Comparable Dopamine 2 Receptor Occupancy

To the Editor: Robert M. Bilder, Ph.D., and colleagues (1) concluded in their article that “patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs” (p. 1018). Although their study was well conducted, we feel it is important to point out a limitation that, in our opinion, has been inadequately addressed.

In the Discussion section, the authors mentioned that in their study, “relatively high doses of all medications, particularly risperidone” (p. 1026), were used. The mean dose levels (milligrams per day) achieved during the first 8 weeks of the study were 20.2 (SD=1.0) of olanzapine, 8.3 (SD=2.2) of risperidone, and 19.6 (SD=2.0) of haloperidol. In our opinion, these dose levels do not reflect similar levels of dopamine D₂ receptor occupancy in each treatment group: about 77% for olanzapine (2), 83% for risperidone (3), and about 94% for haloperidol (2). We were not informed about the mean dose levels during the last weeks of the study; however, the ranges in which doses were allowed to vary also do not reflect comparable levels of D₂ receptor occupancy in each treatment group. Although the mean dose of risperidone may have been higher than considered optimal, the mean dose of haloperidol was much higher than optimal.

Because of these high doses, all patients taking haloperidol also received anticholinergic drugs that are known to lead to cognitive impairments. Given the relationship between dopaminergic neurotransmission and aspects of cognitive functioning (4), differences in D₂ receptor occupancy could partially explain the results achieved by Dr. Bilder et al. (1). The question of whether atypical antipsychotic drugs have cognitive benefits compared to typical antipsychotic drugs should be studied in treatment conditions with comparable D₂ receptor occupancy.