Therapeutics

Valproate

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Overview

Name: Valproate
Synonyms: Depakote, Depakene, Valproic acid , Divalproex sodium
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Abbott Laboratories
Approved for: Epilepsy, Bipolar disorder, Migraine

Background

Valproate is an anti-convulsant and mood-stabilizing drug that is FDA- and EMA-approved to treat seizures, manic episodes associated with bipolar disorder, and to prevent migraine headaches. It is also used off-label for other psychiatric conditions. Valproate products include valproate sodium, divalproex sodium, valproic acid, and generic versions thereof. Side effects include fatigue, nausea, vomiting, tremors, and others.

Valproate increases the levels and functioning of the inhibitory neurotransmitter GABA by inhibiting the deactivating enzyme GABA transaminase and blocking reuptake of GABA into glia and nerve endings. A range of molecular and cellular mechanisms of action for have been proposed for valproate based on cell-based and rodent studies. It may work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels and is thought to also be a histone deacetylase inhibitor.

Findings

There has been extensive interest in the use of valproic acid to treat a variety of neurologic, psychiatric, and proliferative disorders, with hundreds of clinical trials being conducted in amyotrophic lateral sclerosis, spinal muscular atrophy, pain, schizophrenia, agitation, cluster headaches, glioblastoma, lymphoma, ovarian cancer, retinitis pigmentosa, and many other conditions.

In Alzheimer's disease, a Phase 3 trial evaluated whether valproate therapy had symptomatic efficacy to delay agitation and/or psychosis in patients who did not have these symptoms at screening. This was done using the neuropsychiatric inventory (NPI). The trial also assessed whether the drug delays the progression of cognitive and functional decline as measured by the Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog), Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating Sum of Boxes (CDR-SOB) batteries. Called VALID, the trial was sponsored by the Alzheimer's Disease Cooperative Study. Between 2005 and 2009, 46 participating centers in the United States enrolled 313 patients with moderate AD to be treated for two years with doses of valproate that were titrated up according to a patient's body weight and ability to tolerate the drug. One hundred and twenty-two patients completed two years on valproate. The treatment failed to delay the emergence of agitation or psychosis or slow cognitive or functional decline. The treatment group had more side effects such as sleepiness, gait disturbance, tremor, diarrhea, and weakness (Tariot et al., 2011). Full results of this trial are available at clinicaltrials.gov. A volumetric MR imaging substudy in 89 study participants found that patients who took valproate had more volume loss at one year than did those on placebo, and this finding correlated with indications for faster cognitive decline on valproate (Fleisher et al., 2011).

Previously, several smaller trials had evaluated valproate for the treatment of in Alzheimer's or dementia but had not yielded conclusive results (Porsteinsson 2006). For details on these trials, see clinicaltrial.gov.

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References

Paper Citations

  1. . Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011 Aug;68(8):853-61. PubMed.
  2. . Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology. 2011 Sep 27;77(13):1263-71. PubMed.
  3. . Divalproex sodium for the treatment of behavioural problems associated with dementia in the elderly. Drugs Aging. 2006;23(11):877-86. PubMed.

External Citations

  1. clinicaltrials.gov
  2. clinicaltrial.gov

Further Reading

Papers

  1. . A placebo-controlled trial of valproate for agitation and aggression in Alzheimer's disease. Dement Geriatr Cogn Disord. 2007;23(2):116-9. PubMed.
  2. . Use of antiepileptic drugs among community-dwelling persons with Alzheimer's disease in Finland. J Alzheimers Dis. 2011;26(2):231-7. PubMed.
  3. . A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Curr Alzheimer Res. 2005 Dec;2(5):553-8. PubMed.
  4. . A meta-analysis of mood stabilizers for Alzheimer's disease. J Huazhong Univ Sci Technolog Med Sci. 2010 Oct;30(5):652-8. PubMed.
  5. . Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J Neuropsychiatry Clin Neurosci. 2010 Winter;22(1):8-18. PubMed.
  6. . Low-dose divalproex in agitated patients with Alzheimer's disease. J Psychiatr Pract. 2010 Jan;16(1):63-7. PubMed.
  7. . Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med. 2008 Nov 24;205(12):2781-9. PubMed.