Depakene (valproic acid), Depakote (divalproex sodium), Stavzor (valproic acid delayed release), and whatever the hell they call sodium valproate (or valproate sodium) where you live

1.  What’s in a Name?

No, the valproate family isn’t one of the Mafia families with whom the Corleones had issues. It’s a group of three medications, sold in the US under the brand names of Depakote (divalproex sodium), Depakene (valproic acid), Stavzor (valproic acid delayed release), and Depacon (valproate sodium). All three convert, in roughly equivalent dosages, to the same metabolite that does all the work in your brain - valproate ion.

Valproic acid has been around a long time. It was synthesized in the 1880s, and just used as a solvent until 1962 when Pierre Eyrnard found that the solvent seemed to be the key component instead of the other anticonvulsants being investigated on rats. In 1963 it was being tried on humans for a variety of generalized epilepsies. By 1967 it was approved for usage in treating epilepsy in France. Boy, things were different back then. It wasn’t approved in the US until 1983, by which time Tegretol (carbamazepine USP) was already established here as a modern anticonvulsant. Yet with all that time in use in Europe, valproic acid has been studied, studied and studied. Then Abbott synthesizes valproate sodium, and later combines equal parts of the two to produce Depakote. Yet all three meds convert to the same metabolite, so what’s the point?

Does it really make a difference if you take Depakene or Depakote? That depends. It’s almost like the difference between brand and generic drugs. Ultimately Depakene, Depacon and Depakote all convert to the valproate ion, and in theory once a steady state is reached it shouldn’t make any difference if you switch between one or the other. In practice the road from your tummy to your brain and out your liver can vary wildly depending on the form and formulation of the three medications. There aren’t many studies comparing the efficacy of the different meds. This study shows Depakote sucks less (proven repeatedly) but valproic acid is more effective. Is it an outlier? Who the hell knows?
People have reported huge differences in effect and side effects when switching between Depakote and Depakene, usually by accident. By accident? Yes. You see, because the drugs have been around for so long the literature is rather confusing. Sometimes studies and whatnot refer to valproate itself, and I’ve never seen the metabolite of a med referenced outside of the PI sheet or a study on the pharmacokinetics. But because there are three meds that are supposedly interchangeable, if your study refers to “valproate” then you cover all three. The other thing is that the majority of the studies use valproic acid (as all studies use generics to be international and scientific and all that crap) - and valproic acid in the US was Depakene, and is now Stavzor. But Abbott is pushing Depakote, which is divalproex sodium, or a fusion of equal parts of Depakene and Depacon.

Are you confused yet? Then you may understand how this scenario frequently happens:

Somebody is taking brand name Depakote. Circumstances force them to switch to generic, so the prescription is written for valproic acid, because everyone knows that is the generic for Depakote. You don’t have to look that one up. Or their insurance coverage mandates the change regardless what their prescriber wrote.

That misinformation is so prevalent that in the current PI sheets for all three medications the efficacy rates from the clinical trials and the adverse effects are all for Depakote! This practice goes back to 1998 for Depacon, as my 1999 edition of the PDR has a mix of Depakote and Depacon data for Depacon’s entry. In that edition all of Depakene’s data are for Depakene, but in the current PI sheet for Depakene the efficacy and adverse effects are for Depakote. Stavzor is the exception. As it went through trials to get approvals for bipolar disorder and migraines - I guess nobody told the insurance companies that plain old valproic acid wasn’t approved to treat bipolar disorder or migraines, only Depakote was - as well as epilepsy, it has fresh data for itself and not Depakote.

Is anyone at the FDA paying attention? Hello! These are different medications! They may metabolize to the same substance but the way they are metabolized by our hard-working UGT and cytochrome P450 isozymes can be very, very different. Different metabolism can result in different side effects as well as different valproate blood levels. Different blood levels mean different effects, and potentially different side effects as well. The clinical trials and adverse effects for Depakote on the Depacon and Depakene PI sheets are just not acceptable!

OK, now that I got that out of my system, for a lot of people these meds are interchangeable and the effects and side effects will be the same. It’s just for a lot of people they will be different. Mileage will always vary. I’ve read enough accounts of people having nasty experiences when they got the wrong med by accident (e.g. the pharmacy substitutes Depakene for Depakote or vice versa) to know that not everyone can just switch these meds, otherwise why would Abbott have bothered to create Depacon and Depakote in the first place?

And when you run a search on PubMed it’s pointless to specify a particular valproate, as it returns results for all three, as well as papers with the vague “valproate” regardless of which generic name you enter.

Everybody does it, so it’s no surprise if your doctor does it. It doesn’t help the way the drug is named. In the UK, South Africa and in many parts of the world valproic acid is sold in tablets as Convulex, yet in South Africa you can also get Convulex syrup. But that’s sodium valproate. If you want sodium valproate syrup in the UK you ask for Olept. Epilim is sold in many Commonwealth countries as the tablet form of sodium valproate, but in Canada Epival is divalproex sodium while the injectable Epiject is valproic acid. Sodium Valproate is sold in Japan as Depakene and in several other countries as Depakin and Depakine. Hell, in France it’s sold as Depakote. And now, just to make everything more confusing, Sanofi is selling divalproex semisodium, which is the commie unamerican international nonproprietary name (INN) for divalproex sodium, AKA Depakote, as an extended-release version of branded sodium valproate. So in the UK Epilim is sodium valproate and Epilim Chrono is just like Depakote is here, a combination of sodium valproate and valproic acid. All over the world the brand names for sodium valproate are being appended with “chrono” or “retard” for a drug that has two similar active ingredients in addition to something that you can theoretically take less often. As it turns out, it’s still better to take Depakote ER twice a day than once a day.

I understand why some researchers just refer to the valproate ion in their papers or why a doctor that had you on brand name Depakote gives you a prescription for generic Depakene; it’s far too easy to get confused.

2.  Expect the Unexpected

So, what can you expect from the valproate meds? Instant middle age, no matter how old you are. Suddenly you’ll be old.

Maybe Valproate was a mob family in The Godfather. The one to which Abe Vigoda belonged.

As the lithium group has similar side effects all mood stabilizers have been tarred with the same brush. Thus everyone is afraid to take any of them because they don’t want the Depabloat effect. Yet every other anticonvulsant is either weight neutral or you’ll even lose weight with them. And while all anticonvulsants are going to slow you down and make naps a good idea, none is as likely to mess with your tummy or hair like the valproates and lithium tend to do.

But the thing is…those side effects are dosage-dependent, which means the babies who complain about every little thing my fellow travelers in bipolar land are most susceptible to them. Not only that, it’s mostly at the very beginning of treatment when a valproate is rapidly titrated (the dosage is increased) in order to stop you from bouncing off of the ceiling like Tigger jacked up on coke because you’re so manic. After a month or so the dosage is usually decreased and most of those side effects go away and/or become bearable. Taking the ER version of Depakote twice a day also helps, and getting regular blood work will let you and your doctor know about any serious liver problem before it gets seriously serious. You’ll still have to get used to sleeping 7–8 hours a night1, and some extra weight and less hair might still be in your future, but it’s usually not as bad as it seems like it will be. It also means that, given enough time, the side effects will sometimes suck less than other AEDs when treating epilepsy.

So if you’re stuck getting government or HMO healthcare and you’re in Epilepsyland, Bipolarland, and/or Migraineland the odds are you’re going to become acquainted with some form of a generic valproate at some point in your life. Which is a shame because

	The extended release form of Depakote has the best chance of avoiding all of the most common side effects.
	Because valproic acid is such an old med and Abbott has just totally fucked around with the FDA on the PI sheets I’ll lay you good odds that the generics have some wildly different bioavailability than the brand name meds. Which means you’ll need to take more to get the same blood levels, which means more side effects for some people.

That’s twice I’ve mentioned blood levels. Like the lithium meds, the valproates are all about blood levels, not dosage. Your starting dosage will be guessed at based on your weight - hell it’s as good a metric as any. After that you’ll need to have a regular blood panel taken for three important reasons:

    To see where your valproate levels are, and thus to see if the drug is doing you any damn good or if it’s your liver that just isn’t getting things right yet.
    To make sure your white cell count is OK.
    To see if your liver hates you yet, because the valproates are really tough on your liver.

You have to be careful when mixing the valproates with other drugs that give your liver a real workout - alcohol, smoking, Serzone (nefazodone), and Tegretol (carbamazepine) immediately come to mind. You’d have to have a liver made of titanium to be mixing Depakote, Tegretol and tobacco. You also have to watch out for the sudden onset of side effects like bruising, excessive tiredness (on top of what you’ve already been experiencing), weakness, vomiting, edema (especially in your face) and the surprising effect of losing a lot of weight when taking a valproate. Drinking while taking an AED is usually a bad idea, drinking while taking a valproate is especially stupid. You can get away with it now and then, just expect the hangover from hell to remind you why you should never do it very often. If ever.

3.  They’ve Got to be Good for Something, Right?

The valproates have dominance if the anticonvulsant market, due in part to their effectiveness and being the first (and so far only) to have the trifecta of official approval for:

  • Monotherapy (used by itself) for a variety of generalized and partial seizure forms of epilepsy
  • Migraines
  • Mania

Thus when anyone thinks “anticonvulsant” they think of a valproate medication. And when doctors prescribe anticonvulsants for whatever reason, they often go with a valproate first.
Once again, they’re wrong. Neither Depakote nor Stavzor is approved in the US for monotherapy to treat generalized seizures, they’ve just been prescribed off-label for that by so many doctors for so long everyone assumes valproic acid (the non-delayed release form) which has been approved to treat epilepsy only, is approved to treat everything. The only AED that comes close to triple M (in the US) is carbamazepine, but neither branded product.


In the US Tegretol (carbamazapine) is approved as monotherapy to treat generalized and partial epilepsies, and trigeminal neuralgia - which happens in your head, hurts like hell, and is often misdiagnosed as something in the migraine part of the headache spectrum. It is often prescribed for bipolar disorder, but that is an off-label prescription. Equetro, a combination of immediate- and extended-release carbamazepine is approved to treat bipolar disorder. In Canada Tegretol is approved as monotherapy to treat epilepsy, trigeminal neuralgia, and bipolar disorder, so in the Great White North Tegretol has more-or-less reached that lofty goal.

Still, they have good reason to do so. It’s not just the data published in the PI sheets from Depakote’s clinical trials. A variety of studies for a wide type of applications in the epilepsy and bipolar spectra can back up the decision to go with a valproate medication.

4.  How Valproates Work

Primarily they increase the concentration of the neurotransmitter GABA (gama aminobutyric acid) in particular regions of your brain. Other meds affect how GABA works in your head, like benzodiazepines. For some reason increasing the concentration of GABA doesn’t make you feel good like a benzo’s affect on a GABA receptor does. Go figure. So your neurons get to marinate in GABA, similar to the marinating effect of an SSRI but really more like Remeron’s (mirtazapine) serotonergic effect, if I’m understanding everything correctly. Anyway while you don’t get to feel particularly mellow, your brain certainly mellows out by that concentration of GABA, and thus the hyperactivity in neurons that would otherwise cause seizures and/or bipolar activity is halted.

Of equal import, the sodium ion channels, and maybe calcium ion channels (they’re not too sure about the latter) are better regulated. Whenever you hear about “electrical misfiring in the brain” in regards to epilepsy, and sometimes bipolar disorder, that’s what someone is talking about. Even if they don’t even know what they’re talking about. Your brain really does have tiny amounts of current running through it, and many anticonvulsants help keep the voltage running smoothly. As to precisely where, which of the several power lines available, and the various types of malfunctions they solve, the scientists are always cutting up the brains of diverse critters to answer those vary questions.

Additionally valproates inhibit the release of glutamate, too much of which causes epileptic and bipolar flip-outs.

The above are just the popular neurotransmitters, ion voltage channels and amino acids. Like many other anticonvulsants, the valproates work on all sorts of other things that are being looked into with buttloads of grant money. NMDA (N-methyl-D-aspartate), which is on the bleeding edge of research into what makes us mentally interesting in a lot of different ways. Maybe do something with potassium channels. Then there’s taurine and other amino acids.

I don’t know why it works on migraines, but my guess is that it’s for similar reasons. In reading the experiences of people who have had migraines they read very much like types of seizures, right down to the auras. I had one event in my life that I still can’t figure out if it was a migraine or a type of oddball seizure where I had a shitload of pain in my head before I collapsed to the floor. From reading all the abstracts on PubMed on the subject the researchers have pretty much come to the same conclusions. They have to infer that any anticonvulsant they throw at migraines works because it works that way for epilepsy and/or bipolar disorder. After all, how do you know if a critter has a migraine?

5.  Exchange Rates

So how much generic valproic acid do you need to take if your insurance company decided you need to take that instead of Depakote ER? Good question, especially since their answer is going to be, “They’re the same damn thing.” Here’s what I could find:
Depakene (valproic acid) and regular Depakote (divalproex sodium) are substituted at one-to-one. At least that’s what they did in this study of switching epileptic people from valproic acid to Depakote and this study of switching people with various psychiatric conditions from Depakote to valproic acid, and no one seemed to have any problems; although in the second study the people taking valproic acid eventually needed to take a higher dosage than what they used to take of Depakote.
When switching from regular Depakote to Depakote ER the Depakote ER PI sheet has a handy guide for you to adjust your total daily dosage:

DepakoteDepakote ER

It follows you can use the same guide for valproic acid. For Stavzor (valproic acid delayed release) things are slightly confused. As of this writing their website has this:

Depakene Depakote conflation
From epilepsy dosing information for healthcare professionals

In the Stavzor PI sheet that has been corrected to indicate valproic acid is the generic for Depakote Depakene. I really can’t blame whoever put together the Stavzor website. The Depakene PI sheet is so full of Depakote and divalproex sodium references that it’s far too easy to conflate the two.

As for converting to or from valproate sodium - damned if I know.

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1 Which is healthier for you in the long run than operating on 5-6 hours a night. And my heart bleeds for you, as I can't function on less than 9 hours a night, sometimes 10, thanks to my cocktail of two AEDs and an inpatient dosage of a TCA.

Page created by: Jerod Poore. Date created: 21 November 2010 Last edited by: JerodPoore on 2016–04–19

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1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.

2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.

3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.

* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.

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