Adjunctive Galantamine for 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.