Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications

Abstract

SummaryIn the last years, a growing body of literature indicates an association between valproic acid therapy and weight gain. Weight gain during valproate treatment can be observed within the first 3 months of therapy and women seem to be more susceptible than men. The mechanism through which valproic acid may induce a weight gain is still controversial. The scope of this paper is to investigate the possible causal link between treatment and weight gain in epileptic patients. Systematic review of published epidemiological studies has been done in order to evaluate the real extent of this side effect of valproic acid and its clinical implications, such as an increased risk of insulin resistance and other secondary metabolic abnormalities. The knowledge of the potential of valproic acid to cause significant changes in body weight will help in appropriate selection and modification of antiepileptic therapy to minimize the risk for weight abnormalities. Measurements of body weight before initiation of valproic acid therapy should be done as part of the monitoring of patients with epilepsy to detect changes before there are serious adverse consequences; an increase of 2 kg of body weight after 1 month of treatment should imply considerations to change antiepileptic drug therapy.

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

“…Hyperinsulinemia occurred both in VPAtreated patients with epilepsy who gained weight as well as in VPA-treated patients who remained lean (70), and fasting hyperinsulinemia in VPA-treated patients was not associated with increased fasting serum proinsulin or C-peptide concentrations (71). Together, these data do not imply insulin resistance as the cause of hyperinsulinemia; rather, inhibition of insulin metabolism in the liver was suggested to be the cause (reviewed in [68]). It remains to be examined if these side effects of VPA are associated with its HDAC inhibitor function, its effects on the central nervous system or other actions of the drug.…”

“…It remains to be examined if these side effects of VPA are associated with its HDAC inhibitor function, its effects on the central nervous system or other actions of the drug. The fact that VPA is a branched-chain fatty acid may account for these side effects (68). To our knowledge, hyperinsulinemia, insulin resistance and obesity have not been associated with other HDACi in clinical use.…”

“…However, the causal interaction and the role of insulin resistance herein are not clarified. The development of insulin resistance is suggested in many studies, mainly on the basis of the occurrence of hyperinsulinemia and on estimations of the homeostasis model assessment-insulin resistance (HOMA-IR) index (reviewed in [68]). In a study that more directly measured insulin resistance using a modified frequently sampled intravenous glucose tolerance test with tolbutamide, Verrotti et al (69) reported increased insulin resistance only in epileptic patients who gained weight and not in those who remained lean following 1 year of VPA treatment.…”

Metabolic Effects of Sodium Valproate on Atypical Antipsychotics in Japanese Psychotic Patients

“…In the psychiatry clinical setting, it is currently widely used for other indications, such as bipolar disorder, schizophrenia, and schizoaffective disorder as a mood stabilizer, combined with various types of atypical antipsychotics [1,2]. Frequent side effects of valproate treatment include weight gain and/or metabolic effects, although their real incidence or magnitude is unknown and the exact mechanism remains unclear [3][4][5]. Atypical antipsychotics are also associated with metabolic disorders, and vary in their propensity to cause these adverse effects [6].…”

“…Valproate treatment has been reported to be associated with obesity [5]. Valproic acid could directly stimulate the secretion of insulin from the pancreatic β cells [3], but it has also been suggested that valproate may interfere with insulin metabolism in the liver, resulting in higher insulin concentrations in peripheral circulation [4].…”