Alzheimer Disease: Tariot PN

Anonymous00207, Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, Anonymous00208, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ. · No affiliation provided · Am J Psychiatry. · Pubmed #18340692 No free full text.

This publication has no abstract.

Tariot PN. · Memory Disorders Center, Banner Alzheimer's Disease Institute, Phoenix, AZ 85006, USA. · J Clin Psychiatry. · Pubmed #16649847 No free full text.

Abstract: Because of the mild symptomatology associated with its earlier stages, Alzheimer's disease (AD) is most commonly diagnosed in an intermediate to late stage of progression. Patients with moderate to severe AD at diagnosis have already experienced appreciable losses in cognition and functioning. However, such patients may still benefit greatly from the use of antidementia agents such as cholines-terase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA) receptor open-channel antagonist memantine. Monotherapy regimens involving a ChEI or memantine have been shown to slow the progression of cognitive symptoms in patients with moderate to severe AD, although memantine is currently the only agent approved for use in this setting. Furthermore, combination therapy involving memantine and a ChEI has been shown to yield increased cognitive benefits relative to ChEI monotherapy, a result that is believed to be attributable to the distinct therapeutic mechanisms associated with NMDA receptor open-channel antagonists and ChEIs. Nonetheless, recent findings indicate that the therapeutic effects of these antidementia agents are not limited to cognition. For example, emerging data highlight the efficacy of ChEIs and memantine, used either alone or in combination, in improving outcomes related to patient functioning and behavior, 2 domains that may have a great deal of significance for patients and caregivers. Furthermore, recent clinical trial data suggest that antidementia agents may significantly delay nursing home placement, a unique endpoint that can be tremendously distressing to patients with AD and their caregivers. Thus, it is clear that the ChEIs and memantine provide substantial benefits that extend across the spectrum of symptoms of AD, improving outcomes for those who are affected, either directly or indirectly, by this debilitating condition.

Profenno LA, Tariot PN. · Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, NY 14620, USA. · Dement Geriatr Cogn Disord. · Pubmed #14564127 No free full text.

Abstract: A large body of evidence has accrued that neuropsychiatric disturbances, such as agitation, are extremely common in Alzheimer's disease. These disturbances are associated with considerable morbidity including earlier nursing home admission, more rapid progression, exacerbation of functional and cognitive deficits, and increased caregiver distress. When attention to social or environmental causes, medical conditions, or other triggers of the behavioral disturbance fails to yield improvement, a role for medication may be indicated, whereby the most dominant behavioral target symptoms are matched to the most relevant medication class. Evidence is reviewed for various medication classes in treating agitation in the patient with Alzheimer's disease, and future treatment strategies may be aimed at delaying or preventing such neuropsychiatric disturbances.

Tariot PN, Federoff HJ. · Department of Psychiatry, University of Rochester Medical Center, Rochester, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #14512816 No free full text.

Abstract: A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.

Tariot PN. · Program in Neurobehavioral Therapeutics, and Department of Psychiatry, Monroe Community Hospital, Rochester, NY, USA. · J Am Geriatr Soc. · Pubmed #12801387 No free full text.

Abstract: A cure for Alzheimer's disease (AD) is still far off, and clinicians face the burden of caring for patients at all stages of dementia for the foreseeable future. Those with advanced disease suffer neurological symptoms and signs that include incontinence; problems with gait and mobility; marked cognitive, language, and functional impairment; and in about 90% of patients, significant behavior problems. Dementia precludes the ability to initiate meaningful activities or social interactions. Whether patients are resident in the community or living in a nursing home, this composite reflects a highly complex medical and neuropsychiatric management challenge. Predictable medical conditions also must be addressed (i.e., those that accompany dementia, such as parkinsonism, and those that are prevalent in any aging population, such as hypertension). Clinicians can better address these problems with awareness of current treatment options. Placebo-controlled trials of some psychotropic agents have shown modest favorable effects on behavior problems. Use of acetylcholinesterase inhibitors (AChEIs) to treat cognitive impairment and secondary behavioral symptoms derives primarily from results of placebo-controlled clinical trials. Trials in patients with moderate to severe AD, outpatients as well as nursing home residents, show overall effects similar to those seen in outpatients with milder dementia. Treatment with AChEIs may delay institutional placement. Memantine has shown benefit in trials in moderate to severe dementia, although it is not yet approved in the United States. Emerging data have expanded physicians' ability to use pharmacotherapy in patients with advanced dementia. Physicians need to enact the principle that something can be done for our afflicted parents and grandparents.

Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S. · Program in Neurobehavioral Therapeutics, Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Monroe Community Hospital, 435 East Henrietta Road, Rochester, NY 14620, USA. · Adv Drug Deliv Rev. · Pubmed #12453674 No free full text.

Abstract: OBJECTIVE: This paper provides a case study of 'reverse translational research', in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimer's disease (AD) ultimately led to mechanism-based trials addressing aspects of the underlying pathophysiology of Alzheimer's disease. AD is multi-dimensional in nature, characterized not only by cognitive and functional decline but by neuropsychiatric symptoms that develop commonly and are associated with considerable morbidity. There have been a large number of empirical trials of various pharmacological agents to reduce these symptoms, such as agitation. Although antipsychotics are used most frequently for agitation, the usual effect size is modest, and there is a range of tolerability and/or safety issues, leading to the hope that alternatives can be found. Furthermore, most clinical trials addressing psychopathology have not been mechanism-based and none have attempted an alternative approach, namely, to delay or prevent the emergence of psychopathology. FINDINGS: The evidence of clinical trials is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed, leading to the surprising conclusion that neuroprotective properties may account for some of its clinical effects. These mechanisms (including activation of wnt-dependent signaling and upregulation of bcl-2, among others) may be particularly relevant for long-term treatment of AD. CONCLUSIONS: These clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimer's Disease Cooperative Study. The design addresses valproate's potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.

Tariot PN, Ryan JM, Porsteinsson AP, Loy R, Schneider LS. · Department of Psychiatry, University of Rochester Medical Center and Monroe Community Hospital, Rochester, New York, USA. · Clin Geriatr Med. · Pubmed #11375140 No free full text.

Abstract: Behavioral signs and symptoms in dementia are common, morbid, classifiable, and treatable. The current state-of-the-art approach is to evaluate carefully for social or environmental causes, intercurrent medical conditions, or other triggers of the behavior and attempt to deal with those directly. When these conservative steps fail, there may be a role for medication. A rational approach typically hinges on matching the most dominant behavioral target symptoms to the most relevant medication class, the key information of which is summarized.

van Dyck CH, Tariot PN, Meyers B, Malca Resnick E, Anonymous00315. · Yale University School of Medicine, New Haven, CT 06510, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17545739 No free full text.

Abstract: This study examined the efficacy and safety of memantine monotherapy in patients with moderate-to-severe Alzheimer disease (AD). Patients not receiving a cholinesterase inhibitor (N=350) were randomized to receive memantine (20 mg/d) or placebo during this 24-week, double-blind, placebo-controlled trial. Prospectively defined analyses failed to demonstrate a statistically significant benefit of memantine treatment compared with placebo on the Severe Impairment Battery (SIB) at week 24 end point, although a significant advantage was observed for memantine at weeks 12 and 18. The 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL19) did not differ significantly between groups in any analysis. Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus) did not significantly favor memantine at week 24 despite a significant advantage for memantine at weeks 12 and 18. Other secondary outcomes showed no significant treatment differences. Post hoc analyses of potentially confounding covariates and alternative methods of imputing missing data did not substantially alter the results. Because of the violations of normality assumptions for the SIB and ADCS-ADL19, nonparametric analyses were performed; statistically significant benefit of memantine over placebo was demonstrated at week 24 for the SIB but not the ADCS-ADL19. The type and incidence of adverse events were similar in both groups.

Mhyre TR, Loy R, Tariot PN, Profenno LA, Maguire-Zeiss KA, Zhang D, Coleman PD, Federoff HJ. · Center for Aging and Developmental Biology, Aab Institute for Biomedical Research, University of Rochester School of Medicine and Dentistry, Box 645, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Neurobiol Aging. · Pubmed #17521776 No free full text.

Abstract: The molecular profiling of peripheral tissues, including circulating leukocytes, may hold promise in the discovery of biomarkers for diagnosing and treating neurodegenerative diseases, including Alzheimer's disease (AD). As a proof-of-concept, we performed a proteomics study on peripheral leukocytes from patients with AD both before and during treatment with divalproex sodium. Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified 10 differentially expressed proteins: two up-regulated proteins, 14-3-3 protein epsilon and peroxiredoxin 2; and eight down-regulated proteins, actin-interacting protein, mitogen activated protein kinase 1, beta actin, annexin A1, glyceraldehyde 3-phosphate dehydrogenase, transforming protein RhoA, acidic leucine-rich nuclear phosphoprotein 32 family member B, and a currently unidentified protein. A subset was validated on both the transcript and protein levels in normal human peripheral blood mononuclear cell cultures treated with valproic acid. These proteins comprise a number of functional classes that may be important to the biology of AD and to the therapeutic action of valproate. These data also suggest the potential of using peripheral leukocytes to monitor pharmaceutical action for neurodegenerative diseases.

Cummings JL, Schneider E, Tariot PN, Graham SM, Anonymous00245. · Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1769, USA. · Neurology. · Pubmed #16832078 No free full text.

Abstract: OBJECTIVE: To investigate the behavioral effects of memantine in moderate to severe Alzheimer disease (AD). METHODS: The authors conducted a hypothesis-generating, exploratory analysis of a 24-week, double-blind, placebo-controlled trial comparing memantine (20 mg/day) with placebo in subjects with moderate to severe AD on stable donepezil treatment. They employed the Neuropsychiatric Inventory (NPI; 12-item), administered at baseline, week 12, and week 24, to assess the effects of memantine on behavior. Global, cognitive, and functional measures were collected and relationships between these assessments and changes in behavior were determined. The intent-to-treat population was examined using last-observation-carried-forward and observed-cases approaches. RESULTS: Patients treated with memantine had significantly lower NPI total scores than patients treated with placebo. Analyses of the 12 NPI domains revealed significant effects in favor of memantine on agitation/aggression, eating/appetite, and irritability/lability. Of patients who exhibited agitation/aggression at baseline, those treated with memantine showed significant reduction of symptoms compared with placebo-treated patients. Memantine-treated patients without agitation/aggression at baseline evidenced significantly less emergence of this symptom compared with similar patients receiving placebo. Caregivers of patients receiving memantine registered significantly less agitation-related distress. There were significant relationships between the NPI and the global rating scale and performance of activities of daily living, but not between changes in the NPI and cognition. CONCLUSION: Treatment with memantine reduced agitation/aggression, irritability, and appetite/eating disturbances. Memantine reduced agitation/aggression in patients who were agitated at baseline and delayed its emergence in those who were free of agitation at baseline.

Galasko D, Kershaw PR, Schneider L, Zhu Y, Tariot PN. · Department of Neurosciences, University of California at San Diego, San Diego, California, USA. · J Am Geriatr Soc. · Pubmed #15209643 No free full text.

Abstract: OBJECTIVES: To examine the effect of galantamine on activities of daily living (ADLs) with respect to baseline dementia severity, correlation with cognitive and global function, specific ADLs affected, and maintenance of ADL independence. DESIGN: Secondary analysis of a 5-month randomized, placebo-controlled trial. SETTING: Multiple U.S. clinical centers. PARTICIPANTS: Six hundred fifty-nine patients with mild to moderate Alzheimer's disease (AD) who completed 5 months of treatment. INTERVENTION: Galantamine at a maintenance dose of 16 or 24 mg/d. MEASUREMENTS: The AD Cooperative Study ADL Inventory (ADCS/ADL). RESULTS: Galantamine resulted in more improvement in ADCS/ADL scores than placebo regardless of baseline dementia severity, with the greatest differences occurring in patients with more severe disease. Changes in ADCS/ADL scores correlated significantly with change scores on the cognitive subscale of the AD Assessment Scale (r=-0.24). Galantamine treatment resulted in maintenance or improvement of basic and instrumental ADLs, and change from baseline to Month 5 in scores for each individual ADL item favored galantamine over placebo in three of six basic ADLs and six of 17 instrumental ADLs. CONCLUSION: Galantamine has a favorable effect on ADL performance in patients with AD, detectable after 5 months of treatment, regardless of dementia severity. The ADCS/ADL appears to better measure distinct abilities that may be relevant not only in clinical trials but also in individual patients than do cognitive assessments.

Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W. · Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095-1769, USA. · Am J Psychiatry. · Pubmed #14992980 links to  free full text

Abstract: OBJECTIVE: Alzheimer's disease pathology includes both histologic changes and neurotransmitter deficits. The cholinergic deficit contributes to both cognitive and behavioral disturbances, and cholinesterase inhibitors may improve behavior in Alzheimer's disease patients. This analysis was conducted to assess the impact of galantamine, a cholinesterase inhibitor with nicotinic-receptor-modulating properties, on the pattern and evolution of behavioral disturbances in patients with Alzheimer's disease and on caregiver distress related to patients' behavior. METHOD: Data from 978 patients with mild to moderate Alzheimer's disease who were randomly assigned to placebo or galantamine (8, 16, or 24 mg/day) were analyzed. Behavioral changes were assessed with the Neuropsychiatric Inventory, and alterations in caregiver distress were measured by the Neuropsychiatric Inventory distress scale. Data collected at baseline and 12 and 21 weeks postbaseline were analyzed. RESULTS: Neuropsychiatric Inventory scores worsened with placebo, whereas patients treated with 16 or 24 mg/day of galantamine had no change in total Neuropsychiatric Inventory scores. Treated patients, asymptomatic or symptomatic at baseline, had better Neuropsychiatric Inventory subscale scores than did patients receiving placebo. Behavioral improvement in patients symptomatic at baseline ranged from 29% to 48%. Changes were evident in patients receiving 16 or 24 mg/day of galantamine. High-dose galantamine was associated with a significant reduction in caregiver distress. CONCLUSIONS: Galantamine therapy was associated with reduced emergence of behavioral disturbances and improvement in existing behavioral problems in patients with mild to moderate Alzheimer's disease, with a concomitant reduction in reported caregiver distress.

Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, Anonymous00181. · Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, NY 14620, USA. · JAMA. · Pubmed #14734594 links to  free full text

Abstract: CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed. OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial. INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

Porsteinsson AP, Tariot PN, Jakimovich LJ, Kowalski N, Holt C, Erb R, Cox C. · Department of Psychiatry, Program in Neurobehavioral Therapeutics, University of Rochester Medical Center and Monroe Community Hospital, tochester, NY 14620, USA. · Am J Geriatr Psychiatry. · Pubmed #12837672 No free full text.

Abstract: OBJECTIVE: The authors describe an open-label extension of a double-blind, randomized, placebo-controlled study of divalproex sodium in 56 nursing home patients with agitation and dementia. METHODS: Participants (N=46) were treated for 6 weeks in an open fashion with clinically optimal doses of divalproex sodium (range: 250 mg/day-1,500 mg/day; mean: 851 mg/day). Behavior was assessed with the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression of Change (CGI) by new raters. Safety, tolerability, and laboratory data were obtained regularly. RESULTS: The mean BPRS Agitation Factor decreased by 3.1 points from baseline; 86% of those completing the open phase were rated as improved on the CGI. These changes were mirrored by changes in other behavior rating scales. Sixty percent of subjects had no side effects; 33% had side effects that were rated as mild. There were no clinically significant changes in laboratory values. CONCLUSION: Ongoing open-label treatment with divalproex was associated with improvement in measures of agitation. Doses, levels, and tolerability were similar to those in the blinded phase of the study. These findings help confirm and extend the results from the placebo-controlled phase of the trial and suggest that divalproex may be beneficial for some patients with this clinical problem.

Tariot PN, Jakimovich L. · Department of Psychiatry, University of Rochester Medical Center, NY 14620, USA. · J Am Med Dir Assoc. · Pubmed #12837144 No free full text.

Abstract: The following case describes a severely demented, elderly male patient who was placed in a nursing home when he became unmanageable in an assisted-living facility. Upon admission to the nursing facility, the patient was diagnosed with relatively severe Alzheimer's disease (AD)treated with the cholinesterase inhibitor donepezil in the context of a clinical study. This report illustrates that donepezil, and perhaps by analogy other cholinesterase inhibitors as well, can be efficacious in treating the cognitive, functional, and behavioral impairment associated with advanced AD.

Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E. · Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, New York 14620, USA. · J Am Geriatr Soc. · Pubmed #11843990 No free full text.

Abstract: OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S, Hsiao JK, Jeste DV, Katz IR, Olin JT, Pollock BG, Rabins PV, Rosenheck RA, Small GW, Lebowitz B, Lieberman JA. · Clinical Antipsychotic Trials of Intervention Effectiveness Program of the National Institute of Mental Health at the University of North Carolina, Chapel Hill, NC, USA. · Am J Geriatr Psychiatry. · Pubmed #11739062 No free full text.

Abstract: 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.

Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. · Department of Psychiatry, University of Rochester Medical Center, NY 14620, USA. · Neurology. · Pubmed #10881251 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. METHODS: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. RESULTS: After 5 months, the galantamine-placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses). Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. Treatment discontinuations due to adverse events were low in all galantamine groups (6 to 10%) and comparable with the discontinuation rate in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild. CONCLUSIONS: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

Tariot PN, Upadhyaya A, Sunderland T, Cox C, Cohen RM, Murphy DL, Loy R. · University of Rochester Medical Center, Program in Neurobehavioral Therapeutics, Monroe Community Hospital, New York, USA. · Biol Psychiatry. · Pubmed #10435208 No free full text.

Abstract: BACKGROUND: Prior work showed that administration of naloxone HCl had different behavioral effects in patients with Alzheimer's disease (AD) than controls. The aim of the present study was to contrast the physiologic and neuroendocrine responses to administration of a wide range of doses of intravenous naloxone of patients with probable Alzheimer's disease to aged-matched controls. METHODS: This was a double-blind, placebo-controlled, study of 12 patients with probable Alzheimer's disease and 8 age-matched normal controls who each received intravenous infusions of naloxone HCl on 3 different days in doses of 0.1 mg/kg and 2.0 mg/kg preceded by test doses of 0.5 mcg/kg. Order of treatment condition was randomized. Vital signs and plasma cortisol and prolactin were obtained at regular intervals. RESULTS: Both groups showed increased cortisol after naloxone 0.1 mg/kg and 2.0 mg/kg (p < .0001), but the increase was significantly greater and longer lived in controls than in patients. Patients, but not controls, also experienced a significant hypothermic response after naloxone 2.0 mg/kg (p < .05). Prolactin, heart rate, and blood pressure did not change following naloxone and did not differ between groups. CONCLUSIONS: These findings support a growing body evidence that HPA axis activity is increased in AD, and further suggest that at least part of this may be due to decreased opiatergic tonic inhibition.

Tariot PN, Aisen PS. · Banner Alzheimer's Institute, Phoenix, AZ 85006, USA. · J Clin Psychiatry. · Pubmed #19573485 No free full text.

This publication has no abstract.

Zheng L, Mack WJ, Dagerman KS, Hsiao JK, Lebowitz BD, Lyketsos CG, Stroup TS, Sultzer DL, Tariot PN, Vigen C, Schneider LS. · Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA. · Am J Psychiatry. · Pubmed #19369318 No free full text.

Abstract: 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.

Sabbagh MN, Tariot PN. · Cleo Roberts Center, Banner Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #19328441 No free full text.

This publication has no abstract.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, Rosenheck RA, Hsiao JK, Lieberman JA, Schneider LS, Anonymous00049. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Am J Psychiatry. · Pubmed #18519523 links to  free full text

Abstract: 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.

Tariot PN. · Memory Disorders Center, Banner Alzheimer's Institute, Phoenix, AZ 85006, USA. · J Clin Psychiatry. · Pubmed #18402497 No free full text.

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