Giving Valproic Acid a Higher Priority in Bipolar Patients


Is valproic acid dismissed out of hand? Three doctors discuss its potential as a treatment.



We read with interest the article by David N. Osser, MD, “Valproic Acid: Overused in Bipolar Disorder?”. Other authors have taken exception to the National Institute for Health Care and Excellence (NICE) Bipolar Guideline’s similar approach to valproic acid (VPA), namely to avoid this medication in women of child-bearing potential.1,2 Indeed, we think that to give VPA such a low priority for all patients with bipolar seems like an over-response to VPA’s limitations, as this medicine can be effective and well-tolerated in males, as well as in females not of child-bearing potential (especially in very young or older females). Admittedly, VPA needs to have an extremely low priority in women of child-bearing potential due to the important risks of neurodevelopmental delays and polycystic ovary. The article correctly points out this fact; however, it fails to note mitigating information such as treatments for the latter include hormonal contraceptives.

The article stated that the last 2 VPA studies were negative, and VPA has a small effect size in acute mania.3-5 However, even though the last 2 controlled trials were negative, perhaps due to methodological limitations, divalproex sodium and divalproex sodium extended release are currently FDA-approved for the treatment of acute mania in monotherapy, in consideration of the efficacy showed by previous results on adults.6,7 In addition, 1 negative study from the point of view of efficacy was positive from the point of view of safety (rather than efficacy) in children and adolescents.8

The article correctly pointed out that VPA was not FDA-approved for bipolar maintenance treatment. However, this may have been due to the “non-enriched” (for acute valproate response) design of the VPA bipolar maintenance study.9 Indeed, VPA can be an effective bipolar maintenance treatment if using an “enriched” (for acute valproate response) design.10 It can be challenging to link logic to FDA-approval status of medications, as several second-generation antipsychotics (SGA) have already been FDA-approved to add to VPA (or lithium) in drug-resistant bipolar maintenance treatment. Additionally, lurasidone was FDA-approved to add to VPA (or lithium) in treatment-resistant acute bipolar depression.

The piece noted that a few small studies (4 studies with 142 participants) have been consistent with VPA efficacy in acute bipolar depression.11,12 However, in the absence of economic incentive, it may be unlikely that a larger acute bipolar depression VPA study will be undertaken.

VPA may be more effective than lithium in bipolar mania with dysphoria.13 This is an important consideration, given the importance of bipolar mixed states in DSM-IV-TR14 and the emerging importance of mixed depression in DSM-5.0.15

Head-to-head studies suggest more weight gain with valproate versus olanzapine, as noted in the article. However, olanzapine (even with fluoxetine) has been even more widely avoided than valproate due to risks of weight gain and metabolic abnormalities.

The article stated that suicidality (suicide or suicide attempt) was twice as likely with VPA versus controls. However, this statement is problematic if lithium (which has anti-suicide effects) is the control agent. Even compared with placebo, the number of suicide events was too small to allow any conclusion about VPA effect on suicidality. Nevertheless, the FDA has included an anticonvulsant suicidality warning for valproate and other anticonvulsants (including carbamazepine).Carbamazepine appears to be a poor option for women of child-bearing potential as it also entails teratogenicity (including spina bifida) and has multiple drug interactions (including interfering with hormonal contraceptive efficacy).16-18

Liver dysfunction and, less commonly, pancreatitis, thrombocytopenia, and polycystic ovaries are other significant adverse effect issues with VPA, as explained in the article. Although this is true, it also makes it clear in whom VPA needs to be carefully avoided—women of child-bearing potential, patients with low platelets, and hepatic transaminases over twice the upper limit of normal.

The article correctly stated that VPA was widely used in the treatment of bipolar disorder and, in fact, in a recently published multicenter report, including American (Stanford) and Italian (Milan) patients with bipolar disorder, it was the most common individual mood stabilizer (33% of the overall sample). In particular, individual VPA usage was higher in Milan than Stanford for both patients with BDI (44.4% versus 35.9%) and BDII (26.9% versus 11.3%); patients with BDI had significantly higher rates of taking VPA compared to those with BDII (40.1% versus 17.5%).19

Although VPA has utility in bipolar disorder, we agree that clinicians should think of lithium, second-generation antipsychotics, lamotrigine, and carbamazepine prominently in selecting medication for bipolar disorder patients.

Dr Dell’Osso is an associate professor of psychiatry at the University of Milan and Director of the Psychiatric Clinic of the Ospedale Luigi Sacco-Polo Universitario of Milan, Italy. He is also Scientific Advisor at the Department of Psychiatry and Behavioral Sciences of Stanford University and Co-Chair of the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). Dr Macellaro is resident in psychiatry at the University of Milan. Dr Ketter is professor of psychiatry and behavioral sciences, and founder and chief of the Bipolar Disorder Clinic at Stanford University.


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2. Vasudev K, Mead A. Use of valproate in women of childbearing potential: pre- and post-NICE bipolar guidelines. Arch Womens Ment Health. 2010;13(4):371-2.

3. Kowatch RA, Scheffer RE, Monroe E, Delgado S, Altaye M, Lagory D. Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol. 2015;25(4):306-13.

4. Hirschfeld RM, Bowden CL, Vigna NV, Wozniak P, Collins M. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. J Clin Psychiatry. 2010;71(4):426-32.

5. Bowden CL, Davis J, Morris D, Swann A, Calabrese J, Lambert M, et al. Effect size of efficacy measures comparing divalproex, lithium and placebo in acute mania. Depress Anxiety. 1997;6(1):26-30.

6. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 1994 Jun 15;271(23):1830.

7. Bowden CL, Swann AC, Calabrese JR, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J Clin Psychiatry. 2006;67(10):1501-10.

8. Wagner KD, Redden L, Kowatch RA, Wilens TE, Segal S, Chang K, et al. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48(5):519-32.

9. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000;57(5):481-9.

10. Bowden CL, Swann AC, Calabrese JR, McElroy SL, Morris D, Petty F, et al. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Psychopharmacol Bull. 1997;33(4):693-9.

11. Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010;124(3):228-34.

12. Wang PW, Nowakowska C, Chandler RA, Hill SJ, Nam JY, Culver JL, et al. Divalproex extended-release in acute bipolar II depression. J Affect Disord. 2010;124(1-2):170-3.

13. Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997;54(1):37-42.

14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). American Psychiatric Association; 2000.

15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). American Psychiatric Association; 2013.

16. Ketter TA, Post RM, Worthington K. Principles of clinically important drug interactions with carbamazepine. Part I. J Clin Psychopharmacol. 1991;11(3):198-203.

17. Ketter TA, Post RM, Worthington K. Principles of clinically important drug interactions with carbamazepine. Part II. J Clin Psychopharmacol. 1991;11(5):306-13.

18. Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. Epilepsia. 2011;52(2):243-7.

19. Dell’Osso B, Cremaschi L, Arici C, et al. Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode. Int Clin Psychopharmacol. 2019;35:8-18.

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