Aripiprazole (Otsuka Pharmaceutical Co).

Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].