Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile

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

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to atypical antipsychotics. This profile may result from its high affinity partial agonist activity at D 2 and 5-HT1A receptors and its antagonism of 5-HT 2A receptors.

Original languageEnglish
Pages (from-to)375-383
Number of pages9
JournalJournal of Psychopharmacology
Volume18
Issue number3
DOIs
Publication statusPublished - 01-09-2004
Externally publishedYes

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Antipsychotic Agents
olanzapine
Catalepsy
Risperidone
Receptor, Serotonin, 5-HT2A
5-Hydroxytryptophan
Physostigmine
Receptor, Serotonin, 5-HT1A
Aripiprazole
Apomorphine
Prosencephalon
Prolactin
Norepinephrine
Head
Serum
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Hirose, Tsuyoshi ; Uwahodo, Yasufumi ; Yamada, Sakiko ; Miwa, Takashi ; Kikuchi, Tetsuro ; Kitagawa, Hisashi ; Burris, Kevin D. ; Altar, C. Anthony ; Nabeshima, Toshitaka. / Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. In: Journal of Psychopharmacology. 2004 ; Vol. 18, No. 3. pp. 375-383.
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Hirose, T, Uwahodo, Y, Yamada, S, Miwa, T, Kikuchi, T, Kitagawa, H, Burris, KD, Altar, CA & Nabeshima, T 2004, 'Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile', Journal of Psychopharmacology, vol. 18, no. 3, pp. 375-383. https://doi.org/10.1177/026988110401800308

Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. / Hirose, Tsuyoshi; Uwahodo, Yasufumi; Yamada, Sakiko; Miwa, Takashi; Kikuchi, Tetsuro; Kitagawa, Hisashi; Burris, Kevin D.; Altar, C. Anthony; Nabeshima, Toshitaka.

In: Journal of Psychopharmacology, Vol. 18, No. 3, 01.09.2004, p. 375-383.

Research output: Contribution to journalArticle

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AU - Hirose, Tsuyoshi

AU - Uwahodo, Yasufumi

AU - Yamada, Sakiko

AU - Miwa, Takashi

AU - Kikuchi, Tetsuro

AU - Kitagawa, Hisashi

AU - Burris, Kevin D.

AU - Altar, C. Anthony

AU - Nabeshima, Toshitaka

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N2 - The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to atypical antipsychotics. This profile may result from its high affinity partial agonist activity at D 2 and 5-HT1A receptors and its antagonism of 5-HT 2A receptors.

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