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A study of D2 receptor occupancy after multiple oral administration of SLV 310 to healthy male volunteers, using11C-raclopride by means of positron emission tomography (PET)
238 15. N e u r o i m a g i n g , N e u r o c h e m i c a l
INCIPIENT NEUROVULNERABILITYAND NEUROPROTECTION IN EARLY PSYCHOSIS: A PROTON SPECTROSCOPY STUDY OF THE ANTERIOR HIPPOCAMPUS AT 3TESLA
A STUDY OF D 2 RECEPTOR OCCUPANCY AFTER MULTIPLE ORAL ADMINISTRATION OF SLV 310 TO HEALTHY MALE VOLUNTEERS, USING 11C_RACLOPRIDE BY MEANS OF POSITRON EMISSION TOMOGRAPHY (PET)
G. E. Berger,* S. Wood, R. M. Wellard, C. Pantelis, T. Proffitt, M. McCronchie, R. Monfries, D. Velakoulis, W. Brewer, G. Jackson, E D. McGorry
J. Bakker,* C. B o o n , S. R van Marle, C. R de Ruig, J. Pruim, A. van Waarde, M. H. de Vries
Solvay Pharmaceuticals, Weesp, Netherlands SLV 310 is a novel compound combining potent dopamine D 2 receptor a n t a g o n i s m with serotonin reuptake inhibition. To guide the selection of the dose level for the first trial with SLV 310 in patients a multiple dose PET study was performed in healthy male volunteers. The primary objectives of this study were: 1) to describe the relationship between dose and occupancy of dopamine D 2 receptors after administration of multiple doses of SLV 310, 2) to describe the time-course of dopamine D 2 receptor occupancy at steady state. The extent and duration of striatal D 2 receptor occupancy by SLV 310 was investigated using positron emission tomography (PET) with 11C_raclopride" Plasma levels of SLV 310 were measured and the relation with the striatal D 2 receptor occupancy by SLV 310 was investigated. In the pilot part of this study (Group I) two subjects were dosed, once daily (capsules), as follows: 2 mg SLV 310 on days 1-4, 5 mg on days 5-8 and 7 mg on days 9-12. PET scans were performed at baseline and at 8 hours post-dose on days 4, 8 and 12. The results show that oral administration of SLV 310 results in a dose-dependant occupancy of the D 2 receptor population in the striatum. Mean values for the receptor occupancy on day 4, 8 and 12 were 32.5%, 52% and 64% in the caudate nucleus and 26.5%, 49% and 62% in the putamen. Based on these results five subjects in Group 2 were dosed as follows: 5 m g SLV 310 o.d. on days 1-2 and 7 mg o.d. on days 3-10/11. A m a x i m u m of four PET scans were made per subject: one at baseline and one to three at various time points (up to 105 h post-dose) following cessation of dosing on day 10/11. The results show that at steady state the mean striatal D 2 receptor occupancy by SLV 310 at ~ 8 hours post last dosing was 67.4% in the caudate nucleus and 66.6% in the putamen. Following cessation of dosing there was a slow decline of the D 2 receptor occupancy in the h u m a n striatum in parallel with the decline of the SLV 310 concentration in plasma. Investigation of the individual (per subject) relation between (pre-scan) plasma levels of SLV 310 and the D 2 receptor occupancy showed a plasma concentration dependant D 2 receptor occupancy. At plasma levels ranging from 11.1 ng/ml to 42.1 ng/ml the corresponding D 2 receptor occupancy varied between 55.6% to 70.8% in the caudate nucleus and between 51.9% to 70.4% in the putamen. Based on these results 7 mg o.d. was selected as the dose for the first trial with SLV 310 in patients.
Department of Psychiatry, University of Melbourne, ORYGEN Research Centre, Parkville, Melbourne, VIC, Australia Programmed cell death (PCD) and progenitor cell generation (of glial and in some brain areas also neuronal fate) in the CNS is an active process throughout life and is generally not associated with gliosis which means that PCD can be pathologically silent. The striking discovery that progenitor cell generation (of glial and in some brain areas neuronal fate) is widespread in the adult CNS (especially the hippocampus) suggest a much more dynamic scenario than previously thought and transcends the dichotomy between neurodevelopmental and neurodegenerative models of schizophrenia and related disorders. We suggest that the regulatory processes that control the regulation of PCD and the generation of progenitor cells may be disturbed in the early phase of psychotic disorders underpinning a disconnectivity syndrom at the onset of clinically overt disorders. An ongoing 1H-MRS study of the anterior hippocampus at 3 Tesla in mostly drug-naive first-episode psychosis patients suggests no change in NAA, but significant increases in myo-inositol and lactate. The data suggests that neuronal integrity in the anterior hippocampus is still intact at the early stage of illness or mainly only functionally impaired. However the increase in lactate and myo-inositol may reflect a potential disturbance of generation and PCD of progenitor cells (of glial and in selected brain areas also neuronal fate) at the onset of psychosis. If true the use of neuroprotective agents such as lithium or eicosapentaenoic acid (which inhibit PCD and support cell generation)in the early phase of psychotic disorders may be a potent treatment avenue to explore.
INCREASED AMPHETAMINE-INDUCED DOPAMINE RELEASE DURING EXPERIMENTAL SENSITIZATION TO PSYCHOSTIMULANTS: A PET/11CRACLOPRIDE STUDY IN HEALTHY VOLUNTEERS
I. Boileau,* A. Dagher, C. Benkelfat Neurology, Neurosurgery & Psychiatry, McGill University, Montreal, QC, Canada Patients with schizophrenia demonstrate greater amphetamine (AMPH) induced dopamine (DA) release than controls in the mesolimbic DA system, a feature reportedly associated with positive symptom exacerbation (Laruelle et al., 1996; Breier et al., 1997). One of the mechanisms invoked to account for this heightened DA response to stimulants is sensitization. Sensitization is a phenomenon by which cumulative exposure to DA-elevating drugs and/or stress, leads to persistent changes in DA transmission, hence, possibly, increased vulnerability to psychosis triggering and exacerbation in prone individuals.The present study used the PET and 11C-Raclopride method to test the hypothesis that sensitization, experimentally induced in healthy volunteers through subchronic oral AMPH, is associated with increased DA release upon re-exposure. 7 healthy male volunteers participated in a four-dose AMPH (0.3 ml~kg, p.o.)
International Congress on Schizophrenia Research 2003
INCIPIENT NEUROVULNERABILITYAND NEUROPROTECTION IN EARLY PSYCHOSIS: A PROTON SPECTROSCOPY STUDY OF THE ANTERIOR HIPPOCAMPUS AT 3TESLA
A STUDY OF D 2 RECEPTOR OCCUPANCY AFTER MULTIPLE ORAL ADMINISTRATION OF SLV 310 TO HEALTHY MALE VOLUNTEERS, USING 11C_RACLOPRIDE BY MEANS OF POSITRON EMISSION TOMOGRAPHY (PET)
G. E. Berger,* S. Wood, R. M. Wellard, C. Pantelis, T. Proffitt, M. McCronchie, R. Monfries, D. Velakoulis, W. Brewer, G. Jackson, E D. McGorry
J. Bakker,* C. B o o n , S. R van Marle, C. R de Ruig, J. Pruim, A. van Waarde, M. H. de Vries
Solvay Pharmaceuticals, Weesp, Netherlands SLV 310 is a novel compound combining potent dopamine D 2 receptor a n t a g o n i s m with serotonin reuptake inhibition. To guide the selection of the dose level for the first trial with SLV 310 in patients a multiple dose PET study was performed in healthy male volunteers. The primary objectives of this study were: 1) to describe the relationship between dose and occupancy of dopamine D 2 receptors after administration of multiple doses of SLV 310, 2) to describe the time-course of dopamine D 2 receptor occupancy at steady state. The extent and duration of striatal D 2 receptor occupancy by SLV 310 was investigated using positron emission tomography (PET) with 11C_raclopride" Plasma levels of SLV 310 were measured and the relation with the striatal D 2 receptor occupancy by SLV 310 was investigated. In the pilot part of this study (Group I) two subjects were dosed, once daily (capsules), as follows: 2 mg SLV 310 on days 1-4, 5 mg on days 5-8 and 7 mg on days 9-12. PET scans were performed at baseline and at 8 hours post-dose on days 4, 8 and 12. The results show that oral administration of SLV 310 results in a dose-dependant occupancy of the D 2 receptor population in the striatum. Mean values for the receptor occupancy on day 4, 8 and 12 were 32.5%, 52% and 64% in the caudate nucleus and 26.5%, 49% and 62% in the putamen. Based on these results five subjects in Group 2 were dosed as follows: 5 m g SLV 310 o.d. on days 1-2 and 7 mg o.d. on days 3-10/11. A m a x i m u m of four PET scans were made per subject: one at baseline and one to three at various time points (up to 105 h post-dose) following cessation of dosing on day 10/11. The results show that at steady state the mean striatal D 2 receptor occupancy by SLV 310 at ~ 8 hours post last dosing was 67.4% in the caudate nucleus and 66.6% in the putamen. Following cessation of dosing there was a slow decline of the D 2 receptor occupancy in the h u m a n striatum in parallel with the decline of the SLV 310 concentration in plasma. Investigation of the individual (per subject) relation between (pre-scan) plasma levels of SLV 310 and the D 2 receptor occupancy showed a plasma concentration dependant D 2 receptor occupancy. At plasma levels ranging from 11.1 ng/ml to 42.1 ng/ml the corresponding D 2 receptor occupancy varied between 55.6% to 70.8% in the caudate nucleus and between 51.9% to 70.4% in the putamen. Based on these results 7 mg o.d. was selected as the dose for the first trial with SLV 310 in patients.
Department of Psychiatry, University of Melbourne, ORYGEN Research Centre, Parkville, Melbourne, VIC, Australia Programmed cell death (PCD) and progenitor cell generation (of glial and in some brain areas also neuronal fate) in the CNS is an active process throughout life and is generally not associated with gliosis which means that PCD can be pathologically silent. The striking discovery that progenitor cell generation (of glial and in some brain areas neuronal fate) is widespread in the adult CNS (especially the hippocampus) suggest a much more dynamic scenario than previously thought and transcends the dichotomy between neurodevelopmental and neurodegenerative models of schizophrenia and related disorders. We suggest that the regulatory processes that control the regulation of PCD and the generation of progenitor cells may be disturbed in the early phase of psychotic disorders underpinning a disconnectivity syndrom at the onset of clinically overt disorders. An ongoing 1H-MRS study of the anterior hippocampus at 3 Tesla in mostly drug-naive first-episode psychosis patients suggests no change in NAA, but significant increases in myo-inositol and lactate. The data suggests that neuronal integrity in the anterior hippocampus is still intact at the early stage of illness or mainly only functionally impaired. However the increase in lactate and myo-inositol may reflect a potential disturbance of generation and PCD of progenitor cells (of glial and in selected brain areas also neuronal fate) at the onset of psychosis. If true the use of neuroprotective agents such as lithium or eicosapentaenoic acid (which inhibit PCD and support cell generation)in the early phase of psychotic disorders may be a potent treatment avenue to explore.
INCREASED AMPHETAMINE-INDUCED DOPAMINE RELEASE DURING EXPERIMENTAL SENSITIZATION TO PSYCHOSTIMULANTS: A PET/11CRACLOPRIDE STUDY IN HEALTHY VOLUNTEERS
I. Boileau,* A. Dagher, C. Benkelfat Neurology, Neurosurgery & Psychiatry, McGill University, Montreal, QC, Canada Patients with schizophrenia demonstrate greater amphetamine (AMPH) induced dopamine (DA) release than controls in the mesolimbic DA system, a feature reportedly associated with positive symptom exacerbation (Laruelle et al., 1996; Breier et al., 1997). One of the mechanisms invoked to account for this heightened DA response to stimulants is sensitization. Sensitization is a phenomenon by which cumulative exposure to DA-elevating drugs and/or stress, leads to persistent changes in DA transmission, hence, possibly, increased vulnerability to psychosis triggering and exacerbation in prone individuals.The present study used the PET and 11C-Raclopride method to test the hypothesis that sensitization, experimentally induced in healthy volunteers through subchronic oral AMPH, is associated with increased DA release upon re-exposure. 7 healthy male volunteers participated in a four-dose AMPH (0.3 ml~kg, p.o.)
International Congress on Schizophrenia Research 2003