Brexpiprazole in Alzheimer’s Disease-Related Agitation: Modest Gains Amidst Safety Uncertainties

Highlight

• Brexpiprazole exhibits modest efficacy in reducing agitation severity in older adults with Alzheimer’s disease (AD).
• Clinical global impression scores showed modest improvement, whereas neuropsychiatric symptom scores did not significantly change.
• Adverse events such as extrapyramidal symptoms and daytime somnolence were more frequent but with wide confidence intervals indicating safety uncertainty.
• Meta-regression analyses found no evidence that dose or treatment duration modified clinical outcomes.

Background

Agitation is one of the most prevalent and distressing neuropsychiatric symptoms in Alzheimer’s disease, affecting approximately 40-50% of patients during the disease course. It not only exacerbates cognitive decline but also contributes significantly to caregiver stress and increased healthcare utilization. Nonpharmacologic interventions remain first-line, yet often insufficient for managing moderate to severe agitation. Pharmacologic treatments are sought cautiously due to concerns about cognitive worsening and adverse effects in this vulnerable population. Brexpiprazole, a serotonin-dopamine activity modulator with partial agonist and antagonist properties at various receptors, has emerged as a candidate for symptom control given its receptor profile and tolerability in other psychiatric conditions. However, its efficacy and safety in AD-related agitation remain to be systematically evaluated, particularly in older adults who may have heightened sensitivity to side effects.

Study Design

This systematic review and meta-analysis adhered to PRISMA 2020 guidelines and the Cochrane Handbook methodology. Randomized controlled trials (RCTs) were included if they evaluated brexpiprazole doses ranging from 0.5 to 3 mg/day versus placebo in older adults with clinically diagnosed Alzheimer’s disease presenting with agitation. The primary efficacy endpoints were agitation severity quantified using the Cohen-Mansfield Agitation Inventory (CMAI) and overall clinical impression assessed via the Clinical Global Impression-Severity scale (CGI-S). Secondary endpoints included neuropsychiatric symptoms measured by the Neuropsychiatric Inventory (NPI) and a safety profile incorporating adverse events frequency. Both frequentist and Bayesian random-effects meta-analyses were conducted in R (version 4.3.0), supplemented by meta-regression exploring dose and treatment duration as potential effect modifiers. The protocol was registered under PROSPERO CRD 42025646060.

Key Findings

The meta-analysis included five RCTs comprising 1770 participants. The pooled analysis revealed a modest but statistically significant reduction in agitation severity with brexpiprazole compared to placebo, reflected by a mean difference of -5.79 points on the CMAI (95% confidence interval [CI]: -9.55 to -2.04). The prediction interval (-14.07 to 2.49) highlighted variability in effect size, indicating that some future studies might show no benefit or even potential harm.

Regarding the CGI-S, brexpiprazole demonstrated modest improvement with a mean difference of -0.23 (95% CI: -0.32 to -0.13), supporting a slight but consistent clinical impression of symptom improvement. Conversely, no significant differences were observed in NPI scores, suggesting that broader neuropsychiatric symptoms might be less responsive to brexpiprazole or require longer observation.

Safety analyses revealed a higher incidence of extrapyramidal symptoms and daytime somnolence in the brexpiprazole group. However, 95% confidence intervals for these adverse events were wide and crossed the null, reflecting imprecision and limiting firm conclusions about the safety profile.

Meta-regression assessing the influence of dosage and treatment duration on efficacy and safety outcomes showed no significant effect modification, indicating that neither higher doses nor longer treatment times consistently improved efficacy or influenced adverse events rates within the studied ranges.

Expert Commentary

Brexpiprazole’s receptor profile with partial agonism at dopamine D2 receptors and serotonin 5-HT1A receptors, and antagonism at 5-HT2A receptors, theoretically supports a modulation of agitation through dopaminergic and serotonergic pathways implicated in behavioral disturbances in AD. The modest improvement in agitation scores aligns with this pharmacologic rationale, although the lack of significant change in broader neuropsychiatric symptoms underscores the heterogeneity of AD-related behaviors and the need for more granular phenotyping in trials.

It is important to interpret these findings in the context of potential biases inherent to industry-sponsored studies and the generally short duration of included RCTs, which limit the evaluation of long-term safety and sustained effectiveness. The borderline safety findings, especially regarding extrapyramidal symptoms, warrant heightened vigilance, given older adults’ vulnerability to motor side effects that may increase fall risk and functional decline.

Current clinical guidelines do not strongly endorse antipsychotic use for agitation in dementia without severe behavioral disturbance or risk to self/others, emphasizing nonpharmacologic approaches first. Brexpiprazole may represent an alternative to conventional antipsychotics with a possibly more favorable side effect profile, but evidence gaps persist.

Conclusion

Brexpiprazole provides modest short-term benefits in managing agitation symptoms in older adults with Alzheimer’s disease without evidence of cognitive worsening. However, the considerable uncertainty regarding safety and variability in efficacy highlights the necessity for individualized treatment decisions and close clinical monitoring. Larger, longer-term RCTs are needed to elucidate the durability of therapeutic effects and safety outcomes, especially focusing on real-world patient-centered measures such as quality of life and caregiver burden. Until then, clinicians should balance potential benefits against risks and remain circumspect in prescribing brexpiprazole for agitation in this sensitive population.

Funding and Registration

The systematic review and meta-analysis were conducted independent of pharmaceutical funding. The study protocol was registered with PROSPERO under number CRD 42025646060.

References

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