Some people mine for gold. Others dig for archeological remains. Yet Alan
Brown, M.D., an associate professor of clinical psychiatry and clinical
epidemiology at Columbia University, and his colleagues plumb prenatal blood
for factors that contribute to schizophrenia.
During the past several years, for example, Brown and his coworkers have
used frozen blood from pregnant women to find a link between schizophrenia and
toxoplasmosis infections during pregnancy and between schizophrenia and
influenza infections during pregnancy (Psychiatric News, May 6, 2005;
May 21, 2004). And now they have used such archived blood to make a connection
between schizophrenia and high levels of the amino acid homocysteine during
Their findings were published in the January Archives of General
The study was based on blood that had been collected from some 12,000 women
during pregnancy and on a follow-up evaluation of their offspring to see
whether any of them developed schizophrenia. Brown and his group then selected
63 offspring who had been diagnosed for schizophrenia or another
schizophrenia-spectrum disorder and matched them with 122 offspring who had
not developed such illnesses. Cases and controls were matched on age, gender,
maternal age, maternal race, and maternal smoking status.
The stored maternal blood samples from all 185 subjects were then analyzed
for levels of homocysteine, which has been identified as a plausible risk
factor for schizophrenia. For instance, a wealth of evidence has linked
glutamate dysfunction with schizophrenia. Abnormalities in the glutamate NMDA
receptor have been noted in schizophrenia, and homocysteine is known to
influence that receptor. Moreover, high homocysteine levels have been
associated with abnormal placental function and pregnancy complications.
Finally, Brown and his group compared the levels of homocysteine in the
maternal blood samples taken from the schizophrenia subjects with the levels
taken from the control subjects.
The levels of homocysteine in first-trimester maternal blood samples were
higher for the schizophrenia cohort than for the control one, but the
difference was not statistically significant. However, the levels of
homocysteine in third-trimester maternal blood samples were twice as high for
the schizophrenia cohort as for the control cohort—a significant
difference. Thus, "elevated third-trimester homocysteine levels may be a
risk factor for schizophrenia," Brown and his team concluded in their
report. "Elevated third-trimester homocysteine levels may elevate
schizophrenia risk through developmental effects on brain structure and
function and/or through subtle damage to the placental vasculature that
compromises oxygen delivery to the fetus."
The results also have some potential clinical implications, Brown and his
group added. "If future studies both replicate this association and
support a causal link, then the use of folic acid supplementation would merit
evaluation as a strategy for prevention of schizophrenia in
Supplementation with folic acid would merit evaluation, they explained,
because "this B vitamin donates a methyl group to homocysteine,
permitting its transformation to methionine, and folate levels are inversely
related to homocysteine levels. [Also] human pregnancy is a period of
increased susceptibility to folate deficiency because of an increased maternal
requirement, particularly in later gestation."
Psychiatric News asked Brown which of the prenatal factors that
have been linked with schizophrenia most likely contributes to the illness."
That's a tough one [to answer]," he replied, "and it
depends on what criteria you use."
For example, the only prenatal biomarker that has been independently
replicated is an elevated level of IgG antibodies against the parasite that
causes toxoplasmosis. Various studies have linked prenatal hypoxia or paternal
age with schizophrenia, but there are no known biomarkers for these risks.
Rubella infection during pregnancy has been associated with a 10- to 15-fold
greater risk than normal of having a child with schizophrenia, but rubella
exposure during pregnancy is not common, so it probably can't be blamed for
the bulk of schizophrenia cases. In contrast, influenza infection during
pregnancy is more common and has been tied to a 3- to 7-fold increased risk of
having a child with schizophrenia.
"So I think it's premature to say that there is one leading prenatal
factor," Brown said. "From a public health stand-point, it would
be most important to try to replicate, using prenatal biomarkers, those
exposures that are most common in the population, such as influenza,
toxoplasmosis IgG, and folate/B12 deficiency [as evidenced by high
Although it's too early to make public health recommendations about
preventing schizophrenia, Brown continued, there are steps pregnant women can
take to try to safeguard their unborn children from schizophrenia."
Eating a well-balanced diet and vitamin supplementation recommended by
current obstetric guidelines is always a good idea. This will almost always
normalize homocysteine, and folic acid supplementation is known to prevent
against neural tube defects.
"Vaccination against influenza for women who are of reproductive age
and sexually active makes sense. It isn't clear yet whether influenza
vaccination during pregnancy could be helpful or harmful," Brown added."
One needs to weigh the benefit of protecting the woman and fetus from
influenza against the potential risk of a vaccine-induced antibody elevation
that could conceivably predispose to schizophrenia."
Brown added that "the usual recommendation for pregnant women
regarding the avoidance of changing cat-litter boxes and hand washing after
handling cats is also a good idea because it is known to protect the fetus
from a variety of severe and subtle congenital anomalies. If our finding on
toxoplasmosis is replicated further, these measures may also prevent against
schizophrenia in their offspring."
The study was funded by the national institutes of Health and NARSAD.
An abstract of "Elevated Prenatal Homocysteine Levels as a
Risk Factor for Schizophrenia" is posted at<http://archpsyc.ama-assn.org/cgi/content/abstract/64/1/31>.▪