Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications.

Atypical antipsychotic medications are associated with different adverse effects and efficacy profiles compared with conventional antipsychotics (i.e. less extrapyramidal symptoms, improved-efficacy against negative symptoms and cognitive deficits, and most often a greater ability to improve patients' quality of life). However, the atypical antipsychotics may be associated with clinically significant bodyweight gain, increasing the risk of medical comorbidity, including diabetes mellitus, hypertension, cardiovascular disease and hyperlipidaemia. This literature review assesses the various bodyweight gain liabilities associated with atypical antipsychotics, as well as the effects of bodyweight gain on quality of life. The issue of prevention and management of this often neglected adverse effect is also examined. Most studies reviewed indicate that clozapine and olanzapine are associated with more bodyweight gain than the other atypical antipsychotics. There are potential factors that place certain patients at greater risk for bodyweight gain, including low pretreatment body mass index, young age and being of female gender. Furthermore, bodyweight gain associated with the use of atypical antipsychotics has been reported to be associated with clinical improvement, although this has not been substantiated widely. It is unclear whether increased medical comorbidity, including diabetes mellitus, coronary artery disease and/or elevated triglyceride levels, is secondary to the bodyweight gain associated with atypical antipsychotics, or the result of the agents themselves. A patient's quality of life may be greatly affected by excessive bodyweight gain; either by increased comorbid medical illness, an increased relapse rate associated with noncompliance, or the social stigma associated with being obese. However, most studies reveal that treatment with atypical antipsychotic medications is associated with improved quality of life compared with that achieved with conventional antipsychotic medications. Because bodyweight is an important health risk associated with atypical antipsychotics, prevention and effective management of bodyweight are paramount in preventing comorbid medical illness, relapse and possible noncompliance.

A multicenter evaluation of new treatment efficacy instruments for Alzheimer's disease clinical trials: overview and general results. The Alzheimer's Disease Cooperative Study.

Evaluating treatment efficacy in Alzheimer's disease (AD) clinical trials requires optimal assessment methods to determine the extent and clinical meaningfulness of potential therapeutic effects of pharmacologic agents. Development of improved outcome measures for AD clinical trials is a major objective of the Alzheimer's Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS Instrument Development Project evaluated the sensitivity, reliability and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. A total of 306 English-speaking subjects were enrolled in the study, including AD patients stratified by disease severity and cognitively normal, age-matched elderly subjects. Half were retested at 1 month and 2 months after baseline, and all received 6- and 12-month follow-up assessments. Spanish versions of these new measures are currently being evaluated. The development of this multisite study, the common methods and procedures, and a detailed description of the cohort are provided in this overview article. This multisite project demonstrates the feasibility of a consortium approach to instrument development. We were able to develop new instruments and efficiently evaluate their reliability and sensitivity to longitudinal change by capitalizing on the experience and patient resources of the participating ADCS research sites.

A longitudinal study of behavioral pathology across five levels of dementia severity in Alzheimer's disease: the CERAD Behavior Rating Scale for Dementia. The Alzheimer's Disease Cooperative Study.

As part of the Alzheimer's Disease Cooperative Study (ADCS) Instrument Development Project, the CERAD Behavior Rating Scale for Dementia (BRSD) was examined for its sensitivity to degree of cognitive impairment, its test-retest reliability, and its sensitivity to longitudinal change. Sixty-four normal elderly participants and 261 patients with AD stratified into severity groups based on Mini-Mental State Exam (MMSE) scores were rated on the BRSD at baseline and 12-month follow-up visits. A subset of subjects was evaluated at a 1-month follow-up visit. Baseline BRSD Total Score discriminated the normal group from each AD group, and mean Total Score significantly increased with increasing dementia severity. Test-retest reliability between baseline and 1-month Total Scores was satisfactory for all AD groups. Longitudinal change was evaluated by 12-month change scores, which were significant in only the normal and in one AD group. From the results, we argue that the value of behavioral pathology assessment in clinical trials would be enhanced if additive scores were based on groups of correlated items rather than on a broad array of behaviors, some of which may increase and others may decrease in frequency as AD progresses.

The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer's disease. The Alzheimer's Disease Cooperative Study.

Measurement of cognitive dysfunction in the early stages of Alzheimer's disease (AD) has been well studied and there are many objective tests in use for this purpose. However, with the exception of clinical rating scales, such as the Clinical Dementia Rating Scale, Global Deterioration Scale, and Functional Assessment Staging, there are few objective measures of cognition in the more advanced stages of AD. Given a renewed interest in potential AD therapies, objective measures of mental functioning are needed to adequately assess change in more advanced AD patients. As part of an effort by the NIA-Alzheimer's Disease Cooperative Study to evaluate new measures of efficacy for their utility in treatment studies, the Severe Impairment Battery (SIB) was examined in a 1-year evaluation of change across a wide range of AD severity. The data suggest that the SIB is a reliable and valid measure of progression, particularly in persons with moderate to severe AD. The SIB may therefore be a useful outcome measure in clinical trials that include patients with more advanced stages of AD.

The Spanish Instrument Protocol: design and implementation of a study to evaluate treatment efficacy Instruments for Spanish-speaking patients with Alzheimer's disease. The Alzheimer's Disease Cooperative Study.

Development of improved outcome measures for Alzheimer's disease (AD) clinical trials is a major objective of the Alzheimer's Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS is committed to recruiting and following minority patients in clinical trials. At present, a serious impediment to recruiting non-English-speaking minorities is the lack of instruments with adequate translation. Because Spanish is the second most commonly spoken language in the United States and because persons of Hispanic origin represent approximately 10% of the population, we conducted an instrument development protocol for Spanish-speaking patients. Evaluating treatment efficacy in Spanish-speaking AD patients requires the development of assessments that are comparable to those used for English-speaking participants in clinical trials. The ADCS Instrument Development Project evaluated the sensitivity, reliability, and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. These new treatment efficacy instruments were translated for Spanish speakers and a Spanish Instrument Study was conducted in parallel with the English version of the study. This report describes instrument translation, entry criteria, and recruitment procedures. In addition, the demographic and clinical characteristics of the cohort at baseline are presented and compared to the English-speaking cohort. Implications for the development of comparably sensitive Spanish language instruments are discussed.

Multicenter evaluation of new instruments for Alzheimer's disease clinical trials: summary of results. The Alzheimer's Disease Cooperative Study.

The Instrument Development Project of the Alzheimer's Disease Cooperative Study (ADCS) evaluated new assessments in five domains: (a) cognitive function; (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms, and (e) cognition in severely impaired patients. These new instruments demonstrate excellent discrimination between normal controls and patient groups and show adequate validity and reliability. Stability of measurement and sensitivity to longitudinal change were also demonstrated in each of these areas. Examination of several domain-specific questions also contributed new information on the measurement of cognitive function with different subtasks across AD severity levels, the stability of clinical ratings of global change, and the applicability of behavioral assessment across severity levels. The success of this project enhances the state of the art in the measurement of efficacy in AD clinical trials and also provides a basis for future research on improving AD outcome measures.

Behavioral outcomes in clinical trials for Alzheimer disease.

The use of behavioral scales is an important component in determining efficacy of new drugs in clinical trials for Alzheimer disease (AD). Behavioral assessment in clinical trials must be sensitive to disease heterogeneity, disease progression, and drug modification of behavior. Three such scales, the Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Behavior Rating Scale for Dementia (C-BRSD), and the Cohen-Mansfield Agitation Inventory (CMAI), are useful in clinical trials. The BEHAVE-AD reliably assesses the severity of a range of AD symptoms (7 areas with 25 items) and rates behavioral impact on caregivers. The C-BRSD enables reliable assessment of the frequency of behaviors (8 areas with 48 items) in AD and monitors relevant behaviors throughout the course of the disease. However, it does not assess the impact of behaviors on caregivers. The CMAI focuses on assessment of agitation and aggression and is compatible with C-BRSD but does not assess the impact of agitation on caregivers. A recent trial evaluated the C-BRSD and the CMAI in more than 300 AD and normal elderly individuals. Both of these scales discriminated between AD and non-AD patients, were sensitive across disease severity, and could track behavioral changes over 12 months of AD progression. The BEHAVE-AD, C-BRSD, and CMAI scales are valid, reliable, rapid to administer, cover relevant behaviors occurring during the course of the disease, and are appropriate for use in AD clinical trials.

Intrusions in Alzheimer's disease in immediate and delayed memory as a function of presentation modality.

Young and elderly participants, and participants with Alzheimer's disease (AD) were compared via the suffix paradigm, where a not-to-be-recalled item is appended onto sequences to be immediately recalled. This task was followed by delayed tasks. In immediate recall, AD subjects showed both extralist and suffix intrusions. Recall of auditorily as compared with visually presented stimuli was superior, with the difference increasing in older subjects. The auditory but not the visual suffix produced an end-of-sequence decrement, which was greater in AD than in other groups. After delay, the elderly and young showed virtually perfect performance. The AD participants showed relatively high performance; however, extralist intrusions were frequent, resulting in a relatively low hit rate. As in immediate recall, intrusions showed specificity for AD, and in this paradigm appeared to be a marker differentiating AD and normal subjects. However, the sample size limits the power and generalizability of these findings.

A comprehensive support program: effect on depression in spouse-caregivers of AD patients.

Caregivers of Alzheimer's disease patients often suffer from depression. Using a longitudinal treatment/control study, we examined the effects of a comprehensive support program on depression in spouse-caregivers. This psychosocial intervention program treats the primary caregiver and family members over the entire course of the disease through individual and family counseling, the continuous availability of ad hoc counseling, and support group participation. In the first year after intake, the control group became increasingly more depressed, whereas the treatment group remained stable. By the eighth month, treated caregivers were significantly less depressed than those in the control group. These results suggest that enhancing long-term social support can have a significant impact on depression in caregivers.

An intervention that delays institutionalization of Alzheimer's disease patients: treatment of spouse-caregivers.

Spouse-caregivers of Alzheimer's disease patients were randomly assigned to either a treatment group (individual and family counseling, support group participation, and ad hoc consultation) or a control group (only routine support). In the first year after intake, the treatment group had less than half as many nursing home placements as the control group. This suggests that a comprehensive counseling program can reduce the socioeconomic impact of Alzheimer's disease. Nursing home placement also was affected by the patient's need for assistance with activities of daily living, patient income, and the age of the patients and caregivers.