Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Cognitive Dysfunction; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

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
      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:

        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 (i.e., P50) and attention (i.e., 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, i.e., 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.
    

Intervention name(s): galantamine
Intervention type(s): Drug
Intervention description(s): see arm/group description
Intervention MeSH terms: Galantamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: schizophrenia; acetylcholine; cognitive impairments; attention; processing speed; sensory gating; eye-tracking