Valproic Acid: Overused in Bipolar Disorder?

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BIPOLAR UPDATE

Valproate/divalproex appears to be considerably overused in the US; the use of lithium, second-generation antipsychotics, and carbamazepine should be more prominent in treatment decisions for patients with bipolar mania.

Valproate/divalproex was approved by the FDA for use in bipolar mania with the publication of a major study in 1994 that showed efficacy. It was heavily marketed and entered the mainstream practice in the US. It has been used less in Europe and even less in Japan where carbamazepine is more popular as an alternative to lithium. In the 1970s, Japanese researcher Teruo Okuma, MD, PhD, was the first to demonstrate the effect of carbamazepine in mania.

As there have been more studies, the evidence base for the efficacy of this product has become less and less impressive. In the last 2 published placebo-controlled trials of divalproex in acute mania (1 in adults, 1 in adolescents and young adults), there were no differences from placebo; and, in the study published just before those, the effects were statistically significant but quite small.¹ Meta-analyses of controlled studies of medications for acute mania find it to have a smaller effect size than lithium, carbamazepine, and antipsychotics.²

Maintenance trials have not shown efficacy, and the medication does not have FDA approval as a maintenance treatment for bipolar disorder. Its use for that purpose, although common, is off-label. Valproate/divalproex is also not approved for treatment of acute bipolar depression nor for prevention of depressive episodes. However, there are a few small studies that suggest that it could work for bipolar depression; larger studies are needed.³

One group of patients with bipolar disorder that seem to fare better on valproate includes those with acute mixed mania (ie, meeting full criteria for mania but having 3 or more symptoms of depression concomitantly). Valproate may be preferred over lithium for such patients.¹

Clinicians often choose valproate because of a perception that it has a milder adverse effect profile than other bipolar medications. However, head-to-head studies indicate that 1 very important adverse effect—weight gain—is greater with valproate than with lithium, olanzapine, and quetiapine.¹ The risk of suicidal behaviors is twice as high on anticonvulsants such as valproate compared with controls, whereas substantial evidence finds reduced risk of suicidality on lithium. Liver dysfunction and, less commonly, pancreatitis, thrombocytopenia, and polycystic ovaries are other significant adverse effect issues with valproate. It has the most teratogenicity of any medication used in bipolar disorder and has been declared by experts to be a last resort medication for any woman of child-bearing potential.²

In conclusion, valproate/divalproex appears to be considerably overused in the US. Clinicians should think of lithium, second-generation antipsychotics, and carbamazepine more prominently in selecting medication for patients with bipolar mania. Patients should be informed of the evidence-base for efficacy and FDA approval status before being prescribed valproate for acute illness and especially for maintenance usage.

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.

This article was posted ahead of print on June 16, 2020, under the title "Valproic Acid: Its Role in Bipolar Disorder," and has since been updated. -Ed

References
1. Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for acute mania. Harvard Rev Psychiatry. 2014;22:274-294.
2. Cipriani A, Barbui C Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306-1315.
3. Osser DN, Wang D. The psychopharmacology algorithm project at the Harvard South Shore Program: an update on bipolar depression. Bipolar Disord. 2019; DOI: 10.1111/bdi.12860.
4. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? A call to action. J Clin Psychiatry. 2016:77:525-526.
5. Sher J, Frank JW, Doi L, de Caestecker L. Failures in reproductive health policy: overcoming the consequences and causes of inaction. J Pub Health. 2019;41:e209-e215.