If the long and still-unfinished search for the origins of schizophrenia is
like building a house, then Alan S. Brown, M.D., and his colleagues from the
Prenatal Determinants of Schizophrenia Study are among the bricklayers. With
other researchers around the world, they are amassing evidence bit by bit to
pin down the causes of the disease.
Brown, an associate professor of clinical psychiatry and clinical
epidemiology at the New York State Psychiatric Institute and the Mailman
School of Public Health at the College of Physicians and Surgeons of Columbia
University, and his coauthors have published the latest in a series of reports
on the relation of the presence of toxoplasmosis antibodies during pregnancy
to the prevalence of schizophrenia in the offspring.
Brown has also studied the connection between elevated maternal cytokine
interleukin-8 and increased risk of schizophrenia in the offspring and also
how serologically documented maternal influenza and rubella relate to
schizophrenia. Other research has sought to connect schizophrenia with
exposure in the womb to diseases like herpes simplex, polio, or
varicella-zoster or to environmental agents like lead.
Toxoplasma gondii is a protozoan parasite that can be passed to
humans who eat infected, undercooked meat or through exposure to cat litter or
soil containing oocysts of the organism. Infected pregnant women can pass the
parasite to their fetus.
The current report in the April American Journal of Psychiatry is
based on data gathered four decades ago. The Prenatal Determinants of
Schizophrenia Study draws on the Child Health and Development Study cohort
initiated by Jacob Yerushalmy at the University of California at Berkeley in
1959, in collaboration with Kaiser Permanente Medical Care Plan in Northern
The Child Health and Development study included almost all pregnant women
in the Kaiser Foundation Health Plan from 1959 to 1967. Researchers back then
took serum samples from these women and froze them for later study. Of the
19,044 children born to these women, 12,094 were available for follow-up
between 1981 and 1997. Within that group, there were 183 who screened positive
for schizophrenia spectrum disorders, of whom 146 were available for
The Prenatal Determinants of Schizophrenia researchers tested the serum for
Toxoplasma gondii using immunoassays for immunoglobulin G antibody
(IgG), which can persist for years in the bloodstream and is associated with"
both severe and subtle neuropsychiatric abnormalities." Serum
immunoglobulin M antibody (IgM) indicates only recent infection, but was not
found in the mothers of the offspring with schizophrenia.
They divided IgG titers into three groups, negative (<1:16), moderate
(1:16 to 1:64), and high (1:128 to 1:1024). They found an association between
high maternal antibody titers and schizophrenia or schizophrenia spectrum
disorders among the children (odds ratio 2.61, p=0.051). Although the results
fell slightly short of significance, prenatal exposure to toxoplasmosis is a
plausible risk factor for schizophrenia, they said. No association was found
with lower antibody levels.
The research adds to evidence connecting prenatal toxoplasmosis infection
and congenital brain abnormalities, as seen on postmortem and neuroimaging
studies. Primary infection was unlikely to be a cause of schizophrenia in the
Kaiser cohort because samples were negative for IgM, said Brown. The high IgG
antibody levels could be an immune response to an old infection or a
re-emergence of the infection from dormant cysts in the body.
Hypotheses other than simple infection have been proposed to connect
toxoplasmosis and problems with fetal brain development. One suggests that a
known toxin produced by the parasite causes congenital abnormalities in
laboratory animals. Alternatively, given the persistence of IgG antibodies,
toxoplasma IgG antibody, rather than the organism or a toxin, may cross the
placenta and damage the developing fetal brain.
Brown said that research has moved from simply noting maternal exposure to
an epidemic to collecting and analyzing serum samples of cytokines and
"Our methodology is improving," said Brown in an interview."
Of course, it's essential to replicate these findings, but at least it
points to a role for prenatal infections as risk factors for adult
Research elsewhere may be adding more bricks to the wall. A Danish team
recently reported that elevated toxoplasma IgG antibody in newborns was
associated with an increased risk of adult schizophrenia in those
Brown and his colleagues are now doing brain-imaging studies in the
schizophrenic offspring of mothers with high toxoplasmosis antibodies,
comparing those with risk factors for developing schizophrenia with unaffected
matched controls. He also hopes to collect DNA samples from cohort members.
Other researchers are working on other large datasets, like the National
Collaborative Prenatal Project, covering women pregnant in 1959 to 1966.
Work is also continuing on animal models, said Brown. Animals do not
develop schizophrenia, but analogues may be available. Humans with
schizophrenia have deficits in their prepulse inhibition to a second startle
response, for instance. Mice whose mothers were exposed to influenza virus
while pregnant exhibit similar prepulse inhibition deficits, according to
California Institute of Technology biology professor Paul H. Patterson, Ph.D.:"
Maternal viral infection has a profound effect on the behavior of adult
offspring, probably via an effect of the maternal immune response on the
The current study adds some weight to a role for prenatal infection or
environmental exposure, but the full story will likely be complicated by
interaction with inherited influences, too.
"The effect sizes we're observing are comparable to, and in some
cases stronger than, at least some of the effects of individual genes,
although the largest single risk factor for schizophrenia remains a family
history of the illness," said Brown.
A call for more definitive research may be the right conclusion now, said
Brown, but it doesn't rule out action to minimize risk. Inexpensive measures
to prevent infections known to disrupt fetal development of the central
nervous system are already available and can be implemented now.
The Centers for Disease Control and Prevention recommends that pregnant
women take steps to avoid toxoplasmosis by cooking meat thoroughly, washing or
peeling fruits and vegetables, wearing gloves while gardening, and avoiding
changing cat litter, if possible.
This research is funded by grants from the National Institute of Mental
Health, the National Alliance for Research on Schizophrenia and Depression,
the Lieber Center for Schizophrenia Research, and the National Institute for
Child Health and Development.
"Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia
in Adult Offspring" is posted at<http://ajp.psychiatryonline.org/cgi/content/full/162/4/767>.
The CDC report, "Preventing Congenital Toxoplasmosis," is posted
Am J Psychiatry2005162767