Neuroleptic Sensitivity In Dementia With Lewy Body And Use Of Pimavanserin In An Inpatient Setting: A Case Report
Unusual clinical course, Mistake in diagnosis, Diagnostic / therapeutic accidents, Management of emergency care, Adverse events of drug therapy , Clinical situation which can not be reproduced for ethical reasons
Anthony AbadirRyder Dalton
- 1Department of Psychiatry, West Virginia University, Morgantown, USA
- 2West Virginia School of Medicine, West Virginia University, Morgantown, USA
- 3Department of Orthopedics, West Virginia University, Morgantown, USA
- 4Department of Neurology, West Virginia University, Morgantown, USA
- 5Rockefeller Neuroscience Institute, West Virginia University, Morgantown, USA
- *Corresponding Author: Richa Tripathi, e-mail:
- AStudy design/planning
- In Press: 20 September 2022
This paper has been published under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.
Abstract
BACKGROUND: Antidopaminergic medications, including antipsychotics, are known to worsen motor and neuropsychiatric symptoms, including cognition and psychosis, in patients with dementia with Lewy body . The intensity of worsened clinical symptoms may vary and can result in mortality in certain situations. There have been some reports supporting clozapine, quetiapine and pimavanserin use in psychosis control in this population.
Background
Case Report
PREADMISSION HISTORY:
Discussion
Clinical Evidence From Trials In Dementia
A phase II randomized, double-blind, placebo-controlled, single-center clinical trial assessed the safety and efficacy of pimavanserin 34 mg daily versus placebo for the treatment of AD psychosis. Completed in 2016, the study included 181 participants from multiple affiliated nursing-home sites across the United Kingdom . The primary endpoint was the mean change in the Neuropsychiatric Inventory-Nursing Home version psychosis score, from baseline to week 6. At week 6, patients in the pimavanserin group showed significant improvement in the NPI-NH psychosis score compared to patients in the placebo group. Mean change in the NPI-NH psychosis score from baseline at week 6 was 3.76 points for pimavanserin and 1.93 points for placebo . However, in this trial, a significant difference in efficacy between pimavanserin and placebo was not seen at 12 weeks of treatment . Although agitation was higher in patients receiving pimavanserin than in those receiving placebo , the overall adverse event profile was similar in the two groups. No detrimental effect was observed on cognition or motor function in either group .
Table 2 Summary of completed and ongoing clinical trials for pimavanserin in dementia-related psychosis.
About Parkinsons Disease Psychosis
Parkinsons disease is a condition that affects your nervous system. Its a progressive disease, which means that it gets worse over time. Symptoms of Parkinsons disease can include tremors , slow movements, and stiff muscles.
Some people with Parkinsons disease may also experience hallucinations or delusions, which are symptoms of psychosis . Causes of Parkinsons disease psychosis can include medications, delirium, and depression.
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Will Nuplazid Make My Hallucinations Worse
Its not likely that Nuplazid will worsen your hallucinations, but it can happen. In clinical trials:
- 5% of people taking Nuplazid experienced hallucinations
- 3% of people taking a placebo experienced hallucinations
Its not known whether peoples hallucinations got worse during clinical trials, or if their treatment wasnt effective at reducing hallucinations they were already experiencing.
If you notice that your hallucinations are getting worse while taking Nuplazid, talk with your doctor. They may be able to determine if the hallucinations are a side effect of Nuplazid.
Pimavanserin: A Novel Antipsychotic With Potentials To Address An Unmet Need Of Older Adults With Dementia
- 1School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States
- 2School of Pharmacy, Lebanese American University, Byblos, Lebanon
- 3Unaiz College of Pharmacy, Qassim University, Qassim, Saudi Arabia
Dementia affects more than 40 million people worldwide. When it is accompanied by psychosis, symptom management is especially challenging. Although no drug has been approved by the US Food and Drug Administration for psychosis in patients with dementia, atypical antipsychotics are used off-label in severe cases in patients who do not respond to non-pharmacological interventions. However, antipsychotic use in elderly patients with dementia-related psychosis is associated with adverse reactions including motor function disorders, cognitive impairment, cerebrovascular events, and increased risk of death. In 2017, the US FDA granted breakthrough therapy designation to the new antipsychotic pimavanserin for the treatment of DRP. Topline result of the pivotal phase III HARMONY trial suggests that pimavanserin reduces the relapse of psychosis by 2.8-folds compared to placebo. This favorable result may open path for the potential approval of pimavanserin in DRP. In this review, we discuss the pharmacological activity, clinical efficacy and safety of pimavanserin as a novel atypical antipsychotic with potentials to address the unmet needs of older adults with DRP.
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What To Do In Case You Take Too Much Nuplazid
If you think youve taken too much of this drug, call your doctor. You can also call the American Association of Poison Control Centers at 800-222-1222 or use their online tool. But if your symptoms are severe, call 911 or your local emergency number, or go to the nearest emergency room right away.
When you get Nuplazid from the pharmacy, the pharmacist will add an expiration date to the label on the bottle. This date is typically 1 year from the date they dispensed the medication.
The expiration date helps guarantee that the medication is effective during this time. The of the Food and Drug Administration is to avoid using expired medications. If you have unused medication that has gone past the expiration date, talk to your pharmacist about whether you might still be able to use it.
Acadia Pharmaceuticals Initiates Phase Iii Study Of Pimavanserin In Dementia
- Dementia-Related Psychosis Includes Psychosis in Patients with Alzheimers Disease, Dementia with Lewy Bodies, Parkinsons Disease Dementia, Vascular Dementia, and Frontotemporal Dementia
- FDA Grants Breakthrough Therapy Designation to Pimavanserin for Dementia-Related Psychosis
- Conference Call to Be Held Today at 5:00 pm ET to Discuss Phase III Development Program
SAN DIEGO —-Oct. 4, 2017– ACADIA Pharmaceuticals Inc. today announced the initiation of HARMONY, a Phase III study to evaluate pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis, a serious medical condition for which there is no therapy approved by the U.S. Food and Drug Administration . The company also announced that the FDA has granted Breakthrough Therapy Designation to pimavanserin for dementia-related psychosis. Dementia-related psychosis includes psychosis in patients with Alzheimers disease, dementia with Lewy bodies, Parkinsons disease dementia, vascular dementia, and frontotemporal dementia.
If the clinical development program is successful, and pimavanserin is ultimately approved by the FDA for the treatment of dementia-related psychosis, it would represent a significant expansion of the approved use of pimavanserin. Currently, pimavanserin is the only drug approved by the FDA for the treatment of hallucinations and delusions associated with Parkinsons disease psychosis. It is marketed under the trade name NUPLAZID®.
Other
About Pimavanserin
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How Is Lewy Body Dementia Diagnosed
Diagnosing Lewy body dementia can be challenging. Early LBD symptoms are often confused with symptoms found in other brain or psychiatric conditions.
There are no medical tests that can diagnose Lewy body dementia with 100% accuracy. A diagnosis may require a group of specialists, including:
- Neuropsychologists.
Together, they can make the diagnosis of probable LBD based on the combined results of tests and symptoms.
Along with a history of progressive cognitive decline that interferes with daily activities, a diagnosis of LBD is considered probable if two of the following four core features are present and is considered possible if only one is present:
- Fluctuations in cognition and behavior.
- Recurrent visual hallucinations.
- Rapid eye movement sleep behavior disorder.
Some people with Parkinsons disease who develop cognitive symptoms less than a year after the onset of movement problems may be diagnosed with Lewy body dementia.
Healthcare providers use the following strategies to help diagnose LBD and to rule out conditions that cause similar symptoms:
Financial And Insurance Assistance
If you need financial support to pay for Nuplazid, or if you need help understanding your insurance coverage, help is available.
Acadia Pharmaceuticals, the manufacturer of Nuplazid, offers a program called NUPLAZIDconnect. This program may be able to help lower the cost of the drug for you. For more information and to find out if youre eligible for support, call 844-737-2223 or visit the program website.
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Nuplazid For Parkinsons Disease Psychosis
Nuplazid is FDA-approved to treat hallucinations and delusions related to Parkinsons disease psychosis. A hallucination is seeing or hearing something that isnt really there. A delusion is believing something that isnt true, and such beliefs may often be unrealistic.
Parkinsons disease is a condition that affects your nervous system. Its a progressive disease, which means that it gets worse over time. More common symptoms can include tremors , slow movements, and stiff muscles.
Some people with Parkinsons disease may also experience psychosis . Its the hallucinations or delusions caused by this psychosis that Nuplazid is used to treat.
Effectiveness for Parkinsons disease psychosis
Nuplazid has been shown to be effective for treating hallucinations or delusions that are related to Parkinsons disease psychosis.
In clinical trials, the effectiveness of Nuplazid was measured using a test called the Scale for the Assessment of Positive Symptoms of Parkinsons Disease . This scale goes from 0 to 45, and a higher score means more severe symptoms.
In clinical trials:
- people taking Nuplazid had their SAPS-PD scores decrease by 5.79 points
- people taking a placebo had their SAPS-PD scores decrease by 2.73 points
What Is The Prognosis Of Lewy Body Dementia
The prognosis of LBD is generally fair to poor because it gets worse over time.
People with LBD can die from several different complications, such as:
- Swallowing issues.
- Depression leading to suicide
- Reactions to first-generation antipsychotic medications used to treat and manage symptoms of many psychiatric disorders, such as neuroleptic malignant syndrome.
If you or a loved one has been diagnosed with LBD, its important to learn about the condition and all the medications and therapies that can help you be as comfortable and safe as possible.
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Dosage For Parkinsons Disease Psychosis
The typical dose of Nuplazid to treat hallucinations and delusions* related to Parkinsons disease psychosis is 34 mg taken once a day.
In some cases, people taking certain other medications with Nuplazid may only be able to take 10 mg of Nuplazid once a day. Talk with your doctor about any other medications youre taking before you start Nuplazid. They can determine the best dose of Nuplazid for you to take.
* A hallucination is seeing or hearing something that isnt really there. A delusion is believing something that isnt true, and such beliefs may often be unrealistic.
What Is The Life Expectancy For People With Lewy Body Dementia
The average life expectancy of Lewy body dementia is five to eight years after the initial diagnosis. But some people with LBD live up to 20 years after their diagnosis.
This short average life expectancy could be due to a lack of knowledge regarding LBD among healthcare providers and the population and difficulty in distinguishing it from other similar conditions. This often leads to a delay in diagnosis, which delays the onset of specific therapy.
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Acadia Pharmaceuticals Announces Us Fda Accepted For Filing The Supplemental New Drug Application For Nuplazid For The Treatment Of Hallucinations And Delusions Associated With Dementia
– If approved, NUPLAZID would be the first and only treatment indicated for dementia-related psychosis
– Prescription Drug User Fee Act date set for April 3, 2021
– Conference call and webcast to be held today at 4:30 p.m. Eastern Time
today announced that the U.S. Food and Drug Administration has accepted for filing its supplemental New Drug Application for NUPLAZID® for the treatment of hallucinations and delusions associated with dementia-related psychosis .
We are pleased that the FDA has accepted our sNDA for filing and we will be working closely with the FDA to facilitate completion of the review in a timely manner, said Steve Davis , ACADIAs Chief Executive Officer. If approved, NUPLAZID would be the first therapy indicated for the treatment of hallucinations and delusions associated with dementia-related psychosis. We look forward to potentially bringing this important treatment advancement to patients, caregivers and physicians.
The FDA has assigned a standard review with a PDUFA action date of April 3, 2021 . The FDA has also informed the company that it has not identified any potential review issues at this point in their evaluation and at this time they are not planning to hold an Advisory Committee meeting.
Conference Call and Webcast Information
About HARMONY
About Dementia-Related Psychosis
About Pimavanserin
About ACADIA Pharmaceuticals
Forward-Looking Statements
Important Safety Information and Indication for NUPLAZID
Important Safety Information
Changes In Dementia That May Result In Psychosis Pathway Dysfunction
The corticallimbic psychosis pathway provides numerous points where dysfunction could trigger delusions and/or hallucinations. The pathology and dysfunction across the dementias leading to delusions and/or hallucinations may be different in specific dementias but each is positioned to affect the function of the corticallimbic system thought to mediate psychosis. The evidence for dysfunction which could disrupt the corticallimbic psychosis pathway in each dementia is described below.
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Acadia’s Nuplazid Hits The Mark In Late
Shares of ACADIA Pharmaceuticals are soaring in premarket trading after the company announced full positive results from its Phase III HARMONY study evaluating Nuplazid for the treatment of dementia-related psychosis. The stock is up more than 20% to $53.26.
Acadia stopped the HARMONY trial early in September following a pre-planned interim analysis after Nuplazid hit the primary endpoint of significantly reducing the risk of relapse of psychosis compared to placebo. In fact, the company is excited that the data shows patients on Nuplazid are nearly three-times less likely to have a psychosis relapse than placebo patients. In addition to hitting the primary endpoint, Nuplazid hit the key secondary endpoint of significantly reducing the risk of discontinuation for any reason. With the trial results, Acadia plans to head to the U.S. Food and Drug Administration to seek regulatory approval early next year. The FDA previously granted Breakthrough Therapy Designation for pimavanserin for the treatment of dementia-related psychosis.
The company presented full trial data at the 12th Clinical Trials on Alzheimers Disease meeting in San Diego on Wednesday. Serge Stankovic, president of Acadia, hailed the HARMONY study as a landmark in dementia-related psychosis.
Nuplazid was well-tolerated during the study with a low rate of adverse events observed.
Warning About Antipsychotics Important
Per the NIH:
People with Lewy Body Dementia may have severe reactions to or side effects from antipsychotics, medications used to treat delusions, hallucinations, or agitation. These side effects include increased confusion, worsened parkinsonism, extreme sleepiness, and low blood pressure that can result in fainting . Caregivers should contact the doctor if these side effects continue after a few days.
Some antipsychotics, including olanzapine and risperidone , should be avoided, if possible, because they are more likely than others to cause serious side effects.In rare cases, a potentially deadly condition called neuroleptic malignant syndrome can occur. Symptoms of this condition include high fever, muscle rigidity, and muscle tissue breakdown that can lead to kidney failure. Report these symptoms to your doctor immediately.
Antipsychotic medications increase the risk of death in elderly people with dementia, including those with LBD. Doctors, patients, and family members must weigh the risks of antipsychotic use against the risks of physical harm and distress that may occur as a result of untreated behavioral symptoms.
People with Lewy Body Demntia are often sensitive to prescription and over-the-counter medications for other medical conditions. Talk with your doctor about any side effects seen in a person with LBD.
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What Can I Expect If A Loved One Or I Have Lewy Body Dementia
Each persons experience with Lewy body dementia is unique to them. How slowly or quickly the disease progresses is impossible to know, but may be influenced by your general health and any existing conditions you may have.
Because LBD is a progressive disease, difficulties with mind and body functions get worse over time. Currently, theres no known way to stop the progression of the disease.
However, theres always hope. Research on dementia with Lewy bodies, Alzheimers disease and Parkinsons disease with dementia are ongoing. New medications are being developed and new treatment approaches are being investigated.
How Do I Take Care Of Someone With Lewy Body Dementia
If you care for someone who has been diagnosed with Lewy body dementia , its important to learn about the condition and seek professional guidance to help care for them at home. Understanding LBD can help you cope with everyday challenges.
You may need to make changes to your home to make everyday life easier for them. For example, it helps to have a bright, cheerful and familiar environment. Its also important to make sure your home is safe and clear of any obstacles that could cause falls.
Your loved ones healthcare team can help guide you with these changes.
As insight and judgment skills decline in people with LBD, you may need to appoint someone else to oversee their finances. Before their decline in mental function is severe, its also important to clarify their wishes about care and financial and legal arrangements.
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Proposed Mechanism Of Action Of Pimavanserin
Across the underlying causes of corticallimbic psychosis pathway hyperactivation, 5-HT2A receptor antagonism represents a common point of regulation and for treatment intervention with antipsychotics.Reference Hacksell, Burstein, McFarland, Mills and Williams66 Pimavanserin is a selective serotonin inverse agonist/antagonist at 5-HT2A receptors, with 40-fold less activity at 5-HT2C receptors and no affinity for dopaminergic, histaminergic, muscarinic, or adrenergic receptors, and is proposed to act as a targeted serotonergic modulator of circuits .Reference Hacksell, Burstein, McFarland, Mills and Williams66 Pimavanserin is thought to reduce the activity of these receptors to below basal levels and regulate the effects of both cortical GABAergic deficits and excess cortical serotonergic signaling. This is posited to decrease visual hallucinations and attenuate glutamate signaling to the VTA and mesolimbic pathway, further decreasing delusions and hallucinations.
Figure 2. Pimavanserin-mediated 5-HT2A receptor inhibition: hypothesized modulation of signaling through a variety of neurotransmitters. Through 5-HT2A antagonism/reverse agonism, pimavanserin is proposed to act as a targeted serotonergic modulator of circuits, mitigating the effects of GABAergic deficits and excess serotonergic signaling, while also reducing hyperactive glutamatergic signaling and mesolimbic pathway activation.