Antiepileptic Reduces Parkinson's Symptoms Safely

TOKYO, Jan. 2 -- Tremors and other symptoms associated with Parkinson's disease can be reduced significantly by the antiepileptic drug Zonegran (zonisamide) without an increase in dyskinesias, according to Japanese researchers.

Patients with Parkinson's disease resistant to levodopa who received Zonegran in two of three different doses had significant improvements in Parkinson's disease rating-scale scores compared with patients who received placebo, found Miho Murata, M.D., Ph.D., of the National Center of Neurology and Psychiatry here and colleagues.

"Zonisamide treatment improved all main Parkinson disease symptoms in these patients, including tremor and other disabling dyskinesias," wrote Dr. Murata and colleagues in the Jan. 2 issue of Neurology. "This is consistent with findings from other, smaller studies."

The investigators previously published a case report and results of a small open-label study indicating that Zonegran could improve the main symptoms of Parkinson's disease, including limb rigidity, tremor, postural instability, and motor fluctuations that occur during wearing-off from levodopa.

In the current multicenter study, 347 patients with Parkinson's disease who were not well controlled on levodopa were randomly assigned, after a two-week placebo-controlled washout phase, to either Zonegran in doses of 25, 50, or 100 mg daily, or placebo, as an adjunct to levodopa. Patients were treated for 12 weeks, followed by a two-week dose-reduction phase.

The primary efficacy endpoint was change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III at the final assessment point.

Secondary endpoints included change from baseline in total daily "off" time. total scores of UPDRS Parts I, II, and IV, and Modified Hoehn and Yahr Scale scores.

The investigators also looked at the safety of the therapy based on the incidence of adverse events.

They found that among the 279 patients who completed the study, there were significant improvements in the primary endpoint in both the 25-mg and 50-mg groups compared with placebo.

The changes in the UPDRS Part III total score from baseline at final assessment were -2.0 + 0.8 (standard error of the mean) in the placebo group, -6.3 + 0.8 in the 25 mg group, -5.8 + 0.8 in the 50-mg group, and -4.6 + 0.8 in the 100-mg group. The improvement over placebo was significant for both the 25-mg group (P=0.001, Dunnett test) and 50-mg group (P=0.003).

The proportion of responders -- patients with a 30% or greater reduction in UPDRS Part III total score from baseline at final assessment -- was 22% in the placebo group, and 35.1%, 38.8% and 31.7% in the 25, 50 and 100 mg groups, respectively. The difference versus. placebo group was significant for the 50-mg dose.

"The duration of 'off' time was significantly reduced in the 50-mg and 100-mg groups versus placebo," the investigators wrote. "Dyskinesia was not increased in zonisamide groups."

Adverse events that occurred more frequently among patients on Zonegran included somnolence, apathy, weight loss, and constipation. The incidence of adverse events was similar between the 25-mg, 50-mg, and placebo groups, but higher in the 100-mg group.

Although patients on Zonegran appeared to benefit from the drug, it's unclear why, the authors noted.

"Zonisamide has no affinity to dopamine receptors (D1-D5) or dopamine transporter," they wrote. "Zonisamide also has no direct effects on glutamate receptors, adenosine receptors, or serotonin receptors, which have been suggested as possible sites of action for anti-PD drugs, other than the dopaminergic system."

Although they had previously hypothesized that activation of dopamine synthesis and moderate inhibition of monoamine oxidase type B were the primary mechanisms mediating the effects of Zonegran in Parksison's, there were no differences in the efficacy of the antiepileptic when it was administered either with or without a monoamine oxidase type B-inhibitor.