New Experimental Approaches Examining a Viral Etiology of Schizophrenia

  • Anita Feenstra
  • Darrell G. Kirch
  • Mark A. Coggiano
  • Richard Jed Wyatt


Viral infections have been suggested as a possible cause of several chronic disorders of the CNS, including multiple sclerosis (Cook and Dowling, 1980; Koprowski et al., 1985; Reddy et al., 1989; Greenberg et al., 1989), Parkinson’s disease (Ravenholt and Foege, 1982), Alzheimer’s disease (Terry and Davies, 1980), and schizophrenia (Torrey and Peterson, 1976; Tyrrell et al., 1979; Crow, 1983; Wyatt and DeLisi, 1984). Evidence to support a viral etiology of schizophrenia has been based mainly on epidemiological data. These include a season-of-birth effect, where there is an excess of late winter and early spring births (Torrey et al., 1977), and a high prevalence of the disease in some geographic areas (Torrey, 1987). Laboratory attempts to more directly substantiate a viral etiology in schizophrenia have focused on alterations in humoral and cell-mediated immunity (Vartanian et al., 1987; DeLisi et al.,1982; Coffey et al., 1983; Kirch et al., 1985; Roos et al., 1985; DeLisi, 1986; Ganguli et al., 1987), which could reflect a challenge by an infectious agent, and on efforts to identify antibodies to specific viruses in blood (DeLisi and Sarin, 1985; King et al., 1985; Robert-Guroff et al., 1985; Torrey and Kaufmann, 1986), CSF (Torrey et al., 1982; Kaufmann et al., 1983), or postmortem brain material (Stevens et al., 1983). These approaches have led to mixed results with no evidence for a specific virus.


Human Immunodeficiency Virus Multiple Sclerosis Kawasaki Disease Schizophrenic Patient Lymphocyte Culture 
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  1. Baker, H. E, Ridley, R. M., Crow, T. J., Bloxham, C. A., Parry, R. P., and Tyrrell, D. A. J., 1983, An investigation of the effects of intracerebral injection in the marmoset of cytopathic cerebrospinal fluid from patients with schizophrenia or neurological disease, Psychol. Med. 13: 499–511.PubMedCrossRefGoogle Scholar
  2. Bednarik D. P., Mosca, J. D., and Raj, N. B. K., 1987, Methylation as a modulator of expression of human immunodeficiency virus, J. Virol. 61: 1253–1257.PubMedGoogle Scholar
  3. Burns, J. C., Geha, R. S., Schneeberger, E. E., Newburger, J. W., Rosen, E. S., Glezen, L. S., Natale, J., and Huang, A. S., 1986, Polymerase activity in lymphocyte culture supernatants from patients with Kawasaki disease, Nature 323: 814–816.PubMedCrossRefGoogle Scholar
  4. Coffey, C. E., Sullivan, J. L., and Rice, J. R., 1983, T lymphocytes in schizophrenia, Biol. Psychiatry 18: 113–119.PubMedGoogle Scholar
  5. Cook, S. D., and Dowling, P C., 1980, Multiple sclerosis and viruses: An overview, Neurology 30:113–119. Crow, T. J., 1983, Is schizophrenia an infectious disease? Lancet 1: 173–175.Google Scholar
  6. Crow, T. J., 1984, A re-evaluation of the viral hypothesis: Is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br. J. Psychiatry 145: 243–253.PubMedCrossRefGoogle Scholar
  7. Crow, T. J., 1985, Br. J. Psychiatry 146: 674–675.Google Scholar
  8. DeLisi, L. E., 1986, Neuroimmunology: Clinical studies of schizophrenia and other psychiatric disorders, in: Handbook of Schizophrenia: The Neurology of Schizophrenia ( H. A. Nasrallah and D. R. Weinberger, eds.), Elsevier, Amsterdam, p. 674.Google Scholar
  9. DeLisi, L. E., and Sarin, P. S., 1985, Lack of evidence for retrovirus infection in schizophrenic patients, Br. J. Psychiatry 146: 674.PubMedGoogle Scholar
  10. DeLisi, L. E., Goodman, S., Neckers, L. M., and Wyatt, R. J., 1982, An analysis of lymphocyte subpopulations in schizophrenic patients, Biol. Psychiatry 17: 1003–1009.PubMedGoogle Scholar
  11. Doerfler, W., 1983, DNA methylation and gene activity, Annu. Rev. Biochem. 52:93–124. Feenstra, A., Kirch, D. G., Coggiano, M. A., and Wyatt, R. J., 1988, Reverse transcriptase activity inGoogle Scholar
  12. 5-.
    azacytidine-treated lymphocyte cultures of patients with schizophrenia, Schiz. Res. 1:385–389.Google Scholar
  13. Feenstra, A., Kirch, D. G., Bracha, H. S., and Wyatt, R. J., 1989, Lack of evidence for a role of T-cell-associated retroviruses as an etiology of schizophrenia, Biol. Psychiatry 25: 421–430.PubMedCrossRefGoogle Scholar
  14. Ferguson, R. M., Schmidtke, J. R., and Simmons, R. L., 1987, Effects of psychoactive drugs on in vitro lymphocyte activation, in: Neurochemical and Immunological Components of Schizophrenia ( D. Bergsma and A. L. Goldstein, eds.), Liss, New York, pp. 379–402.Google Scholar
  15. Fieve, R. R., Blumenthal, B., and Little, B., 1966, The relationship of atypical lymphocytes, phenothiazines and schizophrenia, Arch. Gen. Psychiatry 15: 529–534.PubMedCrossRefGoogle Scholar
  16. Gallo, R. C., Salahuddin, S. Z., Popovic, M., Shearer, G. M., Kaplan, M., Haynes, B. F., Palker, T. J., Redfield, R., Oleske, J., Safai, B., White, G., Foester, P., and Markham, P. D., 1984, Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS, Science 224: 500–503.PubMedCrossRefGoogle Scholar
  17. Ganguli, R., Rabin, B., Raghu, U., and Ulrich, R. S., 1987, T-lymphocytes in schizophrenics and normals and the effects of varying antipsychotic dosage, in: Viruses, Immunity and Mental Disorders ( E. Kurstak, Z. J. Lipowski, and P V. Morozov, eds.), Plenum Press, New York, pp. 321–326.Google Scholar
  18. Gartner, S., Markovits, P., Markovitz, D. M., Betts, R. E, and Popovic, M., 1986, Virus isolation from and identification of HTLV II JLAV-producing cells in brain tissue from a patient with AIDS, J. Am. Med. Assoc. 256: 2365–2371.CrossRefGoogle Scholar
  19. Gessain, A., Vernant, J. C., Maurs, L., Bann, E, Gout, O., Calender, A., and De The, G., 1985, Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis, Lancet 2: 407–409.PubMedCrossRefGoogle Scholar
  20. Greenberg, S. J., Ehrlich, G. D., Abbott, M. A., Hurwitz, B. J., Waldmann, T. A., and Poiesz, B. J., 1989, Detection of sequences homologous to human retroviral DNA in multiple sclerosis by gene amplification, Proc. Natl. Acad. Sci. USA 86: 2878–2882.PubMedCrossRefGoogle Scholar
  21. Groudine, M., Eisenman, R., and Weintraub, H., 1981, Chromatin structure of endogenous retroviral genes and activation by an inhibitor of DNA methylation, Nature 292: 311–317.PubMedCrossRefGoogle Scholar
  22. Hoffmann, J. W., Steffen, D., Gusella, J., Tabin, C., Bird, S., Cowing, D., and Weinberg, R. A., 1982, DNA methylation affecting the expression of murine leukemia provinsses, J. Virol. 44: 144–157.PubMedGoogle Scholar
  23. Jones, G. H., Kelly, C. L., and Davies, J. A., 1987, HIV and onset of schizophrenia, Lancet 1: 982.Google Scholar
  24. Kacian, D. L., 1977, Methods for assaying reverse transcriptase, in: Methods in Virology, ( K. Maramorosch and H. Koprowski, eds.), Academic Press, New York, p. 143.Google Scholar
  25. Kaufmann, C. A., Weinberger, D. R., Yolken, R. H., Torrey, E. E, and Potkin, S. G., 1983, Viruses and schizophrenia, Lancet 2: 1136–1137.PubMedCrossRefGoogle Scholar
  26. Kaufmann, C. A., Weinberger, D. R., Stevens, J. R., Asher, D. M., Kleinman, J. E., Sulima, M. P., Gibbs, C. J., and Gadjusek, D. C., 1988, Intracerebral inoculation of experimental animals with brain tissue from patients with schizophrenia: Failure to observe consistent or specific behavioral and neuropathological effects, Arch. Gen. Psychiatry 45: 648–652.PubMedCrossRefGoogle Scholar
  27. King, D. J., Cooper, S. J., Earle, J. A. P., Martin, S. J., McFerran, N. V., and Wisdom, G. B., 1985, Serum and CSF antibody titres to seven common viruses in schizophrenic patients, Br. J. Psychiatry 147: 145–149.PubMedCrossRefGoogle Scholar
  28. Kirch, D. G., Kaufmann, C. A., Papadopoulus, N. M., Martin, B., and Weinberger, D. R., 1985, Abnormal cerebrospinal fluid protein indices in schizophrenia, Biol. Psychiatry 20: 1039–1046.PubMedCrossRefGoogle Scholar
  29. Koenig, S., Gendehnan, H. E., Orenstein, J. M., Dal Conto, M. C., Pezeshkpour, G. H., Yungbluth, M., Janotta, F., and Aksamit, A., 1986, Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy, Science 233: 1089–1093.PubMedCrossRefGoogle Scholar
  30. Koprowski, H., DeFreitas, E. C., Harper, M. E., Sandberg-Wollheim, M., Sheremata, W. A., RobertGuroff, M., Saxinger, C. W, and Feinberg, M. B., 1985, Multiple sclerosis and human T-cell lymphotropic retroviruses, Nature 318: 154–160.PubMedCrossRefGoogle Scholar
  31. Maccario, M., and Scharre, D. W, 1987, HIV and acute onset of psychosis, Lancet 2:342. Melish, M. E., Marchette, N. J., Kaplan, J. C., Kihira, S., Ching, D., and Ho, D. D., 1989, Absence ofGoogle Scholar
  32. significant RNA-dependent DNA polymerase activity in lymphocytes from patients with Kawasaki syndrome, Nature 337:288–290.Google Scholar
  33. Mered, B., Albrecht, P., Torrey, E. F., Weinberger, D. R., Potkin, S. G., and Winfrey, C. J., 1983, Failure to isolate virus from CSF of schizophrenics, Lancet 11: 919.CrossRefGoogle Scholar
  34. Navia, B. A., Jordan, B. D., and Price, R. W, 1986a, The AIDS dementia complex: I. Clinical features, Ann. Neurol. 19: 517–524.PubMedCrossRefGoogle Scholar
  35. Navia, B. A., Cho, E. S., Petito, C. K., and Price, R. W., 1986b, The AIDS dementia complex: II. Neuropathology, Ann. Neurol. 19: 525–535.PubMedCrossRefGoogle Scholar
  36. Osame, M., Matsumoto, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., Tara, M., and Igata, A., 1987, Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia-like cells, Ann. Neurol. 21: 117–122.PubMedCrossRefGoogle Scholar
  37. Patou, G., Crow, T. J., and Taylor, G. R., 1986, The effects of psychotropic drugs on synthesis of DNA and the infectivity of herpes symplex virus, Biol. Psychiatry 21: 1221–1225.PubMedCrossRefGoogle Scholar
  38. Poiesz, B. J., Ruscetti, F. W, Gazdar, A. F., Bunn, P. A., Minna, J. D., and Gallo, R. C., 1980a, Detection and isolation of C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma, Proc. Natl. Acad. Sci. USA 77: 7415–7419.PubMedCrossRefGoogle Scholar
  39. Poiesz, B. J., Ruscetti, E W, Mier, J. W, Woods, A. M., and Gallo, R. C., 1980b, T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth factor, Proc. Natl. Acad. Sci. USA 77: 6815–6819.PubMedCrossRefGoogle Scholar
  40. Poiesz, B. J., Ruscetti, E W, Reitz, M. S., Kalyanaraman, V. S., and Gallo, R. C., 1981, Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukemia, Nature 294: 268–271.PubMedCrossRefGoogle Scholar
  41. Ravenholt, R. T., and Foege, W. H., 1982, 1918 influenza, encephalitis lethargica, parkinsonism, Lancet 2: 860–864.Google Scholar
  42. Reddy, E. P., Sandberg-Wollheim, M., Mettus, R. V., Ray, P E., DeFreitas, E., and Koprowski, H., 1989, Amplification and molecular cloning of HTLV I sequences from DNA of multiple sclerosis patients, Science 243: 529–533.PubMedCrossRefGoogle Scholar
  43. Robert-Guroff, M., Torrey, E. E, and Brown, M., 1985, Retroviruses and schizophrenia, Br. J. Psychiatry 146: 326.PubMedCrossRefGoogle Scholar
  44. Roos, R. P., Davis, K., and Meltzer, H. Y., 1985, Immunoglobulin studies with psychiatric diseases, Arch. Gen. Psychiatry 42: 124–128.PubMedCrossRefGoogle Scholar
  45. Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullis, K. B., and Ehrlich, H. E., 1988, Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase, Science 239: 487–491.PubMedCrossRefGoogle Scholar
  46. Salahuddin, S. Z., Markham, P. D., Popovic, M., Sarngadharan, M. G., Orndorff, S., Fladagar, A., Patel, A., Gold, J., and Gallo, R. C., 1985, Isolation of infectious human T-cell leukemia/ lymphotropic virus type-III (HTLV-111) from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) and from healthy carriers: A study of risk groups and tissue sources, Proc. Natl. Acad. Sci. USA 82: 5530–5534.PubMedCrossRefGoogle Scholar
  47. Santi, D. V., Garret, C. E., and Barr, P. J., 1983, On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs, Cell 33: 9–10.PubMedCrossRefGoogle Scholar
  48. Shaw, G. M., Harper, M. E., Hahn, B. E., Epstein, L. G., Gajdusek, D. C., Price, R. W, Navia, B. A., Pitito, C. K., O’Hara, C. J., Groopman, J. E., Cho, E. S., Oleske, J. M., Wong-Staal, F., and Gallo, R. C., 1985, HTLV-Ill infection in brains of children and adults with AIDS encephalopathy, Science 277: 177.CrossRefGoogle Scholar
  49. Stevens, J. R., Albrecht, P, Godfrey, L., and Krauthammer, E., 1983, Viral antigen in the brain of schizophrenic patients? A preliminary report, Adv. Biol. Psychiatry 12: 76–96.Google Scholar
  50. Taylor, S. M., and Jones, P. A., 1982, Mechanism of action of eukariotic DNA methyltransferase. Use of 5-azacytosine-containing DNA, J. Mol. Biol. 162: 679–692.PubMedCrossRefGoogle Scholar
  51. Terry, R. D., and Davies, P, 1980, Dementia of the Alzheimer type, Annu. Rev. Neurosci. 3:77–95. Torrey, E. F., 1987, Prevalence studies in schizophrenia, Br. J. Psychiatry 150: 598–608.CrossRefGoogle Scholar
  52. Torrey, E. F., and Kaufmann, C. A., 1986, Schizophrenia and neuroviruses, in: Handbook of Schizophrenia, Volume I ( H. A. Nasrallah and D. R. Weinberger, eds.), Elsevier, Amsterdam, p. 361.Google Scholar
  53. Torrey, E. F., and Peterson, M. R.,1976, The viral hypothesis of schizophrenia, Schiz. Bull. 2:136–137. Torrey, E. F., Torrey, B. B., and Peterson, M. R., 1977, Seasonality of schizophrenic births in the United States, Arch. Gen. Psychiatry 34: 1065.Google Scholar
  54. Torrey, E. F., Yolken, R. H., and Winfrey, C. J., 1982, Cytomegalovirus antibody in cerebrospinal fluid of schizophrenic patients detected by enzyme immunoassay, Science 216: 892–894.PubMedCrossRefGoogle Scholar
  55. Tyrrell, D. A. J., Crow, T. J., Parry, R. R, Johnstone, E., and Ferrier, I. N., 1979, Possible virus in schizophrenia and some neurological disorders, Lancet 1: 839–841.PubMedCrossRefGoogle Scholar
  56. Varmus, R., and Swanstrom, R., 1984, Replication of retroviruses, in: RNA Timor Viruses ( R. Weiss, N. Teich, H. Varmus, and J. Coffin, eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., p. 369.Google Scholar
  57. Vartanian, M. E., Kolyaskina, G. I., Lozovsky, D. V., Burbaeva, G. S. A., and Ignatov, S. A., 1987, Aspects of humoral and cellular immunity in schizophrenia, Birth Defects 18: 339–364.Google Scholar
  58. Vernant, J. C., Maurs, L., Gessain, A., Barin, F., Gout, O., Delaporte, J. M., Sanhadji, J., and Buisson, G., 1987, Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: A clinical study and seroepidemiological study of 25 cases, Ann. Neurol. 21: 123–130.PubMedCrossRefGoogle Scholar
  59. Wunderlich, V., Vey, F., and Sydow, G., 1980, Antiviral effect of haloperidol on Rauscher murine leukemia virus, Arch. Geschwulstförsch. 50: 758–762.PubMedGoogle Scholar
  60. Wyatt, R. J., and DeLisi, L. E., 1984, Future research directions in the treatment of schizophrenia, in: Guidelines for the Use of Psychotropic Drugs ( H. D. Stancer, P. E. Garfunkle, and V. M. Rakoff, eds.), Medical and Scientific Books, New York, pp. 277–293.Google Scholar

Copyright information

© Plenum Publishing Corporation 1991

Authors and Affiliations

  • Anita Feenstra
    • 1
  • Darrell G. Kirch
    • 1
  • Mark A. Coggiano
    • 1
  • Richard Jed Wyatt
    • 1
  1. 1.Neuropsychiatry Branch, Intramural Research ProgramNational Institute of Mental HealthUSA

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