Kelly Doolin1, Kelly A Allers2, Sina Pleiner2, Andre Liesener2, Chloe Farrell1, Leonardo Tozzi3, Erik O'Hanlon1, Darren Roddy1, Thomas Frodl4, Andrew Harkin5, Veronica O'Keane6. 1. Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. 2. Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, and DMPK, Biberach an der Riss, Germany. 3. Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry and Psychotherapy, University Hospital Otto von Guerick University, 39120 Magdeburg, Germany. 4. Department of Psychiatry and Psychotherapy, University Hospital Otto von Guerick University, 39120 Magdeburg, Germany; German Centre for Neurogenerative Diseases (DZNE), Leipzigerstr. 44, 39120 Magdeburg, Germany. 5. Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie. 6. Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity Centre for Health Sciences, Tallaght Hospital, Tallaght, Dublin 24, Ireland.
Abstract
BACKGROUND: Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC). METHODS: A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC-MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer. RESULTS: Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally. DISCUSSION: This study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.
BACKGROUND:Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC). METHODS: A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDDpatients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC-MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer. RESULTS:Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDDpatients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDDpatients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDDpatients. KYNA and subiculum volume were positively correlated bilaterally. DISCUSSION: This study found evidence of KP metabolism imbalance in MDDpatients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDDpatients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.
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