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Clozapine and Typical Antipsychotics

To the Editor: Margaret G. Woerner, Ph.D., and colleagues reported the interesting observation that clozapine, in comparison with fluphenazine, was similarly efficacious for new-onset patients with schizophrenia or schizoaffective disorder (1). These results were similar to a recent study by Lieberman et al., which they referenced. They also pointed out that these results stand in contrast to the comparisons between clozapine and typical antipsychotics in treatment-resistant patients, which have found that clozapine results in dramatically higher response rates.

Although the lack of an advantage for clozapine in new-onset patients may be disappointing, these studies raise an interesting question: why is clozapine, compared with typical antipsychotics, dramatically more efficacious for treatment-resistant psychosis but merely similarly efficacious for new-onset schizophrenia? We would like to propose an answer to this question.

It long has been thought that patients taking long-term neuroleptic medication experience upregulation of dopamine D₂ receptors in their brains. For example, dopaminergic upregulation in the nigrostriatal tracts is thought to underlie the pathophysiology of tardive dyskinesia, and there now is long-awaited human data to support this idea (2). Typical antipsychotics may cause the upregulation because they dissociate slowly from the D₂ receptor (3), and the neurons respond by trying to overcome the chronic blockade. In contrast, clozapine, which is a fast dissociator (3), may allow endogenous dopamine to activate the receptor enough to avoid the problem of upregulation.

In addition to dopaminergic upregulation in the nigrostriatal tracts, many investigators have suggested that dopaminergic upregulation may occur in mesolimbic or mesocortical tracts, leading to a worsening of psychosis beyond the original level. This phenomenon has been called "tardive psychosis" or "supersensitivity psychosis" (4). Because increasing the dose of the neuroleptic eventually will make the problem worse, tardive psychosis may be a major form of treatment-resistant psychosis. Although not proven, the concept of tardive psychosis may provide heuristic value for understanding the effects of antipsychotic medication.

Clozapine, in comparison with typical antipsychotics, may be more efficacious for treatment-resistant psychosis because it allows the reversal of the dopaminergic upregulation in the mesolimbic or mesocortical tracts, leading to an improvement in tardive psychosis.

On the other hand, clozapine, in comparison with typical antipsychotics, may not be more efficacious for new-onset schizophrenia because these patients have not been medicated previously and do not have dopaminergic upregulation that can be reversed.

Although this explanation may not be the whole story (for example, clozapine probably also has direct therapeutic effects through the D₂ or other receptors), it is a parsimonious interpretation of these data, and it suggests ideas that can be tested empirically.

References

1. Woerner MG, Robinson DG, Alvir JMJ, Sheitman BB, Lieberman JA, Kane JM: Clozapine as a first treatment for schizophrenia. Am J Psychiatry 2003; 160:1514–1516[Abstract/Free Full Text]
2. Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P: Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl) 2000; 152:174–180[CrossRef][Medline]
3. Kapur S, Seeman P: Does fast dissociation from the dopamine D₂ receptor explain the action of atypical antipsychotics? a new hypothesis. Am J Psychiatry 2001; 158:360–369[Abstract/Free Full Text]
4. Chouinard G, Jones BD: Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 1980; 137:16–21[Abstract/Free Full Text]

This article has been cited by other articles:

				M Zink, A Kuwilsky, B Krumm, and H Dressing Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial J Psychopharmacol, May 1, 2009; 23(3): 305 - 314. [Abstract] [PDF]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by ROSS, D. E. Search for Related Content PubMed Citation Articles by ROSS, D. E. Neurotransmitters Atypical Neuroleptics Schizophrenia Spectrum Disorders

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