Valproic acid with mental retardation

Kastner, T., Finesmith, R., and Walsh, K. (1993) Long-term administration of valproic acid in the treatment of affective symptoms in people with mental retardation. / Clin Psychopharmacol 13 448-451. 

Kastner, T., Friedman, D.L., and Plummer, A. (1990) Valproic acid for the treatment of children with mental retardation and mood symptomatology. Pediatrics 86 467-472. 

Pancreatitis is a rare adverse effect of valproate and can occur in isolation or in association with liver toxicity. In a review of the patients of 366 physicians, 23% of patients taking valproic acid had asymptomatic increases in serum amylase activity but there were only 39 cases of valproate-associated pancreatitis (107). Pancreatitis usually presented with epigastric pain, nausea, and vomiting, and was more common in patients aged under 20 years and with mental retardation. In most cases the pancreatitis started within the first 3 months of treatment, but in 18% the onset was after 2 years. 

At least 10 metabolites have been identified, and some may be active. One may account for hepatotoxicity (4-ene-valproic acid), and it is increased by concurrent dosing with enzyme-inducing drugs. At least 67 cases of hepatotoxicity have been reported, and most deaths were in mentally retarded children less than 2 years old who were receiving multiple drug therapy. 

According to the Expert Consensus Panel for Mental Retardation Rush and Frances, (2000), the mainstays of the pharmacological treatment of acute mania or bipolar disorder in adults are anticonvulsant medications (divalproex, valproic acid, or carbamazepine) or lithium. Both divalproex or valproic acid and lithium were preferred treatments for classic, euphoric manic episodes. Divalproex or valproic acid was preferred over lithium and carbamazepine for mixed or dysphoric manic episodes and rapid-cycling mania. For depressive episodes associated with bipolar disorder, the addition of an antidepressant (SSRI, bupropion, or venlafaxine) was recommended. According to the Expert Consensus Panel, the presence of MR does not affect the choice of medication for these psychiatric disorders in adults. 

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Children less than 2 years of age are at considerable increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. 

There are other seizure conditions in which pyridoxine therapy finds a place. Infantile spasm (spastic convulsions), in combination with diffuse electroenceph-alographic abnormalities (hypsarrhythmia), is referred to as West syndrome. Mental retardation is associated with this condition (32). ACTH is effective for the short-term treatment of infantile spasms. In view of the elevated therapy-associated morbidity, valproic acid and vigabatrin have been used (33). Following reports of beneficial effects of high doses of pyridoxine, initial treatment for one to two weeks with high doses of pyridoxine is the established therapy in some European countries and in Japan (34). Combined therapy with high-dose pyridoxine in association with low-dose corticotrophin has also been reported as a promising therapy for seizure control, normalized EEG, and intellectual outcome. 

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