Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment

Department of Psychiatry, University of Rochester, Rochester, New York, United States
Neurology (Impact Factor: 8.29). 08/2006; 67(1):57-63. DOI: 10.1212/01.wnl.0000223333.42368.f1
Source: PubMed


To investigate the behavioral effects of memantine in moderate to severe Alzheimer disease (AD).
The authors conducted a hypothesis-generating, exploratory analysis of a 24-week, double-blind, placebo-controlled trial comparing memantine (20 mg/day) with placebo in subjects with moderate to severe AD on stable donepezil treatment. They employed the Neuropsychiatric Inventory (NPI; 12-item), administered at baseline, week 12, and week 24, to assess the effects of memantine on behavior. Global, cognitive, and functional measures were collected and relationships between these assessments and changes in behavior were determined. The intent-to-treat population was examined using last-observation-carried-forward and observed-cases approaches.
Patients treated with memantine had significantly lower NPI total scores than patients treated with placebo. Analyses of the 12 NPI domains revealed significant effects in favor of memantine on agitation/aggression, eating/appetite, and irritability/lability. Of patients who exhibited agitation/aggression at baseline, those treated with memantine showed significant reduction of symptoms compared with placebo-treated patients. Memantine-treated patients without agitation/aggression at baseline evidenced significantly less emergence of this symptom compared with similar patients receiving placebo. Caregivers of patients receiving memantine registered significantly less agitation-related distress. There were significant relationships between the NPI and the global rating scale and performance of activities of daily living, but not between changes in the NPI and cognition.
Treatment with memantine reduced agitation/aggression, irritability, and appetite/eating disturbances. Memantine reduced agitation/aggression in patients who were agitated at baseline and delayed its emergence in those who were free of agitation at baseline.

Full-text preview

Available from:
    • "These results contrast an earlier study [29] with a smaller sample, which showed rising anxiety and, more significantly, disinhibition, agitation and irritability in later stages; however, severely impaired patients were rare in that study, and they were not stratified according to pharmacological treatment, which could have lessened such symptoms. Also, overall neuropsychiatric symptoms tend to correlate better with functional independence than with cognitive decline [18]. Treatment with ChEis was associated with lower scores for dysphoria in mildly impaired patients, agitation and/or aberrant motor behavior in moderately impaired patients, and irritability in severely impaired patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate correlations of pharmacological treatment with cognitive and behavioral symptoms in patients with dementia due to Alzheimer's disease with low schooling, subjects were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functionality, caregiver burden, APOE haplotypes and pharmacological treatment. Among 217 patients, use of cholinesterase inhibitors with or without Memantine was associated with less neuropsychiatric symptoms, while anti-psychotics and/or anti-epileptic drugs were associated with lower instrumental functionality. Anti-psychotics were also associated with more neuropsychiatric symptoms in moderately impaired patients, possibly reflecting the greater need for such treatment when behavioral symptoms are present. Patients receiving more medications were usually younger, obese, married, with higher schooling and more neuropsychiatric symptoms. APOE4+ haplotypes were correlated with earlier dementia onset, but not with pharmacological treatment. Higher caregiver burden was associated with more psychotropic drugs. A trend was found for treatment with cholinesterase inhibitors and Memantine to be associated with longer lengths of dementia for moderately impaired but not for severely impaired patients, regardless of APOE haplotypes, translating into a synergistic effect among such medications for slowing cognitive decline but not for prolonging survival. Further longitudinal studies may be required to assess dose-response relationships regarding treatment with psychotropics for patients with dementia.
    No preview · Article · Oct 2013 · Journal of the neurological sciences
  • Source
    • "In one randomised, double-blind controlled study in 404 patients with moderate to severe AD, treatment with memantine and donepezil produced significant benefits across cognitive, functional, behavioural and global domains, when compared with donepezil monotherapy (Tariot et al. 2004). Post hoc analyses of this study revealed the superiority of combination treatment over AChEI monotherapy in specific areas such as language and memory (Schmitt et al. 2006), toileting and higher-level functions (Feldman et al. 2006), and agitation/aggression and irritability (including decreased symptom emergence) (Cummings et al. 2006; Gauthier et al. 2005). In addition, more patients responded with symptom improvement or stabilisation in the combination treatment group than in the group receiving monotherapy with donepezil (van Dyck et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually.
    Full-text · Article · May 2013 · Neurotoxicity Research
  • Source
    • "Previous studies26,27 have reported that for patients with AD, addition of memantine to an established donepezil regimen resulted in better outcomes for cognition and activities of daily living, compared with placebo. Further, addition of memantine reduced agitation, irritability, and appetite/eating disturbances, as measured by the NPI. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-D-aspartate receptor antagonist, memantine, in patients with Alzheimer's disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10-22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3-14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.
    Full-text · Article · Feb 2013 · Neuropsychiatric Disease and Treatment
Show more