What is the best way to switch an older adult patient with a history of psychiatric conditions and newly diagnosed Parkinson's disease from Rexulti (brexpiprazole) to Clozapine?

Switching from Rexulti to Clozapine in Parkinson's Disease

Immediate Action: Stop Rexulti and Initiate Clozapine with Cross-Titration

In an older adult with newly diagnosed Parkinson's disease, Rexulti (brexpiprazole) must be discontinued because all antipsychotics except quetiapine, clozapine, and pimavanserin are contraindicated in Parkinson's disease due to worsening motor symptoms. 1

Cross-Titration Protocol

Week 1

• Start clozapine 6.25 mg at bedtime while simultaneously reducing Rexulti from 2 mg to 1 mg daily. 2, 3
• The extremely low starting dose of clozapine (6.25 mg) is critical in Parkinson's disease patients, as effective doses are dramatically lower than in psychiatric populations—typically 6-50 mg daily versus 300-600 mg for schizophrenia. 3

Week 2

• Increase clozapine to 12.5 mg at bedtime and discontinue Rexulti completely. 2
• Monitor for sedation, orthostatic hypotension, and sialorrhea, which are the most common side effects in Parkinson's patients. 4, 3

Weeks 3-4

• Titrate clozapine by 6.25-12.5 mg increments every 3-7 days based on psychiatric symptom control and tolerability. 3
• Target dose range is typically 12.5-50 mg daily for Parkinson's disease psychosis, far below psychiatric dosing. 3
• Do not exceed 100 mg daily unless absolutely necessary, as higher doses increase seizure risk without additional benefit in this population. 3

Critical Monitoring Requirements

Hematologic Monitoring (Non-Negotiable)

• Obtain baseline absolute neutrophil count (ANC) and white blood cell count (WBC) before starting clozapine. 4
• Weekly CBC for first 6 months, then biweekly for months 6-12, then monthly thereafter. 4
• Clozapine carries idiosyncratic agranulocytosis risk (not dose-related), requiring mandatory blood monitoring despite the low doses used in Parkinson's disease. 4, 3

Cardiovascular Monitoring

• Check orthostatic vital signs (lying and standing blood pressure/heart rate) at baseline and each visit during titration. 2, 4, 3
• Orthostatic hypotension is extremely common and may be severe enough to cause falls in older adults with Parkinson's disease. 4, 3

Motor Function Assessment

• Document baseline motor function using standardized Parkinson's rating scales before switching. 5
• Unlike typical antipsychotics and even some "atypicals" like risperidone and olanzapine, clozapine does not worsen motor symptoms and may actually improve tremor. 4, 3
• Reassess motor function at weeks 2,4, and 8 to confirm no deterioration. 5

Psychiatric Symptom Monitoring

• Use standardized scales to track psychiatric symptoms weekly during the switch. 2
• Document specific symptoms (hallucinations, delusions, agitation) at baseline to measure treatment response. 5

Seizure Risk Management

Parkinson's disease patients have inherently lowered seizure threshold, and clozapine further reduces it in a dose-dependent manner. 1

• Consider prophylactic anticonvulsant (valproate 250-500 mg daily) if clozapine dose exceeds 50 mg daily or if patient has seizure history. 1
• The "start low, go slow" approach minimizes seizure risk while achieving therapeutic benefit. 1

Common Pitfalls to Avoid

• Do not continue Rexulti while titrating clozapine beyond week 2. Antipsychotic polypharmacy should be avoided, and the cross-titration should be completed within 2-4 weeks. 1, 2

• Do not use typical antipsychotics or other atypicals (risperidone, olanzapine, aripiprazole) as alternatives. Only quetiapine, clozapine, and pimavanserin are acceptable in Parkinson's disease, with clozapine having the strongest evidence. 1, 4

• Do not assume psychiatric symptoms are purely medication-related. Rule out delirium from infection, metabolic derangement, or hypocalcemia (especially relevant given the abnormal parathyroid levels requiring consultation). 5, 6

• Do not overlook medication interactions. Caffeine and smoking dramatically affect clozapine metabolism through CYP1A2. 7 Document baseline caffeine intake and smoking status, as changes can precipitate toxicity or loss of efficacy.

Adjunctive Considerations

Parkinson's Medication Review

• Simplify anti-Parkinsonian regimen if psychiatric symptoms are intrusive. 5, 6
• Reduce or eliminate dopamine agonists, amantadine, and anticholinergics first, as these are most likely to cause psychosis. 6
• Maintain levodopa at the lowest effective dose, as it is least likely to cause psychiatric symptoms. 3

Anticholinergic Burden

• Avoid anticholinergic medications entirely in this population. 8 The patient is already on buspirone (non-anticholinergic anxiolytic, which is appropriate) and should not receive anticholinergics for Parkinson's motor symptoms given the psychiatric comorbidity.

Alternative if Clozapine Fails or Is Refused

• Quetiapine 12.5-50 mg at bedtime is the second-line option if clozapine cannot be used. 1, 4, 5
• Quetiapine does not require blood monitoring but is less effective than clozapine and may cause mild motor deterioration. 4
• Pimavanserin is FDA-approved specifically for Parkinson's disease psychosis but is extremely expensive and has less robust evidence than clozapine. 1

Follow-Up Timeline

• Week 2: Assess tolerability, check orthostatic vitals, obtain first CBC result. 2
• Week 4: Complete psychiatric symptom assessment and motor function evaluation. 2, 5
• Week 8: Determine if adequate response achieved; if not, consider increasing dose incrementally or adding cholinesterase inhibitor for cognitive symptoms. 5, 6