Letter to the Editor

Dear Editor:

I enjoyed reading the recently published article “Treatment of psychotic symptoms in patients with Parkinson disease.”¹ It provided insight into the underappreciated problem of Parkinson disease psychosis while highlighting limited pharmacological options. In the article, a 5-HT_2A inverse agonist, pimavanserin, is discussed as a novel therapeutic treatment option. To date, 2 open-label studies and 4 placebo-controlled clinical trials, 1 phase II and 3 phase III trials, were completed; however, the results of the only published phase III clinical trial (ACP-103-020) were reviewed.

Touma and colleagues² provided a comprehensive overview of the current literature for pimavanserin, including data from unpublished trials. The primary outcome for the first phase III trial (ACP-103-012) was the difference from baseline in the 20-item hallucination and delusion domains of the scale for the assessment of positive symptoms (SAPS H+D). Pimavanserin (10 mg and 40 mg) did not demonstrate statistically significant improvement in psychosis symptoms from baseline to 6 weeks compared to placebo. The concurrent second phase III study (ACP-103-014), evaluating lower doses of pimavanserin (10 mg and 20 mg), was therefore terminated early.³

The last phase III study (ACP-103-020),⁴ which led to the Food and Drug Administration approval of pimavanserin 40 mg, modified the primary outcome to include 9 of the 20 items of the SAPS H+D. The items were selected only if improvement was demonstrated in the previous failed trials and formed the new nonvalidated scale of positive symptoms-Parkinson's disease (SAPS-PD). Although the trial established a statistically significant difference of SAPS-PD least square mean for pimavanserin at 6 weeks compared to placebo, −3.06 (95% confidence interval –4.91 to –1.20, P = .001), the clinical impact is uncertain.^2,3 This difference is equivalent to a change of 1 in the clinician global impression-improvement scale, which only corresponds to minimal improvement.⁵ This signifies a change of 3 points on the SAPS-PD, which was determined to be statistically significant in the pivotal pimavanserin study but may not be a good indicator of clinical improvement in regards to psychotic symptoms. A change of 5 to 7 points on the SAPS-PD scale may better represent a clinically significant improvement.³

In November 2017, the Institute for Safe Medication Practices released the QuarterWatch™ specifically focusing on the safety of pimavanserin.⁶ In the first year post-Food and Drug Administration approval, more than 20% of patients who received pimavanserin reported hallucinations as an adverse effect, and 15% reported ineffectiveness. Of those taking pimavanserin who achieve a 50% reduction on the SAPS-PD scale, half experienced a serious adverse effect, including reports of hospitalization and death or other life-threatening states. Overall, there was a higher rate of death in the pimavanserin group compared to placebo, 5.3% versus 0.5%, respectively.³ Based on the safety information, the psychiatrist responsible for reviewing the new drug application recommended against Food and Drug Administration approval of pimavanserin.⁷

Review of available clinical evidence and postmarketing safety reports suggest there are significant limitations to the use of pimavanserin for the treatment of Parkinson disease psychosis, and the exact place in therapy is unknown.