Mechanism of Action of Aripiprazole Predicts Clinical Efficacy and a                 Favourable Side-Effect Profile

Hirose, Tetsuro; Uwahodo, Yasufumi; Yamada, Shigehiro; Miwa, Takashi; Kikuchi, Tetsuro; Kitagawa, Hisashi; Burris, Kevin D.; Altar, C. Anthony; Nabeshima, Toshitaka

doi:10.1177/026988110401800308

Cited by 129 publications

(75 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This makes its unlikely that our failure to observe 5-HT 2 occupancy is a methodological or technical effect, and questions whether 5-HT 2 receptors in this species makes a major contribution to the pharmacological effects of aripiprazole in CAR and CAT models on acute administration. Our findings with respect to aripiprazole's 5-HT 2 receptor occupancy are also supported by the fact that in an in vivo model of 5-HT 2 antagonism (MDMT-induced head twitches in mice), aripiprazole exhibited weak inhibition at comparable doses (Hirose et al, 2004). The divergence between in vitro vs in vivo D 2 /5-HT 2 ratios could be often explained by the presence of active metabolites which in turn have different receptor affinity profiles.…”

Section: Discussionsupporting

confidence: 76%

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

180

116

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 76%

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

180

116

View full text Add to dashboard Cite

show abstract

“…However, we cannot exclude that pharmacokinetic peculiarities of some of these drugs (such as slow brain penetration or else: see below) may explain the fact that little or no catalepsy was observed under our experimental conditions (ie observation 1 h after drug administration). In fact, it has been reported that the maximum catalepsy response to aripiprazole occurred at 8 h postadministration (Hirose et al, 2004). This is an interesting observation, considering that in both rats and humans, a major metabolite of aripiprazole is a pure dopamine D 2 antagonist (Lawler et al, 1999), which may mitigate the D 2 receptor partial agonist properties of aripiprazole.…”

Section: Antipsychotic Activity Of the New Generation Of Antipsychotimentioning

confidence: 79%

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Bardin

Kleven

Barret-Grévoz

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT 1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT 1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT 1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT 1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D 2 and 5-HT 1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.

show abstract

“…Aripiprazole has a novel pharmacological profile; partial agonism at dopamine D 2 and D 3 and serotonin 5-HT 1A receptors, and antagonism at 5-HT 2A receptors. [1][2][3][4][5] Aripiprazole has been shown to improve symptoms of acute mania in placebo-controlled studies 6,7 and was superior to placebo in maintaining efficacy for up to 100 weeks in patients with bipolar mania. 8,9 This study used a randomised placebo-controlled study design and included an active haloperidol reference arm to evaluate the acute and continued efficacy of aripiprazole monotherapy in patients with bipolar disorder experiencing acute manic or mixed episodes (trial registration NCT00097266).…”

mentioning

confidence: 99%

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study

et al. 2009

View full text Add to dashboard Cite

BackgroundWell-tolerated and effective therapies for bipolar mania are required.AimsTo evaluate the efficacy and tolerability of aripiprazole as acute and maintenance of effect therapy in patients with bipolar I disorder experiencing manic or mixed episodes.MethodPatients were randomised to double-blind aripiprazole (15 or 30 mg/day; n=167) placebo (n=153) or haloperidol (5–15 mg/day, n=165) for 3 weeks (trial registration NCT00097266). Aripiprazole- and haloperidol-treated patients remained on masked treatment for 9 additional weeks.ResultsMean change in Young Mania Rating Scale Total score (primary end-point) at week 3 was significantly greater with aripiprazole (–12.0; P<0.05) and haloperidol (–12.8; P<0.01) than with placebo (–9.7). Improvements were maintained to week 12 for aripiprazole (–17.2) and haloperidol (–17.8). Aripiprazole was well tolerated. Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole (53.3% v. 23.5%).ConclusionsClinical improvements with aripiprazole were sustained to week 12. Aripiprazole was generally well tolerated.

show abstract

Mechanism of Action of Aripiprazole Predicts Clinical Efficacy and a Favourable Side-Effect Profile

Cited by 129 publications

References 40 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

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study

Contact Info

Product

Resources

About