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Clozapine Withdrawal: Serotonergic or Dopaminergic Mechanisms?-Reply

Philip Seeman, MD, PhD
Arch Gen Psychiatry. 1997;54(8):762-763. doi:10.1001/archpsyc.1997.01830200096015.
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The thoughtful comments of Dr Meltzer and Dr Baldessarini and colleagues are very important in advancing both the clinical practice and the therapeutic basis of antipsychotic medication. This letter provides some additional views and information that may be helpful in this discussion.

What is the basis of rapid relapse on clozapine withdrawal?

To explain those instances of rapid relapse of schizophrenic patients when clozapine therapy is withdrawn, Baldessarini et al1 give 3 reasonable hypotheses, as mentioned in Meltzer's letter.

To consider these different possible mechanisms, it is first important to note that the inhibition constant (ki) of a neuroleptic drug depends on the radioligand used to label the receptor.2,3 Clozapine, for example, at the D2 dopamine receptor has a ki of 390±70 nmol/L (mean[±SD]) using [3H]nemonapride, 186±40 nmol/L using [3H]spiperone, and 83±15 nmol/L using [3H]raclopride. Haloperidol at the D2 receptor has


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