Elsevier

Psychoneuroendocrinology

Volume 62, December 2015, Pages 54-58
Psychoneuroendocrinology

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

https://doi.org/10.1016/j.psyneuen.2015.07.609Get rights and content

Highlights

  • The ratio of kynurenic acid (KynA) to quinolinic acid (QA) was reduced in MDD.

  • KynA/QA was not associated with striatal volume in the MDD group.

  • Activation of the kynurenine pathway was associated with striatal volume in MDD.

Abstract

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.

Introduction

Reductions in hippocampal volume are widely reported in major depressive disorder (MDD) and are thought to reflect dendritic atrophy (Savitz and Drevets, 2009, Stockmeier et al., 2004). We previously reported that the ratio of kynurenic acid (KynA, an NMDA receptor antagonist) to quinolinic acid (QA, an NMDA receptor agonist) in serum was positively correlated with hippocampal volume, raising the possibility of an inflammatory, glutamate-mediated contribution to certain structural brain abnormalities observed in MDD. The current paper builds on this work by addressing the regional specificity of these findings. We focused on the striatum given the relationship between inflammation-induced deficits in incentive motivation and anhedonia (Dantzer et al., 2011, Vichaya et al., 2014, Yirmiya et al., 2000), evidence for reductions in striatal volume in MDD (Kempton et al., 2011), and reports of interferon α-induced changes in glutamatergic neurotransmission in the striatum that correlated with motivation and fatigue (Capuron et al., 2007, Haroon et al., 2014), as well as interferon α and endotoxin-induced decreases in the hemodynamic response to rewarding stimuli in the ventral striatum (Capuron et al., 2012, Eisenberger et al., 2010).

Section snippets

Subjects provided written informed consent as approved by the IRB

The clinical characteristics of the sample, neuroimaging procedures, and kynurenine metabolite measurements have been described in detail elsewhere (Savitz et al., 2015a). Briefly, MDD and HC participants were interviewed with the Structured Clinical Interview for the DSM-IV-TR and in addition, unstructured interviews with psychiatrists were obtained on all MDD subjects. The severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HAM-D, 24-item) and the

Results

After adjusting for sex and supratentorial volume, there was no difference between the MDD and HC groups in the total striatal volume (F3,100 = 1.4, p = 0.240, Table 1). Further, there was no significant association between depression severity or anhedonia rating scale scores and striatal volume in the MDD group although the association between striatal volume and MADRS scores approached significance (r = −0.25, p = 0.071). Because the association between MADRS scores and striatal volume approached

Discussion

The principal findings of this study are that activation of the kynurenine pathway is inversely associated with volume of the striatum in depressed but not healthy participants; this despite the fact that neither the Kyn/TRP quotient nor the striatal volumes differed between the HC and MDD groups. We were unable, however, to extend our previous results demonstrating an association between hippocampal volume and KynA/QA in MDD to the striatum.

Regarding the first finding, IDO activity is

Conflict of interest

Dr. Savitz declares no competing interests but in the spirit of full disclosure notes that in the past 3 years he has received research funding from Janssen Pharmaceuticals for an independent study and a lecture honorarium from University of Kansas-Wichita. Dr. Dantzer has received consulting fees from Ironwood Pharma, Cambridge, MA, and an honorarium from Pfizer, France. Wayne Drevets, M.D. is an employee of Janssen Pharmaceuticals of Johnson & Johnson, Inc., Titusville, NJ, USA, and received

Funding

This study was funded by a grant from the National Institute of Mental Health to JS (K01MH096077). JS, BEW, TAV, BNF, HMM, and JB received support from The William K. Warren Foundation. The funders of the study played no role in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

The funders played no role in study design; in the collection, analysis and interpretation of data; in the writing of the

Authors contribution

Designed the study: JS, RD, WCD, MRI scanning and analysis: TBM, TAV, JB, processing of serum samples: TKT, statistical analysis: JS, initial draft of manuscript: JS, revision of manuscript: all authors. All authors have approved the final version of the article.

Acknowledgements

The authors acknowledge Marieke van der Hart, Ph.D., at Brains Online for excellence in HPLC sample analysis.

The authors also thank all the research participants and wish to acknowledge the contributions of Brenda Davis, Debbie Neal, Chibing Tan, and Ashlee Taylor from the laboratory of TKT at the University of Oklahoma Integrative Immunology Center towards the transport, processing and handling of all blood samples.

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