Valproate in Psychiatry: Approved Indications and Off-Label Uses

By Flavio Guzman, MD . Last updated: November 1, 2016 at 1:44 am

This brief article summarizes the clinical uses of valproate in psychiatry. We discuss FDA-approved indications as well as off-label uses. Instead of an exhaustive review, this is a practical summary for clinicians.

The term valproate includes a number of formulations, such as:

  • Valproid acid
  • Divalproex sodium
  • Divalproex sodium extended release

FDA-approved indications

  • Bipolar disorder
    • Acute mania (Divalproex)
    • Acute mania and mixed episodes (Divalproex ER)
  • Seizures
    • Monotherapy and adjunctive
      • Complex partial seizures
      • Simple and complex absence seizures
    • Adjunctive
      • Multiple seizure types that include absence seizures
  • Migraine prophylaxis

Regarding approved indications in bipolar disorder, FDA labeling varies according to formulations. Divalproex is approved for acute mania , while divalproex extended release is approved for mania and mixed episodes [1] . These are the only FDA-approved indications in bipolar disorder. Valproate is not approved for the treatment of bipolar depression or as maintenance treatment.

Valproate for mania

Valproate was initially studied for this use by Lambert in France in the late 1960’s. The most influential studies were probably those from Pope and Bowden. It was described that serum levels greater than 45–50 ug/mL are associated with antimanic response [2] .




Mixed states and rapid cycling

Valproate indications_mixed episodes and rapid cyclingAccording to randomized studies, valproate might be more effective than lithium for patients with mixed states and rapid cycling [3] . In these studies patients with mixed presentations treated with divalproex, showed greater improvements than those treated with lithium.

Off-label uses

Bipolar depression


Valproate indications_Bipolar depressionValproate is not approved for the treatment of bipolar depression. However, studies suggest it might be effective [4] . The problem with these studies is that they are limited by sample size.
There is a need for trials with larger sample sizes before conclusions can be drawn. Also, the authors of a recent review argue that publication bias cannot be ruled out.



Maintenance treatment

Valproate indications_maintenance treatmentValproate is frequently prescribed as maintenance treatment in bipolar disorder. It may be effective, this is supported mostly by open label studies. A recent Cochrane review [5] studied 6 randomized controlled trials lasting 6 to 24 months.

The reviewers consider there was an lack of clear findings, so the amount of evidence of efficacy is limited.

They state that evidence is more robust for the use of lithium and that lithium and valproate have different side effects profiles. Acceptability and tolerability profile should be considered when choosing between lithium or valproate.

 Adjunctive treatment for schizophrenia

The other off-label use for valproate outside bipolar disorder is as adjunctive for schizophrenia. A study by Casey and colleagues found that the combination of valproate and an antipsychotic was significantly more effective than placebo in reducing positive symptoms [6] .

Also, valproate might speed response in schizophrenia, but there are no data to show that this effect can be sustained over four or more weeks.

A Cochrane review concludes that based on available randomized evidence, there are no data to support or refute the use of valproate as agent for schizophrenia.

Impulsivity, agitation and aggression

Valproate indications_impulsivityValproate is also used off-label for impulsivity, agitation and aggression. This use is based on several case reports and open label trials [7] .

Some of the uses include:

  • Aggression and impulsivity in patients with brain injuries
  • Agitation associated with dementia
  • Impulsivity and affective instability in patients with borderline personality disorder




Alcohol dependence

Valproate indications_alcohol dependence

The other off label use for valproate is the treatment of alcohol dependence. Studies suggest it may have efficacy in relapse prevention. It is a good option for dual diagnosis patients (those with bipolar disorder and alcohol dependence). In this group of patients, valproate may stabilize mood and help in relapse prevention [8] .




References and further reading

  1. (Depakote ER) [Prescribing Information] North Chicago, IL : AbbVie Inc.. Accessed December 2014  ↩
  2. Pope, H. G., et al I. (1991). Valproate treatment of Acute Mania: A Placebo-Controlled. Archives of General Psychiatry, 48(1), 62–68.  ↩
  3. Freeman TW, Clothier JL, Pazzaglia P, et al: A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J sychiatry 149:108–111, 1992  ↩
  4. Reinares, M., et al (2013). A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression. The International Journal of Neuropsychopharmacology, 16(02), 485–496  ↩
  5. Linde, M., et al (2013). Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev, 6.  ↩
  6. Casey, D. et al (2003). Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.Neuropsychopharmacology 28(1), 182–192.  ↩
  7. Schatzberg, A. Essentials of Clinical Psychopharmacology. Washington, DC: American Psychiatric Pub., 2013.  ↩
  8. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM: Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism. Arch Gen Psychiatry. 2005;62:37  ↩

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