In this eight-week, double-blind, placebo-controlled trial of galantamine augmentation, at a maximum dose of 32 mg/day, of antipsychotic treatment in stable outpatient nonsmokers with schizophrenia, the effect of galantamine was inferior to placebo on attention as assessed by the CPT-IP d’ (signal to noise detection), on inhibitory control as assessed by the Stroop Interference T-score, and on one measure of memory, the LNS without reordering. There was also a trend for galantamine to be inferior to placebo for random errors in the CPT-IP measure of attention. Galantamine did not separate from placebo on measures of working memory or psychomotor speed, as assessed with the LNS with reordering and Grooved Pegboard. Galantamine also did not separate from placebo on clinical measures, although the study may have been underpowered to detect an effect on negative symptoms.
These findings are consistent with a recent report of a large, randomized, placebo-controlled study of donepezil for cognitive performance in schizophrenia (Keefe et al., 2007
) in which few beneficial effects of donepezil were observed and placebo was superior to the cholinesterase inhibitor in some cognitive measures. The present study fails to replicate reports of beneficial effects of lower doses of galantamine (16–24 mg/day) in schizophrenia in case series (Allen and McEvoy, 2002
; Bora et al., 2005
; Rosse and Deutsch, 2002
) and in one small, double-blind, placebo-controlled trial in patients taking risperidone (Schubert et al., 2006
At low doses, galantamine acts as an allosteric potentiator of nAChRs, increasing the probability of agonist induced nAChR channel opening, and at higher doses, galantamine acts primarily as an acetylcholinesterase (AChE) inhibitor (Samochocki et al., 2003
; Samochocki et al., 2000
; Schrattenholz et al., 1996
). At low doses, unlikely to inhibit AChE, galantamine, like nicotine, increases burst firing activity of dopaminergic cells in the ventral tegmental area and increases dopamine levels in the pre-frontal cortex, via activation of nAChRs, an effect that is blocked by inhibitors of alpha 4 beta 2 and alpha 7 nAChRs, as well as by an N-methyl-D-aspartate receptor (NMDAR) antagonist (Schilstrom et al., 2007
). Phasic cortical dopamine release has been implicated as important to cognitive performance and as a possible mechanism for a beneficial effect of galantamine on cognitive function and negative symptoms. Galantamine at concentrations of 0.1–1 microM, corresponding to cerebrospinal fluid concentrations in humans on galantamine 16–24 mg daily, appears to act as an APL, but at concentrations >1 microM galantamine does not potentiate nAChR channel opening in the presence of ACh (Schrattenholz et al., 1996
) and at concentrations >10 microM, galantamine, like the selective AChE inhibitor donepezil, may inhibit nAChR-mediated currents in dopaminergic cells (Schilstrom et al., 2007
). It is likely that at high doses, galantamine’s nAChR allosteric modulation effect may be masked by a stronger direct nAChR inhibitory effect. It is not known what oral doses of galantamine in humans would produce such inhibition of nAChR activity.
Our findings are limited by the small sample size, limiting our power to detect medication effects and to control for potential confounders. Smokers were excluded with the hypothesis that any medication effects would be greater in nonsmokers. It is possible, however, that nonsmokers and those who have been able to quit smoking represent a subset of patients with schizophrenia who are less responsive to nicotinic agonist treatment. Additionally, it is possible that upregulation of nAChRs by smoking may potentiate clinical effects of the allosteric potentiating ligand, galantamine. Inclusion of only nonsmokers limits generalizability of the findings to nonsmokers, currently a minority of patients with schizophrenia. The findings are also limited by measurement of cognitive function at only two time points, baseline and endpoint, when most subjects were taking 32 mg/day of galantamine, as positive clinical effects may be greater at lower doses. It is important to note two limitations with regard to SANS scores. First, baseline SANS scores were relatively low, possibly causing a floor effect. Second, SANS scores were decreased by more than 10% in the galantamine group and increased in the placebo group. While it is possible that SANS scores in each group regressed to the mean, narrowing baseline differences between groups, it is also possible that the study simply lacked the power to detect an effect of galantamine on negative symptoms.
In summary, in this double-blind, placebo-controlled trial, galantamine, 32 mg/day, had a directionally opposite effect from placebo on measures of cognitive performance and indeed significantly worsened performance on measures of attention and inhibitory processing compared with placebo, while there was no medication effect on motor speed or clinical symptoms. It is therefore possible that galantamine augmentation at this dose may worsen cognitive functioning in patients with schizophrenia. Future studies should therefore test the effects of galantamine across several levels of smoking and several doses of galantamine.