Chronic Divalproex Sodium to Attenuate Agitation and Clinical Progression of Alzheimer Disease

Tariot, Pierre N.

doi:10.1001/archgenpsychiatry.2011.72

Cited by 185 publications

(118 citation statements)

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“…The primary clinical endpoint was time to emergence of agitation or psychosis, combined with an assessment of the clinical significance of behavioral change rated by the study clinician. 11 Structural MRI scans were acquired at baseline and at 12 months to assess treatment and disease-associated changes in whole brain, hippocampal, and ventricular volumes over time, as a planned secondary analysis in a subset of participants. Randomization was one-toone for the 2 treatment groups in permuted blocks of 4.…”

Section: Methodsmentioning

confidence: 99%

“…Time to emergence of agitation or psychosis was assessed using the Neuropsychiatric Inventory (NPI). 11,13 Secondary clinical aims included delaying the progression of cognitive, functional, other behavioral and global measures associated with AD. These secondary aims were assessed with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinical Dementia Rating (CDR), MMSE, ADCS activities of daily living (ADCS-ADL), the ADCS Clinical Global Impression of Change scale (ADCS-CGIC), Cohen Mansfield Agitation Inventory (CMAI), and the Alzheimer's Disease Quality of Life scale (QOL-AD).…”

Section: Methodsmentioning

confidence: 99%

“…6 -10 This report presents results from an MRI substudy of a 24-month randomized, placebo-controlled clinical trial of divalproex sodium (divalproex) for mild to moderate AD, conducted by the Alzheimer's Disease Cooperative Study (ADCS). 11 The goal of the parent study was to determine whether divalproex delayed or prevented emergence of agitation or psychosis and slowed cognitive or functional decline in AD. The goal of this MRI study was to examine the effects of divalproex treatment on brain volumes, and to assess the effects of divalproex on the relationship between brain morphometry, cognition, function, and neuropsychiatric symptoms.…”

mentioning

confidence: 99%

“…Standard protocol approvals, registrations, and patient consents. Results from the primary randomized treatment trial from which data for this observational MRI subanalysis were obtained are reported separately, 11 and registered at clinicaltrials.gov (NCT00071721). Written informed consent was obtained from the caregiver and either the patient, if possible, or an authorized representative.…”

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confidence: 99%

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease

et al. 2011

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Objective:We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects.Methods: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals.Results: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ⑀4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (Ϫ10.9% and Ϫ12.4% vs Ϫ5.6% and Ϫ6.3%, and Ϫ3.5% vs Ϫ1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p Ͻ 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo ϭ Ϫ2.0 Ϯ 4.3, divalproex ϭ Ϫ3.9 Ϯ 4.0) (p ϭ 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease

et al. 2011

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“…Valproic acid, a treatment for epilepsy and bipolar disorder, showed preclinical efficacy with diverse mechanisms [87][88][89][90]. However clinical studies showed no beneficial effects in AD [91,92].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia

Cummings

Lyketsos

Peskind

et al. 2015

JAMA

162

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Chronic Divalproex Sodium to Attenuate Agitation and Clinical Progression of Alzheimer Disease

Abstract: 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.

Cited by 185 publications

References 47 publications

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia

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