Serotonin 5-HT1A Receptors in Schizophrenia - a PET Investigation

This proposal deals with a second year extension of the project "Serotonin 5-HT1A receptors in schizophrenia - a PET investigation" (J 1793 -MED) which has been started on October 11, 1999. In the first 8 months up to now, 19 healthy volunteers have been enrolled, as well as 4 drug-naive schizophrenic patients suffering from a first psychotic episode. We were able to demonstrate excellent test-retest reliability for quantification of 5-HT1A receptor binding potential (BP) using [ 11 C]WAY- 10063 5 and positron emission tomography. Both, a region-of- interest and a SPM99-based voxel-wise analysis showed a widespread age-dependent decline of cortical 5-HT1A receptor BP in healthy subjects. A preliminary analysis revealed elevated 5-HTIA receptor BP values in frontal cortex of 4 schizophrenic patients. Based on results of post-mortem studies and animal models we expected, that in comparison to age and sex matched controls, antipsychotic naive patients with schizophrenia will show an elevated 5-HT1A receptor BP. Post-mortem. studies consistently showed a 40% increase in 5-HT1A density in schizophrenia. In animal models 5-HT1A agonism added to dopamine-2 receptor antagonism exerted a synergistic antipsychotic effect and delayed the onset of side-effects. In addition to examining drug naive patients, the comparison to chronically ill patients will differentiate the effects of schizophrenia from those of chronicity and drug treatment. It is further planned to explore the relationship between symptom dimensions, cognitive abnormalities and regional 5-HT1A receptor abnormalities, with a focus on regional frontal and temporal cortex changes. Based on the assumption that one would expect at least a 25% increase in 5-HT1A receptor density, as suggested by post-mortem data, a sample of 15 antipsychotic-naive, 15 chronic patients, and 15-20 normal controls will be necessary to provide conclusive and robust evidence to investigate the proposed hypothesis. So far, we are in line with the initially proposed time-frame of 2 years in total. Given the experiences of the last eight months, it seems reasonable to assume that we will be able to examine 11 more drug-naive and 15 chronic patients, who will be recruited through the Schizophrenia and Continuing Care Program of the Centre for Addiction and Mental Health in Toronto. Data analysis will be carried out in parallel, so that that the proposed project can be finished by September 2001.