Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.

BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness- Alzheimer's 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.

Aging and the use of context in ambiguity resolution: complex changes from simple slowing.

Older and younger adults' abilities to use context information rapidly during ambiguity resolution were investigated. In Experiments 1 and 2, younger and older adults heard ambiguous words (e.g., fires) in sentences where the preceding context supported either the less frequent or more frequent meaning of the word. Both age groups showed good context use in offline tasks, but only young adults demonstrated rapid use of context in cross-modal naming. A 3rd experiment demonstrated that younger and older adults had similar knowledge about the contexts used in Experiments 1 and 2. The experiment results were simulated in 2 computational models in which different patterns of context use were shown to emerge from varying a single speed parameter. These results suggest that age-related changes in processing efficiency can modulate context use during language comprehension.

Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.

CONTEXT: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use. OBJECTIVE: To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia. DATA SOURCES: MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial. STUDY SELECTION: Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors. DATA EXTRACTION: Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer. DATA SYNTHESIS: Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis. CONCLUSIONS: Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.

Psychosis of Alzheimer's disease: clinical characteristics and history.

The concept of psychosis of Alzheimer's 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 Alzheimer's disease.

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer's disease trial.

This article describes the development of the protocol for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer's disease trial, which was developed in collaboration with the National Institute of Mental Health to assess the effectiveness of atypical antipsychotics for psychosis and/or agitation occurring in outpatients with Alzheimer's disease. The article provides a detailed description of the methodology used in the trial as well as the clinical outcomes and effectiveness measures incorporated into it, discussing the most salient issues encountered in developing the design of the trial, as well as the unique features of the trial.

Lack of evidence for the efficacy of memantine in mild Alzheimer disease.

OBJECTIVE: We directly assessed the clinical trials' evidence for memantine's efficacy in mild Alzheimer disease (AD). Memantine is indicated in the United States and Europe for moderate to severe AD, which is diagnosed if a patient has a Mini-Mental State Examination (MMSE) score of less than 15 or less than 20, respectively. Yet memantine is very frequently prescribed for mild AD and mild cognitive impairment, and a manufacturer-sponsored meta-analysis claimed its efficacy in mild AD. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Manufacturer-sponsored meta-analyses, registries, presentations, and publications were systematically searched for randomized placebo-controlled, parallel-group clinical trials of memantine in patients with mild to moderate AD. The trials' characteristics and outcomes were extracted by one reviewer and checked by another. Meta-analyses were performed as inverse variance-weighted averages of mean differences using fixed-effects models. Summary results for patients with mild AD were obtained by contrasting the summary results for patients with mild or moderate AD with the summary results for the subset of patients with moderate AD. DATA SYNTHESIS: Three trials were identified that included 431 patients with mild AD (ie, with MMSE scores of 20-23) and 697 patients with moderate AD (ie, with MMSE scores of 10-19). There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined: mean differences (95% confidence intervals [CIs]) on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus), the Alzheimer Disease Cooperative Study-activities of daily living (ADCS-ADL) scale, and the Neuropsychiatric Inventory (NPI) were -0.17 (95% CI, -1.60 to 1.26), -0.09 (95% CI, -0.30 to 0.12), 0.62 (95% CI, -1.64 to 2.71), and 0.09 (95% CI, -2.11 to 2.29), respectively. For patients with moderate AD, there were small differences on the ADAS-cog and the CIBIC-plus, -1.33 (95% CI, -2.28 to -0.38) and -0.16 (95% CI, -0.32 to 0.00), respectively, but no differences on the ADCS-ADL scale (-0.57 [95% CI, -1.75 to 0.60]) or the NPI (0.25 [95% CI, -1.48 to 1.99]). CONCLUSIONS: Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.

Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD.

OBJECTIVE: The impact of the atypical antipsychotics olanzapine, quetiapine, and risperidone on cognition in patients with Alzheimer's disease is unclear. The authors assessed the effects of time and treatment on neuropsychological functioning during the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD). METHOD: CATIE-AD included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior who were randomly assigned to receive masked, flexible-dose olanzapine, quetiapine, risperidone, or placebo. Based on their clinicians' judgment, patients could discontinue the originally assigned medication and receive another randomly assigned medication. Patients were followed for 36 weeks, and cognitive assessments were obtained at baseline and at 12, 24, and 36 weeks. Outcomes were compared for 357 patients for whom data were available for at least one cognitive measure at baseline and one follow-up assessment that took place after they had been on their prescribed medication or placebo for at least 2 weeks. RESULTS: Overall, patients showed steady, significant declines over time in most cognitive areas, including in scores on the Mini-Mental State Examination (MMSE; -2.4 points over 36 weeks) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (-4.4 points). Cognitive function declined more in patients receiving antipsychotics than in those given placebo on multiple cognitive measures, including the MMSE, the cognitive subscale of the Brief Psychiatric Rating Scale, and a cognitive summary score summarizing change on 18 cognitive tests. CONCLUSIONS: In CATIE-AD, atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration compared with placebo. Further cognitive impairment is an additional risk of treatment with atypical antipsychotics that should be considered when treating patients with Alzheimer's disease.

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 Alzheimer's 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 Alzheimer's disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's 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 Alzheimer's disease treated with second-generation antipsychotics should be monitored closely.

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 Alzheimer's disease and psychosis or agitated behavior. METHOD: The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's 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 clinician's 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 Alzheimer's 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.

Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer disease.

CONTEXT: Second-generation antipsychotics (SGAs) are prescribed for psychosis, aggression, and agitation in Alzheimer disease (AD). OBJECTIVE: To conduct a cost-benefit analysis of SGAs and placebo (taken to represent a "watchful waiting" treatment strategy) for psychosis and aggression in outpatients with AD. DESIGN: Randomized placebo-controlled trial of alternative SGA initiation strategies. SETTING: Forty-two outpatient clinics. PARTICIPANTS: Outpatients with AD and psychosis, aggression, or agitation (N = 421). Intervention Participants were randomly assigned to treatment with olanzapine, quetiapine fumarate, risperidone, or placebo with the option of double-blind rerandomization to another antipsychotic or citalopram hydrobromide or open treatment over 9 months. MAIN OUTCOME MEASURES: Monthly interviews documented health service use and costs. The economic perspective addressed total health care and medication costs. Costs of study drugs were estimated from wholesale prices with adjustment for discounts and rebates. Quality-adjusted life-years (QALYs) were assessed with the Health Utilities Index Mark 3 and were supplemented with measures of functioning, activities of daily living, and quality of life. Primary analyses were conducted using all available data. Secondary analyses excluded observations after the first medication change (ie, phase 1 only). Cost-benefit analysis was conducted using the net health benefits approach in a sensitivity analysis in which QALYs were valued at $50,000 per year and $100,000 per year. RESULTS: Average total health costs, including medications, were significantly lower for placebo than for SGAs, by $50 to $100 per month. There were no differences between treatments in QALYs or other measures of function. Phase 1-only analyses were broadly similar. Net-benefit analysis showed greater net health benefits for placebo as compared with other treatments, with probabilities ranging from 50% to 90%. CONCLUSIONS: There were no differences in measures of effectiveness between initiation of active treatments or placebo (which represented watchful waiting) but the placebo group had significantly lower health care costs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00015548.

Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials.

OBJECTIVE: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease (AD) and other dementia. Several clinical trials have not shown efficacy, and there have been concerns about adverse events. The objective of this study was to assess the evidence for efficacy and adverse events of atypicals for people with dementia. METHODS: MEDLINE, the Cochrane Register of Controlled Trials, meetings, presentations, and information obtained from sponsors were used in this study. Published and unpublished randomized, placebo-controlled, double-blind, parallel-group trials in patients with AD or dementia of atypical antipsychotics marketed in the United States were studied. Clinical and trials characteristics, outcomes, and adverse events were extracted. Data were checked by a second reviewer. Fifteen trials including 16 contrasts of atypical antipsychotics with placebo met selection criteria: aripiprazole (k = 3), olanzapine (k = 5), quetiapine (k = 3), and risperidone (k = 5). A total of 3,353 patients were randomized to drug and 1,757 to placebo. Standard meta-analysis methods were used to summarize outcomes. RESULTS: Quality of the reporting of trials varied. Efficacy on rating scales was observed by meta-analysis for aripiprazole and risperidone, but not for olanzapine. Response rates were frequently not reported. There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis. Approximately one-third dropped out without overall differences between drug and placebo. Adverse events were mainly somnolence and urinary tract infection or incontinence across drugs, and extrapyramidal symptoms or abnormal gait with risperidone or olanzapine. Cognitive test scores worsened with drugs. There was no evidence for increased injury, falls, or syncope. There was a significant risk for cerebrovascular events, especially with risperidone; increased risk for death overall was reported elsewhere. CONCLUSIONS: Small statistical effect sizes on symptom rating scales support the evidence for the efficacy of aripiprazole and risperidone. Incomplete reporting restricts estimates of response rates and clinical significance. Dropouts and adverse events further limit effectiveness. Atypicals should be considered within the context of medical need and the efficacy and safety of alternatives. Individual patient meta-analyses are needed to better assess clinical significance and effectiveness.

Increasing ethnic minority participation in Alzheimer disease research.

The Alzheimer's 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.