The New England Journal of Medicine -- August 5, 1999 -- Vol. 341, No. 6 Clozapine for Drug-Induced Psychosis in Parkinson's Disease ------------------------------------------------------------------------ -------- To the Editor: The article by the Parkinson Study Group (March 11 issue) (1) and the accompanying editorial by Cummings (2) emphasize the potential benefits of clozapine for patients with psychosis resulting from medications used to treat Parkinson's disease. However, patients with Parkinson's disease may be at particular risk for one of the most serious complications of clozapine therapy: the neuroleptic malignant syndrome. Not mentioned in either the article or the editorial is the fact that the antipsychotic efficacy of clozapine in patients with schizophrenia is probably due in part to the glutamate-agonist activity of clozapine at N-methyl-d-aspartate receptors. The neuroleptic malignant syndrome has been linked to excessive activity of glutamate at N-methyl-d-aspartate receptors. This may help to explain why clozapine, although it lacks important activity as an antagonist of dopamine D2 receptors, may cause the syndrome. A relative increase in glutamatergic activity has also been described in Parkinson's disease, and therefore Parkinson's disease may itself be a risk factor for development of the neuroleptic malignant syndrome, with or without treatment with clozapine. Because the incidence of the neuroleptic malignant syndrome, even among patients receiving clozapine, is probably 1 percent or less, the likelihood that the study by the Parkinson Study Group would have encountered a case of this syndrome is low. In recommending off-label use of clozapine for a potentially large group of patients, Cummings and the Parkinson Study Group may increase the risk that some patients will have this potentially lethal complication of clozapine therapy. Clinicians who prescribe clozapine for patients with Parkinson's disease should be prepared to intervene swiftly if fever, alterations in mental status, autonomic disturbances, and alterations of extrapyramidal function develop. Thomas M. Brown, M.D. 900 Powell's Pt. Gautier, MS 39553 References 1. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med 1999;340:757-63. 2. Cummings JL. Managing psychosis in patients with Parkinson's disease. N Engl J Med 1999;340:801-3. ------------------------------------------------------------------------ -------- Dr. Friedman replies: To the Editor: Brown's concern with the possibility that clozapine may induce the neuroleptic malignant syndrome is based on an important theoretical consideration. It is reassuring, however, that counting the reports of open-label use and the Parkinson Study Group report, more than 460 patients with Parkinson's disease have been treated with clozapine and described. None have been reported to have a neuroleptic malignant-like syndrome. Neuroleptic malignant syndrome has been described in association with every antipsychotic drug. A similar syndrome has also been described as a result of the sudden withdrawal of anti-Parkinson's medications in patients with Parkinson's disease, as well as an "off"-period phenomenon in patients with Parkinson's disease who have the "on-off" response to levodopa. None of these patients were taking antipsychotic drugs. I agree that physicians should consider neuroleptic malignant syndrome as an explanation in patients with Parkinson's disease who are receiving clozapine and who have fever, altered mental status, and other signs of the syndrome. However, in most cases the explanation will be an infectious process, which, in patients with Parkinson's disease, may cause an identical syndrome. Joseph H. Friedman, M.D. Memorial Hospital of Rhode Island Pawtucket, RI 02860 Copyright © 1999 by the Massachusetts Medical Society. All rights reserved. -- Judith Richards, London, Ontario, Canada [log in to unmask] ^^^^ \ / \ | / Today’s Research \\ | // ...Tomorrow’s Cure \ | / \|/ `````