Earlier Pimavanserin Initiation May Alter Psychosis Symptom Trajectory in Parkinson's Disease, Exploratory Analysis Suggests

An exploratory post hoc analysis presented at the 2026 Advanced Therapeutics in Movement & Related Disorders® (ATMRD) Congress suggests that earlier initiation of pimavanserin (Nuplazid; Acadia Pharmaceuticals) may be associated with a more favorable psychotic symptom trajectory in patients with Parkinson's disease psychosis (PDP).¹ Using pivotal trial data from 171 patients, investigators simulated a delayed-start design to assess whether timing of treatment initiation influences the course of psychotic symptoms over a 10-week window.

Study Design

The analysis divided a 10-week period into a 6-week double-blind randomized controlled trial (RCT) phase and a 4-week open-label extension (OLE). The early-start group received pimavanserin 34 mg/day throughout; the delayed-start group received placebo during the RCT before crossing over to pimavanserin. Led by William Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute in Texas, patients were stratified by time elapsed between PDP symptom onset and treatment initiation, using cutoffs of 6 and 12 months. Psychosis severity was assessed with the Scale for Assessment of Positive Symptoms adapted for Parkinson's Disease (SAPS-PD) and the Clinical Global Impression-Severity (CGI-S) scale.

Key Findings

For the main exploratory endpoint (estimated treatment difference in SAPS-PD score change from baseline at week 10), patients with PDP duration of less than 6 months showed numerically greater improvement in the early-start versus delayed-start group (estimated treatment difference, −5.97; P = .0505). Among those with PDP duration of 6 months or more, scores were similar between groups at week 10 (estimated treatment difference, 0.14; P = .9080).¹ A similar but less pronounced pattern was observed at the 12-month cutoff.

On secondary endpoints, SAPS-PD trajectory slopes in the less-than-6-month subgroup were comparable between groups across both study phases. In the 6-months-or-more subgroup, slopes diverged during the OLE period (estimated difference in slopes, weeks 6 to 10: 0.94; P = .0016), though investigators noted this could reflect regression to the mean or insufficient time on active drug, as the delayed-start group had received only 4 weeks of pimavanserin by week 10.¹

A supportive CGI-S endpoint extending through week 54 suggested the early-start group may maintain a noninferior symptom trajectory versus the delayed-start group over longer follow-up, though this analysis was hypothesis-generating only.¹

Limitations and Disclosures

Sample sizes were small, particularly in the less-than-6-month subgroup (n = 21), and analyses were not powered to detect subgroup differences; all P values are nominal. The source trials were not designed as delayed-start studies, and the delayed-start group's limited time on active therapy constrains interpretation of the primary results.

Three of the five authors are employees of Acadia Pharmaceuticals, which funded the study. The investigators stated that the findings are intended to inform the design of a prospective trial with adequate duration and statistical power to more rigorously test the progression-slowing hypothesis.¹

Pimavanserin received FDA approval in April 2016 as the first therapy indicated for hallucinations and delusions associated with PDP, based on the pivotal phase 3 ACP-103-020 trial.^2,3

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REFERENCES
1. Ondo WG, Mari Z, Zhang P, Chrones L, Brunson G. Pimavanserin in Parkinson's Disease Psychosis: An Exploratory Post Hoc Delayed-Start Analysis. Poster presented at: Advanced Therapeutics in Movement & Related Disorders® (ATMRD) Congress; June 4-8, 2026; Washington, DC. Session A, Poster No. 13.
2. FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease psychosis. News release. US Food and Drug Administration. April 29, 2016. Accessed June 5, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-hallucinations-and-delusions-associated-parkinsons-disease-psychosis
3. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. doi:10.1016/S0140-6736(13)62106-6. https://doi.org/10.1016/S0140-6736(13)62106-6