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Valproic Acid May Be Better Than Divalproex for Psychiatric Patients

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Désirée Lie, MD, MSEd
  • CME Released: 2/3/2005
  • Valid for credit through: 2/3/2006
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Target Audience and Goal Statement

This article is intended for primary care physicians, psychiatrists, and other specialists who treat psychiatric inpatients.

The goal of this activity is to provide the latest medical news to physicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Compare the length of hospital stay, rehospitalization rate, and adverse drug reactions associated with valproic acid vs divalproex sodium in patients admitted for psychiatric conditions.
  • Compare the cost of valproic acid vs divalproex sodium when used for inpatient psychiatric admissions.


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  • Laurie Barclay, MD

    Laurie Barclay is a freelance writer for Medscape.


    Disclosure: Dr. Barclay has reported no significant financial interests.


  • Gary Vogin, MD

    Senior Medical Editor, Medscape


    Disclosure: Dr. Vogin has reported no significant financial interests.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor of Family Medicine; Director, Division of Faculty Development, University of California, Irvine School of Medicine, Irvine, California


    Disclosure: Dr. Lie has reported no significant financial interests.

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Valproic Acid May Be Better Than Divalproex for Psychiatric Patients

Authors: News Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEdFaculty and Disclosures

CME Released: 2/3/2005

Valid for credit through: 2/3/2006


A quasi-experimental clinical trial suggests that initially giving inpatients generic valproic acid and changing to delayed-release divalproex, only if intolerance occurs, may be more cost-effective.

Feb. 3, 2005 -- Psychiatric patients should be treated with valproic acid rather than divalproex, according to the results of a quasi-experimental clinical trial published in the February issue of the American Journal of Psychiatry.

"Valproate is available as a proprietary formulation in enteric-coated delayed-release divalproex sodium tablets ... and as generic immediate-release valproic acid," write Adel A. Wassef, MD, from the University of Texas Health Sciences Center in Houston. "The cost differential between the two formulations has steadily risen in the past decade."

In this six-year, prospective trial comparing the effectiveness and tolerability of divalproex and valproic acid in 9,260 psychiatric admissions, the dependent variables were length of hospital stay, rehospitalization rate, and adverse drug reactions.

Compared with patients who initially received valproic acid, inpatients who initially received divalproex sodium had a 32.7% longer hospital stay and 3.8% higher readmission rate. In patients treated with divalproex and valproic acid during different admissions, initial treatment with divalproex prolonged length of stay by 30.3%. After controlling for other variables using multiway analysis of variance, the hospital stay of patients who continued the initial medication was 15.2% longer (2.0 days) for divalproex than valproic acid.

Partly because of study design, switching medications was more common for valproic acid than for divalproex. Although medication intolerance occurred in approximately 6.4% more patients taking valproic acid than divalproex, switching from valproic acid to divalproex did not significantly prolong length of stay or increase the rehospitalization rate over that for continuous divalproex.

"Lower peak valproate concentrations with divalproex sodium may have enhanced tolerability but may also explain the lower effectiveness," the authors write. "Extended release divalproex could lower effectiveness further and require higher doses. Thus, inpatients are better served by beginning with generic valproic acid and by changing to delayed-release divalproex only if intolerance occurs."

The authors calculate that this strategy would save up to one third of inpatient costs and two thirds of a billion dollars in medication costs annually.

Study limitations include possible physician bias, change in admission criteria over time, lack of structured interviews, dropout of some patients from the mental health system, hospital-based population precluding generalization to outpatients, possibly inadequate divalproex doses, and lack of prospective randomization.

"With no reason to suspect diagnosis-based differences in tolerability, the tolerability of generic valproic acid should extend from psychiatric to epilepsy and migraine patients," the authors conclude. "In a broader perspective, this study and others suggest the value of rigorously comparing the effectiveness of new medications to older ones in real-life settings and conducting cost-effectiveness comparisons before approving the extensively marketed, and more expensive, new medications."

Am J Psych. 2005;162:330-339