Positron emission tomography studies of the D1-dopamine receptor in schizophrenia

Abstract

This thesis is based on investigations of central D1-dopamine receptor (D1R) binding in vivo using positron emission tomography (PET). The aims were i) to examine the antipsychotic effect of a D1R antagonist in schizophrenia and ii) to test the dopamine hypothesis of schizophrenia by comparing D1R binding between patients and healthy subjects. SCH39166, is the first selective D1R antagonist that was developed both as a PET radioligand for D1R and as an antipsychotic drug. The D1-receptor occupancy of SCH39166 was determined with PET and [11C]SCH39166 in a dose-response fashion after single oral doses in healthy volunteers. The D1R occupancy in the putamen was about 70 % after 100 mg. The conclusion was that this dose would be adequate to investigate potential antipsychotic effect of a D1R antagonist in schizophrenia.

SCH39166 was then given orally in escalating doses to 17 acutely ill drug free schizophrenic patients (DSM-IIIR) in an open 4-week study. The drug had to be withdrawn prematurely in ten patients due to deterioration or refusal to take SCH39166. In the nine patients participating for more than 2 weeks, the drug did not have an apparent antipsychotic effect. After withdrawal of SCH39166, the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1R antagonism have antipsychotic effect in schizophrenia.

To better inform statistical evaluation of any cross sectional evaluation of D1R binding a testretest PET study of the D1R selective radioligand [11C]SCH23390 was performed in fifteen healthy subjects to compare different methodologies of image analysis. The binding potential (BPND ) values were compared following manual and automated delineation of regions of interest (ROI’s) as well as with and without frame-by-frame realignment. No significant differences were observed for repeatability using automated and manual delineation methods whereas frame-by-frame realignment generated higher BPND values and improved repeatability. The results suggest that the choice of ROI delineation method is not an important condition for reliability, whereas thorough movement correction is of importance.

A cohort of 18 first-episode neuroleptic-naïve patients with schizophrenia or schizophreniform psychosis and 17 healthy control subjects were examined with PET and [11C]SCH23390. The patients had a statistically significant lower D1R BPND in frontal cortex with a moderate effect size. This suggests a reduction of prefrontal D1R density in the pathophysiology of schizophrenia. Study II and IV provides indirect support for the hypothesis of frontal hypodopaminergia. The observation of a low D1R-binding in schizophrenia may explain why a D1R-antagonist (which further reduces the availability of D1R) has no obvious antipsychotic effect. The findings provide support for current developments of D1R-agonists for the treatment of schizophrenia.