Rexulti (brexpiprazole) differs from Abilify (aripiprazole) in several ways. Both medications are D₂ partial agonist. This property reduces dopamine output when dopamine concentrations are high thus reducing psychotic symptoms and increases dopamine output when dopamine concentrations are low thus improving mood symptoms.

In contrast to Abilify, however, Rexulti has less intrinsic activity at D₂ receptors thus reducing the chance for akathisia—motor restlessness­ and other extra pyramidal symptoms (EPS) such as muscle stiffness, spasms, tremor and jerky movements. Clinical trials confirm that Rexulti has a much lower incidence of akathisia and other motor side effects than Abilify.

In addition Rexulti has more potent serotonin 5HT_2Aantagonism than Abilify providing antipsychotic and antimanic activity with a more auspicious side effect profile. As a more potent serotonin 5-HT_1A partial agonist Rexulti may prove to be a more suitable choice for adjunctive treatment for major depression than Abilify.

The recommended starting dose for Rexulti as adjunctive treatment for Major Depressive Disorder is 0.5 mg or 1 mg daily for one week with an increase to a 2 mg target dose by the second week. The maximum adjunctive dose is 3 mg daily.  With a 91-hour half-life steady state concentration is attained in approximately 2 weeks. 

Akathisia remains the most common side effect of Rexulti but at a much lower rate than found with Abilify. 10% of patients on Rexulti experienced mild weight gain compared to 4% with placebo. There were no clinically relevant changes in lipid profiles or other metabolic parameters. Effects on prolactin levels were minimal. Rexulti does not appear to lengthen the ECG QT_c interval. In a 52-week maintenance study the discontinuation rate due to adverse events was less for the Rexulti treated group than the placebo treated group.