November/December 2023

Treating Parkinson’s Psychosis
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 16 No. 6 P. 22

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by four cardinal motor symptoms: tremor at rest, slowed movement (bradykinesia), rigidity (stiffness of the arms, legs, or neck), and impaired posture and balance. It’s the second most common neurodegenerative disorder after Alzheimer’s disease.1 PD is associated with significant costs to the health care system, high rates of disability, and increased need for care. In addition to PD motor symptoms, many affected will experience PD psychosis (PDP), which causes patients to experience debilitating hallucinations and delusions. PDP is often underrecognized, is challenging to manage, directly reduces patients’ quality of life, and increases mortality and the need for long term care.2 Health care professionals should be aware that patients with PDP often remain silent about their experiences. By discussing the full range of symptoms of PD, including the potential for psychosis with PD patients, their families, and caregivers, health care professionals can help improve the identification and treatment of PDP.

PD Statistics
Over the past 25 years, the prevalence of PD has doubled, with associated disability and death increasing faster than with any other neurological disorder.3 These trends are expected to continue as the population rapidly ages.

According to the Parkinson’s Foundation1:

• More than 10 million people worldwide are living with PD.

• Nearly one million people in the United States live with PD, with nearly 90,000 diagnosed with the disorder each year.

• The incidence of PD increases with age, but an estimated 4% of people with the disease are diagnosed before age 50.

• Men are 1.5 times more likely than women to have PD.

• The combined direct and indirect cost of Parkinson’s, including treatment, Social Security payments, and lost income, is estimated to be nearly $52 billion annually in the United States alone.

• Medications for PD cost an average of $2,500 a year, and therapeutic surgery can cost up to $100,000 per person.

• Geographic regions with the highest incidence of PD include the “Rust Belt” (parts of the Northwestern and Midwestern United States previously regulated by industrial manufacturing), Southern California, Southeastern Texas, Central Pennsylvania, and Florida.

Neurological Changes in PD
In the healthy brain, dopamine and other neurotransmitters work together to help coordinate movement. However, in PD, there is death and depletion of dopamine-generating neurons in the substantia nigra, a structure in the basal ganglia within the mesencephalic portion of the central nervous system that plays a critical role in controlling movement.4 The resulting loss of dopamine is responsible for the characteristic motor symptoms associated with the disease. By the time PD is diagnosed, most people have lost an estimated 60% to 80% of their dopamine-producing cells in the substantia nigra.4,5

Recent studies have revealed that other brain structures that regulate the chemical pathways that depend on norepinephrine, serotonin, and acetylcholine are also damaged, leading to changes in these neurotransmitters, possibly leading to PD nonmotor symptoms.4 The nonmotor symptoms are often more troubling for persons with PD than the motor symptoms and include depression, anxiety, apathy, hallucination, constipation, orthostatic hypotension, sleep disorders, loss of sense of smell, and various cognitive impairments.

PD Medications
Medications used to treat the motor symptoms of PD aim to restore the equilibrium of dopamine and other neurotransmitters in the brain by replacing dopamine or preventing the breakdown of dopamine.

Levodopa
Levodopa is a dopamine precursor converted to dopamine when it crosses the blood-brain barrier. It’s almost always given together with carbidopa, which helps prevent the breakdown of levodopa before it reaches the brain—allowing for lower doses—and helps reduce the side effects of nausea and vomiting. Levodopa/carbidopa is the mainstay treatment and most potent medication for PD. People receiving levodopa/carbidopa often experience “on” and “off” episodes. During “on” episodes, the drug is working, and symptoms are minimal. Conversely, during “off” episodes, the drug’s effects have yet to take effect or are weaning off with worsening symptoms.

Catechol-O-Methyltransferase (COMT) Inhibitors
COMT is an enzyme involved in the breakdown of neurotransmitters, including dopamine, norepinephrine, and epinephrine. COMT can also deactivate levodopa before it enters the brain. COMT inhibitors, such as entacapone, have no direct effects on their own. They are used as adjuncts with levodopa products to extend the effectiveness of levodopa—reducing “off” episodes and extending “on” episodes that occur with the use of levodopa.

Monoamine-Oxidase B (MAO B) Inhibitors
MAO B inhibitors, such as selegiline and rasagiline, increase dopamine in the basal ganglia by inhibiting an enzyme that inhibits dopamine and levodopa. MAO B inhibitors may be used alone early in the treatment of PD or with carbidopa/levodopa to help improve “on” and “off” episodes.

Dopamine Agonists
Dopamine agonists, such as bromocriptine and ropinirole, help manage symptoms by mimicking the effects of dopamine by stimulating dopamine receptors.

Anticholinergic Medications
Anticholinergic medications, such as benztropine and bromocriptine, help reduce tremors by decreasing acetylcholine, a neurotransmitter that influences movement. The lowering of acetylcholine allows a rebalancing of dopamine levels in the brain.

Amantadine
Amantadine increases dopamine levels in the brain. It may be used alone in the early stages of PD treatment or in combination with other medications.

PDP
The American Parkinson’s Disease Association defines PDP as “a nonmotor symptom of Parkinson’s disease that causes patients to experience hallucinations and/or delusions.”5 Psychosis is more common in the advanced stages of PD. More than one-half of all patients with PD eventually develop psychosis symptoms.6 PDP can lead to poor quality of life, increased disability, hospitalization, long term care placement, morbidity and mortality, and significant distress to patients and caregivers.7

Cause of PDP
The underlying cause of psychosis in PD is not entirely understood. It may be a consequence of changes in the brain that occur as part of the natural progression of PD and the result of side effects of dopaminergic medications used to treat PD motor symptoms.

Psychosis Symptoms
PDP symptoms can vary from severe confusion (disordered thinking) to seeing things that aren’t there (hallucinations) to believing things that are not true (delusions). In describing symptoms of PDP, patients may use terms such as seeing things, paranoia, flashbacks, nightmares, false beliefs, or not being in touch with reality.6

Hallucinations
Hallucinations can involve seeing, hearing, tasting, smelling, or feeling things that aren’t true. Whereas auditory hallucinations are most common in primary psychotic disorders (eg, schizophrenia), visual hallucinations are the most common feature of PDP. While auditory hallucinations are rare in PD, when they do occur, they frequently occur along with visual hallucinations. The visual hallucinations in PD are generally nonthreatening and often involve seeing animals, people, or loved ones who have already died. They also tend to occur more frequently in dim lighting, at specific times of the day (most often in the evening), and in specific places such as the patient’s home.7

Delusions
Hallucinations may be accompanied by delusions that are paranoid in nature. Common themes include irrational fears of a spouse cheating, someone stealing money, intruders in the house, or people plotting to harm the patients. Often, the person experiencing psychotic symptoms in PD is aware that their delusions are not based on reality, or someone can convince them as such. However, delusional thinking can also be so intense that it causes significant distress and affects the person’s behavior.

Risk Factors
While it is difficult to predict who will experience PDP symptoms, several risk factors increase the likelihood of developing it.

Risk factors include older age, duration and severity of PD, underlying dementia, delirium or depression, presence of sleep disturbance, reduced vision, and use of dopaminergic agents.6

Importance of Screening
Patients with PDP often remain silent about their experiences, with only 10% to 20% reporting their symptoms to their physicians.6 As such, there is a great need for health care professionals to specifically question patients and caregivers about the presence of hallucinations or delusions. The lack of consistent screening tools also contributes to underreporting of PDP symptoms. To help address the need for improved screening, a panel of experts in neurology and geriatric psychiatry convened to develop a simple screening tool.7 The expert panel recommended two specific previsit screening questions: 1) Does the patient see, hear, or otherwise sense things that others do not? For example, seeing people or animals that are not there, hearing music, or misidentifying objects. And 2) Does the patient believe things others do not believe to be true? For example, that their spouse is cheating or that others are causing them harm, deceiving them, or conspiring against them. Based on the patient/caregiver’s responses, the provider can evaluate the patient’s symptoms for appropriate treatment.

Treatment
A stepwise approach is appropriate for the treatment of PDP and includes the following:

• ruling out external causes of psychosis;
• identifying and removing potential medications that may induce or worsen psychosis; and
• if warranted, utilizing atypical antipsychotics.

Ruling Out External Causes
The treatment of PDP begins with ensuring an accurate diagnosis. The first step includes ruling out external causes of psychosis, such as delirium or comorbid psychiatric conditions. It’s essential to rule out delirium, which can sometimes cause hallucinations and delusions. Common causes of delirium include infections (eg, pneumonia or urinary tract infections), hospitalization, dehydration, constipation, pain, electrolyte abnormalities, sleep disorders, and medications. Identifying a single specific cause may not be possible as delirium is often the result of multiple contributing factors.

Evaluating Medications
The next step includes evaluating medications as the potential cause of psychosis. Medications used to treat the motor and nonmotor symptoms of PD can cause or exacerbate delirium resulting in psychosis symptoms.

Due to the potential to cause psychosis, all non-PD psychoactive medications, including antidepressants, benzodiazepines (eg, lorazepam, diazepam), pain medications (eg, opioids), and anticholinergics (eg, urinary medications), should be reviewed and, when possible, discontinued or reduced to the lowest possible dose.

Once non-PD medications have been reviewed, dopaminergic medications used for the treatment of PD should be adjusted because of their potential to worsen psychosis. If there’s no clear trigger medication, then the slow reduction or discontinuation of those medications thought to be less efficacious/higher risk for psychosis should be discontinued first.8 A suggested order is to stop adjuvant PD medications first, including anticholinergics, selegiline, and amantadine. Next for consideration would be dopamine agonists and COMT inhibitors. Lastly, levodopa may be reduced, but only if other measures fail.9 The complete removal of all dopaminergic medications is not recommended, in order to prevent significant worsening of Parkinsonian symptoms.

Antipsychotic Medications
When the reduction of anti-Parkinsonian drugs does not improve the psychotic symptoms, antipsychotic medications should be considered; however, their use is not without risks and most may worsen Parkinson motor symptoms. Also, treatment with antipsychotic medications is not appropriate for every person experiencing psychosis symptoms. Before using antipsychotic medications, it’s important to evaluate the impact of the psychotic symptoms on the patient. If the symptoms are mild and not causing significant distress, then antipsychotic use should not be implemented. For patients with significant psychotic symptoms, antipsychotics may be appropriate. Regardless, all antipsychotics should be used with caution in patients with dementia and psychosis due to the risk of adverse effects, including falls, pneumonia, increased urinary tract infection risk, increased confusion and cognitive decline, pneumonia, cardiovascular concerns, stroke, and death.

Conventional Antipsychotics
Conventional antipsychotics, also known as traditional antipsychotics, such as haloperidol, are widely known to exacerbate motor symptoms in PD patients due to high postsynaptic dopamine-2 (D2) receptor blockade.8 For this reason, conventional antipsychotics should rarely be used for PDP.

Atypical Antipsychotics
There are three atypical antipsychotics that are less likely to worsen PD motor symptoms—pimavanserin, clozapine, and quetiapine. Clozapine and quetiapine are commonly used off-label for the treatment PDP, while pimavanserin is the only FDA-approved antipsychotic for the treatment of PDP. Clozapine and quetiapine have a low affinity for D2 receptors and may improve psychotic symptoms without dramatically worsening motor symptoms.10 Pimavanserin has no significant affinity for D2 receptors and no concerns of worsening motor symptoms.11 Other atypical antipsychotics such as risperidone and olanzapine are not generally considered for use in PDP due to their increased affinity for D2 receptors and their likelihood of worsening motor symptoms.

Clozapine
Clozapine is a dibenzothiazepine derivative with low affinity for D2 receptors and higher affinity for D1, D3, D4, and 5-HT2A (serotonin) receptors.12 Clozapine has demonstrated antipsychotic benefit in PDP, but its use is limited due to the requirement of frequent blood monitoring for agranulocytosis. The most common adverse effects of clozapine in PD are sedation, orthostatic hypotension, and sialorrhea (excessive salivation).13

Quetiapine
Quetiapine, an atypical dibenzothiazepine that is structurally similar to clozapine, is also frequently used off-label for the treatment of PD psychosis. Quetiapine is associated with a relatively higher affinity for 5-HT2A receptors than for D2 receptors, which makes it another option for the treatment of PDP.13 Quetiapine may be considered for PDP, but it lacks established efficacy.14 Its high affinity for adrenergic and histaminergic receptors can also lead to orthostatic hypotension, daytime somnolence, and other adverse effects.14

Pimavanserin
In April 2016, pimavanserin became the first FDA-approved drug for the treatment of hallucinations and delusions associated with PDP.16 On September 18, 2023, Acadia Pharmaceuticals announced that the FDA made two changes to the pimavanserin (brand name NUPLAZID) labeling clarifying that it may be used in patients with PD-related hallucinations and delusions, with or without dementia.17 The two changes include: 1) Updated language in the Clinical Studies section that restates that the Phase 3 study supporting the approval of NUPLAZID included patients with PD-related hallucinations and delusions, with or without dementia, and 2) Revised Boxed Warning language clarifying that NUPLAZID is approved to treat patients with PD-related hallucinations and delusions who also have dementia. Health care professionals should be reminded that the drug is not indicated for dementia-related psychosis.

Pimavanserin is an antagonist/inverse agonist at 5-HT2A receptors and is the first drug without D2 blocking activity that displays antipsychotic actions and accounts for its ability to treat psychotic symptoms without worsening PD motor symptoms.18 Additionally, pimavanserin does not cause sedation, seen in quetiapine or clozapine. Pimavanserin can cause QT interval prolongation and is metabolized by the CYP3A4 enzyme, so caution should be exercised, and the dose should be reduced if given with strong CYP3A4 inhibitors (ie, itraconazole, ketoconazole, clarithromycin, indinavir). Pimavanserin is not recommended in patients with hepatic impairment or severe renal impairment (creatinine clearance <30 mL/min).19 It should be noted that the pimavanserin’s cost may make it prohibitive for some patients. Patients should be encouraged to check the manufacturer’s website for possible help with financial assistance and insurance approval.20

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Statistics. Parkinson’s Foundation website. https://www.parkinson.org/understanding-parkinsons/statistics

2. Fénelon G, Alves G. Epidemiology of psychosis in Parkinson’s disease. J Neurol Sci. 2010;289(1-2):12-17.

3. WHO releases technical brief on “Parkinson disease: a public health approach.” Disability Insider website. https://disabilityinsider.com/2022/06/15/health/who-releases-technical-brief-on-parkinson-disease-a-public-health-approach

4. Parkinson’s disease: challenges, progress, and promise. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/current-research/focus-disorders/focus-parkinsons-disease-research/parkinsons-disease-challenges-progress-and-promise. Published September 30, 2015.

5. Parkinson’s disease. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/health-information/disorders/parkinsons-disease

6. A guide for understanding Parkinson’s disease psychosis hallucinations & delusions. American Parkinson Disease Association website. https://www.apdaparkinson.org/what-is-parkinsons/symptoms/psychosis/

7. Pahwa R, Isaacson SH, Small GW, Torres-Yaghi Y, Pagan F, Sabbagh M. Screening, diagnosis, and management of Parkinson's disease psychosis: recommendations from an expert panel. Neurol Ther. 2022;11(4):1571-1582.

8. Samudra N, Patel N, Womack KB, Khemani P, Chitnis S. Psychosis in Parkinson disease: a review of etiology, phenomenology, and management. Drugs Aging. 2016;33(12):855-863.

9. Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord. 2000;15(2):201-211.

10. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76:1093-1118.

11. Hawkins T, Berman BD. Pimavanserin: a novel therapeutic option for Parkinson disease psychosis. Neurol Clin Pract. 2017;7(2):157-162.

12. Haidary HA, Padhy RK. Clozapine. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK535399/

13. Fernandez HH, Trieschmann ME, Friedman JH. Treatment of psychosis in Parkinson’s disease: safety considerations. Drug Saf. 2003;26(9):643-659.

14. Farah A. Atypicality of atypical antipsychotics. Prim Care Companion J Clin Psychiatry. 2005;7:268-274.

15. Schleisman A, Spangler M, Knezvich E. Treatment of Parkinson’s disease psychosis. U.S. Pharmacist website. https://www.uspharmacist.com/article/treatment-of-parkinsons-disease-psychosis. Published November 17, 2016.

16. FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease. FDA website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm498442.htm. Published April 29, 2016.

17. Acadia pharmaceuticals announces label update for NUPLAZID (pimavanserin). Acadia website. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-label-update-for-nuplazid-pimavanserin/. Published September 18, 2023.

18. 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;35:881-892.

19. Nuplazid (pimavanserin) package insert. San Diego, CA: Acadia Pharmaceuticals Inc.

20. For patients and caregivers. Acadia website. https://www.acadiaconnect.com/nuplazid/patient-caregivers