medications
 
 
 
Depakote
 
 
Introduction
 
Valproic acid (Depakote and Depekene) is a medication that originally entered the market as an anticonvulsant, an AED (antiepileptic drug).  These drugs are used to control seizures.
 
However, valproic acid is also widely used in psychiatry to treat mood instability (in Bipolar Disorder and Schizoaffective Disorder); aggression, anger outbursts, assaultiveness and combativeness; and impulsive behavior.
 
 
History
 
Valproate was first approved in the United States by the FDA (Food and Drug Administration) for the treatment of absence seizures.  In 1983, Depakote (an enteric-coated formulation that contains valproic acid and valproate sodium) became available and demonstrated less gastrointestinal irritation.  The absorption of Depakote is delayed until it has moved further down the gastrointestinal tract.  
 
Depakote ER (divalproex sodium extended-release tablets) differs in that it is slowly absorbed throughout the day which results in remarkably stable concentrations in the bloodstream between doses.
 
Patients can take their entire daily dose of Depakote ER once a day.  In contrast, Depakote should be taken twice a day, as taking it in a single doses may result in excessively high blood levels and toxic side effects.
 
 
Preparations
 
Depakote is available in 250 and 500 mg tabs and as Depakote Sprinkle Capsules (divalproex sodium coated particles in capsules).  Depakote ER is available in 250 and 500 mg tablets.
 
 
Indications
 
Depakote ER is approved by the FDA (Food and Drug Administration) for the treatment of acute manic or mixed episodes associated with Bipolar Affective Disorder, with or without psychotic features, for certain types of epilepsy and for the prevention of migraine headaches.
 
 
Side Effects
 
The following serious side effects can occur with the use of Depakote:
 
  1. serious liver problems--signs include malaise (feeling ill), weakness, tiredness, facial swelling, and loss of appetite or vomiting  Liver function tests should be checked initially and periodically.  
  2.  
  3. birth defects  
  4.  
  5. pancreatitis (inflammation of the pancreas)--signs include stomach pain, nausea, and loss of appetite or vomiting  
  6.  
  7. elevated ammonia levels--signs include drowsiness, vomiting or changes in mental status (confusion)  
  8.  
  9. fever--associated with rash or enlarged lymph nodes  
  10.  
  11. low platelet counts--bruising easily; this is typically dose related and may resolve with a reduction in dosage
 
Signs of toxicity include:  
 
  1. somnolence  
  2. nausea or vomiting
  3. diarrhea
  4. dizziness
 
 
Contraindications
 
Patients with known hypersensitivity (previous allergic reactions) to Depakote or any of its ingredients should not take this drug.
 
Female patients who become pregnant, are considering pregnancy or who are not using contraception should contact their physician immediately.
 
 
Blood Levels
 
Periodic blood levels (measuring the concentration of medications in the bloodstream) are an essential component of Depakote treatment regardless of the specific disorder.
 
However, the range of therapeutic blood levels for Depakote was established for the treatment of seizure disorders and have nothing to do with its use as a mood stabilizer or as an adjunct treatment for Schizophrenia or other psychiatric disorders.  
 
The “therapeutic range” of 50-100 mcg/ml reported by most labs is only useful in determining if the level is too high (too close to the upper extreme, where toxic side effects might occur).  For most patients, toxic side effects do not occur until they reach levels closer to 150 mcg/ml.
 
It has been established that the relationship between blood levels of Depakote and clinical improvement in psychiatric disorders is linear.1  That is, the higher the concentration, the better the response.  In this study efficacy was significantly greater than placebo for concentrations beginning at the 71.4-85.0 mcg/ml range and levels in the 94.1-107.0 mcg/ml range were even better.  Tolerability was similar for all groups.  
 
As clinicians, we appreciate that for many patients, higher levels of Depakote (like Lithium) may produce greater therapeutic effects.  Recent data (including the study cited above) suggests that patients are more likely to respond favorably to levels of Depakote that are above 95 mcg/ml.  
 
Furthermore, since the introduction of Depakote, reference labs have progressively reduced the upper limit of the therapeutic range based upon its use in the treatment of seizure disorders.  This upper limit was once 150, then 125, and now some labs are reporting it as 100 mcg/ml.  
 
Obviously, if we wish our patients to maintain a level that is at least above 95 mcg/ml, some of them will have measured levels that will be reported by the lab as excessively high.
 
This is a problem that hospital and clinic labs must address, as it is common for patients taking this drug for epilepsy or for the treatment of psychiatric disorders to have blood levels higher than 100 mcg/ml.  This problem is particularly annoying for neurologists treating epilepsy who frequently push levels much higher than 100 mcg/ml.
 
I must also point out that the data suggesting that levels should be at least 95 mcg/ml was obtained from patients who were taking Depakote and not Depakote ER.  This value (95 mcg/ml) was a trough value (the lowest concentration of Depakote in the blood stream between doses).  This means that those patients tended to do better if their minimum Depakote level was 95 mcg/ml or above.
 
Levels measured in patients taking Depakote ER are not trough levels or peak levels (the highest concentration achieved between doses), but reflect levels that are fairly continuous throughout each day.  This means that a blood level from someone taking regular Depakote can not be compared directly to blood levels of Depakote ER.  
 
We might then postulate that minimum effective levels of Depakote ER may be somewhat higher than 95 mcg/ml.
 
 
Disclaimer
 
Any decisions regarding the use of this medication should be made only after consulting your attending physician and its use should be carefully monitored by your treating doctor.
 
1Am J Psychiatry 163:272-275, February 2006
 
 
(Sources: Abbott Laboratories, the FDA (Food and Drug Administration), package insert, the PDR (Physician’s Desk Reference and the author’s knowledge base.)
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