UAMS Reynolds Institute logo - Jan 2016

by Andi Daniel, PharmD Candidate 2017 and Lisa C. Hutchison, PharmD, MPH

At some point during the disease progression, 20 to 40% of patients with Parkinson’s disease (PD) experience hallucinations or delusions, referred to as Parkinson Disease Psychosis (PDP). This commonly occurs about 10 years after PD onset.1, 2 Hallucinations are thought to be a result of overstimulation of serotonin receptors, specifically 5-HT2A, or potentiated by overstimulation of dopamine D2 receptors.4 Other potential causes should be addressed in a patient, such as a dementia-related, medication-induced, or delirium-induced hallucinations. But if these causes are ruled-out, therapy directed at PDP can be considered. Historically, PDP has been managed with the atypical antipsychotics, clozapine or quetiapine, which have been considered probably effective and possibly effective, respectively.3 In April 2016, the FDA approved a new agent, pimavanserin (Nuplazid), specifically for PDP. While all three drugs are considered antipsychotics, their targeted receptor activity is different, which explains differences in effectiveness and adverse effects. Clozapine and quetiapine exhibit antagonistic activity on histamine-1 receptors, which causes somnolence, and alpha-1 receptors, which causes orthostatic hypotension. Pimavanserin does not affect either of these receptors. All three agents affect the serotonin receptor 5-HT2A although pimavanserin is a reverse agonist, and it will depress activity of the receptor as well as block its activation (see table).

Clozapine Quetiapine Pimavanserin
Dopamine-2 receptor Antagonist Antagonist
Histamine-1 receptor Antagonist Antagonist
5-HT1A  receptor Antagonist
5-HT 2A receptor Antagonist Antagonist Inverse agonist/ antagonist
Alpha-1 receptor Antagonist Antagonist
Alpha-2 receptor Antagonist
Adverse Effects  

Granulocytopenia

Somnolence

Tachycardia

Orthostatic hypotension

 

Somnolence

Orthostatic hypotension

Weight gain

QTc prolongation

Peripheral edema

Confusion

Nausea, constipation

Among the atypical antipsychotics, clozapine was effective in decreasing the hallucinations of PDP, but it did not show much benefit for delusions. Of note, clozapine has five black box warnings (e.g., severe neutropenia, CNS depression, seizures/ seizure disorder, cardiomyopathy, bone marrow suppression). Because of the potential for granulocytopenia, patients are required to get weekly blood laboratory which makes therapy difficult.

Quetiapine, is considered to be a first line agent for PDP, primarily due to reduced serious adverse effects compared to clozapine, and lack of weekly blood monitoring requirements.5 It is described as “possibly effective” because of eight open label trials where 80% of treated patients showed improvement. Also, quetiapine was compared to clozapine in another study, and showed similar efficacy in reducing psychosis.6 However, in five placebo-controlled trials, only one showed improvement but patients with delusions were excluded from that study, limiting its generalizability.

Pimavanserin significantly decreased psychosis in patients with PDP when compared to placebo in a 6-week study. It was also beneficial in reducing delusions associated with PDP compared to placebo.8, 9 Furthermore, pimavanserin has a favorable adverse effect profile. The most common adverse effects are peripheral edema (7%), confusion (6%), and nausea (7%). Since the medication is still new to the market, it is important to monitor and assess its long term safety. In addition, the Average Wholesale Price is listed as $2340 per month, which limits affordability. Pimavanserin is supplied in 17 mg tablets with a recommended dose of 34 mg once daily except in patients on certain interacting drugs where the lower dose of 17 mg should be used. Although it is new to the market, pimavanserin has short term data confirming benefit in the management of PDP. Support for clozapine and quetiapine in PDP is not as strong and both have significant adverse effects. Given this evidence, pimavanserin may well become the drug of choice for treatment of PDP.

References:

1. FeÂnelon, G., et al. “Hallucinations in Parkinson’s disease. Prevalence, phenomenology and risk factors. 2000.” Brain 123: 733-45.
2. Lee, Angela H., and Daniel Weintraub. “Psychosis in Parkinson’s disease without dementia: Common and comorbid with other non‐motor symptoms.” Movement Disorders 27.7 (2012): 858-863.
3. Miyasaki, J. M., et al. “Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology.” Neurology 66.7 (2006): 996-1002.
4. Kumar, Santosh, Subhash Soren, and Suprakash Chaudhury. “Hallucinations: Etiology and clinical implications.” Industrial psychiatry journal 18.2 (2009): 119.
5. Tarsy, D. “Management of comorbid problems associated with Parkinson disease.” UpToDate (2015).
6. Shotbolt, Paul, Mike Samuel, and Anthony David. “Quetiapine in the treatment of psychosis in Parkinson’s disease.” Therapeutic advances in neurological disorders 3.6 (2010): 339-350.
7. Fernandez, Hubert H., et al. “Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study.” International Journal of Neuroscience119.12 (2009): 2196-2205.
8. Cummings, Jeffrey, et al. “Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial.” The Lancet 383.9916 (2014): 533-540.
9. Yasue, Ichiro, et al. “Serotonin 2A Receptor Inverse Agonist as a Treatment for Parkinson’s Disease Psychosis: A Systematic Review and Meta-analysis of Serotonin 2A Receptor Negative Modulators.” Journal of Alzheimer’s Disease 50.3 (2016): 733-740.