Clozapine May Improve Levodopa-Induced Dyskinesias in Parkinson's Disease

Laurie Barclay, MD

February 12, 2004

Feb. 12, 2004 — Clozapine may improve levodopa-induced dyskinesias (LID) in Parkinson's disease (PD), according to the results of a randomized, double-blind trial published in the Feb. 10 issue of Neurology.


"Dyskinesias are normally very difficult to treat and pose a serious side effect of levodopa therapy, the most common treatment for Parkinson's patients," lead author Franck Durif, MD, PhD, from the Hôpital Gabriel Montpied in Clermont-Ferrand, France, says in a news release. "Our study supports previous preliminary findings that low-dose clozapine can reduce dyskinesias by around 50% in some patients."

In this 10-week, parallel-group, multicenter trial, 50 patients with PD were randomized to receive clozapine once daily in the evening (mean dosage, 39.4 ± 4.5 mg/day) or placebo. The principal outcome measure was the diurnal change in the "on" time with LID determined by bimonthly self-evaluation of motor performance fluctuations. Subjects also had an acute levodopa challenge at the beginning and end of the study.

After treatment, the duration of "on" periods with LID decreased, favoring the clozapine group (placebo group, day 0: 4.54 ± 0.53 hours, end: 5.28 ± 0.70 hours; clozapine group, day 0: 5.68 ± 0.66 hours, end: 3.98 ± 0.57 hours; P = .003). During the levodopa challenge, the maximal LID score at rest significantly decreased with clozapine treatment (change from day 0 to day 70, +0.15 ± 1.01 in the placebo group and -2.22 ± 0.52 in the clozapine group; P < .05).

"Overstimulation of D1 dopaminergic receptors is believed to be one of the most important mechanisms underlying LIDs in Parkinson's disease," Dr. Durif says.

Adverse events led to study termination in five patients in the clozapine group and in seven patients in the placebo group. Three of these patients in the clozapine group developed eosinophilia, which rapidly resolved when the drug was discontinued.

The French Ministry of Health supported this study. Novartis Pharma supplied the Leponex used in this trial.

In an accompanying commentary, Robert L. Rodnitzky, MD, discusses current therapeutic approaches in PD and the need for additional effective treatments.

"The exact mechanism by which clozapine improves LID is still unclear, mirroring our incomplete understanding of the physiochemical basis of this complication," he writes. "Whereas these data may appropriately lower the clinician's threshold to prescribe clozapine for the treatment of LID, the use of this agent must still be balanced by awareness of its relatively high side effect profile, including the rare, but potentially fatal, complication of agranulocytosis. However, as LID are potentially disabling for so many PD patients, this caveat should be considered a precaution, not a prohibition for the use of this otherwise useful medication."

Neurology. 2004;62:349, 381-388

Reviewed by Gary D. Vogin, MD