Neurocognitive Effects of Ziprasidone: Relationship to Working Memory and Dopamine Blockade

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.

Inclusion Criteria:

- Diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder

- Ages 18 - 50

- Ability to provide written informed consent

- Brief Psychiatric Rating Scale (BPRS) total score > 40 and Clinical Global
Impressions (CGI) > 4 (moderately ill) and/or intolerant to current antipsychotic
drug treatment

Exclusion Criteria:

- History of prior treatment with ziprasidone

- History of medical condition that contraindicates ziprasidone treatment

- Treatment with depot antipsychotic medication in past 3 months

- Current diagnosis of alcohol or psychoactive substance dependence

- Impaired ability to provide written informed consent