Valproic acid, valproate sodium, and divalproex sodium are used for the management of various seizure disorders, including complex partial seizures, absence seizures, and other seizure types. Because there are only minor differences in the pharmacokinetics of the formulations and because all forms of the drug circulate in plasma as valproic acid, the term ''valproic acid'' will mainly be used in the following discussion.
Valproic acid is used alone or with other anticonvulsants (e.g., ethosuximide) in the prophylactic management of simple and complex absence (petit mal) seizures. The drug also may be used in conjunction with other anticonvulsants in the management of multiple seizure types that include absence seizures. Valproic acid is considered a drug of choice for absence or atypical absence seizures.
Valproic acid is used alone or with other anticonvulsants (e.g., carbamazepine, phenytoin) in the prophylactic management of complex partial seizures that occur either by themselves or in association with other seizure types. Some clinicians state that valproic acid may be considered a drug of choice for the management of complex partial seizures. Two randomized, placebo-controlled trials, one of valproic acid as monotherapy and one of valproic acid as adjunctive therapy, demonstrated that the drug decreased the frequency of seizures in patients inadequately controlled by other therapies (e.g., carbamazepine, phenytoin, phenobarbital).
Valproic acid has been used and is considered by some clinicians as a drug of choice for management of other generalized seizures, including primary generalized tonic-clonic seizures, myoclonic seizures, or atonic seizures, especially for those patients with more than one type of generalized seizure. In addition, some clinicians state that valproic acid may be used as a drug of choice for the management of simple partial seizures. Valproic acid also has been administered rectally or by intragastric drip with some success in the management of status epilepticus refractory to IV diazepam. A parenteral formulation of valproic acid has been studied and has been effective when administered IV in the management of status epilepticus.
Valproic acid has been used with some success in the treatment of Lennox-Gastaut syndrome and infantile spasms.
Valproate sodium has been used for the prevention of posttraumatic seizures in patients with acute head injuries. In a randomized, double-blind study comparing the efficacy of IV valproate sodium (administered for 1 week followed by oral valproic acid for 1 or 6 months) with that of IV phenytoin (administered for 1 week followed by placebo) for this use, the mortality rate was found to be higher in patients treated with valproate sodium followed by valproic acid compared with those receiving phenytoin (13 versus 8.5%, respectively). Many of these patients were critically ill with multiple and/or severe injuries and a causal relationship to valproic acid has not been established. However, pending further study, the manufacturer and some clinicians state that it is prudent to not use IV valproate sodium in patients with acute head trauma for posttraumatic seizure prophylaxis.
Divalproex sodium and valproic acid are used in the treatment of acute manic or mixed episodes associated with bipolar disorder; valproate sodium also has been used. Because there are only minor differences in the pharmacokinetics of the formulations and because all forms of the drug circulate in plasma as valproic acid, the term ''valproic acid'' will mainly be used in the following discussion.
Valproic acid has been used as monotherapy or as part of combination therapy (e.g., with lithium, antipsychotic agents [e.g., olanzapine], antidepressants, carbamazepine) in the treatment of acute manic episodes. The American Psychiatric Association (APA) currently recommends combined therapy with valproic acid plus an antipsychotic agent or with lithium plus an antipsychotic agent as first-line drug therapy for the acute treatment of more severe manic or mixed episodes and monotherapy with one of these drugs for less severe episodes. For mixed episodes, valproic acid may be preferred over lithium. Valproic acid or lithium also is recommended for the initial acute treatment of rapid cycling.
A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility.
Efficacy of divalproex sodium (given as Depakote or Depakote ER tablets) in the treatment of manic episodes has been established in several short-term, placebo-controlled, parallel-group trials in patients who were hospitalized for acute mania; response to therapy was assessed using objective rating scales such as the Young Mania Rating Scale (YMRS), an augmented Brief Psychiatric Rating Scale (BPRS-A), the Mania Rating Scale (MRS), and the Global Assessment Scale (GAS). In these studies, valproic acid was found to be substantially superior to placebo in all of the outcome measures assessed. One study specifically enrolled patients who were intolerant of or unresponsive to previous lithium therapy. Up to 40% of patients fail to respond to or are intolerant of lithium therapy for manic episodes; such patients may demonstrate a response to valproic acid, although response to valproic acid appears to be independent of prior response to lithium therapy. Valproic acid therapy appears to be about as effective as lithium for the treatment of manic episodes. In one placebo-controlled trial, 48% of patients receiving valproic acid demonstrated a response to the drug as measured by changes in the Manic Syndrome subscale of the MRS; 49% of patients receiving lithium responded to therapy, while 25% of patients receiving placebo responded. Antimanic response to valproic acid typically occurs within 1-2 weeks of initiating therapy. Valproic acid therapy also appears to be effective in specific types of mania, including rapid-cycling mania and dysphoric mania, which have been reported to be poorly responsive to lithium.
Although the manufacturers state that safety and efficacy of long-term (i.e., longer than 3 weeks) valproic acid therapy have not been established in the treatment of manic episodes, valproic acid also has been used, alone or in combination therapy, for long-term or maintenance antimanic therapy, and APA currently considers the best empiric evidence to support the use of valproic acid or lithium for maintenance therapy. Antimanic efficacy has been maintained from several months to more than 10 years, and such long-term therapy appears to decrease the frequency and severity of bipolar episodes over extended periods of time; however, further study is required to establish the efficacy of valproic acid as maintenance therapy of manic episodes. Valproic acid does not appear to be as effective for the management of the depressive component of bipolar disorder; although some evidence suggests that long-term valproic acid therapy may be moderately effective in the prophylaxis of depressive episodes, its acute effects on depression appear to be limited. Some clinicians recommend that valproic acid therapy be used in patients with bipolar disorder or schizoaffective disorder, bipolar type, who have responded inadequately to or have been unable to tolerate treatment with lithium salts or other therapy (e.g., carbamazepine), particularly if the patient displays residual manic symptoms, or in the presence of rapid cycling, dysphoric mania or hypomania, associated neurologic abnormalities, or organic brain disorder.
Prophylaxis of Chronic Attacks
Divalproex sodium and valproic acid are used in the prophylaxis of migraine headache; sodium valproate also has been used. Because there are only minor differences in the pharmacokinetics of the formulations, and because all forms of the drug circulate in plasma as valproic acid, the term ''valproic acid'' will mainly be used in the following discussion.
Valproic acid should not be used in pregnant women for the prevention of migraine headaches; in such patients, the risks of the drug (e.g., major congenital malformations and cognitive impairment in prenatally exposed children) outweigh any possible benefits
(see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation). Valproic acid also should not be used in women of childbearing potential unless the drug is clearly shown to be essential in the management of their medical condition; this is especially important when the drug is being contemplated or used for the management of a condition not ordinarily associated with permanent injury or risk of death such as migraine headaches.
The US Headache Consortium states that there is good evidence from multiple well-designed clinical trials that valproic acid and divalproex sodium have medium to high efficacy for the prophylaxis of migraine headache. Divalproex sodium (given as Depakote tablets) was demonstrated to be effective in the prophylaxis of migraine headache in 2 randomized, double-blind, placebo-controlled trials in patients with at least a 6-month history of migraine, with or without associated aura. Patients also had to experience at least 2 migraines per month in the 3 months prior to enrollment in the studies; patients were excluded if they had cluster headaches. Although women of childbearing potential were excluded from one study because of the teratogenic properties of valproic acid, they were included in the other, provided that they were practicing an effective form of contraception. In both studies, after a 4-week single-blind placebo baseline period, patients were randomized to receive either valproic acid or placebo during a 12-week treatment period consisting of a 4-week titration period and an 8-week maintenance period. Assessment of treatment outcome was based on 4-week migraine headache rates during the 12-week treatment period. In the first study, dosage titration was guided by the use of actual or sham trough total serum valproate concentrations for patients receiving valproic acid or placebo, respectively. The mean dosage of valproic acid was 1087 mg daily (range: 500-2500 mg daily), with dosages of more than 500 mg being given in 3 divided doses daily. Patients receiving valproic acid experienced a substantial decrease in the mean 4-week migraine headache rate compared with those receiving placebo (3.5 versus 5.7, respectively). In the second study, patients were randomized to receive (after titration from an initial dosage of 250 mg daily) 500, 1000, or 1500 mg of valproic acid daily or placebo, administered as 2 daily doses. Efficacy of valproic acid in the second study was to be determined by comparing the 4-week migraine headache rate in the combined groups of patients receiving 1000 and 1500 mg of valproic acid to that of patients receiving placebo. However, the manufacturer reports that the mean 4-week migraine headache rates in patients receiving valproic acid 500, 1000, or 1500 mg daily were 3.3, 3, or 3.3, respectively, compared to a rate of 4.5 in patients receiving placebo, and that the rate in the combined groups of patients receiving 1000 or 1500 mg daily was substantially lower than that of the placebo group.
In addition, divalproex sodium (given once daily as Depakote ER extended-release tablets) was demonstrated to be effective in the prophylaxis of migraine headache in a 12-week, multicenter, double-blind, placebo-controlled clinical trial in patients with a history of migraine headaches with or without associated aura. In this study, patients receiving extended-release divalproex sodium tablets (initiated at 500 mg once daily for 1 week, then increased to 1 g once daily if tolerated) experienced a substantial mean reduction in 4-week migraine headache rate compared with those receiving placebo (reduction of 1.2 from a baseline mean of 4.4 versus a reduction of 0.6 from a baseline mean of 4.2, respectively).
Other studies also have shown valproic acid to be effective in the prophylaxis of migraine. In one comparative, single-blind, placebo-controlled, crossover study, valproic acid was shown to be as effective in migraine prophylaxis as propranolol.
IV valproate sodium has been used for the acute management of migraine headache; however, the role of the drug relative to other acute therapies (selective serotonin type 1-like receptor agonists [''triptans''], ergot alkaloids, antiemetics, nonsteroidal anti-inflammatory agents [NSAIAs], butalbital-containing analgesics, opiate analgesics) requires further elucidation. Results of several studies, including open-label, comparative, randomized, prospective, retrospective, and/or double-blind, studies and at least one placebo-controlled study, as well as case reports, indicate that IV valproate sodium may alleviate acute migraine attacks in patients with or without aura and generally appears to be well tolerated. Efficacy generally was evaluated in terms of a reduction in headache severity as rated by the patient (i.e., a reduction in pain from severe or moderately severe to mild or absent usually using a 3- or 4-point scale) or by a visual analog pain score (VAS). Limited data indicate that 300-mg to 1-g IV valproate sodium doses (some of which were repeated at the same initial dose or less) were associated with relief of migraine headache, usually within 1 to several hours.
IV valproate sodium also has been used in the management of chronic daily headache in a limited number of patients some of whom have had an inadequate response to dihydroergotamine or when dihydroergotamine was contraindicated.
Further study and experience are needed to more clearly define the role of IV valproate sodium in the management of acute migraine attacks and other headaches.
There is no evidence that orally administered valproic acid or divalproex sodium is useful in the acute treatment of migraine headaches.
Valproic acid or divalproex sodium has been used as an adjunct to antipsychotic agents in the symptomatic management of schizophrenia in patients who fail to respond sufficiently to an adequate trial of an antipsychotic agent alone. The American Psychiatric Association (APA) and some clinicians state that anticonvulsant agents such as valproic acid or divalproex sodium may be useful adjuncts in schizophrenic patients with prominent mood lability or with agitated, aggressive, hostile, or violent behavior. In general, for such adjunctive therapy, valproic acid or divalproex sodium is administered in the same dosage and with the same resulting therapeutic plasma concentrations as that in the management of seizure disorders. The APA states that, with the exception of patients with schizophrenia whose illness has strong affective components, valproic acid or divalproex sodium alone has not been shown to be substantially effective in the long-term treatment of schizophrenia.
While some evidence suggested potential benefit of valproic acid in relieving tardive dyskinesia in patients receiving long-term antipsychotic drug therapy, recent systematic review of randomized controlled trials with nonbenzodiazepine γ-aminobutyric acid (GABA) agonists such as valproic acid found the evidence for such benefit unconvincing, and indicated that any possible benefit may be outweighed by adverse effects.
Some experts recommend use of valproic acid for the treatment of aggressive outbursts in children with ADHD.
Valproic acid used alone or in conjunction with GABA was ineffective in the treatment of chorea (including Huntington's chorea). Valproic acid has been effective in a limited number of patients with organic brain syndrome.