Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile.
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 a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.
Hirose
Tsuyoshi
T
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan. t_hirose@research.otsuka.co.jp
Uwahodo
Yasufumi
Y
Yamada
Sakiko
S
Miwa
Takashi
T
Kikuchi
Tetsuro
T
Kitagawa
Hisashi
H
Burris
Kevin D
KD
Altar
C Anthony
CA
Nabeshima
Toshitaka
T
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000009:adverse effects / Q000494:pharmacology; D001763:Blepharoptosis / Q000139:chemically induced; D002375:Catalepsy / Q000139:chemically induced; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019416:Head Movements / Q000187:drug effects; D008297:Male; D008732:Methoxydimethyltryptamines / Q000009:adverse effects / Q000037:antagonists & inhibitors; D051379:Mice; D008813:Mice, Inbred ICR; D000077152:Olanzapine; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D008732:Methoxydimethyltryptamines; D010879:Piperazines; D015363:Quinolones; D001569:Benzodiazepines; D012701:Serotonin; D004295:Dihydroxyphenylalanine; D000068180:Aripiprazole; D018967:Risperidone; D000077152:Olanzapine