Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia

Abstract

Background

Galantamine, a reversible cholinesterase inhibitor with effects on nicotinic receptors, has shown mixed effects on cognitive impairments in patients with schizophrenia. Given these mixed results we examined whether galantamine compared to adjunctive placebo may improve cognitive functions in patients treated concomitantly with a long acting atypical antipsychotic.

Method

The parent study was a 52-week double-blind, randomized study of treatment with long-acting injectable risperidone 25 mg or 50 mg every two weeks. Adjunctive galantamine or placebo treatment was administered from Month 6 to 12. Outcome measures were neurocognitive, psychopathology, social and quality of life functions. Patients were randomized to blinded galantamine up to 24 mg/day or matching placebo tablets. All patients were maintained on their randomized long-acting injectable risperidone regimen for the duration of the trial.

Results

32 patients were included in the intent-to-treat analysis. No statistically significant differences were found for Attention Vigilance, Declarative Memory, Processing Speed, Reasoning/Problem Solving, Working Memory domains and the Neurocognitive Composite Score. Group specific analysis showed a statistically significant group interaction (p = 0.043) with the Social Cognition domain showing in the galantamine group significantly lower scores at endpoint than placebo patients. The PANSS general psychopathology subscale showed significantly higher scores in the galantamine group at endpoint (p = 0.05). ANCOVA model for within treatment group comparisons showed a significant increase of 7.3 points for the total PANSS score for the galantamine group.

Conclusion

Galantamine showed no ameliorative effects on cognitive measures in this 6 month, double-blind study of patients with schizophrenia treated with an assured and stable antipsychotic medication delivery system. Galantamine may not be an appropriate augmentation agent for cognitive impairments in patients with schizophrenia at the dose used.

Introduction

There is broad consensus that cognitive deficits play a crucial role for functional outcomes of schizophrenia psychoses. Studies have shown that cognitive deficits, especially impairments in the domains of executive functions, memory and vigilance, are significant predictors of community outcome, social problem solving and skill acquisition (Green, 1996, Green et al., 2000). Psychopharmacological treatments with either conventional or second-generation antipsychotics have only modest effects on these cognitive impairments (Keefe et al., 2007). Therefore, various augmentation strategies for the treatment of cognitive deficits have been explored. Among these, cholinesterase inhibitors may be appropriate add on candidates, since muscarinic receptors are reduced in the brains of schizophrenic patients (Crook et al., 2001). Alterations in cholinergic function underlie some of the cognitive symptoms seen in Alzheimer's disease (Holt et al., 1999), which led to the hypothesis that some cognitive symptoms in patients with schizophrenia may have a similar underlying mechanism (Bierer, Haroutunian et al., 1995). Specifically, reduced muscarinic receptors, important to hippocampal functions such as learning and memory (Flynn et al., 1995, McAlonan et al., 1995) may contribute to the memory impairments seen in patients with schizophrenia.

Galantamine is a FDA approved compound for the treatment of dementia of the Alzheimer's type with a dual mode of action for the treatment of mild to moderate AD. It inhibits actetylcholinesterase and is an allosteric potentiator of the nicotinic receptor (Schrattenholz et al., 1996, Samochocki et al., 2003). Galantamine interacts with the nicotinic receptor at sites that are different from those for acetylcholine and nicotine, and it modulates ion channel activity and potentiates the actions of nicotinic receptors in the presence of acetylcholine. Galantamine provides the requisite cholinergic stimulation without producing desensitization. Furthermore, galantamine appears to more powerfully elevate frontal cortical dopamine levels compared to other cholinesterase inhibitors such as donepezil (Zhang et al., 2004, Geerts et al., 2005).

Galantamine has shown potential as an adjunctive treatment for schizophrenia in two open label trials (Allen & McEvoy, 2002, Buchanan et al., 2002) and two double blind trials (Schubert et al., 2006, Buchanan et al., 2008). Schubert et al. (2006) randomized seventeen patients stabilized on risperidone to receive treatment with galantamine up to 24 mg daily or placebo in addition to their established oral risperidone treatment (either 4 or 6 mg daily) and found significant improvements in cognitive performance as measured by the RBANS total scale score. Buchanan et al. (2008) more recently published results of a double blind randomized trial with galantamine up to 24 mg daily added to stable antipsychotic medication. While galantamine's effect for the overall composite cognitive score was not significant, follow-up analyses revealed that the subjects taking galantamine exhibited significant improvements in the WAIS-III digit symbol test. In contrast, the subjects taking placebo showed a significant improvement on the GDS distractibility test. There were no significant between-group differences in motor speed or working memory. In contrast, Lee et al. (2007) published a 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment compared to conventional antipsychotics for cognitive impairments in chronic schizophrenia. They found no statistically significant differences between the two groups for any of the cognitive measures except for the recognition score on the RCFT. Similarly, Dyer et al. (2008) also found no positive effects in a small double-blind trial comparing galantamine add on to placebo.

Given these mixed results and the rationale that cholinergic dysfunction and nicotinic acid receptor hypofunction may underlie some of the cognitive deficits seen in chronic schizophrenia, we examined the question whether galantamine may improve cognitive functions in stable patients treated with a long acting atypical antipsychotic. In contrast to previous studies, all patients were on assured atypical antipsychotic medication, and had first benefited from a stable atypical antipsychotic pre-treatment, which allowed optimal antipsychotic treatment of cognitive deficits. We were also interested to allow for sufficient time to permit cognitive changes associated with galantamine to emerge over time. Finally, this study included several measures of social function in order to examine any galantamine associated changes in the social function domains.