ARTICLE IN BRIEF
Adjunct zonisamide and levodopa were found to improve motor symptoms in patients with parkinsonism associated with dementia with Lewy bodies.
Low-dose adjunctive zonisamide in combination with levodopa proved safe and effective for treating parkinsonism associated with dementia with Lewy bodies (DLB), according to a phase 2, randomized, placebo-controlled trial reported in the January 24 online issue of Neurology.
In the 158-patient study, zonisamide was given as an adjunct to levodopa to three groups of DLB patients at doses of 25 mg daily, 50 mg daily, or placebo. The primary endpoint was a change from baseline to 12 weeks in the motor subscale (Part 3) of the Unified Parkinson's Disease Rating Scale (UPDRS) score. In addition, the investigators assessed cognitive function, behavioral and psychological symptoms of dementia, and caregiver burden.
By week 12, the UPDRS Part 3 total score declined, showing an improvement across the three treatment arms, with significant differences observed in the zonisamide 50 mg group.
Levodopa or dopamine agonists are used for parkinsonian motor symptoms of DLB, but at doses smaller than those used for PD, said the lead author of the study, Miho Murata, MD, PhD, director general of the National Center Hospital of the National Center of Neurology and Psychiatry in Tokyo.
“Neurologists administer smaller doses because patients with DLB are more likely to have psychiatric symptoms such as hallucinations by anti-parkinsonian agents (levodopa) than those with Parkinson's disease,” explained Dr. Murata. “In this study, the levodopa equivalent daily dose for DLB patients was about 300 mg, and in the case of Parkinson's disease trials previously reported it was over 500 mg.”
Dr. Murata said that in DLB, dopaminergic agents can induce dyskinesia, hallucinations, and other psychiatric symptoms, which makes it challenging to treat parkinsonism-related motor symptoms. “These results show that zonisamide in combination with levodopa can improve parkinsonian motor symptoms without aggravating these symptoms,” she said.
The precise mechanism by which zonisamide exerts its anti-parkinsonian effect is unknown, she said, but it is thought to work by activating dopamine synthesis and release, inhibiting MAO-B, as well as by blocking the sodium and T-type calcium channels.
Dr. Murata said that adjunctive zonisamide is approved as an anti-parkinsonism agent in Japan, based on earlier research, including a study she led that was published in Neurology in 2007.
The multicenter, placebo-controlled, randomized, double-blind, parallel-group study included a run-in period of four weeks and a treatment duration of 12 weeks.
“The goal of the run-in period was to make sure that there were no other treatment effects from other anti-Parkinson drugs,” said Dr. Murata.
Patients were eligible if they were taking levodopa for at least 12 weeks before the run-in period, as well as age 20-84 years old, with a UPDRS Part 3 total score of ≥10, and Mini-Mental State Examination total score 10-26. The research team also allowed patients who were taking other PD medications, anti-hypertensives, cardiovascular drugs, gastrointestinal drugs, or Yokukansan, a common Japanese herbal remedy.
The changes from baseline to 12-weeks were -2.1 in UPDRS scores in the placebo arm, -4.4 in the zonisamide 25 mg, and -6.2 in the zonisamide 50 mg.
Adverse events were limited and similar across the treatment arms. The most common events in the 25 mg and 50 groups included somnolence, cognitive disorders, and hallucinations.
“It appears that zonisamide is well tolerated in DLB patients, which is important as DLB patients have increased sensitivity to a wide range of centrally-acting medications,” said James Galvin, MD, MPH, professor and associate dean of the Charles E. Schmidt College of Medicine at Florida Atlantic University in Boca Raton, FL. Dr. Galvin, who is director of the university's Lewy Body Dementia Research Center of Excellence, added: “This type of finding has the potential to advance the field of DLB treatment and open new areas of research.”
In an accompanying editorial in Neurology, Linda A. Hershey, MD, PhD, professor of neurology at the University of Oklahoma Health Sciences Center and David John Irwin, MD, assistant professor of neurology at the Hospital of the University of Pennsylvania, agreed that the study was important, but also noted several limitations with the study, stemming from the “inherent heterogeneity of clinical symptoms seen in DLB patients.”
“A substantial proportion of patients were excluded, including those with mild or no parkinsonism (UPDRS III <10),” they wrote, “and those whose motor symptoms did not respond to dopaminergic therapy. These exclusion criteria were necessary because of the focus of the study, but they limit the generalizability of the results.”
“Furthermore, the treatment group had higher rest tremor scores at baseline, compared to the placebo group, which could bias the response to dopaminergic treatment,” Drs. Hershey and Irwin wrote. “Finally, most (about 75%) patients were taking an anti-dementia drug, such as a cholinesterase inhibitor, which could influence cognitive and functional outcomes.”
While the study showed a benefit with zonisamide, some experts questioned whether the dosages for levodopa were too low (averaging less than 300 mg a day). “The study showed that participants improved when zonisamide was added to their medication regimen, but we don't know if they might have improved more if the levodopa dose was increased instead,” said Melissa Armstrong, MD, MSc, FAAN, director of the Mangurian Clinical-Research Center for Lewy Body and Parkinson's Disease Dementia at the University of Florida in Gainesville, FL.
With no currently approved treatments for DLB, however, the experts interviewed by Neurology Today agreed that a positive study with a currently available agent like zonisamide would be a welcome addition to treating this population.
“The fact that zonisamide helped motor symptoms without worsening behavioral symptoms in DLB is an important finding from this study,” said Dr. Armstrong.
Dr. Murata received honoraria for consulting and/or lecturing from the study sponsor, Sumitomo Dainippon Pharma, Otsuka Kyowa Hakko Kirin, Nippon Boehringer, Ingelheim, Nihon Medi-physics, FUJIFILM Pharma, Hisamitsu Pharmaceutical and AbbVie GK. Dr. Armstrong reported no disclosures related to the study, and receives compensation from the AAN for work as an evidence-based medicine methodology consultant. Dr. Galvin reported no disclosures relevant to the study. Dr. Hershey was the site principal investigator for two studies sponsored by Forum Pharmaceuticals and is a co-investigator for an Alzheimer's Association grant. Dr. Irwin receives grants from the National Institutes of Health, the Penn Institute on Aging, and the Brightfocus Foundation.