Ignite Creation Date:
2024-05-05 @ 11:54 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00176423
Status:
COMPLETED
Last Update Posted:
2020-12-16
First Post:
2005-09-09
Brief Title:
Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
Sponsor:
University of Maryland Baltimore
Organization:
University of Maryland Baltimore
Study Overview
Official Title:
Adjunctive Galantamine for Treatment of Cognitive Impairments in Patients With Schizophrenia
Status:
COMPLETED
Status Verified Date:
2020-10
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:
The purpose of this study is to examine whether adjunctive galantamine is effective in the treatment of cognitive impairments in patients with schizophrenia
Detailed Description:
Patients with schizophrenia are characterized by a broad range of neurocognitive abnormalities These include impairments in attention eye-tracking visual and verbal memory working memory processing speed and sensory gating as measured by P50 These impairments are major determinants of poor functional outcome in patients with schizophrenia Conventional antipsychotics have limited effects on these impairments Second generation antipsychotics SGAs may have modest benefits for cognitive function but whether this represents a direct cognitive enhancing effect has not been established Regardless patients continue to exhibit pronounced cognitive impairments despite adequate new generation antipsychotic treatment Adjunctive pharmacotherapy may offer a viable approach for the treatment of cognitive impairments Adjunctive agents can be used to modulate specific neurotransmitter systems that are hypothesized to be involved in the pharmacology of cognitive functions
Acetylcholine acts at muscarinic and nicotinic cholinergic receptors These receptors are broadly distributed through the brain including the neocortex hippocampus and basal ganglia Cholinergic mechanisms have been implicated in the regulation of attention memory processing speed and sensory gating processes processes which are impaired in patients with schizophrenia Nicotine has previously been shown to improve sensory gating as measured by P50 and eye-tracking in patients with schizophrenia The gene for the alpha-7 nicotinic receptor which is hypothesized to be the nicotinic receptor involved in sensory gating regulation has also been shown to be linked to schizophrenia
Galantamine Trade name Reminyl is a new FDA-approved selective acetylcholinesterase inhibitor AChEI which may also allosterically modulate nicotinic receptors enhance receptor sensitivity and increase nicotinic receptor density Galantamine is marketed by Janssen Research Foundation In animal models of aging galantamine enhanced long-term potentiation ameliorated learning impairments and elevated the number of nicotinic receptors in the hippocampus and neocortex In placebo-controlled studies galantamine has been shown to not only delay deterioration but to improve cognitive function in patients with Alzheimers disease There is also preliminary evidence that galantamine may ameliorate positive psychotic symptoms in these patients
AChEIs have not been extensively studied in patients with schizophrenia We have conducted a 6-week open-labeled pilot study of adjunctive donepezil in patients treated with olanzapine for a minimum of 6 months Fifteen patients entered the study and 14 patients completed the study One patient withdrew with a complaint of sedation The demographic characteristics of the patients who completed the study were mean SD age 431 66 71 male 78 caucasian and mean SD duration of illness 247 72 The mean SD olanzapine dose was 257 119 mgday Two patients were receiving benzodiazepines two were receiving antidepressants and one was receiving valproic acid Donepezil resulted in a modest improvement in sensory gating Nine patients had abnormal P50 at baseline which normalized for five patients following treatment Donepezil had a more pronounced effect on neuropsychological test performance with large and significant effect sizes observed for the visual memory effect size ES57 and manual dexterity ES93 measures There were moderate improvements on the verbal recall memory ES046 and processing speed ES048 measures The only cognitive measure that did not change with treatment was a measure of attention There were no significant changes in either positive symptom mean SD baseline 93 38 week 6 82 38 t-155 df14 p14 or negative symptom meanSD baseline 297 109 week 6 300 126 t015 df14 p88 measures
The results of this study suggest that adjunctive AChEIs may be an effective treatment for cognitive impairments in patients with schizophrenia Moderate to large effect size improvements were observed on verbal and visual memory processing speed and manual dexterity measures Patients exhibited a greater than 20 increase in suppression of their P50 response to repeated auditory stimuli There was no effect of donepezil on a measure of attention Donepezil was well tolerated only one patient dropped out of the study and nine of the remaining subjects chose to continue on the drug beyond the protocol An important aspect of the study was that cognitive function improvement occurred in the context of concurrent olanzapine treatment which is reported to improve P50 and cognitive function Purdon et al 2000 Light et al 2000 Thus donepezil was able to further enhance cognitive function in patients who may have already benefitted from olanzapine treatment
The primary study objectives are
1 To examine whether adjunctive galantamine is more effective than placebo for neuropsychological measures of attention verbal and visual memory working memory processing speed and manual dexterity
2 To examine whether adjunctive galantamine is more effective than placebo for evoked potential measures of sensory gating ie P50 and attention ie P300 and Gamma Band Response GBR and smooth pursuit eye movement
We hypothesize that galantamine will have a significant benefit for these cognitive behaviors based on the role of acetylcholine in the regulation of these behaviors our pilot study with donepezil which demonstrated that AChEIs may have a beneficial effect for verbal and visual memory processing speed and manual dexterity and previous studies that have shown acute nicotine administration to normalize P50 and eye-tracking in patients with schizophrenia
The secondary study objectives are
1 To examine whether adjunctive galantamine is more effective than placebo for positive symptoms and negative symptom measures
2 To examine whether adjunctive galantamine is more likely than placebo to cause nausea vomiting diarrhea anorexia weight loss or dizziness ie common side effects associated with AChEI treatment
3 To examine whether galantamine is more likely than placebo to cause an increase in either extrapyramidal symptoms or dyskinetic movements
4 To examine whether galantamine is more effective than placebo for reducing smoking behavior
We hypothesize that there will not be a significant difference between galantamine and placebo for positive and negative symptoms based on our donepezil pilot study We hypothesize that galantamine will be associated with an increased incidence of AChEI associated side effects We hypothesize that there will not be a significant difference between galantamine and placebo for either extrapyramidal symptoms or dyskinetic movements
Study Design and Methods The proposed study is a randomized parallel group double-blind comparison of adjunctive galantamine or placebo The sample will consist of 90 clinically stable inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder There will be a 2-week stabilization phase a 12-week treatment phase and an optional 6-month open-label phase In the 2-week stabilization phase patients will undergo baseline symptom medical safety antipsychotic level and neurocognitive assessments In the 12-week treatment phase patients will be randomized to either galantamine or placebo Patients will receive biweekly symptom side effect and vital sign assessments At the end of study 12 weeks laboratory tests EKG antipsychotic levels and neurocognitive assessments will be repeated Patients will be monitored at the 3-month and 6-month points of the open-labeled phase during which they will receive laboratory tests EKG and side effect review At the end of the 6-month open-labeled phase patients will again be asked to participate in symptom ratings and neuropsychological tests
Acetylcholine acts at muscarinic and nicotinic cholinergic receptors These receptors are broadly distributed through the brain including the neocortex hippocampus and basal ganglia Cholinergic mechanisms have been implicated in the regulation of attention memory processing speed and sensory gating processes processes which are impaired in patients with schizophrenia Nicotine has previously been shown to improve sensory gating as measured by P50 and eye-tracking in patients with schizophrenia The gene for the alpha-7 nicotinic receptor which is hypothesized to be the nicotinic receptor involved in sensory gating regulation has also been shown to be linked to schizophrenia
Galantamine Trade name Reminyl is a new FDA-approved selective acetylcholinesterase inhibitor AChEI which may also allosterically modulate nicotinic receptors enhance receptor sensitivity and increase nicotinic receptor density Galantamine is marketed by Janssen Research Foundation In animal models of aging galantamine enhanced long-term potentiation ameliorated learning impairments and elevated the number of nicotinic receptors in the hippocampus and neocortex In placebo-controlled studies galantamine has been shown to not only delay deterioration but to improve cognitive function in patients with Alzheimers disease There is also preliminary evidence that galantamine may ameliorate positive psychotic symptoms in these patients
AChEIs have not been extensively studied in patients with schizophrenia We have conducted a 6-week open-labeled pilot study of adjunctive donepezil in patients treated with olanzapine for a minimum of 6 months Fifteen patients entered the study and 14 patients completed the study One patient withdrew with a complaint of sedation The demographic characteristics of the patients who completed the study were mean SD age 431 66 71 male 78 caucasian and mean SD duration of illness 247 72 The mean SD olanzapine dose was 257 119 mgday Two patients were receiving benzodiazepines two were receiving antidepressants and one was receiving valproic acid Donepezil resulted in a modest improvement in sensory gating Nine patients had abnormal P50 at baseline which normalized for five patients following treatment Donepezil had a more pronounced effect on neuropsychological test performance with large and significant effect sizes observed for the visual memory effect size ES57 and manual dexterity ES93 measures There were moderate improvements on the verbal recall memory ES046 and processing speed ES048 measures The only cognitive measure that did not change with treatment was a measure of attention There were no significant changes in either positive symptom mean SD baseline 93 38 week 6 82 38 t-155 df14 p14 or negative symptom meanSD baseline 297 109 week 6 300 126 t015 df14 p88 measures
The results of this study suggest that adjunctive AChEIs may be an effective treatment for cognitive impairments in patients with schizophrenia Moderate to large effect size improvements were observed on verbal and visual memory processing speed and manual dexterity measures Patients exhibited a greater than 20 increase in suppression of their P50 response to repeated auditory stimuli There was no effect of donepezil on a measure of attention Donepezil was well tolerated only one patient dropped out of the study and nine of the remaining subjects chose to continue on the drug beyond the protocol An important aspect of the study was that cognitive function improvement occurred in the context of concurrent olanzapine treatment which is reported to improve P50 and cognitive function Purdon et al 2000 Light et al 2000 Thus donepezil was able to further enhance cognitive function in patients who may have already benefitted from olanzapine treatment
The primary study objectives are
1 To examine whether adjunctive galantamine is more effective than placebo for neuropsychological measures of attention verbal and visual memory working memory processing speed and manual dexterity
2 To examine whether adjunctive galantamine is more effective than placebo for evoked potential measures of sensory gating ie P50 and attention ie P300 and Gamma Band Response GBR and smooth pursuit eye movement
We hypothesize that galantamine will have a significant benefit for these cognitive behaviors based on the role of acetylcholine in the regulation of these behaviors our pilot study with donepezil which demonstrated that AChEIs may have a beneficial effect for verbal and visual memory processing speed and manual dexterity and previous studies that have shown acute nicotine administration to normalize P50 and eye-tracking in patients with schizophrenia
The secondary study objectives are
1 To examine whether adjunctive galantamine is more effective than placebo for positive symptoms and negative symptom measures
2 To examine whether adjunctive galantamine is more likely than placebo to cause nausea vomiting diarrhea anorexia weight loss or dizziness ie common side effects associated with AChEI treatment
3 To examine whether galantamine is more likely than placebo to cause an increase in either extrapyramidal symptoms or dyskinetic movements
4 To examine whether galantamine is more effective than placebo for reducing smoking behavior
We hypothesize that there will not be a significant difference between galantamine and placebo for positive and negative symptoms based on our donepezil pilot study We hypothesize that galantamine will be associated with an increased incidence of AChEI associated side effects We hypothesize that there will not be a significant difference between galantamine and placebo for either extrapyramidal symptoms or dyskinetic movements
Study Design and Methods The proposed study is a randomized parallel group double-blind comparison of adjunctive galantamine or placebo The sample will consist of 90 clinically stable inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder There will be a 2-week stabilization phase a 12-week treatment phase and an optional 6-month open-label phase In the 2-week stabilization phase patients will undergo baseline symptom medical safety antipsychotic level and neurocognitive assessments In the 12-week treatment phase patients will be randomized to either galantamine or placebo Patients will receive biweekly symptom side effect and vital sign assessments At the end of study 12 weeks laboratory tests EKG antipsychotic levels and neurocognitive assessments will be repeated Patients will be monitored at the 3-month and 6-month points of the open-labeled phase during which they will receive laboratory tests EKG and side effect review At the end of the 6-month open-labeled phase patients will again be asked to participate in symptom ratings and neuropsychological tests
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