Infectious Agents in Schizophrenia and Bipolar Disorder
By Robert H. Yolken, MD and E. Fuller Torrey, MD |
June 1, 2006
CMV is another member of the herpes family of viruses. Infection is widespread and is known to occasionally cause encephalitis, primarily in patients with immunosuppression.
In contrast to older studies, recent studies report significantly more CMV antibodies in persons with schizophrenia than in controls. In a study by Leweke and colleagues,19 for example, 36 treatment-naive schizophrenic patients had significantly more antibodies in their sera (P < .001) and CSF (P < .003) than did 73 controls. This confirms earlier CSF findings published by our group.20 Another recent study reports that serum antibodies to CMV are particularly high in schizophrenic persons who have predominantly negative symptoms (the so-called deficit syndrome).21
Finally, a recent treatment trial showed significant symptomatic improvement in schizophrenic patients who were treated with valacyclovir, an antiviral agent effective against herpes viruses.22 Endogenous retroviruses
Endogenous retroviruses are DNA elements that have become part of the human genome through infection and integration into germ line cells of humans and nonhuman primate progenitors. Retroviruses lie dormant most of the time. When activated, however, they can influence the transcription of genes above or below the site of their chromosomal integration. Genetic polymorphisms of endogenous retroviruses have been linked with an alteration in immune response and increased susceptibility to autoimmune disorders.23
Endogenous retroviruses share properties of both genes and infectious agents, and are thus potential links between the two.24 Of particular interest is the fact that endogenous retroviruses may be activated by infections with herpesviruses or protozoan organisms such as Toxoplasma, providing a potential link between infectious agents and genetic elements as causative factors in human psychiatric diseases. Increased retroviral transcription in the CSF and blood of persons with recentonset psychosis supports a possible role for human endogenous retrovirus in the development of schizophrenia.25,26 Implications for clinicians
Proving a causative role for infectious agents in schizophrenia and bipolar disorder would open the door to new treatments and disease prevention strategies. With the support of The Stanley Medical Research Institute, we are conducting several double-blind treatment trials that involve the use of adjunctive antibiotics and antiviral medications in persons with schizophrenia and bipolar illness. To date, these medications show some promise in patients with recent-onset disease. The results are less remarkable in persons with long-standing illness. In the future, it might even be possible to develop a vaccine to protect children against possible infections that contribute to these 2 mental illnesses.
Even with what is known today, in clinical settings, some patients who present initially with symptoms suggestive of schizophrenia or bipolar disorder could instead be in the initial stages of viral encephalitis. Some physicians would argue that patients with first-admission psychosis should have a lumbar puncture and CSF analysis, adding other studies as appropriate if indicated by an increase in CSF protein or lymphocytes. A small sample of the CSF could be frozen and stored for future analysis. With further advances in research at the interface between psychiatry and infectious disease, these samples may eventually provide the key to proving the connection between infection and mental disturbance, and pave the way for pharmacologic treatment specifically targeted to that causative infectious organism.
Dr Yolken is director of the Stanley Division of Developmental Neurovirology and professor, department of pediatrics, The Johns Hopkins University School of Medicine, Baltimore. Dr Torrey is associate director for laboratory research, The Stanley Medical Research Institute, and professor of psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md.
1. Goodall E. The exciting cause of certain states of disease, at present classified under ‘schizophrenia’ by psychiatrists, may be infection. J Ment Sci. 1932;78:746-755.
2. Yolken RH, Torrey EF. Hypothesis of a viral etiology in bipolar disorder. In: Soares JC, Gershon S, eds. Bipolar Disorders: Basic Mechanisms and Therapeutic Implications.New York: Marcel Dekker; 2000:305-315.
3. Pearce BD. Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol Psychiatry. 2001;6:634-646.
4. Caroff S, Mann SC, Gliatto MF, et al. Psychiatric manifestations of acute viral encephalitis. Psychiatr Ann. 2001;31:193-204.
5. Hess A, Buchmann J, Zettl UK, et al. Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder. Biol Psychiatry. 1999;45:795.
6. Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res.;28:1-38.
7. Jones-Brando L, Torrey EF, Yolken R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res. 2003;62:237-244.
8. Webster JP. Rats, cats, people and parasites: the impact of latent toxoplasmosis on behaviour. Microbes Infect. 2001;3:1037-1045.
9. Remington JS, McLeod R, Thulliez P, et al. Toxoplasmosis. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia: WB Saunders; 2001:224, 227.
10. Torrey EF, Yolken RH. Toxoplasma gondii and schizophrenia. Emerg Infect Dis. 2003;9:1375-1380.
11. Brown AS, Cohen P, Greenwald S, Susser E. Nonaffective psychosis after prenatal exposure to rubella. Am J Psychiatry. 2000;157:438-443.
12. Mortensen PB, Yolken RH, Lindum B, et al. Toxoplasmosis and other early infections in relation to schizophrenia risk [abstract]. Schizophr Bull. 2005;31:232. Abstract.
13. Torrey EF, Yolken RH. Could schizophrenia be a viral zoonosis transmitted from house cats? Schizophr Bull. 1995;21:167-171.
14. Torrey EF, Rawlings R, Yolken RH. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000;46:17-23.
15. Buka SL, Tsuang MT, Torrey EF, et al. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001;58:1032-1037.
16. Dickerson FB, Boronow JJ, Stallings CR, et al. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry. 2003;60:466-472.
17. Dickerson FB, Boronow JJ, Stallings C, et al. Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol Psychiatry. 2004;55:588-593.
18. Dickerson FB, Boronow JJ, Stallings C, et al. The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder. Bipolar Disorders. 2006;8:124-132.
19. Leweke FM, Gerth CW, Koethe D, et al. Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatr Clin Neurosci. 2004;254:4-8.
20. Albrecht P, Torrey EF, Boone E, et al. Raised cytomegalovirus- antibody level in cerebrospinal fluid of schizophrenic patients. Lancet. 1980;2:769-772.
21. Dickerson F, Kirkpatrick B, Boronow J, et al. Deficit schizophrenia: association with serum antibodies to cytomegalovirus. Schizophr Bull. 2006;32:396-400.
22. Dickerson FB, Boronow JJ, Stallings CR, et al. Reduction of symptoms by valacyclovir in cytomegalovirus- seropositive individuals with schizophrenia. Am J Psychiatry. 2003;160:2234-2236.
23. Marguerat S, Wang WY, Todd JA, Conrad B. Association of human endogenous retrovirus K-18 polymorphisms with type 1 diabetes. Diabetes. 2004; 53:852-854.
24. Yolken RH, Karlsson H, Yee F, et al. Endogenous retroviruses and schizophrenia. Brain Res Rev. 2000; 31:193-199.
25. Karlsson H, Bachmann S, Schroder J, et al. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci U S A. 2001;98:4634-4639.
26. Karlsson H, Schroder J, Bachmann S, et al. HERVW-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry. 2004;9:12-13.