Valproic acid adverse effects

Genton, P., Gelisse, Ph. Valproic acid - adverse effects. In Levy, R.H., Mattson, R.H., Meldrum, B.S., Perucca, E. (eds) Antiepileptic Drugs, 5th edn. Lippincott Williams Wilkins, Philadelphia, 2002, pp. 837-854. 

Genton P, Gelissse P. Valproic acid Adverse effects. In Levy RH, Mattson RH, Meldrum BS, et al. Anti epileptic Drugs, 5th ed. Philadelphia, Lippincott Williams Wilkins, 2002 837-851. 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

Carbamazepine and valproic acid had equal retention rates for tonic-clonic seizures, but carbamazepine was superior for partial seizures, and valproic acid caused more adverse effects. 

Devilat, M., and Blumel, J.E. Adverse effects of valproic acid in epileptic infants and adolescents [in Spanish]. Rev Chil Pediatr 62 362-366. 

Donovan et al. (1996, 1997) completed an open study evaluating the use of valproic acid (Depakote) in adolescent outpatients with marijuana abuse or dependence and explosive mood disorder (mood symptoms were not classified using the DSM FV Diagnostic System). Eight subjects were prescribed 1000 mg of valproic acid (Depakote) for 5 weeks, in addition to regular therapy sessions, but did not receive any other psychotropic medications. All subjects showed a significant improvement in their marijuana use (p <0.007) and their affective symptoms (p < 0.001), although both outcomes were measured only by self-report. The most common adverse events were nausea and sedation. No subjects discontinued because of these side effects, nor were there any reported interactions between the valproic acid (Depakote) and substances of abuse. 

Adverse effects include anorexia, nausea, vomiting, diarrhoea and/or constipation, weight gain, skin rash hair loss, neutropenia, tremors and ataxia are occasionally reported. Valproic acid is contraindicated in liver disease, especially cirrhosis, pregnancy and hypersensitivity. 

Changes in body weight associated with anticonvulsants have been reviewed (116), including the effects of the antiepileptic drugs that have been most commonly associated with this adverse effect (valproic acid, carbamazepine, vigabatrin, and gabapentin) (117). Unlike most anticonvulsants, topiramate, felbamate, and zonisamide can cause weight loss. 

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

In a 28-year-old woman with psychotic symptoms resistant to monotherapy with clozapine or ziprasidone, the combination produced marked improvement in both positive and negative symptoms along with a reduction in adverse effects body weight fell, blood pressure, pulse, and the electrocardiogram remained normal, and valproic acid, which had been introduced for epileptic seizures during clozapine monotherapy, was successfully withdrawn (23). 

After the addition of stiripentol (50 mg/kg) in 20 children treated with clobazam, mean serum clobazam concentrations increased about twofold and norclobazam concentrations increased about threefold a mean 25% reduction in clobazam dose was required because of adverse effects (15). Serum concentrations of concomitantly administered valproic acid rose by about 20%. These findings are in agreement with evidence that stiripentol is a potent metabolic inhibitor. 

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