Skip to main content Accessibility help

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

  • Ragni H. Mørch (a1) (a2), Ingrid Dieset (a1) (a2) (a3), Ann Færden (a3), Elina J. Reponen (a1) (a2), Sigrun Hope (a1) (a2) (a4), Eva Z. Hoseth (a1) (a2) (a5), Erlend S. Gardsjord (a1) (a2), Monica Aas (a1) (a2), Trude Iversen (a1) (a2), Inge Joa (a6) (a7), Gunnar Morken (a8) (a9), Ingrid Agartz (a1) (a2) (a10), Ingrid Melle (a1) (a2), Pål Aukrust (a11) (a12) (a13), Srdjan Djurovic (a14) (a15), Thor Ueland (a11) (a12) (a13) and Ole A. Andreassen (a1) (a2)...
  • Please note a correction has been issued for this article.



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.


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.


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.


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.


Corresponding author

Author for correspondence: Ragni H. Mørch, E-mail:


Hide All
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, 197209.
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, 207214.
Bergink, V, Gibney, SM and Drexhage, HA (2014) Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biological Psychiatry 75, 324331.
Bloom, J and Al-Abed, Y (2014) MIF: mood improving/inhibiting factor? Journal of Neuroinflammation 11, 11.
Brown, AS and Derkits, EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. The American Journal of Psychiatry 167, 261280.
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, 137145.
Cox, AJ, West, NP and Cripps, AW (2015) Obesity, inflammation, and the gut microbiota. The Lancet. Diabetes & Endocrinology 3, 207215.
Crump, C, Sundquist, K, Winkleby, MA and Sundquist, J (2013) Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry 70, 931939.
Cuthbert, BN (2015) Research Domain Criteria: toward future nosologies. Dialogues Clinical Neuroscience 17, 8997.
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, 169174.
Dieset, I, Andreassen, OA and Haukvik, UK (2016) Somatic comorbidity in schizophrenia: some possible biological mechanisms across the life span. Schizophrenia Bulletin 42, 13161319.
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, 22462253.
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, 521528.
Eaton, WW, Pedersen, MG, Nielsen, PR and Mortensen, PB (2010) Autoimmune diseases, bipolar disorder, and non-affective psychosis. Bipolar Disorders 12, 638646.
Girgis, RR, Kumar, SS and Brown, AS (2014) The cytokine model of schizophrenia: emerging therapeutic strategies. Biological Psychiatry 75, 292299.
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, 16961709.
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, 269275.
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, 726734.
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, 16081616.
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, 3642.
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, 188194.
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, 163173.
Irwin, MR and Miller, AH (2007) Depressive disorders and immunity: 20 years of progress and discovery. Brain, Behavior, and Immunity 21, 374383.
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, 635649.
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, 391402.
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, 258270.
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, 11291134.
Laursen, TM, Munk-Olsen, T and Vestergaard, M (2012) Life expectancy and cardiovascular mortality in persons with schizophrenia. Current Opinion in Psychiatry 25, 8388.
Leboyer, M, Oliveira, J, Tamouza, R and Groc, L (2016) Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology (Berlin) 233, 16511660.
Lee, YH, Kim, JH and Song, GG (2013) Pathway analysis of a genome-wide association study in schizophrenia. Gene 525, 107115.
Libby, P (2002) Inflammation in atherosclerosis. Nature 420, 868874.
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, 337341.
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, 12191228.
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, 189197.
Muller, N (2014) Immunology of major depression. Neuroimmunomodulation 21, 123130.
Muller, N, Krause, D, Weidinger, E and Schwarz, M (2014) Immunological treatment options for schizophrenia. Fortschritte der Neurologie-Psychiatrie 82, 210219.
Najjar, S and Pearlman, DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophrenia Research 161, 102112.
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.
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.
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, 2529.
Sage, AP and Mallat, Z (2017) Readapting the adaptive immune response – therapeutic strategies for atherosclerosis. British Journal of Pharmacology 174, 39243939.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421427.
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, 177183.
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, 7383.
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, 24532458.
Tomasik, J, Rahmoune, H, Guest, PC and Bahn, S (2016) Neuroimmune biomarkers in schizophrenia. Schizophrenia Research 176, 313.
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, 7177.
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, 98103.
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, 167172.
Witkowska, AM (2005) On the role of IL-2R measurements in rheumatoid arthritis and cancers. Mediators of inflammation 3, 121130.


Related content

Powered by UNSILO
Type Description Title
Supplementary materials

Mørch et al. supplementary material
Tables S1-S10

 Word (31 KB)
31 KB

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

  • Ragni H. Mørch (a1) (a2), Ingrid Dieset (a1) (a2) (a3), Ann Færden (a3), Elina J. Reponen (a1) (a2), Sigrun Hope (a1) (a2) (a4), Eva Z. Hoseth (a1) (a2) (a5), Erlend S. Gardsjord (a1) (a2), Monica Aas (a1) (a2), Trude Iversen (a1) (a2), Inge Joa (a6) (a7), Gunnar Morken (a8) (a9), Ingrid Agartz (a1) (a2) (a10), Ingrid Melle (a1) (a2), Pål Aukrust (a11) (a12) (a13), Srdjan Djurovic (a14) (a15), Thor Ueland (a11) (a12) (a13) and Ole A. Andreassen (a1) (a2)...
  • Please note a correction has been issued for this article.


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.

A correction has been issued for this article: