The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: A pet study

Kapur, Shitij; Remington, Gary; Zipursky, Robert B.; Wilson, Alan A.; Houle, Sylvain

doi:10.1016/0024-3205(95)02037-j

Cited by 218 publications

(100 citation statements)

References 12 publications

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“…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: 88%

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

Self Cite

180

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: Discussionmentioning

confidence: 88%

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

Self Cite

180

116

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“…In the human at a 6 mg/day dose, risperidone occupies 78-88% of 5TH 2A receptors and 75-80% of DA 2 receptors (Farde et al, 1988). Again, in humans using 2, 4, and 6 mg, there is a linear dose occupancy of the DA 2 receptors of 66, 73, and 79%, respectively (Kapur et al, 1995). Whereas, DA 2 receptor occupancy was not measured in these animals (Kapur et al, 2003), the dosing was designed to have the 24 h plasma levels match clinical therapeutic levels at low and high doses, with drug delivered continuously.…”

Section: Discussionmentioning

confidence: 94%

Multidose Risperidone Treatment Evaluated in a Rodent Model of Tardive Dyskinesia

Gao

Cooper

Suckow

et al. 2005

Neuropsychopharmacol

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Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (o6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.

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“…14 In a study of D 2 occupancy in individuals receiving risperidone doses of 2, 4, and 6 mg, the mean level of D 2 -receptor occupancy was 66% at 2 mg, 73% at 4 mg, and 79% at 6 mg. 43 D 2 -receptor occupancy of risperidone at doses of ≥ 4 mg is above the threshold associated with EPS and hyperprolactinemia. 43,44 Risperidone is able to occupy D 2 receptors gradually, which is not a property shared with the conventional antipsychotics or olanzapine. 45 Occupancy of 5-HT 2 receptors has been shown to be > 95% with risperidone at dosages of 2 to 4 mg/day.…”

Section: Risperidonementioning

confidence: 99%

Atypicality of Atypical Antipsychotics

Farah¹

2005

Prim. Care Companion CNS Disord.

112

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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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The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: A pet study

Cited by 218 publications

References 12 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

Multidose Risperidone Treatment Evaluated in a Rodent Model of Tardive Dyskinesia

Atypicality of Atypical Antipsychotics

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