Pimavanserin is an atypical antipsychotic approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Unlike traditional antipsychotics, it does not block dopamine receptors, making it a unique option for patients with Parkinson’s disease who are highly sensitive to dopamine antagonism.

Mechanism of Action

Pimavanserin works primarily as a selective serotonin 5-HT2A inverse agonist and antagonist, with minor activity at 5-HT2C receptors. This dopamine-sparing effect is the key reason it does not worsen motor symptoms in Parkinson’s disease.

Adverse Effects

The most commonly reported side effects include peripheral edema, nausea, confusion, and hallucinations. QT interval prolongation is a clinically important concern, especially in patients with existing cardiac risk factors. Somnolence may occur but is generally less prominent compared with dopamine-blocking antipsychotics.

Warnings and Precautions

Pimavanserin carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis, consistent with other antipsychotics. It should not be used in patients with known QT prolongation, a history of ventricular arrhythmias, or in combination with other QT-prolonging agents when possible.

Drug Interactions

Strong CYP3A4 inhibitors, such as ketoconazole or clarithromycin, can significantly increase pimavanserin concentrations and require dose reduction. Strong CYP3A4 inducers, such as rifampin or carbamazepine, may reduce efficacy and should generally be avoided. Additive QT prolongation may occur when combined with other QT-prolonging medications, including certain antiarrhythmics, fluoroquinolones, and macrolide antibiotics.

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