Pharmacology of valproate (Depakote, Epival)

Sodium Valproate

Indications

Valproate is FDA-indicated for treatment of acute mania.  A number of studies have shown it to be at least equivalent to lithium or better than placebo, and there are also controlled data indicating that valproate is superior to lithium in treating the acute mixed episode.

Frequency of dosing

Valproate, also known in generic form as valproic acid, is marketed as divalproex sodium (Depakote).  Divalproex appears to possess a somewhat longer half-life and somewhat less gastrointestinal side effects than valproic acid.  The half-life of valproate is usually greater than 12 hours.  Partly due to many active metabolites with long half-lives, it generally can be dosed once daily, which PL strongly recommends for reasons of compliance.   It seems that multiple daily dosing has been advocated in the epilepsy clinical trials so as to maintain blood levels as stable as possible.  While this effect may be relevant to epilepsy, it has not been studied relative to mania.  

Amount of dosing

The usual dosage of valproate is about 750-1500 mg/d (range 500-2000 mg/d). It is dosed to a serum therapeutic range of 50-120 ng/dl.  In the outpatient setting, we begin with 250 mg at night, then increase by 250 mg/d intervals every 5-7 days until either it is intolerable or therapeutic range doses are achieved.  In the inpatient setting, it is effective to begin with 500 mg at night, increase by 250-500 mg/d intervals every 1-2 days.   A standard level for acute and maintenance treatment is in the 60-90 range.  In the definitive clinical trials for acute mania, the mean level was in the 90s. It should be remembered that those trials were monotherapy trials (valproate vs lithium vs placebo).  If valproate is being used with a neuroleptic, somewhat lower levels may be effective, but levels below 60-70 are probably insufficient for acute mania.  In maintenance treatment, similar levels seem effective, though in the experience of PL editors, levels in the 90s or higher are not frequently necessary.

Lower levels, in the 30-50 range, may be effective in cyclothymia

Toxicity

One of the major advantages of valproate is its decreased toxicity and large therapeutic index.  The difference between a therapeutic level and a toxic level is much larger than with lithium. When levels exceed 100 or 120, toxicity symptoms are not as severe with valproate as with lithium and are usually associated with severe nausea, sedation, and perhaps dizziness, but not usually serious medical conditions.

Mechanisms of action

As with lithium, the psychotropic mechanism of action of valproate is unknown.  Like most antiepileptic agents, valproate blocks sodium channels, but this effect is not thought to be relevant to its psychotropic mechanism.  Valproate also has moderate gabaergic and mild serotonergic effects, which may provide some anti-anxiety benefit, but are not likely prominent components of its mood effect.  It is likely that valproate, like lithium, provides mood-stabilizing effects mainly through second messenger mechanisms.   Recent research found, for instance, that valproate, like lithium, is a potent inhibitor of protein kinase C, an essential ingredient in the second messenger cascades of many monoamine neuronal systems. 

Side effects

Overall, valproate is not limited in its side effects, but, carefully titrated, it is often well tolerated.  Some of valproate’s side effects appear to be, based on clinical experience and available studies, similar in kind and severity to lithium.  These include weight gain, sedation, cognitive impairment, nausea, diarrhea, and tremor. These side effects are generally dose-related, and can respond to lowered serum valproate levels if clinically appropriate.  Valproate-induced nausea or weight gain can also respond to supplementation with Histamine-2 (H2) blockers, such as over-the-counter ranitidine (Zantac).  Valproate also can cause hair loss, which may be treatable with supplemental zinc plus selenium used at higher than recommended daily allowance amounts. 

Medical Risks

Medically serious side effects consist mainly of hepatic failure and pancreatitis.  Other medical effects, which generally are not potentially lethal, include thrombocytopenia, mild anticoagulation, and possible endocrine abnormalities in women with associated polycystic  ovarian syndrome.

Liver effects

Valproate’s hepatic effects are usually the most commonly discussed.  In reality, potentially lethal hepatic risks are extremely rare in adults.  A recent review of mortality due to hepatitis with valproate found only one reported case in an adult receiving valproate monotherapy, and that patient was 19 years old.  Most cases also involved polypharmacy with multiple antiepileptics.  Valproate can cause non-dangerous elevations of liver function tests (LFTs) in many more persons, but it is important to realized that abnormal LFTs are relatively common and unrelated to the rare and sudden cases of severe hepatitis. 

If LFT scores are less than 2-3 fold increased, some clinicians even continue valproate and simply follow the LFT results.  Especially if valproate is uniquely effective for a patient, then mildly elevated but stable LFTs are not a reason for immediate discontinuation of valproate. 

 In most cases, though, abnormal LFTs continue to rise and then discontinuation of valproate is prudent. 

Pancreatitis

In our opinion, the more important medical risk is acute pancreatitis, as this risk is completely unpredictable and can occur at any age.  In adults, pancreatitis poses at least as serious a risk as hepatitis.  Since there is no way to predict this occurrence, any valproate-treated patient who experiences new abdominal pain should be quickly examined by a physician.  If there is any uncertainty, valproate should be held, and amylase and lipase levels drawn.  If abdominal pain is severe, immediate recourse to an emergency room visit is indicated. 

Thromobocytopenia

Clinicians sometimes worry about thrombocytopenia, excessively in our view, as reduced platelet levels rarely fall below 50,000, and even more rarely into the dangerous level of less than 20,000.  Thrombocytopenia is usually mild and stable.  This effect would only be of concern in patients with other risks for bleeding.  Similarly, the anticoagulant effects of valproate, mediated by clotting factors, is mild and usually clinically limited.  Again, patients at risk of even minimal effects, such as those with past cerebral bleeding, should be carefully followed.

No metabolic syndrome

Despite causing weight gain, valproate does not seem to lead to increased risk of metabolic syndrome. Indeed, it seems to do the reverse, with evidence in randomized data with the ER formulation of decreased total cholesterol levels with valproate compared to placebo.  Also, in patients with schizophrenia given antipsychotics like olanzapine which increase lipid levels, co-administration with valproate led to normalization of lipid levels.

Polycystic ovarian syndrome

The research literature seems to be finding more evidence of a likely association between valproate and polycystic ovarian syndrome (PCOS) . PCOS is a condition of elevated concentrations of androgenic hormones in women, with associated cysts on ovaries and increased infertility.  Since valproate causes weight gain, it has been suggested that PCOS may really be a secondary effect of the weight gain, rather than a direct effect of valproate.  If so, one would expect PCOS to occur as frequently with other anticonvulsants or mood stabilizers, like lithium that cause weight gain; yet data from the STEP-BD study find that this does not appear to be the case.  Other in vivo animal studies also seem to find a direct effect of valproate on increasing androgen activity, unrelated to weight gain.

Teratogenicity

Valproate is associated with neural tube defects, as is carbamazepine, and this effect is more frequent than lithium-related teratogenic effects.  Some neurologists continue valproate during pregnancy in some patients with epilepsy, but most psychiatric specialists recommend that it be avoided during pregnancy in patients with bipolar disorder. 

It has also been shown that fetuses exposed to valproate appear to have slower neurobehavioral development in childhood and lower IQ in middle childhood.  Thus valproate appears to have somewhat harmful cognitive effects in children exposed to it in pregnancy.

Use in young women

In our view, despite these drawbacks, the view of some perinatal specialists that one should avoid valproate in general among all young women is an over-reaction.   All drugs have risks; the clinician’s role is to not to take one risk, and then try to avoid that poor outcome from ever happening, but rather the job of the clinician is to weight all risks against benefits, always starting on the benefit side of the equation (see Hippocratic psychopharmacology).  Thus, for me, what matters in all patients with bipolar disorder, including young women, is to get their mood stably euthymic as long as possible. If it takes valproate, it takes valproate. The longer someone is stably euthymic, the longer they will remain so, even after a mood stabilizer is stopped.  Young women often stop drinking alcohol for the 9 months of pregnancy; one does not thereby forbid alcohol in all pregnancy-age women. Similar with mood stabilizers like valproate, if they are otherwise the best choice, I believe they should be used and if stable euthymia is achieved, then they can be tapered before a woman decides to conceive.  In the rare case, given this approach to using valproate in women, where someone might become pregnant by accident, then addition of folate may help with later first or second trimester neural tube risks, or valproate may then be discontinued.

In women who are not stable, or highly noncompliant, or sexually unreliable, despite valproate usage, then it likely should be de-emphasized compared to other agents with less pregnancy risks, like lithium, lamotrigine, or antipsychotics.  However, valproate should not be avoided in general simply because many persons with bipolar disorder experience sexual impulsivity or are non-compliant when they are symptomatic.  It frequently cures them. My point is that if it does not help such individuals after a few month trial, then long-term treatment carries increased risks of unplanned pregnancy, and in that setting, it often should be removed from the treatment mix.

Drug interactions

Valproate is a mild inhibitor of the cytochrome P450 2D6 system, though this effect likely does not lead to much in the way of clinical drug interactions.  On the other hand, valproate is very tightly bound to plasma proteins, and thus can lead to drug interactions with other agents that are highly protein bound.  The most prominent example is combination with lamotrigine, where blood levels of the latter are markedly elevated in the presence of valproate, leading to a higher rash risk.  There are case examples of pedal edema with valproate plus atypical neuroleptics, which may be related to plasma protein binding.  Valproate is also a mild inhibitor of certain clotting factors, which can lead to increased bleeding risk with aspirin or other anticoagulants.  

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