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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.

The post Better Understanding of Parkinson’s Psychosis Needed to Develop New Therapies, Study Suggests appeared first on Parkinson’s News Today.

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