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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

Levodopa May Not Be the Best Option for Parkinson’s Treatment, Study by Students Contends

Levodopa shortcomings

Levodopa improves Parkinson’s patients’ symptoms by binding with two types of receptors for dopamine, a neurotransmitter that helps regulate movement and emotional response.

Although it is considered the gold standard in Parkinson’s treatment, a study from Binghamton University students contends that levodopa’s interaction with the dopamine receptor D2 may cause involuntary muscle movements, compulsive behaviors, and hallucinations.

The research, “Effects of Receptor-Specific Dopamine Drugs on the Treatment of Cognitive Deficits in Parkinson’s Disease,” appeared in the The Undergraduate Journal of Psychology at UCLA.

Parkinson’s is a progressive neurodegenerative disorder that affects movement, muscle function, and speech. It is characterized by gradual loss of nerve cells that contain the neurotransmitter dopamine. They are located in a brain area called substantia nigra that is essential to the control of movement.

Dopamine binds to two classes of receptors — D1 and D2. Levodopa, which is also called L-DOPA, is a naturally occurring molecule that generates dopamine. It binds to both D1 and D2 receptors to replenish the disease-related lower levels of dopamine, improving Parkinson’s symptoms.

The New York State university research team triggered the formation of brain lesions in rats to mimic the loss of nerve cells in Parkinson’s. Rats were then treated with levodopa or compounds that bind with either D1 or D2 receptors, but not both. The next step was for rats to be tested for movement, ability to pay attention, and spatial memory.

Although activating D2 receptors with quinpirole improved the rats’ spatial memory, it led to  attention loss in both rats with brain lesions and controls. In contrast, activating D1 receptors did not lead to significant differences, in comparison with levodopa.

Overall, the findings suggested that, because levodopa stimulates D2 receptors, it may not be the best choice for Parkinson’s treatment.

“Parkinson’s disease is one of the most common neurodegenerative diseases in the world,” Lakshmi Hareendran, a member of the research team, said in a press release. “Knowing that the current treatment isn’t as effective as it could be is important.”

“In conclusion, the quinpirole effects on memory and attention ability is an essential discovery. Uncovering the mechanisms underlying these actions may lead to the development of a more effective treatment for [Parkinson’s] that covers both motor and cognitive deficits in humans,” the researchers wrote.

Hareendran comes from a family with several doctors and has an uncle who is a brain surgeon. “As a kid, just thinking about him being able to understand something as complex as the human brain really inspired me to go down that path,” she said. She plans to work with Doctors Without Borders some day.

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Source: Parkinson's News Today