Antidepressant and Antimanic Medications: Valproic Acid
Valproic acid (di-n-propylacetic acid) is an anticonvulsant drug chemically unrelated to other psychiatric medications. It is produced in various preparations, including syrup, sprinkles, capsules, enteric-coated capsules, and tablets. One of the more commonly used preparations is divalproex sodium (Depakote), 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, because anticonvulsant efficacy is not related to peak levels but rather to total daily bioavailable dose, this variability is thought to be clinically irrelevant. Peak plasma levels are achieved between 2 and 4 hours after ingestion, and the half-life ranges from 6 to 16 hours. More than 90% of plasma valproic acid is protein-bound. The time of dosing is determined by possible side effects, and, if tolerated, a once-a-day dosing could be employed. The therapeutic plasma levels used for the treatment of mania are the same as those used for anticonvulsant therapy (50-100 μg/mL), and the total daily dosage required to achieve these levels ranges from 500 mg to 1,500 mg.
Valproic acid is metabolized by the hepatic CYP2D6 system but, unlike carbamazepine, does not autoinduce its own metabolism. Concomitant administration of carbamazepine will decrease plasma levels of valproic acid, and drugs that inhibit the CYP system (e.g., SSRIs) can cause an increase in valproic acid levels.
At least 16 uncontrolled and 6 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 with mania, demonstrated that divalproex sodium was as effective as lithium and that both divalproex sodium and lithium were more effective than placebo. Valproate seemed to be most effective in lithium nonresponders. The rate of early termination because of side effects was significantly greater for lithium than for divalproex sodium or placebo. This study has been one of the most carefully controlled trials of antimanic drug efficacy and has clearly established the efficacy of valproic acid in the acute treatment of mania.
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 years and in persons with preexisting liver disease. Transient, dose-related elevations in liver enzymes can occur in up to 44% 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%) and other neural tube defects. Other potential side effects include weight gain, inhibition of platelet aggregation, hair loss, and severe dermatological reactions such as Stevens-Johnson syndrome.
Antidepressant and Antimanic Medications
Combined Medication and Psychotherapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: July 5, 2011
Last revised: by Andrew G. Epstein, M.D.