Infectious Agents in Schizophrenia and Bipolar Disorder
Infectious Agents in Schizophrenia and Bipolar Disorder
The idea that schizophrenia and bipolar disorder might be caused by infection is not new. This was a prominent hypothesis in the early years of the last century. For example, an article entitled, Is insanity due to a microbe? was published in Scientific American as early as 1896. Research to test this hypothesis by identifying causative viruses was already being conducted by the 1930s, when data were reported from experiments in which cerebrospinal fluid (CSF) from patients with schizophrenia was injected into rabbit brains.1
New research in the field continues, aided increasingly by impressive technologic advances in microbiology and virology. As recently as the past decade, reports documented the presence of influenza virus, rubella virus, bovine disease virus, and other infectious agents in patients with schizophrenia and bipolar disorder, as well as the presence of other infectious agents in childhood pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) and obsessive-compulsive disorder.
In this article, we briefly highlight the background of such research; discuss our own research on Toxoplasma gondii, herpes simplex virus (HSV), Cytomegalovirus (CMV), and endogenous retroviruses; and consider the future implications of such research for psychiatric clinicians.
Background and rationale
Why should we look for infectious agents in schizophrenia and bipolar disorder? Such a hypothesis is consistent with the known genetic contributions to these disorders. Indeed, a genetic predisposition is well established for most chronic infectious diseases, including tuberculosis, malaria, polio, AIDS, and peptic ulcers caused by Helicobacter pylori.2 The hypothesis is consistent with the role of neurotransmitter abnormalities in schizophrenia and bipolar disorder, because specific infectious agents have been shown to alter dopamine, serotonin, glutamate, γ-aminobutyric acid, and acetylcholine in animal models. The hypothesis is also consistent with neurodevelopmental models of schizophrenia and bipolar disorder. Pearce3 and others developed animal models that show how exposure to specific infectious agents during neurodevelopment correlates with later behavioral alterations in animals.
An additional important reason to look for infectious agents in schizophrenia and bipolar disorder is that CNS infection by specific pathogens frequently mimics the clinical symptoms of primary psychiatric diseases. For example, Caroff and colleagues4 reviewed 108 cases of psychiatric disorders resulting from suspected or confirmed CNS viral infections; in 62 cases, a specific virus was implicated, including HIV, HSV-1, HSV-2, Epstein-Barr, and CMV; and measles, mumps, coxsackie, and influenza viruses. Among bacteria, the fact that the spirochete of syphilis can cause the symptoms of schizophrenia was well known to psychiatric clinicians of an earlier era. More recently, infection with the spirochetal organism Borrelia burgdorferi has also been associated with schizophrenia-like symptoms in some persons.5
Another reason to look for infectious agents in schizophrenia and bipolar disorder is the well-established association between the risk of these disorders and winter-spring seasonal birth.6 There have been more than 200 studies of this phenomenon, and it remains one of the most highly replicated findings of these diseases. Because many infectious diseases occur seasonally, with a peak in the winter or spring, it is reasonable to postulate that fetal or newborn infection could contribute to subsequent mental illness.7
At the present time, we are focusing our research on 4 infectious agents as possible causes of schizophrenia and bipolar disorder. These are T gondii, HSV-1 and HSV-2, CMV, and endogenous retroviruses.
T gondii is a protozoan parasite whose definitive host is the cat family. Humans become infected by ingesting oocysts shed in the feces of infected cats or by eating undercooked meat from an animal that came into contact with infected cat feces. T gondii is one of the most widespread human parasites; 10% to 20% of Americans test seropositive by adulthood. Exposure to T gondii during early pregnancy can cause severe fetal CNS abnormalities. Exposure during late pregnancy was never considered a problem until recently, when animal data showed that late exposure to the organism causes behavioral changes, neurologic symptoms, and stillbirths.8,9
Since 1956, more than 20 studies have compared antibodies to T gondii in adults with and without schizophrenia.10 An overall analysis of the studies indicates that serologic evidence of Toxoplasma infection is almost 3 times more common in persons with schizophrenia than in controls living in the same geographic region.Two additional studies reported an increased level of T gondii antibodies in the late-pregnancy serum of women giving birth to infants in whom schizophrenia later developed. 11,12 Other studies have reported greater childhood exposure to cats among persons with schizophrenia than among controls.13,14 Our research is focusing on the timing of Toxoplasma infections in relation to development, as well as on possible differences in T gondii strains and human genetic susceptibility.
Herpes simplex viruses
Like Toxoplasma, HSV-1 and HSV-2 are common causes of infection in humans. HSV-1 may be spread by either sexual or nonsexual contact with infected persons, while HSV-2 is primarily spread through sexual contact. Both of these viruses are known to cause encephalitis and to be highly neurotropic. Traditionally, however, these viruses have been regarded as relatively benign in the majority of asymptomatic patients who carry them. Recent data suggest that this may not be true. One study evaluated the mothers of patients in whom schizophrenia or bipolar disorder developed. These women had increased levels of HSV-2 serum antibodies just before parturition.15
Comparison studies of persons with and without schizophrenia or bipolar disorder show that HSV-1 infection significantly increases cognitive dysfunction—especially recent memory deficits—in persons with schizophrenia or bipolar disorder.16,17 This did not occur in persons infected with other viruses in the herpes family and also did not occur in persons without schizophrenia or bipolar disorder who were infected with HSV-1.
In a follow-up study, Dickerson and associates18 showed that a polymorphism on the COMT gene (COMT Val 158 Met polymorphism) also increases cognitive dysfunction; this suggests a synergistic effect between HSV infection and the gene. This kind of interaction may be a model for future research that integrates multiple factors in the development of schizophrenia and bipolar disorder.