Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease.

CONTEXT: Agitation and psychosis are common in Alzheimer disease and cause considerable morbidity. We attempted to delay or to prevent agitation and psychosis with the use of divalproex sodium (valproate). OBJECTIVE: To determine whether treatment with valproate could delay or prevent emergence of agitation or psychosis. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind, placebo-controlled trial of flexible-dose valproate in 313 (of 513 screened) individuals with moderate Alzheimer disease who had not yet experienced agitation or psychosis. The study was conducted from November 1, 2005, through March 31, 2009, at 46 sites in the United States. INTERVENTION: Participants were randomly assigned to valproate treatment at a target dose of 10 to 12 mg per kilogram of body weight per day or identical-appearing placebo for 24 months followed by a 2-month period of single-blind placebo treatment. MAIN OUTCOME MEASURE: Time to emergence of clinically significant agitation or psychosis. RESULTS: A total of 122 participants (59 receiving valproate and 63 receiving placebo) completed 24 months of treatment while taking study medication; 42 (27 receiving valproate and 15 receiving placebo) reached 24 months having discontinued study medication; 150 reached month 26. There was no difference between groups in time to emergence of agitation or psychosis (Cox proportional hazard ratio, 0.96; P = .88). There was no difference between groups in change on any secondary outcome. The valproate group had higher rates of somnolence, gait disturbance, tremor, diarrhea, and weakness. Eighty-eight participants underwent magnetic resonance imaging scans at baseline and 12 months; the valproate group showed greater loss in hippocampal and whole-brain volume, accompanied by greater ventricular expansion (P < .001). CONCLUSION: Valproate treatment did not delay emergence of agitation or psychosis or slow cognitive or functional decline in patients with moderate Alzheimer disease and was associated with significant toxic effects.

Extended results of the Alzheimer's disease anti-inflammatory prevention trial.

BACKGROUND: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. METHODS: We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aß(1-42.) RESULTS: Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. CONCLUSIONS: These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

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.

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].).

Efficacy of atypical antipsychotics in elderly patients with dementia.

Pharmacotherapy in patients with dementia aims to improve distressing behavioral and psychological signs of dementia after nonpharmacologic interventions fail, without causing unacceptable side effects or exacerbating underlying cognitive impairment. We review data describing risperidone (3 published placebo-controlled trials), olanzapine (1 abstract regarding a placebo-controlled trial and a published placebo-controlled trial), quetiapine (1 published open-label trial and an abstract regarding a placebo-controlled trial), and aripiprazole (1 abstract regarding a placebo-controlled trial). For example, a 12-week study of risperidone in patients with Alzheimer's disease showed a dose-related improvement in psychosis and agitation. The frequency of extrapyramidal symptoms (EPS) was also significantly greater in patients receiving the highest doses. A 6-week study of olanzapine showed greater improvement than placebo in agitation/aggression and psychosis with doses of 5 and 10 mg/day, but not 15 mg/day, with side effects including gait disturbance and sedation at all doses. A 52-week, open-label trial of quetiapine (median dose = 138 mg/day) in elderly patients with psychosis suggested good tolerability with apparent behavioral benefit; EPS improved or remained unchanged in most patients. Limited data describing aripiprazole have shown inconclusive evidence regarding relief of psychosis in elderly patients with Alzheimer's disease-related dementia, with apparently good tolerability over the short term. It appears that, in the aggregate, atypical antipsychotics are efficacious for treatment of agitation in dementia, with less clear impact on psychosis, but their tolerability profiles clearly differ. The National Institute of Mental Health-funded Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease project will provide the first head-to-head comparisons of atypicals in dementia and will examine possible drug-drug differences between efficacy and effectiveness.

A reality test: How well do we understand psychosis in Parkinson's disease?

Psychosis in Parkinson's disease (PD) is a major source of distress to patients and caregivers. Although the advent of atypical antipsychotic agents has, to some extent, resolved a clinical dilemma by preserving motor function while treating psychosis, our understanding of psychosis in PD remains in a nascent state. In this article the authors address several issues relating to psychosis in PD including the following: 1) prevalence, 2) possible etiologies and risk factors and 3) treatment. They also identify limitations in our understanding of this complex phenomenon and conclude that, despite availability of reasonable treatments for psychosis in PD, the search for a better understanding of the phenomenon must continue.

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.

Use of quetiapine in elderly patients.

Behavioral problems associated with psychosis in the elderly have a significant negative impact on patients' quality of life and can lead to placement in a nursing home. Because of their decreased propensity to produce extrapyramidal symptoms, atypical antipsychotics such as quetiapine hold promise in the treatment of these vulnerable patients. Quetiapine may, in theory, be particularly advantageous in this regard because of its lack of anticholinergic activity and its relatively loose binding to dopamine receptors. This article reviews the somewhat limited number of clinical studies of the use of quetiapine in treating older patients with schizophrenia and other psychotic disorders, patients with psychosis associated with Alzheimer's disease or dementia with Lewy bodies, and patients with Parkinson's disease and drug-induced psychosis.