BACKGROUND: Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. METHODS: Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. RESULTS: Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P < 0.001) than positive symptoms (rpb=0.19; P < 0.001). The associations of CRP with positive and negative symptom dimension scores were similar. At individual symptom level, after adjusting for potential confounders including depressive symptoms, CRP was associated with auditory hallucinations (adjusted OR = 2.22; 95% CI, 1.04-4.76) and anhedonia (adjusted OR = 1.13; 95% CI, 1.02-1.26). CONCLUSIONS: Inflammation is associated with sub-clinical psychotic symptoms in young people in general population. Association of CRP with symptoms commonly shared between mood and psychotic disorders, such as auditory hallucinations and anhedonia, could be one explanation for the apparent trans-diagnostic effect of inflammation.

Centre for Academic Mental Health Department of Population Health Sciences Bristol Medical School University of Bristol Oakfield House Oakfield Grove Bristol BS8 2BN United Kingdom; Institute of Psychological Medicine and Clinical Neurosciences Cardiff University Cardiff CF10 3AT United Kingdom

Department for Symptom Research University of Texas MD Anderson Cancer Center Laboratory of Neuroimmunology Unit 1055 Office Z8 5042 6565 MD Anderson Boulevard Houston TX 77030 USA

Department of Psychiatry University of Cambridge Herchel Smith Building Forvie Site Cambridge Biomedical Campus Cambridge CB2 0SZ United Kingdom; Cambridgeshire and Peterborough NHS Foundation Trust Elizabeth House Fulbourn Hospital Fulbourn Cambridge CB21 5EF United Kingdom

Department of Psychiatry University of Cambridge Herchel Smith Building Forvie Site Cambridge Biomedical Campus Cambridge CB2 0SZ United Kingdom; Department of Kinanthropology Charles University José Martího 31 Prague 165 52 Czech Republic

Division of Psychiatry University College London Maple House 149 Tottenham Court Road London W1T 7NF United Kingdom

Zobrazit více v PubMed

Angold A., Costello E.J., Messer S.C. Development of a short questionnaire for use in epidemiological studies of depression in children and adolescents. Int. J. Methods Psychiatr. Res. 1995;5:237–249.

APA . fifth ed. American Psychiatric Publishing; Arlington, VA: 2013. Diagnostic and Statistical Manual of Mental Disorders.

Baumeister D., Akhtar R., Ciufolini S., Pariante C.M., Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Mol. Psychiatr. 2016;21(5):642–649. PubMed PMC

Benros M.E., Nielsen P.R., Nordentoft M., Eaton W.W., Dalton S.O., Mortensen P.B. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am. J. Psychiatr. 2011;168(12):1303–1310. PubMed

Boozalis T., Teixeira A.L., Cho R.Y., Okusaga O. C-reactive protein correlates with negative symptoms in patients with schizophrenia. Frontiers in public health. 2017;5:360. PubMed PMC

Boyd A., Golding J., Macleod J., Lawlor D.A., Fraser A., Henderson J., Molloy L., Ness A., Ring S., Davey Smith G. Cohort profile: the 'children of the 90s'--the index offspring of the Avon longitudinal study of parents and children. Int. J. Epidemiol. 2013;42(1):111–127. PubMed PMC

Brown A.S., Derkits E.J. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am. J. Psychiatr. 2010;167(3):261–280. PubMed PMC

Brown A.S., Sourander A., Hinkka-Yli-Salomaki S., McKeague I.W., Sundvall J., Surcel H.M. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol. Psychiatr. 2014;19(2):259–264. PubMed PMC

Buka S.L., Tsuang M.T., Torrey E.F., Klebanoff M.A., Bernstein D., Yolken R.H. Maternal infections and subsequent psychosis among offspring. Arch. Gen. Psychiatr. 2001;58(11):1032–1037. PubMed

Capuron L., Pagnoni G., Drake D.F., Woolwine B.J., Spivey J.R., Crowe R.J., Votaw J.R., Goodman M.M., Miller A.H. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch. Gen. Psychiatr. 2012;69(10):1044–1053. PubMed PMC

Chu A.L., Stochl J., Lewis G., Zammit S., Jones P.B., Khandaker G.M. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav. Immun. 2019;76:74–81. PubMed PMC

Dantzer R., O'Connor J.C., Freund G.G., Johnson R.W., Kelley K.W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 2008;9(1):46–56. PubMed PMC

Dickerson F., Stallings C., Origoni A., Boronow J., Yolken R. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr. Res. 2007;93(1–3):261–265. PubMed

Dickerson F.B., Boronow J.J., Stallings C., Origoni A.E., Ruslanova I., Yolken R.H. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch. Gen. Psychiatr. 2003;60(5):466–472. PubMed

Duivis H.E., Vogelzangs N., Kupper N., de Jonge P., Penninx B.W. Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from The Netherlands Study of Depression and Anxiety (NESDA) Psychoneuroendocrinology. 2013;38(9):1573–1585. PubMed

Eisenberger N.I., Berkman E.T., Inagaki T.K., Rameson L.T., Mashal N.M., Irwin M.R. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol. Psychiatr. 2010;68(8):748–754. PubMed PMC

Eraly S.A., Nievergelt C.M., Maihofer A.X., Barkauskas D.A., Biswas N., Agorastos A., O'Connor D.T., Baker D.G., Marine Resiliency Study T. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA psychiatry. 2014;71(4):423–431. PubMed PMC

Fan X., Pristach C., Liu E.Y., Freudenreich O., Henderson D.C., Goff D.C. Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia. Psychiatr. Res. 2007;149(1–3):267–271. PubMed

Felger J.C., Li Z., Haroon E., Woolwine B.J., Jung M.Y., Hu X., Miller A.H. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol. Psychiatr. 2016;21(10):1358–1365. PubMed PMC

Felger J.C., Mun J., Kimmel H.L., Nye J.A., Drake D.F., Hernandez C.R., Freeman A.A., Rye D.B., Goodman M.M., Howell L.L., Miller A.H. Chronic interferon-alpha decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2013;38(11):2179–2187. PubMed PMC

Fraser A., Macdonald-Wallis C., Tilling K., Boyd A., Golding J., Davey Smith G., Henderson J., Macleod J., Molloy L., Ness A., Ring S., Nelson S.M., Lawlor D.A. Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int. J. Epidemiol. 2013;42(1):97–110. PubMed PMC

Goldsmith D.R., Rapaport M.H., Miller B.J. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatr. 2016;21(12):1696–1709. PubMed PMC

Haroon E., Raison C.L., Miller A.H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012;37(1):137–162. PubMed PMC

Harrison N.A., Voon V., Cercignani M., Cooper E.A., Pessiglione M., Critchley H.D. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol. Psychiatr. 2016;80(1):73–81. PubMed PMC

Holm S. A simple sequentially rejective multiple test procedure. Scand. J. Stat. 1979;6:65–70.

Howren M.B., Lamkin D.M., Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 2009;71(2):171–186. PubMed

Johnsen E., Fathian F., Kroken R.A., Steen V.M., Jorgensen H.A., Gjestad R., Loberg E.M. The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. BMC Psychiatr. 2016;16:60. PubMed PMC

Jokela M., Virtanen M., Batty G.D., Kivimaki M. Inflammation and specific symptoms of depression. JAMA psychiatry. 2016;73(1):87–88. PubMed

Kappelmann N., Khandaker G.M., Dal H., Stochl J., Kosidou K., Jones P.B., Dalman C., Karlsson H. Systemic inflammation and intelligence in early adulthood and subsequent risk of schizophrenia and other non-affective psychoses: a longitudinal cohort and co-relative study. Psychol. Med. 2019;49(2):295–302. PubMed PMC

Kappelmann N., Lewis G., Dantzer R., Jones P.B., Khandaker G.M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatr. 2018;23(2):335–343. PubMed PMC

Kelleher I., Connor D., Clarke M.C., Devlin N., Harley M., Cannon M. Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol. Med. 2012;42(9):1857–1863. PubMed

Kelleher I., Keeley H., Corcoran P., Lynch F., Fitzpatrick C., Devlin N., Molloy C., Roddy S., Clarke M.C., Harley M., Arseneault L., Wasserman C., Carli V., Sarchiapone M., Hoven C., Wasserman D., Cannon M. Clinicopathological significance of psychotic experiences in non-psychotic young people: evidence from four population-based studies. The British journal of psychiatry : J. Ment. Sci. 2012;201(1):26–32. PubMed

Khandaker G.M., Cousins L., Deakin J., Lennox B.R., Yolken R., Jones P.B. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. The Lancet Psychiatry. 2015;2(3):258–270. PubMed PMC

Khandaker G.M., Pearson R.M., Zammit S., Lewis G., Jones P.B. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA psychiatry. 2014;71(10):1121–1128. PubMed PMC

Khandaker G.M., Zimbron J., Dalman C., Lewis G., Jones P.B. Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophr. Res. 2012;139(1–3):161–168. PubMed PMC

Khandaker G.M., Zimbron J., Lewis G., Jones P.B. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol. Med. 2013;43(2):239–257. PubMed PMC

Kirkpatrick B., Fenton W.S., Carpenter W.T., Jr., Marder S.R. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr. Bull. 2006;32(2):214–219. PubMed PMC

Kohler-Forsberg O., Buttenschon H.N., Tansey K.E., Maier W., Hauser J., Dernovsek M.Z., Henigsberg N., Souery D., Farmer A., Rietschel M., McGuffin P., Aitchison K.J., Uher R., Mors O. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav. Immun. 2017;62:344–350. PubMed

McGrath J.J., Saha S., Al-Hamzawi A., Andrade L., Benjet C., Bromet E.J., Browne M.O., Caldas de Almeida J.M., Chiu W.T., Demyttenaere K., Fayyad J., Florescu S., de Girolamo G., Gureje O., Haro J.M., Ten Have M., Hu C., Kovess-Masfety V., Lim C.C., Navarro-Mateu F., Sampson N., Posada-Villa J., Kendler K.S., Kessler R.C. The bidirectional associations between psychotic experiences and DSM-IV mental disorders. Am. J. Psychiatr. 2016;173(10):997–1006. PubMed PMC

Messinger J.W., Tremeau F., Antonius D., Mendelsohn E., Prudent V., Stanford A.D., Malaspina D. Avolition and expressive deficits capture negative symptom phenomenology: implications for DSM-5 and schizophrenia research. Clin. Psychol. Rev. 2011;31(1):161–168. PubMed PMC

Metcalf S.A., Jones P.B., Nordstrom T., Timonen M., Maki P., Miettunen J., Jaaskelainen E., Jarvelin M.R., Stochl J., Murray G.K., Veijola J., Khandaker G.M. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: a prospective birth cohort study. Brain Behav. Immun. 2017;59:253–259. PubMed PMC

Miller A.H., Maletic V., Raison C.L. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatr. 2009;65(9):732–741. PubMed PMC

Miller B.J., Buckley P., Seabolt W., Mellor A., Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatr. 2011;70(7):663–671. PubMed PMC

Miller B.J., Culpepper N., Rapaport M.H. C-reactive protein levels in schizophrenia. Clin. Schizophrenia Relat. Psychoses. 2013:1–22. PubMed

Mondelli V., Ciufolini S., Belvederi Murri M., Bonaccorso S., Di Forti M., Giordano A., Marques T.R., Zunszain P.A., Morgan C., Murray R.M., Pariante C.M., Dazzan P. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr. Bull. 2015;41(5):1162–1170. PubMed PMC

Mortensen P.B., Norgaard-Pedersen B., Waltoft B.L., Sorensen T.L., Hougaard D., Yolken R.H. Early infections of Toxoplasma gondii and the later development of schizophrenia. Schizophr. Bull. 2007;33(3):741–744. PubMed PMC

Muthén L.K., Muthén B.O. 6 ed. 1998-2011. Mplus User's Guide. Los Angeles, CA.

Pearson T.A., Mensah G.A., Alexander R.W., Anderson J.L., Cannon R.O., 3rd, Criqui M., Fadl Y.Y., Fortmann S.P., Hong Y., Myers G.L., Rifai N., Smith S.C., Jr., Taubert K., Tracy R.P., Vinicor F., Centers for Disease C., Prevention, American Heart A. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499–511. PubMed

Pomarol-Clotet E., Honey G.D., Murray G.K., Corlett P.R., Absalom A.R., Lee M., McKenna P.J., Bullmore E.T., Fletcher P.C. Psychological effects of ketamine in healthy volunteers. Phenomenological study. The British journal of psychiatry : J. Ment. Sci. 2006;189:173–179. PubMed PMC

Potvin S., Stip E., Sepehry A.A., Gendron A., Bah R., Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatr. 2008;63(8):801–808. PubMed

Poulton R., Caspi A., Moffitt T.E., Cannon M., Murray R., Harrington H. Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Arch. Gen. Psychiatr. 2000;57(11):1053–1058. PubMed

Prasad K.M., Watson A.M., Dickerson F.B., Yolken R.H., Nimgaonkar V.L. Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr. Bull. 2012;38(6):1137–1148. PubMed PMC

Raison C.L., Rutherford R.E., Woolwine B.J., Shuo C., Schettler P., Drake D.F., Haroon E., Miller A.H. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA psychiatry. 2013;70(1):31–41. PubMed PMC

Rossler W., Hengartner M.P., Ajdacic-Gross V., Haker H., Gamma A., Angst J. Sub-clinical psychosis symptoms in young adults are risk factors for subsequent common mental disorders. Schizophr. Res. 2011;131(1–3):18–23. PubMed

Schmidt R., Schmidt H., Curb J.D., Masaki K., White L.R., Launer L.J. Early inflammation and dementia: a 25-year follow-up of the honolulu-asia aging study. Ann. Neurol. 2002;52(2):168–174. PubMed

Schwarcz R., Pellicciari R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J. Pharmacol. Exp. Therapeut. 2002;303(1):1–10. PubMed

Schwarcz R., Rassoulpour A., Wu H.Q., Medoff D., Tamminga C.A., Roberts R.C. Increased cortical kynurenate content in schizophrenia. Biol. Psychiatr. 2001;50(7):521–530. PubMed

Sheffield J.M., Williams L.E., Blackford J.U., Heckers S. Childhood sexual abuse increases risk of auditory hallucinations in psychotic disorders. Compr. Psychiatr. 2013;54(7):1098–1104. PubMed PMC

Stefanis N.C., Hanssen M., Smirnis N.K., Avramopoulos D.A., Evdokimidis I.K., Stefanis C.N., Verdoux H., Van Os J. Evidence that three dimensions of psychosis have a distribution in the general population. Psychol. Med. 2002;32(2):347–358. PubMed

Stochl J., Khandaker G.M., Lewis G., Perez J., Goodyer I.M., Zammit S., Sullivan S., Croudace T.J., Jones P.B. Mood, anxiety and psychotic phenomena measure a common psychopathological factor. Psychol. Med. 2015;45(7):1483–1493. PubMed

Upthegrove R., Manzanares-Teson N., Barnes N.M. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr. Res. 2014;155(1–3):101–108. PubMed

van Os J., Linscott R.J., Myin-Germeys I., Delespaul P., Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol. Med. 2009;39(2):179–195. PubMed

Wohleb E.S., McKim D.B., Shea D.T., Powell N.D., Tarr A.J., Sheridan J.F., Godbout J.P. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol. Psychiatr. 2014;75(12):970–981. PubMed PMC

Zammit S., Horwood J., Thompson A., Thomas K., Menezes P., Gunnell D., Hollis C., Wolke D., Lewis G., Harrison G. Investigating if psychosis-like symptoms (PLIKS) are associated with family history of schizophrenia or paternal age in the ALSPAC birth cohort. Schizophr. Res. 2008;104(1–3):279–286. PubMed

Zammit S., Kounali D., Cannon M., David A.S., Gunnell D., Heron J., Jones P.B., Lewis S., Sullivan S., Wolke D., Lewis G. Psychotic experiences and psychotic disorders at age 18 in relation to psychotic experiences at age 12 in a longitudinal population-based cohort study. Am. J. Psychiatr. 2013;170(7):742–750. PubMed