Valproic Acid (Depakote)

Table of Contents

Clinical Information:

HALF-LIFE: 9-16 hours

METABOLISM: Primarily by liver but not via CYP450 enzymes

STARTING DOSE: 250mg-500mg per day

TARGET DOSING RANGE: 1000mg-1500mg PO daily

BEST TIME TO DOSE: Bedtime (for Extended release)

HOW TO DOSE: Initial 250mg-500mg PO QHS. Increase rapidly to effective dose. Alternatively: Initial 15-20 mg/kg/day (twice daily dosing). Target range 1000mg-1500mg daily. Target serum level: 50mcg/mL – 125mcg/mL. Max dose generally 4000mg/day

PREGNANCY: Avoid – Neural Tube Defects


Side Effects

  • Sedation, Tremor, Dizziness, Ataxia, Asthenia (muscle weakness), Headache, Abdominal Pain, Nausea, Vomiting, Weight gain, Alopecia

Drug Interactions

  • Valproic acid + Topiramate increases risk of encephalopathy
  • Valproate inhibits Lamotrigine metabolism. The dose of lamotrigine must be decreased by half the normal dose when given in combination with valproic acid (valproic acid inhibits lamotrigine metabolism).

Labs to Obtain Before Starting Valproic Acid:

  • Pregnancy test
  • Liver function tests
  • Platelet count

Pregnancy Risks:

  • Neural tube defects (spina bifida, anencephaly, etc)
  • Low IQ
  • Developmental delay
  • Valproic should not be used during pregnancy except in special cases (consult a perinatal psychiatrist)
  • There is actually little evidence that folate supplementation actually prevents or protects against neural tube defects (but it hasn’t been harmful so not a bad idea to use)

FDA Indications

  1. Seizures
  2. Acute Mania associated with Bipolar Disorder
  3. Migraine prophylaxis

Mechanism(s) of Action

  • Blocks voltage sensitive sodium channels
  • Increases brain concentrations of GABA
  • Unlike many other medications, lithium and the antiepileptics alter brain signal transduction by dampening axonal signal transmission and by inhibiting cellular response to excitatory signals.  Part of this is mediated by partial blockade of voltage-dependent sodium channels.  This property alone is not sufficient as anti-epileptics which DO NOT show benefit in bipolar illness also exhibit inhibitory effects at voltage-dependent sodium channels.  
  • To date, the property best correlated with prophylaxis of mood cycling has been depletion of the second-messenger, triphosphoinositol (IP3). 
  • Another candidate mechanism is increased guanine synthase kinase, type 3, activity.  This enzyme plays a role in modulating both voltage and ligand-gated sodium channels.

Additional Information

  • Valproic acid (Valproate) is considered an anticonvulsant with mood stabilizing properties
  • Use of anticonvulsants in mood disorders developed out of research looking at the effects of anticonvulsants on seizure activity and the process of “kindling” in mice (i.e., repeatedly inducing seizures via electrical stimulation results in seizure activity even in the absence of any stimulation). Carbamazepine (Tegretol) was first tried in individuals with bipolar disorder. Carbamazapine (Tegretol) exerted both acute anti-manic and prophylactic effects on cycling rates. Valproic acid (Depakote) was tested next and was found to be superior to lithium in type II bipolar illness and in rapid cycling illness (but anticonvulsants and lithium together showed additive benefits)
  • In manic patients, plasma levels greater than 45 ug/mL may be required for antimanic effects (levels up to 100-125 ug/mL are often tolerated in manic patients)
  • There is no consensus on the therapeutic plasma level range for valproic acid but likely between 50-100 ug/mL
  • Valproic acid associated with dose-related thrombocytopenia in ~24% of patients
  • Commonly associated with elevated liver enzymes
  • Valproic acid has been associated with encephalopathy, specifically from elevated ammonia levels
  • Valproic acid associated with Polycystic Ovarian Syndrome (10% of women)
  • Valproic acid has been shown to be effective in neuropathic pain




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