By: Jonathan Mercado, PharmD Candidate c/o 2019
In April 2016, the FDA approved the first drug specifically indicated for the symptoms of psychosis associated with Parkinson’s disease (PDP).1 Currently, clozapine and quetiapine are used off label to treat symptoms associated with Parkinson disease such as voices in patients’ heads, various hallucinations and delusions. In Parkinson Disease, hypersensitization of dopaminergic receptors causes external stimuli to be received improperly, therefore impairing serotonin, the mood stabilizing neurotransmitter in the brain.2 Pimavanserin acts as a 5HT2A inverse agonist that can act as an antagonist of 5HT2A and suppress the receptor’s signaling.2 The off-label medications mentioned function via a similar critical mechanism of action against serotonin, one of the most negatively affected neurotransmitters by Parkinson’s disease.
Several placebo-controlled and double-blinded phase III randomized clinical trials took place to demonstrate the efficacy of pimavanserin. One in particular, sponsored by the manufacturer Acadia Pharmaceuticals Inc®, studied a large sample size, with 90 patients in the placebo group and 95 in the pimavanserin group, and used the Scale for the Assessment of Positive Symptoms for Parkinson’s disease (SAPS-PD).3 SAPS-PD has a list of 9 symptoms that are measured in severity from a scale of 1 to 5.3 These symptoms are evaluated with scores from anywhere between 0 (meaning no symptoms) to 45 (maximum severity of all symptoms). As the most recent phase III clinical trial completed since the drug’s approval, pimavanserin 40 mg tablet, taken once daily, was given to the experimental group and compared to the placebo group. Both groups spent the first two weeks of the six week trial taking a placebo, and only afterwards was pimavanserin given to the experimental group in order to limit the placebo effect. The primary outcome measure analyzed was antipsychotic efficacy and the reduction in patients’ SAPS-PD score. Of the 90 patients analyzed in the placebo group, there was a mean change from baseline of -2.73.3 Of the 95 patients analyzed in the experimental group there was a mean change from baseline of -5.79. Thus, pimavanserin had a -3.06 difference from the placebo with a 95% confidence interval (-4.91 to -1.20).4 The experiment shows more than a 3-point difference between groups, achieving the desired 5% significance level. Although the sample size was smaller than planned, the outcomes are significant. After conducting the final analysis using a MMRM method instead of a t-test, power was shown to be higher despite the marginally smaller sample size.3
Although pimavanserin does provide a notable reduction in symptoms and significant help in those with low SAPS-PD scores (between about 1, a single minor symptom, and 7, the higher end of pimavanserin’s potential), pimavanserin only decreased scores 3 to 5 points in higher score patients which is insignificant. At this point in time, however, pimavanserin is recommended as first-line treatment for all patients with PDP at a dose of 34 mg once daily, with no titration.4 It holds a place above clozapine because it lacks the notorious potential side effects associated with clozapine, specifically the ability to cause severe neutropenia and progress patients into an immunocompromised state. Patients taking clozapine require close monitoring to prevent complications which involves weekly complete blood counts (CBCs) for the first six months, and biweekly tests afterwards. Other side effects include orthostatic hypotension and sialorrhea. Using clozapine requires the prescriber, pharmacy, patient and distributor to enroll into a REMS (Approved Risk Evaluation and Mitigation Strategies) program to ensure all parties are aware of the drug’s potential and it is safe for the patient.5
Quetiapine is less favored over pimavanserin, although it does not require any monitoring and has significantly less side effects, because it is considered unreliable for this particular indication.4 After compiling and analyzing data from 6 randomized control trials with sample groups ranging from 8-30 patients, depending on the trial, quetiapine has consistently shown to be only marginally better than the placebo and occasionally even performing worse.6 Using the Brief Psychiatric Rating Scale (BPRS), which rates 16 different symptoms of psychosis on a 7-point scale, treatment with quetiapine had mean changes as notable as -2.2 points or as counter-effective as +3.9 points.6,7 The remarkable variability and minimal positive change produced by quetiapine makes it an option worth attempting in patients with minor symptoms of psychosis in Parkinson’s disease to avoid complicated therapy, but it does not have consistency in outcomes when compared to the other options.
Over the years that pimavanserin has been studied, it has shown to have no significant long-term effects, no increase in mortality, and good tolerability with patients.8 However, pimavanserin can prolong QT-intervals. Therefore, health care providers should check for drug interactions with other drugs that can prolong QT intervals.4 Pimavanserin has not been shown to increase mortality, but like most antipsychotics it should be closely monitored in geriatric patients with dementia.8 It can lead to orthostatic hypotension in patients prone to hypotensive episodes. Side effects are confusion (6%), nausea (7%), and peripheral edema (7%) in many cases.9 A major downside is that it is currently only available as the brand name drug, Nuplazid™, manufactured by Acadia Pharmaceuticals Inc® so it is very costly. The cost of a month supply of pimavanserin 17 mg is $2560, whereas a 30-day supply of clozapine 25 mg tablets is $132 and quetiapine 25 mg tablets is $120.10
Pimavanserin is the definitive first-line treatment for patients with PDP but providers should have realistic therapeutic expectations. It holds many advantages over the off-label medications such as clozapine and quetiapine, but it has the potential to cause QT prolongation. Since the drug is still only available as the brand, the financial status of the patient should also be considered. As always, a patient-centered approach is necessary. Pimavanserin is expected to be implemented more in therapy as healthcare providers become more familiar with the drug. It will have a meaningful impact in practice by providing an improvement in patients’ health and opening the gates to further research for drugs that have the same low side effect profile achieved by pimavanserin.
- U.S. Food and Drug Administration. FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease. Updated 05/02/2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm498442.htm. Accessed 03/01/2017.
- Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson’s disease psychosis. Neuropsychopharmacology. 2010;35(4):881-92.
- 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):533-40.
- Sarva H, Henchcliffe C. Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis. Ther Adv Neurol Disord. 2016;9(6):462-473. Epub 2016 Oct 3.
- U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Updated 09/15/2015. http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS= 351 Accessed 3/11/2017.
- Desmarais P, Massoud F, Filion J, Nguyen QD, Bajsarowicz P. Quetiapine for Psychosis in Parkinson Disease and Neurodegenerative Parkinsonian Disorders: A Systematic Review. J Geriatr Psychiatry Neurol. 2016;29(4):227-36.
- Overall J, Gorham D. The Brief Psychiatric Rating Scale. Psychological Reports. 1962;10(3):799-812.
- Tarsy, D. Management of nonmotor symptoms in Parkinson’s disease. In: Uptodate, Hurtig, HI (Ed), Uptodate, Waltham, MA, 2017. Last updated 02/16/2017.
- Lexicomp Online® , Pediatric & Neonatal Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc. Accessed 02/16/2017
- Red Book Online [database online]. Greenwood Village, CO: Truven Health Analytics. http://www.micromedexsolutions.com/. Last Updated 05/16/2016. Accessed 05/23/17.