subjects than HC, but the elevation is not statistically significant. However, when we dichotomize chronological age, the interaction between MDD status and age is significant in L-GAGE model. This effect remains statistically significant even after adjusting for chronological age and sex. We find cytomegalovirus (CMV) serostatus is associated with elevated L-GAGE. We also investigate feature selection methods Random Forest and nearest neighbor projected distance regression (NPDR) to characterize age related genes, and we find functional enrichment of infectious disease and SARS-COV pathways.

Effect of Cytomegalovirus on the Immune System: Implications for Aging and Mental Health.

Human cytomegalovirus (HCMV) is a major modulator of the immune system leading to long-term changes in T-lymphocytes, macrophages, and natural killer (NK) cells among others. Perhaps because of this immunomodulatory capacity, HCMV infection has been linked with a host of deleterious effects including accelerated immune aging (premature mortality, increased expression of immunosenescence-linked markers, telomere shortening, speeding-up of epigenetic "clocks"), decreased vaccine immunogenicity, and greater vulnerability to infectious diseases (e.g., tuberculosis) or infectious disease-associated pathology (e.g., HIV). Perhaps not surprisingly given the long co-evolution between HCMV and humans, the virus has also been associated with beneficial effects, such as increased vaccine responsiveness, heterologous protection against infections, and protection against relapse in the context of leukemia. Here, we provide an overview of this literature. Ultimately, we focus on one other deleterious effect of HCMV, namely the emerging literature suggesting that HCMV plays a pathophysiological role in psychiatric illness, particularly depression and schizophrenia. We discuss this literature through the lens of psychological stress and inflammation, two well-established risk factors for psychiatric illness that are also known to predispose to reactivation of HCMV.

Acute administration of ibuprofen increases serum concentration of the neuroprotective kynurenine pathway metabolite, kynurenic acid: a pilot randomized, placebo-controlled, crossover study.

RATIONALE: At least six different types of antidepressant treatments have been shown to either increase the neuroprotective kynurenine pathway (KP) metabolite, kynurenic acid (KynA), or decrease the neurotoxic KP metabolite, quinolinic acid (QA). Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen have shown some efficacy in the treatment of depression but their effects on the KP have not been studied in humans. OBJECTIVES: To evaluate the effect of ibuprofen on circulating KP metabolites. METHODS: In a randomized, placebo-controlled, crossover study, 20 healthy adults (10 women) received a single oral dose of 200-mg ibuprofen, 600-mg ibuprofen, or placebo in a counterbalanced order (NCT02507219). Serum samples were drawn in the mid-afternoon, 5 h after ibuprofen/placebo administration. KP metabolites were measured blind to visit by tandem mass spectrometry. Data were analyzed with linear mixed effect models. The primary outcome was KynA/QA and the secondary outcome was KynA. RESULTS: After Bonferroni correction, there was a significant effect of treatment on KynA/QA. The effect was driven by an increase in KynA concentration after the 600-mg dose but not the 200-mg dose relative to placebo (Cohen's d = 1.71). In contrast, both the 200-mg (d = 1.03) and 600-mg (d = 2.05) doses of ibuprofen decreased tryptophan concentrations relative to placebo. CONCLUSIONS: Given its KynA-elevating effects, ibuprofen could have neuroprotective effects in the context of depression as well as other neuroinflammatory disorders that are characterized by a reduction in KynA.

Psychiatric symptoms are not associated with circulating CRP concentrations after controlling for medical, social, and demographic factors.

Elevated serum concentrations (>3 mg/L) of the acute-phase protein, C-reactive protein (CRP), is used as a clinical marker of inflammation and is reported to be a strong risk factor for cardiovascular disease. In psychiatric populations, CRP concentration is reported to be higher in depressed versus healthy individuals. Positive associations between CRP and depression have been established in both clinical and community samples, but effect sizes are attenuated after controlling for confounding variables. Similarly, emerging research has begun to draw a link between inflammation, symptoms of anxiety, and substance abuse. Given the high level of comorbid anxiety and substance use disorders in many depressed populations, this study examined whether depression (Patient Health Questionnaire 9 [PHQ-9]) and substance use-related (Drug Abuse Screening Test [DAST]) symptoms were associated with CRP concentrations in the blood after adjusting for relevant medical, social, and demographic covariates in a large sample undergoing screening for several transdiagnostic psychiatric research studies. A total of 1,724 participants were analyzed for association of CRP with variables using multivariate linear regression. An unadjusted model with no covariates showed that PHQ-9 was significantly associated with CRP in All (ß = 0.125), Female (ß = 0.091), and Male (ß = 0.154) participants, but DAST was significantly associated with CRP in males only (ß = 0.120). For the adjusted model, in both males and females, mood-stabilizer treatment (ß = 0.630), opioid medication (ß = 0.360), body mass index (ß = 0.244), percent body fat (ß = 0.289), nicotine use (ß = 0.063), and self-reported sleep disturbance (ß = 0.061) were significantly associated with increased CRP concentrations. In females, oral contraceptive use (ß = 0.576), and waist-to-hip ratio (ß = 0.086), and in males, non-steroidal anti-inflammatory drug use (ß = 0.367) were also associated with increased CRP concentrations. There was no significant association between CRP and individual depressive, anxiety, or substance use-related symptoms when covariates were included in the regression models. These results suggest that associations between circulating CRP and the severity of psychiatric symptoms are dependent on the type of covariates controlled for in statistical analyses.

Association between cytomegalovirus infection, reduced gray matter volume, and resting-state functional hypoconnectivity in major depressive disorder: a replication and extension.

Human cytomegalovirus (HCMV) is a neurotropic herpes virus known to cause neuropathology in patients with impaired immunity. Previously, we reported a reduction in the gray matter volume (GMV) of several brain regions in two independent samples of participants who were seropositive for HCMV (HCMV+) compared to matched participants who were seronegative for HCMV (HCMV-). In addition to an independent replication of the GMV findings, this study aimed to examine whether HCMV+ was associated with differences in resting-state functional connectivity (rsfMRI-FC). After balancing on 11 clinical/demographic variables using inverse probability of treatment weighting (IPTW), GMV and rsfMRI-FC were obtained from 99 participants with major depressive disorder (MDD) who were classified into 42 HCMV+ and 57 HCMV- individuals. Relative to the HCMV- group, the HCMV+ group showed a significant reduction of GMV in nine cortical regions. Volume reduction in the right lateral orbitofrontal cortex (standardized beta coefficient (SBC) = -0.32, [95%CI, -0.62 to -0.02]) and the left pars orbitalis (SBC = -0.34, [95%CI, -0.63 to -0.05]) in the HCMV+ group was also observed in the previous study. Regardless of the parcellation method or analytical approach, relative to the HCMV- group, the HCMV+ group showed hypoconnectivity between the hubs of the sensorimotor network (bilateral postcentral gyrus) and the hubs of the salience network (bilateral insula) with effect sizes ranging from SBC = -0.57 to -0.99. These findings support the hypothesis that a positive HCMV serostatus is associated with altered connectivity of regions that are important for stress and affective processing and further supports a possible etiological role of HCMV in depression.

Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder.

Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV- participants with MDD (cluster size 1316 mm3; pFWE < 0.05, d = -0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p < 0.05, d = -0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may-in at-risk individuals-contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.

Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.

Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but have not been well characterized in primary bipolar disorder (BD), with contradictory results potentially attributable to the presence or absence of psychosis and/or medication effects. In contrast, reductions in hippocampal and amygdalar volume that theoretically reflect dendritic atrophy occurring in the context of a neurotoxic process are commonly reported in unmedicated BD patients. Here we tested whether the concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary BD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-five moderately-to-severely depressed unmedicated subjects and 38 moderately-to-severely depressed medicated subjects who met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Gray matter volumes were measured with the automated segmentation software, FreeSurfer. A putative neuroprotective index, KynA/QA, was significantly lower in the BD subjects relative to the HCs, a finding that was unrelated to current treatment with medication or a prior history of psychosis. Further, another putative neuroprotective index, KynA/3HK was positively associated with hippocampal volume in the BD group after controlling for age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK was significantly associated with total amygdalar volume in the BD group, but after controlling for age, sex, BMI, but not ICV, this association was reduced to a trend. In addition, Kyn/3HK was positively associated with amygdalar volume in the HCs although the association was no longer significant after accounting for the effects of age, sex, and BMI. The results raise the possibility that BD-associated abnormalities in kynurenine metabolism may impact the structure of the hippocampus and amygdala, highlighting a pathway through which inflammation may exert neuropathological effects in the context of depression.

Activation of the kynurenine pathway is associated with striatal volume in major depressive disorder.

Inflammation, which may be present in a subgroup of individuals with major depressive disorder (MDD), activates the kynurenine metabolic pathway to produce kynurenine metabolites kynurenic acid (KynA) and quinolinic acid (QA). We have previously reported an association between the ratio of KynA to QA and hippocampal volume in MDD. In animals, inflammation leads to deficits in incentive motivation. Given the central role of the nucleus accumbens (NAcc) and other regions of the striatum in motivated behavior, reward processing, and anhedonia, we hypothesized that abnormalities in the concentrations of kynurenine pathway metabolites would be associated with striatal volumes. As previously reported, after controlling for relevant confounds, the KynA/QA ratio was reduced in the serum of unmedicated patients with MDD (n=53) versus healthy controls (HC, n=47) and there was a non-significant trend in the correlation between KynA/QA and severity of anhedonia (r=-0.27, p<0.1). There was no significant difference between the MDD and HC groups in any of the individual kynurenine metabolites or volume of the striatum defined as the sum of the volumes of the NAcc, caudate, and putamen. After regressing out the effects of sex, analysis batch, and supratentorial volume, the kynurenine concentration and the ratio of kynurenine to tryptophan were inversely associated with striatal volumes in the MDD sample (p<0.05, uncorrected). Further, striatal volume was correlated with the items, "concentration difficulties", "lassitude", and "pessimism" from the Montgomery-Asberg Depression Rating Scale. Our results raise the possibility that activation of the kynurenine pathway is a marker of an inflammatory process that leads to reductions in striatal volume. However, unlike the hippocampus, the association does not appear to be mediated by the relative balance between KynA and QA.