1. ¹Center for Addiction & Mental Health, Toronto, ON, Canada
2. ²Department of Psychiatry, University of Toronto, Toronto, ON, Canada
3. ³Center for Neurosciences in Mental Disorders, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
4. ⁴Columbia Presbyterian Medical Center, New York, NY, USA
5. ⁵Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

Correspondence: Dr D McDonnell, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 6158, Indianapolis, IN 46285, USA, Tel: +1 317 651 1393, Fax: +1 317 277 5974, E-mail: mcdonnelldp@lilly.com

⁶Current affiliation: Clinical Pharmacology and Discovery Medicine Psychiatry, Hammersmith Hospital and Glaxo Smith Kline, London, UK.

Received 26 June 2006; Revised 5 December 2006; Accepted 27 February 2007; Published online 18 April 2007.

Abstract

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D₂ receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D₂ occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatment-emergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D₂ receptor occupancy, as measured by [¹¹C]-raclopride PET, was 69% on oral olanzapine (5–20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D₂ receptor occupancy and plasma olanzapine concentrations were significantly correlated (r=0.76, P0.001). OP depot resulted in mean D₂ receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.