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L S Pilowsky - One of the best experts on this subject based on the ideXlab platform.
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is regionally selective d2 d3 dopamine occupancy sufficient for aTypical Antipsychotic effect an in vivo quantitative 123i epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, L S PilowskyAbstract:OBJECTIVE: ATypical Antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of aTypical over Typical Antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an aTypical Antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, L S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate aTypical Antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied Typical-Antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than Typical Antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for aTypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, L S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel aTypical Antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by Antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving Typical Antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with Typical Antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all Antipsychotic drugs studied. Conclusions: The aTypical Antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their aTypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of aTypical Antipsychotic drugs.
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in vivo occupancy of striatal and temporal cortical d2 d3 dopamine receptors by Typical Antipsychotic drugs 123i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 1999Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, Caroline Stephenson, L S PilowskyAbstract:BACKGROUND The dopamine hypothesis proposes that Antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride. METHOD [123I]-epidepride SPET scans were performed on 12 patients with schizophrenia treated with Antipsychotics and II age-matched healthy controls. [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by Typical Antipsychotic drugs determined. RESULTS Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS Typical Antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
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in vivo effects on striatal dopamine d2 receptor binding by the novel aTypical Antipsychotic drug sertindole a 123i ibzm single photon emission tomography spet study
Psychopharmacology, 1997Co-Authors: L S Pilowsky, P Oconnell, N Davies, Geraldo F Busatto, D C Costa, Robin M Murray, Robert KerwinAbstract:The novel Antipsychotic drug sertindole has an aTypical pharmacological profile. We have estimated striatal D2 dopamine binding in schizophrenic patients treated with sertindole using 123I iodobenzamide (IBZM) SPET. Patients were recruited from a clinical trial of sertindole's tolerability and efficacy. Striatal D2 binding in sertindole-treated patients (n = 5), was compared with previously reported data from clozapine (n = 10); olanzapine (n = 6); Typical Antipsychotic responsive (n = 10); and risperidone (n = 6)-treated groups. Mean PANSS (structured clinical interview for the positive and negative syndrome scale) scores showed clinical improvement in the sertindole group. Few extrapyramidal side effects (EPS) were recorded [average Simpson-Angus (SAS) score = 2.6]. Sertindole-treated patients had mean D2 binding indices (+/-SE) significantly lower than clozapine-treated patients (1.19 +/- 0.04) versus (1.49 +/- 0.04), and olanzapine-treated patients (1.41 +/- 0.06); and similar to those of risperidone (1.24 +/- 0.04) and Typical Antipsychotic responsive (1.25 +/- 0.05) treated patients. In this patient sample the preliminary evidence suggests that sertindole's decreased tendency to induce EPS at clinically therapeutic doses is not due to limited occupancy of striatal D2 receptors in vivo, and as is the case for risperidone, patients are protected from EPS by some other intrinsic effect of the drug.
P J Ell - One of the best experts on this subject based on the ideXlab platform.
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is regionally selective d2 d3 dopamine occupancy sufficient for aTypical Antipsychotic effect an in vivo quantitative 123i epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, L S PilowskyAbstract:OBJECTIVE: ATypical Antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of aTypical over Typical Antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an aTypical Antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, L S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate aTypical Antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied Typical-Antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than Typical Antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for aTypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, L S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel aTypical Antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by Antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving Typical Antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with Typical Antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all Antipsychotic drugs studied. Conclusions: The aTypical Antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their aTypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of aTypical Antipsychotic drugs.
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in vivo occupancy of striatal and temporal cortical d2 d3 dopamine receptors by Typical Antipsychotic drugs 123i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 1999Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, Caroline Stephenson, L S PilowskyAbstract:BACKGROUND The dopamine hypothesis proposes that Antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride. METHOD [123I]-epidepride SPET scans were performed on 12 patients with schizophrenia treated with Antipsychotics and II age-matched healthy controls. [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by Typical Antipsychotic drugs determined. RESULTS Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS Typical Antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
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dopamine d2 receptor occupancy in vivo by the novel aTypical Antipsychotic olanzapine a123 ibzm single photon emission tomography spet study
Psychopharmacology, 1996Co-Authors: L S Pilowsky, Geraldo F Busatto, D C Costa, T Sharma, P J Ell, M Taylor, T Sigmundsson, V NohriaAbstract:We have studied striatal D2 dopamine binding in schizophrenic patients treated with the novel aTypical Antipsychotic drug, olanzapine.123I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D2 receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D2 binding data from olanzapine treated patients (n=6) were compared with previously reported data from Typical Antipsychotic responsive (n=10); clozapine (n=10); and risperidone (n=6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D2 binding of123I IBZM (reflecting lower levels of D2 occupancy) than Typical Antipsychotic (1.25±0.05) or risperidone (1.24±0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D2 binding in vivo (1.41±0.06) as those treated with clozapine (1.49±0.04). This preliminary evidence suggests olanzapine is another aTypical Antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D2 receptor occupancy in vivo.
Rachel S Mulligan - One of the best experts on this subject based on the ideXlab platform.
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is regionally selective d2 d3 dopamine occupancy sufficient for aTypical Antipsychotic effect an in vivo quantitative 123i epidepride spet study of amisulpride treated patients
American Journal of Psychiatry, 2003Co-Authors: Rodrigo A Bressan, Rachel S Mulligan, P J Ell, K Erlandsson, H M Jones, Robert J Flanagan, L S PilowskyAbstract:OBJECTIVE: ATypical Antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of aTypical over Typical Antipsychotic agents include 1) simultaneous antagonism of dopamine D2 and serotonin 5-HT2A receptors or 2) selective action at limbic cortical dopamine D2-like receptors with modest striatal D2 receptor occupancy. Amisulpride is an aTypical Antipsychotic drug with selective affinity for D2/D3 dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors’ goal was to evaluate whether treatment with amisulpride results in “limbic selective” D2/D3 receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [123I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of recepto...
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, L S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate aTypical Antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied Typical-Antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than Typical Antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for aTypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, L S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel aTypical Antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by Antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving Typical Antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with Typical Antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all Antipsychotic drugs studied. Conclusions: The aTypical Antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their aTypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of aTypical Antipsychotic drugs.
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in vivo occupancy of striatal and temporal cortical d2 d3 dopamine receptors by Typical Antipsychotic drugs 123i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 1999Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, Caroline Stephenson, L S PilowskyAbstract:BACKGROUND The dopamine hypothesis proposes that Antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride. METHOD [123I]-epidepride SPET scans were performed on 12 patients with schizophrenia treated with Antipsychotics and II age-matched healthy controls. [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by Typical Antipsychotic drugs determined. RESULTS Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS Typical Antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
Herbert Y Meltzer - One of the best experts on this subject based on the ideXlab platform.
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discriminative stimulus properties of n desmethylclozapine the major active metabolite of the aTypical Antipsychotic clozapine in c57bl 6 mice
Behavioural Pharmacology, 2012Co-Authors: Jason M Wiebelhaus, Herbert Y Meltzer, Sarah A Vunck, Joseph H PorterAbstract:N-desmethylclozapine (NDMC) is the major active metabolite of the aTypical Antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D2 and cholinergic muscarinic M1/M4 agonist, whereas clozapine is a weak dopamine D2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the Typical Antipsychotic drug haloperidol (dopamine D2 antagonist) and the aTypical Antipsychotic drug aripiprazole (D2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other Antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile.
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phosphodiesterase 4b genetic variants are not associated with Antipsychotic induced tardive dyskinesia
International Clinical Psychopharmacology, 2010Co-Authors: Renan P. Souza, Herbert Y Meltzer, James L Kennedy, Jeffrey A. Lieberman, Gary Remington, Albert H C WongAbstract:Phosphodiesterase 4B (PDE4B) has been evaluated as a genetic risk factor for schizophrenia. Selective PDE4 inhibitor drugs have Antipsychotic-like effects and reduce tardive dyskinesia-like movements in animal models. We investigated whether PDE4B genetic variants are associated with Antipsychotic-induced tardive dyskinesia incidence and severity in schizophrenia patients. Our sample consisted of 169 Caucasian patients taking Typical Antipsychotic medication for at least 1 year. We found two PDE4B gene variants to be nominally associated with tardive dyskinesia (rs1338719 and rs7528545) in the overall population and two other variants nominally associated with the presence of tardive dyskinesia and severity in female patients (rs1890196 and rs783036). None of these results survived correction for multiple testing. Overall, our results do not support a genetic association between tardive dyskinesia and PDE4B.
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Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia.
Pharmacogenetics and Genomics, 2010Co-Authors: Renan P. Souza, Herbert Y Meltzer, Vincenzo De Luca, Jeffrey A. Lieberman, James L KennedyAbstract:Earlier results suggest a minor role of variants in the serotonin 3 receptor (HTR3) subunit genes on Antipsychotic treatment outcome of schizophrenia patients. In this study, we further investigated the role of the subunits A and B of the HTR3 receptor using 140 schizophrenia patients taking clozapine for 6 months. We have found significant allelic association of clozapine response with three variants in the HTR3A receptor (rs2276302, rs1062613, rs1150226) although only rs1062613 association remained significant after permutations (permutated P=0.041). Moreover, rs2276302 and rs1062613 have shown nominally significant genotypic association. The two haplotypes composed of rs2276302-rs1062613-rs1150226 were also nominally significant. Taken together, our results suggest that variants in the HTR3A receptor gene can play a role in the treatment outcome of clozapine in schizophrenia patients that are refractory or intolerant of Typical Antipsychotic therapy. Further studies are necessary to confirm the reported associations.
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effect of buspirone a serotonin1a partial agonist on cognitive function in schizophrenia a randomized double blind placebo controlled study
Schizophrenia Research, 2007Co-Authors: Tomiki Sumiyoshi, Sohee Park, Karu Jayathilake, Ajanta Roy, Aygun Ertugrul, Herbert Y MeltzerAbstract:Inpreviousstudies,wedemonstratedthattandospirone,aserotonin-5-HT1Apartialagonist,addedtoongoingtreatmentwithsmall to moderate doses of Typical Antipsychotic drugs, improved executive function and verbal learning and memory. However, tandospirone is not available in most countries, and aTypical Antipsychotic drugs (AAPDs) have largely replaced Typical Antipsychotic drugsastheprimarytreatmentforschizophrenia.Therefore,thegoalofthisrandomlyassignedplacebo-controlled double-blindstudy wastodetermineiftheadditionofbuspirone,awidelyavailable5-HT1Apartialagonist,wouldenhancecognitivefunction,insubjects with schizophrenia treated with AAPDs. Seventy-three patients with schizophrenia, who had been treated with an AAPD for at least three months, were randomly assigned to receive either buspirone, 30 mg/day, or matching placebo. All other medications remained unchanged. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, and 6 weeks, and 3 and 6 months after baseline. A significant Time×Group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speeded motor performance, due to better performance of the buspirone group compared to the placebo group at 3 months. No significant interaction effects were noted for other domains of cognition. Scores on the Brief Psychiatric Rating Scale (Total, Positive) were improved during treatment with buspirone but not placebo, but the effects did not reach statistical significance. The results of this study showed a possible benefit of buspirone augmentation of AAPDs to enhance attention. However, we did not replicate the results of the previous study with tandospirone, which may be due to the differences between tandospirone and buspirone, between Typical Antipsychotics and AAPDs, or a combination of the above. Further study to determine the usefulness of 5-HT1A agonist treatment in schizophrenia is indicated. © 2007 Elsevier B.V. All rights reserved.
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effect of buspirone a serotonin1a partial agonist on cognitive function in schizophrenia a randomized double blind placebo controlled study
Schizophrenia Research, 2007Co-Authors: Tomiki Sumiyoshi, Sohee Park, Karu Jayathilake, Ajanta Roy, Aygun Ertugrul, Herbert Y MeltzerAbstract:Abstract In previous studies, we demonstrated that tandospirone, a serotonin-5-HT1A partial agonist, added to ongoing treatment with small to moderate doses of Typical Antipsychotic drugs, improved executive function and verbal learning and memory. However, tandospirone is not available in most countries, and aTypical Antipsychotic drugs (AAPDs) have largely replaced Typical Antipsychotic drugs as the primary treatment for schizophrenia. Therefore, the goal of this randomly assigned placebo-controlled double-blind study was to determine if the addition of buspirone, a widely available 5-HT1A partial agonist, would enhance cognitive function, in subjects with schizophrenia treated with AAPDs. Seventy-three patients with schizophrenia, who had been treated with an AAPD for at least three months, were randomly assigned to receive either buspirone, 30 mg/day, or matching placebo. All other medications remained unchanged. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, and 6 weeks, and 3 and 6 months after baseline. A significant Time × Group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speeded motor performance, due to better performance of the buspirone group compared to the placebo group at 3 months. No significant interaction effects were noted for other domains of cognition. Scores on the Brief Psychiatric Rating Scale (Total, Positive) were improved during treatment with buspirone but not placebo, but the effects did not reach statistical significance. The results of this study showed a possible benefit of buspirone augmentation of AAPDs to enhance attention. However, we did not replicate the results of the previous study with tandospirone, which may be due to the differences between tandospirone and buspirone, between Typical Antipsychotics and AAPDs, or a combination of the above. Further study to determine the usefulness of 5-HT1A agonist treatment in schizophrenia is indicated.
V Bigliani - One of the best experts on this subject based on the ideXlab platform.
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striatal and extra striatal d 2 d 3 dopamine receptor occupancy by quetiapine in vivo 123 i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 2000Co-Authors: Caroline Stephenson, V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, H M Jones, L S PilowskyAbstract:Background Selective action at limbic cortical dopamine D2-like receptors could mediate aTypical Antipsychotic efficacy with few extrapyramidal side-effects. Aims To test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo . Method The high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients ( n =6). Quetiapine-, and previously studied Typical-Antipsychotic- and clozapine-treated patients were compared. Results Mean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than Typical Antipsychotics. Conclusions Preliminary data suggest that limbic selective D2/D3 receptor blockade is important for aTypical drug action.
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striatal and temporal cortical d2 d3 receptor occupancy by olanzapine and sertindole in vivo a 123i epidepride single photon emission tomography spet study
Psychopharmacology, 2000Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, R I Ohlsen, V W Pike, P J Ell, Sveto Gacinovic, R W Kerwin, L S PilowskyAbstract:Rationale: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. Objectives: To test the hypothesis that olanzapine, a novel aTypical Antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Methods: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by Antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving Typical Antipsychotic drugs (n=12) and clozapine (n=10). Results: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with Typical Antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all Antipsychotic drugs studied. Conclusions: The aTypical Antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their aTypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of aTypical Antipsychotic drugs.
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in vivo occupancy of striatal and temporal cortical d2 d3 dopamine receptors by Typical Antipsychotic drugs 123i epidepride single photon emission tomography spet study
British Journal of Psychiatry, 1999Co-Authors: V Bigliani, Rachel S Mulligan, P D Acton, P J Ell, R W Kerwin, Dimitris Visvikis, Caroline Stephenson, L S PilowskyAbstract:BACKGROUND The dopamine hypothesis proposes that Antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade. AIM To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride. METHOD [123I]-epidepride SPET scans were performed on 12 patients with schizophrenia treated with Antipsychotics and II age-matched healthy controls. [123I]-epidepride 'specific binding' to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by Typical Antipsychotic drugs determined. RESULTS Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively. CONCLUSIONS Typical Antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
