Schizophrenia
Bradley E. Alger
Thomas Blanpied, Ph.D.
Greg Elmer, Ph.D.
Douglas O. Frost, Ph.D.
Todd Gould, M.D.
James I. Koenig, Ph.D.
Patricio O'Donnell, M.D., Ph.D.
Elizabeth Powell, Ph.D.
Robert Schwarcz, Ph.D.
Paul D. Shepard, Ph.D.
Ashiwel S. Undie, Ph.D.
Michael W. Vogel, Ph.D.
Mission: Researchers in the
Schizophrenia Focus Group study the manifestations, causes and
innovative treatments for schizophrenia, a serious, chronic and
debilitating neuropsychiatric disorder that affects approximately
one percent of the worlds population. Available medications
treat only the positive symptom complex of this diverse, multigenic
disorder frequently leaving the cognitive, affective and social
impairments of the disease unaffected.
Research
Schizophrenia is a clinical syndrome
that comprises several separate disease entities. It involves multiple
genes interacting with environmental insults to form a brain vulnerable
to the illness. The illness usually has subtle manifestations during
development and more remarkable symptom manifestations during early
adulthood. Schizophrenic patients experience reality distortion,
disorganization of thought, and negative symptoms. Additionally,
patients exhibit impairments in cognition with extraordinary difficulties
processing new information, especially visual-spatial information.
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Regions where schizophrenic volunteers
show regional cortical blood flow values that are lower
than normal volunteers during the performance of an auditory
discrimination task; the pseudocolor regions are placed
on top of a gray level structural MR scan.
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Investigations by researchers within
the Schizophrenia Focus Group address many aspects of the disease.
Due to the unknown origins of the disease, preclinical investigators
are exploring potential developmental mechanisms that could contribute
to the pathophysiology of the disease. The advent of new molecular
approaches to modify gene expression in developing brain tissue,
as well as the adult brain, may provide important new targets for
developing pharmacological agents for schizophrenia. New molecular
targets may also be identified by analyses of post-mortem schizophrenic
brain tissue at both the proteomic and genomic levels.
For many years, dopaminergic mechanisms
were thought to play a pivotal role in schizophrenia, however, compelling
evidence to support the integral participation of dopamine has been
slow in coming. As such, other targets like glutamate have become
central foci for investigations. Studies in both preclinical and
clinical arenas are exploring glutamate receptor alterations in schizophrenia
and responsiveness of patients to glutamatergic agents. Nicotine
now figures prominently in focus group research activities since
virtually all schizophrenic patients use tobacco products. Unfortunately,
the beneficial effects of nicotine are only tangentially known. Studies
are underway by members of the focus group to elucidate the effects
of nicotine in information processing paradigms of both normal subjects
and patients with schizophrenia as well as experimental animals.
Antipsychotic medications are effective
in the treatment of the psychotic symptoms of schizophrenia,
like delusions and hallucinations, but they are highly
ineffective in treating the cognitive impairments many schizophrenic
patients have, as well as the negative symptoms of the disease. Clinical
investigators in the Schizophrenia Focus Group are actively involved
in trials of new medications for treating the cognitive and social
impairments of the disease. Our ability to look inside the behaving
human brain using imaging techniques has revolutionized
the study of neuropsychiatric disorders. Through the
use of these sophisticated neuroimaging techniques, new
information about normal cognitive processes is being
generated by focus group investigators. Moreover, by
combining neuroimaging techniques with neuropsychological
testing, glimpses of differences between normal human
subjects and patients with schizophrenia are beginning
to emerge. An additional mechanism to profile brain functioning
is through the use of electrophysiological techniques.
Interestingly, virtually the same electrophysiological
evaluation that is performed in patients can be performed
in experimental animals. Schizophrenia Focus Group studies
show that brain function in schizophrenic patients differs
from normal control function. Clinical investigations
are underway to determine whether antipsychotic medications
or other antischizophrenic compounds are useful in normalizing
the electophysiological abnormality of schizophrenics.
Parallel studies in experimental animals demonstrate
the importance of several neurochemicals, like nicotine,
in normalizing responses in patients. The ability to
perform bench to bedside analyses is a hallmark of the
interdisciplinary approach being taken by Schizophrenia
Focus Group members to gain a better understanding of
the pathophysiology of schizophrenia
Investigators and Extramural Support
The Schizophrenia Focus Group is comprised
of over 30 faculty, fellows and students from numerous academic
departments with the highest concentration of clinical and preclinical
investigators at the Maryland Psychiatric Research Center (MPRC).
Research support is derived from the National Institutes of Health,
numerous research foundations, such as the Stanley Foundation and
National Association for Research in Schizophrenia and Affective
Diseases, and several pharmaceutical and biotechnology companies.
MPRC has a 6-year contract with Novartis Pharma AG to define new
molecular targets for schizophrenia treatment. Research under this
contract will identify new targets using modern proteomic and genetic
analyses, prepare novel animal models that may be useful in evaluating
new compounds and perform human psychopharmacological studies to
evaluate clinical efficacy of new compounds.
Challenges for the Future
There appear to be three primary
challenges for the future in schizophrenia research that are being
actively pursued by focus group members. The first challenge is
to identify the molecular and/or genetic defect that plays a central
role in the ontogeny of the disease. A second major challenge will
be the integration of the new molecular/genetic information into
developing new treatments for schizophrenia that will replace the
antiquated antipsychotic medications currently being used to alleviate
schizophrenic symptoms. The final challenge for investigators will
be to translate the molecular/genetic defect identified as the
main pathophysiological cause of the disease into a functional
context to gain a better understanding of how the symptoms of the
disease of schizophrenia develop. This final set of investigations
will have great need for new animal models of the disease and the
ability to move this information from the bench to the clinical
arena expediently.
For additional information
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