Managing Parkinson’s Disease–Related Hallucinations and Delusions

Paid for by Acadia Pharmaceuticals Inc.

Parkinson’s disease is generally thought of as a movement disorder, characterized by motor symptoms including tremor and rigidity.^1,2 Less commonly known is the fact that about half of patients living with this condition may also experience Parkinson’s-related hallucinations and/or delusions, known as Parkinson’s disease psychosis, over the course of their disease.^1,3 Experiences can vary widely—from seeing shadows or shapes that aren’t there to vivid, detailed visions or firmly held false beliefs.³

The onset of hallucinations and delusions can be subtle; for example, there might be a “sense of presence,” feeling as though someone is in the room but can’t be seen. Over time, these sensations may evolve into more disruptive hallucinations or delusions. For example, a patient might become convinced that their partner is having an affair despite clear evidence to the contrary.³

Parkinson’s-related hallucinations and delusions tend to be progressive and generally worsen over time; therefore, regular check-ins with patients, as well as their care partners and family members are critical for early detection and personalized interventions to treat them before it becomes a crisis.^3,4,5

Khashayar Dashtipour, MD, PhD, director of the Division of Movement Disorders at Loma Linda University recently sat down to discuss the challenges of managing Parkinson’s-related hallucinations and delusions and the need for a holistic understanding of Parkinson’s disease to prioritize these symptoms alongside motor symptoms, and tips on talking to patients about initiating treatment.

What are some of the biggest challenges neurologists face in treating Parkinson’s-related hallucinations and delusions?

Khashayar Dashtipour, MD, PhD: I’ve been treating Parkinson’s disease for over 20 years, and one of the biggest challenges is treating hallucinations and delusions without compromising motor function.⁶

NUPLAZID^® (pimavanserin) is the only FDA-approved treatment for hallucinations and delusions associated with Parkinson’s disease psychosis.⁷ In clinical trials, NUPLAZID has been shown to reduce the frequency and/or severity of Parkinson’s-related hallucinations and delusions (as measured by change in SAPS-PD from baseline) at Week 6 versus placebo. Motor impact was a secondary endpoint evaluated during clinical trials, which showed NUPLAZID worked without impacting motor function or motoric activities of daily living versus placebo at Week 6. The mean change from baseline, as measured by the UPDRS Parts II+III was -1.4 for NUPLAZID (n=92) vs -1.7 for placebo (n=88). The LSM placebo-subtracted difference was 0.3 (95% CI, -2.1, 2.7). ^4,8,9 

It is important for providers to know that NUPLAZID has a Boxed WARNING. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. NUPLAZID is not approved for the treatment of patients with dementia who experience psychosis unless their hallucinations and delusions are related to Parkinson’s disease.⁷ Please see the full Prescribing Information below, including Boxed WARNING.

Another challenge we face is that most patients don’t proactively mention hallucinations and delusions they may be experiencing.¹⁰ The stigma around these symptoms often creates challenges, and care partners also may be hesitant to discuss these symptoms out of concern for their loved ones.^10-13 That’s why it’s important for us as providers to broach the subject, so that we can identify issues early before they snowball and discuss potential options that they may not know are available.

Beyond the Phase 3 data, are there any other data available about NUPLAZID in Parkinson’s disease psychosis (PDP)?

Yes. Long-term safety data and supportive efficacy data from an open-label extension study are available in addition to the Phase 3 clinical trial results.^14,15 There are also findings from retrospective analyses from real-world studies evaluating all-cause mortality risk in patients treated with NUPLAZID versus off-label psychotics.^16,17

How do you approach conversations about Parkinson’s disease-related hallucinations and delusions with your patients and their families?

My best teachers are my patients. Creating a safe space for patients and care partners to discuss their entire experience can provide invaluable insights. Normalizing these conversations from the outset helps people feel more comfortable sharing concerns to help patients receive timely and appropriate care.

Most people don’t know that hallucinations and delusions associated with Parkinson’s can be symptoms of their condition, so they may initially dismiss their symptoms as unrelated, or even hide them due to fear or embarrassment.¹⁰ Early education—before these symptoms fully develop—can reduce stigma and encourage proactive management.

When introducing treatment options, it’s important to listen and validate the concerns of patients as well as their families and care partners. Some people may resist adding a new medication if the symptoms are not severely impacting their lives. In these cases, one important part of the discussion is to explain how treatments for motor and non-motor symptoms can work together to provide synergistic care. I also like to focus on the positives rather than the negatives. Fear can make people more combative, or it can make them shut down entirely.

More than anything, I want my patients to trust that I have their best interests at heart. Open, empathetic communication is key to building that trust.

For more information about Parkinson’s disease psychosis and NUPLAZID, click here.

IMPORTANT SAFETY INFORMATION and INDICATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
• NUPLAZID is not approved for the treatment of patients with dementia who experience psychosis unless their hallucinations and delusions are related to Parkinson’s disease.

• Contraindication: NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Rash, urticaria, and reactions consistent with angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported.
• Warnings and Precautions: QT Interval Prolongation
  • NUPLAZID prolongs the QT interval. The use of NUPLAZID should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval (e.g., Class 1A antiarrhythmics, Class 3 antiarrhythmics, certain antipsychotics or antibiotics).
  • NUPLAZID should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval.
• Adverse Reactions: The adverse reactions (≥2% for NUPLAZID and greater than placebo) were peripheral edema (7% vs 2%), nausea (7% vs 4%), confusional state (6% vs 3%), hallucination (5% vs 3%), constipation (4% vs 3%), and gait disturbance (2% vs <1%).
• Drug Interactions:
  • Coadministration with strong CYP3A4 inhibitors increases NUPLAZID exposure. Reduce NUPLAZID dose to 10 mg taken orally as one tablet once daily.
  • Coadministration with strong or moderate CYP3A4 inducers reduces NUPLAZID exposure. Avoid concomitant use of strong or moderate CYP3A4 inducers with NUPLAZID.

Indication

NUPLAZID is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Dosage and Administration

Recommended dose: 34 mg capsule taken orally once daily, without titration, with or without food.

NUPLAZID is available as 34 mg capsules and 10 mg tablets.

Please read the full Prescribing Information, including Boxed WARNING.

References

¹ Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-Year Population -Based Study of Psychosis in Parkinson Disease. Arch Neurol. 2010;67(8):996-1001.

² Balestrinoa, R, and Schapira, AHV. Parkinson disease. European Journal of Neurology. 2020, 27: 27–42.

³ 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): 1061-8.

⁴ Goetz, CG, Fan, W, Leurgans, S, et al. The malignant course of “benign hallucinations” in Parkinson disease. Archives of Neurology. 2006;63(5), 713–716.

⁵ Minton, L, Perepezko, K, and Pontone, G. Psychosis A Mind Guide to Parkinson’s Disease. National Parkinson Foundation. 2016.

⁶ Fredericks, D, Norton JC, Atchison C, et al. Parkinson’s Disease and Parkinson’s Disease Psychosis: A Perspective on the Challenges, Treatments, and Economic Burden. American Journal of Managed Care. 2017; 23: S86.

⁷ Acadia Pharmaceuticals Inc. NUPLAZID^® [package insert]. San Diego, CA; 2025.

⁸ Cummings J, Isaacson S, Mills R, et al. Pimavanserin for Patients the Parkinson’s Disease Psychosis: A Randomized, Placebo-Controlled Phase 3 Trial. Lancet. 2014;383(9916):533-540

⁹ Acadia Pharmaceuticals Inc., Data on file. Clinical Study Report ACP-103-020. 2013.

¹⁰ Chaudhuri KR, Prieto-Jurcynska, Naidu Y, et al. The Nondeclaration of Nonmotor Symptoms of Parkinson’s Disease to Health Care Professionals: An International Study Using Nonmotor Symptoms Questionnaire. Mov Disord. 2010;25(6):704-9.

¹¹ Henry RS, Perrin PB, Lageman SK, et al. Parkinson’s Symptoms and Caregiver Affiliate Stigma: A Multinational Study. Current Alzheimer Research. 2021; 18:1-10.

¹² Mantri S, Edison B, Azyoud S .M., et al. Knowledge, Responsibilities, and Peer Advice from Care Partners of Patients with Parkinson Disease Psychosis. Frontiers in Neurology. 2021; 12: 633645.

¹³ Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain. 2000;123(Pt4):733-745.

¹⁴ Ballard CG, Kreitzman DL, Isaacson S, et al. Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2020;77:100-106. doi:10.1016/j.parkreldis.2020.06.026

¹⁵ Isaacson SH, Coate B, Norton J, Stankovic S. Blinded SAPS-PD assessment after 10 weeks of pimavanserin treatment for Parkinson’s disease psychosis. J Parkinsons Dis. 2020;10(4):1389-1396. doi:10.3233/JPD-202047

¹⁶ Mosholder AD, Ma Y, Akhtar S, et al. Mortality Among Parkinson’s Disease Patients Treated with Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries. Am J Psychiatry. 2022;179(8):553-561.

¹⁷ Layton JB, Forns, J, McQuay LJ, et al. Mortality in Patients with Parkinson’s Disease-Related Psychosis Treated with Pimavanserin Compared with Other Atypical Antipsychotics: A Cohort Study. Drug Safety. 2023; 46: 195-208.