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valproate/divalproex (divalproex )
(Revised 10/2008)

The following is my original handout for divalproex, with a few updates. The language might sound different here as it was written before the development of this website. 

Update 10/2008

This medication was originally developed as an anti-seizure medication.  In the last 15 years we have found that it also affects mood.  Like other “mood stabilizers”, divalproex can prevent large or rapid changes in mood.  It does not seem to have any effect on day to day mood changes, only “cyclic” or unprovoked changes.  It also has powerful effects on anxiety, agitation, insomnia, panic symptoms, and anger.  

How much do I take?

For most people it takes at least 1 gram per day to work.  Each milligram of this medication doesn’t have much “oomph” so it takes a lot of them.  This is actually about half the dose of divalproex commonly used for seizure control, though.  As a result, at “mood stabilizing” doses, many people have no side effects, or very minor ones.  “Low dose” is 1000mg; medium is 1500, high is 2000-3000 mg.

What are the common side effects?

Most people get no side effects at all at low doses.   But weight gain is a big problem at higher doses.  See “preventing weight gain” below on how to keep that from happening to you.   Some people get nausea when they first start .  This can be reduced by taking the pills with meals at first.  The “extended release” (ER) versions seem to cause nausea less often, when first starting, but in the long run divalproex should not cause nausea at all.

People sometimes notice more hair at the bottom of the shower after they wash their hair, especially if their hair is long.  Actual “hair loss” (which you might see on the pharmacist’s handout) is sometimes a problem at higher doses, but only very rarely an issue at “mood stabilizing” doses, and usually we will have considered switching because of weight gain by that time.   Taking a multi-vitamin with selenium and zinc (e.g. “Centrum Silver”) can prevent this problem for some people. Update 10/06: one mother wrote in to say that her daughter stopped losing hair after using a prenatal vitamin daily. This might be a little cheaper if it works for you.  

Too high a dose causes a “spacey”, foggy feeling; a mild but constant headache; and occasionally mild blurring of vision.  If you notice these, lowering your dose slightly can often make these go away completely, and you'll not have any permanent consequences from having been a little on the high side.  Talk to your doctor before changing your dose on your own, though!

Are there any serious side effects?

Though there have been deaths due liver failure, the patients  were generally less than 2 years old, and were taking other anti-seizure medications.  In adults, on divalproex  only, the rate of liver problems is the same as it is in those not taking any medications at all.   There have been reported cases of pancreatitis from divalproex  also, but this too is very rare.  (How rare? See endnote below)

If your first blood tests are ok, current practice does not require repeat blood tests.  If you find you are bruising or bleeding easily, or if you have nausea and vomiting after you’ve been used to divalproex  for weeks, call for instructions.

What about pregnancy?

This medication can definitely cause abnormalities in all trimesters of pregnancy.  You must avoid a pregnancy while taking it.  Tell your doctor how you will avoid becoming pregnant. 

Preventing weight gain

Weight gain is very common at medium or high doses, but not common at 1000mg or less.   Fortunately, it does not usually “sneak up” on you.   You will notice a huge increase in appetite first.  You want to eat frequently, eat a lot, and even feel hungry just after eating. 

Fortunately again, the appetite increase is like a light switch: it’s either “on”, or “off”.   If you notice your appetite go up, then call your doctor and ask about moving the dose down.  As you lower the dose, the “switch” goes “off” for almost everyone (rarely, some just have to stop).   

Recently the makers of Depakote produced an extremely slow release version of their pills they believe causes less trouble with this unusual appetite increase, and thus does not cause weight gain.  If Depakote ER is available to you at the same cost as divalproex, or close, it may be worth using the ER version .  People can get their dose higher with this version than with divalproex, in most cases, without causing weight gain. And get the same benefit in terms of symptom control. So overall I think the ER version is indeed slightly better, but only barely, and for most people probably not enough to justify a much higher cost (if, as will be true for most people with insurance, the generic divalproex carries a much lower co-pay than the trade name Depakote ER. It might be worth finding out if that's true for you: how big a difference would it be?)  

More on Depakote ER versus divalproex

This gets tricky. If you can't afford the ER anyway, skip over this section.  Here's the deal:  the ER version is only 85% absorbed, so technically 1250 mg ER is equivalent to about 1060 mg of the divalproex.  In other words, they do not produce the same dose, even though both might say "500 mg".  On the other hand, with the ER version, someone may be able to have a lower total blood level and get complete symptom control:  the highest blood level she gets will be lower than with divalproex because less is absorbed (which may also mean less side effects) but the lowest level she ever gets may stay higher because of the prolonged release of medication into the blood from the gut.  Indeed, although the ER thus has a lower average concentration over 24 hours, the final result is close enough to regular divalproex that I usually switch one pill version for the other without changing the dose.  However, to be more precise about maintaining a given blood level, when switching from DR to ER, one should add 500 mg Davis.

How do I start?  
Here are the instructions I give my patients, in most cases (I'd do this differently in someone over 55, for example). Other doctors will often so this somewhat differently, and that's okay. Make sure you understand the approach your doctor is prescribing for you.

A)     divalproex  250 mg tablets
This form requires both a morning and evening dose at first, to get the dose up quickly but lower the potential for nausea.  Taking it with meals makes nausea less likely.  And after you've taken in for a few days, nausea is usually not a problem. At that point, you can take it all at bedtime. 

  Increase by 1 pill per day from 1 in the morning and 1 in the evening, each taken with meals at first.  Later when your dose is stable you can move everything to once a day:  most people won't have any more trouble with side effects or any loss of benefit from taking this medication once daily, usually at bedtime.  But when you are getting started, add a pill to the breakfast dose, then the dinner dose, as you go up  Here are the instructions I give my patients (your doctor may do this differently, and that's okay):  increase every 3-7 days until you’re clearly responding (continue that dose); or get a side effect (decrease until the side effect goes away and contact your doctor for a new plan).  The highest I'll let my patients go before returning to see me is 1500mg (3 pills a.m., and 3 pills p.m. -- we switch to a 500 mg version when things are stable to make things simpler, if possible.

B)    divalproex  500 mg ER

One per night to start; then 2 per night; then 3 per night.  You can increase daily if your symptoms are severe.  But if you can afford to go a bit slower, you can then evaluate what each dose level does for you, and stop at the lowest possible dose.  In that case, you should increase as slowly as every 4 to even every 7 days (there is probably not much benefit in going any slower than that).   Stop at the lowest does that controls your symptoms; go back to a lower dose if you have side effects that are not decreasing quickly. 

Does divalproex  interact with other medications? 

Divalproex  itself does not cause major interaction problems.  Other medications may bump divalproex  off of its riding place in the blood (protein molecules) and raise the amount of divalproex  that actually affects your cells.  So if you start taking another medicine after divalproex  and get new side effects, it could be divalproex  side effects caused by this interaction.  Moderate doses of aspirin can do this, so use Tylenol instead. 

Most of these interactions do not pose any threat to you; most likely would be an increase in side effects from divalproex  or from the other medication.  Hoever, there is one medication interaction that is very important: divalproex can double levels of lamotrigine (Lamictal). Great caution must be used when when one is added to the other (or when divalproex is stopped; lamotrigine levels will fall by roughly half). You can help by making sure your doctor is taking this interaction into account.

Is this addictive?

There is no “addiction”: if you stop, there is no “craving”.  You might just get your old symptoms back.  Because divalproex  is an anti-seizure medication, though, it is best not to stop it suddenly.  In theory, a sudden stop can cause a seizure.  In practice, we have not seen this happen, but just to be safe, do not let yourself run out of this medication.  If you are going to stop, do so by gradually lowering the dose, one pill at a time, over a week.

More about safety
How rare are the liver and pancreas problems with valproate? Here is a stab at "quantifying" -- putting in numbers -- these risks, although the numbers are small enough that most people will have difficulty, I think, getting a realistic feel for how much risk they represent.

1. About liver
In a review of 35 years of experience using valproate (divalproex  is one version), it was noted that severe liver problems with divalproex  occur "with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy."Perucca  Although divalproex  has its problems, a high risk of causing severe liver problems (unless taking an additional anti-seizure medication) is not among them.  A rate of 1/20,000 is pretty close to the rate for the general population not taking any medications.

However, it can cause an increase in liver enzyme levels. These indicate that the liver is not happy with divalproex  but they are not necessarily a marker for the severe liver problem above.  Nevertheless, when we see this increase in liver enzyme levels in a blood test, indicating that some liver cells are being injured, we often watch to see if this is really going to turn out to be a problem.  If the increase is small -- say, up to twice normal levels of those enzymes, and some doctors say up to three times normal levels -- that is okay, at least in the short run. Doubling or tripling enzyme levels might sound like a lot.  Let's take a look at that with some numbers.  The average upper limit of normal for these tests is around 35 in most labs (and thus "three times normal" would be about 100).  By contrast, alcohol can cause these numbers to go up to 300-400, and some forms of viral hepatitis can cause it to go much higher. I saw a patient with enzymes around 1,000 once. So up to "three times normal" is not much and not a cause of any lasting liver damage unless we leave it that way.  Just "watching", for few weeks or a month, then repeating the test, is a routine thing to do. 

2. . About pancreas
I've had difficulty nailing down a similar number for the rate of pancreas problems with divalproex  (is it higher than the 1/20,000 figure above, for example?) An article in 2001 noted that there were 40 reported cases in the world (reported in English).Taira I'm not sure how many patients in the world have taken valproate. But I'll bet that comes to a risk figure quite a bit lower than the liver risk rate. 

Update 2006:  an international team of investigators searched specifically for a connection between using valproate and having pancreas problems.Norgaard  They found a small increase in risk compared to never-users, but this was not higher than for other anti-seizure medications, nor was it higher than for people who had used but were no longer using valproate.  They concluded that these results were not consistent with valproate as a risk factor for pancreatitis. 

Update 2007: a German team found 16 cases in 10 years, in Germany alone.Gerstner  This suggests that the rate of pancreatitis associated with valproate is higher than previous studies might have suggested, but still extremely uncommon.

Update 2008: no new data on this issue.