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NEW STUDY FINDS ZONISAMIDE, AN ANTICONVULSANT, SAFE AND EFFECTIVE FOR PARKINSON DISEASE SYMPTOMS

ARTICLE IN BRIEF

✓ In a placebo-controlled, double-blind trial, Japanese investigators reported that zonisamide, an anticonvulsant, was safe and effective for Parkinson disease; the changes were greatest for those taking either the 25-mg (p=0.001) or 50-mg (p=0.003) daily dose.

A clinical trial has shown for the first time that zonisamide, an anticonvulsant, was safe and effective as an adjunctive treatment for patients with Parkinson disease (PD). The results from the study were published in the Jan. 2 Neurology (2007;68:45–60).

Investigators in Japan, led by Miho Murata, MD, PhD, from the National Center of Neurology and Psychiatry in Tokyo, thought that the anticonvulsant was worthy of study after finding that a patient taking it for epilepsy showed clinical improvement in Parkinson disease symptoms.

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Dr. Alberto Espay: “This is a very interesting foray into a non-dopaminergic approach. If we can expand our repertoire of neurotransmitters without the wearing off of dyskinesia, this could be very important.”

The exact mechanism for zonisamide's effect on Parkinson disease is not known. Invetigators noted that in the dopaminergic system, therapeutic doses of zonisamide (20 and 50 mg/kg) increase intracellular and extracellular dopamine levels in the rat striatum (Curr Pharm Des 2004;10:687–694). They speculated that the primary effect of the drug in PD is to increase dopamine synthesis.

In an open-label trial involving nine patients with PD, investigators reported that the drug produced significant improvement in limb rigidity, tremor, and postural stability. (Neurosci Res 2001;41:397–399). In addition to demonstrating a significant improvement in motor function in patients with advanced, treatment-refractory Parkinson disease, the drug spared patients from dyskinesia, a common side effect of high levodopa doses.

STUDY PROTOCOLS

The investigators expanded their study to a double-blind, placebo-controlled study of 347 patients in 58 medical institutions across Japan, studying three daily doses: 25 mg, 50 mg, and 100 mg. The study design consisted of a two-week run-in period with placebo, a 12-week double-blind treatment period, and a two-week double-blind dose-reduction period. Patients in the study had Parkinson disease for a mean duration of 8.6 years and had an insufficient response to levodopa.

Patients taking adjunctive therapy with zonisamide showed significant improvement in the Part III motor examination scores on the Unified Parkinson's Disease Rating Scale (UPDRS), which rates such functions as speech, facial expression, tremor at rest, and neck rigidity on a scale of 0 (for normal) to 4 (for severe symptoms). Change in the UPDRS was the primary study endpoint. Although all patients on zonisamide showed some improvement in motor function score by the end of the study, the changes were greatest for those taking either the 25-mg (p=0.001) or 50-mg daily dose (p=0.003).

Surprisingly, patients in the 100 mg dose did not show a significant improvement and dose-response was not a factor in outcomes. Ninety-two percent of patients were taking dopamine agonists; 52 percent were taking MAO-B inhibitors.

Responders were defined in terms of having at least a 30 percent reduction in UPDRS total scores from baseline to final assessment. Only the 50 mg group showed significant improvement of 30 percent or more (p=0.01).

Adverse events were comparable for patients in the 25-mg (70.9 percent) and 50-mg groups (72.9 percent). They were highest (79.5 percent) in the patients taking 100-mg daily doses. Somnolence, apathy, decreases in body weight, and constipation were the most common side effects in patients taking zonisamide. However, patients taking zonisamide were less likely to experience dizziness, a decrease in appetite, and increase in serum creatinine phosphokinase.

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Dr. Carl Bazil: “The bottom line is that zonisamide does have multiple mechanisms, including dopaminergic. … While zonisamide could be useful, it is too early to say whether it will be anything more than a minor player. The preliminary trial results suggest an effect, but not a dramatic one.”

EXPERTS COMMENT

Several experts, who were not involved with the trial, expressed cautious optimism about the new findings. “This wouldn't be the first time that a drug [for Parkinson disease] was discovered serendipitously,” said William J. Weiner, MD, professor and chair of neurology and director of the Movement Disorders Center at the University of Maryland.

In an e-mail, Alberto Espay, MD, PhD, assistant professor of neurology at the University of Cincinnati's Movement Disorders Center, elaborated on the anticonvulsant's potential as an adjunct to levodopa: “Levodopa never loses its power. It remains equally effective throughout the course of the disorder. What changes is the density of nigrostriatal neurons in charge of converting the levodopa into dopamine. Since this pool of neurons degenerate over time, other strategies in addition to levodopa become necessary.”

“This is a very interesting foray into a non-dopaminergic approach,” said Dr. Espay. “If we can expand our repertoire of neurotransmitters without the wearing off of dyskinesia, this could be very important.”

Zonisamide is approved as an antiepileptic medication in the United States, but it is not used very frequently, according to Carl W. Bazil, MD, PhD, associate professor of clinical neurology, and director of the Clinical Anticonvulsant Drug Trials at Columbia University's Neurological Institute. However, he added, the anticonvulsant is commonly used to treat epilepsy in Japan.

Dr. Bazil added: “The bottom line is that zonisamide does have multiple mechanisms, including dopaminergic. … While zonisamide could be useful, it is too early to say whether it will be anything more than a minor player. The preliminary trial results suggest an effect, but not a dramatic one.”

All neurologists that were interviewed by Neurology Today said that the study would have to be replicated and assessed in Western populations.

REFERENCES

• Murata M, Hasegawa K, Kanazawa I, and The Japan Zonisamide on PD Group. Zonisamide improves motor function in Parkinson disease. A randomized double-blind study. Neurology 2007;68:45–60.
• Murata M, Horiuchi E, Kanazawa I. Zonisamide has beneficial effects on Parkinson's disease patients. Neurosci Res 2001;41:397–399.
• Murata M, Hasegawa K, Kanazawa I. Randomized, double-blind study of zonisamide with placebo in advanced Parkinson's disease. Mov Disord. 2004;19(suppl 9):S198.