Dopamine D2 and D3 Receptor Occupancy and Clinical Response in Older Patients With Schizophrenia
This study will provide information regarding dopamine D2/D3 occupancy related with clinical/adverse effects in older people with schizophrenia and schizoaffective disorder. The results of this study will also show an appropriate dose range in order to evade undesirable adverse effects while deriving therapeutic effects, which will directly serve to guide physicians in clinical practice. Furthermore, the findings of this study will elucidate mechanisms underlying older people's increased sensitivity to antipsychotic drugs. In addition, the contribution of D2 and D3 in mediating antipsychotic response will be contrasted, using 2 radiotracers, which has never been tested in an older population.
The hypotheses are as follows: First, clinical response (i.e., a ≥ 20% decrease in the Brief Psychiatric Rating Scale total score) will be achieved in older patients with occupancy that is lower than the threshold of 60% in historical young controls. Second, prolactin elevation and EPS will be detected in older patients with occupancies that are lower than the thresholds of 72 and 78% reported in historical young controls. Third, dopamine D2 receptor occupancy will be inversely correlated with subjective well-beings. Fourth, the binding potential and receptor occupancy will be at least 20% lower with [11C]-(+)-PHNO than with [11C]-raclopride in the caudate/putamen. Fifth, the binding of [11C]-(+)-PHNO in the globus pallidus will be higher than that of [11C]-raclopride.
|Study Design:||Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Dopamine D2 and D3 Receptor Occupancy and Clinical Response in Older Patients With Schizophrenia|
- The occupancy of risperidone at the D2 and D3 receptor, using [11C]-raclopride and [11C]-(+)-PHNO, respectively. [ Time Frame: Within 3 months of enrollment ] [ Designated as safety issue: No ]
- Plasma levels of risperidone and 9-hydroxyrisperidone [ Time Frame: Within 3 months of enrollment ] [ Designated as safety issue: No ]
|Study Start Date:||December 2008|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Experimental: Treatment with risperidone
Gradual titration of risperidone according to clinical response
Following the baseline clinical and cognitive assessments, risperidone will be initiated at 0.5-1.0 mg/day and subsequently increased by 0.25 - 1.0 mg on a weekly basis with the target of clinical stabilization (i.e. 20 or more % reduction in the total BPRS score) until a maximum dose of 4.0 mg/day is reached. To achieve this, a weekly assessment with BPRS will be performed. Physicians-of-record will be closely liaised with investigators. Dosage modification will be performed following this dosing schedule, however, this can be changed by treating physicians to meet clinical necessity. For example, in case psychotic symptoms are not controlled by this dosing schedule, facilitated dose increment will be allowed.
Positron Emission Tomography (PET) studies have demonstrated that a therapeutic window of dopamine D2/3 receptor occupancy (60-80%) is associated with clinical response in younger patients with schizophrenia. This observation has been used to predict the therapeutic dose range and contributed to current recommended antipsychotic doses. To date, there is no published report to examine D2/3 receptor occupancy associated with clinical response in older individuals with primary psychotic disorders. This has has impeded the implementation of treatment guidelines.
The investigators therefore propose a prospective study to assess dopamine D2 and D3 receptor occupancy following acute antipsychotic treatment in patients aged 50 and older with schizophrenia who do not currently receive antipsychotic treatment, using both [11C]-(+)-PHNO and [11C]-raclopride PET scans. Dopamine D2/3 receptor occupancy of risperidone that are associated with clinical effects will be measured, using PET, in older patients with schizophrenia. The investigators will also try to contrast the contribution of D2 and D3 in mediating antipsychotic response, using 2 radiotracers.
Our primary goal is to relate changes in clinical outcome, including subjective and objective clinical ratings, to dopamine D2 and D3 receptor occupancy in older patients with schizophrenia, and compare these results with the data for younger patients in the literature.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00825045
|Contact: Ariel Graff-Guerrero, MD, PhD||416-535-8501 ext email@example.com|
|Centre for Addiction and Mental Health||Recruiting|
|Toronto, Ontario, Canada, M5T 1R8|
|Sub-Investigator: Bruce Pollock, MD, PhD|
|Sub-Investigator: Benoit Mulsant, MD, MSc|
|Sub-Investigator: Shinichiro Nakajima, MD, PhD|
|Principal Investigator:||David Mamo, MD, MSc||Centre for Addiction and Mental Health|
|Principal Investigator:||Ariel Graff-Guerrero, MD, PhD||Centre for Addiction and Mental Health|