Article website: https://pubmed.ncbi.nlm.nih.gov/40209740/

Citation: Ward, C., Milovančević, M.P., Kohegyi, E., Hefting, N., Aurang, C., Chen, D., Larsen, K.G., Hobart, M. and Correll, C.U., 2025. Efficacy and safety of brexpiprazole in adolescents with schizophrenia: a multicountry, randomised, double-blind, placebo-controlled, phase 3 trial with an active reference. The Lancet Psychiatry

Article Overview and Purpose

This article is published in The Lancet Psychiatry. The study was multicountry, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 trial with an active reference (aripiprazole). It was conducted at 62 outpatient sites in ten countries. Eligible patients were aged 13–17 years with a primary DSM-5 diagnosis of schizophrenia and a PANSS total score ≥80. The trial aimed to evaluate the short-term efficacy and safety of brexpiprazole in adolescents with schizophrenia.

Key Efficacy Findings

  • The primary efficacy endpoint, change from baseline to week 6 in PANSS total score, showed that brexpiprazole was associated with a statistically significant greater reduction in symptom severity than placebo.
  • Aripiprazole (active reference) also showed a greater PANSS total score change versus placebo (least squares mean difference –6.53; pnominal=0.0032), validating the trial’s methodology.
  • Secondary outcomes with statistically significant improvement in the brexpiprazole group versus placebo included PANSS Positive subscale score, response rate (≥30% improvement in PANSS total score or CGI-I score of 1 or 2), and CGI-I score.
  • Post hoc analysis showed improvement in PANSS General Psychopathology subscale score with brexpiprazole versus placebo.
  • No statistically significant improvement was observed for PANSS Negative subscale score, remission rate, CGAS score, CGI-S score, or P-Q-LES-Q total score with brexpiprazole versus placebo in the analyses presented in Table 2, although some showed numerical improvement.
  • Efficacy results were consistent with studies in adult patients.

 

Safety and Tolerability Findings

  • The overall safety profile of brexpiprazole in adolescents was consistent with trials in adult patients. At least one treatment-emergent adverse event (TEAE) was reported by 40% of patients in the brexpiprazole group, similar to the placebo group (40%), but lower than the aripiprazole group (52%).
  • The most common TEAEs (incidence ≥5%) with brexpiprazole were headache (6%) and nausea (6%). Most TEAEs in all groups were mild or moderate in severity. No patients discontinued due to TEAEs with brexpiprazole. Two patients discontinued due to TEAEs with placebo, and one with aripiprazole.
  • No deaths were reported during the trial.
  • Extrapyramidal symptom-related TEAEs occurred in 6% of brexpiprazole patients, 5% of placebo, and 11% of aripiprazole. The incidence of akathisia specifically was low with brexpiprazole (4%) compared to aripiprazole (7%).
  • The incidence of somnolence with brexpiprazole (5%) was similar to placebo (5%) but lower than aripiprazole (11%). Brexpiprazole is considered neither activating nor sedating in adults, and the low incidence of akathisia and somnolence here aligns with that.
  • Mean change in bodyweight was small in all groups (+0.8 kg with brexpiprazole, 0.0 kg with placebo, +0.5 kg with aripiprazole). Weight gain ≥7% occurred in a small percentage of patients (8% with brexpiprazole, 5% with placebo, 5% with aripiprazole). Age-adjusted and sex-adjusted bodyweight Z score change was 0.0 SD in all groups.
  • No patients had suicidal behavior during treatment or follow-up. Emergence of suicidal ideation was reported by a low and similar percentage across groups (1% brexpiprazole, 2% placebo, 2% aripiprazole).
  • Changes in metabolic parameters (e.g., fasting glucose) were small.
  • Prolactin concentrations increased slightly but were not clinically meaningful in female patients receiving brexpipazole.

 

Conclusion

Brexpiprazole 2–4 mg/day was associated with greater reduction in symptom severity than placebo over 6 weeks in adolescents with schizophrenia. The safety profile was favourable and consistent with that seen in adults. The findings add to the body of evidence supporting brexpiprazole as a treatment option in adolescents with schizophrenia, potentially aiding in clinical decision-making. The trial supports previous extrapolation and pharmacokinetic data for brexpiprazole use in this population