Immediate Impact

A poster was presented on a study leading to European Medicines Agency (EMA) approval of brexpiprazole for adolescents aged 13 to 17 years old with schizophrenia. Although in the United States, the US Food and Drug Administration (FDA) approved brexpiprazole for adolescents with schizophrenia, this approval was based solely on a pharmacokinetic bridging study. 

At the SIRS 2025 meeting, data from a Phase 3, multicenter, randomized, double-blind, placebo-controlled and active-referenced 6-week trial of brexpiprazole in adolescents with schizophrenia showed that brexpiprazole 2 to 4 mg (mean 2.95 mg/d) was superior to placebo regarding the primary outcome, total psychopathology, global illness severity, and treatment response. The aripiprazole group (mean dose: 13.9 mg/d) also separated from placebo for the same outcomes, validating the study methodology and patient population. Both treatments were generally well tolerated, but there was numerically less akathisia, somnolence, and fatigue with brexpiprazole than aripiprazole. Having more evidence-based antipsychotic treatments approved for use in this especially vulnerable population is desirable.  

Dr Correll –

Importance to Science: 9
Importance to the Molecule: 7
Importance to the Medication Class: 5

Dr Mattingly –

Importance to Science: 6
Importance to the Molecule: 8
Importance to the Medication Class: 7

This placebo-controlled, active-referenced trial is important as it provides well-designed information on a treatment for adolescents with schizophrenia. The finding that brexpiprazole significantly improved overall psychopathology, global illness severity, and clinical response with decreased incidence of akathisia, somnolence, and fatigue as compared to aripiprazole is of clinical importance for mental health clinicians caring for adolescents.   

Dr Kunovac –

Importance to Science: 2
Importance to the Molecule: 7
Importance to the Medication Class: 6

There is minimal differentiation for brexpiprazole. The adolescent confirmatory data adds legitimacy to its usage in adolescents with schizophrenia. This update does not add anything to the existing approach.

Dr Cutler –

Importance to Science: 6
Importance to the Molecule: 8
Importance to the Medication Class: 8

In the United States, a new drug has to beat placebo, which brexpiprazole has done many times for many indications, including schizophrenia, and it already has the indication in the United States for patients down to age 13. But for European Medicines Agency (EMA) approval, a study like this with either an active control or an active comparator has to be done. The fact that it seems to have worked as well as aripiprazole, a proven antipsychotic, with clearly better tolerability and safety (which it was designed to do, in addition to having higher affinity than aripiprazole for receptors implicated in depression and mood disorders), is, in my opinion, pretty important. We need more options for treating patients under 18, as most psychiatric illnesses start in that age range. Also, younger patients are more sensitive to a range of side effects, including movement disorders, sedation, and weight gain.

This is important because it should lead to approval for schizophrenia down to age 13 for the EMA. There are not many antipsychotics that have been studied or approved in patients under age 18. The design of the study was probably dictated by the EMA, since it was done to support approval in the European Union. It is not necessarily novel science, but it is still important to have more studies like this. The choice of aripiprazole for the active control was wise since clinicians will want to know how this related molecule performs relative to it. This will help clinical practice in the European Union, as again, there are few approved options for patients under 18. It will help Otsuka to have more approvals in more countries.

Dr Jain – 

Importance to Science: 7
Importance to the Molecule: 7
Importance to the Medication Class: 8 

This is an unusual study in multiple ways! First, it studies schizophrenia in adolescence. Second, it has an active reference arm. Both of these make this a stand-out study. However, not knowing how much difference there was in rates of akathisia or sedation, it is hard to see if this is a clinically meaningful change or a statistically separate change. On top of it, schizophrenia in adolescence is quite a rare condition, and as a result, the commercial benefits of this study are quite limited. I very much would like to look at the efficacy and tolerability results in great detail before I can fully assess if the studies are a game changer, or just “interesting.”

This update does make me look at brexpiprazole and this class of medications in a positive light. The presence of a reference arm is commendable and much appreciated! It really highlights the benefits of brexpiprazole, but without knowing the actual numbers, it is very difficult to fully offer an opinion.

I am impressed with this study! As outlined above, the population being studied is typically ignored, and the presence of a reference arm is highly, highly commendable. I do not believe the study will have a significant impact on the commercial aspects of this medication because schizophrenia in adolescence is an unusual condition. It is not a high-frequency disorder. It is possible that this study will encourage more clinicians to appropriately make the diagnosis of schizophrenia in adolescence, and for them to offer brexpiprazole as a treatment of choice.