BOSTON—Among patients with primary restless legs syndrome (RLS) and without a history of psychiatric disorders, patients who receive de novo dopamine agonist treatment are approximately twice as likely to subsequently develop a mental disorder as those who do not receive dopamine agonist treatment, according to a large-scale retrospective study presented at the 31st Annual Meeting of the Associated Professional Sleep Societies.
Previous research has demonstrated an increased risk of mental disorders among patients with Parkinson’s disease who are treated with dopamine agonists. Many patients with RLS are also treated with dopamine agonists, although at lower doses than patients with Parkinson’s disease. Given these lower doses, clinicians assumed that the risk of dopamine agonist-induced mental disorders in RLS would be small. Clinical case studies suggest a higher-than-anticipated risk, however.
An Examination of Claims Data
To investigate whether dopamine agonists increase the risk of developing mental disorders in patients with RLS, Cheryl Hankin, PhD, President and Chief Scientific Officer of BioMedEcon, a health economics and outcomes research firm in Moss Beach, California, and colleagues examined Truven MarketScan Commercial and Medicare Supplemental databases of claims filed between July 1, 2008, and December 31, 2014. From a pool of 539,399 patients with a diagnosis of RLS, investigators identified adults with two or more years of claims data preceding and following their index RLS diagnosis dates.
Cheryl Hankin, PhD
Patients were excluded from the analysis if, in the two or more years preceding RLS diagnosis, they received a diagnosis of mental disorder or filled a prescription for an antidepressant or antipsychotic. Also excluded were patients who filled a prescription for a dopamine agonist in the two or more years preceding RLS diagnosis. Patients who were ever diagnosed with Parkinson’s disease, kidney disease, iron deficiency, or pregnancy were assumed to have secondary RLS and were also excluded.
The investigators identified 5,419 eligible participants. Of this group, 1,649 patients received dopamine agonists after RLS diagnosis. Specifically, 571 participants received pramipexole, 915 received ropinirole, and 163 received both. Approximately 65% of patients were female. Patients residing in the Northeast were significantly less likely to receive dopamine agonists, compared with patients residing in the Midwest or the South. The investigators found no significant differences in treatment status by comorbid illness burden or by sex. The investigators also found no significant differences in demographic characteristics between patients receiving pramipexole and those receiving ropinirole.
Risk Was Significantly Greater in Patients Receiving Dopamine Agonist
Next, from this pool of eligible subjects, the researchers matched 1,080 patients treated with dopamine agonists with 1,080 dopamine agonist-naïve patients on sex, age at RLS diagnosis, region, employment, and illness burden. Dr. Hankin and colleagues found a significant increase in mental disorder diagnoses (eg, bipolar disorder, anxiety, depression, and substance abuse) among patients treated with dopamine agonists, compared with dopamine agonist-naïve patients. Among patients receiving dopamine agonists, the odds ratio for severe mental disorder (eg, psychoses and bipolar disorder) was 2.2, the odds ratio for moderate to severe mental disorder (eg, posttraumatic stress disorder and major depression) was 1.8, and the odds ratio for mild mental disorder (eg, anxiety disorders) was 1.9, compared with dopamine agonist-naïve patients.
“This is the first large-scale, real-world, claims-based study to examine the association between treatment of RLS with dopamine agonists and the development of psychiatric adverse events. Our findings are compelling, but need to be replicated in other patient populations,” said Dr. Hankin.
“Our retrospective analysis required careful consideration of matching,” said Daniel On-Fai Lee, MD, Clinical Professor of Neurology at the University of Kentucky College of Medicine in Lexington, who collaborated on the study. Although the investigators took care to match participants and to remove cases of secondary RLS from the analysis, they may have inadvertently overlooked one or more important matching variables that could affect the outcome, he added.
Arbor Pharmaceuticals provided funding for the study, but did not influence its methodology, analysis, results, or conclusion, said Dr. Lee.
—Erik Greb
Suggested Reading
Sierra M, Carnicella S, Strafella AP, et al. Apathy and impulse control disorders: yin & yang of dopamine dependent behaviors. J Parkinsons Dis. 2015;5(3):625-636.
Wilt TJ, MacDonald R, Ouellette J, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Intern Med. 2013;173(7):496-505.