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Clozapine and Dopamine D₂ Blockade

To the Editor: Mirjam Talvik, M.D., et al. (1) asserted that there is "no support" for the regionally selective action of clozapine at dopamine D₂ receptors. Much evidence contradicts this view. Chronic treatment with clozapine (in contrast to treatment with classical antipsychotic drugs) up-regulates cortical D₂ receptors at doses that do not affect striatal receptors. Dopamine turnover is also increased by clozapine in the cortex but not in the striatum (2). Our [¹²³I]epidepride single photon emission computerized tomography (SPECT) studies have shown that clozapine preferentially blocks temporal cortical, over striatal D₂, receptors. D₂ occupancy by classical antipsychotic drugs has been shown as not regionally selective (3). Dr. Talvik and colleagues suggested methods limitations (which we discuss comprehensively) in our earlier studies, rendering these findings inconclusive. Nevertheless, they did not cite two short positron emission tomography (PET) reports. These independent studies, using fully validated, long-lived PET probes and quantitative single-tracer PET protocols—[⁷⁶Br]FLB 457 and [¹⁸F]epidepride—have substantiated our data for clozapine and olanzapine, respectively (4, 5). Dr. Talvik et al. (1) now supply findings to the contrary. The reason for discrepant results awaits elucidation. Possibilities include variability in ligand kinetics, the sensitivity of different ligands to regional dopamine concentrations, or receptor status. The majority of in vitro animal and human data still favor a selective action of clozapine at limbic cortical D₂ receptors. This issue remains unresolved in vivo, to be clarified by further studies.

References

1. Talvik M, Nordström A-L, Nyberg S, Olsson H, Halldin C, Farde L: No support for regional selectivity in clozapine-treated patients: a PET study with [¹¹C]raclopride and [¹¹C]FLB 457. Am J Psychiatry 2001; 158:926-930[Abstract/Free Full Text]
2. Lidow MS, Williams GV, Goldman-Rakic PS: The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 1998; 19:136-140[CrossRef][Medline]
3. Bigliani V, Pilowsky LS: The in vivo neuropharmacology of schizophrenia. Br J Psychiatry 1999; 174(suppl 38):23-34
4. Xiberas X, Martinot JL, Mallet L, Artiges E, Loc’H C, Maziere B, Paillere-Martinot ML: Extrastriatial and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 2001; 179:503-508[Abstract/Free Full Text]
5. Meltzer HY, Park S, Kessler R: Cognition, schizophrenia, and the atypical antipsychotic drugs. Proc Natl Acad Sci 1999; 96:13591-13593[Free Full Text]

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