Valproate (valproic acid; usually used as its sodium salt), also referred to as a simple eight-carbon branched-chain fatty acid with unique anticonvulsant properties. Valproic acid was first synthesized in 1882 by Burton (1882), but there was no known clinical use until its anticonvulsant activity was fortuitously discovered by Pierre Eymard in 1962 in the laboratory of G. Carraz, which was published by Meunier et al. (1963). The first clinical trials of the sodium salt of valproate were reported in 1964 by Carraz et al. (1964). It was marketed in France in 1967 and was released subsequently in >100 other countries (in the USA in 1978) for the treatment of epilepsy. Since then, valproate has established itself worldwide as a major antiepileptic drug against several types of epileptic seizures. Clinical experience with valproate has continued to grow in recent years, including use of valproate for diseases other than epilepsy, for example, in bipolar disorders and migraine.
Valproate and lithium have been widely used as first line drugs for treatment of mania as well as for prophylaxis of bipolar mood disorder.
Although its mechanism of action is not clearly understood, it increases GABA though other non- GABAergic mechanisms have been proposed.
Valproate is currently one of the major antiepileptic drugs with efficacy for the treatment of both generalized and partial seizures in adults and children. Furthermore, the drug is increasingly used for therapy of bipolar and schizoaffective disorders, neuropathic pain and for prophylactic treatment of migraine. These various therapeutic effects are reflected in preclinical models, including a variety of animal models of seizures or epilepsy.
It is rapidly and completely absorbed after oral administration. The peak plasma levels are reached at 1-4 hours after a single oral dose. The half-life of valproate is 8-17 hours.
The usual dose of valproate is 1000-3000 mg/day orally in divided doses. The therapeutic blood level is 50-125 mg/ml. Oral loading strategies (20-30 mg/kg/ day) are rapidly effective in the management of acute mania.
In addition to its primary indication as an anticonvulsant, Valproate has several other indications in various psychiatric and neuropsychiatric disorders.
Valproate is probably less effective in maintenance treatment of bipolar disorder than in treatment of acute mania. It has been used alone, as well as along with lithium and other mood stabilisers in the maintenance treatment.
The addition of valproate to lithium has been recognised as a useful treatment for mania refractory to lithium monotherapy.
The patients with rapid cycling, mixed affective episodes, or dysphoric mania are often resistant to lithium treatment and respond better to valproate. Valproate is also effective in management of ultra-rapid cycling mood disorders. Bipolar depression: Valproate appears to be generally more effective in the treatment of acute mania than in bipolar depression.
Valproate has been used for prophylaxis of migraine headaches, as well as for aborting an acute attack (IV route). Valproate has also been used in treatment of trigeminal neuralgia and neuropathic pain.
Valproate is primarily indicated for treatment of absence seizures (both simple and complex), complex partial seizures, myoclonic seizures, and generalised tonic-clonic seizures, as monotherapy as well as adjunct therapy.
Valproate has also been used at times in several other conditions, including behavioural agitation in dementia, severe behavioural symptoms in mental retardation, ADHD and conduct disorder, schizoaffective disorder (bipolar type), alcohol withdrawal, tardive dyskinesia, impulse control disorder, panic disorder and borderline personality disorder. Adverse effects are more common with valproate concentrations above 100 mg/ml.
The common side effects are nausea, seda- tion, tremor, flushing, weight gain, thrombo- cytopenia, menstrual disturbances (in women) and hair loss. There are some reports of polycystic ovaries and hyperandrogenism in young women with epilepsy.
The most serious, though relatively uncommon, side effects include hepatic toxicity (especially in young children), acute haemorrhagic pancreatitis, and Steven-Johnson syndrome.
The use of valproate in pregnancy and lactation should be best avoided. The NICE guidelines for treatment of bipolar disorder recommend that valproate is best avoided in women of childbearing potential.
In overdose, the amount of drug, that is not protein bound, is high. Therefore, dialysis is useful in the management of an overdose with valproate.
Certain drug may increase (such as aspirin, cimetidine, ibuprofen, erythromycin, fluoxetine, fluvoxamine, phenothiazines) or decrease (such as carbamazepine, phenytoin, phenobarbital, ethosuximide, rifampicin, mefloquine) the serum levels of valproate. In addition, valproate increases serum levels of other drugs (such as lamotrigine, tricyclic antidepressants, zidovudine, tolbutamide).