Which drug causes more weight gain, aripiprazole (Abilify) or valproic acid (Depakote)?

Depakote (Valproate) Causes More Weight Gain Than Abilify (Aripiprazole)

Depakote is significantly more likely to cause weight gain compared to Abilify, which is considered weight-neutral and is actually recommended as an alternative when weight gain becomes problematic with other medications. 1

Weight Gain Profile of Each Medication

Depakote (Valproate)

• Valproate is well-established as causing substantial weight gain across multiple patient populations, including those with epilepsy and psychiatric conditions 2, 3
• Weight gain occurs in approximately 71% of patients on valproate, with many experiencing gains exceeding 4 kg 4
• Dose-dependent relationship exists: each 500 mg increase in valproate dose is associated with a +0.52% weight change per month, with the effect most pronounced at doses ≥1,300 mg/day 5
• Weight gain is often sustained and socially significant to patients, leading to treatment discontinuation in some cases 4
• The mechanism involves multiple pathways: reduced insulin sensitivity, hyperinsulinemia, and direct effects on metabolism that can trigger polycystic ovary syndrome (PCOS) in predisposed women 2

Abilify (Aripiprazole)

• Aripiprazole is classified as weight-neutral and is specifically recommended by the American College of Cardiology/American Heart Association as an alternative to antipsychotics that carry higher risks of weight gain 1
• Guidelines explicitly recommend switching to aripiprazole when weight gain becomes problematic with other antipsychotics 1
• In pediatric trials for autism spectrum disorder, aripiprazole showed weight gain and increased appetite as side effects, but these were significantly less severe than with other antipsychotics like olanzapine or risperidone 2

Clinical Decision Algorithm

When Prescribing New Treatment

• If weight gain is a concern, choose aripiprazole over valproate whenever clinically appropriate for the indication 1
• Aripiprazole is preferred alongside ziprasidone and lurasidone as weight-neutral options in psychiatric treatment 1

When Weight Gain Occurs on Valproate

• Consider switching to the lowest effective dose (ideally below 1,300 mg/day) to minimize weight gain if seizure control or mood stabilization allows 5
• Implement dietary counseling and physical activity recommendations immediately rather than waiting for weight gain to become severe 1
• Discontinuation of valproate has been shown to reverse hyperinsulinemia, hyperandrogenism, and metabolic complications within one year 2

Important Clinical Caveats

Patient-Specific Risk Factors

• Patients with normal or below-normal BMI before starting valproate experience the most severe percentage weight gain, making prophylactic counseling especially important in this population 4
• Women are at particular risk for endocrine complications including PCOS, hyperandrogenism, and menstrual irregularities related to valproate-induced weight gain 2

Monitoring Requirements

• Regular weight monitoring is essential during valproate treatment, as weight gain can be progressive and dose-dependent 5, 4
• The weight gain with valproate is not simply due to improvement in underlying condition—it represents a direct metabolic effect of the medication 2, 3

Common Pitfall to Avoid

• Do not assume weight gain will plateau or resolve with continued treatment—valproate-associated weight gain is often sustained and may worsen over time, particularly at higher doses 5, 4
• Some studies have erroneously attributed weight gain to valproate when patients continued gaining weight after switching to carbamazepine, but the preponderance of evidence clearly demonstrates valproate's greater weight gain liability 6