Valproic Acid

Valproic acid (dipropylacetic acid) is currently approved by the FDA for acute treatment of manic episodes associated with bipolar disorder. While it does not have FDA approval for maintenance treatment, it has become the most widely used medication in both acute and maintenance treatment of bipolar disorder in the United States. In a large multisite study, valproic acid did not differ from placebo in the length of time to recurrence of mania or depression in patients with bipolar disorder undergoing maintenance treatment (lithium also failed in this study) (Bowden et al., 2002). It is widely believed that this was a result of the high drop-out and noncompliance rate for all treatments in this study rather than a true reflection of lack of maintenance efficacy. Several open-label studies have shown efficacy for valproic acid in the maintenance therapy of bipolar disorder (American Psychiatric Association, 2002), as discussed below.

Valproic acid is produced in various preparations including syrup, sprinkles, capsules, enteric coated capsules, and tablets. One of the more commonly used preparations is divalproex sodium, a compound of sodium valproate and valproic acid in a 1: 1 molar ratio. Absorption is different across the different preparations and is delayed by food. However, since anticonvulsant efficacy is not related to peak levels but rather related to total daily bioavailable dose, this variability is thought to be clinically irrelevant. Peak plasma levels are achieved between 2 and 4 hr of ingestion and the half-life ranges from 6 to 16 hr. More than 90 percent of plasma valproic acid is protein bound. The time of dosing is determined by possible side effects and, if tolerated, a once/day dosing could be employed. The therapeutic plasma levels used for the treatment of mania are the same as those used for anticonvulsant therapy (50 to 100 ^g/mL) and the daily dose required to achieve these levels ranges from 500 to 1500 mg.

Valproic acid is metabolized by the hepatic P450IID6 system, but unlike carba-mazepine it does not autoinduce its own metabolism. Concomitant administration of carbamazepine will decrease plasma levels of valproic acid, and drugs that inhibit the P450 system (SSRIs) can cause an increase in valproic acid levels.

At least 16 uncontrolled open-label and six controlled studies have been published investigating the efficacy of valproic acid in the treatment of mania. These studies demonstrate considerable efficacy for valproic acid. The first placebo-controlled comparison of divalproex sodium with lithium in 179 inpatients afflicted with mania demonstrates equal efficacy to lithium and greater efficacy than placebo for both lithium and divalproex sodium. The rate of early termination because of side effects was significantly greater for lithium than placebo or divalproex sodium (Bowden et al., 2002).

Valproic acid appears to have the most favorable side effect profile of all available antimanic drugs. Dose-related and common initial side effects include nausea, tremor, and lethargy. Gastric irritation and nausea can be reduced by dividing the dose or using enteric coated preparations. Valproic acid has been associated with potentially fatal hepatic failure, usually occurring within the first 6 months of treatment and most frequently occurring in children under age 2 and individuals with preexisting liver disease. Transient, dose-related elevations in liver enzymes can occur in up to 44 percent of patients. Any change in hepatic function should be followed closely and patients should be warned to report symptoms of hepatic failure such as malaise, weakness, lethargy, edema, anorexia, or vomiting. Valproic acid may produce teratogenic effects including spina bifida (1 percent) and other neural tube defects. Other potential side effects include weight gain, inhibition of platelet aggregation, hair loss, and severe dermatologic reactions such as the Stevens-Johnson's syndrome.

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