Functional Relevance of Dopamine Receptors in Healthy Controls and Patients With Schizophrenia: Characterization Through [11C]NNC-112 and [18F]Fallypride Positron Emission Tomography

Schizophrenia Clinical Trial

Official title: 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

Clinical Trial Summary

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.

Clinical Trial Description

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 and Translational Neuroscience Branch (CTNB), 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 100 patients with schizophrenia, schizoaffective disorder or other psychotic disorders aged 18-60, and 230 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. ;

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

• NCT number: NCT00942981
• Study type: Observational
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Jasmin S Bettina, Ph.D.
• Phone: (301) 640-1048
• Email: jasmins@mail.nih.gov
• Status: Recruiting
• Start date: November 13, 2009