VALPROATE-ASSOCIATED WEIGHT-GAIN - POTENTIAL RELATION TO ENERGY-EXPENDITURE AND METABOLISM IN PATIENTS WITH EPILEPSY

Among the more prevalent and, potentially, therapy-limiting adverse ef fects 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 patien ts. We wished to determine whether alterations occur in either resting energy expenditure (REE), energy intake, or hormonal/biochemical para meters in patients receiving VPA. We also wished to determine whether differences in drug metabolism exist between VPA patients who gain exc essive weight as compared with those who do not experience weight gain . Our study included 17 VPA patients, including 10 patients with signi ficant weight gain (> 5 kg) and 7 patients without significant weight gain. Ten epileptic patients not receiving VPA treatment and 11 health y volunteers served as control subjects. REE was measured by indirect calorimetry and was expressed as a function of Harris-Benedict equatio n predicted values as well as by body mass index (BMI) and body surfac e area. Energy intake was assessed by patient-reported food records. W e quantified VPA metabolism, specifically beta-oxidation, by measuring VPA metabolites recovered in urine (using gas chromatography-mass spe ctrometry, GC-MS), with subsequent calculation of the formation cleara nce of 2-ene-VPA. Both groups of VPA patients appeared to be hypometab olic 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 w as also significantly lower in VPA patients who experienced weight gai n as compared with VPA patients who did not gain weight. Energy intake did not differ significantly between any of the groups. Patients rece iving VPA appear to have lower energy expenditures as compared with co ntrol patients and healthy volunteers. Weight gain does not appear to be primarily a function of increased food intake. Patients who gain ex cessive weight while receiving VPA demonstrate differences in VPA meta bolism as compared with those VPA patients who do not gain excessive w eight.