Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depression and aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.