Pimavanserin May Reduce Symptoms of Parkinson Disease Psychosis Without Increasing Risk of Motor Function Impairment

EBM Focus - Volume 9, Issue 7

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Reference: Lancet 2014 Feb 8;383(9916):523 (level 2 [mid-level] evidence)

Many patients with Parkinson disease will develop psychosis, but there are few options available to manage these symptoms. The American Geriatrics Society Beers Criteria recommends avoiding all antipsychotics except quetiapine and clozapine in patients with Parkinson disease, due to an increased risk of worsening Parkinsonian symptoms (J Am Geriatr Soc 2012 Apr;60(4):616 full-text). In addition, clinical evidence from large studies showing efficacy for reducing psychosis without increased risk of serious adverse events has been lacking. A recent randomized trial compared the new antipsychotic pimavanserin to placebo in patients with Parkinson disease psychosis.

A total of 199 patients ≥ 40 years old with Parkinson disease psychosis were randomized to pimavanserin 40 mg orally once daily vs. placebo for 6 weeks. Pimavanserin is a selective serotonin 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic, or muscarinic affinity. All patients had idiopathic Parkinson disease for at least 1 year with no delirium, and had psychotic symptoms for at least 1 month and occurring at least weekly in the month before screening. Psychosis symptoms were assessed using the Parkinson disease-adapted scale for assessment of positive symptoms (SAPS-PD), consisting of a global assessment of hallucinations, a global assessment of delusions, and assessments of 7 individual symptoms of Parkinson disease (total score range 0-45, with higher scores indicating worse symptoms). At baseline, all patients had a mini-mental status examination score of at least 21 points, and the mean SAPS-PD score was 15.9 in the pimavanserin group vs. 14.7 in the placebo group (not significant). Prior to receiving study medication, all patients participated in a 2-week lead-in period during which they received brief nonpharmacologic psychosocial therapy. Patients were not allowed to receive other antipsychotic drugs during the trial, but they were allowed to receive stable doses of antiparkinsonian medication or deep brain stimulation.

About 88% of patients completed the trial, and 93% of patients were included in the efficacy analyses. The mean reduction in SAPS-PD symptom score was 5.79 with pimavanserin vs. 2.73 with placebo (p = 0.0014). A separate study has estimated the minimal clinically important difference for the SAPS-PD score to be 2.33 points. Similarly, the proportion of patients with at least a 20% reduction in SAPS-PD symptom score was 63% with pimavanserin vs. 47% with placebo (p = 0.0242, NNT 7). The proportion of patients with a clinical global impression of improvement was 49% with pimavanserin vs. 26% with placebo (p = 0.0015, NNT 5). Serious adverse events occurred in 11% of patients receiving pimavanserin and 4% of those receiving placebo (no p value reported). No treatment-related motor function impairment was observed in either group.

There is currently an unmet need for safe and effective treatment options for Parkinson disease psychosis. In this randomized trial, pimavanserin demonstrated a significant reduction in psychosis symptoms across several different outcome measures, and was generally well tolerated. However, the short duration of this trial is an important limitation, and longer follow-up is required for both efficacy and safety analyses. Pimavanserin is not currently available, but a new drug application with the U.S. Food and Drug Administration for use in patients with Parkinson disease is expected later this year.

For more information see the Parkinson disease topic in Dynamed.