24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

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.
    

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.
    

Intervention name(s): ziprazidone
Intervention type(s): Drug
Intervention description(s): 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.
Intervention MeSH terms: Ziprasidone
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
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