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To the Editor: We thank Drs. Meltzer and Shim for their thoughtful comments. Dr. Meltzer raises a valid issue that sertindole’s koff is rather close to the range for typical antipsychotics, although the drug is an atypical antipsychotic. This is a valid concern; however, it is not just the koff of the drug, but also its in vivo occupancy range, that is critical for atypicality. In that regard, sertindole at 8–24 mg/day occupies 61%–72% of D2 receptors (1, 2), which should give rise to response without extrapyramidal symptoms. Further, a patient taking sertindole, 20 mg/day, who had also received 100 mg of fluphenazine decanoate 52 days before brain imaging had 86% D2 occupancy. This patient exhibited akathisia (2), despite the fact that the patient would have had high 5-HT2 occupancy.
We do not suggest that 5-HT2 receptors make no contribution to the overall picture of atypicality. We propose that 5-HT2 receptors are not necessary for atypicality, as shown by studies of amisulpride, remoxipride, and now aripiprazole, and that they are not sufficient for atypicality, as shown by studies of MDL-100907 and fananserin. Even in drugs with mixed 5-HT2 and D2 action, D2 receptor affinity is the biggest factor for atypicality. In fact, Meltzer et al. (3) stated, "The low D2 affinity values of atypical drugs contribute more than their high 5-HT2 affinity values" (emphasis added); 64% of the typical-atypical difference, as revealed by discriminate function analysis, was accounted for by low affinity at the D2 receptor, and only 17% was accounted for by the addition of 5-HT2 receptor affinity (3).
Dr. Shim questions whether a slow kon and low affinity could also give rise to atypicality. The affinity of a drug is the ratio koff/kon (not kon/koff, as Dr. Shim suggests) (4). While current differences among atypical antipsychotics are driven mainly by koff, it is possible in theory that if koff were held constant, there could exist a low-affinity drug by virtue of a very slow kon. However, it is important to understand that kon and koff are rate constants (not the rates of association and dissociation). The rate of association is a function of kon multiplied by the concentration, whereas the rate of dissociation depends on koff alone. Since low-affinity drugs are given at much higher doses than high-affinity drugs, even if the kon (the association rate constant) were low, the rate of association would still be high because of the high concentration. This is why we think that low affinity and fast koff, and not low affinity and slow kon, is important to atypicality.
Thus, "atypicality" should be seen as a continuum rather than as a dichotomy. Antipsychotics become increasingly more atypical (i.e., have less chance of extrapyramidal symptoms) as their affinity at the D2 receptor decreases and their koff increases. We are not suggesting that antipsychotics with no D2 affinity are not possible, only that there are none at present.
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