Effects of Divalproex Sodium on Food Intake, Energy Expenditure, and Posture Allocation
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of the proposed study is to identify the mechanisms responsible for the weight
      gain associated with Depakote treatment, and to identify methods to prevent and treat weight
      gain in people taking Depakote. Both sides of the energy balance equation will be measured in
      a sample of healthy lean and overweight adults. Energy intake will be measured in the
      Pennington Center's Eating Laboratory, and total daily energy expenditure (TEE) and posture
      allocation will be measured with the IDEEA™. Questionnaires that assess food cravings and
      eating attitudes and behaviors will be used to determine if a behavioral phenotype is
      associated with weight gain in response to Depakote treatment. It is hypothesized that
      Depakote treatment will result in increased food intake. It is also hypothesized that the
      time spent engaging in sedentary behavior will increase in response to Depakote treatment.
      Time spent engaging in, and the energy expended during, physical activity is expected to
      decrease significantly. Therefore, it is hypothesized that TEE is expected to decrease
      significantly. The results will be used to identify specific behavioral targets to prevent
      weight gain during treatment with Depakote. Potential targets include interventions to modify
      food intake and physical activity. The degree to which each behavior (food intake or physical
      activity) will be targeted is dependent on the results of this study. For instance, if the
      majority of the weight gain associated with Depakote treatment is due to changes in food
      intake, stronger dietary interventions will be suggested. Additionally, changes in endocrine
      factors (hormones and peptides) will be evaluated during the study to determine if Depakote
      is associated with an altered endocrine response that affects satiety, food intake, or energy
      expenditure. If an altered endocrine response is found, these results will be used to
      identify adjunctive medications or compounds to correct the endocrine response and reduce
      weight gain. Genomic studies will also be possible, since gene sequencing and gene expression
      can be analyzed from archived buffy coat samples.
    

Detailed description: 
      Depakote (Abbott Laboratories, Abbott Park, IL) is an anti-convulsant medication used to
      treat epilepsy [1] and mania associated with bipolar disorder [2, 3]. Depakote also is used
      as a prophylaxis for migraine headache [4]. One side effect of Depakote that negatively
      influences its appeal to health care professionals and consumers is weight gain. It is
      unknown if changes in energy intake, energy expenditure, or a combination of both are
      responsible for this side effect. The purpose of the proposed study is to: 1) test if
      Depakote increases body weight by increasing food intake or decreasing energy expenditure,
      possibly through changes in posture allocation, and 2) identify methods to prevent and treat
      weight gain in people taking Depakote. This randomized placebo-controlled trial will measure
      both sides of the energy balance equation (energy intake and expenditure), and posture
      allocation (the time spent in active and sedentary behaviors, and the energy cost of these
      behaviors). Measurement of both total daily energy expenditure (TEE) and posture allocation
      provides a powerful tool to determine if Depakote decreases energy expenditure by increasing
      the time spent in sedentary behavior. These data, along with the food intake data, provide a
      test of the mechanisms responsible for weight gain associated with Depakote, and these data
      can identify methods to prevent or treat this weight gain.

      Divalproex sodium is a co-ordination compound consisting of sodium valproate and valproic
      acid. The exact mechanism of action of Depakote is unknown, but it is believed to increase
      brain concentrations of gamma aminobutyric acid (GABA). Similarly, the mechanism by which
      Depakote increases body weight is not understood. The balance between energy intake and
      expenditure influences body weight; therefore, Depakote likely alters energy intake, energy
      expenditure, or both. Alterations in energy intake or expenditure can result from, or be
      associated with, changes in biological mechanisms, including hormone and peptide levels. To
      our knowledge, only one study has tested the effects of a compound containing valproic acid
      on energy intake and expenditure, but this study was small (n = 8), uncontrolled, and used
      methods to measure energy intake (food records and recall) that were unlikely to detect
      changes in such a small sample [5]. The study proposed herein is the first study to test the
      effects of Depakote on eating behavior, measured in the laboratory, and energy expenditure
      and posture allocation, measured with the Intelligent Device for Energy Expenditure and
      Activity (IDEEA™; MiniSun LLC, Fresno, CA).

      In vitro, leptin secretion and mRNA levels in adipocytes decrease in response to valproic
      acid, and it is believed that altered leptin levels might influence weight gain in people
      taking compounds containing valproic acid [6]. Other researchers have reported that
      postprandial insulin and proinsulin levels increase in people taking valproic acid, and BMI
      is positively related to two-hour postprandial levels of insulin, proinsulin, and C-peptide
      [7]. Luef and colleagues indicate that treatment with valproic acid might increase glucose
      stimulated pancreatic section, which could be related to higher body weight due to two
      factors that are related to pancreatic beta-cell regulation and insulin secretion. First,
      valproic acid is a free-fatty acid (FFA) derivative that competes with FFAs for albumin
      binding, and, second, valproic acid is a GABA agonist. Thus, valproic acid treatment might
      increase glucose stimulated pancreatic secretion and contribute to weight gain. Evidence from
      other laboratories suggests that valproic acid treatment in children increases insulin levels
      and decreases glucose levels, which might stimulate appetite [8]. Importantly, Demir and
      Aysun note that carnitine levels did not correlate with weight gain, suggesting that valproic
      acid induced weight gain is not due to impairments in beta-oxidation of fatty acids.
      Carnitine is involved in the transfer of fatty acids into the mitochondria for
      beta-oxidation. Due to the potential role of FFA and valproic acid in influencing pancreatic
      beta-cell regulation and insulin secretion, FFA will be measured in the present study at
      baseline (day 0) and day 21, ½ hour before and one hour after the food intake tests at lunch.

      Due to the likelihood that hormones and peptides influence the weight gain associated with
      Depakote, blood samples will be archived for later analysis, pending availability of funds.
      Specifically, a portion of the archives will be used to measure gastric inhibitory
      polypeptide (GIP) and oxyntomodulin. Oxyntomodulin and GIP will not be assayed immediately
      because commercially available assay kits are not yet available. Oxyntomodulin has been
      implicated in the control of food intake and satiety in both humans and animals [9], and GIP
      modulates insulin secretion and might provide new treatments for diabetes [10]. Additionally,
      levels of PYY3-36, glucagon-like peptide-1 (GLP-1), leptin, and ghrelin will be measured.
      PYY3-36 and GLP-1 are distal gut hormones that have been found to reduce food intake [9, 11].
      PYY3-36 decreases food intake by 30% when infused into humans [11], and obese humans and
      rodents have attenuated fasting and post-prandial PYY3-36 levels that are likely associated
      with their obesity [12]. GLP-1 also decreases food intake in rodents and man, and it works
      synergistically with PYY3-36 [13]. Leptin reduces food intake [14] and increases energy
      expenditure in humans [15], while ghrelin increases food intake and is likely an important
      regulator of food intake [16].

      The aforementioned hormones will be sampled ½ hour before and one hour after the start of the
      food intake tests at lunch on days 0 and 21. The timing of these samples is based on the
      finding that PYY3-36 and GLP-1 peak one hour after a meal [17, 18]. Therefore, we will
      compare levels prior to meals and the change after the meals between the Depakote and placebo
      groups. Different pre-meal levels of these hormones and peptides can be correlated with food
      intake between the groups, and differential change in these hormones in response to the meal
      will be evaluated between the groups and correlated with food intake.

      Two factors that likely affect the amount of weight gain with Depakote treatment are gene
      sequencing and gene expression. Although these analyses can be costly, DNA material,
      including RNA, can be archived from whole blood samples and stored for later analysis. This
      method allows cost to be controlled since analyses can be conducted on a sub-sample of the
      participants who displayed specific reactions to treatment during the study. For example,
      genomic studies can be conducted on participants who fall within the lower and upper
      quartiles of weight gain, or a sub-sample of participants from the placebo and treatment
      groups. This provides empirical tests of a priori stated hypothesis without the need to
      endure the costs of running genomic analyses on the entire sample of participants. In the
      present study, both gene sequencing and gene expression studies will be made possible by
      archiving blood samples, as outlined in the Methods section. These analyses will depend on
      the availability of funds and the development of specific testable hypotheses (e.g., weight
      gain in the Depakote group will be associated with the peroxisome proliferator-activated
      receptor-gamma gene).
    

Intervention name(s): divalproex sodium
Intervention type(s): Drug
Intervention description(s): Divalproex sodium vs. placebo
Intervention MeSH terms: Valproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Keywords: divalproex sodium; valproic acid; food intake; energy expenditure; posture allocation; None, the population of study is healthy