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Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors

Published online by Cambridge University Press:  28 January 2019

Ragni H. Mørch Open the ORCID record for Ragni H. Mørch [Opens in a new window] ,
Ingrid Dieset ,
Ann Færden ,
Elina J. Reponen ,
Sigrun Hope ,
Eva Z. Hoseth ,
Erlend S. Gardsjord ,
Monica Aas ,
Trude Iversen  and
Inge Joa
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Ragni H. Mørch*
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Ingrid Dieset
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway Department of Acute Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway
Ann Færden
Affiliation:
Department of Acute Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway
Elina J. Reponen
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Sigrun Hope
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway
Eva Z. Hoseth
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway Division of Mental Health and Addiction, Møre and Romsdal Health Trust, Kristiansund, Norway
Erlend S. Gardsjord
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Monica Aas
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Trude Iversen
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Inge Joa
Affiliation:
Centre for Clinical Research in Psychosis, Psychiatric Division, Stavanger University Hospital, Stavanger, Norway Network for Medical Sciences, Faculty of Social Sciences, University of Stavanger, Stavanger, Norway
Gunnar Morken
Affiliation:
Department of Psychiatry, St. Olav University Hospital, Trondheim, Norway Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology – NTNU, Trondheim, Norway
Ingrid Agartz
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
Ingrid Melle
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
Pål Aukrust
Affiliation:
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway
Srdjan Djurovic
Affiliation:
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway
Thor Ueland
Affiliation:
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway
Ole A. Andreassen
Affiliation:
NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo and Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
*
Author for correspondence: Ragni H. Mørch, E-mail: [email protected]
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Abstract

Background

Inflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account.

Methods

We investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured in n = 992 patients (SCZ, AFF), and n = 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels.

Results

CXCL16 (p = 0.03) and sIL-2R (p = 7.8 × 10−5) were higher, while sCD14 (p = 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p = 0.04) and sIL-2R (p = 1.1 × 10−5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p = 0.001) and lower sCD14 (p = 0.002) remained, also in SCZ (sIL-2R, p = 3.0 × 10−4 and sCD14, p = 0.01). The adjustment revealed lower ALCAM levels (p = 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels.

Conclusion

The results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.

Keywords

Bipolar disordercomorbid cardiometabolic risk factorsimmune activationinflammationschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 49 , Issue 10 , July 2019 , pp. 1749 - 1757
Copyright
Copyright © Cambridge University Press 2019 

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References

Andreassen, OA, Djurovic, S, Thompson, WK, Schork, AJ, Kendler, KS, O'donovan, MC, Rujescu, D, Werge, T, Van De Bunt, M, Morris, AP, Mccarthy, MI, Roddey, JC, Mcevoy, LK, Desikan, RS and Dale, AM (2013) Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. American Journal of Human Genetics, 92, 197–209.Google Scholar
Andreassen, OA, Harbo, HF, Wang, Y, Thompson, WK, Schork, AJ, Mattingsdal, M, Zuber, V, Bettella, F, Ripke, S, Kelsoe, JR, Kendler, KS, O'donovan, MC, Sklar, P, Mcevoy, LK, Desikan, RS, Lie, BA, Djurovic, S and Dale, AM (2015) Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Molecular Psychiatry 20, 207–214.Google Scholar
Bergink, V, Gibney, SM and Drexhage, HA (2014) Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biological Psychiatry 75, 324–331.Google Scholar
Bloom, J and Al-Abed, Y (2014) MIF: mood improving/inhibiting factor? Journal of Neuroinflammation 11, 11.Google Scholar
Brown, AS and Derkits, EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. The American Journal of Psychiatry 167, 261–280.Google Scholar
Cayrol, R, Wosik, K, Berard, JL, Dodelet-Devillers, A, Ifergan, I, Kebir, H, Haqqani, AS, Kreymborg, K, Krug, S, Moumdjian, R, Bouthillier, A, Becher, B, Arbour, N, David, S, Stanimirovic, D and Prat, A (2008) Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nature Immunology 9, 137–145.Google Scholar
Cox, AJ, West, NP and Cripps, AW (2015) Obesity, inflammation, and the gut microbiota. The Lancet. Diabetes & Endocrinology 3, 207–215.Google Scholar
Crump, C, Sundquist, K, Winkleby, MA and Sundquist, J (2013) Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry 70, 931–939.Google Scholar
Cuthbert, BN (2015) Research Domain Criteria: toward future nosologies. Dialogues Clinical Neuroscience 17, 89–97.Google Scholar
Dieset, I, Hope, S, Ueland, T, Bjella, T, Agartz, I, Melle, I, Aukrust, P, Rossberg, JI and Andreassen, OA (2012) Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein. Schizophrenia Research 140, 169–174.Google Scholar
Dieset, I, Andreassen, OA and Haukvik, UK (2016) Somatic comorbidity in schizophrenia: some possible biological mechanisms across the life span. Schizophrenia Bulletin 42, 1316–1319.Google Scholar
Durda, P, Sabourin, J, Lange, EM, Nalls, MA, Mychaleckyj, JC, Jenny, NS, Li, J, Walston, J, Harris, TB, Psaty, BM, Valdar, W, Liu, Y, Cushman, M, Reiner, AP, Tracy, RP and Lange, LA (2015) Plasma levels of soluble interleukin-2 receptor alpha: associations with clinical cardiovascular events and genome-wide association scan. Arteriosclerosis, Thrombosis, and Vascular Biology 35, 2246–2253.Google Scholar
Eaton, WW, Byrne, M, Ewald, H, Mors, O, Chen, CY, Agerbo, E and Mortensen, PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. The American Journal of Psychiatry 163, 521–528.Google Scholar
Eaton, WW, Pedersen, MG, Nielsen, PR and Mortensen, PB (2010) Autoimmune diseases, bipolar disorder, and non-affective psychosis. Bipolar Disorders 12, 638–646.Google Scholar
Girgis, RR, Kumar, SS and Brown, AS (2014) The cytokine model of schizophrenia: emerging therapeutic strategies. Biological Psychiatry 75, 292–299.Google Scholar
Goldsmith, DR, Rapaport, MH and Miller, BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular Psychiatry 21, 1696–1709.Google Scholar
Halmer, R, Davies, L, Liu, Y, Fassbender, K and Walter, S (2015) The innate immune receptor CD14 mediates lymphocyte migration in EAE. Cellular Physiology and Biochemistry 37, 269–275.Google Scholar
Hope, S, Melle, I, Aukrust, P, Steen, NE, Birkenaes, AB, Lorentzen, S, Agartz, I, Ueland, T and Andreassen, OA (2009) Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disorders 11, 726–734.Google Scholar
Hope, S, Dieset, I, Agartz, I, Steen, NE, Ueland, T, Melle, I, Aukrust, P and Andreassen, OA (2011) Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. Journal of Psychiatric Research 45, 1608–1616.Google Scholar
Hope, S, Ueland, T, Steen, NE, Dieset, I, Lorentzen, S, Berg, AO, Agartz, I, Aukrust, P and Andreassen, OA (2013) Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder. Schizophrenia Research 145, 36–42.Google Scholar
Hope, S, Hoseth, E, Dieset, I, Morch, RH, Aas, M, Aukrust, P, Djurovic, S, Melle, I, Ueland, T, Agartz, I, Ueland, T, Westlye, LT and Andreassen, OA (2015) Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls. Schizophrenia Research 165, 188–194.Google Scholar
Idzkowska, E, Eljaszewicz, A, Miklasz, P, Musial, WJ, Tycinska, AM and Moniuszko, M (2015) The role of different monocyte subsets in the pathogenesis of atherosclerosis and acute coronary syndromes. Scandinavian Journal of Immunology 82, 163–173.Google Scholar
Irwin, MR and Miller, AH (2007) Depressive disorders and immunity: 20 years of progress and discovery. Brain, Behavior, and Immunity 21, 374–383.Google Scholar
Janova, H, Bottcher, C, Holtman, IR, Regen, T, Van Rossum, D, Gotz, A, Ernst, AS, Fritsche, C, Gertig, U, Saiepour, N, Gronke, K, Wrzos, C, Ribes, S, Rolfes, S, Weinstein, J, Ehrenreich, H, Pukrop, T, Kopatz, J, Stadelmann, C, Salinas-Riester, G, Weber, MS, Prinz, M, Bruck, W, Eggen, BJ, Boddeke, HW, Priller, J and Hanisch, UK (2016) CD14 is a key organizer of microglial responses to CNS infection and injury. Glia 64, 635–649.Google Scholar
Johansson, V, Jakobsson, J, Fortgang, RG, Zetterberg, H, Blennow, K, Cannon, TD, Hultman, CM, Wetterberg, L and Landen, M (2016) Cerebrospinal fluid microglia and neurodegenerative markers in twins concordant and discordant for psychotic disorders. European Archives of Psychiatry and Clinical Neuroscience 267, 391–402.Google Scholar
Khandaker, GM, Cousins, L, Deakin, J, Lennox, BR, Yolken, R and Jones, PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. The Lancet. Psychiatry 2, 258–270.Google Scholar
Kim, YK, Myint, AM, Lee, BH, Han, CS, Lee, HJ, Kim, DJ and Leonard, BE (2004) Th1, Th2 and Th3 cytokine alteration in schizophrenia. Progress in Neuropsychopharmacology & Biological Psychiatry 28, 1129–1134.Google Scholar
Laursen, TM, Munk-Olsen, T and Vestergaard, M (2012) Life expectancy and cardiovascular mortality in persons with schizophrenia. Current Opinion in Psychiatry 25, 83–88.Google Scholar
Leboyer, M, Oliveira, J, Tamouza, R and Groc, L (2016) Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology (Berlin) 233, 1651–1660.Google Scholar
Lee, YH, Kim, JH and Song, GG (2013) Pathway analysis of a genome-wide association study in schizophrenia. Gene 525, 107–115.Google Scholar
Libby, P (2002) Inflammation in atherosclerosis. Nature 420, 868–874.Google Scholar
Louveau, A, Smirnov, I, Keyes, TJ, Eccles, JD, Rouhani, SJ, Peske, JD, Derecki, NC, Castle, D, Mandell, JW, Lee, KS, Harris, TH and Kipnis, J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341.Google Scholar
Mckibben, RA, Margolick, JB, Grinspoon, S, Li, X, Palella, FJ, Kingsley, LA, Witt, MD, George, RT, Jacobson, LP, Budoff, M, Tracy, RP, Brown, TT and Post, WS (2015) Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. The Journal of Infectious Diseases 211, 1219–1228.Google Scholar
Morch, RH, Dieset, I, Faerden, A, Hope, S, Aas, M, Nerhus, M, Gardsjord, ES, Joa, I, Morken, G, Agartz, I, Aukrust, P, Djurovic, S, Melle, I, Ueland, T and Andreassen, OA (2016) Inflammatory evidence for the psychosis continuum model. Psychoneuroendocrinology 67, 189–197.Google Scholar
Muller, N (2014) Immunology of major depression. Neuroimmunomodulation 21, 123–130.Google Scholar
Muller, N, Krause, D, Weidinger, E and Schwarz, M (2014) Immunological treatment options for schizophrenia. Fortschritte der Neurologie-Psychiatrie 82, 210–219.Google Scholar
Najjar, S and Pearlman, DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophrenia Research 161, 102–112.Google Scholar
Rahman, F, Blumenthal, RS, Jones, SR, Martin, SS, Gluckman, TJ and Whelton, S. P. (2018) Fasting or non-fasting lipids for atherosclerotic cardiovascular disease risk assessment and treatment? Current Atherosclerosis Reports 20, 14.Google Scholar
Ringen, PA, Engh, JA, Birkenaes, AB, Dieset, I and Andreassen, OA (2014) Increased mortality in schizophrenia due to cardiovascular disease – a non-systematic review of epidemiology, possible causes, and interventions. Frontiers in Psychiatry 5, 137.Google Scholar
Russell, A, Ciufolini, S, Gardner-Sood, P, Bonaccorso, S, Gaughran, F, Dazzan, P, Pariante, CM and Mondelli, V (2015) Inflammation and metabolic changes in first episode psychosis: preliminary results from a longitudinal study. Brain, Behavior, and Immunity 49, 25–29.Google Scholar
Sage, AP and Mallat, Z (2017) Readapting the adaptive immune response – therapeutic strategies for atherosclerosis. British Journal of Pharmacology 174, 3924–3939.Google Scholar
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.Google Scholar
Sekar, A, Bialas, AR, De Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M, Van Doren, V, Genovese, G, Rose, SA, Handsaker, RE, Daly, MJ, Carroll, MC, Stevens, B and Mccarroll, SA (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183.Google Scholar
Simonsen, C, Sundet, K, Vaskinn, A, Birkenaes, AB, Engh, JA, Faerden, A, Jonsdottir, H, Ringen, PA, Opjordsmoen, S, Melle, I, Friis, S and Andreassen, OA (2011) Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophrenia Bulletin 37, 73–83.Google Scholar
Smedbakken, L, Jensen, JK, Hallen, J, Atar, D, Januzzi, JL, Halvorsen, B, Aukrust, P and Ueland, T (2011) Activated leukocyte cell adhesion molecule and prognosis in acute ischemic stroke. Stroke 42, 2453–2458.Google Scholar
Tomasik, J, Rahmoune, H, Guest, PC and Bahn, S (2016) Neuroimmune biomarkers in schizophrenia. Schizophrenia Research 176, 3–13.Google Scholar
Ueland, T, Gullestad, L, Nymo, SH, Yndestad, A, Aukrust, P and Askevold, ET (2015) Inflammatory cytokines as biomarkers in heart failure. Clinica Chimica Acta 443, 71–77.Google Scholar
Wagner, M, Bilinska, M, Pokryszko-Dragan, A, Sobczynski, M, Cyrul, M, Kusnierczyk, P and Jasek, M (2014) ALCAM and CD6 – multiple sclerosis risk factors. Journal of Neuroimmunology 276, 98–103.Google Scholar
Walter, S, Doering, A, Letiembre, M, Liu, Y, Hao, W, Diem, R, Bernreuther, C, Glatzel, M, Engelhardt, B and Fassbender, K (2006) The LPS receptor, CD14, in experimental autoimmune encephalomyelitis and multiple sclerosis. Cellular Physiology and Biochemistry 17, 167–172.Google Scholar
Witkowska, AM (2005) On the role of IL-2R measurements in rheumatoid arthritis and cancers. Mediators of inflammation 3, 121–130.Google Scholar
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