Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Abstract

Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/ QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…Microglial activation of the kynurenine pathway can also ultimately lead to the production of neuroactive glutamatergic compounds, including 3-hydroxykynurenine and quinolinic acid, which have a key role in neuronal death by stimulating NMDA receptors and promoting oxidative stress (Campbell et al, 2014;Dantzer and Walker, 2014;Stone et al, 2012). In support of this notion, brain or cerebrospinal fluid concentrations of kynurenine neurotoxic metabolites are elevated in several neuropsychiatric or neurodegenerative diseases (Campbell et al, 2014;Schwarcz et al, 2001;Steiner et al, 2011;Stone et al, 2012) and have been related to the stretch of brain damages, impaired neurogenesis, and development of neuropsychiatric symptoms (Savitz et al, 2015a;Savitz et al, 2015b;Stone et al, 2012;Zunszain et al, 2012). In line with clinical findings, preclinical studies performed in rodents treated with an immune challenge have documented associations between emotional/cognitive alterations and both peripheral and brain IDO activation (Andre et al, 2008;Corona et al, 2013;Frenois et al, 2007;Gibney et al, 2013;Lawson et al, 2013;Lestage et al, 2002;Moreau et al, 2005Moreau et al, , 2008Salazar et al, 2012;Xie et al, 2014).…”

Tryptophan pathway alterations in the postpartum period and in acute postpartum psychosis and depression

“…After pregnancy, both free and bound tryptophan levels gradually return to pre-pregnancy levels (Handley et al, 1977;Schrocksnadel et al, 1996;Schrocksnadel et al, 2003). The downstream tryptophan pathway beyond the degradation to kynurenine has never been investigated in women with severe postpartum mood disorders, but there is evidence for major alterations in severe mood disorders outside the postpartum period (Myint et al, 2007a;Myint et al, 2007b;Ogawa et al, 2014;Savitz et al, 2015a;Savitz et al, 2015b). Increased breakdown via the tryptophankynurenine pathway augments serotonin deficiency, which could serve as a potential etiological factor for mood disorders.…”

“…This is in contrast with finding in psychiatric disorders outside the postpartum period. Reduced levels of kynurenic acid have been observed in patients with major depressive disorder, bipolar disorder and schizophrenia (Hughes et al, 2012;Savitz et al, 2015a;Savitz et al, 2015b). This strong reduction of the protective KynA has been described as an important etiological mechanism (Myint et al, 2007a;Myint et al, 2007b;Ogawa et al, 2014).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Dysregulation of either of these systems or a loss of the balanced function of these systems is hypothesized to contribute to the pathogenesis and pathophysiology of several neuropsychiatric disorders. For example, increases in KYNA activation are associated with schizophrenia, whereas QUIN increases are associated with depression, suicidality, and neurodegeneration (Brundin et al, 2015;Erhardt et al, 2013;Guillemin, 2012;Savitz et al, 2015;Schwarcz et al, 2012).…”