Parkinson’s Disease Psychosis
Parkinson’s Disease Psychosis (PDP): An Important Nonmotor Manifestation of Parkinson’s Disease
Burden and Clinical Manifestations
- PDP is an important complication of Parkinson’s disease that accompanies progressive motor and nonmotor symptoms (Figure 1)1
- This nonmotor complication of Parkinson’s disease affects an estimated 30% to 60% of the roughly 1 million patients in the United States with Parkinson’s disease1-3
- Manifestations of PDP may include hallucinations, including hallucinations of a nonvisual character that may be auditory, tactile, gustatory, or visceral in nature3-5
- PDP is also characterized by delusions, which is a form of disordered thinking that involves firmly held beliefs not based in reality3-5
- The features of PDP are based in the neurochemistry of Parkinson’s disease6
Figure 1: Progression of Parkinson’s Disease and the Development of Parkinson’s Disease Psychosis1
Pathophysiology of PDP
- Multiple neurotransmitters are involved in the pathophysiology of PDP, including dopamine, acetylcholine, norepinephrine, and serotonin, as well as the imbalanced expression of these neurotransmitters in specific areas of the brain6-10
- PDP may also relate to the accumulation of misfolded proteins in certain brain regions, such as the hippocampal, frontal, and parietal regions7
- The role of serotonin 2A receptors (5HT2A) in the brain is a crucial element of the pathophysiology of PDP, and is thought to have an important role in induction of hallucinations in patients with PDP5, 11
- In support of this hypothesis, 1 study found that 5HT2A receptors were upregulated by 45% in visual processing regions of the brain in patients with PD who had experienced visual hallucinations10
Figure 2: The 5HT2A Receptor
Treatment of PDP
- Second-generation antipsychotics have an important liability in the treatment of PDP in that they block multiple receptors, such as the dopamine 2 receptor, which may worsen motor symptoms in Parkinson’s disease11-14
- Other off-target effects of antipsychotics such as blockade of the histamine 1 receptor, alpha receptors, or muscarinic receptors may lead to off-target effects, which may increase the potential for adverse events and side effects11-13
- In the development of pimavanserin, scientists addressed the off-target effects of previous antipsychotic medications and developed a unique medication that was specifically targeted at the 5HT2A receptor and eliminated off-target effects of the dopamine 2 receptor, histamine 1 receptor, alpha receptors, and muscarinic receptors11‑13
- In addition, scientists designed pimavanserin with a unique pharmacologic of inverse agonist activity at the 5HT2A Inverse agonist activity goes beyond the effect of a normal antagonist; it not only blocks agonists but also reduces the baseline ordinary signaling that occurs in the absence of an agonist13
- Finally, unlike antipsychotic medications that were previously used off-label for PDP, such as clozapine or quetiapine, pimavanserin is specifically approved by the US Food and Drug Administration for PDP management
Table 1: Receptor Blockade Profile of Atypical Antipsychotics Versus Pimavanserin15-17
D2 = dopamine type 2; H1 = histamine 1 receptor; alpha = adrenergic-alpha receptor; M = muscarinic receptor.
- Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896-912. doi:10.1016/S0140-6736(14)61393-3
- Parkinson’s Foundation. Statistics. https://www.parkinson.org/Understanding-Parkinsons/Statistics.
- Fenelon G, Soulas T, Zenasni F, Cleret de Langavant L. The changing face of Parkinson’s disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord. 2010;25(6):763-766.
- Recognizing and managing Parkinson’s disease psychosis in long-term care facilities. 2019. https://cte-15a60.kxcdn.com/imagesvts/shows/lag1/ex_files/f125df32-1dbf-4885-98f8-23928da0f6e5.pdf.
- Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS, NIMH work group. Mov Disord. 2007;22(8):1061-1068.
- Thanvi BR, Lo TC, Harsh DP. Psychosis in Parkinson’s disease. Postgrad Med J. 2005;81(960):644-646. doi:10.1136/pgmj.2004.032029
- Klein JC, Eggers C, Kalbe E, et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010;74(11):885-892. doi:10.1212/WNL.0b013e3181d55f61
- Holmqvist S, Chutna O, Bousset L, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128(6):805-820. doi:10.1007/s00401-014-1343-6
- Rogers S. Parkinson’s dementia and related conditions. http://parkinsonfoundation.org/ wp-content/uploads/2017/04/PD_Dementia-SeanRogers.pdf.
- Lenka A, Hegde S, Jhunjhunwala KR, Pal PK. Interactions of visual hallucinations, rapid eye movement sleep behavior disorder and cognitive impairment in Parkinson’s disease: a review. Parkinsonism Relat Disord. 2016;22:1-8. doi:10.1016/j.parkreldis.2015.11.018
- Combs BL, Cox AG. Update on the treatment of Parkinson’s disease psychosis: role of pimavanserin. Neuropsychiatr Dis Treat. 2017;13:737-744. Published March 8, 2017. doi:10.2147/NDT.S108948
- Hacksell U, Burstein ES, McFarland K, Mills RG, Williams H. On the discovery and development of pimavanserin: a novel drug candidate for Parkinson’s psychosis. Neurochem Res. 2014;39(10):2008-2017. doi:10.1007/s11064-014-1293-3
- Kellog J, Saffel D. Parkinson’s disease psychosis post: treating hallucinations and delusions associated with Parkinson’s disease. Psychosis in the long-term care setting. https://cdn.ymaws.com/www.ascp.com/resource/resmgr/docs/sponsored/parkinsons_disease_psychosis.pdf.
- Parkinson’s Foundation. Psychosis: a mind guide to Parkinson’s disease. https://www.parkinson.org/pd-library/books/Psychosis-A-Mind-Guide-to-Parkinsons-Disease.
- Pimavanserin (Nuplazid®) PI 2020 (https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/207318s010lbl.pdf).
- Clozapine (Clozaril®) PI 2014 (https://www.accessdata.fda.gov/drugsatfda_docs/ label/2014/019758s073lbl.pdf).
- Quetiapine (Seroquel®) PI 2016 (https://www.accessdata.fda.gov/drugsatfda_docs/ label/2016/020639s064lbl.pdf).