24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study

• Status: Completed
• Trial end date: 2011-06-01
• Target enrollment: 0
• Participant gender: All

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. 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.

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre for Addiction and Mental Health
• Collaborator: Pfizer
• Treatments: Dopamine; Dopamine Agents; Ziprasidone

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• 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