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Nuplazid Shows Sustained Easing of Psychosis in Patients in Phase 3 Trial

Nuplazid trial results

Daily use of Nuplazid (pimavanserin) leads to strong and sustained reductions in the frequency and severity of hallucinations and delusions in people with Parkinson’s disease psychosis, according to data from a long-term extension study.

These findings, “Improvement and Durability in SAPS-PD Assessment over 10 Weeks of Pimavanserin Treatment for Parkinson’s Disease Psychosis,” were presented at the at the 2020 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, which was held virtually due to the COVID-19 pandemic.

Nuplazid, marketed by Acadia Pharmaceuticals, is a selective serotonin inverse agonist that works by blocking the activity of serotonin receptors called 5HT2A. These receptors have been associated with several mental health disorders, including psychosisdepression and schizophrenia.

The medication is currently approved in the U.S. to treat hallucinations and delusions associated with Parkinson’s disease psychosis (PDP).

Nuplazid’s approval was supported by findings in several clinical trials, including a completed Phase 3 study (NCT01174004), that assessed its safety and efficacy compared with a placebo in 199 people with Parkinson’s psychosis.

Patients were randomly assigned to either Nuplazid (34 mg) or placebo tablets, both taken once-a-day for six weeks.

Study findings showed that compared to a placebo, Nuplazid reduced the frequency and severity of hallucinations and delusions without worsening patients’ motor symptoms.

All patients who completed this and earlier Nuplazid studies were then invited to enroll in an open-label extension study (NCT00550238) to either continue or start (previous placebo group patients) treatment with Nuplazid for four weeks.

The prospective analysis presented at ASCP was based on data from 171 patients who completed the original Phase 3 trial and entered in its long-term extension. Of these, 148 (87%) completed the extension study.

Findings showed that Nuplazid’s use led to strong and durable reductions in the frequency and severity of hallucinations and delusions, as measured by the Scale for the Assessment of Positive Symptoms – Parkinson’s disease (SAPS-PD), since the beginning of the original study up until the end of its extension study. This scale is a structured patient interview that consists of five domains: hallucinations, delusions, bizarre behavior, positive formal thought disorder, and inappropriate affect. Higher scores indicate more severe psychosis.

Such benefits were seen both in patients who started treatment in the original trial and were given Nuplazid for a total of 10 weeks (mean reduction of 6.86 points), and in those who only started treatment in the extension study and were on the medication for four weeks (mean reduction of 6.28 points).

In people previously given a placebo, SAPS-PD scores decreased by an average of 3.43 points since the beginning of the extension study until its completion one month later. Among those given Nuplazid in the original trial, SAPS-PD scores remained nearly constant over this trial’s four weeks (slight increase of 0.43 points).

Improvements as assessed by the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I) scales were also seen, particularly in patients who switched from a placebo in the original trial to Nuplazid in the extension study.

Among these patients, nearly half (46.6%) felt they had very much improved or much improved by the second week of the extension study, and more than half (57.1%) reported the same at week four.

Adverse events observed during the extension study were identical to those reported in the original trial. The most common included falls, hallucinations, urinary tract infections, and swelling.

Most adverse events were only mild or moderate in severity. A total of 14 (8.2%) patients had to stop treatment due to side effects.

“Overall, the sustained improvement in the severity of psychotic symptoms was suggested in patients with PDP [Parkinson’s disease psychosis] receiving treatment with pimavanserin 34 mg daily for 10 weeks,” the researchers wrote.

During the meeting, Acadia also presented data on the long-term safety and tolerability of Nuplazid with Parkinson’s patients, and new findings from trials enrolling people with other central nervous system (CNS; the brain and spinal cord) disorders, including major depressive disorder and schizophrenia.

“Our research presentations at ASCP underscore the potential clinical utility of pimavanserin in serious CNS disorders,” Serge Stankovic, MD, MSPH, president of Acadia, said in a press release.

“Pimavanserin has demonstrated the potential to be an important treatment option for patients [with schizophrenia and major depressive disorder and showed promising] long-term safety and tolerability … in Parkinson’s disease psychosis,” Stankovic added.

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Long-term Nuplazid Safe, Well-tolerated by Parkinson’s Psychosis Patients, Extension Study Shows

Nuplazid extension study

Nuplazid (pimavanserin), an approved therapy for treating hallucinations associated with Parkinson’s disease psychosis, is generally safe and well-tolerated in the long run, and may be associated with reduced mortality in this particular patient population, findings from a long-term extension study suggest.

The results were presented at the 2020 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, which was held virtually due to the COVID-19 pandemic. The poster was titled “Long-Term Evaluation of Open-Label Pimavanserin Safety and Tolerability in Parkinson’s Disease Psychosis.”

In addition to the motor symptoms of Parkinson’s disease, some patients with the condition experience psychosis, which causes them to experience hallucinations or delusions that affect their quality of life and increase burdens on their caregivers.

Nuplazid, developed by Acadia Pharmaceuticals, was approved by the U.S. Food and Drug Administration (FDA) in 2016 to treat these symptoms of Parkinson’s disease psychosis. It blocks the signaling of certain serotonin receptors in the nervous system, which have been associated with mental disorders such as depression and epilepsy.

Nuplazid has been deemed safe and well-tolerated across a number of randomized clinical trials, but the oral treatment is designed to be taken daily for extended periods and little is known about its safety and tolerability in the long term.

To address that, Acadia designed an open-label Phase 3 extension trial (NCT00550238) that included Parkinson’s disease psychosis patients who completed two prior randomized, six-week Phase 3 trials (NCT00477672 and NCT00658567) and a prior open-label extension Phase 2 study (NCT01518309).

In total, 459 patients were included in extension study, most of whom were men (61.7%), with an average age of 71.2 years. They are receiving once-daily Nuplazid, at an oral dose of 34 mg (the approved dose), with assessments scheduled at two weeks, one month, and three months after entering the trial, every three months thereafter until 12 months, and every six months in the following years.

The study has been going on for more than 10 years, and researchers now are reporting data after a median of 454 days (about 1.2 years) on treatment. Some of these patients have been on Nuplazid for nearly nine years.

Over the follow-up period, 85.4% of patients experienced at least one adverse event (side effect) related to treatment, with most being mild to moderate in intensity. Serious treatment-related adverse events were reported in 41% of patients, and included pneumonia, urinary tract infection, and hip fracture. In total, 29% of patients discontinued treatment due to an adverse event related to Nuplazid.

Findings also demonstrated that disease symptoms remained stable over time, with scores on the Clinical Global Impression (CGI) severity scale and improvements scale being similar at week 192 on treatment (about 3.5 years) compared to study start.

This also was observed among the 43 patients who responded to Nuplazid during the randomized studies — defined as those with a score of zero on the Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis at week 6 — whose mean CGI-S scores were similarly maintained over time through 150 weeks (roughly 2.8 years).

Caregiver burden scores, meanwhile, increased progressively from baseline (28.2 points) to week 192 (32.5 points).

To date of the report, 61 patients have died, amounting to a mortality rate of 6.45 deaths per 100 patient-years. This was similar to the mortality rate seen in Parkinson’s patients of the same age across a Medicare database (7.3 per 100 patient-years), but lower than the mortality usually seen in people with Parkinson’s disease psychosis (28.2 per 100 patient-years), the team noted.

Also, no disease origin or adverse events were consistently associated with deaths in these patients.

This was the largest Parkinson’s disease psychosis study in which patients were followed for long periods, but the team noted that its open-label nature, the lack of a control group, and that the inability to follow patients after treatment discontinuation are clear limitations.

Still, they concluded that “long-term study showed pimavanserin treatment to be generally safe and well tolerated. No new or unexpected safety findings were observed.”

The post Long-term Nuplazid Safe, Well-tolerated by Parkinson’s Psychosis Patients, Extension Study Shows appeared first on Parkinson’s News Today.

Top 10 Parkinson’s Stories of 2018

Top 10, Parkinson's

Parkinson’s News Today provided you with daily coverage of important findings, treatment developments, and clinical trials related to Parkinson’s during 2018.

We look forward to bringing more news to Parkinson’s patients, as well as their family members and caregivers, during 2019.

Here are the Top 10 most-read articles of 2018, with a brief description of what made them interesting to the Parkinson’s community.

 No. 10 – “Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Results of a Phase 2 trial (NCT02954978) of Novartis’ nilotinib in 75 patients with mid-stage Parkinson’s and mild cognitive impairment suggested the therapy increased production and metabolism of dopamine within one to four hours after a single treatment. Also, low-dose nilotinib (150 mg and 200 mg) — marketed as Tasigna for certain types of leukemia — was associated with lower levels of an altered and toxic form of alpha-synuclein, the main component of Parkinson’s hallmark protein clumps known as Lewy bodies.

No. 9 – “Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

The long-term safety, tolerability, and immune response associated with an experimental vaccine called Affitope PD01A were studied in a series of four consecutive Phase 1 trials: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188), and AFF008AA (NCT02618941). Twenty-one treated and five control patients completed the series. The results showed that both 15 μg or 75 μg doses of Affitope were well-tolerated, only causing mild injection-site reactions. The vaccine, being developed by Affiris, induced a clear immune response against its target — alpha-synuclein — that was stabilized with “boost” injections. At week 26 of treatment, it induced a trend toward lower levels of a toxic form of alpha-synuclein in the blood and cerebrospinal fluid, the liquid surrounding the brain and the spinal cord.

No.8 – “MRI-Focused Ultrasound Undergoing Phase 3 Clinical Trial for Parkinson’s Treatment

A Phase 3 trial (NCT03319485) of a potential nonsurgical treatment, known as magnetic resonance imaging (MRI)-guided focused ultrasound, also attracted significant interest. The InSightec-sponsored study — still recruiting patients with advanced disease — is exploring the procedure’s safety and effectiveness. It follows a pilot trial demonstrating lesser upper-limb tremors in patients with tremor-dominant Parkinson’s who did not respond to other therapies. In this non-invasive approach, ultrasound waves destroy damaged tissue in a brain structure called the globus pallidus, which is involved in the regulation of voluntary movement. The team expects to enroll 80 to 100 participants.

No. 7 – “Key to Effective Parkinson’s Treatment May Lie in Stem Cells, Researchers Say

Advancements in stem cell therapy for Parkinson’s were also of clear interest to our readers. Two articles assessed the replacement of dopamine-producing neurons, progressively lost during the course of disease. The first focused on patient-derived induced pluripotent stem cells (iPSCs), fully matured cells that researchers are able to reprogram in vitro (in the laboratory) to revert them to a stem cell state in which they are able to grow into any type of cell, including dopaminergic nerve cells. The second study focused on an alternative approach to stem cell therapy that, instead of iPSCs, uses parthenogenetic-derived neural stem cells. These cells are obtained by chemical manipulations in unfertilized human oocytes, or immature egg cells, which are also able to grow into neurons. A Phase 1 trial (NCT02452723) of this approach is underway in patients with moderate to severe disease at a single site in Australia.

No. 6  “Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

Atrophy, or shrinkage, of the hippocampus — a critical brain area involved in memory — correlates with psychosis in patients with Parkinson’s disease. Specifically, researchers found that the volume of distinct subzones of the hippocampus was associated with psychosis severity and impaired cognitive functions. Greater volume was also seen in another specific brain area, the hippocampal fissure, and seems to correlate with poorer visual memory and visuospatial functions. Previous data had suggested that change in this area is a radiological hallmark of ongoing brain atrophy in the hippocampus.

No. 5 – Tiny Brain Bleeds Associated with Parkinson’s Disease Dementia, Study Reports

The link between tiny bleeds in the brain — cerebral microbleeds (CBMs) — with both cognitive impairment in Parkinson’s disease and risk of associated dementia was No. 5 among the year’s most-read stories. CBMs are small (2-10 mm as assessed by MRI), chronic brain hemorrhages believed to be caused by structural abnormalities of the brain’s small vessels. Scientists found that CBMs were more common in Parkinson’s patients with dementia than in those without dementia, and were associated with lower cognitive scores. Other findings showed that patients with CBMs were older, and had more severe Parkinson’s symptoms and cerebrovascular lesions.

No. 4 – “Vitamin B12 Supplements May Help Slow Parkinson’s Progression, Study Finds

Patients at early stages of Parkinson’s with low levels of vitamin B12 may experience faster motor and cognitive decline. Prior work had shown that B12 deficiencies can induce neurological and motor symptoms associated with Parkinson’s, including depression, paranoia, muscular numbness, and weakness. This study differed in that it was conducted in untreated patients earlier in the disease course, and found slower progression in those taking a multivitamin supplement. Overall, the findings suggest that vitamin supplements may help slow symptom progression.

No. 3  “Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggest

Pain is a frequent non-motor symptom of Parkinson’s disease. A review study found that its management may be most effective with Xadago (safinamide, by US WorldMeds) or with cannabinoids and opioids.  Other approaches, such as multidisciplinary team care, Comtan (entacapone) and Tasmar (tolcapone) may also provide pain relief. In turn, the investigational treatment pardoprunox (SLV-308) and surgery reported only moderate benefits on reducing pain severity.

No. 2 – “Medical Cannabis Helps Older People with Parkinson’s, Other Diseases, Study Finds

Medical cannabis is a safe and effective option to ease pain in older patients with Parkinson’s, cancer, or other illnesses. In a study involving 2,736 people 65  years or older, its use over six months enabled a reduction or discontinuation of opioid pain medications in over 18% of patients. Participants also reported an improved quality of life. The most common adverse events were dizziness and dry mouth, reported by 7.1% of patients.

No. 1 – “Vitamin B3 Compound May Prevent Motor Decline in Parkinson’s Disease, Study Says

Out most widely read article of 2018 reported that a form of vitamin B3 — nicotinamide riboside — prevented the loss of motor function and lessened nerve cell death in a fly model of Parkinson’s. It also increased the levels of a metabolic compound called NAD+ and improved energy balance in fish neurons with a defective GBA gene — the most frequent gene risk for Parkinson’s — and defects in mitochondria, the cell’s powerhouse. The researchers suggested that this form of vitamin B3 may help treat impaired mitochondria function, which has been linked to Parkinson’s development.

 

At Parkinson’s News Today, we hope that these articles,  along our continuing reporting throughout 2019, help to educate, inform, and improve the lives of patients and their loved ones.

We wish all our readers a happy 2019.

 

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Nuplazid’s Mortality Risk Not Different from Seroquel, Combo Treatment, Study Finds

Treatment with Nuplazid (pimavanserin) does not lead to a different mortality risk compared to the antipsychotic medication Seroquel (quetiapine), or to combination treatment with both medications, in patients with Parkinson’s psychosis, according to results from a large study.
The study, “Mortality in patients with Parkinson disease psychosis receiving pimavanserin and quetiapine” was published in the journal Neurology.
In April 2016, Acadia Pharmaceuticals’ Nuplazid became the first therapy approved by the U.S. Food and Drug Administration (FDA) for hallucinations and delusions associated with Parkinson’s psychosis.
However, two years later, a CNN report cited an analysis by the nonprofit Institute for Safe Medication Practices, which found a total of 700 deaths in the FDA’s Adverse Event Reporting System — including 500 among Parkinson’s patients in which Nuplazid was the only therapy likely involved — in the nine months following Nuplazid’s arrival on the market in June 2016.
Now, researchers at University of California San Diego School of Medicine explored the medication’s safety further. “We wanted to better understand and assess the risks of using pimavanserin (Nuplazid) within our own patient community, either alone or in combination with other commonly prescribed medications,” Fatta B. Nahab, MD, the study’s senior author, said in a press release.
Besides Nuplazid, the team focused on Seroquel, a second-generation antipsychotic (SGA), which is often used to treat Parkinson’s psychosis. Results were mixed. Use of Seroquel and other SGAs led to concerns about increased morbidity and mortality in patients with dementia or those with Parkinson’s, prompting an FDA black box warning.
Unlike Seroquel, Nuplazid does not affect dopamine receptors, so it does not interfere with the effectiveness of Parkinson’s treatments for motor symptoms.
The team conducted a retrospective analysis of 4,478 UC San Diego Health patients with Parkinson’s, of whom 676 were being prescribed Nuplazid, Seroquel, or both, between April 29, 2016 and April 29, 2018.
Results showed that patients treated with Nuplazid alone (113 patients, mean age 75.9 years) had a lower mortality percentage when compared to those treated with quetiapine only (505 patients, mean age 75.2 years), or with both compounds (58 patients, mean age 74.1 years ). However, the differences were not statistically significant.
When compared to 784 Parkinson’s patients not on these medications (mean age 80 years), the results revealed a significantly greater risk (74%) of mortality in the Seroquel-only group and a trend toward increased risk in the combination treatment group.
“It’s reasonable to assume, however, that individuals requiring these medications have greater disease severity and are at a higher risk of complications and death,” Nahab noted.
A subset of the patients receiving both medications exhibited the highest rate of mortality, although not statistically different. Importantly, the team noted that the combination therapy’s safety is not yet established, as the pivotal Phase 3 trial of Nuplazid (NCT01174004) excluded individuals on antipsychotics.
“Our findings provide the largest comparative report of mortality risk in [Parkinson’s psychosis],” researchers wrote.
However, Nahab noted limitations on the study’s design and nature, which precluded the determination of cause of death or duration of antipsychotic treatment.
“While the results pertaining to [Nuplazid] provide some reassurance for clinicians, patients, and families, future studies

Source: Parkinson's News Today

Benefits of Acadia’s Nuplazid Outweigh Risks for Parkinson’s Psychosis Patients, FDA Reports

Nearly half a year after news reports surfaced about deaths allegedly linked to Nuplazid (pimavanserin) — a therapy for Parkinson’s patients with disease-related psychosis — the U.S. Food and Drug Administration says it could not find any new or unexpected safety concerns with the controversial treatment.
The agency said in a Sept. 20 press release that “after a thorough review, the FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis.”
San Diego-based Acadia Pharmaceuticals, which produces Nuplazid, welcomed the announcement.
“As the only drug currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, Nuplazid is filling an important and previously unmet need,” Doral Fredericks, Acadia’s vice president for U.S. medical affairs, said in a statement emailed to Parkinson’s News Today.
She added that “we remain confident in the efficacy and safety of Nuplazid that supported its approval by the FDA and the reaffirmation the agency has given for the positive benefit-risk profile of Nuplazid in its most recent review.”
In that review, the FDA said it considered the fact that patients with Parkinson’s psychosis are more likely to die in the first place due to their older age, advanced disease, and other medical conditions.
“Moreover, Nuplazid is primarily distributed through a patient support program and a specialty pharmacy network, which increases the likelihood that deaths will be reported to the manufacturer,” said the agency, referring to its FDA Adverse Event Reporting System (FAERS). “In FAERS reports that included a cause of death (many reports did not provide sufficient information to assess drug cause and effect), there was no evident pattern to suggest a drug effect.”
It added that “overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis.”
The recommended dosage is 34 mg, taken orally as two 17 mg tablets once daily, with or without food.
The FDA’s recognition of Nuplazid’s complex safety profile after the medication’s April 2016 approval, the agency said in an April 2018 statement, “led to the inclusion of a Boxed Warning and the addition of other important warnings and precautions in the product labeling, so that healthcare professionals could have the risk/benefit information needed to make prescribing decisions.”
Concern over Nuplazid first surfaced following a CNN report in April. An article on the network’s website cited an analysis by the nonprofit Institute for Safe Medication Practices, which found that FAERS showed a total of 700 deaths — including 500 among Parkinson’s patients in which Nuplazid was the only treatment likely involved — in the nine months following Nuplazid’s June 2016 appearance on the market.
Nuplazid is targeted at treating Parkinson’s psychosis, which affects about 40 percent of the 1 million Americans believed to have the disease. According to CNN, the therapy — Acadia’s only product — generated $125 million in 2017 sales for the company.
The New York-based Michael J. Fox Foundation for Parkinson’s Research posted a bulletin about the FDA’s review on its website but offered no independent

Source: Parkinson's News Today

Nuplazid’s Risks in Treating Parkinson’s Psychosis Don’t Appear Exceptionally High, Experts Say

Nuplazid and Parkinson's psychosis

The controversy surrounding Nuplazid (pimavanserin), Acadia Pharmaceuticals‘ approved treatment for psychosis in Parkinson’s patients, has made its way to scientific journals. But experts appear to take a more questioning view of the medication’s risks than that aired by general media.

A clinical trial comparing the effectiveness and benefits of Nuplazid to other antipsychotics used to treat these patients would be warranted, and ideally pit the medication against clozapine, an editorial in The Lancet said. But the piece also noted that clozapine, a schizophrenia treatment, is not approved for Parkinson’s disease and is used off-label, complicating matters.

The editorial, “Difficult choices in treating Parkinson’s disease psychosis,” was published on May 29.

Focusing on the “relative risk of pimavanserin” in comparison to psychosis medications like clozapine and quetiapine, it also noted that “it is important to remember that safety concerns were expected and deaths can occur commonly in patients with Parkinson’s disease psychosis — a fact acknowledged by the FDA during its assessment — because these patients are frail, and are usually in the end stages of the disease.”

Still, the editorial recommended that a randomized clinical trial assessing Nuplazid’s risks and benefits in Parkinson’s patients be pursued, and research “continue into novel drugs for psychosis in frail populations.”

In the journal Neurology Todaymeanwhile, three neurologists questioned reports of an unusual risk to Parkinson’s patients being treated with Nuplazid for psychosis.

“In my personal experience with pimavanserin, it is effective in a majority of PD [Parkinon’s] psychosis patients,” said Rajesh Pahwa, MD, a professor of neurology and chief of the Parkinson & Movement Disorders Division at the University of Kansas Medical Center in Kansas City. “We need to further study the reports of increased mortality, but in a scientific manner.”

The journal’s “Article in Brief,” published June 7, recounted the controversy concerning Nuplazid, the first medication approved by the U.S. Food and Drug Administration to treat Parkinson’s psychosis, or disease-related hallucinations and delusions, in 2016.

Nuplazid works differently from other anti-psychotic medications in that it does not block dopamine — a brain neurotransmitter crucial to movement and motivation, and the target of treatments for Parkinson’s movement difficulties — focusing instead on a subfamily of serotonin receptors (5 HT2A) of importance to cognition, memory, and the ability to learn.

The news channel CNN reported in April that the FDA’s Adverse Event Reporting System (FAERS) showed a total of 700 deaths, including 500 in Parkinson’s patients in which the medication was the only agent likely involved.

The FDA initially responded by noting that “FAERS data by themselves are not an indicator of the safety profile of the drug or biologic,” and emphasizing it had placed a “boxed warning” on Nuplazid highlighting its risks. A boxed warning is the strictest warning on product labeling that can be given an approved medication, but one — warning of an increased risk of mortality and morbidity in people with dementia — given on all antipsychotics, The Lancet commentary noted.

Later, the FDA acknowledged that is was continuing to keep close watch on Nuplazid and its use in Parkinson’s patients. The CNN report led to a 20 percent drop in Acadia’s stock in the days after its airing.

But, as Pahwa argued, the U.S. Medicare database show that mortality rates (per 100 patient years) are 7.3 for Parkinson’s patients without psychosis, and 28 for patients with psychosis — with a mortaility rate of 18.6 for those using quetiapine off-label, compared to 12.4 in post-marketing data for pimavanserin.

Joseph Jankovic, MD, director of the Parkinson’s Disease Center at Baylor College of Medicine in Houston, told Neurology Today that his patients largely have responded well to Nuplazid treatment.

“While not all patients are completely satisfied, many of my patients have experienced marked improvement in their visual hallucinations, paranoia, and other psychotic symptoms,” Jankovic said. “I suspect that the death rates in elderly patients with advanced PD and psychosis are higher than in a control population without these problems, so it’s not surprising to see deaths in such patients who are taking pimavanserin, but the cause-effect relationship has not been established.”

He preferred to recommend that physicians simply continue to closely monitor their patients.

A similar view was voiced by Cynthia Comella, MD, a professor of neurology at Rush University Medical Center’s Parkinson’s Disease and Movement Disorders Section in Chicago.

“I think it is too soon to be concerned specifically about this drug,” Comella said. “I feel that we need to be cautious with all of these drugs. I especially have concerns prescribing them in elderly patients because they are more fragile and usually have additional disorders and health conditions.”

According to the Neurology Today article, Pahwa has received consulting fees from about a dozen pharmaceuticals and government agencies including Acadia, but no research grants from Acadia. Jankovic and Comella reported no conflicts of interest.

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Source: Parkinson's News Today

Early Symptoms May Predict Future Psychosis in Parkinson’s Patients, Study Finds

psychotic symptoms Parkinson's

Early sleep-related and autonomic symptoms — related to automatic or involuntary body functions — are associated with an increased risk of future psychotic symptoms in Parkinson’s disease patients, according to a recent study.

These symptoms are also associated with a reduction of specific nerve cells in a region of the brain involved in memory, attention, and perception — suggesting these changes could be used as a biomarker to predict psychosis in Parkinson’s patients.

The study, “Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease,” was published in the journal Neurology.

The non-motor symptoms of Parkinson’s disease include cognitive declines; psychiatric disturbances, such as psychosis and depression; autonomic symptoms, related to gastrointestinal, heart, urinary, sexual, and thermoregulation functions; sleep difficulties; and pain.

Psychotic symptoms are a marker of advanced Parkinson’s disease, and strongly reduce the quality of life of patients and caregivers. Identifying baseline predictors of future psychotic symptoms may help identify patients at risk of a more rapidly progressive disease, and provide effective and preventive treatment.

Degeneration or volume reduction of the nucleus basalis of Meynert (NBM) — an area of the brain related to memory, attention, and perception — has been linked to Parkinson’s.

Loss of nerve cells, known as Ch4 nerve cells, which produce acetylcholine — a chemical messenger used for communication between nerve cells — in the NBM region has been associated with cognitive and psychiatric symptoms of Parkinson’s.

University of Virginia researchers studied a group of patients with newly diagnosed, untreated Parkinson’s to identify baseline clinical risk factors for future psychotic symptoms and to investigate the association between the density of Ch4 cells — an indirect measure of NBM volume — and future development of psychotic symptoms.

The study involved 423 untreated Parkinson’s patients, who did not have dementia at the time of enrollment, and 101 healthy individuals included in the Parkinson’s Progression Markers Initiative (PPMI) — a prospective, longitudinal, observational study to identify biomarkers of Parkinson’s progression.

Assessment of Parkinson’s symptoms was performed at the beginning of the study, every three months during the first year, and every six months from one to five years, based on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). This scale includes an item focused on psychotic symptoms, where a score above zero is considered indicative of these issues.

At the study’s start, researchers also assessed patients’ autonomic symptoms using the Scales for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), and sleep-related symptoms, such as REM sleep behavior disorder (RBD), through the RBD screening questionnaire, and excessive daytime sleepiness, through the Epworth Sleepiness Scale.

Ch4 cells’ density at baseline was determined for 228 Parkinson’s patients and 101 controls, using brain magnetic resonance imaging (MRI) data from the PPMI database.

Patients’ mean age at enrollment was approximately 61.5 years old, and about one-third of the patients were women. The last visit occurred at a median of 54 months after the start of the study.

The presence of more autonomic symptoms, REM sleep behavior disorder, and excessive daytime sleepiness at baseline was associated with an increased risk for experiencing psychotic symptoms on two or more occasions.

“Our finding that these 3 nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease,” the researchers wrote.

Lower Ch4 density was associated with the presence of two to three of these symptoms at baseline, as well as with patients who later reported psychotic symptoms.

“The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to […] predict more rapid disease progression,” the researchers concluded.

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Source: Parkinson's News Today

Nuplazid and Clozaril Are Most Reliable Parkinson’s Psychosis Therapies, Review Finds

Parkinson's psychosis therapies

The antipsychotics Nuplazid (pimavanserin) and Clozaril (clozapine) are the only therapies shown to improve Parkinson’s disease psychosis (PDP) symptoms without impairing motor function, in double-blind, placebo-controlled clinical trials, according to a review.

The study, “Pharmacological interventions for psychosis in Parkinson’s disease patients,” was published in the journal Expert Opinion on Pharmacotherapy. 

Parkinson’s disease psychosis is a non-motor symptom that causes patients to experience hallucinations and delusions. More than half of Parkinson’s patients will develop psychosis over the course of their disease.

While hallucinations — seeing, hearing, or feeling things that do not exist — are usually harmless, with no associated emotion, delusions — distorted interpretations of reality — are usually paranoid, creating stressful situations.

Researchers believe the risk factors of Parkinson’s disease psychosis include medication, disease duration, dementia, and delirium — a short-term, reversible symptom usually caused by abnormalities in metabolism, medical conditions, or reactions to medication.

In most cases, Parkinson’s-related psychosis is believed to be a side effect of the medication to treat Parkinson’s. For that reason, treatment involving medication reduction, which can result in aggravated motor symptoms, is only performed when psychosis symptoms become a problem for the patient or caregivers.

In his report, the author argues that before doctors evaluate medication reduction, medical conditions — specially infections — that can cause psychosis should be treated, and psychoactive medication — such as antidepressants, pain killers, and anti-anxiety medication — reduced, if possible.

There is no consensus on the order in which Parkinson’s medications may be reduced, or the speed at which they should be reduced. Clinicians must make those decisions based on the specifics of each patient and their reaction to therapy.

After reducing Parkinson’s medication towards lower levels that can be tolerated by patients, doctors may recommend the use of antipsychotic drugs, such as Nuplazid (pimavanserin), Clozaril (clozapine), or Seroquel (quetiapine, or QTP), to balance abnormal chemical levels in the brain.

Nuplazid and Clozaril are the only therapies which have seen their efficacy supported by double-blind, placebo-controlled clinical trials. Both were shown to reduce psychosis symptoms without impairing motor function.

Nuplazid, the only FDA-approved treatment for PDP, takes four to six weeks to show benefits. On the other hand, Clozaril takes only one week to show responses, but requires frequent blood tests, which makes it inconvenient for elderly patients.

These tests are meant to monitor neutropenia, or reduced levels of neutrophils — a type of white blood cell. This adverse event is reported in some patients under Clozaril.

As for Seroquel, double-blind, placebo-controlled clinical trials showed that it does not improve psychotic symptoms in PDP, even though it does not affect motor function. The author noted that, interestingly, despite the non-positive results in those trials, he and other Parkinson’s experts often use it and find it useful to treat PDP.

Two other antipsychotics, Zyprexa (olanzapine) and Melperone, were also subject to trials. However, none showed benefits for psychosis symptoms. And Zyprexa was shown to induce harmful motor effects, making it a therapy to be avoided.

Dementia drugs, such as cholinesterase inhibitors, showed potential improvements in psychosis features, but additional studies are required to confirm those effects.

As of January 2018, the current position of the International Parkinson Disease and Movement Disorders Society on psychosis, which has not yet been updated to include the positive Nuplazid results, recommends Clozaril over Seroquel. Additional clinical trials are needed to clarify the benefits of other antipsychotic drugs to treat PDP.

The author, Joseph H. Friedman of the Department of Neurology, Warren Alpert Medical School, of Brown University, has received research funding from the National Institutes of Health and the Michael J. Fox Foundation.

The post Nuplazid and Clozaril Are Most Reliable Parkinson’s Psychosis Therapies, Review Finds appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

Nuplazid Review Endorses Treatment, But Pinpoints Additional Study Needs

Nuplazid Review

Even though 60 percent of Parkinson’s Disease patients develop psychotic symptoms, it was only in 2016 that a treatment for the condition was approved.

Nuplazid (pimavanserin) employs an entirely different mechanism to control psychotic symptoms compared to the bulk of antipsychotic medications on the market.

The review, Pimavanserin, a novel antipsychotic for management of Parkinson’s disease psychosis,” took a look at the drug’s specific features, and its potential to early on prevent psychotic symptoms from bringing on more severe disease and premature death among Parkinson’s patients.

Researchers from Feinberg School of Medicine at Northwestern University, published the review in the journal Expert Review of Clinical Pharmacology.

Why not common antipsychotics?

Treatments capable of treating hallucinations and delusions have existed since the 1950s. So, why then do people with Parkinson’s disease require a specific type of medication?

People with Parkinson’s disease suffer neurodegeneration, particularly affecting neurons producing the neurotransmitter dopamine; medications aim to replace lost dopamine signaling by adding more of the substance.

The problem is that the majority of antipsychotic treatments work to block dopamine receptors. Using such drugs, therefore, would worsen motor symptoms. Moreover, some studies show that antipsychotics may increase the risk of death among Parkinson’s patients, although the issue is a topic of debate.

The brain, however, is complex and some newer compounds exist that target other signaling substances to treat psychosis.

Clozapine is considered the most effective antipsychotic on the market. But its widespread use, in Parkinson’s as well as other patients, is prevented by severe and potentially fatal side effects linked to the treatment. Patients need to be closely monitored with blood cell counts because a loss of neutrophil cells can be life-threatening.

Another so-called atypical antipsychotic, quetiapine, is sometimes used in Parkinson’s psychosis. But clinical trials have failed to prove the treatment is more effective than a placebo.

Moreover, both clozapine and quetiapine cause sedation and postural hypotension, which can be difficult to tolerate for someone with Parkinson’s disease, and may increase the risk of falls and worsen cognition, researchers underscored.

The novelty of Nuplazid

Unlike these medications, Nuplazid blocks brain receptors for the neurotransmitter serotonin. The drug has been studied in five Phase 2 or 3 clinical trials, and a sixth is ongoing. So, there is plenty of data showing the safety and effectiveness of this approach.

An analysis of pooled data from four of these trials showed that Nuplazid effectively reduced hallucinations and delusions in patients with Parkinson’s disease psychosis. It also has a good benefit-safety balance, researchers say.

While the side effects of earlier antipsychotics often made doctors delay treating Parkinson’s patients until the hallucinations and delusions became more severe, Nuplazid’s safety profile allows early treatment, the Feinberg researchers underscored.

Studies show that psychotic symptoms in Parkinson’s disease are linked to worsening disease and early death. Moreover, a psychotic Parkinson’s patient is extremely difficult to manage for family caregivers, often making early nursing home placements necessary.

Early treatment, researchers argued, may prevent this development. Since it takes several weeks for the drug to be fully effective, it also is important to start treatment early to prevent a potential exacerbation, they said.

More studies are needed, however, to explore if early treatment really does change the course of negative outcomes linked to psychosis in Parkinson’s disease.

Future directions

Nevertheless, although Nuplazid is approved for use in Parkinson’s disease, it carries a boxed warning that patients with dementia taking antipsychotics are at an increased risk of death.

Many patients with Parkinson’s psychosis also develop dementia, so more information is needed to assess the safety and effectiveness of Nuplazid in this patient group, the reviewers noted.

Acadia Pharmaceuticals, Nuplazid’s developer, recently launched a Phase 3 trial (NCT03325556) testing the drug in patients with dementia-related psychosis. The study enrolls patients with Parkinson’s disease, among others.

The review, however, pointed out that further studies examining the drug are necessary. For instance, the treatment is available in one dose only. Studies should explore other doses, and assess the safety of combining Nuplazid with atypical antipsychotics for people who fail to respond to Nuplazid alone.

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Source: Parkinson's News Today