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) and Depacon (valproate sodium). All three convert, in 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. 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 is Depakene. 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.

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.

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?

Remedy Find lumps them all together. Who knows what the people there have actually been taking.

Raymott conflates valproic acid and divalproex sodium, including Depakote with Depakene.

Instant middle age, no matter how old you are. Suddenly you'll be old.

• You'll get fat.
• You'll go bald, or your hair will thin or change in some way.
• You'll always have heartburn, diarrhea, nausea, abdominal pain or similar stomach complaints.
• You'll be tired all the time.
• Your hearing won't be as good as it used to be.
• You'll have the shakes a lot. Gee, and this is an anticonvulsant?
• Your liver will hate you.
• You just won't feel that sexual any more.  As if all the the above weren't enough to turn you off, valproates and other anticonvulsants mess with your testosterone.

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 anticonvulsants/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.

It's just that the valproates have dominance of 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:

1. Monotherapy for a variety of generalized and partial seizure forms of epilepsy
2. Migraines
3. 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.

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.

So, how do these meds work on your brain? I once had a fabulous article online, but it vanished when the site went up for sale.  Bummers.   But I'll give you the short form I've picked up from said site, the Depakote PI sheet, and the books listed in the bibliography and the references below (specifically Antiepileptic Drugs, Essential Psychopharmacology of Antipsychotics and Mood Stabilizers, Essential Psychopharmacology of Depression and Bipolar Disorder, and A Primer of Drug Action). 

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 conclussions.  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?

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:

1. 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.
2. To make sure your white cell count is OK.
3. 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, Serzone (nefazodone), Wellbutrin (bupropion) and Zyprexa (olanzapine) immediately come to mind. You'd have to have a liver made of titanium to be mixing Depakote and Serzone (nefazodone). 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. Normally mixing booze and anticonvulsants is weird but not necessarily a big deal. With the valproates it's best to give up drinking all together, or at least restrict it to just very little booze on very few occasions. Valproate and alcohol just doesn't mix. Your liver will thank you for your temperance.

I'll add a little more for each med, but that's the gist of it for all three.