There are no published double-blind, placebo-controlled studies of the use of valproic acid in children and adolescents for the treatment of bipolar disorders. Valproate was the first alternative mood stabilizer to be studied. First introduced as an antiepileptic in France in 1967, it was first introduced into the United States in 1978, and received approval for the treatment of mania in 1995. Valpromide, a primary amide of valproic acid, is reported to be twice as potent as the parent compound. Vaproate has antiepileptic activity against a variety of seizure disorders and has also antikindling properties. Divalproex obtained FDA approval for mania in 1995. Valproate increases the concentration of GABA by activating its synthesis and inhibiting its catabolism. Divalproex causes a reduction of the GABA plasma levels, which correlate with the improvement of manic symptomatology.
Sodium valproate and valproic acid attain peak concentration within two hours and divalproex within three to eight hours. Valproex, the extended release form, is absorbed faster. Absorption is delayed if the drug is taken with food. Valproate is highly protein bound. The binding is increased by a low-fat diet and decreased by high-fat diets. Only the unbound form of the drug crosses the brain-blood barrier (BBB). Valproate is metabolized primarily in the liver by glucoronidation. Oxidative pathways produce a number of metabolites some with antiepileptic, others with toxic effects. Less that 3% of the drug is excreted unchanged by urine and feces. Valproate is the only major antiepileptic that does not induce hepatic chromosomal enzymes.
Wassefetal. (2005) report lower effectiveness of divalproex versus valproic acid in a large sample (N = 9,260) of patients resulting in a longer inpatient length of stay for subjects on divalproex in comparison to patients on valproic acid. The length of stay difference is maintained even if the patients on valproic acid are switched to divalproex. Valproic acid’s higher peak serum concentration might account for its association with a shorter length of stay. Extended release divalproex (Depakote ER) has an even lower peak serum concentration.
The authors now switch patients who cannot tolerate valproic acid to delayed release, not to extended release, divalproex. Allen, Hirschfeld, Wozniak, Baker, and Bowden (2006) demonstrated a linear relationship of valproic serum concentration to response and optimal serum levels for the treatment of acute mania. Evidence from their study indicates that higher valproate levels are associated with greater efficacy (as measured by effect sizes) across the groups defined in the study.
Valproate antiepileptic and mood-stabilizing mechanisms are unknown. Valproate inhibits the catabolism of GABA, increases its release, decreases GABA turnover, increases GABA-Beta receptor density, and may also increase neuronal responsiveness to GABA. Valproate increases GABA levels in the brain and enhances neuronal responsiveness to GABA. Other theories as to how valproate works are discussed in an endnote.
As far back as 1996, Bowden et al. determined that the therapeutic range of valproate was between 45 and 125 mcg/ml. Although, a linear relationship regarding therapeutic effectiveness and valproex level has been demonstrated in the treatment of acute mania, see above, in cyclothymia and bipolar II disorders, patients may respond to therapeutic levels below 50 mcg/mL. Levels above 100 mcg/mL increase the risk of hematologic side effects (decrease white blood and platelet count), sedation, and appetite increase. More over, levels above 100 mcg/mL are less efficacious than levels between 75 and 100 mcg/mL.
Only the unbound drug crossed the blood-brain barrier and is bioactive. Thus when valproic is displaced from protein binding sites through drug interactions, the total drug concentration may not change [the relationship between dose and total valproate concentration is nonlinear], however the pharmacological active unbound drugs does increase and may produce signs and symptoms of toxicity (Idem).
Valproate has FDA approval for mania in adults, sole or adjunctive treatment of simple and complex absence seizures, for adjunctive treatment of a variety of absence seizure, and other seizure disorders, and for prophylaxis of migraine.
Seven controlled trials (four placebo-controlled, one haloperidol-controlled, one lithium-controlled, and one placebo- and lithium-controlled) have demonstrated valproate effectiveness in acute mania. Antimanic effects could be augmented by the coadministration of lithium, carbamazepine, or antipsychotics. Valproate may also be effective in the treatment of secondary manias. Valproate is more effective than lithium in manic patients with rapid cycling and in bipolar patients with substance abuse, and is less effective with schizoaffective disorder, bipolar type.
Prophylactic Treatment Effects
Valproate reduces the intensity and frequency of episodes (mania and depression) in adults and extends the time to new episodes, including patients with rapid cycling, mixed bipolar disorder, bipolar II disorder, and schizoaffective disorder.
Valproate reduces impulsive aggression in patients with personality disorders.
Cotherapy in Schizophrenia
Coadministration of antipsychotics and valproate produces a significant improvement of the Positive and Negative Syndrome scale (PANSS) scores. It is proposed that antipsychotics should be limited to breakthrough manias in patients treated with valproate.
GABAergic drugs like valproate may be beneficial in the treatment of catatonia. Benzodiazepines have an established role in the management of catatonia.
Valproate increases the levels of phenobarbital, phenytoin, and TCAs. Carbamazepine decreases the levels of valproate and fluoxetine may boost valproate concentrations. Coadministration of valproate and lamotrigine should be done with extreme caution. The risk of Steven-Johnsons syndrome increases with this combination. Children are particularly vulnerable to this potentially fatal outcome.