Valproate-associated weight gain: Potential relation to energy expenditure and metabolism in patients with epilepsy

Among the more prevalent and, potentially, therapy-limiting adverse effects of valproate (VPA) is excessive weight gain. Recent studies have suggested that as many as 50% of patients will experience significant weight gain, necessitating discontinuation of the drug in some patients. We wished to determine whether alterations occur in either resting energy expenditure (REE), energy intake, or hormonal/biochemical parameters in patients receiving VPA. We also wished to determine whether differences in drug metabolism exist between VPA patients who gain excessive weight as compared with those who do not experience weight gain. Our study included 17 VPA patients, including 10 patients with significant weight gain (> 5 kg) and 7 patients without significant weight gain. Ten epileptic patients not receiving VPA treatment and 11 healthy volunteers served as control subjects. REE was measured by indirect calorimetry and was expressed as a function of Harris-Benedict equation predicted values as well as by body mass index (BMI) and body surface area. Energy intake was assessed by patient-reported food records. We quantified VPA metabolism, specifically beta-oxidation, by measuring VPA metabolites recovered in urine (using gas chromatography-mass spectrometry, GC-MS), with subsequent calculation of the formation clearance of 2-ene-VPA. Both groups of VPA patients appeared to be hypometabolic as compared with matched non-VPA epileptic and healthy controls. Energy expenditure in VPA weight-gain patients was significantly lower than that in healthy controls. The formation clearance of 2-ene-VPA was also significantly lower in VPA patients who experienced weight gain as compared with VPA patients who did not gain weight. Energy intake did not differ significantly between any of the groups. Patients receiving VPA appear to have lower energy expenditures as compared with control patients and healthy volunteers. Weight gain does not appear to be primarily a function of increased food intake. Patients who gain excessive weight while receiving VPA demonstrate differences in VPA metabolism as compared with those VPA patients who do not gain excessive weight.