Galantamine for the Treatment of Cognitive Impairments in People With Schizophrenia

Department of Psychiatry, University of Maryland, Baltimore, MD, USA.
American Journal of Psychiatry (Impact Factor: 13.56). 02/2008; 165(1):82-9. DOI: 10.1176/appi.ajp.2007.07050724
Source: PubMed

ABSTRACT People with schizophrenia are characterized by a broad range of cognitive impairments. Despite appropriate treatment with conventional or second-generation antipsychotics, they continue to exhibit pronounced impairments. The current study was designed to examine the efficacy and safety of galantamine, an acetylcholinesterase inhibitor that also acts as an allosteric modulator at the alpha(4)beta(2) and alpha(7) nicotinic receptors, for the treatment of these impairments.
Eighty-six people with schizophrenia were entered into a 12-week double-blind, placebo-controlled, randomized clinical trial. Forty-two subjects were assigned to galantamine and 44 were assigned to placebo. The efficacy of galantamine for cognitive impairments was evaluated with neuropsychological measures of attention, motor speed, processing speed, verbal and visual memory, and working memory.
The treatment effect for the overall composite score was not significant, but the heterogeneity of treatment effect analysis was significant. Follow-up analyses revealed that the subjects taking galantamine exhibited significant improvements on the WAIS-III digit symbol and verbal memory measures. In contrast, the subjects taking placebo showed a significant improvement on the GDS distractibility test. The group differences on the WAIS-III digit symbol and GDS distractibility test remained significant after correction for multiple comparisons. There were no significant between-group differences in motor speed or working memory. In general, safety analyses revealed that galantamine was well tolerated.
Study results suggest that galantamine may have selective benefits for aspects of processing speed and verbal memory but interferes with practice effects during the performance of an attention task.

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Available from: Dwight Dickinson, Aug 19, 2015
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    • "Galantamine is a weak inhibitor of acetylcholinesterase and acts as an allosteric modulator of the nicotinic acetylcholine receptor (Santos et al., 2002). In both humans and animal models, galantamine is frequently used to treat memory impairments associated with Alzheimer 0 s disease and is being considered for use in schizophrenia (Alexander et al., 2012; Buchanan et al., 2008; Knopman and Morris, 1997; Wang et al., 2007). In addition, in the developmental NMDA receptor antagonist model, du Bois et al. (2009b) reported perinatal phencyclidine treatment alters the developmental expression of prefrontal and hippocampal muscarinic receptors. "
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    ABSTRACT: Early life blockade of the NMDA receptor by using MK-801, a non-competitive NMDA receptor antagonist, induces behavioral changes that mimic several features of schizophrenia. In the current study, we first examined the effects of neonatal MK-801 treatment in male Sprague-Dawley rats on locomotor activity, prepulse inhibition and spatial working memory in adolescence (postnatal day 35, PND35) and adulthood (PND63). Next, we investigated the effects of an acetylcholinesterase inhibitor, galantamine, on working memory deficits induced by MK-801 treatment. Rats were treated with either saline or MK-801 (0.25mg/kg twice daily) at PND 5-14, and the long-term behavioral effects were investigated. MK-801 treated rats showed moderate working memory impairments in adolescence but a pronounced deficit in adulthood. However, locomotion and prepulse inhibition at two life stages were not affected by this treatment. Systemic administration of galantamine (1mg/kg) 30min before each training session significantly improved neonatal MK-801-induced working memory deficits in adulthood. In conclusion, these results suggest that the neonatal MK-801 treatment-induced selective working memory deficit is related to a change in brain cholinergic systems.
    European journal of pharmacology 01/2014; 725(1). DOI:10.1016/j.ejphar.2014.01.007 · 2.68 Impact Factor
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    • "Adjunctive medication Pharmacological targets Study Effect size (95% CI) n % Dyer et al (2008) 17 Schubert et al (2006) 15 Akhondzadeh et al (2008) 44 Fagerlund et al (2007) 9 Friedman et al (2002) 10 Buchanan et al (2007) 21 Tsai et al (1998) 20 Goff et al (1999) 49 Goff et al (2001) 51 Tsai et al (1999) 22 Goff et al (2008) 50 Goff et al (2008) 52 Galantamine Galantamine Donepezil Donepezil Donepezil D-cycloerine D-serine D-cycloerine CX516 D-serine D-cycloerine CX516 AChEI AChEI AChEI AChEI AChEI Glutamate agonist Glutamate agonist Glutamate agonist Glutamate agonist Glutamate agonist Glutamate agonist Glutamate agonist 70.06 0.21 1.37 0.62 0.34 0.75 0.85 0.78 1.49 0.96 70.07 0.68 (70.94 to 0.82) (70.79 to 1.2) (0.56 to 2.11) (70.71 to 1.84) (70.52 to 1.18) (0.34 to 1.15) (0.06 to 1.59) (0.16 to 1.37) (0.36 to 2.48) (70.01 to 1.85) (70.48 to 0.34) (70.05 to 1.37) 20 16 30 11 26 104 29 46 18 20 92 33 4.5 3.6 6.7 2.5 5.8 23.4 6.5 10.3 4.0 4.5 20.7 7.4 < < < < < < < < < < < < 70.5 0 0.5 1.0 1.5 2.0 Fig. 1 "
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    ABSTRACT: A growing number of studies have investigated the efficacy of novel, adjunctive pharmacotherapies for treatment of cognitive deficits in schizophrenia with conflicting results. To investigate the comparative efficacy of these agents on cognition and symptoms in schizophrenia, and to identify promising cognitive domains and candidate medications that can be incorporated in treatment trials combined with cognitive remediation to maximise treatment effects. A total of 26 double-blind, placebo-controlled studies investigating medications targeted at cholinergic, glutamatergic or serotonergic receptor classes and with participants with schizophrenia or schizoaffective disorder were identified. Medications targeted at the cholinergic receptor class produced marginal improvements in verbal learning and memory (d = 0.23, P = 0.06), and donepezil, a specific type of cholinergic agonist, produced a moderate effect (d = 0.58) on spatial learning and memory. Cholinergic and glutamatergic agents produced moderate effect-size improvements on negative symptoms (d = 0.54 and d = 0.62 respectively), and small effect-size improvements on general symptoms (d = 0.46 and d = 0.41 respectively). Serotonergic agents produced small effect-size improvements in positive symptoms (d = 0.33). Cholinergic medications produced marginal improvement in verbal learning and memory and moderate improvements on spatial learning and memory, although there was no evidence to support the use of glutamatergic or serotonergic medications as a stand-alone treatment for improving cognitive function. Cholinergic and glutamatergic agents improved negative and general symptoms, whereas serotenergic medications improved positive symptoms.
    The British journal of psychiatry: the journal of mental science 09/2013; 203(3):172-8. DOI:10.1192/bjp.bp.111.107359 · 7.34 Impact Factor
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    • "Finally, the VH transient inactivation animal model exhibits some degree of predictive validity toward the treatment of cognitive disorders in SZ. The beneficial effects of SSR180711 in our animal model are consistent with several recent reports, in patients with SZ, of modest cognition-enhancing properties of a7 nAChR agonists in tasks that do not involve an ID/ED shift (Buchanan et al, 2008; Martin and Freedman, 2007; Olincy et al, 2006; Schubert et al, 2006; Tregellas et al, 2011; but see Lindenmayer & Khan (2011) for conflicting results). Collectively, these studies suggest that transient inactivation of the developing VH represents a useful animal model for the study of cognitive deficits in SZ and that drugs designed to enhance activity at a7 nAChRs may represent rational targets for the development of adjunctive medication for treating this disorder. "
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    ABSTRACT: Cognitive deficits represent a core symptom cluster in schizophrenia that are thought to reflect developmental dysregulations within a neural system involving the ventral hippocampus (VH), nucleus accumbens (NAC), and prefrontal cortex (PFC). The present experiments determined the cognitive effects of transiently inactivating VH in rats during a sensitive period of development. Neonatal (postnatal day 7, PD7) and adolescent (PD32) male rats received a single bilateral infusion of saline or tetrodotoxin (TTX) within the VH to transiently inactivate local circuitry and efferent outflow. Rats were tested as adults on an attentional set-shifting task. Performance in this task depends upon the integrity of the PFC and NAC. TTX infusions did not affect the initial acquisition or ability to learn an intra-dimensional shift. However, TTX rats required a greater number of trials than did controls to acquire the first reversal and extra-dimensional shift (ED) stages. These impairments were age and region-specific as rats infused with TTX into the VH at PD32, or into the dorsal hippocampus at PD7, exhibited performance in the task similar to that of controls. Finally, acute systemic administration of the partial α7 nicotinic acetylcholine receptor (nAChR) agonist SSR 180711 (3.0 mg/kg) eliminated the TTX-induced performance deficits. Given that patients with schizophrenia exhibit hippocampal pathophysiology and deficits in the ED stages of set-shifting tasks, our results support the significance of transient hippocampal inactivation as an animal model for studying the cognitive impairments in schizophrenia as well as the pro-cognitive therapeutic potential of α7 nAChR agonists.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(11):2476-86. DOI:10.1038/npp.2012.106 · 7.83 Impact Factor
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