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

Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japant_hirose{at}research.otsuka.co.jp

Yasufumi Uwahodo

Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan

Sakiko Yamada

Aripiprazole Project, Product Planning and Management Group, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan

Takashi Miwa

Tetsuro Kikuchi

Hisashi Kitagawa

Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan

Kevin D. Burris

Palatin Technologies, Cranbury, NJ, USA

C. Anthony Altar

Psychiatric Genomics, Inc., Gaithersburg, MD, USA

Toshitaka Nabeshima

Nagoya University Graduate School of Medicine, Department of Neuropsychopharmacology and Hospital Pharmacy, Japan

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 usingseveral 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 a typical antipsychotics. This profile may result from its high affinity partialagonist activity at D₂ and 5-HT_1A receptors and its antagonism of 5-HT_2A receptors.

Key Words: aripiprazole • efficacy • olanzapine • risperidone • side-effects

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