Depakote (divalproex sodium) is a medication regularly prescribed for the management of epilepsy, bipolar disorder, and migraine headaches. Other medical conditions for which Depakote is occasionally utilized as a complementary (i.e. adjunct) therapy include: AIDS, cancer, dopamine dysregulation syndrome (associated with Parkinson’s disease), schizophrenia.
Most who are familiar with this drug understand that Depakote (divalproex sodium) is essentially a reformatted version of “valproic acid” (i.e. valproate), a compound that was: first synthesized in 1882 by Beverly Burton (as an analogue of valeric acid) and later discovered by Pierre Eymard to exhibit anticonvulsant properties in 1962. When administered, Depakote is understood to: inhibit voltage-gated sodium channels, increase GABA concentrations, and inhibit histone deacetylases.
Although the action of Depakote on voltage-gated sodium channels, GABA, and histone deacetylases make it an effective treatment option for numerous neuropsychiatric disorders, some prospective users might be concerned with its side effects. One particular side effect that many Depakote users want more information about is weight gain; specifically, they want to know whether the medication causes weight gain, and if it does, the amount to expect.
Does Depakote cause weight gain? (If so, how much?)
Yes. Evidence suggests that Depakote (divalproex sodium) can cause clinically relevant weight gain (7% increase in body weight from baseline) as a side effect. Moreover, research indicates that weight gain an extremely common side effect of Depakote – occurring in a significant percentage of users.
For this reason, if you plan on using Depakote, it is important to realize that weight gain might occur during treatment. According to Verrotti et al. (2011), clinically relevant weight gain is generally noticed within the first 3 months of valproic acid treatment – and is slightly more common in females than males.
Adults: 1.09 lbs. to 26.88 lbs. (57% to 70% of users)
A short-term study by Martin et al. (2009) with 26 adults reported a weight increase of 1.09 lbs. following the administration of valproic acid for 21 days. This weight gain was accompanied by increased hunger, binge eating, cravings for fast food fats, and depressed mood.
Another study by El-Khatib et al. (2007) with 106 epileptic adults documented significant weight gain following valproic acid treatment for 6 months. The weight gain occurred in both males and females, but was more prevalent and significant among females. Leptin resistance and carbohydrate cravings were proposed causes of the weight gain.
Research by Biton et al. (2001) noted that 68 valproate users gained a significant amount of weight within 10 weeks of treatment. Over the span of 32 weeks, the 68 valproate users gained an average of 12.8 lbs. (whereas 65 lamotrigine users did not experience significant weight change).
An analysis by Corman et al. (1997) of 70 adults treated with valproic acid for at least 3 months reported that 70% of users experienced a weight gain exceeding 8.81 lbs. Additionally, a case report by Bittencourt (1986) noted that a 19-year-old female gained 26.88 lbs. from using 1000 valproic acid per day.
An earlier study by Dinsen et al. (1984) also reported weight gain in 36 of 63 adults (57%) with epilepsy as a result of valproic acid treatment. Similar to the analysis by Corman et al., this study documented the average weight increase as exceeding 8.81 lbs.
Pediatrics: 53% of users
Research by Kanemura et al. (2012) discovered that 8 of 15 children (53%) using valproic acid for 6 months experienced weight gain. This weight gain was accompanied by increased appetite, increased insulin, and increased insulin/glucose ratios.
A study by Gungor et al. (2007) also reported weight gain in 35 children with epilepsy following 6 months of valproic acid treatment. A longer-term study by Novak et al. (1999) involving 55 children documented significant increases in body weight and BMI following the administration of valproic acid for at least 8 months.
In summary, all trial data suggest that Depakote is likely to cause weight gain in over half (50%) of users – regardless of age or preexisting medical diagnoses; zero studies suggest that Depakote causes weight loss. The amount of weight gain reported from Depakote in the research ranges from 1.09 lbs. to 26.88 lbs. Most Depakote users who are prone to weight gain will notice body weight increase within the first 3 months of treatment.
Depakote & Weight Gain (Why It Occurs)
Although it is known that Depakote and related compounds (e.g. valproic acid) cause weight gain in over half of all users, the specific mechanisms by which the medication induces weight gain remain unclear. That said, researchers have attempted to identify and/or hypothesize the primary mechanisms by which Depakote induces weight gain.
Included below is a list of hypothetical ways by which Depakote might cause weight gain. If you experience weight gain as a side effect of Depakote, understand that the specific mechanism(s) by which you’re gaining weight on Depakote might differ from those associated with another user who’s gaining weight.
Adipokine expression: A proposed mechanism by which Depakote might cause weight gain is via modifying expression of adipokine genes within the brain. These adipokine genes encode for neuropeptides (e.g. adiponectin, resistin, fasting-induced adipose factor, angiopoietin-like protein 4) which are implicated in the regulation of central energy metabolism.
Resistin is upregulated in obesity and plays a role in the pathogenesis of insulin resistance and activates protein kinases implicated in hypothalamic appetite regulation and glucose metabolism. Downstream signaling from resistin and fasting-induced adipose factor could influence leptin and insulin status.
Researchers believe that Depakote administration could modify adipokine genes in ways that increase resistin (which increases SOCS-3, an intracellular inhibitor of leptin signaling) and simultaneously suppress fasting-induced adipose factor. The consequences of its effect on adipokine gene expression might be: leptin resistance, insulin resistance, glucose intolerance, and weight gain.
Appetite increase: While some studies suggest that Depakote can cause weight gain even without unchanged appetite and/or increased calorie intake – other studies suggest that Depakote may cause weight gain primarily by increasing appetite. Treatment with Depakote has been proposed to increase appetite primarily via modulation of hormones (e.g. leptin, ghrelin, insulin, etc.) and hypothalamic activity.
If you experience an appetite increase with Depakote treatment, it may be difficult to refrain from overeating (or eating more calories than your body burns in a day). Assuming your appetite skyrockets while taking Depakote and it leads you to consume more food than you did pre-treatment – weight gain should be expected.
Binge eating behavior: A short-term study by Martin et al. (2009) in which valproic acid was administered for 21 days reported increases in binge eating behavior as a side effect. Although this study was relatively short-term and small-scale, it suggests that valproic acid treatment could increase rates of binge eating in otherwise healthy adults.
If valproic acid treatment provokes binge eating episodes (in persons with no history of binge eating) and/or increases binge eating frequency (in persons with a history of binge eating) – this could be a means by which the medication causes weight gain. Evidence suggests that binge eating (especially high-frequency binge eating) is associated with weight gain, even among persons who are actively trying to lose weight.
Cognitive impairment: Another way in which Depakote might indirectly cause weight gain is through cognitive impairment. If cognitive impairment is moderate and/or severe (as a result of Depakote treatment), it’s possible that this impairment might alter feeding behavior in certain users.
For example, if aspects of cognition such as: self-regulation and planning are compromised from the medication, it may be difficult to restrain oneself around food (to prevent overeating) and/or plan healthy meals in advance (to avoid calorie-dense, unhealthy options). If Depakote-induced cognitive impairment occurs along with increased appetite and/or food cravings – this combination might prove too overwhelming for some users to manage such that they overeat and gain weight.
Decreased physical activity: As a medication that increases GABAergic signaling, Depakote might cause fatigue, drowsiness, or lethargy as a side effect. If your energy level seems as though it’s taken a major hit from Depakote treatment, it’s reasonable to suspect that the energy reduction might’ve contributed to your weight gain.
Fatigue and low energy might lead a person to exercise less frequently, intensely, or for a shorter duration than they did pre-treatment. Moreover, fatigue might cause an individual to move less throughout the day such that they exhibit less non-exercise activity thermogenesis (NEAT).
Possible reductions in exercise (frequency, intensity, duration) coupled with decreased non-exercise activity thermogenesis: will reduce the total number of calories burned from physical activity, cause resting metabolic rate to decrease, and might alter body composition.
Depression: Depression is a side effect of Depakote that could alter appetite, feeding behavior, hormones, resting metabolic rate, and physical activity – all of which can affect body weight. Assuming you become depressed while using Depakote, this depression might: increase your appetite, promote binge eating, alter your hormones, reduce your resting metabolic rate, and decrease your physical activity level.
Additionally, it’s known that some individuals may be at increased risk for consuming hyperpalatable (high-fat, high-salt, high-sugar) and/or calorie-dense foods as a coping mechanism for their depressed mood. If you become depressed while using Depakote, understand that the myriad of physiologic changes that occur with depression could directly or indirectly contribute to weight gain.
Fat accumulation: The hormonal changes induced by Depakote, energy substrate utilization, and/or preferences for fatty fast foods might increase body fat accumulation. More specifically, Depakote-mediated hormonal changes (e.g. adiponectin, insulin, resistin, et al.) might slow metabolism, increase the rate at which the body stores fat, and/or decrease the rate at which the body burns fat stores for energy – a combination of which would promote fat gain.
In animal models and cell cultures, valproic acid therapy has been shown to increase intrahepatic fat (i.e. fat within the liver). Moreover, in several clinical trials, patients receiving valproic acid underwent ultrasonic liver examination, the results of which revealed 61% exhibited non-alcoholic fatty liver disease. Though it is unclear as to whether valproic acid causes subcutaneous and/or visceral fat accumulation in humans, preliminary data indicate that it’s a possibility.
Food cravings: Multiple studies have reported increased food cravings among valproic acid users. One study reported cravings for “fast food fats” among valproic acid users (compared to placebo users), and another study reported cravings for carbohydrates – especially among females using valproic acid.
In the study that reported carbohydrate cravings while using valproic acid, rates of carbohydrate craving by sex were as follows: 25.8% females and 14.3% males. Obviously if you’re constantly craving foods (e.g. carbohydrates or fast food fats) while using Depakote, it may be difficult to resist these cravings.
Assuming you’re unable to resist Depakote-induced food cravings, you might end up consuming a greater quantity of calories while using Depakote than before treatment. If you’re gaining weight on Depakote, realize that incessant food cravings could be culpable.
Gut bacteria modulation: The effect of Depakote on populations of gut bacteria (i.e. microbes) remains unclear. However, it is thought that gut bacteria can influence hormone production, neurotransmission (centrally and peripherally), oxidative stress, inflammation, brain activity, resting metabolic rate, etc. – all of which could affect one’s body weight.
Furthermore, there’s evidence to suggest that a subset of pharmaceutical medications impact gut bacteria in deleterious ways as to promote fat storage and weight gain. In the event that Depakote treatment increases populations of pathogenic microbes and/or decreases populations of healthy microbes in the gut – this could increase appetite, fat storage, and/or bloating – all of which could contribute to weight gain.
Hormone modulation: Research suggests that Depakote treatment might modulate concentrations of hormones such as: adiponectin, ghrelin, insulin, leptin, resistin, DHEA, follicle stimulating hormone, luteinizing hormone, and estradiol. Alterations in concentrations of the aforementioned hormones might directly cause weight gain by increasing fat storage and/or slowing metabolic rate – or indirectly cause weight gain by stimulating appetite (leading to increased energy intake).
Valproic acid seems to decrease adiponectin and ghrelin, but increase resistin, leptin (in obese users), and insulin – in both men and women. In men, valproic acid increases DHEA, reduces follicle-stimulating hormone, and reduces luteinizing hormone. The cumulative effect of Depakote on hormone levels could contribute to weight gain and unfavorable changes in body composition among certain users.
Hypothalamic modulation: Direct and indirect actions of Depakote upon the hypothalamus are possible mechanisms by which the medication might induce weight gain. Data from experimental studies suggest that valproic acid can cause hypothalamic dysregulation via enhancement of GABAergic neurotransmission within the hypothalamic axis.
Researchers believe that modulation of hypothalamic function by Depakote may lead to increased appetite and thirst. As a result of the increased appetite and thirst stemming from hypothalamic stimulation, patients consume more calories than they did before treatment – and end up gaining weight.
Pancreatic beta-cells & insulin secretion: According to Verrotti et al. (2010) one way that Depakote treatment may lead to weight gain is by altering the activation of pancreatic beta-cells and insulin secretion. It is known that the neurotransmitter GABA aids in the regulation of pancreatic beta-cells and insulin secretion.
By increasing GABA concentrations and activating GABA receptors, Depakote induces membrane depolarization and insulin secretion. Ex-vivo studies support the idea that valproic acid directly stimulates pancreatic beta cells.
When islet cells from pancreases of organ donors are incubated with valproic acid, a time-dependent and dose-dependent increase of insulin levels is observed. This suggests that Depakote treatment could cause hyperinsulinemia. Valproic acid also seems to interfere with GLUT-1, an insulin transduction pathway.
Inhibition of GLUT-1 within astrocytes and fibroblasts could reduce the transport of glucose and downregulate GLUT-1 mRNA expression. Researchers believe that effect of Depakote on beta-cell activation, insulin release, and signal transduction could enhance appetite and/or increase energy storage to cause weight gain.
Slower metabolic rate: Your resting metabolic rate (RMR), or the number of calories that your body burns at rest, might slow significantly while using Depakote. There are many reasons as to why your resting metabolic rate might slow (relative to your current body weight) during Depakote treatment, including: hormone changes, reductions in physical activity (including non-exercise activity thermogenesis), and decreased catecholamine signaling (and physiologic arousal).
If your resting metabolic rate slows substantially while using Depakote, it might be extremely difficult to avoid weight gain. In fact, the only way to avoid weight gain from a slowing of your metabolic rate is to decrease calorie intake (something that most people probably aren’t willing to do).
Social eating: Although “social eating” isn’t a specific mechanism by which Depakote causes weight gain, it’s a behavior that could lead to weight gain among a subset of Depakote users. It is known that certain persons with untreated neuropsychiatric disorders (e.g. epilepsy, bipolar disorder, et al.) isolate themselves socially – usually due to a combination of their symptoms and stigma associated with their condition.
However, assuming Depakote effectively manages neuropsychiatric symptoms, users might begin to socialize more frequently – and partake in social events like going out to eat at restaurants (a popular social activity). Though dining out doesn’t guarantee weight gain, most restaurant entrees are calorically-dense with large serving sizes.
If you’re not diligently tracking your calories, increased social eating while using Depakote (e.g. dining out with friends) could be culpable for your weight gain. Moreover, it’s worth mentioning that one study with Depakote reported increased “fatty fast food” cravings, which if experienced, could increase the allure of “going out to eat” among users.
Sympathetic modulation: Another mechanism proposed by Verrotti et al. (2010) as a way in which Depakote could cause weight gain is via altering activation of the sympathetic nervous system. During Depakote treatment, the body’s catecholamine response to glucose seems to decrease.
Researchers believe that this change in sympathetic activation could impact the activation of neurons within the hypothalamus to increase appetite and/or increase energy storage – ultimately leading to weight gain. Interestingly, weight gain that isn’t associated with excessive calorie intake in obese persons is frequently explained by abnormal functioning of the sympathetic nervous system.
Note: There could be alternative reasons as to why someone might gain weight from Depakote (other than those listed above). If you know of additional mechanisms by which Depakote might induce weight gain, mention them in the comments.
Depakote & Weight Gain (The Studies)
Included below are scientific reports in which the effect of Depakote (divalproex sodium) or valproic acid on body weight was evaluated and/or discussed. To date, nearly all published journal articles reflecting upon Depakote’s effect on body weight indicate that the medication can cause significant weight gain as a side effect.
While there are limitations associated with some of the studies below, the data derived from these reports are unanimous in suggesting that Depakote causes weight gain. In other words, there aren’t any studies to suggest that Depakote does not cause weight gain. For more information about a specific study, click on the hyperlink citation listed beneath the summary.
2016: Cytochrome P450 2C19 polymorphisms and valproic acid-induced weight gain.
Noai, Soraoka, Kajiwara, et al. noted that valproic acid (VPA) is understood to cause weight gain in a subset of patients as an adverse reaction. Because weight gain can vary significantly among valproic acid users, researchers sought to determine whether polymorphisms of genes implicated in drug metabolism (i.e. biotransformation) might influence the likelihood and/or significance of valproic acid-induced weight gain.
Researchers conducted a retrospective longitudinal study in which data were collected and analyzed from: 85 young adults (with epilepsy) who underwent treatment valproic acid and 93 young adults (with epilepsy) who underwent treatment with carbamazepine – for at least 6 months. The CYP2C19 genotype of each patient was assessed, as was change in body mass index (BMI) from baseline through 6+ months of treatment.
Results indicated that body mass index (BMI) significantly increased among females using valproic acid with 1 or 2 loss-of-function CYP2C19 alleles – compared to females with normative CYP2C19 function. There were no correlations between CYP2C19 expression and weight change in males using valproic acid – nor carbamazepine users of either sex.
It was concluded that there is a noteworthy association between the CYP2C19 polymorphism and valproic acid-induced weight gain among females with epilepsy. This study supports the idea that valproic acid can cause weight gain when administered for at least 6 months among young adults with epilepsy, and indicates that the weight gain might be most substantial among female users with CYP2C19 abnormalities.
2012: Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-blind, randomized controlled trial.
Jeong, Lee, Ko, et al. conducted a randomized controlled trial to determine the efficacy of combination therapies in patients experiencing bipolar mania. For the trial, 28 patients were assigned to receive a combination of “valproic acid + aripiprazole” and 14 were assigned to receive a combination of “valproic acid + haloperidol” – over an 8-week duration.
In addition to assessing the efficacy of each combination therapy, researchers documented incidence rates of adverse effects – one of which was weight gain. Results indicated that the average weight gain among participants was: 9.65 lbs. (valproic acid + aripiprazole) and 4.18 lbs. (valproic acid + haloperidol).
Clinically significant weight gain occurred in 64.3% of “valproic acid + aripiprazole” users and in 28.6% of “valproic acid + haloperidol” users. Considering the results of this trial, it’s reasonable to hypothesize that valproic acid promotes weight gain – especially when administered with antipsychotic medications.
2012: Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy.
Kanemura, Sano, Maeda, et al. organized an open-label clinical trial to assess the effect of valproate sodium on the body weight of 15 children with epilepsy. Researchers measured: body weight, body mass index (BMI), serum glucose, serum insulin, serum valproate sodium, and serum free carnitine – at baseline and after 6 months.
Within 6 months of treatment initiation, 8 of the 15 children (53%) exhibited significant weight gain. Among those who gained weight from valproate sodium, significant increases were observed in: appetite, serum insulin, and insulin/glucose ratios – from baseline.
Researchers speculated that valproate sodium-induced weight gain may have been caused by increased serum insulin and/or insulin/glucose ratios which enhanced appetite – and led to excessive calorie intake. However, it’s also possible that the opposite might be true: drug-induced weight gain led to increases in serum insulin and insulin/glucose ratios.
Implementation of intensive behavioral therapy was discovered to effectively attenuate valproate sodium-induced weight gain (without discontinuation). Although this study involved children, was small-scale, and uncontrolled – it suggests that valproate sodium may cause weight gain in over 50% of users.
2011: Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications.
Verrotti, D’Egidio, Mohn, et al. published a report in which weight gain was highlighted as a side effect of valproic acid. Authors noted that weight gain among valproate users tends to be more common among females (than males) and is generally observable within the first 3 months of treatment.
Additionally, authors mentioned that weight gain from valproic acid might put certain patients at increased risk of developing insulin resistance and other metabolic abnormalities. Because weight gain is a side effect of valproic acid, authors recommend exploring alternative antiepileptic medications in patients who gain more than 4.4 lbs. (2 kg) within 1 month of initiating treatment.
2009: Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial.
Martin, Han, Anton, et al. conducted a double-blind, randomized controlled trial to examine the effect of valproic acid on: (1) body weight; (2) food and beverage intake; (3) physical activity levels; (4) endocrine responses to a meal; and (5) eating attitudes and behaviors. A total of 52 healthy adults participated in the trial and were assigned to receive either: valproic acid (up to 1500 mg per day) or a placebo for 3 weeks.
Researchers grouped participants such that BMIs (low and high) were equally represented in the 2 groups (valproic acid and placebo); each group consisted of 26 adults. After an initial 3-week (21-day) treatment phase, participants were discontinued from each treatment (valproic acid or placebo) and scheduled for follow-up measures 4 weeks later.
Trial results indicated that valproic acid was associated with weight gain of ~1.08 lbs. over the 21-day period, whereas placebo use was associated with weight loss of ~0.17 lbs. It was noted that neither energy intake (from food and beverages) nor macronutrient preferences changed from baseline to Day 21 – within groups and between groups.
Data collected from accelerometers revealed no significant differences in minutes per day of: sedentary behavior, light activity, or moderate activity – between valproic acid recipients and placebo recipients. That said, valproic acid recipients exhibited reductions in minutes of sedentary behavior from baseline to Day 21 – and increases in minutes of light physical activity; placebo recipients did not exhibit changes in these measures.
Endocrine responses to meals did not differ between the groups from baseline through Day 21 –evidenced by concentrations of: ghrelin, GLP-1, leptin, and PYY. However, within-group analyses revealed significant increases in GLP-1 among valproic acid users (from baseline through Day 21).
An analysis of eating attitudes and behaviors discovered zero changes between the groups from baseline to Day 21. However, valproic acid recipients experienced significant increases in hunger at Day 21 in comparison to baseline. (Still, it should be noted that valproic acid recipients exhibited higher hunger levels at baseline than placebo recipients).
Trial results also indicated that valproic acid recipients exhibited significant increases in: cravings for fast food fats, binge eating, and depression – compared to the placebo group. A reduction in diastolic blood pressure was observed among valproic acid users – and decreases in: albumin, total cholesterol, LDL, glucose, and platelets were observed among valproic acid recipients compared to placebo recipients.
Researchers concluded that results of this trial support the idea that valproic acid causes weight gain in healthy persons when administered for a limited duration (3 weeks). It was suggested that weight gain from valproic acid might be a byproduct of drug-induced: hunger, binge eating, cravings for fast food fats – and possibly mood changes like depression.
2007: Valproate, weight gain and carbohydrate craving: a gender study.
El-Khatib, Rauchenzauner, Lechleitner, et al. organized a study to compare the rate and magnitude of weight gain attributable to valproic acid – among male and female patients. The purpose of this study was to elucidate whether weight gain and its magnitude might be more common and/or significant in one sex (e.g. females) versus the other (e.g. males).
A total of 106 patients (55 females, 51 males) with epilepsy participated in the study in which valproic acid was administered as a monotherapy. Throughout the trial, researchers documented: weight change, frequency of carbohydrate cravings, physical exercise, socio-psychological problems, and family history for diabetes. Other measures included: body-impedance, body mass index, waist-to-hip ratio, and various biomarkers (leptin, glucose, lipids, insulin, C-reactive protein, TNF-alpha).
Results indicated that valproic acid therapy caused significant weight gain in all users regardless of sex (female versus male), however, female users exhibited more pronounced increases in body weight than male users. Among females who gained weight from valproic acid, significant biomarker changes were observed including: increased serum leptin, high HDL, and low triglycerides.
Rates of carbohydrate craving by sex were: 25.8% for females and 14.3% for males. Furthermore, a greater number of women attempted to lose or control their body weight through dietary changes than men (22.6% versus 7.1%). For this reason, researchers considered weight gain to be a more substantial socio-psychological problem for females than males.
It was concluded that females are at increased risk of weight gain while using valproic acid than men, which might be due to a combination of: leptin-resistance and frequent carbohydrate cravings. Although this was a relatively small-scale study, it supports the idea that valproic acid can cause significant weight gain when used for at least 6 months.
2007: The role of ghrelin in weight gain and growth in epileptic children using valproate.
Gungor, Yücel, Akinci, et al. recruited 70 children (ages 3 to 15) for participation in a study to determine the effect of valproic acid on hormone concentrations. Researchers hypothesized that valproic acid treatment might modify certain hormones levels to promote weight gain and/or alter body growth in pediatric patients.
Half of the participants (35) were diagnosed with epilepsy, whereas the other half (35) were non-epileptic healthy children. Blood work was collected from all patients at baseline and after 6 months of treatment to evaluate: fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3.
Results revealed significant increases in measures of: body weight, body mass index (BMI), and height (after 6 months) among the 35 children with epilepsy receiving valproic acid. When compared directly to the healthy (non-epileptic) controls, the children with epilepsy exhibited substantially greater increases in growth velocity and weight gain within 6 months of treatment.
Additionally, researchers discovered significant increases in serum ghrelin concentrations and decreases in insulin-like growth factor-1 and insulin-like growth factor binding protein-3 – among prepubertal children with epilepsy receiving valproic acid for 6 months. These changes were not observed in pubertal children with epilepsy (receiving valproic acid) or healthy controls.
In summary, this study supports the idea that valproic acid can cause significant weight gain in pediatrics when used for 6 months, and that for prepubertal children, weight gain might be caused by increases in ghrelin.
2005: Psychotropic-Induced Weight Gain and Potential Pharmacologic Treatment Strategies.
Gracious and Meyer published a paper documenting weight gain associated with psychotropic medications, one of which was valproic acid. Researchers reflected upon several studies in which valproic acid treatment induced clinically significant weight gain.
Study #1: A total of 57% of adults with epilepsy treated with valproic acid gained more than 8.81 lbs. (ranging from 8.81 lbs. to 37.47 lbs.). The other 43% of users maintained a stable body weight throughout treatment. Factors such as: family history, diagnosis of Type 2 diabetes, weight gain during pregnancy – did not determine which users gained weight.
Study #2: A group of pediatric patients with epilepsy received valproic acid for up to 3 years. Height and weight of each participant was recorded throughout the study. Results discovered significant increases in weight and BMI when compared to healthy age-matched children. Moreover, valproic acid reduced growth rates among girls – and the magnitude of growth rate reduction was associated with total length of treatment.
Study #3: Adolescents and adults were assigned to receive either: valproic acid or lamotrigine. Within 10 weeks of treatment, significant weight gain was observed among recipients of valproic acid. Furthermore, weight gain continued in valproic acid recipients beyond the initial 10-week period. The average weight gain observed among valproic acid users in this study was 12.8 lbs. (Dose did not influence total weight gain).
2001: Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
Biton, Mirza, Montouris, et al. investigated the effects of valproate and lamotrigine monotherapies on the body weights of patients with epilepsy. Specifically, researchers sought to determine the rate and magnitude of weight change associated with each medication.
A total of 133 patients with epilepsy were assigned at random to receive either: valproate (68 patients) or lamotrigine (65 patients) for 32 weeks (8-week escalation phase followed by a 24-week maintenance phase). The target maintenance doses were: 10-60 mg/kg/day for valproate and 100-500 mg/day for lamotrigine.
Although body weight remained stable in lamotrigine users, significant weight gain was observed in valproate users within 10 weeks of treatment. After 32 weeks of treatment, average weight gain was significantly greater in valproate users (~12.8 lbs.) compared to lamotrigine users (~1.3 lbs.).
It was concluded that valproate monotherapy is associated with significantly greater weight gain – compared to lamotrigine monotherapy. Moreover, weight gain resulting from valproate treatment was clinically significant within 10 weeks of treatment initiation.
1999: Risk of excessive weight gain in epileptic children treated with valproate.
Novak, Maytal, Alshansky, et al. organized a study in which 55 children (30 girls, 25 boys) were followed for 8.6 to 33.8 months after initiating treatment with valproate for epilepsy. The aim of the study was to identify risk factors associated with weight gain during valproate treatment.
Hypothesized risk factors included: sex; age at the beginning of treatment; valproate monotherapy (at treatment initiation); mental retardation; seizure type; seizure etiology; and dosage of valproate. Researchers documented the body weight and height of each participant before treatment – as well as at follow-ups.
Results indicated that valproate treatment led to significant increases in body weight and body mass index; these increases were associated with high body weight and body mass index at the start of treatment. For this reason, researchers concluded that valproate causes weight gain in children, and that risk and/or magnitude of weight gain may be greater among children who are overweight/obese at the start of treatment.
1997: Weight gain in epileptic patients during treatment with valproic acid: a retrospective study.
Corman, Leung, and Guberman noted that weight gain is considered a common adverse reaction to valproic acid treatment. For this reason, researchers conducted a retrospective study to determine the prevalence of weight gain among valproic acid users – and identify risk factors for their weight gain.
Researchers collected data from 70 adult patients who received valproic acid (monotherapy or polytherapy) – for between 3 and 189 months (median: 27 months). Patients were categorized into groups based upon magnitude of weight change: non-weight gainers (less than 5% change in weight from baseline); mild-to-moderate gainers (5-10% change in weight from baseline); and marked weight gainers (over 10% change in weight from baseline).
Additionally, researchers evaluated variables such as: age, body mass index, drug dose, familial/personal history of obesity, sex, and monotherapy vs. polytherapy – to determine whether they might’ve influenced risk of weight gain. Results indicated that 71% of valproic acid users exhibited weight gain.
In 70% of valproic acid users, the average weight gain exceeded 8.81 lbs. It was noted that the weight gain was sustained throughout treatment and regarded as being “socially significant” to patients. Interestingly, patients below or within normal body mass index before treatment initiation exhibited the most significant increases in weight. Furthermore, patients with zero history of weight problems experienced the greatest initial weight increases.
1986: Valproic acid, curly hair and weight gain.
Bittencourt authored a case report in which a 19-year-old female who received valproic acid for the management of seizures – gained 28.66 lbs. during treatment. In addition to the weight gain, the patient experienced a change in natural hair color (from light blonde to dark) and style (it became thicker, darker, and curlier).
The patient had been using valproic acid at a dosage of 1000 mg per day and exhibited a serum concentration of 138.9 mcg/ml. After reducing the patient’s dosage by 500 mg per day and attaining a serum concentration of 80.5 mcg/ml – the patient lost 15.43 lbs.
Despite the dosage reduction and weight loss, the changes to the patient’s natural hair color and style remained unchanged. This case report indicates that valproic acid can cause significant weight gain, and also reveals that it may be possible to reduce the magnitude of weight gain via dosage adjustments.
1984: Weight gain during treatment with valproate.
Dinesen, Gram, Andersen, et al. published one of the first reports documenting weight gain as a side effect of valproate treatment. Researchers analyzed weight changes exhibited by 63 adult patients with epilepsy who underwent treatment with valproate.
A total of 36 patients (57%) had gained more than 8.81 lbs. during treatment, whereas 27 patients (43%) exhibited zero clinically relevant weight change. There were no differences between patients who gained weight and patients who didn’t in terms of: age, sex, pretreatment weight, length of treatment, dosage, or serum valproate concentrations.
Furthermore, structured patient interviews reported no differences between weight gainers and non-weight gainers in: appetite, thirst, predisposition to obesity/diabetes. Nevertheless, this study supports the finding that valproate causes weight gain in a significant percentage of users.
Variables that influence Depakote induced weight gain
There are many variables to consider as possible influencers of weight gain on Depakote. Such variables probably include: duration of Depakote use; dosage & format; concurrent substance use; individual factors (e.g. medical conditions, genetics, sex, body weight/composition, age, lifestyle, prior substance use). It is the combination of these variables that likely explains why certain Depakote users gain a significant amount of weight from treatment – yet others don’t.
Duration of Depakote treatment
The duration over which you’ve used Depakote could determine whether you’re likely to have experienced significant weight gain as a side effect. If Depakote is administered for a short-term (e.g. under 1 month), clinically relevant weight gain (7% body weight increase from baseline) is unlikely to occur.
One study in which valproic acid was administered for 21 days (3 weeks) discovered that valproic acid users exhibited an average weight gain of ~1.08 lbs. – whereas placebo recipients exhibited slight weight loss. Considering the results of this short-term study, it’s reasonable to expect that although weight gain can occur over a short-term from Depakote – it’s unlikely to be significant.
That said, all studies in which valproic acid was administered for a moderate-term (exceeding 3 months) or long-term have noted clinically relevant weight gain as a side effect in a significant percentage of users. Most data indicate that clinically significant weight gain from Depakote becomes noticeable within 3 months of treatment.
One long-term study mentioned that weight gain among valproic acid users became “clinically significant” at Week 10 of treatment. As a general rule of thumb, if you’ve only been using Depakote for a short-term, realize that you may not have used the medication for a long enough term to induce substantial weight gain.
Moreover, understand that incremental weight gain may occur throughout Depakote treatment such that more weight may have been gained after 1 year than 6 months, after 6 months than 3 months, and after 3 months than 1 month, etc. Nevertheless, it’s also possible that most who are prone to weight gain from Depakote eventually plateau (e.g. gain ~10 lbs. and experience no additional weight increase) over a long-term (e.g. after a year of treatment).
Depakote dosage & format
The dosage and format of Depakote administered could also influence likelihood of weight gain during treatment – as well as the magnitude of weight gain (among those who experience it). Some evidence suggests that high doses of Depakote may be more likely to cause weight gain than lower doses, and that the standard format is more likely to cause weight gain than the extended-release format.
Dosage (High vs. Low): It is known that Depakote is prescribed at a variety of doses based upon a prospective user’s neuropsychiatric condition, body weight, and concomitant medication use. Theoretically, high doses of Depakote (relative to body weight) should modulate the neurotransmission of GABA and other aspects of physiology (e.g. hormone levels, gene expression, metabolic rate, etc.) to a greater extent than lower doses.
In those who are prone to weight gain as a side effect, greater physiologic modulation (resulting from high doses of Depakote) likely bolsters the underlying actions (i.e. mechanisms) by which the medication induces weight gain. For this reason, it’s logical to expect that high doses of Depakote increase risk and/or magnitude of weight gain – whereas low doses of Depakote decrease risk and/or magnitude of weight gain.
Although some reports claim that there’s not a dose-dependent effect of Depakote on body weight, evidence from a case report supports the idea that high doses are more likely to cause weight gain than lower doses. In the case report, a 19-year-old taking 1000 mg Depakote per day gained 26.88 lbs. – and was able to lose 15.33 lbs. by reducing the dosage to 500 mg per day. Other reports indicate that high serum concentrations of Depakote are more likely to cause weight gain than lower serum concentrations; these are usually a byproduct of dosing.
Format (ER vs. IR): It’s possible that the format of Depakote administered could influence likelihood and/or magnitude of weight gain during treatment. Depakote is manufactured in 2 formats: “immediate release” (IR) and “extended release” (ER). Standard Depakote (IR) may require dosing multiple times per day (e.g. b.i.d.), whereas Depakote ER allows for once-per-day dosing and provides sustained therapeutic serum levels of the divalproex sodium throughout the entire day.
According to an analysis by Smith et al. (2004) of open-label trials involving 321 patients, weight gain is significantly less likely to occur among users of Depakote ER compared to users of standard Depakote IR. In the open-label trial analysis by Smith et al., weight gain occurred in 29 of 103 (28%) of patients using standard Depakote. When these patients switched from standard Depakote to Depakote ER, nearly half reported improvements in body weight; zero additional weight gain and weight loss.
Concurrent substance use
Any substances (prescriptions, supplements, over-the-counter meds, etc.) that you’re using along with Depakote could influence whether you’re likely to experience weight gain as a side effect and/or the amount of weight gain that you experience. Assuming you’re using one or multiple substances with Depakote, it’s important to understand that they might: prevent OR enhance the mechanism(s) by which Depakote promotes weight gain.
For example, if you’re using the medication aripiprazole (an atypical antipsychotic) with Depakote, the physiologic actions of aripiprazole might enhance the mechanisms (e.g. increased appetite; hormonal modulation; slowing metabolic rate; et al.) by which Depakote promotes weight gain. As a result, you may end up gaining more weight with the combination of Depakote and aripiprazole than you would’ve gained with standalone Depakote.
In the aforementioned example, some of the weight gain that you’re experiencing is probably partially attributable to influence of the concurrently-administered medication. For general reference, one study reported weight gain of ~9.65 lbs. over an 8-week duration from the combination of Depakote and aripiprazole.
Another possibility could be that you’re using Depakote with a medication that promotes weight loss (e.g. a psychostimulant). In this case, the physiologic effects and/or side effects of Depakote associated with weight gain (e.g. appetite increase; catecholamine decrease; slowing of metabolic rate; etc.) might be offset by the physiologic effects and/or side effects of the psychostimulant (e.g. appetite suppression; catecholamine increase; enhancement of metabolic rate; etc.) such that weight gain never occurs.
Individual Depakote user
A combination of user-specific or individual factors including: age, body weight/composition (at the beginning of treatment), gene expression, lifestyle, preexisting medical conditions, prior substance use, and sex – could determine whether weight gain occurs as a side effect of Depakote.
Age: Depakote has been shown to cause weight gain in both pediatrics and adults. Nevertheless, it’s possible that weight gain [relative to baseline body weight] might be more significant in adult users versus pediatrics (or vice-versa) – possibly due to age-related hormone levels and/or organ function. Although it’s unknown as to whether age influences likelihood and/or magnitude of weight gain on Depakote – it’s a factor that warrants consideration.
Body weight/composition: Body weight and/or composition prior to using Depakote might influence odds of gaining weight during treatment, however, this factor might interact with age. Specifically, it seems as though being obese/overweight as a pediatric (prior to using Depakote) increases risk of significant weight gain during treatment, whereas being underweight or normal weight as an adult seems to increase risk of significant weight gain during treatment.
Research by Novak et al. (1999) discovered that preexisting obesity in pediatrics before treatment is associated with greater risk of weight gain while using valproic – compared to pediatrics with a normal body weight before treatment. Whereas a study by Corman et al. (1997) discovered that adults with below or normal BMIs before using valproic acid are more likely to gain significant weight during treatment.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/10456757/
- Source: https://www.ncbi.nlm.nih.gov/pubmed/9276111
Genetics: The expression of a user’s genes might determine likelihood of significant weight gain as a side effect. Research by Noai et al. (2016) has identified a relationship between increased rates of weight gain and 1 or 2 loss-of-function CYP2C19 alleles among female valproate users.
This suggests that genes implicated in CYP2C19 expression might influence risk of weight gain while using valproate. Perhaps decreased CYP2C19 function yields higher plasma concentrations of Depakote and a greater physiologic impact (relative to dose) – ultimately increasing risk of weight gain.
Lifestyle: The lifestyle choices made by a person using Depakote might determine whether he/she will experience significant weight gain during treatment. Someone who constantly tracks calories and/or adjusts calorie intake to prevent weight gain – probably won’t gain as much weight while using Depakote than someone who consumes food ad-libitum and never attempts to track and/or modulate caloric intake [to negate weight gain].
Furthermore, someone who exercises regularly with aerobic and strength training may be at lower risk of experiencing weight gain and/or unfavorable changes in body composition during Depakote treatment compared to someone who remains relatively sedentary throughout treatment.
Medical conditions: Preexisting medical diagnoses (including the condition for which you’re using Depakote) could influence the amount of weight that you gain during treatment. For example, if you’ve been diagnosed with bipolar disorder and are in a “manic phase” before using Depakote, the mania may have increased physical activity and metabolic rate to promote weight loss.
In this case, if Depakote stabilizes mood by counteracting mania, you might gain some weight simply because you’re no longer exhibiting physiologic changes associated with mania (that promote weight loss). Furthermore, any medications being used to treat preexisting medical diagnoses could interact with Depakote in ways that promote weight gain.
Prior substance use: Any substance(s) that you used and discontinued just prior to initiating Depakote treatment could influence whether you notice weight change in Depakote treatment. Assuming you discontinued a medication like Topamax (an anticonvulsant medication associated with weight loss) just before starting Depakote, some of the weight gain that you experience in the early stages of Depakote treatment might be attributable to the fact that Topamax is no longer in your system promoting weight reduction.
On the other hand, if you discontinued a medication that’s associated with weight gain just before starting Depakote, you might not experience much weight change while using Depakote due to the fact that Depakote is simply maintaining the weight you gained with the previously-used substance. Moreover, if you previously used a substance that caused major weight gain (and this amount is greater than the weight gain induced by Depakote), you might notice weight loss after starting Depakote (attributable to discontinuation of the former substance that induced substantial weight gain).
Sex: Though both males and females can gain significant weight on Depakote, weight gain as a Depakote side effect has been noted [by some researchers] as being more prevalent and of greater magnitude in female users. It is unknown as to why females are at increased risk of weight gain on Depakote compared to males, however, some speculate that the increased risk of weight gain among female users could be due to sex-specific hormone levels.
More specifically, perhaps sex-specific differences in baseline levels of testosterone, luteinizing hormone, DHEA, estradiol, et al. are what makes weight gain more likely to occur in females than males while using Depakote. It’s possible that greater baseline levels of testosterone and luteinizing hormone in men could somehow decrease odds and/or magnitude of Depakote-induced weight gain in men compared to women.
Potential strategies to reduce Depakote-related weight gain
Weight gain as a side effect of Depakote can become severe for a subset of users – possibly to the extent of endangering health via induction of insulin resistance, metabolic disorders, lipid abnormalities, and/or cardiovascular disorders. If you’ve experienced significant weight gain on Depakote and want to reverse it – or if you’re a new Depakote user and want to prevent or reduce treatment-related weight gain, below are some strategies to consider trying. Prior to trying any of the strategies listed below, talk to a medical doctor [to ensure that they are safe].
- Minimal therapeutic dose: Although some studies report that there’s no effect of Depakote dose on incidence of weight gain, other research has noted that risk of weight gain increases with greater serum concentrations of the medication (and serum concentrations are usually relative to the dose). Additionally, one case report documented that a patient was able to lose 15.33 lbs. (of 26.88 lbs. gained from valproic acid) by reducing the dosage from 1000 mg per day to 500 mg per day. If you’re gaining weight, you may want to ask your doctor about a dose reduction and/or help in finding the “minimal effective dose” (lowest quantity needed to manage your symptoms – and nothing more).
- Try Depakote ER (extended-release): If you’re gaining weight on the standard version of Depakote, you may want to try switching to the “extended-release” format. A review of open-label trial data reported lower rates and magnitude of weight gain among Depakote ER users (compared to those taking the standard version). Similarly, around half of patients who gained weight on the standard Depakote version reportedly lost weight after switching to Depakote ER.
- Limit calorie intake: Assuming you’re using the minimal necessary dose and have tested the “ER” version of Depakote (in attempt to counteract weight gain), you may want to focus on limiting your calorie intake. Depakote may reduce your resting metabolic rate via modulation of gene expression, hormones, and neuropeptides – causing you to burn fewer calories than pre-treatment. For this reason, you might need to lower your daily calorie intake slightly to avoid weight gain.
- Exercise regularly: Regular exercise (aerobic and resistance training) leads the body to burn more calories and helps maximize resting metabolic rate. Exercise may help offset metabolic slowing and/or fat gain that some users believe occurs during Depakote treatment. If you’re gaining weight from Depakote, yet never exercise much, try increasing your physical activity to counteract the gain.
- Adjust diet: Although unconfirmed, some believe that Depakote treatment might influence energy substrate utilization. Specifically, some hypothesize that Depakote might alter fat oxidation such that the body burns less fat than it did before treatment. If this is the case, then you might want to alter the macronutrient composition of your diet such as by consuming a high-protein, high-carbohydrate, lower-fat diet.
- Discontinue unneeded substances: If you’re taking substances (supplements, medications, etc.) along with Depakote that aren’t medically-necessary (according to a medical doctor), you may want to discontinue them and assess whether your weight improves. As was mentioned, some substances may enhance the mechanisms by which Depakote causes weight gain – leading to greater weight gain with the combination than standalone Depakote. Certain individuals may notice weight stabilization and/or weight loss after discontinuation of medically-unnecessary adjuncts.
- Adjunct interventions: If Depakote effectively treats your neuropsychiatric condition, yet nothing seems to counteract its side effect of weight gain – you may want to ask your doctor about adjunct interventions (to offset the weight gain). In one study, intensive behavioral therapy effectively counteracted weight gain from valproic acid. Researchers Ness-Abram and Apovian (2005) proposed that adjunct use of metformin may help counteract weight gain from valproic acid. Any medications and/or supplements that enhance appetite control and/or metabolic rate could be considered.
Note: If you don’t benefit from any of the strategies outlined above and gain an unhealthy amount of weight from Depakote, alternative treatments should be considered. Some researchers recommend that patients undergo Depakote withdrawal and explore alternative antiepileptic therapies if weight gain exceeds 4.4 lbs. within the first month of treatment initiation.
Have you gained weight on Depakote?
If you’ve used Depakote and gained weight during treatment, how much weight did you gain – and how long did it take for you to notice the weight gain (after beginning treatment)? From what you can tell, did your body composition significantly change (such as by gaining fat, losing muscle, etc.) throughout treatment?
In order for others to get an accurate understanding of your situation, provide extra details such as your: sex (male vs. female); age; Depakote dosage; Depakote format (e.g. ER); duration of use (e.g. 1 year); and the medical condition for which you were prescribed Depakote. Also note whether you use other medications (or substances) along with Depakote – and reflect upon whether these substances could be [at least partially] culpable for your weight gain.
Assuming you’ve gained a substantial amount of weight on Depakote, why do you believe the weight gain occurred? (Examples of answers include: increased appetite, food cravings, hormone changes, lethargy (interfering with your ability to exercise), slower metabolism, etc.).
In your experience, do the therapeutic benefits of Depakote outweigh the side effect of “weight gain?” Have you found any behaviors, strategies, or adjunct medications effective for reducing and/or preventing weight gain on Depakote?