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Abstract for study group with gerhard grunder

G Gründer1, I Vernaleken1, Ch Boy2, A Bröcheler1, Ch Fellows2, H Janouschek1, S Hellmann1, Ch Hiemke4, P Bartenstein3, F Rösch5, U Büll2 1Department of Psychiatry and Psychotherapy, RWTH Aachen University, 52074 Aachen, Germany; 2Department of Nuclear Medicine, RWTH Aachen University, 3Department of Nuclear Medicine, University of Mainz, 4Department of Psychiatry and Psychotherapy, University of Mainz, 5Institute of Nuclear Chemistry, University of Mainz Introduction: It is now widely accepted that the antip-
all brain regions (mean ± standard deviation, putamen 80 ± sychotic effects of dopamine receptor antagonists occur 11%, range 60-92%; caudate 83 ± 9%, range 66-93%; within a “therapeutic window” between 60 and 80% thalamus 80 ± 9%, range 68-90%; superior temporal cortex D2 receptor occupancy. The incidence of extrapyrami- 79 ± 9%, range 70-90%), with slightly higher values in ex- dal side effects increases above the 80% threshold trastriatal regions at very low plasma concentrations only. (Farde et al., Arch Gen Psychiatry 1992, 49: 538-544). D2/D3 receptor occupancy was still in the range between 71 Although clozapine and quetiapine seem to be excep- and 83% in a patient who had received his last dose 78 h tions, this rule does also apply for most of the “atypi- prior to the PET scan. Aripiprazole plasma concentrations cal” antipsychotics. However, our [11C]raclopride PET ranged from 27 ng/ml to 484 ng/ml. Nonlinear regression study in normal volunteers to determine the optimal analysis revealed Emax (maximum attainable receptor occu- dose of aripiprazole for clinical trials in schizophrenia pancy) values close to saturation in all brain regions. EC50 demonstrated that these rules apply to antagonists only. (plasma concentration predicted to provide 50% of the Here we showed that aripiprazole occupies more than maximum attainable occupancy) values ranged from 4 90% of striatal D2 receptors at clinically effective ng/ml in the superior temporal cortex to 14 ng/ml in the pu- doses without extrapyramidal side-effects (Yokoi et al., Neuropsychopharmacology 2002, 27: 248-259; Gründer et al., Arch Gen Psychiatry 2003, 60: 974-977). In order to further characterize aripiprazole’s ex- trastriatal and temporal binding characteristics, we per- formed PET studies with [18F]fallypride ([18F]FP) in patients with schizophrenia at varying time points after Methods: D2-like dopamine receptors were quantified
with positron emission tomography and [18F]FP in 12 patients suffering from schizophrenia (DSM-IV). The PET scans were performed at varying time points after the last drug administration (range 5-78 h). Time activ-ity curves were generated after normalization using a template for cerebellum, caudate nucleus, putamen, temporal and frontal cortices, thalamus, amygdala, pi- Aripiprazole Plasma Concentration [ng/ml]
tuitary, colliculi, and substantia nigra. Binding poten- Relationship between aripiprazole plasma concentration and tials were calculated by means of the simplified refer- D2/D3 dopamine receptor occupancy in the putamen (black cir- ence tissue model. Receptor occupancy was calculated cles) and in the inferior temporal cortex (white triangles) in eight as percent reduction in binding potential, with un- patients with schizophrenia (daily doses 5 - 30 mg blocked values taken from a sample of 12 age-matched normal volunteers. Aripiprazole plasma concentrations Discussion: Our preliminary analyses suggest that aripipra-
were determined immediately before injection of the zole due to its high affinity to D2/D3 receptors and its very radiotracer. Plasma concentrations and percent binding long elimination half-life of about 72 hours at clinically data were fit to a simple one-site ligand binding model used doses occupies very high amounts of its target receptor homogenously throughout the brain and that dissociation from those receptors is very slow. It can be calculated from Results: Analysis of the data of six of the patients re-
our results that in patients with plasma concentrations above vealed very high mean D2/D3 receptor occupancies in approximately 400 ng/ml D2/D3 receptors are still almost saturated for nearly one week after the last dose.


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