Research Article: Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer’s disease

Date Published: June 20, 2011

Publisher: BioMed Central

Author(s): Steven H Ferris, Frederick A Schmitt, Judith Saxton, Sharon Richardson, Joan Mackell, Yijun Sun, Yikang Xu.

http://doi.org/10.1186/alzrt84

Abstract

Progressive language impairment is among the primary components of cognitive decline in Alzheimer’s disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients’ functional needs, language plays a critical role in patients’ emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.

In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician’s Interview-Based Impression of Severity-plus caregiver input/Clinician’s Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.

At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.

Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.

Partial Text

An estimated 5.1 million Americans over 65 years of age have Alzheimer’s disease (AD), and more than half of these individuals are classified as having moderate or severe disease [1]. As disease severity increases, patients progressively lose the ability to communicate, express their needs and participate in their accustomed relationships [2-4]. In patients with more advanced disease, this often leads to an inability to sustain social relationships, express needs for medical attention and relate or respond to caregivers. Moreover, caregivers often become frustrated by difficulties in understanding and meeting patients’ loved ones’ needs, which can lead to further patient distress [3,5-7]. The ability to use language to communicate helps to maintain emotional connections between the patient and his or her caregiver and/or family, and loss of language ability is among the most distressing factors associated with AD [3]. Thus, treatment that can delay or even improve language abilities is an important focus of AD therapy.

The already fragile relationships in the lives of patients with AD can become profoundly disrupted as patients lose the ability to communicate coherently. Attachment to caregivers and others becomes compromised, and the effect of such detachment on caregivers can be deleterious. Furthermore, it is difficult for clinicians and caregivers to render optimal care in the absence of clear input from patients regarding what they are feeling or concerned about. When language comprehension deteriorates, it is also likely to further increase caregiving stress, as patients have difficulty understanding conversation and even simple directions. Moreover, decline in language is associated with increased risk of mortality [24]. Therefore, therapy to slow or reduce the loss of language abilities has the potential to result in additional quality time for patients and caregivers alike.

The results of this analysis suggest that donepezil 23 mg/day may result in improvements in the critical factor of language in advanced AD as measured by SIB-derived language scales. These findings indicate that increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical. Supporting communication in patients with a progressive disease such as AD may have the potential, even in advanced stages of AD, to improve patients’ quality of life and reduce the burden of AD experienced by caregivers.

AD: Alzheimer’s disease; ADCS-ADL-sev: Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory; CIBIC-plus: Clinician’s Interview-Based Impression of Change-plus caregiver input; CIBIS-plus: Clinician’s Interview-Based Impression of Severity-plus caregiver input; ITT: intention to treat; LOCF: last observation carried forward; LS: least squares; MMSE: Mini-Mental State Examination; SD: standard deviation; SIB: Severe Impairment Battery; SIB-L: Severe Impairment Battery-Language scale; SIB[lang]: 21-item Severe Impairment Battery-derived language scale.

The analyses described in this article derive from a phase III clinical study (ClinicalTrials.gov identifier: NCT00478205) that was sponsored by Eisai Inc. Editorial assistance was provided by PAREXEL Inc. and was funded by Eisai Inc. and Pfizer Inc. The article-processing charge was financed by Eisai Inc. and Pfizer Inc. SHF has served as a paid scientific consultant to Pfizer Inc related to donepezil and several investigational compounds (≤$10,000/year; there was no payment for participation in this article). His institution has received grant/contract support from Pfizer Inc for the conduct of clinical trials of dementia and to support educational programs. He has also served as a scientific consultant to other companies marketing or developing drugs for cognition, including Lundbeck, Elan, Janssen AI, Eli Lilly, Merz, Novartis, Toyama, Bellus Health, Bayer Healthcare, Accera, Otsuka, Sunovion, Symphony Icon and Torrey Pines, and his institution has received grant/contract support for clinical trials from Pfizer, Eli Lilly, Janssen AI, Baxter and Bristol-Myers Squibb. He also has stock options from Accera, Intellect Neurosciences, MedAvante and Symphony Icon. FAS has no financial competing interests to report. He has served on a Data Safety Monitoring Committee for Pfizer Inc for which the University of Kentucky received reimbursement (<$4,000). JS has been paid as a consultant to Eisai Inc., Pfizer Inc, Forest Pharmaceuticals and Novartis. JS currently receives royalties from the original Severe Impairment Battery on which this reduced scale is based. SR is an ex-employee of Eisai Inc. JM is an employee of Pfizer Inc. YS is an employee of Eisai Inc. YX was an employee of Pfizer Inc. SHF, FAS, SR and JM helped to conceive and design the described analyses, participated in the data analysis and assisted in the drafting, editing and interpretation of the manuscript. JS developed the original Severe Impairment Battery scale, helped to conceive and design the described analyses, participated in the data analysis and assisted in the drafting, editing and interpretation of the manuscript. YS and YX assisted in the statistical planning and performance of the post hoc analyses and assisted in the drafting, editing and interpretation of the manuscript. All authors read and approved the final version of the manuscript.   Source: http://doi.org/10.1186/alzrt84

 

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