Can Depakote (valproate) cause hyperhomocysteinemia due to vitamin B12 deficiency?

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Last updated: March 18, 2025View editorial policy

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From the Guidelines

Depakote (valproate) is not directly associated with causing hyperhomocysteinemia due to vitamin B12 deficiency, according to the provided evidence. The provided study 1 discusses the side effects of drugs prescribed for Parkinson's disease, including levodopa, and its potential to cause hyperhomocysteinemia due to vitamin B12 deficiency. However, it does not mention Depakote (valproate) as a cause of hyperhomocysteinemia or vitamin B12 deficiency. Some key points to consider:

  • The study 1 highlights the importance of nutritional status in patients with Parkinson's disease, particularly those taking levodopa, which may be associated with impaired nutritional status and risk for malnutrition.
  • Levodopa use has been linked to hyperhomocysteinemia, which may be dependent on vitamin B status, including folate, vitamin B12, and vitamin B6 1.
  • Patients on levodopa may have higher requirements for these vitamins to maintain normal homocysteine levels, and supplementation might be warranted 1. However, since the question is about Depakote (valproate) and not levodopa, the recommendation is to monitor patients taking Depakote for any signs of vitamin B12 deficiency or hyperhomocysteinemia, but not to attribute these conditions directly to Depakote use without further evidence.

From the Research

Relationship Between Depakote (Valproate) and Hyperhomocysteinemia

  • The relationship between Depakote (valproate) and hyperhomocysteinemia due to vitamin B12 deficiency is complex and has been studied in various research papers 2, 3, 4, 5, 6.
  • Some studies suggest that valproate may not be associated with a decrease in vitamin B12 levels, and in some cases, may even be associated with higher vitamin B12 levels 2, 3.
  • However, other studies have found that valproate monotherapy can lead to an increase in homocysteine levels and a decrease in folate levels, which can be a risk factor for hyperhomocysteinemia 5.
  • Vitamin B12 deficiency can cause hyperhomocysteinemia, and it is essential to monitor vitamin B12 levels in patients taking valproate, especially those with a history of malabsorptive disorders or other risk factors for vitamin B12 deficiency 6.

Effects of Valproate on Vitamin B12 and Homocysteine Levels

  • A study published in 2018 found that valproic acid was associated with a higher vitamin B12 level in adults and children 2.
  • Another study published in 2011 found that treatment with valproate was associated with higher vitamin B12 levels compared to the entire group of patients, untreated patients, and healthy controls 3.
  • However, a study published in 2015 found that valproate monotherapy was associated with a non-significant decrease in vitamin B12 levels in epileptic children 5.
  • The same study found that valproate monotherapy was associated with a significant increase in homocysteine levels and a significant decrease in folate levels 5.

Monitoring and Treatment

  • Patients taking valproate should be monitored for possible atherogenic effects due to increased homocysteine levels 5.
  • Screening for vitamin B12 deficiency should be considered in high-risk patients, such as those with malabsorptive disorders 6.
  • Oral administration of high-dose vitamin B12 (1 to 2 mg daily) can be effective in correcting vitamin B12 deficiency, regardless of etiology 6.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

A case of pancytopenia.

Journal of psychopharmacology (Oxford, England), 2006

Research

Update on vitamin B12 deficiency.

American family physician, 2011

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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