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Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder

Molecular Psychiatry volume 17, pages 486–493 (2012)Cite this article

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Abstract

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case–control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case–control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

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References

  1. Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W et al. Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 1985; 228: 755–756.

    Article  CAS  Google Scholar 

  2. Amsterdam J, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R et al. Borna Disease Virus: a possible etiologic factor in human affective disorders? Arch Gen Psychiatry 1985; 42: 1093–1096.

    Article  CAS  Google Scholar 

  3. Hornig M, Briese T, Lipkin WI . Borna disease virus. J Neurovirol 2003; 9: 259–273.

    Article  CAS  Google Scholar 

  4. Chalmers RM, Thomas DR, Salmon RL . Borna disease virus and the evidence for human pathogenicity: a systematic review. QJM 2005; 98: 255–274.

    Article  CAS  Google Scholar 

  5. Yolken RH, Torrey EF . Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995; 8: 131–145.

    Article  CAS  Google Scholar 

  6. Lipkin WI, Hornig M . Neurovirology. Microbes and the brain. Lancet 1998; 352 (Suppl 4): SIV21.

    Article  Google Scholar 

  7. Schlitt M, Lakeman FD, Whitly RJ . Psychoses and herpes simplex encephalitis. South Med J 1985; 78: 1347–1350.

    Article  CAS  Google Scholar 

  8. Steinberg D, Hirsch SR, Marston SD, Reynolds K, Sutton NP . Influenza infection causing manic psychosis. Br J Psychiatry 1972; 120: 531–535.

    Article  CAS  Google Scholar 

  9. Goswami U, Shankar SK, Channabasavanna SM, Chattopadhyay A . Psychiatric presentations in rabies. A clinico-pathologic report from South India with a review of literature. Trop Geogr Med 1984; 36: 77–81.

    CAS  PubMed  Google Scholar 

  10. Menninger KA . Psychoses associated with influenza, I. General data: statistical analysis. JAMA 1919; 72: 235–241.

    Article  Google Scholar 

  11. Mednick SA, Machón RA, Huttunen MO, Bonett D . Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988; 45: 189–192.

    Article  CAS  Google Scholar 

  12. O'Callaghan E, Sham P, Takei N, Glover G, Murray RM . Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 1991; 337: 1248–1250.

    Article  CAS  Google Scholar 

  13. Lipkin WI, Schneemann A, Solbrig MV . Borna disease virus: implications for neuropsychiatric illness. Trends Microbiol 1995; 3: 64–69.

    Article  CAS  Google Scholar 

  14. Ludwig H, Bode L, Gosztonyi G . Borna disease: a persistent disease of the central nervous system. Prog Med Virol 1988; 35: 107–151.

    CAS  Google Scholar 

  15. Stitz L, Krey H, Ludwig H . Borna disease in rhesus monkeys as a model for uveo-cerebral symptoms. J Med Virol 1981; 6: 333–340.

    Article  CAS  Google Scholar 

  16. Kistler AL, Gancz A, Clubb S, Skewes-Cox P, Fischer K, Sorber K et al. Recovery of divergent avian bornaviruses from cases of proventricular dilatation disease: identification of a candidate etiologic agent. Virol J 2008; 5: 88.

    Article  Google Scholar 

  17. Honkavuori KS, Shivaprasad HL, Williams BL, Quan PL, Hornig M, Street C et al. Novel borna virus in psittacine birds with proventricular dilatation disease. Emerg Infect Dis 2008; 14: 1883–1886.

    Article  CAS  Google Scholar 

  18. Horie M, Honda T, Suzuki Y, Kobayashi Y, Daito T, Oshida T et al. Endogenous non-retroviral RNA virus elements in mammalian genomes. Nature 2010; 463: 84–87.

    Article  CAS  Google Scholar 

  19. Belyi VA, Levine AJ, Skalka AM . Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes. PLoS Pathog 2010; 6: e1001030.

    Article  Google Scholar 

  20. Bode L, Ferszt R, Czech G . Borna disease virus infection and affective disorders in man. Arch Virol Suppl 1993; 7: 159–167.

    Article  CAS  Google Scholar 

  21. Rackova S, Janu L, Kabickova H . Borna disease virus (BDV) circulating immunocomplex positivity in addicted patients in the Czech Republic: a prospective cohort analysis. BMC Psychiatry 2010; 10: 70.

    Article  Google Scholar 

  22. Heinrich A, Adamaszek M . Anti-Borna disease virus antibody responses in psychiatric patients: longterm follow up. Psychiatry Clin Neurosci 2010; 64: 255–261.

    Article  Google Scholar 

  23. Evengård B, Briese T, Lindh G, Lee S, Lipkin WI . Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome. J Neurovirol 1999; 5: 495–499.

    Article  Google Scholar 

  24. Bode L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE et al. Borna disease virus-specific circulating immune complexes, antigenemia, and free antibodies—the key marker triplet determining infection and prevailing in severe mood disorders. Mol Psychiatry 2001; 6: 481–491.

    Article  CAS  Google Scholar 

  25. Wolff T, Heins G, Pauli G, Burger R, Kurth R . Failure to detect Borna disease virus antigen and RNA in human blood [letter]. J Clin Virol 2006; 36: 309–311.

    Article  CAS  Google Scholar 

  26. Kishi M, Nakaya T, Nakamura Y, Kakinuma M, Takahashi TA, Sekiguchi S et al. Prevalence of Borna disease virus RNA in peripheral blood mononuclear cells from blood donors. Med Microbiol Immunol 1995; 184: 135–138.

    Article  CAS  Google Scholar 

  27. Wolff T, Burger R, Kurth R . Re: Absence of Borna virus in human blood [reply to letter]. J Clin Virol 2006; 36: 314.

    Article  CAS  Google Scholar 

  28. Lipkin WI, Hornig M, Briese T . Borna disease virus and neuropsychiatric disease—a reappraisal. Trends Microbiol 2001; 9: 295–298.

    Article  CAS  Google Scholar 

  29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Text Revision (DSM-IV-TR). American Psychiatric Press: Washington, DC, USA, 2000.

  30. First MB, Gibbon M, Spitzer RL, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders. Biometrics Research: New York, NY, USA, 1996.

    Google Scholar 

  31. Guy W . ECDEU Assessment Manual for Psychopharmacology. U.S. Department of Health, Education and Welfare: Washington, DC, USA, 1976, pp 218–222.

    Google Scholar 

  32. Hamilton M . A rating scale for depression. Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  Google Scholar 

  33. Williams JBW . A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45: 742–747.

    Article  CAS  Google Scholar 

  34. Young RC, Biggs JT, Zeigler VE, Meyer DA . A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–433.

    Article  CAS  Google Scholar 

  35. Kay SR, Opler LA, Lindenmayer JP . Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res 1988; 23: 99–110.

    Article  CAS  Google Scholar 

  36. Amsterdam JD, Hornig-Rohan M . Treatment algorithms in treatment-resistant depression. In: Hornig-Rohan M, Amsterdam JD (eds). Psychiatric Clinics of North America: Treatment-Resistant Depression. W.B. Saunders: Philadelphia, 1996, pp 371–386.

    Google Scholar 

  37. Khot V, DeVane CL, Korpi ER, Venable D, Bigelow LB, Wyatt RJ et al. The assessment and clinical implications of haloperidol acute-dose, steady-state, and withdrawal pharmacokinetics. J Clin Psychopharmacol 1993; 13: 120–127.

    Article  CAS  Google Scholar 

  38. Van Putten T, Marder SR, Mintz J, Poland RE . Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry 1992; 149: 500–505.

    Article  CAS  Google Scholar 

  39. Tamura K, Dudley J, Nei M, Kumar S . MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 2007; 24: 1596–1599.

    Article  CAS  Google Scholar 

  40. Briese T, Hatalski CG, Kliche S, Park YS, Lipkin WI . An enzyme-linked-immunosorbent assay for detecting antibodies to Borna disease virus-specific proteins. J Clin Microbiol 1995; 69: 348–351.

    Google Scholar 

  41. Billich C, Sauder C, Frank R, Herzog S, Bechter K, Takahashi K et al. High-avidity human serum antibodies recognizing linear epitopes of Borna disease virus proteins. Biol Psychiatry 2002; 51: 979–987.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by NIH award MH57467 (WIL). We thank Meera Bhat for data derived from linkage to the United States Census Bureau database, and Vishal Kapoor for assistance with Western immunoblot analyses.

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Authors and Affiliations

  1. Center for Infection and Immunity, Columbia University Mailman School of Public Health, New York, NY, USA

    M Hornig, T Briese, U Siemetzki, K Honkavuori & W I Lipkin

  2. Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA

    M Hornig, T Briese & W I Lipkin

  3. John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

    J Licinio

  4. Centers for Disease Control and Prevention, Atlanta, GA, USA

    R F Khabbaz

  5. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA

    L L Altshuler, J Mintz & P C Whybrow

  6. University of California Irvine, Irvine, CA, USA

    S G Potkin & W E Bunney

  7. Department of Virology, Universitätsklinikum, Freiburg, Germany

    M Schwemmle

  8. Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA

    H C Kraemer

  9. Clinical Neuroscience, Merck & Company, North Wales, PA, USA

    M F Egan

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  1. M Hornig
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  8. U Siemetzki
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Correspondence to M Hornig or W I Lipkin.

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Hornig, M., Briese, T., Licinio, J. et al. Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder. Mol Psychiatry 17, 486–493 (2012). https://doi.org/10.1038/mp.2011.179

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  • DOI: https://doi.org/10.1038/mp.2011.179

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