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Gary Remington - One of the best experts on this subject based on the ideXlab platform.
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tardive dyskinesia in relation to estimated dopamine d2 Receptor Occupancy in patients with schizophrenia analysis of the catie data
2014Co-Authors: Kazunari Yoshida, Gary Remington, Robert R Bies, Takefumi Suzuki, Bruce G Pollock, Yuya Mizuno, Masaru MimuraAbstract:Abstract Objective The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 Receptor Occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods The dataset from 218 subjects (risperidone, N = 78; olanzapine, N = 100; ziprasidone, N = 40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥ 6 months, was used. Peak and trough dopamine D2 Receptor Occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 Receptor Occupancy levels were compared between patients who presented an AIMS score of ≥ 2 at endpoint and those with a score of zero, using the Mann–Whitney U test. Results Estimated dopamine D2 Receptor Occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N = 23) than those who did not (N = 195) (71.7 ± 14.4% vs. 64.3 ± 19.3%, p Conclusion Greater dopamine D2 Receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.
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estimated dopamine d2 Receptor Occupancy and remission in schizophrenia analysis of the catie data
2013Co-Authors: Sho Moriguchi, Gary Remington, David C Mamo, Robert R Bies, Takefumi Suzuki, Koichiro Watanabe, Masaru Mimura, Bruce G Pollock, Hiroyuki UchidaAbstract:In treating schizophrenia, 65% to 80% Occupancy of dopamine D₂ Receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D₂ Receptor Occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D₂ Receptor Occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D₂ prediction model. Estimated mean ± SD peak and trough D₂ Receptor Occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D₂ Occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D₂ Receptor Occupancy 5% or greater. These results extend our previous findings and suggest that sustained D₂ Receptor Occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.
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antipsychotics dopamine d2 Receptor Occupancy and clinical improvement in schizophrenia a meta analysis
2012Co-Authors: Gary Remington, Steve Mann, Zeynep Yilmaz, Clement C Zai, Rudi Hwang, Tamara ArenovichAbstract:Abstract Objective Treatment of schizophrenia (SCZ) was revolutionized with the development of the antipsychotic medications. Although imaging studies have linked antipsychotic D2 Receptor Occupancy and clinical response in SCZ, heterogeneity between cohorts and methods has made it challenging to generalize findings across studies. The main objective of this meta-analysis was to analyze the relationship between in vivo estimation of typical and atypical antipsychotic D2 Receptor Occupancy and treatment response in SCZ. Methods Using the keywords “dopamine D2 Receptor Occupancy,” “schizophrenia,” “PET/SPECT” and “antipsychotics,” and further refining our search to journal articles with information on % striatal D2 Occupancy and % change in clinical symptoms as indexed by either the BPRS or the PANSS, our final analysis consisted of 16 imaging studies (20 cohorts; N = 206). Results The first step of the meta-analysis confirmed the positive relationship between antipsychotic medication and clinical improvement in SCZ (ES = 1.36; 95% CI: 1.13–1.60). The second step of our analysis revealed that when D2 Occupancy was limited to less than 80% in order to control for the appearance of extrapyramidal symptoms, high D2 Occupancy was correlated with reduction in clinical scores (r = 0.4, p Conclusions Our results suggest that D2 Occupancy is a contributing factor for the mechanism of antipsychotic effect in SCZ for some but not all antipsychotic medications.
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a pet study of dopamine d2 and serotonin 5 ht2 Receptor Occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
2004Co-Authors: David C Mamo, Shitij Kapur, Chekkera Shammi, George Papatheodorou, Steve Mann, Francois Therrien, Gary RemingtonAbstract:OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 Receptors compared with dopamine D2 Receptors in vitro. The affinity of ziprasidone for these Receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D2 Occupancy (using [11C]raclopride) and 5-HT2 Occupancy (using [18F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12–16 hours after the last dose. RESULTS: The mean 5-HT2 Receptor Occupancy was significantly higher than the mean D2 Receptor Occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 Receptor Occupancy was al...
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a pet study of dopamine d2 and serotonin 5 ht2 Receptor Occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
2004Co-Authors: David C Mamo, Shitij Kapur, Chekkera Shammi, George Papatheodorou, Steve Mann, Francois Therrien, Gary RemingtonAbstract:OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 Receptors compared with dopamine D2 Receptors in vitro. The affinity of ziprasidone for these Receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D2 Occupancy (using [11C]raclopride) and 5-HT2 Occupancy (using [18F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12–16 hours after the last dose. RESULTS: The mean 5-HT2 Receptor Occupancy was significantly higher than the mean D2 Receptor Occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 Receptor Occupancy was al...
Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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a pet study with 11c az10419369 to determine brain 5 ht1b Receptor Occupancy of zolmitriptan in healthy male volunteers
2013Co-Authors: Katarina Varnas, Aurelija Jucaitė, Dennis J Mccarthy, Per Stenkrona, Magdalena Nord, Christer Halldin, Stephen KanesAbstract:AIM: To investigate the Occupancy at brain 5-hydroxytryptamine (5-HT) 1B Receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean Receptor Occupancy was 4-5%. No consistent changes in 5-HT1B Receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B Receptor Occupancy of a triptan. The findings are consistent with the low Receptor Occupancy previously reported in PET studies with agonists at other G protein coupled Receptors.
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suggested minimal effective dose of risperidone based on pet measured d2 and 5 ht2a Receptor Occupancy in schizophrenic patients
1999Co-Authors: Svante Nyberg, Christer Halldin, Bo Eriksson, Gabriella Oxenstierna, Lars FardeAbstract:OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A Receptor Occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 Receptor Occupancy and [11C]N-methylspiperone to measure 5-HT2A Receptor Occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 Receptor Occupancy was 82% (range=79%–85%), 5-HT2A Receptor occupanc...
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a pet study of 5 ht2 and d2 dopamine Receptor Occupancy induced by olanzapine in healthy subjects
1997Co-Authors: Svante Nyberg, Lars Farde, Christer HalldinAbstract:Olanzapine is a new antipsychotic drug with affinity for 5-HT2, D2, D1, and muscarinic Receptors. Positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP were used to measure D2 and 5-HT2 Receptor Occupancy in three healthy subjects after 10 mg olanzapine orally. After seven hours D2 Receptor Occupancy was 63%, 62% and 59%, respectively. After 9.5 hours 5-HT2 Receptor Occupancy was 74%, 86% and 92%. D2 and 5-HT2 Receptor Occupancy was comparable to that found in patients continuously treated with clozapine. Clinical efficacy has been demonstrated for olanzapine in the dose range 5 to 15 mg per day. Extrapolation from our present observations after a 10 mg single-dose suggest, that at the lower end of the clinically examined dose range the D2 and 5-HT2 Receptor Occupancy should be similar to that induced by standard doses of clozapine. Detailed evaluation of the dose-response characteristics of olanzapine and direct clinical comparison to clozapine will thus provide valuable leads to the clarification of atypical antipsychotic action.
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d2 dopamine Receptor Occupancy during low dose treatment with haloperidol decanoate
1995Co-Authors: Svante Nyberg, Lars Farde, Christer Halldin, M L Dahl, L BertilssonAbstract:Objectives: The aim of this study was to examine the relationships among clinical effects, central D 2 dopamine Receptor Occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. Method: During a 4-week interval of haloperidol decanoate dosage (dose range=30-50 mg), the patients' D 2 Receptor Occupancy was determined withpositron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. Results: One week after injection of haloperidol decanoate, the mean D 2 Receptor Occupancy was 73% (range=60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range=2.9-9.7). After 4 weeks, the mean D 2 Receptor Occupancy had decreased to 52% (range=20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range=1.0-4.4). Conclusions: The D 2 Receptor Occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D 2 Receptor Occupancy during the latter part of the treatment interval. These observations indicate that continuously high D 2 Receptor Occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies
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Central D2 Receptor Occupancy and effects of zuclopenthixol acetate in humans.
1995Co-Authors: Svante Nyberg, Lars Farde, A Bartfai, Christer HalldinAbstract:Repeated positron emission tomography (PET) measurements of D2 Receptor Occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 Receptor Occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 Receptor Occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 Receptor Occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 Receptor Occupancy calls for careful assessment of acute extrapyramidal symptoms.
Shitij Kapur - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of aripiprazole dose plasma concentration Receptor Occupancy and response implications for therapeutic drug monitoring
2010Co-Authors: Anna Sparshatt, David Taylor, Maxine X Patel, Shitij KapurAbstract:Objective To evaluate relationships between aripiprazole dose, plasma level, pharmacologic activity, and clinical outcome in order to evaluate the potential for therapeutic drug monitoring. Data sources In August 2008, we searched Embase, MEDLINE, and PubMed databases using the keywords aripiprazole, plasma levels, plasma concentration, and therapeutic drug monitoring. Study selection Twenty-one reports were retrieved. Eight studies investigating the relationship between blood concentrations of aripiprazole and dose, dopamine D(2)/D(3) Occupancy, and/or outcome and adverse effects were then selected. Data extraction All data concerning plasma or serum concentrations of aripiprazole were included if concentrations were reported in relation to a dose, dopamine Occupancy, or clinical outcome. Those reports solely investigating drug interactions were not included. Data synthesis A strong correlation exists between aripiprazole dose and plasma concentration. Positron emission tomography analyses suggest that there are significant relationships between dopamine Receptor Occupancy and both aripiprazole dose and blood concentration. Dopamine Receptor Occupancy appears to reach a plateau at doses above 10 mg, supporting the observation found in dose-response studies that 10 mg/d is the optimal dose for aripiprazole. Conclusions The dose range for aripiprazole is well defined, and it reliably predicts plasma level, dopamine Receptor Occupancy, and clinical response. Plasma level variation appears to have minimal impact on clinical response, but it may predict some adverse effects. A putative target plasma level range of between 150 and 210 ng/mL is suggested. Therapeutic drug monitoring has limited value in the clinical use of aripiprazole, but it may be useful in assuring adherence and optimizing response in individuals.
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d2 Receptor Occupancy of olanzapine pamoate depot using positron emission tomography an open label study in patients with schizophrenia
2008Co-Authors: David C Mamo, Shitij Kapur, Matcheri S Keshavan, Marc Laruelle, Cindy C Taylor, Prajakti A Kothare, Penny Barsoum, David McdonnellAbstract:A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D2 Receptor Occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D2 Occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D2 Receptor Occupancy, as measured by [11C]-raclopride PET, was 69% on oral olanzapine (5–20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, Occupancy returned to 84% of baseline oral olanzapine Occupancy after six injections. Over the study period, D2 Receptor Occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, P⩽0.001). OP depot resulted in mean D2 Receptor Occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.
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a pet study of dopamine d2 and serotonin 5 ht2 Receptor Occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
2004Co-Authors: David C Mamo, Shitij Kapur, Chekkera Shammi, George Papatheodorou, Steve Mann, Francois Therrien, Gary RemingtonAbstract:OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 Receptors compared with dopamine D2 Receptors in vitro. The affinity of ziprasidone for these Receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D2 Occupancy (using [11C]raclopride) and 5-HT2 Occupancy (using [18F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12–16 hours after the last dose. RESULTS: The mean 5-HT2 Receptor Occupancy was significantly higher than the mean D2 Receptor Occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 Receptor Occupancy was al...
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a pet study of dopamine d2 and serotonin 5 ht2 Receptor Occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
2004Co-Authors: David C Mamo, Shitij Kapur, Chekkera Shammi, George Papatheodorou, Steve Mann, Francois Therrien, Gary RemingtonAbstract:OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 Receptors compared with dopamine D2 Receptors in vitro. The affinity of ziprasidone for these Receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D2 Occupancy (using [11C]raclopride) and 5-HT2 Occupancy (using [18F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12–16 hours after the last dose. RESULTS: The mean 5-HT2 Receptor Occupancy was significantly higher than the mean D2 Receptor Occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 Receptor Occupancy was al...
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increased dopamine d2 Receptor Occupancy and elevated prolactin level associated with addition of haloperidol to clozapine
2001Co-Authors: Shitij Kapur, Gary Remington, Paul Roy, Jeff Daskalakis, Robert B ZipurskyAbstract:OBJECTIVE: The authors added haloperidol, a potent D2 blocker, to ongoing treatment with clozapine in patients with schizophrenia to determine the effects of this combination on dopamine D2 Receptor blockade, prolactin level, and extrapyramidal side effects. METHOD: At baseline and 4–8 weeks after the addition of haloperidol (4 mg/day) to ongoing clozapine treatment, five patients were examined for prolactin elevation, extrapyramidal side effects, drug plasma levels, and D2 Receptor Occupancy measured with [11C]raclopride and positron emission tomography imaging. RESULTS: Adding haloperidol significantly increased D2 Receptor Occupancy, from a mean of 55% to 79%, and significantly increased the prolactin level. One patient developed akathisia, and another manifested mild extrapyramidal side effects. CONCLUSIONS: Adding a modest dose of haloperidol to clozapine results in the high D2 Receptor Occupancy and sustained prolactin elevation usually associated with typical antipsychotics. These findings suggest ...
David C Mamo - One of the best experts on this subject based on the ideXlab platform.
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estimated dopamine d2 Receptor Occupancy and remission in schizophrenia analysis of the catie data
2013Co-Authors: Sho Moriguchi, Gary Remington, David C Mamo, Robert R Bies, Takefumi Suzuki, Koichiro Watanabe, Masaru Mimura, Bruce G Pollock, Hiroyuki UchidaAbstract:In treating schizophrenia, 65% to 80% Occupancy of dopamine D₂ Receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D₂ Receptor Occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D₂ Receptor Occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D₂ prediction model. Estimated mean ± SD peak and trough D₂ Receptor Occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D₂ Occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D₂ Receptor Occupancy 5% or greater. These results extend our previous findings and suggest that sustained D₂ Receptor Occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.
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hyperprolactinemia and estimated dopamine d2 Receptor Occupancy in patients with schizophrenia analysis of the catie data
2013Co-Authors: Takashi Tsuboi, David C Mamo, Robert R Bies, Takefumi Suzuki, Masaru Mimura, Bruce G Pollock, Ariel Graffguerrero, Hiroyuki UchidaAbstract:Abstract Background Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 Receptor Occupancy in patients with schizophrenia treated with antipsychotics. Methods The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 Receptor Occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 Occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 Occupancy were calculated. Results The multivariate general linear model revealed that estimated D2 Occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68–70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). Conclusion The threshold for hyperprolactinemia in D2 Occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65–80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.
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dopamine d2 Receptor Occupancy and cognition in schizophrenia analysis of the catie data
2013Co-Authors: Hitoshi Sakurai, David C Mamo, Robert R Bies, Takefumi Suzuki, Bruce G Pollock, Scott Stroup, Richard S E Keefe, Tarek K Rajji, Koichiro WatanabeAbstract:Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 Receptors in the treatment of schizophrenia. However, effects of D2 Receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 Receptor Occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 Receptor Occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 Occupancy levels, on neurocognitive functions. Results: D2 Occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 Receptor Occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 Occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
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dopamine d2 Receptor Occupancy and clinical effects a systematic review and pooled analysis
2011Co-Authors: Hiroyuki Uchida, Takefumi Suzuki, Koichiro Watanabe, Hiroyoshi Takeuchi, Ariel Graffguerrero, David C MamoAbstract:AbstractPositron emission tomography (PET) studies proposed a therapeutic window of D2 Receptor Occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET
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dopamine d2 Receptor Occupancy and clinical effects a systematic review and pooled analysis
2011Co-Authors: Hiroyuki Uchida, Takefumi Suzuki, Koichiro Watanabe, Hiroyoshi Takeuchi, Ariel Graffguerrero, David C MamoAbstract:Positron emission tomography (PET) studies proposed a therapeutic window of D2 Receptor Occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 Occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 Occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 Occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing Occupancy within this therapeutic window.
Svante Nyberg - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and d2 Receptor Occupancy of long acting injectable risperidone risperdal consta in patients with schizophrenia
2005Co-Authors: O. Gefvert, Bo Eriksson, Per Persson, Lars Helldin, Annika Bjorner, Erik Mannaert, Bart Remmerie, Marielle Eerdekens, Svante NybergAbstract:Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 Receptor Occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4-5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 Receptor Occupancy ranged from 25-48%, 59-83% and 62-72% respectively, while plasma active-moiety levels ranged from 4.4-8.8, 15.0-31.1 and 22.5-26.3 ng/ml respectively. The results indicate that brain D2 Receptor Occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2-6 mg of oral risperidone.
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suggested minimal effective dose of risperidone based on pet measured d2 and 5 ht2a Receptor Occupancy in schizophrenic patients
1999Co-Authors: Svante Nyberg, Christer Halldin, Bo Eriksson, Gabriella Oxenstierna, Lars FardeAbstract:OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A Receptor Occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 Receptor Occupancy and [11C]N-methylspiperone to measure 5-HT2A Receptor Occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 Receptor Occupancy was 82% (range=79%–85%), 5-HT2A Receptor occupanc...
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a pet study of 5 ht2 and d2 dopamine Receptor Occupancy induced by olanzapine in healthy subjects
1997Co-Authors: Svante Nyberg, Lars Farde, Christer HalldinAbstract:Olanzapine is a new antipsychotic drug with affinity for 5-HT2, D2, D1, and muscarinic Receptors. Positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP were used to measure D2 and 5-HT2 Receptor Occupancy in three healthy subjects after 10 mg olanzapine orally. After seven hours D2 Receptor Occupancy was 63%, 62% and 59%, respectively. After 9.5 hours 5-HT2 Receptor Occupancy was 74%, 86% and 92%. D2 and 5-HT2 Receptor Occupancy was comparable to that found in patients continuously treated with clozapine. Clinical efficacy has been demonstrated for olanzapine in the dose range 5 to 15 mg per day. Extrapolation from our present observations after a 10 mg single-dose suggest, that at the lower end of the clinically examined dose range the D2 and 5-HT2 Receptor Occupancy should be similar to that induced by standard doses of clozapine. Detailed evaluation of the dose-response characteristics of olanzapine and direct clinical comparison to clozapine will thus provide valuable leads to the clarification of atypical antipsychotic action.
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d2 dopamine Receptor Occupancy during low dose treatment with haloperidol decanoate
1995Co-Authors: Svante Nyberg, Lars Farde, Christer Halldin, M L Dahl, L BertilssonAbstract:Objectives: The aim of this study was to examine the relationships among clinical effects, central D 2 dopamine Receptor Occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. Method: During a 4-week interval of haloperidol decanoate dosage (dose range=30-50 mg), the patients' D 2 Receptor Occupancy was determined withpositron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. Results: One week after injection of haloperidol decanoate, the mean D 2 Receptor Occupancy was 73% (range=60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range=2.9-9.7). After 4 weeks, the mean D 2 Receptor Occupancy had decreased to 52% (range=20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range=1.0-4.4). Conclusions: The D 2 Receptor Occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D 2 Receptor Occupancy during the latter part of the treatment interval. These observations indicate that continuously high D 2 Receptor Occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies
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Central D2 Receptor Occupancy and effects of zuclopenthixol acetate in humans.
1995Co-Authors: Svante Nyberg, Lars Farde, A Bartfai, Christer HalldinAbstract:Repeated positron emission tomography (PET) measurements of D2 Receptor Occupancy, plasma concentrations of zuclopenthixol and reaction time were performed in three healthy subjects after injection of 12.5 mg zuclopenthixol acetate (ZPTA) in an open study design. Five control subjects were examined for reaction time only. D2 Receptor Occupancy was 51%, 71% and 75% after 7 h and 75%, 83% and 87% after 31 h in the three subjects. The subjects reported sedation, but reaction time was not prolonged. After the low dose of 12.5 mg ZPTA, D2 Receptor Occupancy exceeded the 70% assumed to be required to induce antipsychotic effect. Extrapolation of data to a clinical dose interval indicates that 50-150 mg ZPTA should induce very high D2 Receptor Occupancy lasting several days after injection. Such high doses may be required to induce sedation and to avoid frequent intramuscular injections in acutely psychotic patients. However, the simultaneously induced very high D2 Receptor Occupancy calls for careful assessment of acute extrapyramidal symptoms.
