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

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.

• 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: Karen Berman, 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.: Karen Berman, MD) or NIH protocol 89-M-0160 "Inpatient Evaluation of Neuropsychiatric Patients" (PI: Daniel Eisenberg, M.D.). Most included patients, with schizophrenia, schizoaffective disorder or other non-excluded psychotic disorders, will be managed on the NIMH inpatient ward for the duration of their participation.
• 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. In addition, to study age effect on DA receptors, healthy controls will be included up to the age of 90 years.
• Control subjects must be healthy based on history, laboratory and physical exam obtained through the above mentioned protocols.

Exclusion criteria

-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.

• NIMH employees and staff and their immediate family members will be excluded from the study per NIMH policy.
• Pregnant or breast feeding
• Current psychiatric illness except for patients with 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
• 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 moderate to severe substance use disorder (or DSM-IV-defined substance dependence).
• Cumulative lifetime history of any (excepting nicotine -related) DSM5-defined mild substance use disorder (or any DSM-IV-defined substance abuse), either in excess of 5 years total or not in remission for at least 6 months.
• Severe systemic disease, such as 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