In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.
From the *Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; †Division of Clinical Pharmacology, Indiana University School of Medicine ‡Indiana Clinical and Translational Sciences Institute, Indianapolis, IN; §Geriatric Mental Health Program, Centre for Addiction and Mental Health; ∥Department of Psychiatry, University of Toronto; ¶Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; #Department of Psychiatry, Inokashira Hospital, Tokyo, Japan; and **Department of Psychiatry, University of Malta, Valetta, Malta.
Received May 8, 2012; accepted after revision November 9, 2012.
Reprints: Hiroyuki Uchida, MD, PhD, Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan (e-mail: firstname.lastname@example.org).
The study was supported by NIMH Contract #N01MH90001 to the University of North Carolina at Chapel Hill. This study was also supported by grant R01MH064173 from the National Institutes of Mental Health and was ancillary to Clinical Antipsychotic Trials of Intervention Effectiveness, N01MH90001, from the National Institute of Mental Health.
The present analysis was also funded by Grant-in-Aid for Young Scientists-B from the Ministry of Education, Culture, Sports, Science and Technology (HU), Takeda Science Foundation (HU), Kanae Foundation for the Promotion of Medical Science (HU), and Keio Gijuku Academic Development Funds (HU). The funding organizations had no role in the study design of the present analysis; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Disclaimer: This manuscript reflects the views of the authors and may not reflect the opinions or views of the CATIE-Sz study investigators or the NIH.