TY - JOUR
T1 - Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile
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
PY - 2004/9
Y1 - 2004/9
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.
AB - 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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U2 - 10.1177/026988110401800308
DO - 10.1177/026988110401800308
M3 - Article
C2 - 15358981
AN - SCOPUS:6044224986
SN - 0269-8811
VL - 18
SP - 375
EP - 383
JO - Journal of Psychopharmacology
JF - Journal of Psychopharmacology
IS - 3
ER -
