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Cognition and Schizophrenia: Is It What You Think?
Spring 2005
Table of Contents
Symptoms
The positive symptoms of schizophrenia, i.e. delusions, hallucinations,
and disorganized thinking, are considered to be hallmarks of this psychiatric
disorder. Negative symptoms and cognitive deficits are often overlooked
(see box below for descriptions). These features of schizophrenia, especially
cognitive impairments, may be less apparent, but are more closely associated
with social, vocational, and functional outcomes than are positive symptoms.
In fact, researchers consider cognitive impairments a core feature of this
disorder. For example, problems with cognition are often observed before
or at the onset of psychotic symptoms. In addition, cognitive impairments
tend to be stable features of the illness, whereas positive symptoms tend
to wax and wane.
| Positive Psychotic Symptoms |
- Hallucinations
- Delusions
- Disorganized thinking
- Bizarre behavior
|
| Negative Psychotic Symptoms |
- Emotional flatness or lack of expression
- Inability to start and follow through with activities
- Lack of pleasure or interest in life
|
| Cognitive Deficits |
- Working memory
- Attention/vigilance
- Verbal learning and memory
- Visual learning and memory
- Reasoning and problem solving
- Speed of processing
- Social cognition
|
Cognitive deficits in schizophrenia are important as treatment targets
because they have a substantial impact on outcome. MIRECC researcher, Michael
Green, Ph.D., has demonstrated that there are consistent relationships between
cognitive impairments measured in the laboratory and functional outcome,
including social and vocational outcome and success in rehabilitation programs.
In contrast, positive symptoms are only weakly associated with functional
outcomes.
There is emerging evidence that the second generation of antipsychotic
medications (also known as "atypical antipsychotics") have cognitive benefits
when compared to the older (first generation) antipsychotic medications.
However, these medications cannot restore cognitive functioning to levels
seen in those without schizophrenia. While the first generation medications
were directed primarily at the dopamine neurotransmitter system, the second
generation medications also influence the serotonin systems. It is possible
that the next generation of drugs will target other chemicals in the brain
and have a larger beneficial effect on the cognitive deficits of schizophrenia,
and consequently, improve functioning.
In the past, the development of drugs to treat schizophrenia has focused
almost exclusively on reducing positive symptoms. Recently the National
Institute of Mental Health (NIMH) and several VISN 22 MIRECC researchers
lead by MIRECC Director, Stephen Marder, M.D., have initiated collaborations
with academics, pharmaceutical companies, and the FDA to facilitate the
development of pharmacological agents to improve the cognitive problems
often seen in schizophrenia. The "Measurement and Treatment Research to
Improve Cognition in Schizophrenia" (MATRICS) initiative brings together
experts from many fields to select assessment instruments and study methods
that will be used to investigate the effect of promising drugs on cognition
and functioning. This unique partnership is timely and essential. In order
for industry to develop new medications, they need to know what aspects
of schizophrenia to target and how best to measure them. To this end, MATRICS
researchers have identified a "gold standard" by which to assess cognition
and functioning. The goal of the MATRICS is to promote the development of
new drugs that may improve cognition and functioning in schizophrenia, to
develop standards by which to assess these outcomes that are acceptable
to academia, industry, and government, and to get these agents tested in
clinical trials as quickly as possible.
To facilitate drug development in this area, NIMH has also sponsored an
initiative called Treatment Units for Research on Neurocognition in Schizophrenia
(TURNS). This national consortium of seven academic centers, including UCLA
and the West LA VA, will provide the resources to test the safety and efficacy
of these new compounds.
UInformation about MATRICS is available at the following website: www.matrics.ucla.edu.
For information about TURNS, see www.turns.ucla.edu.
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From Neuroscience to Client Outcomes: Translation Required
The process by which a neuroscientist's discovery in a laboratory is translated
into improvements in the functioning of a person with a psychiatric disorder
is lengthy and involves collaboration among many types of researchers. The
VISN 22 MIRECC is unique in that it consists of a group of scientists that
span basic research in animals to laboratory research in humans to clinical
trials in persons with schizophrenia. Recent scientific advances and productive
collaborations, such as the ones in the MIRECC, have provided a unique opportunity
to develop and test new drugs for the treatment of schizophrenia.
Previous research, which targeted the dopamine neurotransmitter system,
led to the development of first generation or "typical" antipsychotic medication.
Disruption in this brain system is believed to produce symptoms such as
hallucinations, delusions and bizarre behavior, also termed "positive symptoms".
While first generation antipsychotic medications have provided effective
relief for positive symptoms, clinicians recognized other symptoms associated
with schizophrenia. These other important symptom groups include negative,
cognitive and mood symptoms. The term "negative symptoms" refers to lack
of emotional expression, social isolation, and low motivation or interest
in life. Cognitive symptoms include difficulty with memory, concentration
and other tasks important for learning, processing information and problem
solving. Both negative and cognitive symptoms are more closely associated
with poor social and vocational functioning and are more difficult to measure
compared to positive symptoms. Because these deficits are more subtle and
often unrecognized, less attention has historically been given to developing
new medications and treatments. As we increase our understanding of the
roles of other neurotransmitters, such as the glutamate and serotonin systems,
the opportunities for improving cognitive and negative symptoms emerge.
Often this understanding begins in the laboratory using animal models
of disease. MIRECC investigator Mark Geyer, Ph.D., Director of the Neuropsychopharmacology
Unit of the MIRECC has developed a model called sensorimotor gating, that
can be used in both animals and humans to help study compounds with potential
for improving negative symptoms and cognitive impairments. Sensorimotor
gating is the ability to ignore information that is irrelevant to the current
task. People are constantly bombarded with a multitude of external and internal
stimuli, and most individuals are able to select those stimuli that are
most relevant to current activities and goals, while screening out or the
closing of the “gate” to irrelevant stimuli. Persons with schizophrenia
have an inability to inhibit, or "gate" irrelevant stimuli, and therefore,
are unable to filter trivial from essential information or stimuli in everyday
sensory input. Consequently, they have trouble navigating in everyday life
activities because they are easily distracted, confused and likely to become
disorganized.
Together with his colleague, David Braff, M.D., Director of the MIRECC
Clinical Neuroscience Unit, Dr. Geyer has used sensorimotor gating and other
psychophysiological techniques in persons with and without schizophrenia
to study this disorder and its treatment. (Psychophysiological tests measure
automatic sensory or motor functions to infer how the brain processes information).
These researchers have been able to show measurable differences in the responses
to particular external stimuli between normal control groups and individuals
with schizophrenia, and have found that medications to treat schizophrenia
reduce the differences in psychophysiological responses between those with
and without schizophrenia.
Once a promising compound is identified using these and other animal screening
models, the next step is to test it in persons with schizophrenia. During
a clinical trial, the effects of the medication on positive, negative and
cognitive symptoms are evaluated. In addition, the effects on psychophysiological
measures, such as sensorimotor gating, can also be studied. Other MIRECC
researchers, including Michael Green, Ph.D. and Stephen Marder, M.D. use
a battery of specialized cognitive tests to investigate the effects of antipsychotic
medications on cognition. Most studies have found that the second generation
antipsychotic medications do improve cognitive functioning, however, the
level is rarely restored to that of a person without schizophrenia. Still,
small gains can have important results. For example, improved memory may
allow a patient to retain more from a class on independent living skills.
Thomas Patterson, Ph.D., develops methods to study this aspect of treatment
in a laboratory situation. The goal of his research is to measure how improvements
in cognition translate into gains in functioning. For example, Dr. Patterson
and colleagues have developed tests that measure how well a person can perform
everyday tasks, such as taking medication. If a new compound demonstrates
an improvement on these tests, then it is highly likely that it will show
meaningful improvement of functioning in the daily lives of persons with
schizophrenia. The process by which new drugs for treating symptoms of schizophrenia
are identified and developed into effective treatments is complex. It begins
in the basic science laboratory and is translated into persons with schizophrenia.
A final step is to determine the overall impact on life functioning, such
as the ability to be successful socially and occupationally. The VISN 22
MIRECC provides an opportunity for scientists to collaborate and coordinate
their research activities, thus, facilitating the process of developing
effective treatments.
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