02. Is Valproate Weight Gain Dose-Dependent?

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Valproate Dose and Weight Gain

I wouldn’t suggest that many of the side effects of valproate including thrombocytopenia, elevated liver enzymes, elevated serum ammonia and alopecia are dose dependent.

Weight gain is also a common side effect of valproate. But is the amount of weight gain also dependent on dose?

Would a smaller dose of valproate minimize weight gain along with other metabolic risk factors?

New Study Provides Insights

Luckily, a new study was published recently in the Journal of Clinical Psychiatry to answer this question. The study sample included 215 patients who were starting valproate, with subsequent followup for up to a year. The sample was split evenly between males and females. This even distribution is of note considering caution among clinicians due to the increased risk of congenital disabilities during pregnancy.

Scatter Plot Reveals Trends

A mentor once told me that the best way to approach any dataset is with the simple scatter plot. In this case, if the dose was on the x-axis and the weight gain was on the y-axis, you would see an apparently random collection of dots each representing one of the 215 subjects. In this rectangular collection, you would see some subjects on the largest doses of 2000 mg a day that lose 10% of body weight and patients that gain 15% to 20% of body weight on the smallest doses of 500 mg and less. It is easy to miss the statistically significant positive correlation of 0.13 between weight gain and dose of valproate.

Factors Influencing Weight Gain

To make this more useful in advising our patients, the authors implemented a linear mixed effect model to control for sex, age, baseline body mass index, smoking status, diagnosis of schizoaffective disorder and schizophrenia and other concurrent medications known to cause weight gain including antipsychotic medication.

Only three of these factors were significant:

• Baseline body mass index was negatively correlated with weight gain as the subjects with lower BMI gained a greater percentage of weight.
• Female sex was positively correlated with weight gain.
• The co-prescription of other medications known to cause weight gain was also positively correlated with weight gain.

After controlling for these factors, the authors found that each additional month of valproate is associated with a statistically significant weight gain of 0.16% of body weight. That would be almost 2% weight gain after a year.

The authors also found a significant correlation with dose with weight gain of 0.5% for each 500 mg of valproate over the course of treatment.

To summarize, a patient taking 1500 mg of valproate for a year could expect a 3.5% increase in body weight.

For the typical 70 kg subject, this would be 2.5 kg or for us Americans about 5 lbs for a patient weighing 155 lbs.

Lowest Effective Dose Beneficial

The primary clinical value of this finding is the suggestion that part of the weight gain associated with valproate could be avoided by prescribing the lowest effective dose.

The authors cite a starting dose of 20 mg/kg/day for patients with bipolar disorder or 1400 mg of valproate for a patient weighing 70 kg.

In my informal survey of practicing clinicians, patients are started on smaller daily doses, typically 500 mg possibly in divided doses with adjustments based on valproic acid level and clinical response. This study highlights the benefit of the starting low and going slow model, in which it may be possible to find the lowest effective dose to reduce weight gain.

Early Weight Monitoring Essential

In addition, the authors noticed that weight gain was not evenly distributed over the course of the first year but occurred primarily in the first three months. By implementing a piecewise model, the authors found the weight gain to be over four times greater in the first three months at 0.56% of body weight per month than later in the course.

This finding highlights the need for attention to weight at the start of a course of valproate.

No associations were found between valproate dose and other metabolic markers including blood glucose, lipid levels or blood pressure over six months, but one could wonder if six months is long enough to detect these effects with moderate weight gain.

Study Limitations

This study has a few limitations, including that the dose was not random but based on clinical factors. It is very difficult to control for every possible clinical factor that could account for weight gain independent of the dose of valproate.

Conclusion

Nevertheless, my take-home point is the suggestion of less risk of weight gain and subsequent metabolic risk factors with smaller doses of valproate.

This highlights the benefit of determining the lowest effective dose to avoid weight gain but also other adverse effects.

Abstract

Associations of Valproate Doses With Weight Gain in Adult Psychiatric Patients: A 1-Year Prospective Cohort Study

Claire Grosu, PhD; William Hatoum, PharmD; Marianna Piras, PharmD, PhD; Nermine Laaboub, PhD; Setareh Ranjbar, PhD; Franziska Gamma, M.D., M.Sc.; Kerstin J. Plessen, PhD; Armin von Gunten, MPhil, M.D.; Martin Preisig, MD, MPH; Philippe Conus, M.D.; and Chin B. Eap, PhD

Objective: The aim of this study was to evaluate valproate dose association with weight change, blood glucose, lipid levels, and blood pressure in a psychiatric population.

Methods: Data from 215 patients taking valproate for up to 1 year were collected from 2 longitudinal studies that monitored metabolic variables between 2007 and 2022. Linear mixed-effect models and logistic regressions were used to analyze the associations between valproate doses and metabolic outcomes.

Results: An increase in valproate dose of 500 mg was associated with a weight change of +0.52% per month over a year (P < .001). The association between valproate dose and weight change was evident both before and after 3 months of treatment. Weight increase was greater for treatment durations of < 3 months compared to ≥ 3 months (+0.56%, P < .001 and +0.12%, P = .02 per month, respectively). Using piecewise regression, a significant association between dose and weight gain was observed in patients receiving doses equal to or above the median dose (1,300 mg/d), with a +0.50% increase in weight for each dose increment of 500 mg (P = .004). Among men, each 500 mg dose increment was associated with weight increases of +0.59% per month (P = .004), whereas a trend was observed for women (+0.40%, P = .09). No associations were found between valproate doses and blood glucose, lipid levels, or blood pressure over a 6-month treatment period.

Conclusions: This study provides evidence that valproate dose, mainly for doses at or above 1,300 mg/d, is associated with weight gain in psychiatric patients, suggesting that the lowest effective doses should be prescribed to minimize weight gain.

Reference

Grosu, C. PhD; Hatoum, W. PharmD; Piras, M. PharmD, PhD; Laaboub, N. PhD; Ranjbar, S. PhD; Gamma, F. M.D., M.Sc.; Plessen, K. PhD; Von Gunten, A. M.D.; Preisig, M. M.D., Conus, P. M.D.; & Eap, C. PhD. (2024). Associations of Valproate Doses With Weight Gain in Adult Psychiatric Patients: A 1-Year Prospective Cohort Study. The Journal of Clinical Psychiatry, 27;85(2):23m15008.