The New England Journal of Medicine -- August 5, 1999 -- Vol. 341, No.
6

Clozapine for Drug-Induced Psychosis in Parkinson's Disease
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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.
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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
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