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‘Inappropriate’ Antipsychotics to Treat Depression in Elderly Parkinson’s Patients Linked to Pneumonia Risk

antipsychotics

Inappropriate antipsychotic medications — those approved for ills like schizophrenia but used to treat depression — given to elderly people with Parkinson’s disease increase their risk of pneumonia, a study suggests.

The study, “Risk of pneumonia associated with atypical antipsychotic use in nursing home residents with Parkinson’s disease,” was published in the Journal of Psychiatric Research.

Certain antipsychotic medications can be prescribed to help handle some of the behavioral problems evident in Parkinson’s disease (PD). But use of antipsychotics in these patients must be done cautiously, since many affect dopamine signaling — which is dysregulated in PD — and can aggravate other disease symptoms.

According to the 2019 American Geriatrics Society (AGS) Beers criteria, atypical antipsychotics are not appropriate for Parkinson’s patients, with exceptions being Nuplazid (pimavanserin), clozapine (brand names, Clozaril and FazaClo), and quetiapine (Seroquel). (Nuplazid, an oral Parkinson’s psychosis treatment that does not impact motor abilities, was approved in 2016, outside the years of this study.)

Atypical antipsychotics are considered inappropriate due to the risk of worsening Parkinson symptoms, like voluntary movements in general and swallowing abilities in particular.

Researchers in the U.S. investigated the link between inappropriate antipsychotic use and pneumonia, which can be a serious complication when swallowing or breathing are impaired.

Using Medicare data, they identified 16,161 nursing home residents diagnosed with Parkinson’s and depression (mean age, 82; two-thirds female), who were treated with antipsychotic medications between 2007 and 2010. Over a third of these individuals (37.62%; 6,126 people) were given an inappropriate antipsychotic, while the remainder were prescribed an appropriate one, with the most common being quetiapine.

Among these elderly patients, rates of dysphagia (difficulty swallowing), dementia, and levodopa use were similar between groups treated with appropriate and inappropriate antipsychotics.

Rates of pneumonia were significantly higher in patients prescribed inappropriate antipsychotics, 18.78% vs. 16.35%, than in those given appropriate ones over a six-month follow-up. Inappropriate antipsychotic use was also associated with a 20% greater chance of pneumonia, statistical analyses found; this finding was validated through sensitivity analyses that work against uncertainty in given sets of assumption.

Researchers also noted that rates of stopping antipsychotics were higher among those on inappropriate medications (21.17% vs. 15.22%).

“The risk of pneumonia was significantly higher for inappropriate AAP [antipsychotic] users in comparison to the appropriate AAP users,” the researchers wrote.

“The study findings suggest that selection of appropriate antipsychotics in PD is critical to prevent serious adverse events related to antipsychotic use in PD, given that pneumonia is one of the most common causes of mortality in PD patients. Further research is needed to evaluate the risk of pneumonia in PD patients using newer antipsychotic medications,” they concluded.

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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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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 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