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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00825045
Recruitment Status : Recruiting
First Posted : January 19, 2009
Last Update Posted : November 30, 2017
Information provided by (Responsible Party):
Ariel Graff, Centre for Addiction and Mental Health

Brief Summary:

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 or disease Intervention/treatment Phase
Schizophrenia Schizoaffective Disorder Schizophreniform Disorder Drug: risperidone Not Applicable

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Dopamine D2 and D3 Receptor Occupancy and Clinical Response in Older Patients With Schizophrenia
Actual Study Start Date : December 2008
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: Treatment with risperidone
Gradual titration of risperidone according to clinical response
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.

Primary Outcome Measures :
  1. The occupancy of risperidone at the D2 and D3 receptor, using [11C]-raclopride and [11C]-(+)-PHNO, respectively. [ Time Frame: Within 3 months of enrollment ]

Secondary Outcome Measures :
  1. Plasma levels of risperidone and 9-hydroxyrisperidone [ Time Frame: Within 3 months of enrollment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00825045

Contact: Ariel Graff-Guerrero, MD, PhD 416-535-8501 ext 34834

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
Principal Investigator: Ariel Graff-Guerrero, MD, PhD Centre for Addiction and Mental Health

Additional Information:
Responsible Party: Ariel Graff, MD, PhD, Centre for Addiction and Mental Health Identifier: NCT00825045     History of Changes
Other Study ID Numbers: 270/2008
First Posted: January 19, 2009    Key Record Dates
Last Update Posted: November 30, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Ariel Graff, Centre for Addiction and Mental Health:
globus pallidus
Brief Psychiatric Rating Scale

Additional relevant MeSH terms:
Psychotic Disorders
Pathologic Processes
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Dopamine Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Cardiotonic Agents
Autonomic Agents
Peripheral Nervous System Agents
Protective Agents