Does aripiprazole (Abilify) interact with Parkinson's disease or amantadine?

Aripiprazole Should Be Avoided in Patients with Parkinson's Disease

Aripiprazole is contraindicated in patients with Parkinson's disease due to high risk of motor symptom worsening, and it has significant potential for drug interactions with amantadine through additive CNS toxicity. 1, 2, 3

Evidence Against Aripiprazole Use in Parkinson's Disease

Guideline-Based Contraindication

• The 2019 American Geriatrics Society Beers Criteria explicitly removed aripiprazole from the list of preferred antipsychotics for treating psychosis in Parkinson's disease patients, recognizing only quetiapine, clozapine, and pimavanserin as acceptable exceptions to the general recommendation to avoid all antipsychotics in this population. 1
• This represents a significant shift from prior guidance and reflects accumulating evidence of harm. 1

Clinical Trial Evidence of Motor Worsening

• In an open-label pilot study of 14 Parkinson's disease patients treated with aripiprazole (1-5 mg/day), 8 subjects (57%) discontinued due to adverse effects: 3 from worsened Parkinsonism alone, 2 from worsened psychosis alone, 2 from worsening of both motor and psychiatric symptoms, and 1 from lack of efficacy. 3
• A separate case series of 8 Parkinson's disease patients treated with aripiprazole showed that only 2 of 8 patients experienced near-complete resolution of psychosis, while 2 patients discontinued specifically due to motor worsening within 40 days. 2
• These studies demonstrate that aripiprazole exacerbates the core motor symptoms of Parkinson's disease in the majority of patients, even at low doses. 2, 3

Mechanism of Motor Toxicity

• Despite being marketed as a "partial agonist" at D2 receptors, aripiprazole functions as a functional antagonist in the dopamine-depleted striatum of Parkinson's disease patients, blocking the therapeutic effects of levodopa and dopamine agonists. 2, 3
• The FDA label confirms aripiprazole has been evaluated in Parkinson's disease patients with concerning safety signals. 4

Interaction Between Aripiprazole and Amantadine

Additive CNS Toxicity Risk

• Both aripiprazole and amantadine carry significant CNS toxicity risks that are additive when combined. 5, 4
• Aripiprazole's FDA label warns of potential for cognitive and motor impairment, seizures, confusion, and delirium. 4
• Amantadine causes CNS side effects in 13% of patients at standard dosing, including nervousness, anxiety, difficulty concentrating, and lightheadedness, with serious toxicity including marked behavioral changes, delirium, hallucinations, agitation, and seizures at higher plasma concentrations. 1, 5

Specific Concerns in Elderly Patients

• Elderly Parkinson's disease patients are at highest risk for amantadine toxicity, requiring maximum daily doses of 100 mg (not the standard 200 mg), with many requiring further dose reduction below 100 mg/day. 5, 6
• Elderly women are at particularly high risk due to smaller body size. 5
• Renal function declines with age, and amantadine is excreted unchanged in the urine, necessitating dose reduction in all elderly patients with creatinine clearance ≤50 mL/min/1.73m². 5, 6

Monitoring Requirements if Combination Cannot Be Avoided

If the combination is unavoidable (which it should be avoided):

• Verify renal function before initiating amantadine and reduce dose to maximum 100 mg/day in elderly patients. 5, 6
• Monitor closely for CNS toxicity (confusion, hallucinations, agitation, myoclonus, delirium) especially in the first week. 5, 6
• Watch for seizure activity in patients with seizure history. 5
• Monitor for worsening motor symptoms (increased rigidity, bradykinesia, tremor). 2, 3
• Reduce dose or discontinue immediately if serious side effects emerge. 5

Clinical Algorithm for Psychosis Management in Parkinson's Disease

First-Line Approach

• Use quetiapine, clozapine, or pimavanserin as the only acceptable antipsychotic options per AGS Beers Criteria. 1
• Optimize antiparkinsonian medications to reduce psychosis triggers (reduce anticholinergics, amantadine, dopamine agonists before reducing levodopa). 1

Amantadine-Specific Considerations

• If amantadine is being used for dyskinesia control or motor symptoms, consider whether it may be contributing to psychosis and whether dose reduction or discontinuation is feasible. 7, 8
• Amantadine has insufficient evidence for efficacy in treating core Parkinson's disease symptoms but is sometimes used for dyskinesia management. 7, 8

What to Avoid

• Never use aripiprazole in Parkinson's disease patients. 1, 2, 3
• Avoid combining multiple CNS-active agents (amantadine + antipsychotics) without careful dose adjustment and monitoring. 5, 4
• Do not use standard adult dosing of amantadine (200 mg/day) in elderly patients. 5, 6