Tsuyoshi Hirose

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 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-HT1A receptors and its antagonism of 5-HT2A receptors.

Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone.

Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.

THE EFFECT OF ARIPIPRAZOLE ON PREPULSE INHIBITION OF THE STARTLE RESPONSE IN NORMAL AND HYPERDOPAMINERGIC STATES IN RATS

This study compared the D2 partial agonists, aripiprazole, (R(+)-terguride; S(−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S(−)-3-PPP]; 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone [OPC-4392]) and D2 antagonists (haloperidol, olanzapine, clozapine, risperidone, and quetiapine) on prepulse inhibition (PPI) of the startle response, and the ability to reverse apomorphine-induced deficits in the PPI response. Aripiprazole did not essentially affect PPI in naïve rats but dose-dependently restored apomorphine-induced PPI disruption. R(+)-terguride restored PPI disruption but suppressed PPI significantly in naïve rats, S(−)-3-PPP partially restored whereas OPC-4392 did not restore PPI disruption. Haloperidol and risperidone restored PPI disruption whereas olanzapine and quetiapine partially restored PPI disruption and clozapine had no restorative effect. In conclusion, aripiprazole, unlike other antipsychotic agents, failed to suppress PPI significantly and restored PPI disruption.