Original Research Article
A Placebo-Controlled Trial of Valproate for Agitation and Aggression in Alzheimer’s DiseaseHerrmann N.a, b, d, e · Lanctôt K.L.a-d · Rothenburg L.S.a, b · Eryavec G.d-f
aNeuropharmacology Research Program and bDepartment of Psychiatry, Sunnybrook Health Sciences Centre, and Departments of cPharmacology, dPsychiatry and eMedicine, University of Toronto, Toronto, and fSeniors’ Health Centre, North York General Hospital, North York, Canada
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background/Aims: To assess the efficacy and tolerability of valproate for the treatment of agitation and aggression in moderate-to-severe Alzheimer’s disease (AD). Methods: This was a randomized, double-blind, placebo-controlled crossover trial of valproate in institutionalized AD patients. Patients were assessed with the Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory at baseline and after 6 weeks of treatment with valproate and placebo, with 2 weeks between phases to allow for placebo washout and tapering. Results: Fourteen patients (8 male/6 female) aged 85.6 ± 4.5 years with baseline Mini Mental State Examination scores of 4.5 ± 4.6 and NPI agitation/aggression scores of 6.4 ± 3.5 were randomized to treatment. NPI agitation/aggression treatment change scores significantly worsened during valproate treatment compared with placebo (Z = –2.03, p = 0.04). Tolerability of valproate was also poor, with patients experiencing a significantly greater mean number of adverse events during valproate therapy compared to placebo (Z = –2.82, p = 0.005). Conclusion: Valproate is not effective for the management of agitation in moderate-to-severe AD, and may be poorly tolerated in this population.
© 2007 S. Karger AG, Basel
Finkel S: Introduction to behavioural and psychological symptoms of dementia (BPSD). Int J Geriatr Psychiatry 2000;15(suppl 1):S2–S4.
- Marx MS, Cohen-Mansfield J, Werner P: Agitation and falls in institutionalized elderly persons. J Appl Gerontol 1990;9:106–117.
- Evans LK, Strumpf NE: Tying down the elderly. A review of the literature on physical restraint. J Am Geriatr Soc 1989;37:65–74.
- Lopez OL, Wisniewski SR, Becker JT, Boller F, DeKosky ST: Psychiatric medication and abnormal behavior as predictors of progression in probable Alzheimer disease. Arch Neurol 1999;56:1266–1272.
- Moritz DJ, Fox PJ, Luscombe FA, Kraemer HC: Neurological and psychiatric predictors of mortality in patients with Alzheimer disease in California. Arch Neurol 1997;54:878–885.
- Keene J, Hope T, Fairburn CG, Jacoby R, Gedling K, Ware CJ: Natural history of aggressive behaviour in dementia. Int J Geriatr Psychiatry 1999;14:541–548.
- Herrmann N, Lanctôt KL, Sambrook R, Lesnikova N, Hebert R, McCracken P, Robillard A, Nguyen E: The contribution of neuropsychiatric symptoms to the cost of dementia care. Int J Geriatr Psychiatry 2006;21:972–976.
- Herrmann N, Lanctôt KL: Do atypical antipsychotics cause stroke? CNS Drugs 2005;19:91–103.
- Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934–1943.
Herrmann N: Recommendations for the management of behavioral and psychological symptoms of dementia. Can J Neurol Sci 2001;28(suppl 1):S96–S107.
- Tariot PN, Schneider LS, Mintzer JE, Cutler AJ: Safety and tolerability of divalproex sodium in treatment of signs and symptoms of mania in elderly patients with dementia: results of a double-blind placebo-controlled trial. Curr Ther Res Clin Exp 2001;62:51–67.
- Porsteinsson AP, Tariot PN, Erb R, Cox C, Smith E, Jakimovich L, Noviasky J, Kowalski N, Holt CJ, Irvine C: Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry 2001;9:58–66.
- Sival RC, Haffmans PM, Jansen PA, Duursma SA, Eikelenboom P: Sodium valproate in the treatment of aggressive behavior in patients with dementia – A randomized placebo controlled clinical trial. Int J Geriatr Psychiatry 2002;17:579–585.
Lonergan ET, Cameron M, Luxenberg J: Valproic acid for agitation in dementia. Cochrane Database Syst Rev 2004;2:CD003945.
- Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
- Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314.
- Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, Russell RW, Symon L: Cerebral blood flow in dementia. Arch Neurol 1975;32:632–637.
- Cohen-Mansfield J, Billig N: Agitated behaviors in the elderly. 1. A conceptual review. J Am Geriatr Soc 1986;34:711–721.
- Tariot PN, Raman R, Jakimovich L, Schneider L, Porsteinsson A, Thomas R, Mintzer J, Brenner R, Schafer K, Thal L: Divalproex sodium in nursing home residents with possible or probable Alzheimer disease complicated by agitation: a randomized, controlled trial. Am J Geriatr Psychiatry 2005;13:942–949.
Lanctôt KL, Herrmann N, Rothenburg L, Eryavec GM: Behavioral correlates of GABAergic disruption in Alzheimer’s disease. Int Psychogeriatr 2006, published online.
Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N: GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry 2004;49:439–453.
- Trannel TJ, Ahmed I, Goebert D: Occurrence of thrombocytopenia in psychiatric patients taking valproate. Am J Psychiatry 2001;158:128–130.
- Sival RC, Duivenvoorden HJ, Jansen PA, Haffmans PM, Duursma SA, Eikelenboom P: Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study. Int J Geriatr Psychiatry 2004;19:305–312.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.