Pimavanserin Use Linked With Greater Risk of Hospitalization, Mortality in Patients With Parkinson Disease


Pimavanserin (Nuplazid) initiation among patients with Parkinson disease was associated with greater risk of 30-day hospitalization and mortality up to one year compared with non-users.

Use of pimavanserin, sold as Nuplazid, may increase risk of hospitalization and mortality in patients with Parkinson disease (PD), according to study findings published in Neurology.

As a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, pimavanserin was approved by the FDA in 2016 for the treatment of hallucinations and delusions associated with PD psychosis. Although associated with durable efficacy against PD psychosis, the researchers note that safety concerns have been previously reported which showed an elevated risk of mortality in users of the drug compared with placebo.

“The FDA later reviewed 893 deaths reported in postmarketing surveillance–an unexpected number in a new drug,” they added. “It 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%.”

Seeking to further evaluate the risk of hospitalization and mortality among users of pimavanserin, study authors conducted a retrospective cohort study of patients with PD aged 65 and older residing in Medicare-certified long-term care facilities between November 1, 2015, through December 31, 2018 (N = 318,152).

Participants were assessed for the primary outcomes of all-cause hospitalization at 30 and 90 days and all-cause mortality at 30, 90, 180, and 365 days following pimavanserin initiation, as measured via Fine-Gray competing risk and Cox proportional hazards regression models.

Researchers used propensity score–based inverse probability of treatment weighting (IPTW) as the primary approach to determine the association of pimavanserin use with the outcomes, in which pimavanserin users and nonusers were balanced according to 24 baseline characteristics.

Of the patient cohort, 5853 (1.8%) received pimavanserin. After performing risk-set sampling and excluding confounding variables, the final cohort included 2186 pimavanserin users and 18,212 non-users.

In findings adjusted for IPTW, patients with PD treated with pimavanserin exhibited a significant 24% higher risk of 30-day hospitalization than non-users (adjusted HR [aHR], 1.24, 95% CI, 1.06-1.43). There was no significant difference between both groups when assessing risk of 90-day hospitalization (aHR, 1.10; 95% CI, 0.99–1.24).

Furthermore, risk of mortality among pimavanserin users vs non-users was found to rise over time, in which risk of 30-day mortality was found to be non-significant (aHR, 0.76, 95% CI, 0.56–1.03), whereas risk was significantly increased after 90 days (aHR, 1.20, 95% CI, 1.02–1.41), 180 days (aHR, 1.28, 95% CI, 1.13–1.45), and 1 year (aHR, 1.56, CI 1.42–1.72) after initiation.

Addressing their Class II evidence linking patients with PD prescribed pimavanserin and elevated risk of hospitalization and mortality, researchers said that findings may help to inform decisions regarding the drug’s risk-benefit balance among these populations.


Hwang YJ, Alexander GC, An H, Moore TJ, Mehta HB. Risk of hospitalization and death associated with pimavanserin use in older adults with Parkinson disease. Neurol. Published online August 13, 2021. doi:10.1212/WNL.0000000000012601

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