Is brexpiprazole (an atypical antipsychotic) safe to use in elderly patients with Parkinson's disease?

Brexpiprazole Should Be Avoided in Elderly Patients with Parkinson's Disease

Brexpiprazole is NOT safe for use in elderly patients with Parkinson's disease and should be avoided—it is classified as an inappropriate antipsychotic for this population according to the 2019 American Geriatrics Society Beers Criteria. 1

Guideline-Based Contraindication

The 2019 AGS Beers Criteria explicitly removed aripiprazole (brexpiprazole's predecessor) from the list of acceptable antipsychotics for Parkinson's disease patients, recognizing only three exceptions: quetiapine, clozapine, and pimavanserin. 1 Brexpiprazole is not among these exceptions and falls under the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease due to the risk of worsening Parkinsonian motor symptoms. 1

Evidence of Harm in Parkinson's Disease

Real-world data from long-term care facilities demonstrates that brexpiprazole is classified among the "inappropriate antipsychotics" for PD patients, alongside olanzapine, risperidone, and ziprasidone. 2 A national cohort study of over 12,000 older adults with Parkinson's disease and depression found that inappropriate antipsychotic use (which includes brexpiprazole) was associated with:

• 13% increased risk of all-cause mortality compared to appropriate antipsychotics (HR 1.13,95% CI: 1.01-1.28) 3
• Higher pneumonia-mediated mortality risk 3
• More than one-third of PD patients inappropriately received these medications when antipsychotics were prescribed 2

Why Brexpiprazole Is Problematic in Parkinson's Disease

Brexpiprazole's mechanism of action—partial dopamine D2 receptor agonism—poses specific risks in Parkinson's disease: 4, 5

• Worsening of motor symptoms: Dopamine receptor blockade or modulation can exacerbate bradykinesia, rigidity, and tremor in PD patients 1
• Increased mortality: Like other antipsychotics, brexpiprazole carries an FDA black box warning for increased mortality in elderly patients with dementia 4, 6
• No safety data in PD: Clinical trials of brexpiprazole specifically excluded patients with Parkinson's disease, studying only Alzheimer's disease-related agitation 4, 6

Safer Alternatives for Psychosis in Parkinson's Disease

If antipsychotic treatment is absolutely necessary for psychosis in an elderly PD patient, use ONLY these three options: 1

1. Pimavanserin (preferred, added to 2019 Beers Criteria as acceptable)
2. Quetiapine (low-dose, though efficacy data are limited)
3. Clozapine (most effective but requires hematologic monitoring)

All three have significant limitations, but they do not worsen motor symptoms to the same degree as other antipsychotics. 1

Clinical Decision Algorithm

When considering antipsychotic use in elderly PD patients:

• First: Attempt non-pharmacological interventions and treat underlying causes (infection, pain, medication side effects) 5
• Second: If psychosis persists and is dangerous, choose pimavanserin as first-line pharmacologic option 1
• Third: Consider quetiapine (starting 12.5-25 mg) or clozapine if pimavanserin fails or is unavailable 1
• Never: Use brexpiprazole, risperidone, olanzapine, or other typical/atypical antipsychotics not listed above 1, 2, 3

Critical Pitfall to Avoid

The approval of brexpiprazole for agitation in Alzheimer's disease does NOT extend to Parkinson's disease. 4, 5 Clinicians must not extrapolate its use to PD patients, as the dopaminergic pathology in Parkinson's disease creates fundamentally different risks compared to Alzheimer's disease. 1, 3 Patients taking levodopa or other dopaminergic medications are at particularly high risk for motor deterioration with inappropriate antipsychotics. 2