Our May Palliative Pearls Case Study highlights a patient who has a primary diagnosis of Parkinson’s Disease. In this case, we will explore and review the patient’s history of drug-induced psychosis, which has been brought on by the common medications used to improve tremor and stiffness in patients with Parkinson’s. We will outline and make further recommendations to help control and minimize these occurrences. We encourage you to download this month’s case study to share with your colleagues or continue reading below.
AK is a 78-year-old male with a primary diagnosis of Parkinson’s Disease with hypertension, type II diabetes, and depression as comorbid conditions. He lives at home with his wife who is the primary caregiver. AK was admitted to hospice yesterday.
- Morphine 15mg immediate-release; 1 tablet by mouth every 4 hours as needed
- Carbidopa-levodopa (Sinemet® CR) 50mg-200mg; 1 tablet by mouth every 4 hours
- Pimavanserin (Nuplazid®) 34mg; 1 capsule by mouth daily
- Citalopram (Celexa®) 10mg; 1 tablet by mouth daily
- Senna; 1 tablet by mouth at bedtime
The hospice nurse is going to make her first visit. AK has mild pain throughout his body, which is responsive to “as needed” morphine. Prior to admission, his blood pressure was consistently low, so his primary care doctor discontinued his ACE inhibitor, lisinopril. AK has also had a decrease in food intake. To avoid hypoglycemia his glipizide was discontinued as well. His current blood pressure is 110/74 and morning fasting glucose is 160mg/dl. He presents as coherent and alert, however his wife states that he has hallucination episodes and can become verbally aggressive at times. She states that both hallucination episodes and aggressive behavior have recently become frequent (from 3-4 episodes per week for about 6 months to daily). AK was started on pimavanserin over a year ago and it helped initially to control psychotic symptoms. Pimavanserin will be covered by hospice and the nurse is preparing to educate the patient and family on their options to manage these symptoms so they can make an informed decision.
PARKINSON’S DISEASE PSYCHOSIS
Parkinson’s disease is a common and slowly progressing neurological disorder associated with death of dopaminergic neurons in the substantia nigra of the brain occurring early in the disease process. Dopamine regulates movement and a decrease results in movement disturbances and motor symptoms that worsen over time. Motor symptoms include bradykinesia, muscular rigidity, resting tremor and postural and gait impairment.1
Drug-induced psychosis is common in patients with Parkinson’s disease as the medications commonly used to improve tremor and stiffness can also cause hallucinations and delusions.2 The psychosis assessed is patient-specific and ranges in presentation to include one or more of the following: a sense of presence or passage hallucinations (the patient may describe the sensation of someone nearby or passing in their peripheral vision when no one is actually there); well-formed visual hallucinations and, less commonly, non-visual hallucinations (auditory, tactile, olfactory) and illusions or delusions (often with paranoia).1
Initial management includes assessment and treatment of precipitants and/or underlying causes:2,3
- Conditions, such as endocrine disorders, hepatic or renal disease, vitamin deficiencies, trauma, delirium or dementia
- Dose reduction or discontinuation of exacerbating medications:
- Begin with non-Parkinson’s medications such as anticholinergics (e.g., atropine, scopolamine, glycopyrrolate), sedatives, anxiolytics and antidepressants
- If inadequate response from above, consider adjustment of Parkinson’s medications first by temporal relationship (e.g., symptoms began after the addition of a COMT inhibitor), then by the balancing their importance in managing Parkinson’s symptoms with the likelihood of exacerbating psychosis symptoms. In descending order below:
- Anticholinergics (e.g., benztropine) (least essential/most likely to exacerbate)
- Dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
- Levodopa (most essential/least likely to exacerbate)
ANTIPSYCHOTICS AND PARKINSON’S DISEASE
Managing refractory psychosis is challenging in Parkinson’s disease. Initial pharmacologic management of psychosis in non-Parkinson’s psychiatric illness is largely patient-specific but may gravitate to the antipsychotic class. When the assessment for a precipitant or underlying cause of psychosis yields an inadequate response or is not feasible in a patient with Parkinson’s disease, antipsychotic therapy may be necessary.3 Conventional antipsychotics, such as haloperidol (Haldol®) and chlorpromazine (Thorazine®), and many atypical (second generation) antipsychotics, such as olanzapine (Zyprexa®), block dopamine receptors to exert their effect and cause extrapyramidal symptom (EPS) side effects (akathisia, dystonia, secondary parkinsonism).4 Recall that these patients already have dopamine deficiency as a mechanism of the disease – most antipsychotics exacerbate motor symptoms and can lead to severe, sometimes fatal, reactions.1
Clozapine (Clozaril®) was the first atypical antipsychotic proven effective in treating patients with refractory schizophrenia and is the prototype for antipsychotics developed thereafter. Unlike most other atypical agents, clozapine is thought to work in part from inhibition of dopamine receptors and serotonin 5-HT2A receptors, the latter with a higher affinity.4 It is the lesser affinity for dopamine receptors, and thus a lower incidence of extrapyramidal symptoms, that makes clozapine useful for drug-induced psychosis in Parkinson’s Disease, yet it is underutilized. A high side effect profile and stringent hematologic lab monitoring requirements (weekly to biweekly), due to risks of leukopenia, neutropenia and agranulocytosis, make it a difficult medication to manage.3,4
Quetiapine (Seroquel®), also an atypical antipsychotic, is structurally similar to clozapine and shares its action and side effect profile. Quetiapine is well-tolerated in patients with Parkinson’s disease-related psychosis however efficacy evidence is mixed.3,5 Observational studies show improvement in psychosis in approximately 80 percent of patients, and two partially-blinded randomized trials comparing quetiapine and clozapine showed similar efficacy for Parkinson’s Disease-related psychosis.3,6 It should be noted, however, that only 1 of 5 placebo-controlled trials has shown a benefit for quetiapine compared with placebo. Nevertheless, there seems to be some value of quetiapine in clinical practice and it remains widely used in this population.3,4
Pimavanserin (Nuplazid®), released to market in April 2016, is an alternative to quetiapine and clozapine. Pimavanserin is similarly characterized as an atypical antipsychotic, acting selectively at the serotonin 5-HT2A receptor. In placebo-controlled studies, pimavanserin showed a 3-point greater reduction in scores on a 45-point scale that assessed positive symptoms (hallucinations, delusions) from baseline to day 43.3 Patients did not experience worsening motor symptoms in either the placebo or pimavanserin groups.7 Long-term safety data for pimavanserin is not yet available.
One concern with pimavanserin is that it does not provide a large enough benefit managing psychosis. There is also concern that the use of pimavanserin in elderly patients, similarly to antipsychotics, can cause an increased risk of major adverse events including death.2 Pimavanserin carries a black box warning for increased mortality in elderly patients with dementia-related psychosis. In addition, it is costly, with an average cost of $2000 for a 15-day supply.
Quetiapine is commonly prescribed in practice, is considerably less expensive than pimavanserin (average < $25 for a 15-day supply) and has a better side effect profile than clozapine.2,3 A recent retrospective cohort study of patients with Parkinson’s disease or Lewy Body Dementia concluded that patients discontinued pimavanserin more frequently than quetiapine due to lack of improvement while patients were more likely to discontinue quetiapine than pimavanserin due to side effects. There was no statistically significant difference in mortality between the two medications.10
Patients opting to discontinue pimavanserin should be advised to taper the medication gradually over several weeks.8 Specifically, there should be no more than a 50% decrease in the medication dose every 2 weeks. If switching to another antipsychotic, like quetiapine, there are two recommended options:9
- Cross taper by decreasing the pimavanserin dose while titrating up on the new antipsychotic dose at about the same rate over a 2 to 3-week period
- Abruptly stop the medication the patient is on and start an effective dose of the other antipsychotic
PATIENT CASE ASSESSMENT
AK’s episodes of Parkinson’s disease psychosis have increased recently despite pimavanserin use for the last year and are now occurring more frequently. He was assessed for underlying causes at which time a UTI was diagnosed and treated. AK’s wife now reports fewer psychotic episodes. During interdisciplinary team discussions, it is noted that antidepressants may exacerbate psychosis however the team recommended maintaining use of citalopram with AK’s history of depression and long-term use unassociated with psychosis. AK’s wife was advised to continue to monitor for episodes of hallucinations and delusions and if episodes increase, they will revisit and potentially switch pimavanserin therapy to quetiapine as follows:8,9
Week 1, Day 1:
- Initiate quetiapine at 25mg BID and
- Decrease dose of pimavanserin by 50% to 17mg/day
Week 2, Day 1
- Consider increasing quetiapine to 50mg BID, based on symptom assessment and
- Decrease dose of pimavanserin by another 50% to 10mg/day
Week 3, Day 1:
- Consider does adjustment of quetiapine based on symptom assessment and
- Discontinue pimavanserin
Week 4 and weekly ongoing:
- Assess patient for need to adjust quetiapine dose
- Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015; 386:896-912.
- Article, Consider New Nuplazid for Some Patients with Parkinson’s Psychosis, Pharmacist’s Letter, August 2016.
- Chahine L, Tarsy D. Management of nonmotor symptoms in Parkinson disease In: UpToDate, Hurtig HI, Eichler AF, eds. Wantham, MA; UpToDate, Inc; Updated May 17, 2019.
- Clinical Pharmacology [database online]. Tampa, FL: Elsevier/Gold Standard, Inc.; 2020. Accessed 2020 Mar.
- Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011; 26 Suppl 3:S42.
- Shotbolt P, Samuel M, David A. Quetiapine in the treatment of psychosis in Parkinson’s disease. Ther Adv Neurol Disord. 2010; 3:339.
- Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. 2014;383(9916):533.
- PL Detail-Document, Common Oral Medications that May Need Tapering. Pharmacist’s Letter/Prescriber’s Letter. March 2016.
- Professional Resource, Parkinson’s Dementia and Dementia with Lewy Bodies. Pharmacist’s Letter/Prescriber’s Letter. August 2016.
- Horn S, Richardson H, Xie SX, et al. Pimavanserin versus quetiapine for the treatment of psychosis in Parkinson’s disease and dementia with Lewy bodies. Parkinsonism and Related Disorders. 2019; 69:119–124.