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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

#AAN2018 – Real-life Use Supports Nuplazid’s Safety, Efficacy in Treating Parkinson’s Psychosis

Nuplazid studies

Nuplazid (pimavanserin) is well-tolerated and can lead to clinical improvement in people with Parkinson’s disease psychosis (PDP), according to the results of studies into its real-life use.

Acadia will present these data at the 2018 American Academy of Neurology ANN Annual Meeting, taking place in Los Angeles from April 21–27.

Nuplazid is an oral medication, approved by the U.S. Food and Drug Administration (FDA) in 2016 to treat psychosis in Parkinson’s patients. It belongs to a class of compounds known as selective serotonin inverse agonists. Unlike other agonists, which activate the receptors they bind to, inverse agonists induce the opposite response when binding to a cell’s receptors and block or inactivate them.

Specifically, Nuplazid binds to serotonin’s 5HT2A receptors, setting a difference from antipsychotics that interfere with the dopamine system. As loss of dopaminergic neurons is a hallmark of Parkinson’s disease, many experts think it key to avoid antipsychotics that further impair neuronal communication mediated by dopamine.

But reports on patients’ real-world experience using Nuplazid is scarce. To address this gap, researchers evaluated the therapy’s prescribing patterns and clinical efficacy in a large ambulatory group.

The study, “Clinical Experience with Pimavanserin for Treatment of Parkinson’s Disease Psychosis,” to be presented as a scientific poster on April 22, identified patients prescribed with Nuplazid between May 2016 and August 2017.

Researchers performed a retrospective chart review, determining from medical records a patient’s clinical presentation, concomitant medications, medication effectiveness, and side effects.

Nuplazid was prescribed to 70 Parkinson’s patients (76% men, mean age 71), and 59 began using it. The most common indication was visual hallucinations (97%), with 39 patients (66%) also experiencing delusions. Two (3%) had delusions only.

Thirty-nine patients exhibited persistent symptoms despite treatment in a previous trial with other antipsychotics, such as quetiapine and Clozaril (clozapine, HLS Therapeutics). Of these, 10 were able to gradually discontinue these medications after starting Nuplazid, while 18 continued or restarted another antipsychotic while on Acadia’s treatment. Twenty patients received Nuplazid as first-line therapy.

Data shows that 42  patients reported clinical improvement. The treatment was well-tolerated in 50 of the 59 patients, with the most common adverse events being worsening gait instability and weakness, observed in five people.

Of the 37 patients still on Nuplazid, 14 are also taking quetiapine and one is taking olanzapine, the study reports. Of the roughly 20 people who “failed” at treatment with Nuplazid, five found their symptoms eased using a different antipsychotic.

“This study provides relevant clinical data on prescribing patterns of pimavanserin (Nuplazid) in a large [Parkinson’s] cohort. Future studies will assess patient characteristics that predict medication efficacy,” the researchers wrote.

Another study, “Pimavanserin use in a movement disorders clinic: a single center experience,” to be presented April 26 as a scientific poster, also assessed Nuplazid’s clinical use by collecting information on demographics, psychotic features, sleep, and adverse events through telephone interviews with patients and caregivers.

Researchers classified hallucination severity as mild if reported as less than one episode per week, moderate if the range was one per week to less than one per day, and severe if such episodes were daily or continuous.

Of a total of 17 patients, 16 were diagnosed with Parkinson’s psychosis and one with Lewy body dementia. Mean duration of disease was 11.8 years, with 2.6 years as mean duration of psychotic symptoms. At the start of treatment, 93% of the 17 patients reported severe hallucinations, while 7% had moderate hallucinations.

Three had discontinued treatment by the time of the interview.

A total of 71.4% of patients reported improvements in the nature and degree of their hallucinations.

Of six patients taking Nuplazid as a sole or monotherapy, 33.3% had no change in the severity of their hallucinations, 50% improved from the severe to mild on the researchers’ scale, and 16.6% from severe to moderate.

Of the eight patients taking Nuplazid and a dopamine receptor blocker to treat their psychosis, two had no change in severity, 25% reported improvement that moved them from severe to mild hallucinations, 37.5% from severe to moderate, and 12.5% reported hallucination episodes that dropped to mild from moderate.

Of note, five of the nine patients on dopamine receptor blockers — quetiapine and olanzapine — discontinued using these after starting Nuplazid. No major adverse events were reported.

“Our survey, based on real-life experience shows that pimavanserin (Nuplazid) is well-tolerated and efficacious in treatment of PDP. It appears to be effective as both monotherapy and adjuvant treatment for moderate to severe psychosis for most patients,” the researchers wrote.

The post #AAN2018 – Real-life Use Supports Nuplazid’s Safety, Efficacy in Treating Parkinson’s Psychosis appeared first on Parkinson’s News Today.

Source: Parkinson's News Today