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Review Highlights Questions That Remain for Fecal Transplant in Parkinson’s

fecal transplant

There currently is not enough data to support the use of fecal transplants as a treatment in Parkinson’s disease, a new review suggests.

Published in the Journal of Parkinson’s Disease, the review is titled “Faecal Transplantation, Pro- and Prebiotics in Parkinson’s Disease; Hope or Hype?

The gut microbiome — the bacteria that live in the gut — have a documented impact on human health. Recent research has suggested that the gut microbiome in people with Parkinson’s disease (PD) is dysregulated and does not work properly. However, the exact changes that happen in PD are still unclear, with many studies finding conflicting results, and none able to demonstrate a cause-and-effect relationship between Parkinson’s and bacteria, one way or the other.

Fecal microbiome transplantation (FMT) is a category of procedures that aim to transplant fecal material — and, by extension, gut bacteria — from healthy individuals into sick people. The treatment is designed to put “good” bacteria back into the digestive tract, helping to replenish the bacterial balance.

In the new review, the researchers assessed the current state of evidence for the use of FMT, also called bacteriotherapy, and other gut-bacteria-targeted treatment strategies in Parkinson’s.

“FMT is an interesting option for restoring the changes in the microbiome of PD patients. It is an attractive technique because the administration is relatively simple and in general it has only a mild pattern of adverse effects,” Teus van Laar, MD, PhD, a professor at the University of Groningen, director of the Parkinson Expertise Center Groningen, and co-author of the review, said in a press release.

“However, no rigorous clinical trials have been performed yet, which leaves multiple questions open about the presumed optimal content of FMT, the route of administration, the volume of FMT and the long-term effects,” van Laar said.

There is virtually no available data on FMT in Parkinson’s, the researchers noted.

“References [in published scientific literature] to the potential use of FMT in PD are restricted to a recent Chinese case study on a PD patient with severe constipation,” they said. While this patient experienced improvement in both constipation and PD symptoms, it is virtually impossible to draw any conclusions from a sample size of one.

The researchers further noted that basic questions about using fecal transplant in PD still need to be addressed. For instance, FMT requires a “healthy’ donor” — but exactly what that means could be debated. This is especially true given that fact that the actual changes in gut microbiome that happen in PD aren’t fully understood.

Additionally, practical issues, like the best route — enema, nasogastric tube, etc. — or frequency of administration, will need to be worked out before FMT can be confidently recommended in PD.

The first clinical trial of FMT in 40 people with Parkinson’s (NCT03808389) is currently ongoing and is scheduled to be completed at the end of 2019. That trial, currently enrolling in Belgium, aims to recruit 40 Parkinson’s patients who will receive FMT from healthy donors while a control group receives autologous (self) FMT.

The results from this trial may help answer some of the questions researchers have about fecal transplant — in particular, whether it is beneficial at all for a significant portion of people with PD. However, many questions will remain unanswered following this study. For instance, the researchers noted that the inclusion criteria for Parkinson’s patients “do not in- or exclude constipation, which may complicate the interpretation of results.”

The researchers also pointed out that, while FMT is generally regarded as a low-risk procedure, there have been reported instances of serious — even fatal — complications. As such, the safety profile of fecal transplant in PD will need further evaluation.

The review also touched on other techniques used to influence gut bacteria, namely the use of probiotics and prebiotics. Probiotics are the “good” bacteria of the kind found in yogurt — though again, such definitions are highly subjective and context-dependent. Forms of fiber, prebiotics can help facilitate the growth of certain types of bacteria, rather than administration of the bacteria themselves.

Several studies have demonstrated that some kinds of probiotics — namely the bacteria groups Lactobacillus and Bifidobacterium — can help alleviate constipation in PD, the researchers said. However, whether these treatments have any effect on other symptoms of PD is currently unknown.

Prebiotics have not been tested in humans with Parkinson’s. The researchers noted that, in animal models of the disease, prebiotic treatment has “indicated beneficial effects on the PD symptoms.” Much more research will need to be done, however, to determine whether this has any bearing on human health.

“FMT is a black box with too many unanswered questions at the moment, also with respect to safety concerns,” van Laar said. “FMT or the use of pro- and prebiotics might become standard treatments in selected subgroups of PD patients in the future, but there are no good data yet in the public domain to support their use in PD patients.”

The researchers called for new studies investigating the use of such transplants in Parkinson’s.

“We hope this review will activate colleagues to start proper research on this topic as soon as possible, rather than to begin therapy without conclusive clinical data,” van Laar said.

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Better Understanding of Parkinson’s Psychosis Needed to Develop New Therapies, Study Suggests

psychosis

Improved understanding of Parkinson’s disease psychosis (PDP) and a unified approach for its clinical evaluation are key for developing new therapeutics, a review study suggests.

The research, “Treating Hallucinations and Delusions Associated With Parkinson’s Disease Psychosis,” was published in the journal Current Psychiatry Reports.

PDP has been increasingly recognized as a distinct clinical symptom linked with Parkinson’s progression, dementia, and medications. Both its diagnosis and symptom management remain challenging.

PDP is a non-motor symptom that causes patients to experience hallucinations and delusions, with more than half of Parkinson’s patients developing psychosis over the course of their disease.

PDP involves diverse neurotransmitter systems. Altered functioning of serotonin 5-HT2A receptors may affect how PDP patients process what they see.

Visual hallucinations — seeing, hearing, or feeling things that do not exist — are the most frequent feature in PDP patients, but non-visual hallucinations also may occur. Delusions  — distorted interpretations of reality — are more often paranoid and related to persecution or infidelity.

Both visual hallucinations and delusions are risk factors for nursing home placement, which has been associated with a 100 percent mortality rate in a two-year follow-up study. This underscores “the severity with which psychosis correlates with the disease state,” authors wrote. PDP also may impact caregivers, who have shown greater risks for chronic illnesses, depression, and mortality.

As for risk factors underlying the development of psychotic symptoms, dementia and cognitive impairment have been demonstrated extensively. Older age, Parkinson’s duration and severity, and sleep disturbances also are associated with greater risk of PDP.

Regarding treatment, non-pharmacological approaches are an important initial option. Potential reversible medical problems and patients’ non-Parkinson’s related medications — in particular antidepressants, sedatives, and narcotics — should be assessed carefully. Clinicians should then focus on Parkinsonian medications with the greatest risk of inducing psychosis, and always be on the lookout for worsening of motor symptoms.

Regarding pharmacological options, until recently patients had no approved treatments, leading to off-label use of atypical antipsychotics, which may worsen motor symptoms. These medications differ from typical antipsychotics because they induce fewer extrapyramidal symptoms, which are drug-induced movement disorders that include acute and late symptoms.

Pharmacological approaches should be considered if non-pharmacologic strategies and reducing doses of anti-parkinsonian medications are not able to reduce PDP symptoms without affecting motor function, the authors noted.

Several studies demonstrated the safety and tolerability of low-dose Clozaril (clozapine, HLS Therapeutics), an atypical antipsychotic, in PDP patients, without worsening their motor symptoms. Supporting research included multi-center, double-blind trials, which reported benefits with doses ranging between 6.25–50 mg/day. However, patients’ white blood cell counts should be monitored.

Seroquel (quetiapine, AstraZeneca) is a more potent blocker of 5-HT2A receptors than Clozaril. Studies found better results with lower doses, but lack of superior effectiveness over placebo has been consistent.

Zyprexa (olanzapine), which has higher affinity for 5-HT2A receptors than for dopaminergic D2 receptors, showed effective reduction of psychosis, but several studies showed worsened motor function, while others failed to observe differences compared to placebo. As a result, the American Academy of Neurology concluded that olanzapine should not be routinely used for PDP.

More recently, Acadia Pharmaceuticals developed Nuplazid (pimavanserin), a selective 5-HT2A/C receptor inverse agonist with no activity on dopamine receptors, which is an important feature given Parkinson’s patients’ loss of dopaminergic neurons. Inverse agonists induce pharmacological responses opposite to agonists though binding to the same receptors. Doses between 25 and 60 mg/day showed good safety and tolerability results without worsening motor symptoms.

In a larger Phase 3 clinical trial with 199 patients taking either Nuplazid 40 mg/day or placebo over six weeks, the therapy improved both sensory hallucinations and delusions, improved sleep and cognition, and did not lead to declined motor function. Nuplazid became the first medication approved by the U.S. Food and Drug Administration to treat PDP.

Several other atypical antipsychotics and non-antipsychotic medications have been assessed for PDP, but their variable effectiveness and potential motor-worsening falls short of a recommendation for standard use. These include risperidone, ziprasidone, aripiprazole, and melperone.

“While new therapeutics and targets continue to be investigated, a more complete understanding of PDP pathology is needed to further refine drug targets,” the researchers wrote.

“Ultimately, investigation into novel agents will require exploration of not only selective receptor targets, but also a unified approach to the clinical evaluation of PDP itself,” they added.

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Source: Parkinson's News Today

Deep Brain Stimulation for Parkinson’s Disease: The Past and What the Future Holds

deep brain stimulation

Despite being used for the past 30 years to treat chronic neurological diseases, including Parkinson’s disease (PD), deep brain stimulation (DBS) “remains a fascinating puzzle to scientists, physicians, and engineers,” the lead author of a new review study said.

Challenges the technique presents for both clinicians and engineers include the design of novel, more efficient DBS therapies, the existence of redundancy in clinical outcomes, and a high variability in patients’ responses to the therapy, according to the review, which summarizes what has been achieved so far and what lies ahead for deep brain stimulation.

The review “Systems approaches to optimizing deep brain stimulation therapies in Parkinson’s disease” appeared in the journal WIREs Systems Biology and Medicine.

Deep brain stimulation involves surgically implanting an electrode in the brain that is connected to an implanted pulse generator through subcutaneous wires. The pulse generator is programmed to deliver charge-balanced, voltage-controlled electric pulses.

Currently, deep brain stimulation is recommended to Parkinson’s disease patients in relatively advanced stages of the disease, who are still responsive to anti-PD medications, but have developed medication-induced dyskinesia — in which patients experience involuntary, jerky movements.

The therapy helps improve dyskinesia and other motor complications, and is linked to a more efficient and prolonged management of disease symptoms and a lower usage of anti-PD medications (up to 50 percent).

“Although effective and generally safe, DBS [deep brain stimulation] remains a fascinating puzzle to scientists, physicians, and engineers,” lead author Dr. Sabato Santaniello, of the University of Connecticut, said in a press release. “The therapeutic mechanisms of DBS, in fact, are still elusive and the current, semi-permanent stimulation protocols have often motivated the investigation of ways to make DBS less invasive and more efficient.”

“The set of therapeutic DBS programs is overall larger than initially hypothesized. New tools and methods are therefore necessary to search this set and to systematically identify the most adequate DBS program for each patient,” the authors write in their review. “These solutions are still in their early stages and need to translate from preclinical testing phases to clinical trials.”

Developing more efficient deep brain stimulation therapies has proven challenging. The relatively poor understanding of the cellular mechanisms underlying deep brain stimulation therapeutic effects has impaired its progression.

In the review, the authors gather current data which suggests that novel, low-power deep brain stimulation solutions can be devised, preserving the clinical benefits of current DBS therapies while addressing its major limitations, such as inefficient battery consumption, the need for lengthy manual programming, and the widespread influence on nearby cognitive loops with possible adverse side effects.

There is currently little information on how variations in the different deep brain stimulation programs may lead to potential different outcomes.

There is also a high variability in patients’ responses to deep brain stimulation, which requires careful adjustments to the electric stimulation. Networks involving brain structures are made up of interconnected large groups of nerve cells where information may be corrupted and communicated with delays.

The technique also influences brain dynamics in a nontrivial way, as it changes the extracellular environment in surrounding structures, which in turn can affect the activity of each nerve cell.

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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.

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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