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Day # 55: Valproic Acid (VPA)

We are continuing our conversation on the medications classified as "mood stabilizers" in the treatment of bipolar disorder and other conditions. Today we will discuss valproic acid (VPA) and in the next lessons will move on to discuss the other anti-epileptic drugs (AEDs) such as lamotrigine, carbamazepine, and topiramate.

Today's content level: Beginner, Intermediate


•Valproic acid (VPA) = Valproate = Depakote (PO) = Depacon (IV) = Sprinkles (SOL).

•The primary indication for this mood stabilizer is the treatment of seizure disorders, so it is classified as an anti-epileptic drug (AED).

The major mechanisms of action of valproate includes:

  • Blocks voltage-dependent sodium channels.

  • Increases GABA concentrations in the brain. Increased central GABA is due to blockade of the enzyme GABA transaminase +/- enhanced GABA synthesis/release, however it is not fully understood.

•The vast majority of valproate metabolism occurs in the liver. Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5.

•It is also a CYP450 3A4 inhibitor -> which leads to increased drug levels of specific medications to include lamotrigine, carbamazepine, aspirin, warfarin, diazepam, and clonazepam. Of note, reduce lamotrigine and VPA dose by 50% if using in combination.

•Full activity may take days to weeks.


FDA approved indications:

  • Epilepsy: FDA-approved to treat complex partial seizures as well as simple and complex absence seizures. It can also be used as adjunctive treatment in a variety of other seizure types.

  • Bipolar disorder: Can be used as a first line option for mood stabilization in bipolar disorder. Proven efficacy in treating acute mania and preventing mood episodes, but may be less effective in treating and preventing depressive episodes. Some data shows that it is more effective than other options in "mixed episodes". May require antipsychotics and/or benzodiazepines when initiating treatment of acute mania. 1

  • Migraine prophylaxis: Approved for migraine prophylaxis in adults. IV formulation also available for intractable migraines.

Other off-label indications:

  • Agitation/Aggression: There is little high-quality evidence for this use, however a case series demonstrated a significant reduction in agitation in TBI patients over a two year period. Used for the treatment of agitation/aggression in TBI, dementia, and parkinsonism. 2

  • Schizophrenia: May be useful as adjunctive treatment with antipsychotics. Limited data.

  • Neuropathic pain: Sometimes used in the treatment of neuropathic pain, fibromyalgia, and trigeminal neuralgia. 3


Common side effects include:

  • GI upset: most common side effect, particularly nausea.

  • Somnolence

  • Tremor

  • Dizziness

  • Alopecia (hair loss)

  • Weight gain / metabolic syndrome

  • Amenorrhea: May occur in the context of polycystic ovarian syndrome (PCOS), which is also an established adverse effect of valproate.

Serious side effects include:

  • Hepatotoxicity: Black box warning. Fatal hepatotoxicity is most common in initial 6 months of therapy, children <2 years, and mitochondrial disorders (especially POLG mutations or urea cycle defects). Contraindicated in patients with these mitochondrial disorders.

  • Pancreatitis: Black box warning. More often with IV formulation.

  • Teratogenicity: Black box warning. Neural tube defects such as spina bifida. Ensure women of child-bearing potential are appropriately counseled

  • Platelet dysfunction: Thrombocytopenia is not uncommon. It is caused by a dose-related suppression of marrow platelet production. CBC with platelets should be monitored at baseline and during therapy. PT/PTT should be checked prior to surgery.

•Contraindications include liver impairment, pancreatitis, mitochondrial disorders, pregnancy, and allergy to valproate.


•The therapeutic range of valproate is from 50 to 120 mg/L. Obtain drug levels after 3-4 doses of starting the medication or changing the dose.

Prior to starting valproic acid:

  • CBC with differential & platelets

  • Liver FunctionTests (LFTs)

  • Weight

  • Pregnancy test for women of childbearing potential

Serial monitoring should include:

  • LFT's and CBC every 3-6 months.

  • VPA drug levels with changes in clinical state and after 3-4 days of a dose change.

  • PT/PTT should be checked prior to any surgery.

  • Serum ammonia should be assessed in patient with mental status changes or lethargy.


Great work today. In our next post we will discuss lamotrigine.

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