Neurocognitive Effects of Ziprasidone: Relationship to Working Memory and Dopamine Blockade
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      Ziprasidone is a newer drug intended for the treatment of the symptoms of schizophrenia. This
      new drug may have an added benefit of being able to help with some of the difficulties in
      problem solving and memory that many patients with schizophrenia experience. The present
      study wants to look at ziprasidone and two other drugs frequently used to treat the symptoms
      of schizophrenia (risperidone and olanzapine) to see if problem solving and memory get better
      with ziprasidone treatment. Moreover, we will look at symptoms and how they change with
      treatment.
    

Detailed description: 
      Typical neuroleptics (i.e., haloperidol, chlorpromazine) are effective at ameliorating the
      positive psychotic symptoms of schizophrenia but are less efficacious in the treatment of
      negative symptoms, and there is limited evidence to support their ability to attenuate the
      cognitive dysfunction observed in schizophrenia (Meltzer et al. 1999). The primary mechanism
      through which typical neuroleptics achieve their effect is through dopamine (DA) blockade,
      but recent data suggest that DA blockade may be associated with diminished cognitive
      improvement despite effective clinical treatment. For example, in a recent molecular genetics
      study we have shown that subjects with greater DA availability display better cognitive
      performance on a task of executive functioning (Malhotra et al. in press). Thus, DA blockade
      may interfere with potential cognitive improvements associated with antipsychotic drug
      treatment.

      Atypical antipsychotics have a higher 5-hydroxytryptamine-2 (5-HT2) to D2 receptor binding
      ratio than typical agents, and therefore may be more effective in the treatment of cognitive
      impairments.Unfortunately, there is limited data on the cognitive properties of the new
      atypical agent, ziprasidone. In addition to having a high 5-HT2 to D2 receptor binding ratio,
      like the other atypicals, ziprasidone also has weak anticholinergic effects and minimal
      activity at muscarinic (M1), histaminergic (H1) and alpha1-adrenergic receptors (Casey, 2001)
      which may also beneficially influence cognitive performance (Byerly et al., 2001). Therefore,
      ziprasidone may have a unique ability to improve the cognitive performance of patients with
      schizophrenia.

      Evidence from neuropsychology (Gold, Carpenter, Randolph, Goldberg, & Weinberger, 1997),
      brain imaging (Buchsbaum et al., 1992) and electrophysiology (Shelley et al., 1996) all
      converge to implicate impaired working memory (WM) function in schizophrenia. As such, the
      neural substrates that subsume WM, the temporal course of information flow through this
      system, and importantly whether ziprasidone intervention can aid in normalization of
      function, are critical issues in schizophrenia research. In the present study, we propose to
      integrate:

        1. A novel cognitive electrophysiological assessment specifically designed to detect subtle
           differences in the stages of information processing where WM deficits become manifest.

        2. A state of the art computerized neuropsychological battery that assesses WM and other
           cognitive domains.

        3. Positron emission tomography (PET) of dopamine D2 receptor occupancy.

      These methods will provide a means to specifically characterize the effects of ziprasidone on
      cognitive performance and dopamine blockade in patients with schizophrenia. The primary
      hypotheses to be tested are 1) that ziprasidone treatment will be associated with
      improvements in WM and, 2) WM performance will be associated with D2 occupancy in ziprasidone
      treated patients.

      Data will be collected in the context of an open label, randomized clinical trial comparing
      the efficacy of ziprasidone to the atypical agents, olanzapine and risperidone. This trial
      will compare the effects of ziprasidone with risperidone or olanzapine on positive and
      negative psychotic symptoms, mood, and side effects, as well as provide the first
      comprehensive data on the effects of these drugs on information processing, working memory
      and dopamine D2 receptor occupancy. These pilot data will allow us to test the hypotheses
      that 1) ziprasidone will be associated with improvements in information processing and
      working memory. 2) ziprasidone will be associated with improvements in psychotic symptoms and
      mood. 3) ziprasidone associated improvements in cognition and behavioral symptoms will be at
      least as significant as those associated with treatment with olanzapine or risperidone.
      Finally, we will examine the relative D2 occupancies of these drugs using PET

      Subjects will be randomized to drug treatment with ziprasidone, olanzapine or risperidone,
      such that 30 subjects will receive ziprasidone, and 30 will receive either risperidone or
      olanzapine. Patients who enter the study on risperidone or with a history of risperidone
      treatment within the past 6 months will be randomized to either ziprasidone or olanzapine.
      Patients entering on olanzapine or with a history of olanzapine treatment within the past 6
      months will be randomized to either ziprasidone or risperidone. Patients on other
      medications, with no history of olanzapine, risperidone or ziprasidone treatment, will be
      will be randomized to any of the three drugs. Patients treated with ziprasidone, at any time
      in the past, will be excluded. The final groups will consist of 30 subjects receiving
      ziprasidone, and 30 subjects receiving risperidone or olanzapine depending on their treatment
      history. Target dose for ziprasidone will be 160 mg/d with this dosage achieved within two
      weeks of initiation of drug treatment. Target dose for olanzapine will be 20 mg/d with this
      dosage achieved within two weeks of initiation of drug treatment. Target dose for risperidone
      will be 4 mg/d with this dosage achieved within two weeks of initiation of drug treatment.
      Dosage will be fixed at the target dose for the remainder of the trial. Patients who cannot
      tolerate the target dose will continue in the study, if feasible, and maintained at a lower
      dose. Extra-pyramidal side effects, if any, will be treated with benztropine as needed.
      Concomitant medications will not be permitted.

      Patients will be re-assessed every month following the initiation of treatment for the 3
      months following baseline. Subjects will be re-assessed with the information processing
      assessment, neurocognitive battery , behavioral and side effect ratings, and information
      about drug dosage and compliance with treatment at each visit. Moreover, subjects will be
      asked to participate in a PET study of dopamine D2 occupancy at the third month visit .
      Trained raters blind to patient's drug condition will conduct behavioral and side effect
      ratings.

      The cognitive electrophysiological assessment will employ a parametrically designed A-X
      Continuous Performance Test (AX-CPT) task with increasing levels of difficulty proven to
      elicit traditional behavioral measures of WM function such as reaction time (RT) and accuracy
      (Bates et al, 2000). This paradigm provides a means to evaluate the efficacy of ziprasidone
      treatment in remitting cognitive dysfunction in patients with schizophrenia. However,
      accuracy and RT only index the final motor response and do not capture information about
      antecedent stages of information processing. Visual evoked response potentials (ERP's) will
      be collected while subjects perform the AX-CPT tasks allowing for assessment of early sensory
      registration of stimuli (N1), and the time course of subsequent cognitive analysis (P3)
      (Bates et al, 2000). This methodology will facilitate assessment of the stage of information
      processing where schizophrenia deficits in WM become manifest. Topographical analysis will
      assess whether schizophrenia patients display amplitude attenuation over scalp sites
      correlating to prefrontal cortex while performing the WM tasks, and if functioning improves
      over the course of ziprasidone intervention.

      Visual ERP's will be employed for the following reasons. Auditory P3 attenuation has proven
      not to change with administration of typical neuroleptics in longitudinal designs
      (Pfefferbaum et al., 1989). Visual P3, however, may provide a more sensitive measure for
      detecting changes in illness severity as it is though to be related more to clinical state
      (Duncan, 1988). The proposed study could possibly reveal improved functioning that has gone
      undetected in studies employing auditory ERPs. The proposed study would be the first to
      assess the longitudinal effects of ziprasidone treatment on WM functioning using
      parametrically altered WM tasks while concurrently obtaining visual ERP's.

      The neurocognitive battery will employ tasks of WM, executive functioning, memory, motor
      function and verbal fluency. This paradigm provides a means to evaluate the effects of
      ziprasidone treatment in improving cognitive function across multiple domains in patients
      with schizophrenia.

      PET imaging with [carbon-11 (11C)]-raclopride provides an in vivo measure of dopamine D2
      receptor occupancy during ziprasidone treatment and will be used to assess the relationship
      between ziprasidone's D2 occupancy and measures of WM and cognition. It is hypothesized that
      moderate D2 occupancy is associated with clinical improvement and the degree of occupancy
      will be correlated with WM performance. The [11C]-raclopride studies will be performed in a
      subset of 30 patients after twelve weeks of ziprazidone treatment. As [11C]-raclopride
      studies of the D2 receptor have consistently shown comparable levels of binding in controls
      and untreated patients with schizophrenia (e.g. Farde et al.1990), the treated patients can
      be compared to the untreated controls. We are using this approach because it may not be
      feasible to scan the patients in the unmedicated state. It is extremely difficult to justify
      a two to four week drug free period that would be needed to assess baseline D2 receptor
      availability.

      The PET studies will be performed at the PET Center at the North Shore University Hospital.
      On the day of the PET scan an intravenous line will be placed in an antecubital vein for
      radiotracer administration, and to draw a plasma drug level at the time of scanning. The
      subject will be positioned in the General Electric (GE) Advance scanner. A fifteen-minute
      transmission scan will be obtained. Then, 15 millicuries (mCi) of [11C]-raclopride will be
      injected. Scanning will begin immediately after radiotracer injection and will last for 60
      minutes.

      Radiotracer: [11C]-raclopride is a relatively selective radiotracer for the dopamine (D2/D3)
      receptor and is a commonly used radiotracer in normal controls and psychiatric patients (e.g.
      Smith et al., 1995, Volkow et al., 1994, Farde et al., 1990).

      An magnetic resonance (MR) scan will be performed to rule out structural brain pathology, for
      image registration with the PET scan and correction for the effects of cerebral atrophy. The
      MR scans will be performed with a GE Signa 1.5 Tesla scanner.
    

Intervention name(s): ziprasidone vs risperidone or olanzapine
Intervention type(s): Drug
Intervention description(s): ziprasidone target dose is 160 mg/day risperidone target dose is 4 mg/day olanzapine target dose is 20 mg/day
Other intervention name(s): Geodon vs Risperdal or Zyprexa
Intervention MeSH terms: Olanzapine; Risperidone; Ziprasidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment