Dopamine D2 and D3 Receptor Occupancy and Clinical Response in Older Patients With Schizophrenia

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Centre for Addiction and Mental Health
Sponsor:
Information provided by (Responsible Party):
Ariel Graff, Centre for Addiction and Mental Health
ClinicalTrials.gov Identifier:
NCT00825045
First received: January 16, 2009
Last updated: March 19, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention
Schizophrenia
Schizoaffective Disorder
Schizophreniform Disorder
Drug: risperidone

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Centre for Addiction and Mental Health:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • Plasma levels of risperidone and 9-hydroxyrisperidone [ Time Frame: Within 3 months of enrollment ] [ Designated as safety issue: No ]

Estimated Enrollment: 10
Study Start Date: December 2008
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: risperidone
    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.
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age of 50 and older at time of scanning
  • Inpatients or outpatients
  • DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder
  • Having NOT been treated with oral antipsychotic treatment for at least 2 weeks or long-acting antipsychotics for at least 6 months (Please note that patients will not be withdrawn from antipsychotic medications for the purpose of meeting inclusion criteria for this study).

Exclusion Criteria:

  • Known history of intolerance or inefficacy to risperidone
  • Participation in this study would result in exceeding the annual radiation dose limits (20 mSv) for human subjects participating in research studies.
  • Substance abuse or dependence (within past six months)
  • Positive urine drug screen
  • Positive serum pregnancy test at screening or positive urine pregnancy test before PET scan
  • Metal implants or a pace-maker that would preclude the MRI scan
  • History of head trauma resulting in loss of consciousness >30 minutes that required medical attention
  • Unstable physical illness or significant neurological disorder including a seizure disorder
  • Inappropriate size of head, neck, and body to be able to fit the PET and MRI scans
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00825045

Contacts
Contact: Ariel Graff-Guerrero, MD, PhD 416-535-8501 ext 34834 ariel.graff@camh.ca

Locations
Canada, Ontario
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         
Sponsors and Collaborators
Centre for Addiction and Mental Health
Investigators
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
  More Information

Additional Information:
No publications provided

Responsible Party: Ariel Graff, MD, PhD, Centre for Addiction and Mental Health
ClinicalTrials.gov Identifier: NCT00825045     History of Changes
Other Study ID Numbers: 270/2008
Study First Received: January 16, 2009
Last Updated: March 19, 2014
Health Authority: Canada: Health Canada

Keywords provided by Centre for Addiction and Mental Health:
dopamine
D2
D3
caudate
putamen
globus pallidus
antipsychotic
risperidone
geriatric
Brief Psychiatric Rating Scale
PET
radiotracer
[11C]-(+)-PHNO
[11C]-raclopride

Additional relevant MeSH terms:
Disease
Psychotic Disorders
Schizophrenia
Mental Disorders
Pathologic Processes
Schizophrenia and Disorders with Psychotic Features
Dopamine
Dopamine Agents
Risperidone
Antipsychotic Agents
Autonomic Agents
Cardiotonic Agents
Cardiovascular Agents
Central Nervous System Agents
Central Nervous System Depressants
Dopamine Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Psychotropic Drugs
Serotonin Agents
Serotonin Antagonists
Sympathomimetics
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on October 21, 2014