From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Hyperammonemia should also be considered in patients who present with hypothermia Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered
Yes, Depakote (valproate) can cause hyperammonemia.
- Key points to consider:
- Hyperammonemia may occur despite normal liver function tests.
- Patients with unexplained lethargy, vomiting, or changes in mental status should be evaluated for hyperammonemic encephalopathy.
- Hypothermia can be a manifestation of hyperammonemia.
- Asymptomatic elevations of ammonia require close monitoring, and persistent elevations may necessitate discontinuation of valproate therapy 1
From the Research
Yes, Depakote (valproic acid/divalproex sodium) can cause high ammonia levels in the blood, a condition known as hyperammonemia, as evidenced by a recent case report in 2022 2. This is a recognized side effect that occurs in some patients taking this medication, which is commonly prescribed for epilepsy, bipolar disorder, and migraine prevention. The risk appears higher with long-term use, higher doses, and in patients with certain metabolic disorders or liver dysfunction. Depakote affects the way the body processes ammonia by inhibiting enzymes in the urea cycle, which is responsible for converting ammonia to urea for excretion. When this cycle is disrupted, ammonia can accumulate in the bloodstream. Symptoms of elevated ammonia may include confusion, lethargy, vomiting, decreased appetite, or in severe cases, altered consciousness or coma. Regular monitoring of ammonia levels may be necessary for patients on Depakote, especially those showing unexplained changes in mental status. If hyperammonemia develops, dose reduction or discontinuation of Depakote may be required under medical supervision, and treatment with L-carnitine may be beneficial in reducing ammonia levels, as suggested by a study in 2007 3. It is also important to consider the possibility of an underlying inherited metabolic disorder, such as ornithine transcarbamylase deficiency, in patients with hyperammonemia, as highlighted in a case report in 2018 4. In severe cases, hyperammonemia can be life-threatening, and prompt treatment is necessary to prevent permanent neurological injury, as reported in a case of fatal hyperammonemic brain injury in 2012 5. Overall, the risk of hyperammonemia associated with Depakote use should not be underestimated, and clinicians should be aware of this potential complication, especially in patients with risk factors, as emphasized in a review of valproate-induced hyperammonemic encephalopathy in 2012 6.
Some key points to consider when prescribing Depakote include:
- Monitoring ammonia levels in patients on Depakote, especially those with risk factors or showing unexplained changes in mental status
- Being aware of the potential for hyperammonemia, even in patients with normal liver function and serum valproate levels
- Considering the diagnosis of an underlying inherited metabolic disorder in patients with hyperammonemia
- Promptly treating hyperammonemia with dose reduction or discontinuation of Depakote, and considering treatment with L-carnitine or other agents as needed.