SynopsisValproic acid, a simple branched-chain fatty acid, was originally developed for the treatment of epilepsy, but also has mood-stabilising, anxiolytic, antimigraine and antinociceptive effects, and has been evaluated in the management of various other disorders, particularly psychiatric conditions.Valproic acid has been shown to be effective in patients with bipolar and schizoaffective disorders, including those resistant to lithium and carbamazepine. Response was achieved in approximately 50 to 70% of patients treated with valproic acid monotherapy for acute manic episodes in noncomparative and placebo-controlled studies. Long term prophylaxis against recurrent manic and depressive episodes has been demonstrated in approximately 65 to 70% of patients receiving the drug as monotherapy or in combination with other drugs in noncomparative studies. Moreover, valproic acid appears to be effective in rapidcycling patients and those with mixed or dysphoric mania or neurological abnormalities, who tend to respond poorly to lithium. Evidence from preliminary studies and case reports suggests that valproic acid may prove useful for management of other psychiatric conditions, including panic attacks and aggressive behaviour.Valproic acid was found to provide prophylaxis against migraine with or without aura, and also showed promise in the treatment of acute migraine attacks, and as prophylaxis against refractory chronic daily headache. Preliminary findings suggest that valproic acid may be of value in the management of severe refractory pain, including trigeminal neuralgia, lancinating pain, and neuropathic pain associated with advanced cancer.Valproic acid is generally well tolerated, does not induce hepatic drug metabolism and has a low propensity for interactions with psychotropic agents. However, as has been observed with several other antiepileptic drugs, it is teratogenic and can cause elevated hepatic enzyme levels and rare, fatal hepatotoxicity. Weight gain and alopecia are relatively common.Thus, while few comparative data are available, valproic acid has demonstrated considerable potential as a first-line therapy for the management of bipolar or schizoaffective disorder, particularly for patients resistant to, or intolerant of, lithium or carbamazepine and those with rapid cycling or mixed mania. It has also shown potential in the treatment of refractory migraine and other types of chronic headache. Further studies are warranted in other psychiatric conditions, including panic attacks, and in severe refractory pain.PharmacologyIn addition to its anticonvulsant activity, valproic acid has demonstrated anxiolytic, mood-stabilising, antimigraine and antinociceptive effects. These activities appear to be mediated, at least in part, by its effects on &ggr;-aminobutyric acid (GABA) -mediated neurotransmission. Valproic acid increases CNS concentrations of GABA. possibly by increasing its synthesis and/or inhibiting its catabolism. Valproic acid has also been reported to decrease neurotransmission by the excitatory amino acids &ggr;-hydroxybutyric, aspartic and glutamic acids, to inhibit cell firing induced byN-methyl-D-aspartate, and to exert a direct neuronal membrane depressant effect, via modulation of sodium and potassium conductance. Moreover, it may also modulate noradrenergic and serotonergic neurotransmission. Valproic acid has also been reported to alter circadian rhythms in animals, possibly via effects on GABAergic functions, and this may be important in its mood-stabilising and antimigraine effects.As with other antiepileptic drugs, valproic acid has been shown to adversely affect psychomotor performance, but it appears to cause less psychomotor and cognitive impairment than phenobarbital (phenobarbitone) or phenytoin.Oral formulations of valproic acid are almost completely absorbed after administration, and dose-proportional peak plasma concentrations are attained within 1 to 3 hours (uncoated tablets), 3 to 5 hours (enteric-coated tablets) or 5 to 10 hours (controlled-release tablets). Administration with food decreases the rate, but not the extent, of absorption. Maximum plasma concentrations range from 25 to 100 mg/L following administration of 250 to 1000mg doses, in uncoated tablet or capsule form. The apparent volume of distribution (Vd) is small (0.1 to 0.4 L/kg) and plasma protein binding is approximately 90% in healthy persons, although the unbound proportion increases at total plasma valproic acid concentrations >80 mg/L. Metabolism occurs by at least 5 major pathways, and the drug is eliminated by renal and faecal routes, mostly (97%) in metabolised form. Plasma clearance ranges from 0.4 to 0.6 L/h, and plasma elimination half-life (t½&bgr;) from 9 to 16 hours, in healthy volunteers. Plasma clearance of valproate is enhanced by coadministration with hepatic enzyme-inducing drugs, resulting in decreased t½&bgr;. Plasma protein binding was decreased in pregnancy and in patients with impaired renal function or diabetes mellitus, while decreased clearance of unbound valproate was noted in patients with alcoholic cirrhosis of the liver. The t½&bgr;, Vd and proportion of unbound valproate were increased in neonates, while plasma clearance was increased and t½&bgr;decreased in children. In the elderly, unbound valproate concentrations were increased, as a result of decreased clearance and plasma protein binding.Therapeutic PotentialValproic acid has been shown to be effective and well tolerated in the treatment of patients with bipolar and schizoaffective disorders, including those resistant to lithium and carbamazepine. When given alone or (more commonly) in combination with other agents in noncomparative studies, it provided prophylaxis against recurrent manic and depressive episodes for prolonged periods in approximately 65 to 70% of patients. A small number of comparative and noncomparative studies have shown that valproic acid monotherapy is effective in controlling acute manic episodes in approximately 50 to 70% of patients, and efficacy comparable to that of lithium was demonstrated in one double-blind, placebo-controlled study involving 179 patients. Moreover, oral loading to reach therapeutic concentrations within 24 hours achieved control of acute mania within 5 days. Valproic acid was more effective in mania than depression, and appeared particularly effective in patients with rapid-cycling bipolar disorder, dysphoric or mixed mania, electroencephalographic abnormalities or psychiatric illness following closed head injury. Evidence from preliminary studies and case reports suggests that valproic acid may prove useful in the treatment of other psychiatric disorders, including panic attacks and aggressive behaviour.In several studies, mostly in small numbers of patients, valproic acid provided prophylaxis against migraine with or without aura, including that resistant to standard therapies, decreasing the frequency of attacks versus baseline or placebo. Valproic acid was also reported to be effective in 58% of acute migraine attacks, and to provide prophylaxis against refractory chronic daily headache in 2 small noncomparative studies.Preliminary data, mostly from nonblinded case series, suggest that valproic acid may prove useful in the management of severe refractory pain, including trigeminal neuralgia, lancinating pain and neuropathic pain associated with advanced cancer.TolerabilityThe majority of tolerability data on valproic acid are derived from patients receiving the drug for management of epilepsy. However, the pattern of adverse events appears similar in epileptic and nonepileptic indications. The most common adverse effects are gastrointestinal disturbances (dyspepsia, nausea, anorexia, particularly at the start of therapy), weight gain, CNS effects (tremor, drowsiness, ataxia) and transient hair loss. Enteric coated formulations of valproic acid are associated with a considerably lower incidence of gastrointestinal adverse events (3 to 6% of patients) than uncoated preparations. Elevated liver enzymes and hyperammonaemia are relatively common in patients receiving valproic acid, but are not usually clinically significant. However, fatal hepatotoxicity, which is more common in patients ≤2 years old. and those receiving polytherapy, occurs rarely. Other serious adverse events include haemorrhagic pancreatitis, which is sometimes fatal, and haematological disorders (thrombocytopenia, leucopenia. disturbance of platelet function).Use of valproic acid during pregnancy is associated with an increased risk of birth defects, particularly spina bifida, as observed with several other antiepileptic agents.Drug InteractionsValproic acid can increase the plasma concentrations of coadministered drugs by inhibiting their metabolism and/or by displacement from plasma protein binding sites. Such interactions have been reported to occur between valproic acid and phenytoin, phenobarbital, carbamazepine, ethosuximide, lamotrigine, felbamate, diazepam and warfarin.Coadministration of drugs that induce hepatic drug metabolism (e.g. phenytoin, carbamazepine, phenobarbital, primidone) can decrease plasma concentrations of valproic acid. Adjustment of valproic acid dosage may therefore be necessary when such drugs are initiated or withdrawn. Salicylates increase free and total plasma valproate concentrations by inhibition of valproate metabolism and displacement of valproate from plasma binding sites. In contrast with other antiepileptic agents, valproic acid does not impair the efficacy of oral contraceptives.Dosage and AdministrationEnteric-coated and controlled-release preparations of valproic acid are usually administered once or twice daily, and uncoated tablets 3 to 4 times daily. Tablets or capsules should be swallowed whole with or after food, in order to minimise gastrointestinal disturbance.Valproic acid is usually initiated at a low dosage (e.g. 500 to 1000 mg/day). which is titrated upwards until response is achieved or dose-limiting adverse events are noted. However a higher initial dose of 20 mg/kg/day was effective and well tolerated for achieving control of acute manic episodes in hospitalised patients. Plasma valproate concentrations of approximately 50 to 100 mg/L are generally required to achieve a good therapeutic effect.Valproic acid should not be given to patients with hepatic disease or significant hepatic dysfunction. Patients aged ≤2 years and/or receiving cotherapy with several antiepileptic drugs are at increased risk of developing hepatotoxicity, as are those with genetic disorders of metabolism (carnitine or ornithine carbamoyl-transferase deficiency, family history of severe hepatic disease), or severe epilepsy associated with cerebral lesions, mental retardation or other hereditary pathology.Elderly patients may require a lower dosage of valproic acid. Dosage adjustments based on total plasma drug concentrations should be made with caution in the elderly and patients with renal dysfunction or uncompensated diabetes mellitus, as the unbound fraction of valproic acid is increased in such patients.Use of valproic acid during pregnancy should be avoided if possible, because of an increased risk of neural tube defects. Platelet count and coagulation parameters should be monitored before therapy, at periodic intervals during therapy, and before elective surgery in patients receiving valproic acid.