ADHD Boosts Risk of Early-Onset Parkinson's, Other Diseases

Megan Brooks

September 14, 2018

UPDATED September 19, 2018 // Having attention-deficit/hyperactivity disorder (ADHD) may raise the risk developing Parkinson's disease (PD) and related disorders, results of a population-based study suggest.

Having attention-deficit/hyperactivity disorder (ADHD) may raise the risk developing Parkinson's disease (PD) and related disorders, results of a population-based study suggest.

Investigators found that patients with ADHD were more than twice as likely to develop early-onset Parkinson's and PD-related disorders relative to matched individuals who did not have ADHD. The risk was sixfold to eightfold higher in ADHD patients prescribed stimulant medications.

"This link between ADHD and its treatment with psychostimulants and Parkinson's disease–like disorders (PDLDs) has not been shown before," senior author Glen Hanson, PhD, professor of pharmacology and toxicology, University of Utah, Salt Lake City, told Medscape Medical News.

"That there is a link between pediatric mental health problems (eg, ADHD) and their treatment (eg, stimulants) and neurodegenerative diseases (eg, PDLDs) that typically express in older, and even geriatric, populations is a relatively new and somewhat disturbing concept," said Hanson.

The study was published online September 12 in Neuropsychopharmacology.

Side Effect of Stimulants?

The investigators examined associations between ADHD and PD and related disorders using the Utah Population Database (UPDB).

They created a cohort of 31,769 individuals who had a history of ADHD, of whom 4960 were treated with stimulant medications, and a non-ADHD comparison cohort of 158,790 individuals matched (5:1) for sex and age.

None of the participants had a prior diagnosis of PD or related disorders of the basal ganglia and cerebellum or a history of substance abuse. All participants were at least 20 years old in 2011. The development of PD and related disorders was tracked until age 60 years.

In the ADHD cohort, the rate of incident PD and related diseases was 0.52%, compared with 0.19% in the non-ADHD cohort. The median age at disease onset was slightly younger in the ADHD than the non-ADHD cohort (43 years vs 45 years).

Overall, ADHD was associated with a 2.4-fold increased risk for PD and related diseases (adjusted hazard ratio [aHR], 2.4; 95% confidence interval [CI], 2.0 - 3.0; P < .0001), the research team found.

The risk was significantly higher in ADHD patients who took stimulants (aHR, 6.0; 95% CI, 3.9 to 9.1; P < .0001) than it was for those who had not taken stimulants (aHR, 1.8; 95% CI, 1.4 - 2.3; P < .0001).

ADHD patients who were only prescribed methylphenidate had an eightfold increased risk for PD and related diseases compared to persons who did not have ADHD (aHR, 8.0; 95% CI, 4.2 - 15.1; P < .0001).

In their article, the researchers caution that it may be that the apparent association between being prescribed stimulant medication and being at higher risk for PD and related diseases is a result of the fact that the phenotype of patients who are prescribed stimulant medication is more severe than that of persons who are not prescribed a stimulant, rather than a direct association between prescribed stimulant use and these diseases.

"The jury is still out. The increased risk we observed in people could be linked to having ADHD itself or perhaps a more severe form of ADHD, which may be more likely to be treated with medications," first author Karen Curtin, PhD, from the University of Utah, said in a news release.

She also noted that the absolute risk of developing PD remained low. "If we were to follow 100,000 adults prescribed treatment for ADHD over time, we estimate that over a year, eight to nine patients will develop Parkinson's disease before age 50," she noted. By comparison, in a population of 100,000 persons who did not have ADHD, one to two would develop PD.

Prior studies provide some support for their findings. Preclinical studies have shown that exposure to high doses of amphetamine or its analogue, methamphetamine, causes persistent basal ganglia dopaminergic deficits. In clinical studies, basal ganglia dopaminergic deficits have been found in people who have a history of methamphetamine abuse, which is of "particular interest," given epidemiologic reports that people who abuse amphetamine/methamphetamine are more likely to develop PD, the researchers say.

In addition, in a prior study using the UPDB, they found that individuals with a history of amphetamine/methamphetamine abuse were two to three times more likely to develop PD or related disorders.

More Study Needed

The researchers note the current results should be considered preliminary. One limitation of the study is that it is possible that persons may have been misclassified as not having ADHD. Such misclassification could have occurred as a result of individuals being diagnosed with the disorder in a state other than Utah, or as a result of missed or incorrect diagnosis of PD-like disease, or through the lack of information on the duration of use and dosage of ADHD medication prescribed, they point out.

Nonetheless, Hanson said the findings have several "important clinical implications."

"First, our findings suggest that a significant fraction of patients who develop PDLD have a history of ADHD with stimulant treatment. Perhaps by studying this ADHD population we can discover some important causative factors for PDLDs that can lead to be treatment or even prevention," he explained.

"Second, if it is determined that treatment of ADHD with the psychostimulants is responsible for the substantial increase in PDLD expression in ADHD patients (going from a 2.3-fold to an 8.6-fold increase), it would be very important to find other drugs to treat ADHD that do not have this side effect," he said.

"Finally, while our findings absolutely do not mean that ADHD patients should no longer be treated with the stimulant drugs if needed, hopefully it would be considered in the benefit/risk discussion for deciding the best approach for managing these persons," said Hanson.

Caution Urged

Asked to comment by Medscape Medical News, Brian Lebowitz, PhD, clinical associate professor of neurology, Stony Brook University Medical Center, New York, agreed with Hanson. "It is important to not overinterpret the findings of a single preliminary study," said Lebowitz, who was not involved with the research.

"At this point, there is not enough known about the relationship between physician-monitored stimulant therapy for ADHD and true risk for Parkinson's later in life. In other words, this study alone should not discourage parents from initiating stimulant therapy for their children with ADHD when necessary and monitored by a physician," he said.

Lebowitz also said the finding that the rate of early-onset PD was higher in ADHD patients who were never treated with stimulant medication is notable for several reasons.

"A number of studies have found abnormalities in the substantia nigra of children with ADHD. This same region is known to be abnormal in individuals with Parkinson's disease. Thus, it may be the case that having ADHD is a risk factor for later-life Parkinson's disease because of neurodevelopmental vulnerabilities in a brain region and brain systems common to both conditions," he explained.

In addition, it's worth noting that abuse of stimulant drugs has also been associated with abnormality in the substantia nigra, said Lebowitz, and in this new study, stimulant-treated ADHD was associated with a significantly increased risk for early-onset PD. "Although the study is preliminary, and having early-onset Parkinson's disease was found to be very rare even in those individuals with ADHD and stimulant treatment, more research is clearly needed," said Lebowitz.

Ankur Butala, MD, assistant professor of neurology, psychiatry, and behavioral sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, also urged caution in interpreting the findings.

"This is an interesting observation, but there is a lot of uncertainty and caveats, so it's particularly important to be cautious in overinterpretation of the results," he told Medscape Medical News.

"For these kinds of studies, your interpretation of the data is only as good as the quality of the data itself. This is particularly relevant for a retrospective chart review like this, where you have to read between the lines of whatever is documented," added Butala.

Neuropsychopharmacol. Published online September 12, 2018. Abstract

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