Rexulti calms restlessness linked to Alzheimer’s dementia


NEW ORLEANS – Brexpiprazole (Rexulti) helped relieve agitation in people with Alzheimer’s dementia, according to a phase III study.

During the 12-week trial, patients receiving a daily dose of 2 mg or 3 mg of the atypical antipsychotic saw significant improvement in the Cohen-Mansfield Agitation Inventory (CMAI) total score by versus placebo (treatment difference -5.32, 95% CI -8.77 to -1.87, P= 0.0026), reported George T. Grossberg, MD, of St. Louis University School of Medicine in Missouri, and colleagues.

Patients receiving either dose of brexpiprazole saw a mean 22.6 point drop in CMAI total score at week 12 compared to a 17.3 point drop seen with placebo, meeting criterion for main evaluation of the study. The change was significantly different from placebo at week eight of treatment, Grossberg’s group said in a poster at Psych Congress 2022.

In a separate poster, researchers evaluated brexpiprazole as a treatment for symptoms of borderline personality disorder (BPD) and found less encouraging results.

Alzheimer’s hustle

There are currently no FDA-approved treatments specifically indicated for Alzheimer’s disease-related agitation. Acting as a dopamine D A partial receptor agonist, brexpiprazole is approved as an add-on treatment for major depressive disorder in adults and schizophrenia in adults and adolescents (aged 13 years and older). The agent’s label contains a boxed warning for an increased risk of death in older people with dementia-related psychosis.

For the current trial, 225 patients (mean age 74 years; vast majority Caucasian) were randomized to receive brexpiprazole (73 for the 2 mg dose and 152 for the 3 mg dose), while 116 patients were assigned to placebo. All lived in a care or community facility and likely had Alzheimer’s disease as defined by the NINCDS-ADRDA diagnostic criteria.

At baseline, participants had a Mini Mental State Examination (MMSE) score between 5 and 22; meets criteria for agitation as defined by the International Psychogeriatric Association criteria and the Cohen-Mansfield Agitation Inventory Factor 1; and had a score of 4 or greater on the Neuropsychiatric Inventory for Agitation/Aggression.

The mean time since diagnosis of Alzheimer’s disease was 34 months for placebo and 37 months for brexpiprazole, and the mean time since first episode of agitation was 21.5 months and 24.2 months, respectively. Just over half of the participants scored moderate on the MMSE, while around 23% and 20% had mild and severe cognitive impairment, respectively.

The researchers reported that headache was the only adverse event (AE) in 5% or more of patients (6.9% placebo versus 6.6% brexpiprazole). Other AEs reported in 2% to 5% of patients on treatment included nasopharyngitis, urinary tract infection, dizziness, somnolence and diarrhea.

With respect to some other AEs of interest in this older patient population, an incidence of sedation, falls, akathisia, extrapyramidal disorder, or weight gain of 7% or more has been reported in less than 2% of patients. patients on brexpiprazole. Only one death occurred in the group receiving 3 mg of brexpiprazole, but it was deemed unrelated to the study drug.

Most participants completed the 12-week trial (88.9% placebo; 86.8% brexpiprazole), according to the researchers.

The trial also achieved a key secondary endpoint, the change from baseline in the CGI-S (Clinical Global Impression-Severity of Illness) score related to agitation. This was marked by a 0.93 point drop from placebo compared to a 1.22 point drop seen with brexpiprazole (treatment difference -0.29, 95% CI -0.5 to -0.09 , P=0.0055). Likewise, this improvement was statistically significant at week 8 of treatment.

All three CMAI subscale scores were also significantly better with either dose of brexpiprazole compared to placebo at week 12:

  • Aggressive subscale score: -7.13 for placebo versus -9.09 for brexpiprazole
  • Physically non-aggressive: -5.04 vs -6.45
  • Verbally agitated: -3.14 vs -4.39

When the doses were split, the 2mg and 3mg groups showed significant improvement in symptoms at the same time.

Developers Otsuka Pharmaceutical and Lundbeck have announced plans to submit a additional new drug application to the FDA requesting this additional indication later this year.

“We believe the effective dose is 2 mg,” said Pedro Such, MD, senior medical advisor to co-developer Lundbeck. MedPage today.

“We mainly tested the 3mg dose for safety and durability, and we find that the effectiveness is the same,” he added. “We think it’s good enough with 2mg.”


Borderline personality disorder has no treatments specifically indicated for the disorder, and outpatient psychotherapy is the most common therapy.

In a phase II trial, brexpiprazole failed to improve symptoms associated with the personality disorder, reported Brian Rothman, PhD, of Otsuka in Princeton, New Jersey, and colleagues.

The trial randomized 324 patients (aged 18-65) with DSM-5-diagnosed borderline personality disorder to receive brexpiprazole 2 mg or 3 mg daily (n=159) or placebo (n=165).

Treatment with brexpiprazole was not significantly better at improving mean Zanarini-BPD rating scale (Zan-BPD) total scores versus placebo at week 10 (-7.27 for brexpiprazole vs -6.25 for placebo, P=0.24), the researchers reported. And the mean change from week 1 in the CGI-S score was not significantly better with brexpiprazole at week 10 (secondary endpoint).

“However, brexpiprazole was associated with nominally significant improvements over placebo at weeks 8 and 12 on Zan-BPD and at week 12 on CGI severity,” Rothman pointed out.

  • Kristen Monaco is a writer, specializing in endocrinology, psychiatry and nephrology news. Based in the New York office, she has been with the company since 2015.


The trials were supported by Otsuka and Lundbeck. Some co-authors are employees of Otsuka or Lundbeck.

Grossberg disclosed relationships with Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche and Takeda.


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