Yes, Rexulti (brexpiprazole) is an atypical antipsychotic. It was first approved by the FDA in 2015 and is currently used for three distinct conditions: as an add-on treatment for major depressive disorder in adults, for schizophrenia in patients 13 and older, and for agitation associated with Alzheimer’s disease. That third use, approved in May 2023, made it the first drug specifically cleared to treat agitation in Alzheimer’s-related dementia.
What “Atypical Antipsychotic” Means
Antipsychotics fall into two broad generations. Older “typical” antipsychotics primarily block dopamine receptors and tend to cause significant movement-related side effects. Atypical (or second-generation) antipsychotics like Rexulti interact with a wider range of brain receptors, which generally makes them more tolerable.
Rexulti works as a partial agonist at dopamine D2 receptors. In practical terms, that means it doesn’t fully block dopamine the way older antipsychotics do. Instead, it dials dopamine signaling down in areas where it’s overactive (which helps with psychosis) while providing just enough stimulation to avoid the flat, sedated feeling that full blockers can cause. It also acts on serotonin receptors, which contributes to its mood-related benefits and further lowers the risk of movement side effects like stiffness and tremor.
Why It’s Prescribed for Depression
Despite being classified as an antipsychotic, Rexulti is widely prescribed for depression. This is not unusual for atypical antipsychotics. When standard antidepressants aren’t doing enough on their own, Rexulti can be added on top of the existing antidepressant to boost its effectiveness. For this use, it’s taken at lower doses than it would be for schizophrenia, with a maximum of 3 mg per day compared to 4 mg for schizophrenia.
Its activity at serotonin receptors likely plays a role in mood improvement, though the exact reasons atypical antipsychotics help with depression aren’t fully understood. What matters from a practical standpoint is that “antipsychotic” describes the drug class, not the only condition it treats. If your prescriber recommended Rexulti for depression, it doesn’t mean they suspect psychosis.
How Rexulti Compares to Abilify
Rexulti is closely related to aripiprazole (Abilify), another atypical antipsychotic. Brexpiprazole was actually designed to improve on aripiprazole’s tolerability. Both drugs work through similar mechanisms, but Rexulti has lower intrinsic activity at dopamine D2 receptors, meaning it’s a gentler partial agonist. This translates into real clinical differences.
Aripiprazole is known for causing activation-type side effects: restlessness, agitation, and akathisia (an uncomfortable urge to keep moving). Rexulti produces fewer of these effects. It also causes less sedation and fewer sleep disturbances. These differences were a deliberate goal of its development, not just a lucky accident.
Common Side Effects
The most frequently reported side effect of Rexulti is akathisia, that restless, can’t-sit-still sensation, which occurred in 4 to 14% of patients in clinical trials. While this is the most common complaint, the rate is still lower than what’s typically seen with aripiprazole.
Weight gain is the other notable concern. In short-term studies (around 6 weeks), patients on Rexulti gained an average of 1.2 kg (about 2.6 pounds) compared to 0.2 kg on placebo. Over longer treatment, the average gain was 3.2 kg (about 7 pounds) at 58 weeks. Changes in blood sugar and cholesterol were small and not significantly different from placebo in short-term use, making Rexulti’s metabolic profile relatively mild compared to some other atypical antipsychotics.
How Long It Takes to Work
Rexulti has a long elimination half-life of about 91 hours, meaning it takes a while for the drug to fully build up and fully leave your system. Steady-state levels, the point where the amount in your body stabilizes, are reached after 10 to 12 days of daily dosing. Because of this slow buildup, doses are typically increased gradually over the first one to two weeks rather than starting at the target dose.
For depression, the starting dose is 0.5 or 1 mg once daily. For schizophrenia in adults, it starts at 1 mg daily for the first four days before being increased. For adolescents aged 13 to 17 with schizophrenia, the starting dose is 0.5 mg. In all cases, the medication is taken once a day with or without food.
The Alzheimer’s Agitation Approval
Rexulti’s 2023 approval for agitation in Alzheimer’s-related dementia was a notable milestone. No drug had previously been approved specifically for this purpose. The approval covers ongoing daily treatment, not as-needed use for acute episodes. This is an important distinction: Rexulti is meant to be taken regularly to reduce the overall frequency and severity of agitation symptoms like pacing, verbal aggression, and physical restlessness in people with Alzheimer’s disease.