Increased Risk for Hospitalization, Death with Parkinson's Drug

Anna Goshua

August 19, 2021

Pimavanserin, a novel antipsychotic drug used to manage hallucinations and delusions in Parkinson's disease, may lead to increased hospitalizations and deaths, according to a new study.

A retrospective cohort study of elderly patients with Parkinson's disease who were in long-term care facilities found that the use of pimavanserin (Nuplazid) was associated with an increased risk of 30-day hospitalization and mortality for up to a year.

"Given that a previous study showed typical and atypical antipsychotics more than doubled mortality risk in patients with Parkinson's disease, we aimed to assess the risk of hospitalization and death associated with pimavanserin," wrote lead author Y. Joseph Hwang, MD, Johns Hopkins University, Baltimore, and colleagues in the paper. "These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk-benefit balance among patients with Parkinson's disease."

The findings were published online Aug. 13 in Neurology.

The researchers enrolled 2,186 patients with Parkinson's disease aged 65 years and older in Medicare-certified long-term care facilities who also had a pimavanserin prescription and 18,212 nonusers of pimavanserin between Nov. 1, 2015, and December 31, 2018. Patients in the pimavanserin group used the drug over the course of the entire study period. Hospitalization and mortality were calculated from the date of pimavanserin prescription. Propensity score–based inverse probability of treatment weighting (IPTW) was used to balance the two groups on 24 baseline characteristics such as age, sex, and comorbidities.

Pimavanserin use was associated with a 24% higher risk of 30-day hospitalization (adjusted hazard ratio, 1.24; 95% confidence interval, 1.06-1.43). However, "the association did not reach statistical significance in a smaller subcohort of propensity score-matched users and nonusers," Hwang and colleagues wrote.

Pimavanserin use was also linked to higher mortality at:

  • 90 days (aHR, 1.20; 95% CI, 1.02-1.41).

  • 180 days (aHR, 1.28; 95% CI, 1.13-1.45).

  • 365 days (aHR, 1.56; 95% CI, 1.42-1.72).

No associations were found between pimavanserin use and 90-day hospitalization (aHR, 1.10; 95% CI, 0.99-1.24) nor with 30-day mortality (aHR, 0.76; 95% CI, 0.56-1.03).

Important Considerations

"This study raises three important points to consider for any practicing neurology provider: 1) how to address and interpret risks associated with pimavanserin use in this patient population 2) utility of pimavanserin 3) interpretation of data showing increased mortality in patients being treated for Parkinson's disease psychosis," wrote Farwa Ali, MBBS, of the Mayo Clinic, Rochester, Minn., in an accompanying editorial published in Neurology.

Hallucinations and delusions are highly prevalent in Parkinson's disease; as many as 60% of patients will develop psychosis over the course of their illness. Pimavanserin is a selective serotonin inverse agonist which targets 5-HT2A serotonin receptors in the brain, decreasing their activity in order to attenuate hallucinations and delusions.

"Pimavanserin has been approved by the FDA [Food and Drug Administration] for Parkinson's disease psychosis, but its safety has been called into question based on previous reports of increased mortality risk, compared with a rather modest benefit seen in a 6-week clinical trial, the duration of which limits determination of long-term safety," wrote Ali.

Pimavanserin carries a boxed warning that elderly patients with dementia may be at an increased risk of death. After its approval in 2016, the U.S. FDA later reviewed 893 deaths in association with pimavanserin during the postmarketing surveillance period – "an unexpected number in a new drug," Hwang and colleagues noted. "It [the FDA] noted that most reports occurred in a population with high underlying death rates and did not signal any additional risk beyond the current warning for all antipsychotics, which could have resulted in annual mortality rates of up to 60%."

As the first cohort study to examine hospitalization and death between pimavanserin users and nonusers, "the study confirms previous concerns regarding safety of pimavanserin and more importantly brings to attention the importance of carefully considering risks and benefits of pharmacotherapy in Parkinson's disease psychosis, clear communication with patients and families, and close observation to ensure safety," wrote Ali.

The study limitations include its observational design, which subjected the findings to residual confounding.

"While we developed models to maximize the strength of causal inference, our comparison group was pimavanserin nonusers and the very reason for prescription of pimavanserin could have predisposed its users to the outcomes of hospitalization and death, introducing confounding by indication," Hwang and colleagues wrote in the paper.

Additionally, "while robust analyses were conducted to ensure pimavanserin users and nonusers were comparable, Hwang et al. did find that pimavanserin users were more likely to concomitantly use other antipsychotic drugs which has been demonstrated as increasing the mortality risk," Ali pointed out.

Since patients living in long-term care facilities may have a higher risk of mortality because of more severe or later-stage Parkinson's disease, the study results "may not be generalizable to community-dwelling PD patients," Ali wrote. "These factors are important to consider while making individual management decisions."

Hwang and Ali disclosed no relevant financial relationships. The study authors reported no targeted funding.

This article originally appeared on, part of the Medscape Professional Network.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.