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Letter to the Editor   |    
Dr. Bilder and Colleagues Reply
ROBERT M. BILDER, Ph.D.; JAN VOLAVKA, M.D., Ph.D.; LESLIE CITROME, M.D., M.P.H.; PÀL CZOBOR, Ph.D.; MATTHEW HOPTMAN, Ph.D.; MIRANDA CHAKOS, M.D.; JOSEPH P. McEVOY, M.D.; THOMAS B. COOPER, M.A.; JEFFREY A. LIEBERMAN, M.D.
Am J Psychiatry 2002;159:2118-a-2119. doi:10.1176/appi.ajp.159.12.2118-a

To the Editor: We appreciate the comments of Drs. de Haan and van Amelsvoort regarding our recent article and are happy to expand on speculation regarding putative mechanisms underlying the observed treatment effects. First, we should highlight that our comments regarding the doses used in our study referred to clinical practice in the management of patients with suboptimal treatment response—not to putative levels of receptor occupancy—and readers should recognize the unique challenges inherent in treating this patient population.

Second, we believe that the contention of Drs. de Haan and van Amelsvoort that higher D2 receptor occupancy limited cognitive improvement is not supported by our data. Several facts argue against this interpretation. The mean dose levels (milligrams per day) achieved in the second period of the study (last observation carried forward) were 526.6 (SD=140.3) for clozapine, 30.4 (SD=6.6) for olanzapine, 11.6 (SD=3.2) for risperidone, and 25.7 (SD=5.7) for haloperidol, as described elsewhere (1). We thus believe that at follow-up all patients in the olanzapine, risperidone, and haloperidol groups likely had levels of D2 receptor occupancy well in excess of 80% and within the range at which D2 occupancy asymptotes (2). Therefore, the possible discrepancies between groups in D2 occupancy were probably subtler than suggested by Drs. de Haan and van Amelsvoort.

It is still conceivable that even subtle differences in overall D2 occupancy or other differences, such as rates of D2 receptor dissociation (2, 3), may help explain the differences in neurocognitive function observed in our study. If the differences between treatments were mediated primarily by differences in D2 receptor occupancy, changes in motor function (the strongest correlates of D2 receptor availability in the striatum [Volkow et al., 1998]) should have differed between groups, but this was not the case. Moreover, if neurocognitive improvement had been limited by high D2 occupancy, the clozapine-treated patients might have been predicted to show the greatest improvement, but they did not (despite good clinical efficacy).

We examined the effects of all antipsychotic doses and anticholinergic treatment effects (using benztropine doses and extrapyramidal symptom ratings) and found that these variables did not substantially influence our findings. In summary, we believe that our data do not support a simple explanation of neurocognitive improvement in terms of lower D2 receptor occupancy, and thus we highlighted in our Discussion not only the possible D2 receptor effects but also a broad range of other possible mechanisms that might be responsible, including serotonergic, adrenergic, cholinergic, histaminergic, and non-D2 dopaminergic receptor effects, that may have differed among treatments.

We believe further that our findings agree well with a larger literature, suggesting that attempts to explain complex clinical effects in terms of receptor binding profiles have been challenging at best (4). We agree that it would be valuable to conduct research comparing the neurocognitive effects of antipsychotic treatments, specifically targeting levels of D2 receptor occupancy, as an experimental manipulation. It is important to recognize, however, that any strategy of reducing D2 receptor occupancy for cognitive augmentation might best target patients with a history of treatment response more favorable than our patients showed to minimize the possible clinical risks of relapse.

Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Cooper TB, Chakos M, Lieberman JA: Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry  2002; 159:255-262
[PubMed]
[CrossRef]
 
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
[PubMed]
[CrossRef]
 
Kapur S, Remington G: Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry  2001; 50:873-883
[PubMed]
[CrossRef]
 
Citrome L, Volavka J: Optimal dosing of atypical antipsychotics in adults: a review of the current evidence. Harv Rev Psychiatry  2002; 10:280-291
[PubMed]
[CrossRef]
 
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References

Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Cooper TB, Chakos M, Lieberman JA: Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry  2002; 159:255-262
[PubMed]
[CrossRef]
 
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
[PubMed]
[CrossRef]
 
Kapur S, Remington G: Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry  2001; 50:873-883
[PubMed]
[CrossRef]
 
Citrome L, Volavka J: Optimal dosing of atypical antipsychotics in adults: a review of the current evidence. Harv Rev Psychiatry  2002; 10:280-291
[PubMed]
[CrossRef]
 
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