Karen S. Dagerman

Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer’s Disease: Phase 1 Outcomes from the CATIE-AD Effectiveness Trial

OBJECTIVE The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimers disease and psychosis or agitated behavior. METHOD The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimers Disease (CATIE-AD) Alzheimers disease effectiveness study included 421 outpatients with Alzheimers disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinicians discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. RESULTS In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. CONCLUSION In this descriptive analysis of outpatients with Alzheimers disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer Disease Trial Methodology

The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Metabolic Changes Associated With Second-Generation Antipsychotic Use in Alzheimer’s Disease Patients: The CATIE-AD Study

OBJECTIVE The second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimers disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects. METHOD The authors assessed 186 male and 235 female Alzheimers disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimers Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models. RESULTS Women showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., > or = 7% of body weight) was seen among patients with antipsychotic use < or = 12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and > 24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (-0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides. CONCLUSION Second-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimers disease treated with second-generation antipsychotics should be monitored closely.

Psychosis of Alzheimer's disease: clinical characteristics and history

The concept of psychosis of Alzheimers disease and dementia is developed with respect to prevalence, incidence, clinical characteristics, clinical course, and potential response to treatment. Psychosis frequently occurs subsequent to the onset of dementia. Published prevalence estimates of psychosis in patients with AD range from 10 to 73% with an overall median of 34% within clinic populations, and from 7 to 20% in community and clinical trials populations depending on definitions used. Among people with AD who have no psychotic symptoms there appears to be an annualized incidence of psychosis of about 20% in outpatients, and a much higher rate in nursing home patients. Female gender, somewhat greater cognitive impairment among outpatients, somewhat lesser cognitive impairment among nursing home patients, and physical aggression are more associated with psychotic signs and symptoms than not. Right frontal hypometabolism and greater frontal neuropsychological deficits occur in AD patients with psychosis in comparison to those without. Among nursing home patients with dementia who have clinically significant agitation, the substantial majority have delusions or hallucinations. Among patients in nursing homes with dementia and psychosis, nearly two-thirds have persistent symptoms over at least 12 weeks, and among outpatient studies, hallucinations and delusions may persist in approximately 40-50% over periods of 3 months to one year. There is some evidence that psychotic symptoms improve modestly with antipsychotic medication treatment. There is sufficient descriptive and empirical research to support the validity of a syndrome of psychosis of Alzheimers disease.

Increasing ethnic minority participation in Alzheimer disease research

The Alzheimers Association and National Institutes of Health have emphasized the need for participation of racial/ethnic populations in Alzheimer disease (AD) clinical research. Many articles have described strategies to enhance participation including establishing enduring ties to the community and tailoring the site to be more culturally welcoming or user-friendly to the community. Yet, most of these reports are not data driven. To get a better indication of the knowledge base, this review summarizes research across a broad range of domains (e.g., cancer, kidney disease, AD) that used systematic approaches to identify methods and factors that reduce barriers to recruitment, participation, and retention of a more racially and ethnically diverse population. Overall, 121 reports were found with 8 of these in AD. As a relatively new area of investigation, the literature was primarily descriptive; outcome data were seldom provided. While these studies help to identify areas of potential importance in racial/ethnic participation, hypothesis-driven research remains necessary to tease apart the key techniques that engender racial/ethnic participation in AD studies. This article suggests several recommendations, including the need for prospective research of specific recruitment methods. Fundamentally, researchers should consider that these strategies apply to all potential research participants, and not simply to traditionally underserved racial/ethnic populations.

Citalopram compared to atypical antipsychotics for Alzheimer patients who did not previously benefit from treatment: The catie-AD study

observed in any Aß-degrading protease knockout mouse studied to date. Remarkably, this increase was selective for Aß42, resulting in elevated Aß42/ Aß40 ratios comparable to those induced by presenilin mutations that cause early-onset AD. Cultured neurons from CatD-KO mice also showed selective defects in the catabolism of Aß42, but not Aß40. Furthermore, relative to age-matched controls, the brains of CatD-KO mice showed pronounced increases in the levels of tau and phosphorylated forms thereof, while showing no increases in the levels of several other cytosolic proteins. Conclusions: Our findings demonstrate that, in vivo, CatD deficiency leads to large and highly selective increases in the two protein species most strongly linked to the pathogenesis of AD_Aß42 and tau. Combined with human molecular genetic data on the CatD gene (CTSD) to be presented at this meeting (Burgess et al.), our findings suggest that CatD plays a protective role in the pathogenesis of AD by mediating the catabolism of Aß42 and tau.

National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness- Alzheimers Disease (CATIE-AD): Baseline Characteristics

CATIE-AD was a multicenter effectiveness trial of atypical antipsychotics in patients with agitation and psychosis associated with AD who resided in the community. The study enrolled 421 participants. In this paper we present and discuss baseline characteristics of participants (demographics, cognitive, behavioral, and functional assessments), caregivers (demographics and caregiver burden) and settings at randomization. Those enrolled suffered from a wide range of cognitive impairment, were medically complex and experienced acute psychopathology requiring intervention with atypical antipsychotics. Family members providing the equivalent of institutional care experienced significant depression and caregiver burden. With the increasing prevalence of AD, clinicians and health care planners should look into future needs of those AD sufferers who are residing in community.

P4-394: Lack of evidence for the efficacy of memantine in mild Alzheimer's disease and modest effects in moderate Alzheimer's disease

is over 6,600 men in the U.S., Canada, and Puerto Rico in collaboration with the NCI-sponsored prostate prevention study. The accuracy of the primary, brief memory screening tool is critical for identifying possible incident cases of dementia, and triggers a second-level mental status exam that can trigger a medical evaluation for AD. Objectives: (1) Provide validation results for screening tools from a prevention trial. (2) Compare results of the Memory Impairment Screen (MIS) to expanded measures of memory. Methods: PREADVISE participants are screened annually with the Memory Impairment Screen (MIS). A Normal Aging (NAG) validation sub-sample is given an expanded battery annually that includes CERAD measures supplemented with tests (e.g., NYU paragraph recall, phonemic fluency, clock drawing). The current analysis evaluates the correspondence between MIS performance and memory scores from 410 men (mean: age 70.6 5.6; education 15.6 2.3; 10% African-American). Results: MIS performance for 84.4% of the sample was 7 or 8 (8 max), while 5.4% scored in the low normal range (5 or 6) and 10.2% scored at or below the cutoff of 4. Age, but not education differed between the 3 MIS groups. ANCOVA’s (age covariate) revealed group differences for multiple expanded memory measures. A follow-up multiple linear regression model shows a statistically significant prediction of MIS scores by measures of recognition errors (false positives) plus category fluency (R 0.59) and delayed recall (10-item word list; NYU paragraph; R 0.10). Conclusions: These data suggest that the 3-minute MIS has utility as a screening tool for prevention trials based on its association with other episodic memory tests. Sensitivity and specificity will be ascertained as more incident AD cases are identified. Further, as PREADVISE progresses, these validation methods can also indicate if the MIS could be improved through the addition of other cognitive components, providing an effective tool for AD detection in general clinical settings.