SchizophreniaNCT00818298
24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study
A study testing ziprazidone in people with Schizophrenia and Schizoaffective Disorder, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial summary
Ziprasidone is recommended to be dosed twice daily for the treatment of schizophrenia, based on peripheral pharmacokinetics and a knowledge of its half life in plasma level (5-10 hours). However, the plasma kinetics do not always mirror what occurs in the brain. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder
- What is being tested?
- ziprazidone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteCanada
- Study dates
- Jan 2009to Jun 2011
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Age of 18 - 60 years.
- DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or psychotic disorder NOS
- In- or outpatients
- Physician-of-record's agreement to switch a previous antipsychotic to ziprasidone due to concern about tolerability/ineffectiveness/potential side effects of the previous drug when prescribed
Who cannot join
- Incapacity to provide consent to psychiatric treatment
- 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
- History of clinically significant physical illness or risk factors for drug-induced arrhythmias secondary to QT/QTc interval prolongation
Show all 19Show fewer
- Presence of risk factors for significant electrolyte disturbances, including diuretic therapy, protracted diarrhea/vomiting, water intoxication, eating disorder, and alcoholism
- A known history of QT prolongation (including congenital long QT syndrome), recent acute myocardial infarction or uncompensated heart failure
- Clinically significant ECG abnormality at screening including a QT/QTc of 450 msec and greater
- Being treated with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, methadone, or clozapine
- A previous history of intolerance or hypersensitivity to ziprasidone or lactose
- History of treatment with long-acting (depot) neuroleptic antipsychotic medication within 6 months
- Subjects at immediate risk of committing harm to self or others
- 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
- Size of head, neck, and body being unable to fit PET and MRI scanners
- Refusal to give consent to investigator to communicate with physician of record for the entire duration of the study
- Psychiatric concerns raised by the physician-of-record regarding participation in the study
Trial locations and contacts
1 site in 1 country.
Canada1 site
Centre for Addiction and Mental Health - PET Centre
Toronto, Ontario, M5T 1R8
About this study
Ziprasidone is recommended to be dosed twice daily for the treatment of schizophrenia, based on peripheral pharmacokinetics and a knowledge of its half life in plasma level (5-10 hours). However, the plasma kinetics do not always mirror what occurs in the brain. Antipsychotics with a high-affinity at D2 receptors attach for a relatively long time to their binding sites even after plasma levels declined. Based on this observation, another antipsychotic with a similar high-affinity at D2 receptors, ziprasidone, would also be expected to keep a sufficiently high D2 receptor occupancy even 24 hours after the last dose.
Given >60% D2 occupancy is required to maximize chance of therapeutic efficacy, it would be valuable to assess the D2 receptor occupancy 24 hours postdose to predict the therapeutic effects of once-daily regimen. In this study, we will measure D2 receptor occupancy 6, 12, and 24 hours after the last dose of ziprasidone in patients with schizophrenia.
The hypotheses are as follows: First, based on the known affinity of ziprasidone, the dopamine D2 occupancy 24 hours after the last administered dose of 80 mg will be >60%. Second, the difference in dopamine D2 occupancy between scan at 6 hours and 24 hours will be less than 15%. Third, the difference in dopamine D2 occupancy between scan at 12 hours and 24 hours will be less than 10%. Fourth, ED50 24 hours post dose will be higher that those 6 and 12 hours postdose.
Read the detailed description
PET studies have demonstrated a therapeutic window of dopamine D2 receptor occupancy (60-80%) in patients with schizophrenia. This observation has been used to predict the therapeutic dose range. Ziprasidone is recommended to be dosed twice daily, based on a knowledge of its half life in plasma level (5-10 hours). However, the plasma kinetics do not always mirror the central kinetics. Antipsychotics with a high-affinity at D2 receptors like risperidone attach for a relatively long time to their binding sites even after plasma levels declined. Based on this observation, another antipsychotic with a similar high-affinity at D2 receptors, ziprasidone, would also be expected to keep a sufficiently high D2 receptor occupancy even 24 hours after the last dose. Given >60% D2 occupancy is required to maximize chance of therapeutic efficacy, it would be valuable to assess the D2 receptor occupancy 24 hours postdose to predict the therapeutic effects of once-daily regimen.
To date, there is no published report to examine D2 receptor occupancy of ziprasidone 24 hours after the last dose in patients with schizophrenia. This study will provide information on 24-hour time course of D2 occupancy of this drug, with which the dissociation between peripheral and central kinetics of this drug will be discussed. The results of this study will also test the feasibility of once daily dosing of ziprasidone, which will directly serve to guide physicians in clinical practice. Furthermore, the findings of this study will elucidate the relationship between D2 receptor occupancy and long-term outcome.
The primary objective to determine the difference in dopamine D2 occupancy of ziprasidone at expected peak plasma levels (6 hours) and 12 and 24 hours postdose. The secondary objectives are to compare ED50 (the plasma levels of ziprasidone resulting in 50% maximal receptor occupancy) 24 hours postdose with those 6 and 12 hours postdose.
Male or female patients aged 18-60 years suffering from schizophrenia or schizoaffective disorder will be eligible to participate in this study (Visit 1). Following the baseline clinical assessments (Visit 2), previous antipsychotics will be discontinued while initiating ziprasidone at 20mg BID and subsequently increasing the dose to 60mg BID (Visit 2-4). For patients already treated with ziprasidone 60 mg BID, no titration will be necessary. If patients are on a lower dose, they will only be included in the study if the treating clinician recommends an increase of the dose to 60 mg BID. Participants will undergo a total of 3 raclopride PET scans (6, 12, and 24 hours postdose) (Visits 5-7) after they have been on ziprasidone for at least 14 days. Psychopathology and side effects will also be assessed on these PET visits. MRI scan will be completed when possible (Visit 8). In the subsequent 6-month follow-up phase (Visit 9-17), participants will have clinical assessments biweekly in the first 3 months and monthly in the following three months. The dose will be titrated according to clinical response and tolerability in an open-labeled manner to a maximum dose of 80 mg BID.
- Conditions
- Schizophrenia, Schizoaffective Disorder
- Being tested
- ziprazidone
- Keywords
- schizophrenia, schizoaffective disorder, PET Scan, ziprasidone, dopamine, D2, receptor, antagonist, occupancy, dissociation, affinity, constant, Ki, ligand, raclopride, half-life, striatal, plasma dynamics, central dynamics, plasma drug level
- Medical subject headings
- Schizophrenia, Psychotic Disorders, Dissociative Disorders, Patient Compliance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ziprazidoneDrug
Up to and including the time of the third PET scan, subjects will be titrated to 60 mg BID of ziprazidone. Thereafter they will receive 20-80 mg BID of ziprazidone, according to clinical effectiveness and side effects.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | ziprasidone Receives: Drug: ziprazidone |
What is being measured
The primary outcome is the main question the study is designed to answer.
PET Scan
Measured: intermittent
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2009 (estimated)
- Study startJan 2009
- Primary completionJan 2011
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer
- Responsible party
- Principal investigator, David Mamo, Centre for Addiction and Mental Health
- Investigators
- David Mamo, MD, MSc, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00818298
- Sponsor's protocol ID
- 245/2008
- Status last verified
- Jul 2012
- First submitted
- 6 Jan 2009
- Last updated
- 9 Jul 2012
- Results posted
- No
- Data monitoring committee
- No
Publications
Suzuki T, Graff-Guerrero A, Uchida H, Remington G, Caravaggio F, Borlido C, Pollock B, Mulsant B, Deluca V, Ismail Z, Mamo D. Dopamine D(2)/(3) occupancy of ziprasidone across a day: a within-subject PET study. Psychopharmacology (Berl). 2013 Jul;228(1):43-51. doi: 10.1007/s00213-013-3012-1. Epub 2013 Feb 17.
PubMed 23417515
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study
- ClinicalTrials.gov ID
- NCT00818298
- Acronym / sponsor ID
- 245/2008
- Conditions
- Schizophrenia, Schizoaffective Disorder
- Keywords
- schizophrenia, schizoaffective disorder, PET Scan, ziprasidone, dopamine, D2, receptor, antagonist
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Collaborators
- Pfizer
- Study start
- Jan 2009
- Primary completion
- Jan 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 7 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ziprasidone is recommended to be dosed twice daily for the treatment of schizophrenia, based on peripheral pharmacokinetics and a knowledge of its half life in plasma level (5-10 hours). However, the plasma kinetics do not always mirror what occurs in the brain. Antipsychotics with a high-affinity at D2 receptors attach for a relatively long time to their binding sites even after plasma levels declined. Based on this observation, another antipsychotic with a similar high-affinity at D2 receptors, ziprasidone, would also be expected to keep a sufficiently high D2 receptor occupancy even 24 hours after the last dose.
Given >60% D2 occupancy is required to maximize chance of therapeutic efficacy, it would be valuable to assess the D2 receptor occupancy 24 hours postdose to predict the therapeutic effects of once-daily regimen. In this study, we will measure D2 receptor occupancy 6, 12, and 24 hours after the last dose of ziprasidone in patients with schizophrenia.
The hypotheses are as follows: First, based on the known affinity of ziprasidone, the dopamine D2 occupancy 24 hours after the last administered dose of 80 mg will be >60%. Second, the difference in dopamine D2 occupancy between scan at 6 hours and 24 hours will be less than 15%. Third, the difference in dopamine D2 occupancy between scan at 12 hours and 24 hours will be less than 10%. Fourth, ED50 24 hours post dose will be higher that those 6 and 12 hours postdose.
Detailed description
PET studies have demonstrated a therapeutic window of dopamine D2 receptor occupancy (60-80%) in patients with schizophrenia. This observation has been used to predict the therapeutic dose range. Ziprasidone is recommended to be dosed twice daily, based on a knowledge of its half life in plasma level (5-10 hours). However, the plasma kinetics do not always mirror the central kinetics. Antipsychotics with a high-affinity at D2 receptors like risperidone attach for a relatively long time to their binding sites even after plasma levels declined. Based on this observation, another antipsychotic with a similar high-affinity at D2 receptors, ziprasidone, would also be expected to keep a sufficiently high D2 receptor occupancy even 24 hours after the last dose. Given >60% D2 occupancy is required to maximize chance of therapeutic efficacy, it would be valuable to assess the D2 receptor occupancy 24 hours postdose to predict the therapeutic effects of once-daily regimen.
To date, there is no published report to examine D2 receptor occupancy of ziprasidone 24 hours after the last dose in patients with schizophrenia. This study will provide information on 24-hour time course of D2 occupancy of this drug, with which the dissociation between peripheral and central kinetics of this drug will be discussed. The results of this study will also test the feasibility of once daily dosing of ziprasidone, which will directly serve to guide physicians in clinical practice. Furthermore, the findings of this study will elucidate the relationship between D2 receptor occupancy and long-term outcome.
The primary objective to determine the difference in dopamine D2 occupancy of ziprasidone at expected peak plasma levels (6 hours) and 12 and 24 hours postdose. The secondary objectives are to compare ED50 (the plasma levels of ziprasidone resulting in 50% maximal receptor occupancy) 24 hours postdose with those 6 and 12 hours postdose.
Male or female patients aged 18-60 years suffering from schizophrenia or schizoaffective disorder will be eligible to participate in this study (Visit 1). Following the baseline clinical assessments (Visit 2), previous antipsychotics will be discontinued while initiating ziprasidone at 20mg BID and subsequently increasing the dose to 60mg BID (Visit 2-4). For patients already treated with ziprasidone 60 mg BID, no titration will be necessary. If patients are on a lower dose, they will only be included in the study if the treating clinician recommends an increase of the dose to 60 mg BID. Participants will undergo a total of 3 raclopride PET scans (6, 12, and 24 hours postdose) (Visits 5-7) after they have been on ziprasidone for at least 14 days. Psychopathology and side effects will also be assessed on these PET visits. MRI scan will be completed when possible (Visit 8). In the subsequent 6-month follow-up phase (Visit 9-17), participants will have clinical assessments biweekly in the first 3 months and monthly in the following three months. The dose will be titrated according to clinical response and tolerability in an open-labeled manner to a maximum dose of 80 mg BID.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: ziprazidoneziprasidone |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Age of 18 - 60 years.
- DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or psychotic disorder NOS
- In- or outpatients
- Physician-of-record's agreement to switch a previous antipsychotic to ziprasidone due to concern about tolerability/ineffectiveness/potential side effects of the previous drug when prescribed
Key exclusion criteria (19 listed)
- Incapacity to provide consent to psychiatric treatment
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ziprazidoneUp to and including the time of the third PET scan, subjects will be titrated to 60 mg BID of ziprazidone. Thereafter they will receive 20-80 mg BID of ziprazidone, according to clinical effectiveness and side effects. | Drug | 1 |
Primary outcome
PET Scan
Time frame: intermittent
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2012.
- Derived from this study: PubMed 23417515Suzuki T, Graff-Guerrero A, Uchida H, Remington G, Caravaggio F, Borlido C, Pollock B, Mulsant B, Deluca V, Ismail Z, Mamo D. Dopamine D(2)/(3) occupancy of ziprasidone across a day: a within-subject PET study. Psychopharmacology (Berl). 2013 Jul;228(1):43-51. doi: 10.1007/s00213-013-3012-1. Epub 2013 Feb 17.
- Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching hospital. It is fully affiliated with the University of Toronto, and is a PAHO/WHO Collaborating CentreLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Mamo, MD, MSc principal investigator
Centre for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing ziprazidone in people with Schizophrenia and Schizoaffective Disorder, run by Centre for Addiction and Mental Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jul 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PET Scan (time frame: intermittent). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00818298, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2012.