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Safety and Efficacy of Oral Cannabidiol in Treating Parkinson’s Psychosis Focus of Phase 2 Study in UK

cannabidiol

A planned Phase 2 clinical trial will assess the safety and effectiveness of pharmaceutical-grade cannabidiol (CBD) in treating Parkinson’s-related psychosis.

The trial was announced by Parkinson’s UK, which is investing £1.2 million (roughly $1.5 million) to support the study, due to begin enrolling patients in 2020.

Psychosis is estimated to affect more than half of people with Parkinson’s disease. It is characterized by hallucinations (seeing, hearing, or feeling things that are not really there) and delusions (fixed beliefs that are demonstrably untrue).

These symptoms are typically managed by reducing or stopping the use of medications used to treat Parkinson’s, but such choices have the obvious drawback of arresting any benefits those treatments provide. Antipsychotics are sometimes also used, but they can carry side effects or worsen motor symptoms.

Nuplazid (pimavanserin, by Acadia Pharmaceuticals) is the only medicine currently approved to treat Parkinson’s-related psychosis in the United States; no approved therapies for this condition are available in the United Kingdom.

“Current treatments prescribed by clinicians for psychosis typically work by blocking dopamine receptors, which can increase the problems people with Parkinson’s experience with movement and other symptoms of the condition,” Sagnik Bhattacharya, a professor at King’s College London who will help lead the trial, said in the press release.

This trial will “will determine, for the first time, whether CBD can correct the abnormal functioning of the brain that is causing symptoms such as hallucinations and delusions,” Bhattacharya added.

Cannabidiol is a non-psychoactive component of the cannabis plant, meaning it is found in cannabis, but unlike tetrahydrocannabinol or THC does not induce a feeling of being “high.” CBD is currently undergoing a renaissance of interest for its potential medical uses.

“We know from a recent survey we carried out, that people with Parkinson’s would continue to use, or start using, cannabis-derived products if robust evidence became available that they are safe and effective in treating Parkinson’s symptoms,” said Arthur Roach, PhD, the director of research at Parkinson’s UK. “One of the key questions this clinical trial will address is if CBD is safe to use for Parkinson’s-related psychosis, which has never been done before.”

The two-part study will begin with a six-week pilot phase to evaluate the safety, tolerability and effectiveness of CBD in people with Parkinson’s-related psychosis. Participants will be given daily oral CBD capsules at doses up to 1 gram per day to find the optimum dose. Then, 120 patients will be randomized to treatment with either CBD or a placebo for 12 weeks.

In addition to safety, trial goals (endpoints) will include a detailed assessment of psychotic, motor and non-motor symptoms, as well as brain imaging.

“We will be assessing how safe CBD is for people with Parkinson’s, what the correct dosage is and how it is tolerated alongside the different medications someone with the condition may already be on,” Bhattacharya said. “The study will also look at the effect of CBD on other symptoms which will pave the way for scientists to investigate the potential of the compound in treating these in future studies.

“We hope that this will progress to large-scale clinical trials — the final step towards becoming a new treatment that will improve the lives of people with Parkinson’s,” Bhattacharya added.

If successful, this study “could result in a regulated cannabinoid-based medicine being prescribed and used in the clinic, as opposed to self-administration of expensive supplements that have not been monitored for their composition or effects,” Roach said.

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Nuplazid ‘Significantly’ Slows Relapses in Dementia-Related Psychosis, Phase 3 Trial Shows

psychosis and Nuplazid

Interim results from the ongoing Phase 3 HARMONY study show that treatment with Nuplazid (pimavanserin) significantly delays time to a psychosis relapse in patients with dementia-related disorders, such as Parkinson’s and Alzheimer’s disease.

Evaluation by an independent data monitoring committee recommended an early stop to this placebo-controlled trial based on the treatment’s “robust” efficacy, Acadia Pharmaceuticals — Nuplazid’s manufacturer — announced in a press release. The study’s primary goal — that of a statistically significant longer time to a psychosis relapse — was met in this early analysis.

Nuplazid was approved by the U.S. Food and Drug Administration (FDA) to treat hallucinations and delusions associated with Parkinson’s disease psychosis in 2016. The therapy is not approved to treat dementia-related psychosis, schizophrenia, or major depressive disorder.

After closing the study in the coming months, Acadia plans to meet with the FDA to explore the possibility of filing a supplemental application in 2020, requesting that Nuplazid’s label be expanded to allow its use as a treatment for dementia-related psychosis based in part on the effectiveness seen in HARMONY.

“We are very excited that today’s results bring us one step closer to the potential of offering patients with dementia-related psychosis a critically needed treatment option,” said Serge Stankovic, MD, MSPH, Acadia’s president.

“We look forward to speaking with the FDA about a supplemental new drug application to support pimavanserin for the treatment of dementia-related psychosis,” Stankovic added. “I want to thank all of the patients, their families, and the investigators for their participation in this important study.”

These and other recent HARMONY results will be discussed at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting set for Dec. 4–7, 2019, in San Diego. The oral presentation, “HARMONY Relapse-Prevention Study: Pimavanserin Significantly Prolongs Time to Relapse of Dementia-Related Psychosis,” will be given by Erin Foff, MD, PhD, clinical director at Acadia Pharmaceuticals.

Nuplazid is a selective serotonin inverse agonist that targets serotonin receptors called 5HT2A. These receptors have been associated with mental disorders such as psychosis, depression, schizophrenia, and other neuropsychiatric disorders. Inverse agonists such as Nuplazid bind to the same receptors as agonists, but induce the opposite pharmacological response, blocking the activity of the targeted receptors.

HARMONY (NCT03325556) was designed to explore Nuplazid’s ability to safely and effectively treat delusions and hallucinations associated with dementia-related psychosis across a broad population of patients, and was scheduled to end in August 2020.

It enrolled people with the most common subtypes of dementia, including Alzheimer’s and Parkinson’s disease, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia spectrum disorders, at sites across the U.S., Europe and in Chile.

For an initial 12 weeks, all were treated with Nuplazid at 34 mg once daily until dementia was stable, or with a reduced 20 mg dose if clinically justified within the first four weeks.

After this stabilization period, patients showing a sustained treatment response were then randomly assigned to continue treatment with Nuplazid (34 mg or 20 mg each day) or to switch to placebo for 26 weeks (six months). About 20% failed to show a sustained response during this early period.

All participants were followed through this double-blind period, or until a relapse of psychosis symptoms. A relapse, or significant disorder worsening, was defined as hospitalization due to dementia-related psychosis, significant deterioration of dementia-related symptoms on clinical scales, or the need to use an off-label antipsychotic medication to treat dementia-related delusions and/or hallucinations.

A “number of these patients” completed the full six months of treatment, as well as the initial three-month stabilization period, showing a sustained response, Acadia said in an investor report. Exact patient numbers were not available, as a rolling enrollment was underway.

The preliminary efficacy analysis revealed that those treated with Nuplazid had significantly longer periods of time without a psychosis relapse compare to the placebo treated group. “The interim analysis results … clearly demonstrates the strong durability of treatment with pimavanserin,” the company said. Analyses are continuing.

Safety was also comparable to what was seen in earlier trials, with no new safety concerns identified.

About 15% of the people in the trial had Parkinson’s dementia; a majority, or about 67%, were Alzheimer’s patients with related dementia.

“With no approved treatment options available today for dementia-related psychosis, the pimavanserin study results represent a meaningful advance that will potentially bring us a much needed therapy for this debilitating disease,” Jeffrey Cummings, MD, ScD, director emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said.

The FDA designated Nuplazid a breakthrough therapy for the treatment of Parkinson’s disease psychosis.

Recent results of a Phase 2 clinical trial showed that treatment with Nuplazid can ease depression and sleep problems in patients with Parkinson’s disease.

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Phase 2 Trial of SEP-363856, Potential Oral Treatment of Parkinson’s Psychosis, Enrolling in US

SEP-363856 psychosis trial

A Phase 2 clinical trial of SEP-363856, an oral treatment candidate for people with Parkinson’s psychosis, is now recruiting patients across the U.S.

SEP-363856 is a candidate therapy being developed by Sunovion to treat schizophrenia, and the hallucinations and delusions linked to Parkinson’s disease. It is designed to act as an antipsychotic agent, but through a mechanism distinct from currently available antipsychotics. Specifically, it does not bind to dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors, as current antipsychotics are thought to do.

The 21-week, multi-part Phase 2 SEP361-203 trial (NCT0299369) is expected to enroll up to 36 patients, ages 55 and older, at 24 sites. Among them, 24 people will initially be randomized to SEP-363856 treatment and 12 will be given a placebo.

Eligible patients must have been diagnosed at least one year before study’s start, and have been experiencing such psychosis symptoms as visual hallucinations or paranoia (delusions). Participants also need to have a caregiver able to attend an estimated 13 on-site visits.

Following an initial screening, patients will be randomly assigned to either SEP-363856 oral capsules at 25, 50, or 75 mg once daily, or to a matching placebo, for six weeks. This treatment period will be followed by 12 weeks of an open-label extension phase, during which all participants will be given SEP-363856.

Researchers will evaluate the safety, tolerability, and effectiveness of the candidate therapy.

They will assess changes in the Scale for Assessment of Positive Symptoms–Parkinson’s Disease (SAPS-PD) total score, which addresses manifestations of hallucinations and delusions. Researchers will also evaluate, as secondary trial goals, disease severity and patients’ cognitive function.

The roughly five-month study is expected to expected to conclude in May 2020.

SEP-363856 was designated a breakthrough therapy as a potential treatment of schizophrenia by the U.S. Food and Drug Administration in May, based largely on results from a Phase 2 trial and an open-label extension study. The designation offers FDA guidance to the company in developing the potential treatment, and priority review should a request be filed for approval.

Currently, Nuplazid (pimavanserin), by Acadia, is the only FDA-approved medication for treating hallucinations and delusions associated with Parkinson’s disease.

More information on the SEP361-203 study is available on its website.

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Depression and Psychosis Are Markers of More Severe Disease, Database Study Says

mental illness and Parkinson's

Mental illness in people with Parkinson’s disease, more frequently found in female and older patients, appears to associate with more severe disease, a new study reports.

Titled, “Comorbid Depression and Psychosis in Parkinson’s Disease: A Report of 62,783 Hospitalizations in the United States,” the study was published in the journal Cureus.

Although Parkinson’s disease is best known for its motor symptoms, non-motor symptoms can play an impactful role too. Depression and psychosis (difficulty discerning what’s real and what isn’t) are both psychiatric disturbances known to occur in Parkinson’s patients, and these conditions can, understandably, seriously impact their quality of life.

Researchers across the U.S. set out to examine the interplay between these mental illnesses in Parkinson’s and disease severity, patient demographics, and hospital outcomes.

They analyzed data from the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS) covering 2010–14; this included information on 62,783 people with Parkinson’s, of whom 11,358 (18.1%) were diagnosed with depression and 2,475 (3.9%) experienced psychosis.

Both mental health conditions were significantly more common in female patients; women made up 37.2% of the total population, but 44.9% of those with depression and 41.8% of those with psychosis.

Depression was more common among white patients (84.9% with depression were white, compared to 80.6% white in the total population), whereas a disproportionate percentage of people with psychosis were black (8.7% vs. 6.5% of total population) and were in the lowest quartile of household income (28.6% vs. 22.4% in the total population).

Older patients were also more likely to experience mental illness, with those older than 80 years at a 5.3-fold greater risk than patients in their 40s and 50s.

Having psychosis was associated with more severe disease: 78.8% of Parkinson’s patients with psychosis had moderate or severe disease compared to 66.2% of the total population, meaning patients with psychosis were 1.38 times more likely to have more severe disease. In those with depression, 67.9% had moderate or severe disease, a similar rate as seen in the total population.

Additionally, around a quarter of the total population received deep brain stimulation (DBS) as part of their treatment. A similar proportion of patients with depression were given DBS, but only 3.9% of patients with psychosis did.

Patients with psychosis also tended to have longer average hospital stays (7.3 vs. 4.1 days in the psychosis and total cohorts, respectively), but, interestingly, lower average total hospital charges ($31,240 vs. $39,688 in the total cohort). Both average length of hospital stay and average costs were similar for the total population and those with depression.

These results are all only associations; the study was not designed to find cause-and-effect relationships, and regardless, such relationships are likely affected by the combination of many factors. More research will be needed to better understand the interplay between these factors, but this work does highlight the impact of mental health in Parkinson’s disease.

“The results of our study suggest that healthcare providers should actively screen for psychiatric comorbidities like depression and psychosis in patients with PD [Parkinson’s disease],” the researchers concluded, adding, “[p]sychiatric comorbidities in PD should be considered an integral part of the disease, and a multidisciplinary approach to managing this disease is crucial to improve the overall outcome and the health-related quality of life of PD patients.”

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High Levels of Zinc Found in Hair of Parkinson’s Patients with Depression, Psychiatric Symptoms, Study Says

zinc, depression, Parkinson's

Parkinson’s disease patients with either depression or psychiatric symptoms such as hallucinations, confusion, or illusion may have higher levels of the mineral zinc in their hair, researchers report.

Their study, “Higher zinc concentrations in hair of Parkinson’s disease are associated with psychotic complications and depression,” was published in the Journal of Neural Transmission.

Besides the typical motor symptoms, Parkinson’s patients may also experience non-motor symptoms such as cognitive impairment, sleep difficulties, depression, anxiety, and psychosis. Psychosis, although not fully understood, is common in Parkinson’s, particularly in its later stages. Symptoms include minor illusions, vivid dreams, occasional visual hallucinations, paranoia, and panic attacks.

Evidence indicates an imbalance of metal compounds is somewhat associated with Parkinson’s disease mechanism. In fact, too much iron has been found within patients’ substantia nigra and striatum — two brain regions involved in motor control that are extensively damaged in Parkinson’s — as well as in other peripheral tissues.

In this neurodegenerative disorder, calcium has also been suggested to play a role by promoting cellular death, while zinc may influence non-motor features of the disease.

These minerals are strongly correlated to psychiatric complaints and mood disorders in Parkinson’s, but the exact relationship between calcium, iron, and zinc levels in Parkinson’s patients with psychiatric complaints remains to be clarified.

Therefore, researchers at the University of Copenhagen in Denmark, along with collaborators in Brazil and Ireland, set out to investigate the link between these metal compounds and the co-occurrence of depression, anxiety, and psychotic symptoms in Parkinson’s disease.

Twenty-two patients (15 men and seven women, with a mean age of 69.8 years), who were registered in the 13th Regional Health Board in Jequié, Bahia (Brazil), had their mood and psychiatric complications assessed by clinically validated scales. Using the participants’ hair samples, scientists also quantified calcium, iron, and zinc levels.

To do so, the investigators applied a technique called flame atomic absorption spectroscopy (FAAS), which uses the absorption of electromagnetic radiation to measure the concentration of gas-phase atoms. The results were compared to 33 healthy individuals.

Significantly higher zinc levels were found to be correlated with depression or with one or more psychotic complications, including hallucinations, illusion, paranoid ideation (when the patient believes he or she is being harassed or persecuted), altered dream phenomenon, and confusion, compared with patients without these symptoms and healthy controls.

Altered concentrations of calcium and iron were not associated with Parkinson’s-related psychiatric disturbances.

Although the sample size was small, the study seemed to suggest that zinc levels could be a biomarker for psychiatric manifestations in Parkinson’s, and as such, a potential target for novel disease management therapies.

“FAAS is simple to implement, and low in cost, and as it can be used with a biological sample easy to obtain, such as hair, this methodology offers the real advantage of being feasible for a wide range of clinics to implement,” the team said, adding that further research and larger studies are still warranted.

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Review Study Provides Update on Treatments for Parkinson’s Non-motor Symptoms

non-motor symptoms, Parkinson's

Although there are now more treatment options available for non-motor symptoms in Parkinson’s disease, a lack of evidence on their effectiveness and safety means that more studies and new therapeutic strategies are needed, according to a review study.

The study, “Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease — An Evidence‐Based Medicine Review,” appeared in the journal Movement Disorders.

The International Parkinson and Movement Disorders Society Evidence-Based Committee reviewed research published from 2011 through 2016 on Parkinson’s non-motor symptoms to help physicians select the most effective treatments and provide an update to a 2011 study.

Two online databases were searched, resulting in the inclusion of 37 studies with 20 patients or more. In all of the included studies, treatment lasted a maximum of six months, except for one low-quality safety study, meaning the recommendations do not cover long-term symptom management, the team noted. The studies included pharmacological, surgical, and nonpharmacological interventions, which had to be available in at least one country.

According to their level of evidence, the different approaches were classified as efficacious, likely efficacious, unlikely efficacious, non-efficacious, or with insufficient evidence. To address practice implications, the team also rated the interventions as clinically useful, possibly useful, and unlikely useful, not useful, or investigational.

Christopher G. Goetz, MD, president of the International Parkinson and Movement Disorders Society, noted the differences between this approach and practice guidelines issued by medical associations such as the American Academy of Neurology. In a Neurology Today article written by Susan Fitzgerald, titled “Which are the Most Efficacious Therapies for Nonmotor Parkinson Disease Symptoms?” he said that “guidelines are really culturally based,” and take into account “regulatory issues, access issues, and insurance issues.”

“With evidence-based methodology, we are strictly looking at the published evidence. We don’t tell you whether we recommend it (a specific therapy),” he added.

No clinical trials met the inclusion criteria for the treatment of anxiety disorders, excessive sweating, rapid eye movement behavior disorder, and olfactory or ophthalmologic dysfunction.

Six new studies were reviewed for depression. One addressed venlafaxine, characterized as efficacious, with an acceptable safety risk and no need for specialized monitoring, and clinically useful. This contrasted to amitriptyline, which has insufficient efficacy evidence to treat depression in Parkinson’s patients and was rated as possibly useful. Paroxetine, citalopram, fluoxetine and sertraline, all selective serotonin reuptake inhibitors (SSRIs), were categorized in a similar way.

Rotigotine, marketed as Neupro, was found unlikely efficacious based on the results of one study, and rated as investigational regarding practice implications. Rasagiline, marketed as Azilect, also showed insufficient evidence of efficacy and was classified as investigational as well.

As for nonpharmacological interventions, two studies on repetitive transcranial stimulation showed inconsistent effects on depression. However, its benefits in the general population and in specific measures in people with depression make this approach possibly useful for short-term treatment of Parkinson’s.

Cognitive-behavioral therapy (CBT) could only be rated as likely efficacious and has insufficient safety evidence in the treatment of depression in Parkinson’s due to the lack of replication of its benefits, the investigators cautioned.

Treatments for apathy were also evaluated. Rivastigmine, marketed as Exelon, was found efficacious in one study, but its small group of patients mean that this medication is only possibly useful in the clinic. A similar conclusion was reached for piribedil following deep brain stimulation. In contrast, Neupro was classified as unlikely efficacious based on one trial.

As for the treatment of impulse control disorders, naltrexone, marketed as ReVia, showed insufficient efficacy and safety evidence, while CBT was rated as likely efficacious and possibly useful clinically based on one new study.

Regarding dementia, Aricept (donepezil) and Razadyne (galantamine) still have insufficient efficacy evidence, but were rated possibly useful in clinical practice due to their established benefits outside Parkinson’s.

Both rasagiline and rivastigmine have insufficient efficacy evidence to treat cognitive impairment. A similar conclusion was reached for transcranial direct current stimulation and for cognitive rehabilitation in patients on computer-based cognitive training.

Three new studies were evaluated for psychosis. While olanzapine, marketed as Zyprexa, is not efficacious and therefore not useful from a clinical perspective, Nuplazid (pimavanserin) was characterized as efficacious over six weeks and clinically useful. Seroquel (quetiapine) has insufficient evidence though it is possibly useful in the clinic.

Studies of sleep disorders indicated that Lunesta (eszopiclone) and melatonin have insufficient evidence for the treatment of insomnia, but are possibly useful. Modafinil, marketed as Provigil, is also possibly useful for excessive daytime somnolence and sudden onset of sleep in people with Parkinson’s. Continuous positive airway pressure was considered likely efficacious and possibly useful in lessening daytime sleepiness in patients with obstructive sleep apnea, and Neupro was rated the same for improving sleep quality in Parkinson’s patients.

Assessed treatments of orthostatic hypotension — defined as a drop in blood pressure when standing up — included midodrine and fludrocortisone, marketed as Florinef. Although both have insufficient efficacy evidence, they are classified as possibly useful in the clinic due to benefits seen in clinical trials.

The only trial concerning urinary dysfunction addressed solifenacin, marketed as VESIcare, as a treatment for overactive bladder. It showed that this medication has insufficient evidence on efficacy, but is possibly useful in clinical practice due to benefits observed outside Parkinson’s, while having an acceptable safety risk without specialized monitoring.

One other study addressed erectile dysfunction. Viagra (sildenafil) was considered efficacious and clinically useful, with data in the general population indicating an acceptable safety risk.

Similar efficacy and clinically utility conclusions were presented for botulinum toxin B as a therapy for drooling. Both botulinum toxin type A and B should be administered by well-trained physicians with access to specialized monitoring tools, the researchers emphasized.

Three studies evaluated approaches for gastrointestinal dysfunction. Results of one trial led to lubiprostone, marketed as Amitiza, being considered likely efficacious and possibly useful to treat constipation in people with Parkinson’s. Its safety data in the general and elderly populations indicate that lubiprostone has an acceptable risk in Parkinson’s patients.

Probiotics were categorized as efficacious and clinically useful, which support their over-the-counter use and lack of safety concerns. In contrast, abdominal massages with lifestyle advice have insufficient evidence on safety and efficacy to ease constipation.

Rasagiline was also evaluated as an approach for fatigue, considered efficacious and possible useful based on one small study. One trial analyzed acupuncture in Parkinson’s, but although benefits were found, this approach still has insufficient efficacy evidence.

For pain, prolonged-release oxycodone-naloxone has insufficient evidence, but is possibly useful for Parkinson’s patients with chronic pain, with an acceptable safety risk without specialized monitoring. Rotigotine also has insufficient evidence as a way to lessen pain in Parkinson’s patients, despite benefits seen in one trial.

Overall, despite the substantial growth in the evidence base of approaches for non-motor symptoms in Parkinson’s, this update shows that treatment options remain limited, making the development and testing of new therapies “a top priority,” the team said.

According to Daniel Weintraub, MD, research on Parkinson’s psychiatric and cognitive symptoms is key due to the specificity of the disease compared with the same manifestations found in the general population. He also said this update may help investigators spot areas in need of clinical trials, such as anxiety.

Laura Marsh, MD, a professor of psychiatry and neurology at Baylor College of Medicine, cautioned that although the new review provides “a useful analysis for clinicians to consider,” they still have to practice “the art of medicine.” This involves challenges such as evaluating if dopaminergic therapies for motor function are causing non-motor side effects and what symptom to address first in people with more than one of these complications, she said.

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Lack of Research and Way of Measuring Visual Hallucinations in Parkinson’s Hinders Its Treatment, Study Says

visual hallucinations

Research into the best ways of managing visual hallucinations in patients with Parkinson’s disease over the long term is severely limited and affecting treatment, a review study has found.

In particular, the lack of a universal rating scale renders data interpretation and comparison between studies difficult. To overcome this limitation, researchers propose the creation of a specific scale suitable to monitoring the effects of pharmacological and non-pharmacological treatments for visual hallucinations.

The study, “Management of visual hallucinations in dementia and Parkinson’s disease,” was published in International Psychogeriatrics.

Visual hallucinations — seeing something that is not real — is a common symptom of Parkinson’s and other types of dementia, including Alzheimer’s diseasedementia with Lewy bodies and frontotemporal dementia. These symptoms can be quite disturbing for patients, and are associated with rapid cognitive decline and increased mortality.

Although a large number of pharmacological and non-pharmacological therapies have been proposed to treat such hallucinations, an optimal management strategy is yet to be found.

This systematic review examined the prevalence and risk factors of visual hallucinations, as well as rating scales and therapeutic approaches that have been proposed to monitor and minimize their occurrence.

After a thorough literature search in the PubMed database, a total of 89 relevant studies (11 meta-analyses, 34 randomized controlled trials, six other trials, and a number of relevant review articles) were selected.

Previous studies estimated the prevalence of visual hallucinations for Alzheimer’s disease to range from 3% to 76%, and from 22% to 38% in people with Parkinson’s disease.

The high variability in prevalence, especially in Alzheimer’s disease “may be due to the setting of the study population (clinic vs. nursing home) and differences in who the informant is; whether patient, relative, or professional,” the researchers wrote.

Among Parkinson’s patients, the biggest challenge to determining prevalence of visual hallucinations seems to be separating “the contribution of dopaminergic and anticholinergic drugs from that of the disease.”

In dementia with Lewy bodies and frontotemporal dementia patients, prevalence is estimated to be 15-20% and 14.4%, respectively.

Non-pharmacological strategies have been proposed mainly as a first-line treatment for visual hallucinations. However, solid evidence from controlled trials that might demonstrate therapeutic benefit specifically for visual hallucinations is lacking.

“[R]eviewers have recommended increased socialization, as well as improving lighting and reducing visual triggers, but admit this because they are useful and inexpensive rather than based on trial evidence,” the researchers wrote.

Antipsychotics — both typical and atypical — are commonly used to treat psychosis and depression, but when used in patients with dementia are associated with a series of adverse side effects, including increased risk of stroke and death. Still, these medicines may continue to be prescribed off-label to these patients, mostly due to a lack of better alternatives.

In Parkinson’s disease, several antipsychotic treatments have been tested over the last few years. While some, like melperone and Zyprexa (olanzapine), clearly failed to ease psychosis and delusions, Clozaril (clozapine) and Nuplazid (pimavanserin) were seen to treat psychosis and hallucinations without impairing patients’ motor functions. The effects of others, like Seroquel (quetiapine), vary substantially across studies and are difficult to interpret.

In any case, these medications — even Nuplazid, the only medication approved by the U.S. Food and Drug Administration (FDA) for Parkinson’s delusions and hallucinations — “still carry the same black box warning as other antipsychotics for older people with dementia” and should be used with caution.

One of the key limitations encountered by the researchers that affects not only data interpretation, but also its generation, was the lack of a specific universal rating scale to assess visual hallucinations. Rather, symptoms tend to be “grouped together as all ‘hallucinations’ or ‘psychosis’. This over simplifies symptoms and prevents an understanding of what treatments may or may not work,” they said.

“We recommend the development of a specific scale suitable for natural history and treatment studies of VH, and for larger multi-site studies of both non-pharmacological and pharmacological treatments for VH [visual hallucinations],” the researchers concluded.

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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

Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

psychosis in Parkinson's

Psychosis and cognitive impairment in patients with Parkinson’s disease may be linked to structural changes in the brain, namely a decrease in volume of an area that controls memory formation, a study suggests.

The study, “Hippocampal subfield atrophy in patients with Parkinson’s disease and psychosis,” was published in the Journal of Neural Transmission.

Psychosis, which usually manifests as visual hallucinations, is one of the most frequently observed non-motor symptoms of Parkinson’s disease.

More than 50 percent of Parkinson’s patients will experience psychosis in their lifetimes, and the condition is associated with poor quality of life and more use of healthcare resources.

The causes underlying psychosis in Parkinson’s disease remain unclear, but some studies suggest it may be linked to structural and functional alterations of the hippocampus, a brain region that plays a key role in memory formation.

Using magnetic resonance imaging (MRI), researchers analyzed the hippocampus of 51 Parkinson’s patients without psychosis, 42 Parkinson’s patients with psychosis, and 48 healthy people matched by age, gender, and education, used as controls.

Patients were recruited from the National Institute of Mental Health and Neurosciences in Bangalore, India.

Additional parameters analyzed included participants’ overall cognitive performance, measured using the Montreal Cognitive Assessment Scale (MoCA), and frontal executive functions — the skills a person uses to plan, organize and complete tasks — evaluated using the frontal assessment battery (FAB), which assesses the brain’s frontal lobe function.

Overall cognitive performance was significantly higher in healthy controls than in Parkinson’s patients both with and without psychosis. There were no significant differences in cognition between the Parkinson’s patients, regardless of whether they had psychosis or not.

FAB scores were also significantly lower in both groups of Parkinson’s patients than controls, highlighting an impairment in executive functions in patients both with and without psychosis.

Researchers observed that the overall volume of the hippocampus was reduced in Parkinson’s patients with psychosis compared with healthy controls, and that the volumes of different subzones in the hippocampus of these patients correlated with psychosis severity and cognitive functions.

However, Parkinson’s patients with psychosis had increased volume of a specific region within the hippocampus called the hippocampal fissure. The higher the volume in this area, the lower the capacity of visual memory and visuospatial functions.

Mouse studies have previously demonstrated that an increase in hippocampal fissure volume is highly correlated with a decrease in overall hippocampal volume, and can be considered a radiological hallmark of ongoing brain atrophy.

“We demonstrated that the trajectory of psychosis severity could be mapped using hippocampal subfield volumes,” the researchers wrote.

These results support the involvement of specific hippocampal regions in psychosis and cognitive impairment in Parkinson’s disease.

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Source: Parkinson's News Today

Man-made Cannabis Induced Psychosis in Parkinson’s Patient, Case Report Says

Cannabis and psychosis

A recent case report describes a 70-year-old woman with Parkinson’s disease who developed psychosis after taking nabilone, a man-made form of cannabis often used to treat severe nausea caused by cancer chemotherapy.

The study, “Exacerbation of psychosis triggered by a synthetic cannabinoid in a 70-year-old woman with Parkinson disease,” was published in the Canadian Medical Association Journal (CMAJ).

Psychosis, although not fully understood, is common in Parkinson’s disease, particularly in its later stages. Symptoms include minor illusions, vivid dreams, occasional visual hallucinations with loss of insight, paranoia and panic attacks. More than half of all Parkinson’s patients eventually develop some kind of non-motor symptoms over the course of their disease.

There’s no predicting with certainty which Parkinson’s patients will go on to develop symptoms like hallucinations or delusions. Several risk factors are associated with the disorder, including age, duration and severity of Parkinson’s disease and dopamine therapy.

There’s no reliable evidence to support cannabinoid use as a management therapy for Parkinson’s symptoms and some studies suggest cannabis may trigger or worsen psychosis even in the absence of a psychiatric history. However, when desperate for symptom relief, some patients may use medical marijuana and cannabinoids.

Canadian clinicians reported the case of the woman, diagnosed with Parkinson’s for more than 12 years, who complained of chronic, painful, involuntary and repetitive twisting, plus sustained muscle contractions (dystonia). The patient also was resistant to multiple Parkinson’s drugs.

Her family doctor prescribed nabilone to relieve symptoms. “The patient took two doses (1 mg) that resulted in intrusive visual hallucinations, panic and paranoia within hours. Despite stopping treatment with nabilone after the two doses, the patient’s psychosis worsened over the next three weeks. She had delusions that her neighbors were engaged in illegal and dangerous activities,” the team reported.

Before nabilone’s ingestion, the patient had occasional visual hallucinations for years and mild cognitive impairment, but she was able to independently lead her daily life at home.

No changes were made to her medication — levodopa/carbidopa (1,000/250 mg per day), entacapone (1,000 mg per day), pramipexole (4.5 mg per day) and amantadine (300 mg per day) — prior to the onset of non-motor symptoms.

Three-weeks after nabilone, cognitive assessment revealed the patient’s orientation, attention, delayed recall and abstraction deteriorated, in comparison to her cognitive state prior to taking nabilone.

Even though doctors adjusted her medication after psychosis occurred, her symptoms worsened, and two months after ingesting nabilone the patient was admitted to the hospital.

After a few weeks and several medication adjustments, the patient’s psychosis subsided, and she was discharged with a new drug protocol, which included levodopa/carbidopa (1,000/250 mg/d), entacapone (1,000 mg/d), controlled-release levodopa/carbidopa (100/25 mg/d), fludrocortisone (0.1 mg in the morning) and clozapine (37.5 mg at bedtime).

While not so severe, the patient’s visual hallucinations and delusions were still occurring three months after discharge.

“Although the patient’s Parkinson disease, anti-parkinsonian drugs and previous psychiatric symptoms may have provided a predisposition to the development of psychosis, ingestion of nabilone was the clear trigger that caused her psychotic symptoms to become established and then spiral out of control,” the authors wrote.

Given the observed effects of cannabinoid use in a susceptible Parkinson patient, clinicians have developed a patient information sheet to alert for cannabinoids’ potential side effects in Parkinson’s disease.

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Source: Parkinson's News Today