Section 3.4.3

Valproate (Valproic Acid)

General Description

Valproate (depakene), also called valproic acid (because it is rapidly converted to the acid form in the stomach) is effective in a range of epileptic conditions. In addition, valproate has been shown to be effective in the treatment of bipolar disorder.

Although lithium is still considered the first-line drug in the treatment of bipolar disorder, many clinicians consider valproate at least equal in efficacy to carbamazepine as a second line drug.

Valproate comes in a variety of preparations, available in the United States. These preparations include valproic acid, sodium valproate, divalproex sodium and divalproex sodium coated particles in capsules. Unlike carbamazepine, divalproex sodium is approved for the treatment of manic episodes.

Indications for Medication

Valproate has been shown to be effective in the treatment of acute mania in bipolar disorder patients. Valproate is also an effective prophylactic treatment in the control of manic and depressive episodes. Literature studies have highlighted valproate's efficacy, especially with the subgroup of rapid cycling bipolar patients.

Nevertheless, valproate should usually be reserved for the treatment of bipolar patients who either do not respond to or cannot tolerate lithium or carbamazepine. Some studies have shown that the addition of valproate to lithium can convert a lithium-nonresponsive bipolar patient into a lithium-responsive bipolar patient.

Valproate has also been shown to be effective in the short-term and prophylactic treatment of schizoaffective disorder, bipolar type. Literature reports have suggested that valproate may be effective in the rapid cycling schizoaffective disorders and in the mood disorders due to brain disease.

Other studies have indicated that valproate may be effective in controlling psychotic symptoms of both schizophrenic patients and cognitive disorder patients. The co-administration of valproate and antipsychotic drugs may increase the plasma level of both medications.

Clinical Guidelines

Valproate should be initiated at a low dose and titrated gradually to minimize the risk of the common adverse effects of nausea, vomiting, and sedation. Valproate is often started at 250mg a day, taken with a meal. The valproate dose can be raised up to 250mg given orally three times daily in the course of 3-6 days.

Plasma concentrations should be taken in the morning before the first daily dose. The therapeutic plasma concentration for valproic acid, which is effective for the control of seizures, is between 50-100mcg per ml. It is reasonable to use that same target plasma level for the treatment of psychiatric disorders. Most patients obtain these plasma levels on a valproate dose of 1200-1500mg a day in divided doses. But some patients will need higher dosages, up to 4000mg a day.

Adverse Effects

The most common adverse effects from valproate are nausea, vomiting, sedation, weight gain, hair loss, and tremor. Tolerance to these side effects often develops in patients. These adverse effects can be minimized by increasing the dose slowly and by taking the drug with meals.

Other uncommon neurological adverse effects include hand tremor, asterixis, and more rarely ataxia, headache, anxiety, and depression. Also uncommon are thrombocytopenic and platelet dysfunction, occurring most at high dosages and resulting in prolongation of bleeding times.

Serious adverse effects can involve the pancreas and the liver. Rare cases of pancreatitis have been reported, occurring more often in the first six month of treatment and occasionally resulting in death. Transient increases in transaminase and lactate dehydrogenase occur in approximately 25% of patients.

Liver chemistry levels should be monitored on a regular basis. Laboratory abnormalities do not evidence themselves clinically and usually resolve in the first six months of treatment. Rare cases of hepatitis have been reported, occurring in approximately 1 in 20,000 patients. Hepatitis occurs most often in the first 3-6 months of treatment.

Valproate should not be administered to pregnant women. The drug passes into breast milk. Valproate should not be given to nursing mothers.

Drug-Drug Interactions

There are complex drug-drug interactions between valproate and other anticonvulsants. The clinician should consider consulting a neurologist before adding valproate to an existent antiepileptic regimen. The combination of valproate with antipsychotics may result in increased sedation and increased severity of extrapyramidal symptoms.

Valproate has additive depressant effects with CNS depressants, including alcohol. The hematological effects of valproate may potentiate the anticoagulant effects of aspirin and warfarin. Valproate may potentiate the effects of monamine oxidase inhibitors and other anti-depressants, possibly necessitating a reduction in the antidepressant drug.

Fluoxetine raises the plasma levels of valproic acid.

The consent form for this medication is "Mood Stabilizer (Anti-convulsant)."