Ignite Creation Date:
2024-05-05 @ 12:02 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00225498
Status:
COMPLETED
Last Update Posted:
2015-09-10
First Post:
2005-09-21
Brief Title:
Neurocognitive Effects of Ziprasidone Relationship to Working Memory and Dopamine Blockade
Sponsor:
Northwell Health
Organization:
Northwell Health
Study Overview
Official Title:
Neurocognitive Effects of Ziprasidone Relationship to Working Memory and Dopamine Blockade
Status:
COMPLETED
Status Verified Date:
2015-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 ie 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 impairmentsUnfortunately 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 mgd with this dosage achieved within two weeks of initiation of drug treatment Target dose for olanzapine will be 20 mgd with this dosage achieved within two weeks of initiation of drug treatment Target dose for risperidone will be 4 mgd 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 patients 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 ERPs 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 ERPs 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 ERPs
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 ziprasidones 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 eg Farde et al1990 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 D2D3 receptor and is a commonly used radiotracer in normal controls and psychiatric patients eg 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 15 Tesla scanner
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 impairmentsUnfortunately 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 mgd with this dosage achieved within two weeks of initiation of drug treatment Target dose for olanzapine will be 20 mgd with this dosage achieved within two weeks of initiation of drug treatment Target dose for risperidone will be 4 mgd 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 patients 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 ERPs 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 ERPs 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 ERPs
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 ziprasidones 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 eg Farde et al1990 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 D2D3 receptor and is a commonly used radiotracer in normal controls and psychiatric patients eg 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 15 Tesla scanner
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None