Therapeutic Window for Striatal Dopamine D2/3 Receptor Occupancy in Older Patients with Schizophrenia: A Pilot PET Study

Objective: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D-2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D-2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. Design: Open-label intervention. Setting: Centre for Addiction and Mental Health, Toronto. Participants: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. Intervention: A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. Measurements: Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [C-11] raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. Results: Nine subjects (mean +/- SD age: 58 +/- 7 years; mean +/- SD baseline risperidone dose: 3.4 +/- 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D-2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D-2/3 RRO. Conclusion: EPS diminished less than 70% D-2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.