Funding/financial disclosures. The authors have no conflict of interest relevant to the content of this letter. Our studies are supported by the following grants: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Innov Clin Neurosci. 2023;20(1–3):8–9.

Dear Editor:

Psychosis is considered one of the most common disabling nonmotor symptoms in Parkinson’s disease (PD), with a prevalence ranging from 20 to 70 percent, depending on the stage of the disease.1 In 2016, pimavanserin became the first antipsychotic to be recommended by the United States (US) Food and Drug Administration (FDA) for the treatment of PD psychosis, opening a new therapeutic avenue in its treatment.1 Along these lines, we enjoyed reading the excellent article titled, “Pimavanserin in the Treatment of Parkinson’s Disease Psychosis: Meta-analysis and Meta-regression of Randomized Clinical Trials” by Mansuri et al.2 The authors concluded that there was a significant improvement in psychosis symptoms in patients with PD who took pimavanserin.2 However, there have been concerns about an increased risk of mortality associated with this drug.3 It has been successfully demonstrated that pimavanserin use in patients with PD who are at least 65 years of age is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.4 We also consider it pertinent to evaluate the risk of premature mortality among antipsychotic-treated patients with PD, as antipsychotics have been at the forefront of medical care in recent years.5,6

PD is one of the most common progressive, incurable, and systemic neurodegenerative disorders, with high mortality rates compared to the general population, and sudden unexpected death (SUDPAR) has been considered an important cause of mortality in patients with in PD.5 This observance is worrisome, since studies on SUDPAR have shown that an average of 14 percent of individuals with PD die suddenly.5 

The cause of SUDPAR is uncertain, but a cardiac dysfunction is thought to underlie its occurrence due to the high percentage of patients with PD (60%) having structural and functional heart changes.5 SUDPAR likely arises from a combination of multiple risk factors, but polypharmacy has been considered one the most significant factors associated with fatal events in PD.5 Psychosis represents a relevant burden in PD, and the pharmacological treatment of psychotic symptoms considerably increases mortality in PD.1,6 Importantly, recent studies indicate that adverse cardiovascular effects occur due to inappropriate use of antipsychotic medications, ranging from abnormal heart rate to sudden death.1,6 Specifically, a study developed by Heranval et al6 accurately evaluated the cardiac risk associated with treatments prescribed for PD. In their results, 33.3 percent of patients who died were using one or more drugs with potential cardiac adverse effects, including antipsychotic drugs.6 Additionally, previous studies have clearly reported data on mortality outcomes in individuals exposed to antipsychotic drugs. As such, current findings4 can be corroborated by other measures of similarity, demonstrating that antipsychotic drug exposure is associated with an approximately 1.5-fold increased mortality risk, occurring prominently in patients with PD and those over 65 years of age.7

Overall, what lessons did we learn in the last few years? First, the study by Mansuri et al2 has clear implications for clinical research and practice. Second, PD is a disease with cases of premature death.3 Furthermore, the pharmacological treatment of psychosis increases mortality rates in PD.1,5–7 Finally, pimavanserin should not be considered a “gold standard” treatment of psychosis in PD, and we are convinced that comparative pharmacovigilance analyses can balance measures of PD antipsychotic mortality.


  1. Kianirad Y, Simuni T. Pimavanserin, a novel antipsychotic for management of Parkinson’s disease psychosis. Expert Rev Clin Pharmacol. 2017;10(11):1161–1168.
  2. Mansuri Z, Reddy A, Vadukapuram R, et al. Pimavanserin in the treatment of Parkinson’s disease psychosis: meta-analysis and meta-regression of randomized clinical trials. Innov Clin Neurosci. 2022;19(1–3):46–51.
  3. Ali F. Pimavanserin: a friend or foe in Parkinson disease psychosis. Neurology. 2021;97(13):613–614.
  4. Hwang YJ, Alexander GC, An H, et al. Risk of hospitalization and death associated with pimavanserin use in older adults with Parkinson disease. Neurology. 2021;97(13):E1266–e1275.
  5. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1–5.
  6. Heranval A, Lefaucheur R, Fetter D, et al. Drugs with potential cardiac adverse effects: retrospective study in a large cohort of parkinsonian patients. Rev Neurol. 2016;172(4–5):318–323.
  7. Yang C, Hao Z, Tian J, et al. Does antipsychotic drug use increase the risk of long term mortality? A systematic review and meta-analysis of observational studies. Oncotarget. 2018;9(19):15101–15110.

With regards,

Josef Finsterer, PhD; Carla A. Scorza, PhD; Antonio-Carlos G. de Almeida, PhD; and Fulvio A. Scorza, BSc, MSc, PhD

Dr. Finsterer is with Neurology and Neurophysiology Center in Vienna, Austria. Drs. Finsterer, C. Scorza, de Almeida, and F. Scorza are with Centro de Neurociências e Saúde da Mulher “Professor Geraldo Rodrigues de Lima,” Escola Paulista de Medicina/Universidade Federal de São Paulo (EPM/UNIFESP) in São Paulo, Brazil. Drs. C. Scorza and F. Scorza are with Disciplina de Neurociência. Escola Paulista de Medicina/Universidade Federal de São Paulo (EPM/UNIFESP) in São Paulo, Brazil. Dr. de Almeida is with Laboratório de Neurociência Experimental e Computacional, Departamento de Engenharia de Biossistemas, Universidade Federal de São João del-Rei (UFSJ) in São João del-Rei, Brazil.