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

NCT00818298 | Completed

• 1 other identifier: 245/2008
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Schizophrenia; Schizoaffective Disorder

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; compliance; antipsychotic; pharmacotherapy; twice daily dosing; BID dosing; once daily dosing; od dosing; qd dosing; dosing schedule

Outcome Measures

Primary Outcomes (1)

• PET Scan

  intermittent

Study Arms (1)

1

EXPERIMENTAL

ziprasidone

Drug: ziprazidone

Interventions

ziprazidone DRUG

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.

1

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead
• Pfizer: collaborator

Study Sites (1)

Centre for Addiction and Mental Health - PET Centre

Toronto, Ontario, M5T 1R8, Canada

Location

Related Publications (1)

• 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.

  PMID: 23417515 DERIVED

Related Links

• 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 Centre

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; Dissociative Disorders; Patient Compliance

Interventions

ziprasidone

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Patient Acceptance of Health Care; Treatment Adherence and Compliance; Health Behavior; Behavior

Study Officials

• David Mamo, MD, MSc

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Psychiatrist

Study Record Dates

• First Submitted: January 6, 2009
• First Posted: January 7, 2009
• Study Start: January 1, 2009
• Primary Completion: January 1, 2011
• Study Completion: June 1, 2011
• Last Updated: July 9, 2012

Record last verified: 2012-07

Locations

CA (1)