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What drives hyperammonemic encephalopathy in AED users: monotherapy risks or polypharmacy perils?
Qing Shan1,2, Lei Wang3, Xia Liu4
1Department of Clinical Pharmacy, The 960 Hospital, Jinan, Shandong, China.
Frontiers in Pharmacology
|July 3, 2025
Summary
Sodium valproate (VPA) and perampanel (PER) pose risks for hyperammonemic encephalopathy (HE). Combining VPA with topiramate (TPM), olanzapine (OLZ), or quetiapine (QTP) also increases HE risk, necessitating ammonia level monitoring in patients on antiepileptic drugs.
Area of Science:
- Pharmacovigilance
- Neurology
- Clinical Pharmacology
Background:
- Hyperammonemic encephalopathy (HE) is a serious adverse effect associated with sodium valproate (VPA).
- Emerging evidence suggests newer antiepileptic drugs (AEDs) may also precipitate HE, either as monotherapy or in combination with VPA.
- This study aimed to identify risk factors for HE among various AEDs, with a specific focus on VPA co-administration.
Purpose of the Study:
- To investigate the risk factors associated with hyperammonemic encephalopathy (HE) across ten commonly prescribed antiepileptic drugs (AEDs).
- To evaluate the specific impact of co-administering sodium valproate (VPA) with other AEDs and antipsychotics on HE risk.
- To identify patient and drug-related factors contributing to the occurrence of HE.
Main Methods:
- Analysis of FDA Adverse Event Reporting System (FAERS) data from Q1 2013 to Q3 2024 for ten AEDs.
- Utilized reporting odds ratios (ROR) to detect HE signals for individual AEDs and combinations.
- Employed multivariate logistic regression to assess risk factors including age, gender, indication, and drug combinations, with a focus on VPA combinations.
Main Results:
- A total of 1,456 HE-related events were identified, with 93.06% linked to AEDs. Sodium valproate (VPA) showed the highest association (ROR=122.14), followed by perampanel (PER) (ROR=52.62).
- Eight other AEDs also showed positive associations, often influenced by VPA. Lower HE risk was observed in minors (OR=0.61) and for psychiatric indications (OR=0.74).
- Combinations of VPA with topiramate (TPM) (OR=3.38), olanzapine (OLZ) (OR=1.65), or quetiapine (QTP) (OR=1.95) significantly increased HE risk.
Conclusions:
- Antiepileptic drugs (AEDs), particularly sodium valproate (VPA) and perampanel (PER), are associated with a significant risk of hyperammonemic encephalopathy (HE).
- Polypharmacy involving VPA, especially with topiramate (TPM), olanzapine (OLZ), or quetiapine (QTP), markedly elevates HE risk.
- Close monitoring of ammonia levels is crucial for patients receiving AEDs, particularly those on multiple medications.
Keywords:
antiepileptic drugshyperammonemic encephalopathyolanzapineperampanelquetiapinesodium valproatetopiramateMore Related Videos
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