High Levels of Zinc Found in Hair of Parkinson’s Patients with Depression, Psychiatric Symptoms, Study Says

zinc, depression, Parkinson's

Parkinson’s disease patients with either depression or psychiatric symptoms such as hallucinations, confusion, or illusion may have higher levels of the mineral zinc in their hair, researchers report.

Their study, “Higher zinc concentrations in hair of Parkinson’s disease are associated with psychotic complications and depression,” was published in the Journal of Neural Transmission.

Besides the typical motor symptoms, Parkinson’s patients may also experience non-motor symptoms such as cognitive impairment, sleep difficulties, depression, anxiety, and psychosis. Psychosis, although not fully understood, is common in Parkinson’s, particularly in its later stages. Symptoms include minor illusions, vivid dreams, occasional visual hallucinations, paranoia, and panic attacks.

Evidence indicates an imbalance of metal compounds is somewhat associated with Parkinson’s disease mechanism. In fact, too much iron has been found within patients’ substantia nigra and striatum — two brain regions involved in motor control that are extensively damaged in Parkinson’s — as well as in other peripheral tissues.

In this neurodegenerative disorder, calcium has also been suggested to play a role by promoting cellular death, while zinc may influence non-motor features of the disease.

These minerals are strongly correlated to psychiatric complaints and mood disorders in Parkinson’s, but the exact relationship between calcium, iron, and zinc levels in Parkinson’s patients with psychiatric complaints remains to be clarified.

Therefore, researchers at the University of Copenhagen in Denmark, along with collaborators in Brazil and Ireland, set out to investigate the link between these metal compounds and the co-occurrence of depression, anxiety, and psychotic symptoms in Parkinson’s disease.

Twenty-two patients (15 men and seven women, with a mean age of 69.8 years), who were registered in the 13th Regional Health Board in Jequié, Bahia (Brazil), had their mood and psychiatric complications assessed by clinically validated scales. Using the participants’ hair samples, scientists also quantified calcium, iron, and zinc levels.

To do so, the investigators applied a technique called flame atomic absorption spectroscopy (FAAS), which uses the absorption of electromagnetic radiation to measure the concentration of gas-phase atoms. The results were compared to 33 healthy individuals.

Significantly higher zinc levels were found to be correlated with depression or with one or more psychotic complications, including hallucinations, illusion, paranoid ideation (when the patient believes he or she is being harassed or persecuted), altered dream phenomenon, and confusion, compared with patients without these symptoms and healthy controls.

Altered concentrations of calcium and iron were not associated with Parkinson’s-related psychiatric disturbances.

Although the sample size was small, the study seemed to suggest that zinc levels could be a biomarker for psychiatric manifestations in Parkinson’s, and as such, a potential target for novel disease management therapies.

“FAAS is simple to implement, and low in cost, and as it can be used with a biological sample easy to obtain, such as hair, this methodology offers the real advantage of being feasible for a wide range of clinics to implement,” the team said, adding that further research and larger studies are still warranted.

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Globin Protein Levels May Help Assess Efficacy of Dopamine Agonists in Parkinson’s Patients, Study Shows

globin dopamine therapy

Evaluation of two specific proteins circulating in the blood, called alpha- and beta-globin, may help monitor treatment efficacy and risk of side effects among patients with Parkinson’s disease, a study suggests.

The study, “2D-DIGE as a strategy to identify serum protein biomarkers to monitor pharmacological efficacy in dopamine-dictated states of Parkinson’s disease and schizophrenia,” was published in Neuropsychiatric Disease and Treatment.

Parkinson’s disease is triggered by the death of dopamine-producing neurons in the midbrain, which control movement. Lack of dopamine — a crucial chemical messenger that allows nerve cells to communicate — causes impaired body control and induces the motor symptoms that are commonly associated with this disease, such as tremors, gait, and balance problems.

Given the underlying mechanisms of Parkinson’s disease, patients are commonly prescribed dopamine agonists to overcome dopamine loss and manage symptoms. However, the use of these therapeutic compounds is linked to several adverse effects including hallucinations, which are due to increased activity of dopamine in the brain.

Despite research efforts, no tests are currently available to help recognize if a treatment is effective or if a treated patient is reaching a point of dopamine over-activity and increased risk of side effects. As such, clinicians still rely almost completely on patients’ compliance and symptoms to assess therapeutic efficacy.

Therefore, researchers in the study explored whether a simple blood test could identify patients’ at risk of experiencing treatment-related adverse reactions. The team recruited five patients with Parkinson’s disease and five patients with schizophrenia who had never been treated with dopamine-related therapies.

The psychotic symptoms of schizophrenia are known to be caused by overactivity of dopamine in the brain — similar to what occurs as a side effect of dopamine-agonist use in Parkinson’s patients.

Comparing the different proteins in the participants’ blood samples revealed that alpha- and beta-globin proteins were consistently present in Parkinson’s patients but absent in schizophrenia patients.

To better understand if these two proteins could be used as biomarkers of dopamine status, the team further analyzed them in a group of 100 individuals

The cohort included six Parkinson’s patients who had not received any therapy, 44 patients who had received treatment, and five patients who had undergone treatment with different dopamine agonists and had experienced treatment-related adverse effects such as visual or auditory hallucinations.

The remaining participants had been diagnosed with schizophrenia, among whom five had not received prior treatment (treatment-naïve), 36 were treated with dopamine inhibitors, and four were treated and experienced Parkinson’s-like symptoms.

The levels of alpha- and beta-globin were three-fold higher in treatment-naïve Parkinson’s patients compared with treatment-naïve schizophrenic patients. In addition, the expressions of both proteins were significantly higher in patients treated for Parkinson’s disease than in those treated for schizophrenia.

Overall, the amount of these two proteins circulating in the blood was found to be inversely correlated with mid-brain dopamine concentrations. This means that schizophrenic untreated patients (who have the highest dopamine activity) had the lowest levels of alpha- and beta-globin proteins, while Parkinson’s untreated patients (who have the lowest dopamine activity) had the highest levels of both proteins.

Disease scoring, gender, and age had no impact on the levels of the two proteins.

“The inverse relationship between globin expression and dopamine concentration in the brain holds value as a translational tool in the therapeutics of Parkinson’s disease,” the researchers wrote.

Moni­toring the levels of alpha- and beta-globin proteins could be a useful “tool for clinicians to efficiently and effectively treat Parkinson’s disease and schizophrenia,” they said.

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


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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Most Parkinson’s Patients Show Non-movement Symptoms Like Depression, Sleep Problems, Survey Finds

non-movement symptoms

Nearly all Parkinson’s disease patients experience non-movement symptoms, such as sleep disturbances or depression, which affect their quality of life as much as movement-related symptoms, according to an online survey of 700 participants, nearly 600 of whom completed it in full.

Patients’ caregivers are those most likely to detect non-movement manifestations of the disease.

These are the two main conclusion of the online survey, conducted by the Parkinson & Movement Disorder Alliance (PMDAlliance) with the support of Acadia Pharmaceuticals, as part of Parkinson’s Disease Awareness Month.

Of the survey’s respondents, 286 were Parkinson’s patients; 377 were care partners; 10 were noncare partners or family members of Parkinson’s patients; and 27 were categorized as “others.”

The survey, conducted online with members of the PMDAlliance from March 19-31, 2018, revealed that 90% of Parkinson’s patients show non-movement symptoms, manifested as sleep problems (84%), cognitive challenges (75%), anxiety (65%), depression (55%), hallucinations (41%), and delusions (24%).

The negative impact of non-movement symptoms on quality of life was recognized by 84% of the respondents, with nearly half of the patients (49%) finding coping with these symptoms even more challenging that Parkinson’s-related movement symptoms.

The non-movement side of the disease has a generally negative impact on the lives of patients, affecting their social activities with friends and family (70%), intimacy with their partner (68%), and with daily activities, such as household chores (68%) and running errands (67%).

“This survey clearly shows that non-movement symptoms of Parkinson’s disease make it difficult for people with Parkinson’s and their care partners to participate in activities most of us take for granted — running errands, going to the movies, eating out, or simply cooking and cleaning,” Sarah Jones, the CEO of PMDAlliance, said in a press release.

“We urge the entire Parkinson’s community — from the people with Parkinson’s and care partners, to healthcare professionals and support groups — to continue initiating conversations about Parkinson’s symptoms, especially the non-movement ones that greatly impact day-to-day living,” Jones said.

Despite its negative impact on quality of life, care partners detected the non-movement side of Parkinson’s two to four times more than patients themselves.

Hallucinations were observed by 51% of care partners and 23% of patients, and delusions were spotted by 32% of caregivers compared to 8% of patients.

These results both highlight and correlate with literature reporting that non-movement symptoms, like hallucinations and delusions, are often not reported to clinicians — only 10-20% of the cases are actually reported. This may be due to embarrassment or a misunderstanding that the symptoms are associated with the disease, since most of the time devoted to a patient’s visit with a doctor is generally focused on motor symptoms.

Other non-motor symptoms, such as cognitive challenges, anxiety, and depression were more easily detected by caregivers than patients.

“Parkinson’s disease changes how both people with PD [Parkinson’s disease] and care partners think about their future and cope with day-to-day living,” Jones said.

“Care partners are particularly attuned to how the disease is progressing in their loved one, which is why PMDAlliance added new educational resources to our website about the onset and impact of non-movement symptoms of PD,” she said.

“We want to encourage people to report symptoms to their healthcare providers, seek support, and participate in the community. This spring, we’re also hosting several Learn, Live, Connect educational conferences across the country where people can learn more about Parkinson’s disease and its many symptoms,” Jones added.

Doral Fredericks, PharmD (doctor of pharmacy), vice president of medical affairs at Acadia Pharmaceuticals, said Acadia is “honored to partner with PMDAlliance to highlight the impact of non-movement symptoms on both people with Parkinson’s and their care partners.

“We encourage people with Parkinson’s and caregivers to join the effort to raise awareness about this important aspect of Parkinson’s disease,” Fredericks added.

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#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.

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Man-made Cannabis Induced Psychosis in Parkinson’s Patient, Case Report Says

Cannabis and psychosis

A recent case report describes a 70-year-old woman with Parkinson’s disease who developed psychosis after taking nabilone, a man-made form of cannabis often used to treat severe nausea caused by cancer chemotherapy.

The study, “Exacerbation of psychosis triggered by a synthetic cannabinoid in a 70-year-old woman with Parkinson disease,” was published in the Canadian Medical Association Journal (CMAJ).

Psychosis, although not fully understood, is common in Parkinson’s disease, particularly in its later stages. Symptoms include minor illusions, vivid dreams, occasional visual hallucinations with loss of insight, paranoia and panic attacks. More than half of all Parkinson’s patients eventually develop some kind of non-motor symptoms over the course of their disease.

There’s no predicting with certainty which Parkinson’s patients will go on to develop symptoms like hallucinations or delusions. Several risk factors are associated with the disorder, including age, duration and severity of Parkinson’s disease and dopamine therapy.

There’s no reliable evidence to support cannabinoid use as a management therapy for Parkinson’s symptoms and some studies suggest cannabis may trigger or worsen psychosis even in the absence of a psychiatric history. However, when desperate for symptom relief, some patients may use medical marijuana and cannabinoids.

Canadian clinicians reported the case of the woman, diagnosed with Parkinson’s for more than 12 years, who complained of chronic, painful, involuntary and repetitive twisting, plus sustained muscle contractions (dystonia). The patient also was resistant to multiple Parkinson’s drugs.

Her family doctor prescribed nabilone to relieve symptoms. “The patient took two doses (1 mg) that resulted in intrusive visual hallucinations, panic and paranoia within hours. Despite stopping treatment with nabilone after the two doses, the patient’s psychosis worsened over the next three weeks. She had delusions that her neighbors were engaged in illegal and dangerous activities,” the team reported.

Before nabilone’s ingestion, the patient had occasional visual hallucinations for years and mild cognitive impairment, but she was able to independently lead her daily life at home.

No changes were made to her medication — levodopa/carbidopa (1,000/250 mg per day), entacapone (1,000 mg per day), pramipexole (4.5 mg per day) and amantadine (300 mg per day) — prior to the onset of non-motor symptoms.

Three-weeks after nabilone, cognitive assessment revealed the patient’s orientation, attention, delayed recall and abstraction deteriorated, in comparison to her cognitive state prior to taking nabilone.

Even though doctors adjusted her medication after psychosis occurred, her symptoms worsened, and two months after ingesting nabilone the patient was admitted to the hospital.

After a few weeks and several medication adjustments, the patient’s psychosis subsided, and she was discharged with a new drug protocol, which included levodopa/carbidopa (1,000/250 mg/d), entacapone (1,000 mg/d), controlled-release levodopa/carbidopa (100/25 mg/d), fludrocortisone (0.1 mg in the morning) and clozapine (37.5 mg at bedtime).

While not so severe, the patient’s visual hallucinations and delusions were still occurring three months after discharge.

“Although the patient’s Parkinson disease, anti-parkinsonian drugs and previous psychiatric symptoms may have provided a predisposition to the development of psychosis, ingestion of nabilone was the clear trigger that caused her psychotic symptoms to become established and then spiral out of control,” the authors wrote.

Given the observed effects of cannabinoid use in a susceptible Parkinson patient, clinicians have developed a patient information sheet to alert for cannabinoids’ potential side effects in Parkinson’s disease.

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