Introduction ‘Atypical’ antipsychotics such as risperidone or olanzapine are highly effective in treating psychoses (e.g. positive and negative symptoms of schizophrenia) and induce a low incidence of cardio- vascular or other adverse events compared to ‘typical’ antipsy- chotics (Buckley, 2001; Kapur and Remington, 2001). They have gradually penetrated the market for treatment of schizophrenia in the USA and Europe, slowly replacing treatment with the ‘typical’ antipsychotics such as haloperidol and chlorpromazine (Borison, 1997; Martin et al., 2002). The atypical antipsychotics are also called ‘serotonin–dopamine antagonists’ and are 10-fold more potent at blocking 5-HT 2A than D 2 receptors (Altar et al., 1986; Meltzer and Nash, 1991). The more favourable side-effect profiles of atypical anti- psychotics have been attributed to their potent antagonistic action Journal of Psychopharmacology 18(3) (2004) 375–383 © 2004 British Association for Psychopharmacology ISSN 0269-8811 SAGE Publications Ltd, London, Thousand Oaks, CA and New Delhi 10.1177/0269881104044569 Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile Tsuyoshi Hirose Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan. 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 Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan. Tetsuro Kikuchi Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan. 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 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-HT 1A receptors and its antagonism of 5-HT 2A receptors. Keywords aripiprazole, efficacy, olanzapine, risperidone, side-effects Abstract Corresponding author: Tsuyoshi Hirose, Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, 463-10 Kagasuno Kawauchi-cho, 7 Tokushima, 771–0192, Japan. Email: t_hirose@research.otsuka.co.jp Original Papers