Although akathisia is not uncommon in patients receiving aripiprazole, other extrapyramidal side effects of this drug were equivalent to placebo in controlled trials.

Induction of adverse extrapyramidal reaction by aripiprazole within the therapeutic dose range was first reported in 2006. That report, describing a patient aged 56 years with no relevant medical comorbidities who developed extrapyramidal side effects 5 weeks after initiating aripiprazole, emphasized the importance of slowly escalating the dose. Two other reports of extrapyramidal manifestations in childrenwith high dosage of aripiprazole have suggested the possibility of dose-dependent induction of extrapyramidal side effects.

Although aripiprazole is known to have high affinity to D2 receptors in the striatum, this effect is partially agonistic, and clearly differs from the purely antagonistic effects of other conventional or atypical antipsychotics. This may account for its high margin of safety with regard to extrapyramidal side effects (other than akathisia) which have been comparable to placebo. The occurrence of extrapyramidal side effects of aripiprazole in the case reported here is likely attributable to multiple drug interaction. This may be explained by hepatic cytochrome P450-dependent metabolism of aripiprazole, in particular the enzyme subtypes 2D6 and 3A4, both of which have been shown to be inhibited by sertraline. Sertraline-inhibited metabolism of aripiprazole would cause serum aripiprazole levels to become elevated, resulting in greater occupancy of striatal D2 receptors and producing the observed extrapyramidal side effects.