Clozapine is Superior to Rexulti for Parkinson's Disease Psychosis
Clozapine is the only antipsychotic with Level A evidence for treating psychosis in Parkinson's disease, while brexpiprazole (Rexulti) is contraindicated and should be avoided entirely in this population. 1, 2
Why Clozapine is the Correct Choice
Guideline-Based Recommendations
The 2019 American Geriatrics Society Beers Criteria explicitly recognizes only three antipsychotics as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease: quetiapine, clozapine, and pimavanserin. 1
Brexpiprazole (Rexulti) is NOT among these exceptions and falls under the "strong" recommendation to avoid, meaning harms clearly outweigh benefits in Parkinson's disease patients. 1
Clozapine has Level A evidence (the highest quality) supporting its use in PD patients with psychosis, whether demented or not. 2
Clinical Efficacy Evidence
In a 5-year follow-up study of 32 PD patients with psychosis, 19 patients (59%) continued clozapine successfully at a mean dose of 50 mg daily, with 9 patients able to discontinue after symptom resolution. 3
A retrospective review of 64 PD patients treated with clozapine showed 50 of 61 patients (82%) reported improvement in their target symptoms (psychosis and/or tremor). 4
The effective dosage of clozapine in PD psychosis is very low (mean 33.3 mg daily, range 6.2-100 mg) compared to psychiatric patients, with no motor deterioration observed. 5
Critical Safety Distinction
Brexpiprazole is a D2 antagonist that will worsen motor symptoms in Parkinson's disease, the exact problem that makes typical and most atypical antipsychotics contraindicated in this population. 1, 2
Clozapine does not worsen motor function at the low doses used for PD psychosis, and some patients even experience improvement in tremor. 4, 5, 3
Practical Implementation Algorithm
Starting Clozapine in PD Psychosis
Initiate clozapine at nighttime starting at 6.25-12.5 mg and titrate slowly until clinical effect appears or intolerable side effects occur. 5
Target dose range is typically 25-50 mg daily (much lower than schizophrenia dosing). 5, 3
Maintain or even increase dopamine agonist dosages as tolerated, since clozapine allows for better motor symptom management. 5
Monitor for agranulocytosis with required blood count monitoring per clozapine protocols. 3
Expected Outcomes
Complete and constant improvement occurs in approximately 46% of patients, with satisfactory improvement in an additional 33%. 5
Some patients (approximately 28% in one study) achieve symptom resolution and can discontinue clozapine after 1-24 months. 3
Side Effects to Monitor
Sialorrhea (excessive salivation) is common but manageable. 5
Sedation may occur and can be dose-limiting in some patients. 5, 3
Orthostatic hypotension requires monitoring, especially given the PD population's baseline autonomic dysfunction. 5
Common Pitfalls to Avoid
Do not use brexpiprazole, aripiprazole, risperidone, or olanzapine in PD psychosis—these will worsen motor symptoms. 1, 6
Do not use typical antipsychotic doses of clozapine; PD patients respond to much lower doses (25-50 mg vs 300-600 mg for schizophrenia). 5, 3
Do not assume quetiapine is equivalent to clozapine despite its inclusion in the Beers Criteria exceptions—randomized controlled trials have failed to demonstrate efficacy for quetiapine, while clozapine has Level A evidence. 6, 2
Do not skip the required hematologic monitoring for clozapine; while agranulocytosis risk exists, no cases occurred in the long-term PD studies reviewed, but monitoring remains mandatory. 5, 3