What medication is used to treat psychosis in Parkinson's disease?

Treatment of Psychosis in Parkinson's Disease

For psychosis in Parkinson's disease, use pimavanserin, quetiapine, or clozapine—these are the only antipsychotics that should be considered, with pimavanserin and clozapine having the strongest evidence for efficacy without worsening motor symptoms. 1

First-Line Medication Choices

The 2019 American Geriatrics Society Beers Criteria specifically identifies three exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease: pimavanserin, quetiapine, and clozapine. 1 However, none of these agents is ideal, and each has distinct limitations that must be considered. 1

Pimavanserin

• Pimavanserin demonstrates significant improvement in psychotic symptoms compared to placebo without worsening motor function, making it a preferred first-line option. 2
• This agent has strong evidence from multiple randomized controlled trials specifically in Parkinson's disease psychosis. 2

Clozapine

• Clozapine is highly effective for treating psychosis in Parkinson's disease and does not exacerbate motor symptoms. 2, 3
• Typical effective dosing ranges from 25-150 mg/day, with most patients responding to lower doses (mean 50-66.7 mg/day initially). 4, 3
• The major limitation is the risk of agranulocytosis, requiring mandatory weekly blood monitoring through a restricted distribution program. 5, 6
• Long-term follow-up data shows sustained efficacy over 5 years, with 19 of 32 patients continuing treatment successfully. 3
• In one series, 50 of 61 patients reported symptom improvement, though 26 eventually discontinued for various reasons including agranulocytosis (1 patient), worsening motor symptoms (4 patients), and intolerable adverse effects (9 patients). 7

Quetiapine

• Quetiapine is frequently used due to ease of administration and lack of mandatory blood monitoring. 6
• However, evidence for efficacy is weaker—meta-analysis shows quetiapine does not demonstrate significant differences in reducing psychotic symptoms compared to placebo. 2
• May cause mild deterioration of motor function, sedation, and orthostatic hypotension. 6
• Despite limited controlled trial evidence, cumulative reports involving >200 Parkinson's disease patients suggest reasonable tolerability. 6

Medications to Avoid

All other antipsychotics should be avoided in Parkinson's disease psychosis as they worsen motor symptoms. 1

• Risperidone causes deterioration of motor function in many patients despite initial tolerability in some studies. 6
• Olanzapine worsens motor functioning despite an initial study suggesting otherwise. 6, 2
• Traditional neuroleptics are contraindicated due to severe exacerbation of parkinsonian symptoms. 6

Common Adverse Effects to Monitor

With Clozapine:

• Sedation (often beneficial as patients have worse behavioral problems at night) 6
• Orthostatic hypotension 6, 3
• Sialorrhea 6
• Agranulocytosis (idiosyncratic, not dose-related—requires weekly CBC monitoring) 5, 6
• Anticholinergic toxicity, especially at higher doses 5
• Fever (transient, typically within first 3 weeks) 5
• Pulmonary embolism and deep-vein thrombosis 5

With Quetiapine:

• Sedation 6
• Orthostatic hypotension 6
• Mild motor function deterioration 6

Treatment Algorithm

1. Before initiating antipsychotics, search for and correct infectious, toxic, or metabolic causes of psychosis. 6

2. Attempt to reduce anti-Parkinson's medications slowly (anticholinergics first, then amantadine, then dopamine agonists, then MAO-B inhibitors, preserving levodopa). 6

3. If psychosis persists and is problematic, initiate pimavanserin as first-line therapy based on strongest evidence for efficacy without motor worsening. 1, 2

4. If pimavanserin is unavailable or ineffective, consider clozapine starting at 12.5-25 mg at bedtime, titrating slowly to 25-100 mg/day based on response. 4, 3

   • Ensure patient can comply with mandatory weekly blood monitoring for agranulocytosis. 5, 7
   • Higher doses (up to 150 mg/day) may be needed for long-term management. 4

5. Quetiapine may be considered if monitoring requirements for clozapine cannot be met, though efficacy evidence is weaker. 6, 2

Critical Pitfalls to Avoid

• Never use typical antipsychotics or risperidone/olanzapine in Parkinson's disease—they will worsen motor symptoms. 1, 6, 2
• Do not abruptly discontinue clozapine as this causes cholinergic rebound (profuse sweating, headache, nausea, vomiting, diarrhea) and recurrence of psychosis. 5
• Do not overlook the need for weekly blood monitoring with clozapine—agranulocytosis can be fatal if undetected. 5, 7
• Avoid combining clozapine with other anticholinergic medications due to increased risk of anticholinergic toxicity and severe gastrointestinal adverse reactions. 5
• Do not assume quetiapine is equally effective to pimavanserin or clozapine—controlled trial evidence does not support this. 2