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Valproic Acid as a Potentiator of Metabolic Syndrome In Institutionalized Residents on Concomitant Antipsychotics: Fat Chance, or Slim to None?

Silu Zuo PharmD
Brant E. Fries PhD
Kristina Szafara PhD
Randolph Regal PharmD

INTRODUCTION

Valproic acid (Depakene, AbbVie), including divalproex sodium and valproate, is used for the treatment of seizure disorders, bipolar disorder, and dementia and for the prophylaxis of migraines. Valproic acid (VPA) is one of the most commonly prescribed antiepileptic medications and a first-line mood stabilizer for both acute bipolar mania and bipolar depression.1,2 The widespread use of VPA has led to increasing awareness of a spectrum of problematic side effects, including hepatotoxicity, nausea, vomiting, ataxia, lethargy, alopecia, thrombocytopenia, hyperammonemia, increased appetite, and weight gain.1,3 Among these side effects, weight gain is especially concerning, as long-term treatment can lead to significant weight gain in 10% to 70% of patients and has been shown to lead to a number of metabolic disturbances that may foster the emergence of metabolic syndrome.4,5

Metabolic syndrome includes a cluster of medical conditions and risk factors that are often grouped together, including hypertension, dyslipidemia, abdominal obesity, a proinflammatory state, and insulin resistance. According to the diagnostic criteria outlined in the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III modified criteria for metabolic syndrome, an individual has this condition if he or she has at least three of the following five components: elevated waist circumference (more than 40 inches for men, more than 35 inches for women), elevated triglycerides (150 mg/dL or higher), reduced high-density lipoprotein-cholesterol (HDL-C, less than 40 mg/dL for men and less than 50 mg/dL for women), elevated blood pressure (130/85 mm Hg or higher or use of medication for hypertension), and elevated fasting glucose (more than 100 mg/dL or use of medication for hyperglycemia). All of these components of metabolic syndrome increase the risk of cardiovascular disease and type-2 diabetes mellitus.6

Since VPA is commonly used as a mood-stabilizing agent in bipolar disorder and other psychiatric conditions, this produces comorbid implications in terms of metabolic side effects.2 The treatment of bipolar disorder and other psychiatric illnesses often requires a combination of multiple psychotropic medications, including antipsychotics (APs), mood stabilizers, and antidepressants.2,3,7 Several of these medications, particularly second-generation (atypical) APs—especially clozapine and olanzapine—may cause significant weight gains of up to 17 kg.7,8 Of note, bipolar disorder itself has been linked to a higher incidence of obesity and metabolic disorders. This is thought to result not only from weight-gain-inducing medications, but also from lifestyle factors associated with mental illness, including a poor diet and a low level of physical activity.9,10 Therefore, there is a need not only to investigate the degree of metabolic disturbance associated with these psychoactive agents, but also to develop strategies to mitigate these adverse effects.

BACKGROUND LITERATURE REVIEW

Weight gain and metabolic disorders related to VPA have been investigated in several studies. A recent cross-sectional study by Chang et al. compared metabolic-related outcomes among Taiwanese healthy control subjects, patients with bipolar disorder without VPA treatment, and patients with bipolar disorder treated with VPA only (with no other psychoactive agents). The study determined that VPA treatment was associated with significantly higher plasma insulin, BMI, triglycerides, and fasting blood glucose and lower HDL-C.5 A systematic review by Verrotti et al. also implicated the effects of VPA in inducing weight gain and metabolic disorders such as insulin resistance in patients with epilepsy.11 Studies specifically evaluating VPA-induced weight gain have focused mainly on patients with epilepsy, comparing VPA to other antiepileptics including carbamazepine, lamotrigine, and topiramate. These studies showed a higher prevalence or magnitude of weight gain for VPA than for other antiepileptics.4 Hyperinsulinemia or insulin resistance induced by VPA may be directly related to VPA-induced weight gain. However, this may also occur independent of weight effects, as VPA treatment has been associated with fasting hyperinsulinemia in lean patients.4 Furthermore, the mechanisms by which VPA induces weight gain and metabolic disorders have been investigated, including increased thirst and hunger caused by dysregulation of the hypothalamus through increased gamma-aminobutyric acid transmission; modification of adipokine genes, which code for neuropeptides involved in central energy metabolism; and VPA-induced deficiency of fatty acid beta oxidation.4,12,13 This study aims to further investigate the implications of VPA’s effects on weight gain and metabolic syndrome factors in patients with psychiatric disease that have not yet been investigated, including the use of concomitant APs and the effect of VPA dose magnitude.

METHODS

Study Design

This cross-sectional study was conducted using data collected on all patients in the four state-operated psychiatric hospitals in Michigan using a comprehensive assessment instrument (interRAI Mental Health [MH]). The broad assessment included both physical and cognitive measures as well as complete drug profiles for 748 patients. The assessment was performed by trained personnel employed by the Michigan Public Health Institute between May 2010 and October 2010 using all available sources of information, including patient interviews, facility staff interviews, and medical record reviews. Patients were assessed for function, mental and physical health, social support, medication use, and various other clinical and functional measures. Medications were determined directly from the drug profile in patients’ medical records at the time of the assessment. The data were coded and entered into a database at the Michigan Department of Gerontology with patient information appropriately de-identified.

Patients taking antipsychotics without VPA served as the control group (APs), and patients taking VPA with other antipsychotics served as the study group (VPA plus APs). To eliminate possible exogenous causes of metabolic changes, subjects were excluded if they had eating disorders, were pregnant, or had a history of nonadherence (e.g., refusing psychotropic medications in the past 90 days) (Figure 1). Subjects’ records were analyzed for the presence of the following indicators of metabolic syndrome that could be determined from the interRAI MH instrument, adapted from the NCEP ATP III guideline’s definition of metabolic syndrome:

  • Weight gain of 5% or more in the last 30 days or 10% or more in the last 180 days
  • High BMI (30 or more)
  • Very high BMI (40 or more)
  • Diabetes mellitus (type-1 or type-2)
  • Prescribed statin medication
  • Hyperlipidemia or dyslipidemia
  • Hypertension
  • Combination of any three: high BMI, hyperlipidemia or dyslipidemia, diabetes, or hypertension

Statistical Analysis

Categorical and continuous data were generated and analyzed using SAS 9.3 software. An initial analysis was performed to assess differences in dosage, in defined daily dosage (DDD) units, or first-versus second-generation APs as defined by the Anatomical Therapeutic Chemical (ATC) classification system, with a t-test for differences of means. This was done to control for the confounding factors of metabolic effects of second-generation APs. The ATC/DDD system was developed by the World Health Organization to research drug utilization across drug classes. The DDD of each drug is the average daily maintenance dose for adults.14

To assess the association between VPA and the presence of metabolic side effects, a chi-square test or Fisher’s exact test was performed for each metabolic syndrome–related outcome to look for significant differences in the prevalence of each outcome between the two groups (with P < 0.05 indicating statistical significance).

To assess the dose effect of VPA, patients taking VPA and APs were partitioned into four dosage categories based on total daily dosage. The prevalence of each of the metabolic indicators (weight gain, high BMI, etc.) was determined for each dosage category. With the reference being the lowest dosage category, a chi-square test was performed for each metabolic syndrome–related outcome to assess the difference between each higher dosage category with the reference for each outcome. The odds ratio for each dosage category was calculated based on the comparison of odds of each outcome.

RESULTS

Baseline characteristics, including age, sex, weight, and ethnicity, were similar among groups. Statistically significant differences were seen in age groups (more patients in the 18–45 years of age group in the VPA plus APs group and more patients in the 0–18 years and 65 years and older age groups in the APs group [P = 0.03]) and ethnicity (more Caucasians in the APs group than the VPA plus APs group [50% versus 41%, P = 0.04]). The baseline weight of patients in the APs group was statistically significantly lower than that of the VPA plus APs group (89.7 kg versus 92.9 kg, P = 0.05) (Table 1).

A preliminary analysis for the mean dosages of APs in the control and study groups showed no statistically significant difference between the mean DDD of first- or second-generation APs for the two groups (Tables 2 and 3). This eliminates the potential confounding effect of second-generation AP medications, known to cause metabolic side effects. In addition, the differences in the percentages of patients taking any AP in both groups, with the exception of haloperidol, were not statistically significant. Most notably, there was no statistically significant difference between the two groups in the proportion of the two APs most highly implicated for metabolic side effects, clozapine and olanzapine (Table 4).

Analysis of metabolic outcomes showed a higher prevalence of high and very high BMI, diabetes, and hypertension in the VPA plus APs group compared with the APs group, as well as the combination of any three of the following diagnoses: high BMI, hyperlipidemia/dyslipidemia, diabetes, or hypertension. Interestingly, the prevalence of weight gain (4% versus 5.2%, P = 0.52) and hyperlipidemia/dyslipidemia (27.5% versus 34%, P = 0.48) were slightly lower in the VPA plus APs group than the APs group. However, none of the differences in outcomes between the control and study groups were statistically significant (Table 5).

For the analysis of the dose-related effect of VPA on metabolic side effects, the dosage ranges were divided as follows (Table 6): With the dosing range of 1 g or less per day as the reference, an odds ratio was calculated for each metabolic outcome by comparing the odds of having each subsequent dosing range to that of having the reference dose. Results of this analysis showed no significant difference between dose and metabolic side effects for any metabolic outcome at any dosing range, with P > 0.05 for all outcomes. In addition, no apparent pattern was seen with the magnitude of dose effect. For example, the odds ratios of weight gain for dose ranges 1 g to 1.5 g, 1.5 g to 2 g, and 2 g to 4 g relative to 1 g or less are 7.16, 1.54, and 7.0, respectively, showing that the odds ratio does not increase commensurately with dose magnitude. This was common among all outcomes (Table 7).

DISCUSSION

The absence of a statistically significant association between VPA and metabolic side effects in patients taking APs in this study differs from results of previous studies. These studies addressing VPA and metabolic syndrome included only uncontrolled studies in patients with bipolar disorder, cross-sectional studies in patients with psychiatric conditions without concomitant APs, and controlled studies in patients with epilepsy.4,5,9,11,12 All of these studies showed significantly increased weight or higher incidences of metabolic syndrome–related factors such as hyperinsulinemia, dyslipidemia, and increased abdominal obesity. However, in a similar study by Elmslie et al. of metabolic syndrome–related factors in overweight patients with bipolar disorder taking VPA versus control subjects without psychiatric disorders, the frequency of metabolic syndrome was not statistically significantly higher in the patients with bipolar disorder treated with VPA than in the control subjects (50% versus 32%, P = 0.06).15 Frequencies of insulin resistance, abdominal obesity, hypertension, and fasting hyperglycemia were also similar in both groups. Only dyslipidemia was significantly higher for the patients with bipolar disorder taking VPA, who had lower HDL-C than the control subjects (P = 0.006). The common outcomes in this study and those in the study by Elmslie et al., including a BMI greater than 30 and frequency of hypertension, dyslipidemia, and statin use, were not similar; they were higher in the Elmslie et al. study, mostly because it included only overweight patients. Nonetheless, the fact that many of the Elmslie findings in the bipolar group were not significantly different than the control group may corroborate the null findings of this paper.

The lack of association between VPA and metabolic side effects in this study may indicate the true absence of risk that VPA will cause metabolic side effects in patients taking APs. However, it should be noted that the endpoints used in this study were not all direct measures of metabolic syndrome. Because of the structure and questions of the data collection instrument, we lacked the ability to assess direct indicators of metabolic syndrome, such as lipid profile, blood pressure, blood glucose, hemoglobin A1c, and waist circumference. Instead, indirect outcome measures including diagnosis of hypertension, hyperlipidemia/dyslipidemia, and diabetes were used as representative endpoints to assess metabolic outcomes. However, the diagnosis of these conditions, whether chronic or acute, may not correlate as well to the effects of VPA as the laboratory values that more closely reflect metabolic syndrome. Of note, the mean weight of the VPA plus APs patients was higher than that of the APs patients by 3.2 kg to begin with, at a borderline significance of P = 0.05. While no assumptions can be made on this finding alone, it could indicate that the effects of weight gain had already occurred before the beginning of this study.

The difference may be explained in part by variations in VPA’s effects on males and females. Because of evidence that young females may be at higher risk for VPA-induced weight gain, we feel it would be prudent to conduct subgroup analyses by sex in future research.16,17

Strengths and Limitations

This is the first controlled study to evaluate VPA’s effects on weight gain and metabolic side effects in patients with psychiatric conditions taking APs. The control and study groups were evaluated for potential confounding factors, most notably weight gain and metabolic side effects of second-generation APs (especially clozapine and olanzapine). Furthermore, this is the first study to evaluate the dose effects of VPA on metabolic side effects. This is important considering the wide dosing range of the drug, from 20 mg/kg daily (the starting dose) to up to 60 mg/kg daily for the treatment of bipolar disorder.4 In this study, the doses ranged from 500 mg to more than 4 g per day.

One major limitation of this study is its cross-sectional design. Cross-sectional data in this study is based on a snapshot of the current state of medication doses and metabolic outcomes, and does not account for changes in medication doses or transient factors that may affect outcomes. Also, since medication use was based on medical records at the day of the assessment, the important factor of chronicity, or length of time on a given drug or dose, could not be characterized. Thus, we were unable to determine whether a given patient had been taking a certain drug or dose long enough to elicit a full metabolic effect. Nonetheless, metabolic factors related to VPA have been studied in randomized trials involving patients with epilepsy, yielding insight into significant metabolic dysregulation in the epileptic population.4,12

Sample size may also have been a limitation in terms of adequate power. Since we worked with pre-existing data, we included the maximum possible number of subjects for each group. We analyzed several variables, so the sample size may not have been adequate to detect a certain percentage change in each of the variables. However, the sample size was at least adequate to detect a 10% difference in diabetes and a 15% difference in BMI greater than 30, hyperlipidemia, and hypertension with 80% power at a significance level of 5% based on proportions of the U.S. population.

Because of the manner in which the interRAI MH instrument was designed, only categorical data about each metabolic outcome could be collected. For example, information about weight gain is defined only as the presence or absence of weight gain in each patient (defined as gaining 5% or more of body weight in the previous 30 days or 10% or more in 180 days). The amount of weight gain or continuous data about other factors, including blood pressure and lipid levels, were not available. These continuous data would have been helpful for quantifying the association between VPA and metabolic outcomes. Similarly, VPA serum concentrations, a more direct measure of systemic availability of the drug than the dose, were not available for assessment.

Finally, we did not limit the assessment only to patients with bipolar disorder. Diagnosis in psychiatry is not always definitive, and patients often have a working diagnosis that may change with time depending on their symptoms. Patients with symptoms of mania or who otherwise require treatment with VPA may not necessarily have a formal diagnosis of bipolar disorder I or II. Although this may introduce variability in the study, it is a more accurate representation of the use of VPA in the psychiatric population at large.

Future Direction

Given the null findings of metabolic side effects in this group of patients well controlled for potential confounding effects of atypical APs, conducting a similar study in this group of patients with direct measures of metabolic syndrome is the next step in confirming the true presence or absence of metabolic syndrome potentiation with VPA. If no difference is found, then a distinction should be made between VPA’s effects on metabolic side effects in patients with bipolar disorders on concomitant APs and patients with epilepsy, in whom metabolic side effects are more definitively established. A randomized controlled trial of the combination of VPA and atypical APs is also warranted to assess the potential for additive metabolic side effects. Also, because this study was done in a relatively young subset of patients and probably cannot be generalized to the sizable geriatric population receiving VPA and APs in long-term-care facilities—often for behaviors related to dementia—future studies should also focus on this population.

CONCLUSION

According to this cross-sectional study of 626 patients taking antipsychotics in four state psychiatric hospitals, VPA does not appear to be associated with a statistically significant dose-related increase in metabolic side effects. However, analysis of baseline characteristics showed that the VPA plus APs group was 3.2 kg heavier than the APs-only group (P = 0.05). Further assessment of this population with more direct measures of metabolic syndrome seems warranted, as well as randomized controlled trials studying these effects in patients on both VPA and atypical antipsychotics in younger and older populations.

Figure and Tables

Study Design

APs = antipsychotics; VPA = valproic acid

Patient Characteristics

APs VPA + APs P Value
Age
  0–18 6 (1.4%) 1 (0.5%) 0.03
  > 18–45 181 (42.5%) 98 (49%)
  > 45–65 206 (48.4%) 96 (48%)
  > 65 33 (7.7%) 5 (2.5%)
Sex
  Male 321 (75.4%) 158 (79%) 0.32
  Female 105 (24.6%) 42 (21%)
Mean weight (kg) 89.7 92.9 0.05
Ethnicity
  Hispanic 8 (1.9%) 7 (3.5%) 0.22
  American Indian 2 (0.5%) 1 (0.5%) 0.96
  Asian 6 (1.4%) 1 (0.5%) 0.31
  Black 196 (46%) 107 (53.5%) 0.08
  Hawaiian 0 (0%) 1 (0.5%)
  White 213 (50%) 82 (41%) 0.04

APs = antipsychotics; VPA = valproic acid

Mean Antipsychotic Defined Daily Dose (DDD)

First-Generation Antipsychotics DDDs
Mean DDD Std Dev P Value
APs 6.3 16.6 0.70
VPA + APs 6.8 11.9
Second-Generation Antipsychotics DDDs
Mean DDD Std Dev P Value
APs 1.8 5.2 0.98
VPA + APs 1.8 5.4
First- and Second-Generation Antipsychotics DDDs
Mean DDD Std Dev P Value
APs 8.1 17.0 0.72
VPA + APs 8.6 12.6

APs = antipsychotics; Std Dev = standard deviation; VPA = valproic acid

Defined Daily Dose of Antipsychotics

Oral Parenteral* Depot Rectal
First-Generation Antipsychotics
  Chlorpromazine 300 mg
  Fluphenazine 10 mg
  Haloperidol 8 mg 8 mg 3.3 mg
  Loxapine 100 mg
  Molindone 50 mg
  Perphenazine 30 mg 10 mg 7 mg 16 mg
  Prochlorperazine 100 mg 50 mg 100 mg
  Trifluoperazine 20 mg 8 mg 20 mg
Second-Generation Antipsychotics
  Aripiprazole 15 mg 15 mg
  Asenapine 20 mg
  Clozapine 300 mg 300 mg
  Olanzapine 10 mg 10 mg 10 mg
  Paliperidone 6 mg 2.5 mg
  Quetiapine 400 mg
  Risperidone 5 mg 2.7 mg
  Ziprasidone 80 mg 40 mg

*Parenteral = intravenous, subcutaneous, or intramuscular administration

Distribution of Antipsychotics

APs VPA + APs P Value
First-Generation Antipsychotics
  Chlorpromazine 12 (2.8%) 7 (3.5%) 0.64
  Fluphenazine 43 (10.1%) 20 10%) 0.97
  Haloperidol 70 (16.4%) 54 (27%) 0.00
  Loxapine 8 (1.9%) 2 (1%) 0.41
  Molindone 3 (0.7%) 0 (0%) 0.23
  Perphenazine 10 (2.4%) 3 (1.5%) 0.49
  Prochlorperazine 1 (0.2%) 0 (0%) 0.49
  Trifluoperazine 2 (0.5%) 0 (0%) 0.33
Second-Generation Antipsychotics
   Aripiprazole 73 (17.1%) 28 (14%) 0.32
  Asenapine 14 (3.3%) 11 (5.5%) 0.19
  Clozapine 60 (14.1%) 25 (12.5%) 0.59
  Olanzapine 119 (27.9%) 64 (32%) 0.30
  Paliperidone 27 (6.3%) 8 (4%) 0.24
  Quetiapine 97 (22.8%) 50 (25%) 0.54
  Risperidone 113 (26.5%) 52 (26%) 0.89
  Ziprasidone 33 (7.8%) 14 (7%) 0.74

APs = antipsychotics; VPA = valproic acid

Metabolic Outcomes in the APs and VPA + APs Groups

APs VPA + APs Odds ratio (95% CI) P Value
Weight gain 22 (5%) 8 (4%) 0.77 (0.33–1.75) 0.52
High BMI (BMI > 30) 161 (38%) 84 (42%) 1.19 (0.85–1.68) 0.26
Very high BMI (BMI > 40) 27 (6%) 21 (11%) 1.73 (0.95–3.15) 0.07
Diabetes mellitus 59 (14%) 34 (17%) 1.27 (0.80–2.02) 0.30
Prescribed statin 132 (31%) 57 (29%) 0.89 (0.61–1.28) 0.53
Hyperlipidemia or dyslipidemia 145 (34%) 55 (28%) 0.87 (0.60–1.27) 0.48
Hypertension 122 (29%) 59 (30%) 1.04 (0.72–1.51) 0.82
Combination of 3: BMI > 30, hyperlipidemia/dyslipidemia, diabetes, hypertension 91 (21%) 48 (24%) 1.16 (0.78–1.73) 0.46

APs = antipsychotics; BMI = body mass index; CI = confidence interval; VPA = valproic acid

VPA Total Daily Dose

VPA Total Daily Dose (Grams) Number of Patients Percent of Patients
≤ 1 78 39%
> 1–1.5 47 23.5%
> 1.5–2 51 25.5%
> 2–4 24 12%

VPA = valproic acid

VPA Dose Effect on Metabolic Outcomes

VPA Daily Dose (Grams) Odds Ratio (95% CI) P Value
Weight gain ≤ 1 Reference 0.13
> 1–1.5 7.16 (0.77–66.14)
> 1.5–2 1.54 (0.09–25.19)
> 2–4 7.00 (0.61–80.86)
High BMI (BMI > 30) ≤ 1 Reference 0.96
> 1–1.5 0.98 (0.47–2.04)
> 1.5–2 1.18 (0.58–2.41)
> 2–4 1.03 (0.41–2.60)
Very high BMI (BMI > 40) ≤ 1 Reference 0.47
> 1–1.5 2.56 (0.76–8.57)
> 1.5–2 1.95 (0.56–6.75)
> 2–4 2.09 (0.46–9.45)
Diabetes mellitus ≤ 1 Reference 0.24
> 1–1.5 2.34 (0.89–6.17)
> 1.5–2 1.43 (0.51–3.98)
> 2–4 2.56 (0.80–8.12)
Statin ≤ 1 Reference 0.76
> 1–1.5 1.19 (0.54–2.62)
> 1.5–2 0.78 (0.35–1.77)
> 2–4 1.27 (0.48–3.40)
Hyperlipidemia or dyslipidemia ≤ 1 Reference 0.89
> 1–1.5 0.99 (0.43–2.28)
> 1.5–2 1.33 (0.61–2.89)
> 2–4 1.20 (0.43–3.30)
Hypertension ≤ 1 Reference 0.45
> 1–1.5 0.83 (0.36–1.92)
> 1.5–2 1.48 (0.69–3.17)
> 2–4 1.63 (0.62–4.28)
Combination of 3: BMI > 30, hyperlipidemia/dyslipidemia, diabetes, hypertension ≤ 1 Reference 0.33
> 1–1.5 1.44 (0.61–3.42)
> 1.5–2 1.29 (0.55–3.05)
> 2–4 2.52 (0.93–6.85)

BMI = body mass index; CI = confidence interval; VPA = valproic acid

Author bio: 
Dr. Zuo is PGY1 Pharmacy Practice Resident at the University of Washington Medical Center in Seattle, Washington. Dr. Fries is Professor of Health Management and Policy at the University of Michigan (UM) School of Public Health in Ann Arbor, Research Professor in the Geriatric Centers of the UM School of Medicine, and Chief of Health Systems Research at the Ann Arbor Veterans Affairs Healthcare Center Geriatric Research, Education, and Clinical Center. Dr. Szafara is Research Fellow at the Institute of Gerontology of the UM School of Medicine. Dr. Regal is Clinical Associate Professor at the UM College of Pharmacy and a Clinical Pharmacist, Internal Medicine, with UM Health System Pharmacy Services. Disclosure: The authors report no commercial or financial relationships in regard to this article.

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