Functional Relevance of Dopamine Receptors in Healthy Controls and Patients With Schizophrenia: Characterization Through [11C]NNC-112 and [18F]Fallypride Positron Emission Tomography
| Status: | Recruiting |
|---|---|
| Conditions: | Schizophrenia, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 2/13/2019 |
| Start Date: | July 17, 2009 |
| Contact: | Jasmin Czarapata, Ph.D. |
| Email: | js733c@nih.gov |
| Phone: | (301) 435-7645 |
Background:
- Some illnesses, such as schizophrenia, have effects on brain cells called dopamine
receptors, which are required for normal brain function. People with schizophrenia have
difficulty thinking and experience hallucinations and delusions. Medications that change
brain dopamine receptors can decrease these hallucinations and delusions.
- The cause of schizophrenia and its association with brain dopamine receptors is not
known but may be clarified by studying dopamine receptors in people who have dopamine
disorders (such as schizophrenia) and those who do not. Researchers are interested in
studying the dopamine system to gain a better idea of how dopamine disorders develop,
which may lead to better medical care for people with schizophrenia.
Objectives:
- To study the amount and distribution of two types of dopamine receptors.
Eligibility:
- Individuals between the ages of 18 and 60 who have schizophrenia.
- Healthy volunteers between the ages of 18 and 90.
Design:
- Participants will undergo a full screening, with physical and psychological history, a
neurological examination, and blood and urine samples.
- Participants will have a blood flow map of the brain recorded with a positron emission
tomography (PET) brain scan. A magnetic resonance imaging (MRI) scan will also be
performed to determine brain anatomy.
- To study the amount and distribution of dopamine receptors in the brain, participants
will receive a small amount of a radioactive chemical in the vein, followed by a PET
scan.
- The procedure will be performed twice in two separate sessions, once for [18F]fallypride
and once for [11C]NNC-112.
- Some illnesses, such as schizophrenia, have effects on brain cells called dopamine
receptors, which are required for normal brain function. People with schizophrenia have
difficulty thinking and experience hallucinations and delusions. Medications that change
brain dopamine receptors can decrease these hallucinations and delusions.
- The cause of schizophrenia and its association with brain dopamine receptors is not
known but may be clarified by studying dopamine receptors in people who have dopamine
disorders (such as schizophrenia) and those who do not. Researchers are interested in
studying the dopamine system to gain a better idea of how dopamine disorders develop,
which may lead to better medical care for people with schizophrenia.
Objectives:
- To study the amount and distribution of two types of dopamine receptors.
Eligibility:
- Individuals between the ages of 18 and 60 who have schizophrenia.
- Healthy volunteers between the ages of 18 and 90.
Design:
- Participants will undergo a full screening, with physical and psychological history, a
neurological examination, and blood and urine samples.
- Participants will have a blood flow map of the brain recorded with a positron emission
tomography (PET) brain scan. A magnetic resonance imaging (MRI) scan will also be
performed to determine brain anatomy.
- To study the amount and distribution of dopamine receptors in the brain, participants
will receive a small amount of a radioactive chemical in the vein, followed by a PET
scan.
- The procedure will be performed twice in two separate sessions, once for [18F]fallypride
and once for [11C]NNC-112.
OBJECTIVES
Dopaminergic (DA) modulation of brain function is disturbed in several disabling psychiatric
disorders and represents the target of key psychopharmacologic agents, such as neuroleptics.
Schizophrenia has been considered a prototype of dysregulated DA signaling, with associated
prefrontal cortex (PFC) dysfunction. Prevailing views attribute key symptoms of schizophrenia
to deficient DA signaling within mesocortical DA tracts. Little is known, however, about the
pre-, intra-, and post-synaptic processes that contribute to dopaminergic dysregulation.
Regional cortical DA activity, critical to these processes, has been difficult to measure in
patients with the available imaging techniques. The current clinical study aims to address
this open issue by taking advantage of two recently developed positron emission tomography
(PET) radioligands, [(11)C]NNC-112 and [(18)F]Fallypride, that bind differentially and with a
higher binding potential (BP) than previous compounds to the D(1) (NNC-112) or D(2/3)
(fallypride) receptors. By measuring the regional BP of these two compounds, cortical and
subcortical DA receptor anomalies will be characterized in schizophrenia. Within the Clinical
Brain Disorders Branch (CBDB), this PET protocol is expected to add crucial information about
DA receptor status to ongoing regional cerebral blood flow (rCBF), magnetic resonance imaging
(MRI), magneto-encephalography (MEG) and genetic studies. It will lead to an improved
understanding of the modulatory influence of DA on frontal lobe functioning and facilitate
the study of how genetic polymorphisms interact with regional changes in D(1) and D(2/3)
receptors to increase the risk for schizophrenia.
Some specific hypotheses to be tested are as follows:
D1 BP in frontal cortex will be affected by age, elevated in schizophrenia and inversely
correlated with cognitive performance in patients and healthy controls.
Cortical D2/3 receptor BP will be affected by age and inversely correlated with performance
on tests of frontal lobe function in patients and healthy controls.
Striatal D2/3 receptor BP will be altered in patients.
Polymorphisms in the catechol-O-methyl transferase (COMT), D1 and D2 genes as well as other
schizophrenia risk genes will affect DA receptor BP in frontal cortex.
The ratio of cortical D1 and D2/3 receptor BPs will be affected by age and related to risk
for schizophrenia, cognitive performance and polymorphisms in the COMT gene and other
schizophrenia risk genes
STUDY POPULATION
It will include 50 patients with schizophrenia, schizoaffective disorder or other psychotic
disorders aged 18-55, and 150 healthy controls, aged 18-90. Fifty of the controls will be
matched to the patients by age and sex.
DESIGN
Dopamine D(1) and D(2/3) receptor regional binding potentials (BP) will be quantified by PET
in medication-free patients and controls. High resolution T1-weighted magnetic resonance
imaging (MRI) scans will be obtained for co-registration purposes. Additionally, through
enrollment in other ongoing protocols (00-M-0085, 90-M-0014, 01-M-0232, 95-M-0150,
89-M-0160), rCBF, functional MRI, cognitive and genetic data will be obtained and compared
with D(1) and D(2/3) receptor BP data obtained from this protocol.
OUTCOME MEASURES
Brain dopamine D(1) and D(2/3) receptor regional binding potentials measured by
[[(11)C]NNC-112 and [(18)F]Fallypride PET.
Dopaminergic (DA) modulation of brain function is disturbed in several disabling psychiatric
disorders and represents the target of key psychopharmacologic agents, such as neuroleptics.
Schizophrenia has been considered a prototype of dysregulated DA signaling, with associated
prefrontal cortex (PFC) dysfunction. Prevailing views attribute key symptoms of schizophrenia
to deficient DA signaling within mesocortical DA tracts. Little is known, however, about the
pre-, intra-, and post-synaptic processes that contribute to dopaminergic dysregulation.
Regional cortical DA activity, critical to these processes, has been difficult to measure in
patients with the available imaging techniques. The current clinical study aims to address
this open issue by taking advantage of two recently developed positron emission tomography
(PET) radioligands, [(11)C]NNC-112 and [(18)F]Fallypride, that bind differentially and with a
higher binding potential (BP) than previous compounds to the D(1) (NNC-112) or D(2/3)
(fallypride) receptors. By measuring the regional BP of these two compounds, cortical and
subcortical DA receptor anomalies will be characterized in schizophrenia. Within the Clinical
Brain Disorders Branch (CBDB), this PET protocol is expected to add crucial information about
DA receptor status to ongoing regional cerebral blood flow (rCBF), magnetic resonance imaging
(MRI), magneto-encephalography (MEG) and genetic studies. It will lead to an improved
understanding of the modulatory influence of DA on frontal lobe functioning and facilitate
the study of how genetic polymorphisms interact with regional changes in D(1) and D(2/3)
receptors to increase the risk for schizophrenia.
Some specific hypotheses to be tested are as follows:
D1 BP in frontal cortex will be affected by age, elevated in schizophrenia and inversely
correlated with cognitive performance in patients and healthy controls.
Cortical D2/3 receptor BP will be affected by age and inversely correlated with performance
on tests of frontal lobe function in patients and healthy controls.
Striatal D2/3 receptor BP will be altered in patients.
Polymorphisms in the catechol-O-methyl transferase (COMT), D1 and D2 genes as well as other
schizophrenia risk genes will affect DA receptor BP in frontal cortex.
The ratio of cortical D1 and D2/3 receptor BPs will be affected by age and related to risk
for schizophrenia, cognitive performance and polymorphisms in the COMT gene and other
schizophrenia risk genes
STUDY POPULATION
It will include 50 patients with schizophrenia, schizoaffective disorder or other psychotic
disorders aged 18-55, and 150 healthy controls, aged 18-90. Fifty of the controls will be
matched to the patients by age and sex.
DESIGN
Dopamine D(1) and D(2/3) receptor regional binding potentials (BP) will be quantified by PET
in medication-free patients and controls. High resolution T1-weighted magnetic resonance
imaging (MRI) scans will be obtained for co-registration purposes. Additionally, through
enrollment in other ongoing protocols (00-M-0085, 90-M-0014, 01-M-0232, 95-M-0150,
89-M-0160), rCBF, functional MRI, cognitive and genetic data will be obtained and compared
with D(1) and D(2/3) receptor BP data obtained from this protocol.
OUTCOME MEASURES
Brain dopamine D(1) and D(2/3) receptor regional binding potentials measured by
[[(11)C]NNC-112 and [(18)F]Fallypride PET.
- INCLUSION CRITERIA:
- Subjects will be recruited among individuals volunteering for NIH protocol 95-M-0150 A
Neurobiological Investigation of Patients with Schizophrenia Spectrum Disorders and
Their Siblings (PI: Daniel Weinberger, M.D.), NIH protocol 00-M-0085 Structural and
Functional Imaging of Neuropsychiatric Patients and Normal Volunteers with 3.0 Tesla
MRI and Magnetoencephalography. (P.I.: Venkata Mattay, MD) or NIH protocol 89-M-0160
Inpatient Evaluation of Neuropsychiatric Patients (PI: Jose Apud, M.D. Ph.D).
- Only adult subjects who are able to provide informed consent will be studied.
- Patients will be between 18 and 60 years of age. Healthy controls will be matched by
age and sex to the patients.
- Control subjects must be healthy based on history, laboratory and physical exam
obtained through the above mentioned protocols and will be included up to the age of
90 years.
EXCLUSION CRITERIA: (for patients and controls except where indicated)
- Subjects will be excluded if they don t fit the study requirements regarding age,
ability to provide informed consent, absence of significant general medical,
neurological or psychiatric disorders (except the disorder object of study), or intake
of substances that interfere with central dopaminergic signaling.
- Pregnant or breast feeding.
- Current psychiatric illness except for patients with schizophrenia, schizoaffective
disorder or other psychotic disorder
- Current or prior use (within 4 weeks) of substances that interfere with central
dopaminergic signaling (e.g. antipsychotics, dopamine receptor agonists,
anticholinergics, MAO-B inhibitors)
- History of any (excepting nicotine- related) DSM5-defined substance dependence).
- Cumulative lifetime history of any (excepting nicotine -related) DSM5-defined mild
substance use disorder (or any DSM-IV-defined substance abuse
- Controls with current psychiatric illness other than schizophrenia, schizoaffective
disorder, or other psychotic disorder
- Secondary causes of schizophrenia-like syndromes, e.g. amphetamine abuse, brain
infarction, tumor, or trauma
- Neurological disorders except those of exclusively peripheral location
- Significant prior or current substance abuse, severe systemic disease, hypothyroidism
not compensated by medication
- Laboratory tests with clinically significant abnormalities
- History of a significantly abnormal EEG, cranial CT or MRI
- Conditions that increase risk for MRI (pacemaker devices, ferromagnetic metal
implants, etc.)
- Prior participation in other research protocols such that radiation exposure would
exceed the annual NIH RSC limits
- Any medical condition that, in the opinion of the investigators, would interfere with
the safe conduct of the study.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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