Hostname: page-component-76fb5796d-vfjqv Total loading time: 0 Render date: 2024-04-26T02:19:12.493Z Has data issue: false hasContentIssue false
  • English
  • Français

Effect of interferon-α on cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study

Published online by Cambridge University Press:  10 May 2013

M. J. Taylor ,
B. Godlewska ,
J. Near ,
D. Christmas ,
J. Potokar ,
J. Collier ,
P. Klenerman ,
E. Barnes  and
P. J. Cowen
M. J. Taylor*
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford, UK Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK
B. Godlewska
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford, UK
J. Near
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford, UK FMRIB Centre, Department of Clinical Neurology, University of Oxford, UK
D. Christmas
Affiliation:
Academic Unit of Psychiatry, School of Social and Community Medicine, University of Bristol, UK
J. Potokar
Affiliation:
Academic Unit of Psychiatry, School of Social and Community Medicine, University of Bristol, UK
J. Collier
Affiliation:
John Radcliffe Hospital, Oxford, UK
P. Klenerman
Affiliation:
NIHR Oxford Biomedical Research Centre, UK The Peter Medawar Building for Pathogen Research, University of Oxford, UK
E. Barnes
Affiliation:
NIHR Oxford Biomedical Research Centre, UK The Peter Medawar Building for Pathogen Research, University of Oxford, UK
P. J. Cowen
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford, UK
*
*Address for correspondence: Dr M. J. Taylor, Department of Psychosis Studies, Institute of Psychiatry, PO63, London SE5 8AF, UK. (Email: matthew.j.taylor@kcl.ac.uk)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α (IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-α and ribavirin.

Method

MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4–6 weeks of treatment with IFN.

Results

IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan.

Conclusions

We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.

Keywords

Depressionglutamateglutaminehepatitis Cinterferon-α
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 4 , March 2014 , pp. 789 - 795
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alcaro, A, Panksepp, J, Witczak, J, Hayes, DJ, Northoff, G (2010). Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach. Neuroscience and Biobehavioral Reviews 34, 592–605.CrossRefGoogle Scholar
Bonaccorso, S, Meltzer, H, Maes, M (2000). Psychological and behavioural effects of interferons. Current Opinion in Psychiatry 13, 673–677.CrossRefGoogle Scholar
Byrnes, V, Miller, A, Lowry, D, Hill, E, Weinstein, C, Alsop, D, Lenkinski, R, Afdhal, NH (2012). Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. Journal of Hepatology 56, 549–556.CrossRefGoogle ScholarPubMed
Capuron, L, Ravaud, A, Neveu, PJ, Miller, AH, Maes, M, Dantzer, R (2002). Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Molecular Psychiatry 7, 468–473.CrossRefGoogle ScholarPubMed
Constant, A, Castera, L, Dantzer, R, Couzigou, P, de Ledinghen, V, Demotes-Mainard, J, Henry, C (2005). Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. Journal of Clinical Psychiatry 66, 1050–1057.CrossRefGoogle ScholarPubMed
Danbolt, NC (2001). Glutamate uptake. Progress in Neurobiology 65, 1–105.CrossRefGoogle ScholarPubMed
Dowlati, Y, Herrmann, N, Swardfager, W, Liu, H, Sham, L, Reim, EK, Lanctot, KL (2010). A meta-analysis of cytokines in major depression. Biological Psychiatry 67, 446–457.CrossRefGoogle ScholarPubMed
First, MB, Spitzer, RL, Gibbon, M, Williams, JBW (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Biometrics Research, New York State Psychiatric Institute: New York.Google Scholar
Forton, DM, Allsop, JM, Main, J, Foster, GR, Thomas, HC, Taylor-Robinson, SD (2001). Evidence for a cerebral effect of the hepatitis C virus. Lancet 358, 38–39.CrossRefGoogle ScholarPubMed
Hauser, P, Khosla, J, Aurora, H, Laurin, J, Kling, MA, Hill, J, Gulati, M, Thornton, AJ, Schultz, RL, Valentine, AD, Meyers, CA, Howell, CD (2002). A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Molecular Psychiatry 7, 942–947.CrossRefGoogle ScholarPubMed
Häussinger, D, Laubenberger, J, vom Dahl, S, Ernst, T, Bayer, S, Langer, M, Gerok, W, Hennig, J (1994). Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 107, 1475–1480.CrossRefGoogle ScholarPubMed
Krupp, LB, LaRocca, NG, Muir-Nash, J, Steinberg, AD (1989). The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Archives of Neurology 46, 1121–1123.CrossRefGoogle ScholarPubMed
Kupfer, DJ, Frank, E, Phillips, ML (2012). Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379, 1045–1055.CrossRefGoogle ScholarPubMed
Leutscher, PDC, Lagging, M, Buhl, MR, Pedersen, C, Norkrans, G, Langeland, N, Morch, K, Farkkila, M, Hjerrild, S, Hellstrand, K, Bech, P (2010). Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C. Hepatology 52, 430–435.CrossRefGoogle ScholarPubMed
Lim, C, Olson, J, Zaman, A, Phelps, J, Ingram, KD (2010). Prevalence and impact of manic traits in depressed patients initiating interferon therapy for chronic hepatitis C infection. Journal of Clinical Gastroenterology 44, e141–e146.CrossRefGoogle ScholarPubMed
Mardini, H, Smith, FE, Record, CO, Blamire, AM (2011). Magnetic resonance quantification of water and metabolites in the brain of cirrhotics following induced hyperammonaemia. Journal of Hepatology 54, 1154–1160.CrossRefGoogle ScholarPubMed
McNally, L, Bhagwagar, Z, Hannestad, J (2008). Inflammation, glutamate, and glia in depression: a literature review. CNS Spectrums 13, 501–510.CrossRefGoogle ScholarPubMed
Mekle, R, Mlynárik, V, Gambarota, G, Hergt, M, Krueger, G, Gruetter, R (2009). MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3 T and 7 T. Magnetic Resonance in Medicine 61, 1279–1285.CrossRefGoogle Scholar
Miller, AH, Maletic, V, Raison, CL (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological Psychiatry 65, 732–741.CrossRefGoogle ScholarPubMed
Ongür, D, Jensen, JE, Prescot, AP, Stork, C, Lundy, M, Cohen, BM, Renshaw, PF (2008). Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biological Psychiatry 64, 718–726.CrossRefGoogle ScholarPubMed
Provencher, SW (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine 30, 672–679.CrossRefGoogle ScholarPubMed
Rush, AJ, Trivedi, MH, Ibrahim, HM, Carmody, TJ, Arnow, B, Klein, DN, Markowitz, JC, Ninan, PT, Kornstein, S, Manber, R, Thase, ME, Kocsis, JH, Keller, MB (2003). The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological Psychiatry 54, 573–583.CrossRefGoogle ScholarPubMed
Raison, CL, Borisov, AS, Broadwell, SD, Capuron, L, Woolwine, BJ, Jacobson, IM, Nemeroff, CB, Miller, AH (2005). Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. Journal of Clinical Psychiatry 66, 41–48.CrossRefGoogle ScholarPubMed
Raison, CL, Capuron, L, Miller, AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 24–31.CrossRefGoogle ScholarPubMed
Raison, CL, Dantzer, R, Kelley, KW, Lawson, MA, Woolwine, BJ, Vogt, G, Spivey, JR, Saito, K, Miller, AH (2010). CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Molecular Psychiatry 15, 393–403.CrossRefGoogle ScholarPubMed
Rajkowska, G, Miguel-Hidalgo, JJ (2007). Gliogenesis and glial pathology in depression. CNS and Neurological Disorders – Drug Targets 6, 219–233.CrossRefGoogle ScholarPubMed
Sanacora, G, Zarate, CA, Krystal, JH, Manji, HK (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery 7, 426–437.CrossRefGoogle ScholarPubMed
Spielberger, CD, Gorsuch, RL, Lushene, RE (1970). The State-Trait Anxiety Inventory: Test Manual. Consulting Psychologist Press: Palo Alto, CA.Google Scholar
Strakowski, SM, Adler, CM, Almeida, J, Altshuler, LL, Blumberg, HP, Chang, KD, DelBello, MP, Frangou, S, McIntosh, A, Phillips, ML, Sussman, JE, Townsend, JD (2012). The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disorders 14, 313–325.CrossRefGoogle ScholarPubMed
Tavares, RG, Tasca, CI, Santos, CES, Alves, LB, Porciuncula, LO, Emanuelli, T, Souza, DO (2002). Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochemistry International 40, 621–627.CrossRefGoogle ScholarPubMed
Théberge, J, Bartha, R, Drost, DJ, Menon, RS, Malla, A, Takhar, J, Neufeld, RW, Rogers, J, Pavlosky, W, Schaefer, B, Densmore, M, Al-Semaan, Y, Williamson, PC (2002). Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. American Journal of Psychiatry 159, 1944–1946.CrossRefGoogle ScholarPubMed
Wichers, MC, Maes, M (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. Journal of Psychiatry and Neuroscience 29, 11–17.Google ScholarPubMed
Wijtenburg, SA, Knight-Scott, J (2011). Very short echo time improves the precision of glutamate detection at 3 T in 1H magnetic resonance spectroscopy. Journal of Magnetic Resonance Imaging 34, 645–652.CrossRefGoogle ScholarPubMed
Yüksel, C, Öngür, D (2010). Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biological Psychiatry 68, 785–794.CrossRefGoogle ScholarPubMed