Alzheimer Disease: Tariot PN

Rosenheck RA, Leslie DL, Sindelar JL, Miller EA, Tariot PN, Dagerman KS, Davis SM, Lebowitz BD, Rabins P, Hsiao JK, Lieberman JA, Schneider LS, Anonymous00401. · Northeast Program Evaluation Center (182), VA Connecticut Health Care System, West Haven, Connecticut 06516, USA. · Arch Gen Psychiatry. · Pubmed #17984395 links to  free full text

Abstract: 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.

Tariot PN. · No affiliation provided · CNS Spectr. · Pubmed #17712915 links to  free full text

This publication has no abstract.

Ismail MS, Dagerman K, Tariot PN, Abbott S, Kavanagh S, Schneider LS. · University of Rochester Medical Center, Program in Neurobehavioral Therapeutics, Monroe Community Hospital, 435 East Henrietta Road, Rochester, NY 14620, USA. · Curr Alzheimer Res. · Pubmed #17627490 No free full text.

Abstract: 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.

Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA, Anonymous00024. · Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. · N Engl J Med. · Pubmed #17035647 links to  free full text

Abstract: 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].).

Tariot PN, Schneider L, Katz IR, Mintzer JE, Street J, Copenhaver M, Williams-Hughes C. · Memory Disorders Center, Banner Alzheimer's Disease Institute, Phoenix, Arizona, USA. · Am J Geriatr Psychiatry. · Pubmed #16905684 No free full text.

Abstract: OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, and tolerability of quetiapine for treating psychosis in patients with probable/possible Alzheimer disease and assess its impact on other psychopathology and social and daily functioning. METHOD: The authors conducted a multicenter, double-blind, placebo-controlled, randomized trial of flexibly dosed quetiapine and haloperidol. Primary outcomes were change in total Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness (CGI-S) scores at week 10. Secondary outcomes included BPRS factors, Neuropsychiatric Inventory (NPI), Multidimensional Observation Scale for Elderly Subjects (MOSES), and Physical Self-Maintenance Scale (PSMS). RESULTS: Two hundred eighty-four participants (mean age: 83.2 years) were randomized; 63.4% completed; and mean Mini-Mental State Examination score was 12.8. Median of the mean daily dose was 96.9 mg for quetiapine and 1.9 mg for haloperidol. No differential benefit was seen on any psychosis measure. BPRS agitation factor scores improved with quetiapine versus placebo and not quetiapine versus haloperidol. BPRS anergia scores worsened with haloperidol versus quetiapine but not quetiapine versus placebo. No NPI factors showed change, including the agitation factor. MOSES Withdrawal Subscale and PSMS total scores worsened with haloperidol versus quetiapine. Somnolence occurred in 25.3%, 36.2%, and 4.1% of the quetiapine, haloperidol, and placebo groups, respectively; parkinsonism was most prevalent in the haloperidol group; other safety and tolerability measures differed little among groups. CONCLUSION: All treatment groups showed improvement in measures of psychosis without significant differences between them when planned comparisons were performed. Participants treated with quetiapine or haloperidol showed inconsistent evidence of improvement in agitation. Tolerability was better with quetiapine compared with haloperidol.

Profenno LA, Jakimovich L, Holt CJ, Porsteinsson A, Tariot PN. · Department of Psychiatry, University of Rochester Medical Center, NY 14620, USA. · Curr Alzheimer Res. · Pubmed #16375658 No free full text.

Abstract: OBJECTIVE: The Alzheimer's Disease Cooperative Study (ADCS) is conducting a clinical trial to address whether chronic valproate treatment can delay emergence of behavioral symptoms in outpatients with AD. Since there were no data on the safety and tolerability of divalproex sodium in outpatients with dementia, we undertook a pilot study to inform the design of the ADCS study. METHODS: We recruited 20 outpatients with probable AD, MMSE 10-20, without history of agitation or psychosis. This was a 10-week randomized, double-blind, placebo-controlled study assessing the safety and tolerability of 1,000 mg/day and 1,500 mg/day of divalproex sodium delayed-release for 8 weeks followed by extended-release for 2 weeks. Other outcome measures addressed cognition, function, global status, side effects, and laboratory data. RESULTS: Participants assigned to active treatment ingested approximately 30% less of their prescribed study medication compared to those receiving placebo (p < .05 Wilcoxon Rank Sum test). The average tolerated dose for all participants at week 8 was 810 mg/day or 11.5 mg/kg/day, similar to the dose tolerated by nursing home patients. The most common side effects were sleepiness and tiredness, with worse cognitive performance in those assigned to 1500 mg/day. CONCLUSIONS: These results were used to design the multi-center ADCS trial. Doses of less than 1000 mg/day of divalproex sodium were the maximum tolerated by these outpatients with AD. A larger study of divalproex sodium dose tolerability is needed to define treatment in outpatients with Alzheimer's disease.

Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M. · Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA. · Curr Alzheimer Res. · Pubmed #16375657 No free full text.

Abstract: CONTEXT: Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results. OBJECTIVE: To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type. DESIGN: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial. SETTING: Outpatient clinics of universities and private research centers specialized in dementia. PATIENTS: 513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug. INTERVENTION: 26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo. MAIN OUTCOMES: Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). RESULTS: There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE. CONCLUSION: The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.

Tariot PN, Raman R, Jakimovich L, Schneider L, Porsteinsson A, Thomas R, Mintzer J, Brenner R, Schafer K, Thal L, Anonymous00302, Anonymous00303. · Department of Psychiatry, The Center for Aging and Developmental Biology, Univ. of Rochester Medical Center, Rochester, NY, USA. · Am J Geriatr Psychiatry. · Pubmed #16286437 No free full text.

Abstract: OBJECTIVE: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. RESULTS: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. CONCLUSIONS: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.

Kim SY, Kim HM, McCallum C, Tariot PN. · Department of Psychiatry, Center for Behavioral and Decision Sciences in Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. · Neurology. · Pubmed #16275826 No free full text.

Abstract: BACKGROUND: Research involving decisionally incapable adults remains an unsettled and controversial policy issue, especially for protocols that involve significant risk to participants. Few data exist to guide policymakers and IRBs OBJECTIVE: Survey the views of persons at heightened risk for dementia regarding the acceptability of surrogate consent for biomedical research of varying levels of risks and potential benefits. METHODS: Using a mail survey, the authors surveyed the participants at one of the sites of the Alzheimer's Disease Anti-inflammatory Prevention Trial (all participants are 70 years old or older with at least one first-degree relative with dementia) and measured responses regarding the acceptability of surrogate consent for 10 research scenarios of varying degrees of risks and benefits (ranging from an observation study to a gene transfer protocol), given from the perspectives of social policy, personal preferences for self, and preferences when deciding on behalf of a loved one. RESULTS: Two hundred twenty-nine of 259 eligible participants responded (88%). A large majority (>90%) found minimal risk studies as well as randomized clinical trials of new medications acceptable for surrogate consent. A smaller majority found the more invasive studies acceptable. Participants were more cautious when deciding for a loved one. General attitude toward biomedical research and scenario-specific risk perception were strong independent predictors. Demographic and personal history variables had relatively little effect. CONCLUSIONS: Laypersons at heightened risk of Alzheimer disease discriminate among research scenarios of varying risks and burdens. They are supportive of surrogate consent-based research even when the risks and burdens are significant to the subjects; these opinions appear to be based in part on their assessment of risks as well as on their general attitude toward biomedical research.

Tariot PN. · Department of Psychiatry, University of Rochester Medical Center, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #14512814 No free full text.

This publication has no abstract.

Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, Pfeiffer E, Ryan JM, Sultzer DL, Tariot PN. · Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA. · Schizophr Bull. · Pubmed #12908661 links to  free full text

Abstract: 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.

Loy R, Tariot PN. · Department of Neurology, Program in Neurobehavioral Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA. · J Mol Neurosci. · Pubmed #12540056 No free full text.

Abstract: Neuropsychiatric disturbances are extremely common in Alzheimer's disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.

Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD. · Adult and Geriatric Treatment and Preventive Interventions Research Branch, National Institute of Mental Health, Bethesda, MD 20892-9635, USA. · Am J Geriatr Psychiatry. · Pubmed #11925273 No free full text.

Abstract: The authors, a group of investigators with extensive research and clinical experience related to both late-life depression and Alzheimer disease (AD), propose provisional affective and behavioral inclusion and exclusion diagnostic criteria for Depression of AD.

Tariot PN. · Department of Psychiatry, University of Rochester Medical Center, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #11669506 No free full text.

Abstract: Cognitive impairment, a core feature of Alzheimer disease (AD), is highly correlated with functional decline and caregiver time. Over 12 months, patients with mild-to-moderate AD deteriorate by 5-6 points from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Stabilizing cognitive decline is, therefore, an important treatment outcome in AD. Cognitive deficits are thought to result in part from central cholinergic impairment, which provides the rationale for the enhancement of cholinergic neurotransmission as a treatment approach for AD. Acetylcholinesterase (AChE) inhibition has, to date, produced the most promising outcomes in clinical trials. Galantamine appears to be novel among marketed agents in that it inhibits AChE and modulates cholinergic nicotinic receptors, perhaps increasing neurotransmission via both mechanisms. Long-term effects of AChE inhibitors and galantamine on ADAS-cog scores of patients with mild-to-moderate AD have been studied in placebo controlled trials as well as open-extension studies that followed randomized, double-blind studies for up to 6 months. Conventional AChE inhibitors (rivastigmine and donepezil) have maintained ADAS-cog baseline scores for up to 40 weeks in open extension studies, and Mini-Mental State Examination (MMSE) scores for up to 52 weeks in a placebo-controlled study. The mean ADAS-cog score of galantamine-treated patients did not change from baseline at 12 months (6 months double-blind study followed by 6 months open-label extension), suggesting that cognitive function had been maintained. These results suggest that cholinergic treatments, including galantamine, may stabilize cognitive decline of AD patients. This outcome is likely to make an important difference to patients and caregivers.

Mack JL, Patterson MB, Tariot PN. · Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA. · J Geriatr Psychiatry Neurol. · Pubmed #10616870 No free full text.

Abstract: We studied 555 Alzheimer's disease patients on the Behavior Rating Scale for Dementia (BRSD), which uses informant interviews to measure behavioral pathology in demented patients. For the 45 items, ratings of present ranged from 5% to 66% of the subjects, with 39 rated present in at least 10%. Twenty-nine items were significantly correlated with dementia severity. The mean number of items present per subject was 13.5; only two subjects had none rated present. Factor analysis identified six factors common to mildly and moderately demented subjects. Six subscales were developed: Depressive Symptoms, Inertia, Vegetative Symptoms, Irritability/Aggression, Behavioral Dysregulation, and Psychotic Symptoms. Interitem consistency was high for three subscales (alpha's from .75 to .80) and moderate for three (alpha's from .48 to .56). Four subscale scores and total scores were significantly but weakly correlated with dementia severity. Detailed results and test instructions are presented in the BRSD manual, available from The Consortium to Establish a Registry for Alzheimer's Disease.

Tariot PN, Ogden MA, Cox C, Williams TF. · Department of Psychiatry, University of Rochester Medical Center, NY, USA. · J Am Geriatr Soc. · Pubmed #10203117 No free full text.

Abstract: OBJECTIVES: To examine the presence or absence of dementia, and the prevalence rates for different dementias, in patients with and without adult onset diabetes (AODM). DESIGN: Chart survey. SETTING: A public long-term care facility in Rochester, New York, chosen to provide an enriched sample with respect to the diseases and demographic variables of interest. PARTICIPANTS: All long-term care residents in the facility aged 50 years or older (n = 476), mean age 74.8 years. Thirty-six (7.6%) had probable Alzheimer's disease (AD), 49 (10.3%) had possible AD, 38 (8.0%) had clinically diagnosed vascular dementia, 84 (17.6%) had unspecified dementias, and 269 (56.5%) were not demented. MEASUREMENTS: Demographic data, dementia and diabetes determined on the basis of extraction of chart data, and hypertension, myocardial infarction, congestive heart failure, and hypercholesterolemia determined on the basis of chart diagnoses. RESULTS: There were 99 residents with AODM in the sample, a prevalence rate of about 21%. The rates of both dementia and AODM were as expected for this age group and setting. Patients with probable or possible AD had the lowest rates of AODM (0 and 6.1%, respectively), and patients with vascular dementia had the highest rates of AODM (47.4%). Age, sex, and race influenced both the risk of having a dementia and the type of dementia. When these variables were adjusted for in multiple logistic regression, however, AODM remained a robust predictive factor because of its significant negative association with AD. Patients with unspecified dementias and no dementia showed rates of AODM (about 20%) that were roughly comparable and intermediate between vascular dementia and AD. CONCLUSIONS: In our study, AD diagnosed clinically and AODM did not co-occur, whereas AODM was associated with vascular dementia diagnosed clinically. Conversely, in non-Alzheimer, nonvascular dementias diagnosed clinically, the rates of AODM were equivalent to those in nondemented patients. These findings are in agreement with some, but not all, previous studies.

Grossberg GT, Corey-Bloom J, Small GW, Tariot PN. · Departments of Psychiatry and Internal Medicine, St. Louis University Health Center and Wohl Clinic, St. Louis, MO, USA. · J Clin Psychiatry. · Pubmed #15003082 No free full text.

This publication has no abstract.