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Chemical Maps Hint at Drugs' Effects on Schizophrenia

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Duke Health News 919-660-1306

DURHAM, N.C. -- Antipsychotic drugs do most of their work in
the brain, but they also leave behind in the bloodstream a
trail of hundreds of chemicals that may be used in the future
to direct better treatment for schizophrenia and other
psychiatric conditions, say Duke University Medical Center
researchers.

The study is among the first to use metabolomics -- the
measurement of thousands of chemical byproducts of the body's
cellular processes -- to look at a psychiatric disease and its
response to therapy, according to the researchers.

"Doctors draw blood every day to look at metabolites such
glucose and cholesterol and determine whether someone is at
risk of diabetes or heart disease," said lead study
investigator Rima Kaddurah-Daouk, Ph.D., an associate professor
of biological psychiatry. "With metabolomics, we can look at
thousands of metabolites to attain a more finely tuned map of
an individual's overall health and gain information about how
an individual is responding to a particular therapy."

Chemical signatures measured by metabolomics were different
for schizophrenia patients than for people without the disease,
Kaddurah-Daouk said. In patients treated with three different
antipsychotic medications, the signatures differed according to
which drug was used, giving researchers a tool to explore the
metabolic side effects of these and other drugs.

The team's findings appear in the online issue of the
journal
Molecular Psychiatry
. The work was funded by the Stanley Medical Research
Institute
and NARSAD,
both national mental health research associations.

Kaddurah-Daouk thinks this technology could lead to earlier
diagnosis of schizophrenia. It may also begin to explain what
makes some people more susceptible to schizophrenia, and why
some people respond better to treatment than others or develop
metabolic side effects, she added.

Schizophrenia is a devastating mental illness that is
characterized by hallucinations, delusions and changes in
outlook and personality. Currently there are no biological
markers that can be used to establish a diagnosis or reliably
predict response to treatment or how the disease will
progress.

Although the prevailing theory has been that schizophrenia
is caused by an imbalance in neurotransmitter molecules that
help send messages between nerve cells in the brain, scientists
recently have begun to investigate whether lipids, small fatty
molecules such as cholesterol and triglycerides, also may play
a role in the disease and in response to therapy.

The researchers, in collaboration with Lipomics Technologies, measured
300 different lipids in blood drawn from 50 patients with
schizophrenia before and after treatment with the atypical
antipsychotic drugs olanzapine, risperidone or aripiprazole.
Lipomics specializes in diagnostic discovery with an emphasis
on lipid metabolism. Atypical antipsychotics, a newer group of
prescription medications used to treat psychiatric conditions,
have fewer side effects than the older antipsychotics, but
several still induce weight gain and diabetes.

Schizophrenic patients were found to have lower levels of
the lipids used to make membranes involved in storing and
communicating information in the brain. These lipid changes
were partially reversed in patients treated with antipsychotic
medications, said Joseph McEvoy, M.D., associate professor of
biological psychiatry and study co-investigator.

"This technique allows us to identify the specific metabolic
changes that are caused by the most commonly used drugs for
schizophrenia," McEvoy said.

"This study is extremely important because it is giving us
more information about how these drugs work," added Ranga
Krishnan, M.D., chairman of psychiatry and senior study
investigator. "Now we can begin to develop better medicines
that target the specific metabolites important for the disease
but not those that could lead to detrimental side effects."

Although some lipids are known to have detrimental effects
on human health -- such as high levels of cholesterol that lead
to heart disease -- many lipids have positive effects on basic
human functions, including communication among all the cells of
the body. Scientists are still trying to sort out which of the
lipids that are modified in schizophrenia are beneficial and
which ones result in metabolic side effects.

"Clearly we need to put forth a major effort to link the
changes in the blood to what happens in the brain,"
Kaddurah-Daouk said. "If we can apply these findings to the
mysteries occurring in the brain, then perhaps we can finally
unlock the secrets of these devastating diseases."

Kaddurah-Daouk believes that this and other studies that
explore metabolism at the global level have the potential to
greatly impact medical practice. Future experiments focused on
correlating these lipid signatures with the clinical outcomes
of patients could yield an important tool for designing the
best treatment for each patient, Kaddurah-Daouk said.

Other researchers participating in the study were Joseph
McEvoy, Donna Lee and Murali Doraiswamy of Duke; Rebecca
Baillie of Lipomics
Technologies
, located in West Sacramento, Calif.; and
Jeffrey Yao of the VA Pittsburgh Healthcare System and the
University of Pittsburgh.

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