First thing's first. What's the deal with all the confusing names for Depakote?

The basic, irreducible molecule here is valproic acid, also known as valproate, and the brand name of this is "Depakene", not Depakote. Depakene is a carboxylic acid with 8 carbons, a bunch of hydrogens, and two oxygens.

Depakote is known generically as "sodium divalproex," a term that should only be used when you want to appear intelligent while giving lectures. Depakote is formed by adding sodium hydroxide to two valproic acid molecules, yielding a molecule that is double the size of Depakene, but which gets broken right back down to humble valproic acid in the stomach.

The "kote" in Depakote refers to the fact that it comes in an enteric-coated tablet. It tends to cause fewer GI side effects than Depakene, is absorbed more slowly, and has a somewhat longer half life (12 hours vs. 8 hours). Depakote ER is an extended release version of Depakote that is FDA approved for migraines and siezures in once-daily dosing, but it's likely that any of the versions of valproic acid are effective when dosed once-a-day.

Depakote's benefits
Depakote is very effective for acute mania, and rapidly so, usually quelling manic symptoms within a week, and this is what Depakote is FDA-approved for. Start at 250-500 mg QHS and increase rapidly to achieve a blood level of 70-80 mcg/ml.

Beyond treating mania, does Depakote help prevent relapse to either depression or mania? While most of us would say "yes" based on our clinical experience, there is surprisingly not a speck of randomized, controlled, double- blind evidence that it works for prophylaxis. Recently, Bowden and colleagues tried to assess this issue. They successfully treated 372 manic patients acutely, then randomly assigned them to three groups: Depakote (levels maintained between 71-125 mcg/ml), lithium (levels 0.8-1.2 meq/L), and placebo. These patients were seen for weekly visits for 3 months, then monthly visits. The three treatments were compared to see whether there were any differences in the time elapsed to a recurrence of either mania or depression. The result? No differences among the three treatments. Digging around a fair amount, the authors (all of whom were funded by Abbott Laboratories, makers of Depakote, to conduct the study) were able to report some outcome measures favoring Depakote, but all in all, the results were discouraging, not only for Depakote but for lithium as well. Unlike Depakote, however, lithium at least has beat placebo in several prior studies of bipolar disorder prophylaxis.

Rapid Cycling Bipolar Disorder
There's a myth out there that Depakote works better than lithium for rapid cycling bipolar disorder (RCBD). This was based on one of the pivotal studies leading to FDA approval for Depakote (2). In this study, Depakote was effective in patients with RCBD; lithium did not help such patients, but only because there were no RC patients in the lithium arm of the study! The truth, in fact, appears to be that RC patients, who make up about 15% of all bipolar patients, are incredibly hard to treat, regardless of the molecule you choose for treatment. A definitive meta-analysis of RC bipolar treatment was just published in July 2003, and after having exhaustively reviewed every single clinical trial on RC patients, these researchers concluded that no treatment works well in these patients, and that there is no evidence that anticonvulsants work better than lithium.

The other, somewhat less mythological impression, is that Depakote is better than lithium at treating mixed mania. This is based largely on a single study reported in 1997 of 179 patients who were hospitalized for acute mania. Patients were randomized to Depakote, LiCO3, or placebo. Those manic patients with significant depressive symptoms mixed into their mania did better on Depakote than lithium.

So, what to conclude about Depakote? Certainly it is a good treatment for acute mania, but controlled evidence for its effectiveness in any other aspect of bipolar treatment is remarkably sparse, considering how widely it is used.

TCR VERDICT:
Depakote: Not as Hot as Advertised

<sub>1. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57:481-489.
2. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA. 1994;271:918-924
3. Tondo L, Hennen J, and Baldessarini RJ. Rapid-cycling bipolar disorder: Effects of long-term treatments. Acta Psychiatr Scand. 2003;108:4-14.
4. Swann AC, Bowden CL, Morris D, et al. Depression during mania: Treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997;54:37-42.</sub>