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Valproic Acid (Valproate)

Brands and Forms

  • Depakote (divaproex sodium)
    • delayed-release tablet: 125mg, 250mg, 500mg
    • capsule, sprinkle: 125mg
  • Depakote ER (divalproex sodium)
    • extended-release tablet: 250mg, 500mg
  • Depakene
    • capsule: 250 mg (as valproic acid)
    • syrup: 250mg/5ml (as sodium valproate)
  • Depakon (sodium valproate)
    • intramuscular injection: 100mg/m

How Valproic Acid Works

Valproic Acid is considered an Anticonvulsant and also a Mood Stabilizer. Its mechanisms of actions are not completely known, but it seems to block voltage-gated sodium channels and to increase brain concentrations of GABA.

It usually takes about 1-3 weeks for Valproic Acid to have a clinical effect.

Uses of Valproic Acid

Valproic Acid is very commonly used for Bipolar Disorder; it is particularly effective for treating Manic, Hypomanic and Mixed Episodes, and can also be used to treat the Depressive Episodes.

Valproic Acid is sometimes used to help treat Schizophrenia, and is also used to help reduce impulsive or agitated behaviors in conditions like Dementia and Borderline Personality Disorder.

Outside of psychiatry, Valproic Acid is used for treating Seizure Disorders and also for preventing migraines.

Cautions when Using Valproic Acid

For people with liver disease, pancreatitis, urea cycle disorder, polycystic ovary disease, or thrombocytopenia, advice from the appropriate medical specialist should be obtained before starting Valproic Acid.

Valproic Acid overdoses can be potentially life-threatening (see Valproic Toxicity)

Women in childbearing years should consider taking contraceptives while using Valproic Acid, given the risk of pregnancy complications.

Dosing of Valproic Acid

Valproic Acid doses are determined based on blood serum concentrations. Serum levels should be measured 5 days after starting Valproic Acid or 5 days after any dose change, and 12 hours after the last dose.

The therapeutic range for Valproic Acid is at serum levels of 350-700 mmol/L (50-150 µg/ml). The starting dose is usually 250mg twice a day, though 250mg in the morning and 500mg at night is also acceptable. The dose is then adjusted upwards as indicated by serum levels, or until clinical improvement has been achieved. For adults with acute Mania, a starting dose of 20-30mg/kg/day can be used.

Once a stable dose has been reached, Valproic Acid is usually prescribed twice or three times a day. The extended-release form, Depakote ER, can be taken once a day. A dose of Depakote ER usually needs to be about 10-20% higher than an equivalent dose of regular Valproic Acid (checking serum levels is the best way to determine the proper dose).

When wanting to stop Valproic Acid, the dose should be lowered gradually over a period of several weeks.

Side-effects of Valproic Acid

Below is a list of most of the reported side-effects of Valproic Acid. Most of these side-effects occur in only a minority of individuals taking this medication, and many also resolve with time while Valproic Acid is continued. If side-effects occur that are not tolerable, then the first step should be to lower the dose (except in the case of serious side-effects, where it should be stopped). With proper medical monitoring Valproic Acid is a safe and effective treatment.

Cardiovascular: arrythmias; palpitations; blood pressure changes; peripheral edema.

Central Nervous System: tremor; headaches; sedation (try lowering daytime dose); dizziness; insomnia; nervousness; unsteadiness; cognitive dulling (includes memory problems and feeling mentally slowed); emotional lability (occurs rarely, includes dysphoria and anxiety); abnormal dreams;

Dermatologic: hair loss (zinc and selenium supplements can help for this); rash (in very rare cases can include erythema multiforme and Stevens-Johnson syndrome).

Endocrine: SIADH; hyperglycemia.

Eyes, Ears, Nose and Throat: blurred vision; dry mouth; pharyngitis, nystagmus; tinnitus (ear ringing); conjunctivitis; hearing difficulties; dry eyes; photophobia; taste perversion; hearing loss (rare).

Gastrointestinal: weight gain (can be substantial, and may or may not be associated with increased appetite); nausea; vomiting; abdominal pains; diarrhea; constipation; flatulence; gastroenteritis; hypoproteinemia; hepatitis (rare); pancreatitis (rare).

Genitourinary: amenorrhea (loss of menstruation); cystitis; painful menstruation; painful or burning urination; heavy menses; urinary frequency; urinary incontinence; vaginitis; polycystic ovary disease (controversial).

Hematologic: thrombocytopenia; easy bruising; anemia; increased bleeding time; leukopenia; myelosuppression; acute intermittent porphyria; pancytopenia; infections.

Musculoskeletal: muscle pains; muscle weakness; twitching.

Respiratory: flu-like syndrome; shortness of breath; hiccups; increased cough; pneumonia; sinusitis.

Common side-effects of Valproic Acid

Tremor, headache, somnolence, nausea, vomiting, abdominal pain, diarrhea, weakness, dizziness, insomnia, nervousness, hair loss, double or blurred vision, loss of appetite, dyspepsia, weight gain, muscle pain, flu-like symptoms.

Rare but serious side-effects of Valproic Acid

  • hepatoxicity (liver impairment)
  • pancreatitis
  • low blood counts (leukopenia, pancytopenia, myelosuppression)

Valproic Acid overdose

Confusion, restlessness, delirium, dizziness, blurred vision, nausea and vomiting, and can lead to coma and death.

Valproic Acid and pregnancy

Valproic Acid causes potentially serious neural tube defects in 5-9% of pregnancies when it is used in the first trimester. This risk may be partially moderated by giving large doses of Folic Acid. Valproic Acid can also cause cardiovascular defects, cerebral haemorrhage, growth retardation, and coagulopathies in the fetus.  If used in the third trimester, vitamin K should be given in last month of pregnancy and to neonate.

Medical Monitoring of Valproic Acid

Before starting Valproic Acid, and then every six months, the following laboratory tests should be performed in order to monitor for the development of potentially serious side-effects:

  • Complete Blood Count (to monitor for myelosuppression, anaemia, thrombocytopenia, pancytopenia)
  • Electrolytes (hyponatremia, SIADH)
  • Liver function tests, including Albumin level (hepatotoxicity)
  • INR, PT-PTT (increased bleeding time)
  • Amylase (pancreatitis)
  • Consider pregnancy tests

Drug-interactions with Valproic Acid

  • Lamotrigine levels can be doubled by Valproic Acid.
  • Valproic Acid can increase blood concentrations of Amitriptyline, Nortriptyline, barbiturates, Diazepam, Ethosuximide, hydantoins (eg, Phenytoin), Lorazepam, Phenobarbital, Primidone, Warfarin, and Zidovudine
  • Valproic Acid can lower blood concentrations of Carbamazepine.
  • Valproic Acid levels can be lowered by Carbamazepine, Pheytoin, Ethosuximide, Lamotrigine, Olanzapine, Phenobarbital, Rifampin, Cholestyramine, and Meropenem.
  • Valproic Acid levels can be increased by Aspirin, Ibuprofen, Chlorpromazine, Cimetidine, Eruthromycin, Felbamate, Fluoxetine, Fluvoxamine, salicylates, and Topiramate.
  • Combining Valproic Acid with Topiramate can cause hyperammonemia.