Valproate under threat

To the Editor

The European Regulatory Authority is moving towards restricting valproate use in the treatment of women. Noting that some general practitioners are unaware of the dose limitations in relation to valproic acid (VPA), its use in childbearing women has been restricted, without consultation with experts who actually use the drug.

VPA was discovered as a solvent for barbiturates and found to be more effective than the latter. It gained acceptance in treating a variety of epilepsy syndromes.

In the 1960s, reports of side effects emerged, the major being teratogenicity attributed to the almost exclusive use of VPA in treating patients in Southern France. South American studies failed to confirm teratogenicity.

Valproate later became widely used in treating bipolar disorders, rivalling the use of lithium. The mechanisms of action of valproate and lithium at the cellular level are strikingly similar. Adverse effects of VPA include hair loss, weight gain, encephalopathy and hepatic failure, affecting children suffering from metabolic disorders.

In women, polycystic ovaries and a syndrome characterised by diabetes, amenorrhoea, hirsutism and anovulatory changes have been attributed to valproate.

Since 2004, VPA has come under close scrutiny in relation to foetal malformations. The Australian Register reported that VPA 1100 mg/day was a critical upper dose limit in pregnancy. Above this, a sharp increase in the teratogenicity was detected. The International Pregnancy Register EURAP recommended not exceeding 430 mg/per day in pregnant women. Subsequently, cognitive and behavioural problems emerged in infants exposed to high-dose valproate in utero.

Psychiatrists are currently the main users of high-dose valproate. Frequently, in the event of pregnancy, VPA is abruptly ceased. It may be advisable to use VPA as a last resort in women of childbearing age. If VPA use is unavoidable, it should be used in the lowest possible dose, supplemented by drugs such as lamotrigine, which is synergistic. Lamotrigine is minimally teratogenic. VPA-related foetal malformations comprise limb abnormalities, harelip, cleft palate, cardiac abnormalities, hypospadias and renal problems. Most severe abnormalities involve neural tube defects. VPA doses associated with less severe defects are 400 to 500 mg/day; the threshold for spina bifida is double this figure.

Lithium has a different spectrum of side effects, but its teratogenicity is less well characterised. Transferring a patient on valproate to lithium is a difficult decision for a psychiatrist. The threat to valproate may affect our practices adversely and may result in the removal of a most valuable drug.