Mortality in patients with Parkinson disease psychosis receiving pimavanserin and quetiapine

Abstract

Parkinson disease (PD) is a complex neurodegenerative disorder. Cognitive dysfunction and psychosis are leading contributors to nursing home placement. 1 Psychosis onset is associated with cognitive decline, levodopa supplementation, and visual dysfunction. 2 Treatment of PD psychosis (PDP) centers on levodopa dose adjustment, use of second-generation antipsychotics (SGAs), and cholinesterase inhibitors. SGAs function via serotonergic modulation and dopamine receptors blockade. Quetiapine, a structural analogue to clozapine, is often used to treat PDP, although evidence of its efficacy is mixed in randomized controlled trials. 3 Furthermore, there is a concern for increased morbidity and mortality with use of quetiapine and other SGAs in patients with dementia or those with PD, prompting a black box warning by the Food and Drug Administration (FDA). 4 The FDA approved pimavanserin (Acadia Pharmaceuticals Inc., San Diego, CA) on April 29, 2016, as the first agent indicated for treatment of PDP. Its mechanism of action is novel, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor and having no appreciable blockade of D2 receptors. 5 Pimavanserin's safety was recently highlighted in a report by the Institute for Safe Medication Practices, 6 including an expanded set of adverse events and risk of increased mortality. This report has led to concerns among prescribers, patients, and caregivers. Here we report on our institutional experience with pimavanserin for the treatment of PDP since its FDA approval. Methods We conducted a retrospective study with inclusion criteria of (1) PD diagnosis and (2) prescribed pimavanserin, quetiapine, or both agents during April 29, 2016-April 29, 2018. Standard protocol approvals, registrations, and patient consents All patients received their care at the University of California San Diego Health System. Anonymized records were obtained from the Epic electronic health record system. Since we only utilized de-identified electronic health records, no consents were required or obtained. Data analyzed included age, sex, and whether patients were living or deceased. Descriptive statistics are reported for the group characteristics along with 2-sample t tests for significance (p < 0.05) (table). Logistic regression with adjustment for age and sex was used to calculate odds ratios for mortality between each drug exposure group and controls. Results Of 4,478 patients with PD, 676 fulfilled the selection criteria. Despite a higher percentage mortality between quetiapine vs pimavanserin and combination vs pimavanserin, these differences were not different (p = 0.17 and p = 0.28, respectively). Mean age of the deceased cohorts was also similar

Pimavanserin for Psychosis in Parkinson’s Disease-Related Disorders: A Retrospective Chart Review

“…As noted, we did not see increased mortality rates in the group that started pimavanserin compared to those who did not start the medication. There has been recent discussion on whether patients taking pimavanserin carry a higher mortality risk [ 25 ], and our real-world data does not support this assertion, in keeping with other real-world reports [ 11 ]. However, this retrospective study was not powered to make claims on mortality risk with pimavanserin, and we report our clinical findings with this important caveat.…”

“…To date, reports of real-world experience with pimavanserin have been limited by small sample sizes ( n = 2 and 15) [ 9 , 10 ] or limited scope [ 11 ], preventing a meaningful analysis of real-world efficacy and patient characteristics, including PD or DLB diagnosis, presence and severity of dementia, deep brain stimulation (DBS) use, and prior antipsychotic failure. In this retrospective chart review, we sought to evaluate the clinical efficacy of pimavanserin in a larger cohort and describe prescribing patterns, concomitant antipsychotic use, titration strategies, and tolerability in patients with various clinical presentations.…”

Update on treatments for nonmotor symptoms of Parkinson's disease—an evidence‐based medicine review

“…Recently, preliminary research has shown an increased risk of mortality and morbidity with antipsychotic use in PD patients, too, and not specific to dementia . Additional controlled research is needed to determine if antipsychotics increase mortality risk in PD and if pimavanserin is similar to other antipsychotics in this regard . Moreover, rivastigmine may be another treatment option for psychotic behavior specifically in patients with PD and dementia based on a post hoc analysis of a large, placebo‐controlled study of rivastigmine in PD dementia that showed improvement of hallucinations on rivastigmine …”

“…143,144 Additional controlled research is needed to determine if antipsychotics increase mortality risk in PD and if pimavanserin is similar to other antipsychotics in this regard. 145 Moreover, rivastigmine may be another treatment option for psychotic behavior specifically in patients with PD and dementia based on a post hoc analysis of a large, placebo-controlled study of rivastigmine in PD dementia that showed improvement of hallucinations on rivastigmine. 146 It is critical for PD patients to be monitored closely for the development of ICRDs as part of routine clinical care, which ideally would include caregiver reports, because ICRDs may have potentially devastating psychological, social, legal, and economic consequences, including divorce, bankruptcy, incarceration, and attempted suicide.…”

Hallucinations in Parkinson’s disease: new insights into mechanisms and treatments

“… 26 Initial concerns of higher rates of mortality were shown to be no higher than those in this already frail patient group. 27 …”