In a patient with Parkinson disease and psychosis, which antipsychotic is recommended as first‑line treatment?

Antipsychotic Selection for Parkinson's Disease Psychosis

Pimavanserin is the recommended first-line antipsychotic for Parkinson's disease psychosis, as it is FDA-approved specifically for this indication and does not worsen motor symptoms. 1, 2

Treatment Algorithm

First-Line: Pimavanserin

• Pimavanserin 34 mg once daily (without titration) is the preferred initial choice based on American Psychiatric Association and American College of Physicians guidelines, due to its FDA approval and superior safety profile regarding motor function 1, 2
• Does not cause motor deterioration, sedation, or orthostatic hypotension unlike other antipsychotics 3, 4
• A 2025 expert consensus and 2024 systematic review both support pimavanserin as first-line therapy 4, 5
• Black box warning exists for increased mortality in elderly patients with dementia-related psychosis, though this applies to all antipsychotics 2

Second-Line: Clozapine

• If pimavanserin is unavailable or ineffective, clozapine is the next choice as it has the strongest evidence for efficacy without worsening motor symptoms 3, 1, 6, 7, 5
• Clozapine demonstrated superiority over placebo in reducing psychotic symptoms in meta-analysis 7
• Requires weekly blood monitoring for agranulocytosis risk, which limits its use 8
• Common side effects include sedation (often beneficial for nighttime symptoms), orthostatic hypotension, and sialorrhea 8

Third-Line: Quetiapine

• Quetiapine is a reasonable option when clozapine monitoring is not feasible, though evidence for efficacy is less robust 3, 6
• Start with 25 mg at bedtime and increase gradually 3
• Associated with high dropout rates due to adverse events and may cause mild motor deterioration 8, 7
• Risk in patients with cognitive impairment 4

Critical Contraindications

Avoid These Antipsychotics

• Olanzapine is contraindicated in Parkinson's disease psychosis despite being an atypical antipsychotic, as its striatal D2 receptor blockade causes motor deterioration 3
• Risperidone causes motor function deterioration and should be avoided 8
• All typical antipsychotics (haloperidol, phenothiazines) worsen motor symptoms and are contraindicated 3

Pre-Treatment Steps

Before initiating any antipsychotic, systematically address reversible causes: 6, 8

• Rule out infectious causes (UTI, pneumonia)
• Identify toxic causes (anticholinergics, other medications)
• Exclude metabolic derangements (electrolyte abnormalities, renal/hepatic dysfunction)
• Slowly reduce anti-Parkinson's medications in this order: anticholinergics first, then amantadine, MAO-B inhibitors, dopamine agonists, and finally reduce levodopa if necessary 6

Common Pitfalls

• Do not combine olanzapine with metoclopramide, phenothiazines, or haloperidol due to excessive dopamine blockade risk 3
• Avoid strong or moderate CYP3A4 inducers with pimavanserin; reduce pimavanserin dose to 10 mg daily if using strong CYP3A4 inhibitors 2
• Do not assume all "atypical" antipsychotics are safe—only pimavanserin, clozapine, and quetiapine are acceptable options 3, 1