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Population Study Finds Association Between Psychostimulant Use for ADHD and Parkinson's-Related Disorders Later in Life

Rukovets, Olga

doi: 10.1097/01.NT.0000550493.88446.4b
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The likelihood of developing a Parkinson's disease-related movement disorder was two to three times higher in individuals with attention deficit-hyperactivity disorder (ADHD) than in those who did not have the diagnosis, and eight to nine times higher in those who were prescribed psychostimulants for the condition. But whether it is the underlying ADHD or the psychostimulants that cause the movement disorders is a question that requires further research, independent experts said.

A history of psychostimulant use for attention deficit-hyperactivity disorder (ADHD) was associated with a higher risk for a Parkinson's disease (PD)-related movement disorder later in life, a retrospective review of data from a population-based database found.

The likelihood of developing a PD-related movement disorder was two to three times higher in individuals with ADHD than in those who did not have the diagnosis, and eight to nine times higher in those who were prescribed psychostimulants for the condition, the study authors reported in the December issue of Neuropsychopharmacology.

The study raises many questions, the lead study author Glen R. Hanson, DDS, PhD, vice dean and professor of pharmacology at the University of Utah School of Dentistry in Salt Lake City, told Neurology Today. “Amphetamines damage the same pathway that is involved in Parkinson's — the nigrostriatal dopamine pathway... What is going on at the molecular level? Can we do something to stop it?”

Perhaps, he said, if there was an understanding of the connection between ADHD and PD or PD-like disorders, there would be hints for PD treatment, Dr. Hanson said. These types of experiments may be difficult to do in humans, he noted, so it will be important to look at animal models of hyperactivity in the future.

In the meanwhile, “neurologists could perhaps start to pay more attention to the medical history of patients from their youth and look to see if there could be some linkages with other childhood mental health disorders,” said Dr. Hanson, who has been studying the neurobiology of psychostimulants and their connection with PD for many years.

Indeed, given that three-quarters of children with ADHD are prescribed amphetamine- or methylphenidate-based products for their ADHD symptoms — according to a recent report from the Centers for Disease Control and Prevention — the findings of the current analysis are “provocative,” pediatric neurologists not involved with the study told Neurology Today.

But they advised caution in interpreting the results. The study authors have generated a hypothesis that should inspire more research, they said. For now, the findings underscore the need to discuss the risks and benefits of treatments for ADHD.

The study was funded by grants from the National Institute on Drug Abuse. Partial support for the database was provided by: the National Cancer Institute; the University of Utah's Program in Personalized Health and Center for Clinical and Translational Science; and a National Center for Research Resources grant, with additional support from the Utah State Department of Health.

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This retrospective cohort study reviewed data from the Utah Population Database, which contains records from more than 11 million individuals born between 1950 and 1992 who live or have lived in Utah. Those with HIV and a history of drug or alcohol abuse were excluded from the study to avoid confounding the data. The study authors wanted to determine if ADHD treatments affect the risk of diseases of the basal ganglia and cerebellum, including PD.

The final ADHD cohort included 31,769 patients; in this group, 4960 (or 15.6 percent) had been prescribed stimulants: 2716 received mixed-amphetamine salts (Adderall); 1941 received methylphenidate (Concerta, Daytrana, Metadate, Methylin, Ritalin); and 303 received both agents. The investigators also included a cohort of 158,790 individuals with no history of ADHD and no diseases of the basal ganglia and cerebellum prior to baseline who were randomly selected from the Utah database and individually matched to ADHD patients based on sex and birth year at a ratio of 5:1. They also controlled for psychotic comorbidities (as a proxy for antipsychotics use) and tobacco use.



The median duration of follow-up was 21 years. The rates of incident basal ganglia and cerebellum diseases in non-ADHD and ADHD patients were 0.19 percent and 0.52 percent, respectively. The risk of basal ganglia and cerebellum disease was increased by 2.4-fold in patients with ADHD (p< 0.0001). The risk was even higher for those prescribed psychostimulants compared with non-ADHD-matched subjects, (p< 0.0001) and ADHD patients without known stimulant treatment (p< 0.0001). The risk was eightfold for ADHD patients who were only prescribed methylphenidate for treatment, compared to their corresponding non-ADHD subjects.

“What does it mean that being treated for ADHD with these drugs increases risk [of basal ganglia and cerebellum disorders] substantially?” Dr. Hanson asked. “Does that mean that the drug itself combined with whatever the ADHD is bringing to the table causes this eight to 10-fold increase in risk? Or does it mean that the drug was given to ADHD patients who had more severe disorders?

“We can't look at the older population for another 20 years,” he continued. “So are we going to see the same increase in that older population of Parkinson's in individuals who have a history of ADHD treated with Ritalin or similar kinds of drugs?”

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That question deserves future research, independent experts agreed, but for now, there are more questions than answers, they said. The current study had strengths, including the large number of subjects included with long-term follow up data, said Karen Ballaban-Gil, MD, professor of neurology and pediatrics, director of the child neurology residency training program, and director of outpatient child neurology services at the Albert Einstein College of Medicine. But, she stressed, the association found using the database does not prove causation.

“Indeed, the finding that patients with ADHD who were not treated with medication also had an increased risk of developing basal ganglia [BG] compared to non-ADHD patients suggests that the disorder itself increases risk of later BG disease,” she added.

Jonathan W. Mink, MD, PhD, FAAN, chief of the division of child neurology and vice chair of neurology at the University of Rochester Medical Center, also had concerns about the study's limitations. “The authors refer to ‘any adult-onset diseases of the basal ganglia and cerebellum,’ but they really limited their ascertainment to specific ICD-9 codes for Parkinson's disease, secondary parkinsonism, ‘other degenerative diseases of the basal ganglia,’ and essential tremor,” Dr. Mink said. “A large number of basal ganglia and cerebellar diseases were not included.”



The authors' inability to assess dose of the stimulant medication or treatment duration was also a limitation, he said. “Having some relationship to total exposure [to thte drugs] would strengthen the possibility of a meaningful biological link.”

Dr. Mink said he favored the authors' interpretation “that the findings may reflect a relationship between treatment and higher severity of ADHD symptoms and that higher severity ADHD may be a marker of underlying neurodevelopmental differences that may be harbingers of adult-onset disorders. It would have been a strength had they looked at a disease control group with dementias to see if the relationship is specifically related to parkinsonism/essential tremor as opposed to adult-onset progressive neurologic diseases more generally,” he said.

At this time, Dr. Mink said these findings would not influence any treatment or prescribing patterns for patients with ADHD, but they do provide “hypotheses to be tested in future research.”

Dr. Ballaban-Gil agreed, adding: “I always discuss the risks versus benefits of treatment (and medication) with families, so this data won't really change that discussion.”

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•. CDC: ADHD in young children:
    •. Curtin K, Fleckenstein AE, Keeshin BR, et al Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder Neuropsychopharmacol 2018; 43(13):2548–2555.
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