Weight and fat distribution in patients taking valproate: A valproate‐discordant gender‐matched twin and sibling pair study

Abstract

SUMMARYObjectives: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. Methods: Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dualenergy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. Results: We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat% WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. Significance: This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity

“…Furthermore, chronic administration of VPA is shown to contribute to obesity in patients [29][30][31]. The present study found that FTO expression was up-regulated in VPA-treated cells and knockdown of FTO deprived the effect of VPA on the downregulation of MBD2 and upregulation of Na V 1.3 (Fig.…”

“…A significant side effect of VPA is that chronic administration of VPA in patients or animal models can lead to abnormal metabolic phenotypes including obesity [29][30][31]. In view of the fact that fat mass and obesity-associated (FTO) protein is strongly associated with body weight mass [32][33][34][35][36], and FTO has been shown to catalyze m 6 A demethylation on RNAs [37,38]; thus, it is possible that VPA could posttranscriptionally regulate gene expression through a FTO-mediated epigenetic pathway, since a link between FTO, RNA epigenetics, and epilepsy has been previously put forward [39].…”

Does Chronic Administration of Sodium Valproate to Juvenile Rats Induce Movement Disorder and Cognitive Dysfunction during Adulthood?

“…The authors suggested that children treated with SV who became obese, might develop metabolic syndrome, hence careful monitoring is required. There are many such reports with respect to valproate-monotherapy-induced fat deposition and abnormal weight gain [19]. Possible reasons for the weight gain could be an increase in the consumption of calorie-rich foods and beverages as a result of a greater appetite and thirst, defective sympathetic nervous system activity, impaired beta-oxidation of fatty acids caused by Volume 12, No 1, January-Fabruary2018; http://www.ijt.ir carnitine deficiency, ineffective leptin activity in spite of high leptin levels (leptin-resistance) or increased secretion of β cells causing hyperinsulinemia [20,21].…”

Management of Adverse Effects of Mood Stabilizers

“…A recent study on epileptic patients in long-term treatment with VPA showed a relationship between long-term VPA use and abdominal adiposity, which could have significant health implications. Despite its limited sample size, the long-term follow-up of more than 10 years adds valuable information due to the potentially lifelong use of this drug [82]. The duration of monotherapy VPA is significantly associated with acceleration of atherosclerosis in patients with epilepsy [28].…”

“…Metabolic Syndrome and Weight Gain A constant monitoring of weight, BMI, and blood pressure for patients taking valproate is recommendable [82]. Anyway, given the early age at which cardiovascular diseases manifest among people with BD, a systematic screening for and treating cardiovascular risk factors in this population should be performed irrespectively of the treatment used [110].…”