Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

Yokoi, Fuji

doi:10.1016/s0893-133x(02)00304-4

Cited by 270 publications

(164 citation statements)

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“…In the animals tested with aripiprazole, D 2 RO exceeded 80% in 13 out of 25 animals and there was no evidence of CAT (Figure 2). These results concur with a study in normal volunteers where no functional impact of D 2 blockade was observed on motor function despite occupancies exceeding 80% D 2 RO (Yokoi et al, 2002). Aripiprazole's characterization as a partial agonist could explain these findings.…”

Section: Discussionsupporting

confidence: 92%

“…In vivo occupancy and functional effects of aripiprazole S Natesan et al idol and risperidone are clinically active from B60% D 2 RO, aripiprazole is effective only at doses 485% D 2 RO (Farde et al, 1992;Kapur et al, 1995;Kapur et al, 1996;Kane et al, 2002;Yokoi et al, 2002;Marder et al, 2003). This finding can also be understood using the same assumption of functional in vivo intrinsic efficacy of aripiprazole as a partial agonist made earlier to explain lack of motor side effects.…”

Section: Discussionmentioning

confidence: 89%

“…In a study of aripiprazole, healthy volunteers treated for 2 weeks with a dose of 2 mg/day showed D 2 RO between 70 and 80% of dopamine receptors in the putamen, while a dose of 30 mg/day showed an occupancy of nearly 95% with an incidence of extrapyramidal symptoms (EPS) no higher than with placebo (Yokoi et al, 2002). Two important facts emerge.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

176

116

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The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

176

116

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“…Receptor occupancy increased from below 40% at 0.5 mg to over 90% at 30 mg/day. 66 These results suggest that administration of high doses of aripiprazole would lead to an increased risk of EPS; however, no EPS were observed in patients receiving high doses (30 mg/day) of aripiprazole in this study. The authors suggest that the lack of EPS may have to do with the partial agonistic activity of aripiprazole.…”

Section: Aripiprazolecontrasting

confidence: 55%

Atypicality of Atypical Antipsychotics

Farah¹

2005

Prim. Care Companion CNS Disord.

108

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Objective: To review the current definition of atypicality, discuss the unique features of each atypical antipsychotic, and determine whether the available drugs in this class really meet the classical definition of atypicality.Data Sources: A PubMed search was conducted to identify literature on the subject of this review, supported by additional articles based on the author's clinical knowledge and experience.Study Selection and Data Extraction: Relevant references were extracted and summarized in order to meet the objective of the article.Data Synthesis: Atypical antipsychotics are considered a major advance over conventional antipsychotics, primarily because they offer effective treatment alternatives that are relatively free of extrapyramidal symptoms. In fact, the term atypicality was originally used to describe antipsychotic agents with a minimal risk of causing extrapyramidal symptoms. However, over the years the definition has been modified such that there is currently no consensus on a true definition of atypicality for these agents. Each of the atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) commercially available in the United States is unique in terms of its pharmacologic profile, differing with respect to receptor-binding affinity, mechanism of action, and adverse events. Of the available atypical antipsychotics, clozapine and quetiapine have shown the lowest propensity to cause extrapyramidal symptoms. Although the risk of extrapyramidal symptoms is lower with risperidone and olanzapine than with conventional antipsychotics, risk increases with dose escalation. Data for ziprasidone indicate that the risk of extrapyramidal symptoms may be similar to that of risperidone and olanzapine. There is a concern of akathisia with aripiprazole; however, more experience with this agent is needed before definitive conclusions are made.Conclusion: If the definition of "atypical" antipsychotic is considered to be freedom from extrapyramidal symptoms, then, based on a comprehensive review of available data and clinical experience, clozapine and quetiapine appear to be the only true atypicals.( Prim Care Companion J Clin Psychiatry 2005;7:268-274)

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“…This would allow optimal efficacy to be achieved without incurring unwanted side effects. Such a profile is not achieved even by the dopamine D 2 receptor partial agonist which requires very high levels of D 2 RO for antipsychotic efficacy (Yokoi et al 2002); aripiprazole is a partial agonist both pre-and post-synaptically and has a higher affinity for D 2 over 5-HT 2A receptors, in contrast to the pre-synaptic partial agonism and post-synaptic antagonism at D 2 receptors by ITI-007 and potent 5-HT 2A receptor antagonism. Moreover, ITI-007 has minimal interaction with histamine, serotonin 5-HT 2C , and muscarinic acetylcholine receptors that translate to a lack of sedation, metabolic disturbance, and cognitive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

et al. 2015

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RationaleCentral modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. ObjectivesThe purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT 2A receptors, dopamine D 2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. MethodsCarbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT 2A receptors, D 2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. ResultsOral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT 2A receptors and low occupancy of striatal D 2 receptors (~12 %). D 2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2 = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D 2 receptors and 33 % of striatal serotonin transporters. ConclusionsThe results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

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Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

Abstract: Aripiprazole (OPC 14597

Cited by 270 publications

References 53 publications

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Atypicality of Atypical Antipsychotics

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

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