Monthly Administration of Long-Acting Injectable Risperidone and Striatal Dopamine D₂ Receptor Occupancy for the Management of Schizophrenia

Hiroyuki Uchida, M.D., Ph.D.; David C. Mamo, M.D., M.Sc., F.R.C.P.C.; Shitij Kapur, M.D., Ph.D., F.R.C.P.C.; Alain Labelle, M.D., F.R.C.P.C.; Chekkera Shammi, M.B.B.S., F.R.C.P.C.; Erik J. L. Mannaert, Ph.D.; Steve W. Mann, B.A.; and Gary Remington, M.D., Ph.D., F.R.C.P.C.

Objective: Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D₂ binding of long-acting risperidone administered intramuscularly once a month.

Method: Following at least 3 maintenance monthly injections of 50 mg long-acting risperidone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder underwent PET using [¹¹C]raclopride to measure D₂ binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation.

Results: The mean ± SD D₂ receptor occupancy was 56% ± 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D₂ occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean ± SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 ± 12.3 ng/mL (range, 5.7-40.8).

Conclusion: As with plasma levels, there was considerable variability in D₂ occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D₂ occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development.

Trial Registration: clinicaltrials.gov Identifier: NCT00236353

(J Clin Psychiatry 2008;69:1281-1286. Online Ahead of Print July 15, 2008.)

Received Dec. 11, 2007; accepted Jan. 30, 2008. From the Centre for Addiction and Mental Health, Toronto, Ontario, Canada (Drs. Uchida, Mamo, Kapur, Shammi, and Remington and Mr. Mann); the Department of Psychiatry, University of Toronto, Ontario, Canada (Drs. Uchida, Mamo, Kapur, Shammi, and Remington); the Institute of Psychiatry, De Crespigny Park, London, England (Dr. Kapur); Royal Ottawa Mental Health Center, Ottawa, Ontario, Canada (Dr. Labelle); and Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium (Dr. Mannaert).

The study was funded by Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.

The authors gratefully acknowledge Armando Garcia, B.Sc., for his technical assistance and Alan Wilson, Ph.D., for supervising the radiochemical syntheses (both are from the Centre for Addiction and Mental Health, Toronto, Ontario, Canada). They report no financial or other relationships with other organizations, including pharmaceutical companies.

Financial disclosure appears at the end of the article.

Corresponding author and reprints: David C. Mamo, M.D., M.Sc., F.R.C.P.C., Centre for Addiction and Mental Health, Schizophrenia Research Group, PET Centre, 250 College St., Toronto, Ontario, M5T1R8, Canada (e-mail: david_mamo@camh.net).