Topiramate (Topamax®) vs Divalproex (Depakote®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Topiramate advantages over Divalproex

  • Unlike topiramate, divalproex may cause serious and potentially fatal hepatotoxicity, life-threatening pancreatitis.
  • Topiramate is a preferrable choice for patients who wish to avoid weight gain as well as for patients for whom weight loss is highly desirable.
  • Topiramate requires little monitoring and has a relatively favorable pharmacokinetic profile.
  • No contraindications.

Divalproex advantages over Topiramate

  • Valproate has a long history of use and is the best established broad-spectrum antiepileptic drug.
  • Divalproex is effective for impulsivity and aggressive behavior not only in bipolar disorder but also in dementia and personality disorders.


Topiramate Divalproex sodium
Brand names
• Topamax®
• Trokendi® XR
• Qudexy® XR
• Depakote®
• Depakote® ER
• Depakote® Sprinkle
Drug class
• Anticonvulsants
• Sulfamate-substituted monosaccharide • Mood stabilizer
• Compound comprised of sodium valproate and valproic acid
Dose formulations
• Tablets
• Capsules, sprinkle
• Capsules, extended-release
• Tablets, delayed-release
• Tablets, extended-release
• Capsules
FDA-approved indications
• Migraine headaches prophylaxis
• Epilepsy - generalized tonic-clonic seizures, partial onset seizures or primary generalized tonic-clonic seizures
• Seizures associated with Lennox-Gastaut syndrome
• Epilepsy - absence seizures (petit mal), complex partial seizures, simple partial seizures, generalized seizures
• Manic episodes of bipolar disorder
"Off-label" uses
• Bipolar disorder
• Binge-eating disorder
• Obesity
• Drug-induced weight gain
• Maintenance treatment of bipolar disorder
• Bipolar depression
• Psychosis
• Schizophrenia
Mechanism of action
• Topiramate produces multiple effects on receptors and ion channels.
• Topiramate blocks voltage-dependent sodium channels and potentiates the activity of GABA.
• Topiramate also suppresses excitatory glutamatergic transmission.
• Divalproex sodium dissociates to the valproate ions in the gastrointestinal tract.
• Valproate increases the inhibitory effect of GABA.
• Also valproate blocks high frequency repetitive firing by slowing the rate of Na+ recovery.
• 20 to 30 hours • 9 to 16 hours
Oral bioavailability
• 80-95% • Divalproex is almost completely absorbed from the gastrointestinal tract.
• Divalproex extended-release tablets have decreased oral bioavailability.
Metabolism, Elimination
• Topiramate is not extensively metabolized.
• Topiramate is mainly eliminated unchanged in the urine.
• Valproate is metabolized in the liver by beta and omega oxidation.
• Valproate metabolites are excreted in the urine.
• No contraindications • Hypersensitivity to divalproex sodium, valproic acid, sodium valproate
• Mitochondrial disorders
• Liver disease
• Urea cycle disorders
Side effects
• Weight loss
• Paresthesia
• Cognitive problems
• Word-finding difficulty
• Anorexia
• Fatigue
• Dizziness
• Difficulty with memory, concentration
• Weight gain
• Hair loss
• Abdominal pain
• Constipation
• Dyspepsia
• Blurred vision
• Lack of muscle coordination
• Weakness
• Increased appetite
• Dizziness
Drug interactions
• At high doses topiramate may interfere with oral contraceptives. • Concomitant use of divalproex with drugs metabolized by CYP2C9 may result in significant drug interactions.
Pregnancy category
D D / (X - for migraine prophylaxis )
topamax pills depakote pills

Topamax® vs Depakote® for Migraines

Both anticonvulsants topiramate and divalproex sodium have been FDA approved for prophylaxis of migraine headaches and are recommend as first-line agents for migraine prevention.

Despite their proven efficacy in migraine prevention, there are no head-to-head randomized studies comparing topiramate and divalproex sodium. According to the open-label nonrandomized investigation topiramate and divalproex have quite similar effectiveness, but differ in their side effects profile 6.

Results of prospective "real-world" study of topiramate vs divalproex sodium in the preventive treatment of migraine 6 Topiramate Divalproex sodium
Reduction in headache frequency of >50% at 3 months
40 patients of 69
26 patients of 51
Most common side effects
(% of patients who completed the study)
weight loss (50%),
paresthesia (48%),
cognitive disturbances (20%)
weight gain (24%),
hair loss (24%),
gastrointestinal symptoms (24%)

Topiramate appears to be equivalent in efficacy and safety to sodium valporate. Both agents cause significant decrease in duration, monthly frequency, and intensity of headache 5.

Results of 24-week, randomized, double-blind, crossover, trial of topiramate and sodium valporate in migraine prevention 5 Topiramate Valproate
Regimen 25 mg daily increment over 1 week to 50 mg for a total of 2 months. 200 mg daily increment over 1 week to 400 mg for 2 months
Monthly migraine frequency decrease, episode per month from 5.4 to 3.2 from 5.4 to 4.0
Headache intensity decrease by visual analog scale from 6.9 to 3.7 from 7.7 to 5.8
Headache duration decrease, hours from 17.3 to 3.9 from 21.3 to 12.3


Topamax® vs Depakote® for Seizures

Depakote (divalproex sodium) is indicated for:

  • Complex partial seizures
  • Simple and complex absence seizures.

Divalproex is effective against most types of seizures.

Topamax (topiramate) is indicated for:

  • Partial-onset seizures
  • New-onset generalized tonic-clonic ("grand mal")
  • Seizures associated with Lennox-Gastaut syndrome

Topiramate is widely used for the treatment of epilepsy. It is effective against most seizure types, and is considered a broad-spectrum anticonvulsant. Topiramate seems to work better for patients who experience localization-related epilepsy than for those who experience generalized epilepsy.

Topiramate and valproate have similar effectiveness for initial treatment of newly diagnosed epilepsy: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment 2.

Results of randomized open-label observational study comparing topiramate and valproate in juvenile myoclonic epilepsy 10 Topiramate Valproate
Patients free of myoclonic seizures for 24 weeks
7 patients of 11
9 patients of 16
Adverse effects severity of adverse effects was favourable for topiramate
Conclusion: valproate may be replaced with topiramate, especially for the patients with juvenile myoclonic epilepsy who do not tolerate valproate.

Further reading


  • 1. Physicians’ Desk Reference, 59th ed; Thomson PDR: Montvale, NJ; 2005.
  • 2. Privitera MD, Brodie MJ, Mattson RH, Chadwick DW, Neto W, Wang S; EPMN 105 Study Group. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand. 2003 Mar;107(3):165-75. PubMed
  • 5. Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V. Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache. 2006 Apr;46(4):642-8. PubMed
  • 6. Krymchantowski AV, Jevoux CC. Topiramate vs divalproex sodium in the preventive treatment of migraine: a prospective "real-world" study. Headache. 2011 Apr;51(4):554-8. PubMed
  • 10. Park KM, Kim SH, Nho SK, Shin KJ, Park J, Ha SY, Kim SE. A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy. J Clin Neurosci. 2013 Aug;20(8):1079-82. PubMed

Published: March 31, 2008
Last updated: February 01, 2018


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