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Which are the Most Efficacious Therapies for Nonmotor Parkinson Disease Symptoms?

Article In Brief

A study group of the Movement Disorders Society Evidence-Based Committee reviewed the findings of studies on nonmotor symptoms of Parkinson's disease, published between 2011 and 2017, offering an update on findings that ranged from clinically useful to not useful.

An updated review of therapies for the nonmotor symptoms of Parkinson's disease should help physicians select the most effective treatments for their patients, according to a study group of the Movement Disorder Society that conducted an evaluation of the latest clinical trial evidence as a follow-up to a 2011 review.

The latest review, published in the February issue of Movement Disorders, concluded that treatment options for nonmotor symptoms of PD “overall remain limited given the high prevalence and adverse impact of these disorders,” but it identified clinically useful or likely useful interventions for a number of problems that patients with PD face, including depression, psychosis, gastrointestinal issues, and erectile dysfunction.

Of interventions to treat dementia and other cognitive impairments in PD, rivastigmine was determined to be clinically useful based on available evidence. Clozapine and pimavanserin were determined to be clinically useful intervention to treat psychosis in PD, with the caveat that the represent an “acceptable risk with specialized monitoring.”

The committee noted in its review that although nonmotor symptoms are common, they are frequently missed or undeclared; moreover, there is a dearth of well-performed, large-scale randomized clinical trials for treating these symptoms. Such trials need to be a key priority in PD research, the authors of the report stressed, noting that these nonmotor symptoms tend to be “a key driver in quality of life.”

The International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee began doing periodic reviews of published findings on nonmotor symptoms of PD in 2002. The goal then and now is to provide clinicians with the latest evidence on therapies so that they can consider the information along with other factors that go into treatment decision-making.

Christopher G. Goetz, MD, FAAN, president of the International Parkinson and Movement Disorders Society, said the review is not the same as practice guidelines issued by medical associations such as the American Academy of Neurology.

“Guidelines are really culturally based,” he said, noting that they take into consideration “regulatory issues, access issues, and insurance issues.”

“With evidence-based methodology, we are strictly looking at the published evidence. We don't tell you whether we recommend it (a specific therapy),” said Dr. Goetz, professor of neurological sciences and pharmacology at Rush University. He said other factors, such as patient preference and medical history, the doctor's personal clinical experience and insurance coverage, are also part of making a treatment decision.

Dr. Goetz said focusing on nonmotor symptoms is important is because “the nonmotor components of Parkinson's disease progressively affect quality of life as the disease progresses.”

He said that the nonmotor aspects of PD may get too little attention amid all the emphasis on treating motor symptoms, and patients may be reluctant to bring up concerns about poor sleep, constipation or sexual dysfunction, thinking perhaps they sound trivial compared to other issues.

Review Methodology

For the latest review update, a team of experts identified 37 new studies published from January 2011 through December 2016. The review included pharmacological, surgical, and nonpharmacological interventions. The interventions had to be commercially available in at least one country and been assessed in a level I randomized, controlled trial in which nonmotor symptoms were the primary endpoint measured with an established rating scale or well-described outcome. The studies had to have at least 20 patients who were followed for four weeks or more.

No clinical trials for PD-related anxiety disorders, excessive sweating, rapid eye movement behavior disorder, and olfactory or ophthalmologic dysfunction met the inclusion criteria for the review.

The Review Methodology

The review committee used the rating Scale for Quality of Evidence to assess the findings in each of the studies. Based on its quality rating, each intervention was then assigned an efficacy conclusion: either efficacious, likely efficacious, unlikely efficacious, non-efficacious, or insufficient evidence. The interventions were also assigned a safety descriptor, such as acceptable risk with no specialized monitoring or unacceptable risk.

To make the review as clinically relevant as possible, the reviewers had another category called “practice implications” where the descriptors included the designations of clinically useful, possibly useful, and unlikely useful, not useful, or investigational. Because the focus was on therapies as they relate to patients with PD, a drug with proven efficacy outside of PD may have earned an inconclusive rating in this review.

While the published review contains a lot of text, clinicians will likely find its tables most useful, Dr. Goetz said. Each nonmotor symptom has a table or chart that characterizes the various possible interventions, including the new ones.

Six new clinical trials for depression for PD were reviewed, for example. One involved venlafaxine, which is characterized as efficacious, having an acceptable safety risk with no need for specialized monitoring, and clinically useful. A new trial on the drug paroxetine was also reviewed, but it was designated as offering insufficient evidence and was “possibly useful.”

There was still insufficient evidence to make any firm conclusions about amitriptyline in the treatment of PD-related depression. though it was deemed possibly useful, while rotigotine was characterized as unlikely efficacious. Two new studies evaluated the use of repetitive transcranial stimulation and the approach was clinically characterized as “possibly useful” for short-term treatment.

Three new studies were evaluated for psychosis. The review concluded that olanzapine was not efficacious, and not useful from a clinical perspective. Pimavanserin, on the other hand, was characterized as efficacious and clinically useful, while new PD-related research on quetiapine was listed as insufficient evidence though possibly useful.

Among the new trials reviewed for cognitive impairment was one for computer-based cognitive training, which has garnered some attention among doctors and patients. The research to date in PD was characterized as “insufficient evidence” and “investigational.”

Daniel Weintraub, MD, professor of psychiatry at the University of Pennsylvania who specializes in the psychiatric and cognitive complications of PD, was a member of the review committee.

He said that while there are still many gaps in treatments for nonmotor symptoms of PD, in particular mild cognitive impairment, there has been some progress.


“With evidence-based methodology, we are strictly looking at the published evidence. We don't tell you whether we recommend it (a specific therapy).”


“In the case of depression, you have four or five possible interventions that have been shown to work in this population, which is better than it is for Alzheimer's and better than it was five years ago,” Dr. Weintraub said.

Dr. Weintraub said PD-specific research for psychiatric and cognitive symptoms is critical because the pathophysiology may be different than what is found in the general population. That is likely particularly true when it comes to depression, a symptom that can affect up to 25 percent of patients with PD, according to the review. Also, psychosis in PD, he said, is not comparable with psychosis in the general population.

Besides being useful in everyday practice, the review could have another benefit, Dr. Goetz said. He recommends that PD researchers study the tables and identify areas in need of a clinical trial.

“I look upon these tables as a remarkable opportunity for every young investigator interested in Parkinson's disease,” he said. Anxiety is a good example because there were no clinical trials of anxiety therapies that met the inclusion criteria for the review.

“Anxiety is a frequent symptom and disability in people in the general population and it also is a frequent complication of aging,” Dr. Goetz said. “But it is also an aspect of Parkinson's.”

Expert Commentary

Laura Marsh, MD, professor of psychiatry and neurology at Baylor College of Medicine and director of mental health at Michael E. DeBakey Veterans Affairs Medical Center in Houston, said: “The new review provides a useful analysis for clinicians to consider, but you still have to practice the art of medicine. It is not a checklist.”

She said sorting out the psychiatric and cognitive symptoms that Parkinson's patients experience is challenging because the clinician must consider whether PD medications such as dopamine agonists that help with motor function are causing unwanted nonmotor side effects, or whether the patient may have a pre-existing condition separate from Parkinson's. When a patient experiences multiple nonmotor symptoms, such as cognitive impairment, depression, anxiety, and psychosis, “it is not always clear what treatment to initiate first,” Dr. Marsh said.

She often asks patients to keep diaries to track symptoms to see if timing of medication is an issue. Teaching coping skills, such as breathing techniques for anxiety, is also important, said Dr. Marsh, whose research focuses on anxiety in Parkinson's disease. She is also a scientific advisor for the Parkinson's Foundation.

Ergun Uc, MD, professor of neurology and director of the Division of Movement Disorders and Parkinson's Foundation of Excellence at University of Iowa, said the new review was conducted by “top-notch researchers and clinicians” and he found the symptom-specific tables to be especially useful.

Dr. Uc said: “Parkinson's disease is increasingly being seen as a condition that requires an organized multidisciplinary approach because of its array of nonmotor symptoms.”

He said he wished the review had focused also on deep brain stimulation and its impact on nonmotor symptoms.

“Deep brain stimulation is becoming more and more common and it has a number of effects on these nonmotor symptoms,” both positive and negative, among them a possible subtle decline in cognitive ability, he said.

He also would have liked the review to address exercise as a treatment option. There are now exercise classes aimed at Parkinson's patients, but evidence on the benefits of exercise in Parkinson's is limited, he said.

This summer, Dr. Uc is launching a randomized clinical trial funded by the U.S. Department of Veterans Affairs that will look at the effect of an aerobic exercise regimen on motor and nonmotor aspects of PD, in particular cognition, vision, and driving.


No competing interests were disclosed for authors of the report.

Link Up for More Information

• Seppi K, Chaudri KR, Coelho M, et al; of the Parkinson's Disease Update on Nonmotor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Committee. Update on treatments for nonmotor symptoms of Parkinson's disease—An evidence-based medicine review Mov Disord 2019; 34(2):180–189.