Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
|First Received Date ICMJE||September 9, 2005|
|Last Updated Date||June 26, 2007|
|Start Date ICMJE||May 2002|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00176423 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia|
|Official Title ICMJE||Adjunctive Galantamine for Treatment of Cognitive Impairments in Patients With Schizophrenia|
The purpose of this study is to examine whether adjunctive galantamine is effective in the treatment of cognitive impairments in patients with schizophrenia.
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 Alzheimer’s 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: 43.1 6.6; 71% male; 78% caucasian; and mean (SD) duration of illness: 24.7 7.2. The mean (SD) olanzapine dose was 25.7 11.9 mg/day. 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 (ES)=.57) and manual dexterity (ES=.93) measures. There were moderate improvements on the verbal recall memory (ES=0.46) and processing speed (ES=0.48) 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: 9.3 3.8; week 6: 8.2 3.8; t=-1.55, df=14, p=.14) or negative symptom (mean(SD), baseline: 29.7 10.9; week 6: 30.0 12.6; t=0.15, df=14, p=.88) 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:
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:
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 Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
|Intervention ICMJE||Drug: galantamine|
|Study Arm (s)||Not Provided|
|Publications *||Buchanan RW, Conley RR, Dickinson D, Ball MP, Feldman S, Gold JM, McMahon RP. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry. 2008 Jan;165(1):82-9. Epub 2007 Nov 6.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||December 2006|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 60 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00176423|
|Other Study ID Numbers ICMJE||01T-411|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||University of Maryland|
|Information Provided By||University of Maryland|
|Verification Date||June 2007|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP