ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacoepidemiology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1477127
What Drives Hyperammonemic Encephalopathy in AED Users: Monotherapy Risks or Polypharmacy Perils?
Provisionally accepted
- 1Department of Clinical Pharmacy, the 960 Hospital, Shandong Jinan, China 250031, Jinan, China
- 2Jinan Key Laboratory of Individualised Clinical Drug Safety Monitoring and Pharmacovigilance Research, Jinan, China
- 3Department of Orthopedic, the 960 Hospital, Shandong Jinan, China 250031, Jiji, China
- 4Department of Clinical Pharmacy, School of Pharmacy, Naval Medical University, China 200433, Shanghai, China
- 5Department of Medical Service, the 960 Hospital, Shandong Jinan, China 250031, Jinan, China
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Background and objectives: Hyperammonemic encephalopathy (HE) is a serious side effect linked to sodium valproate (VPA). Recent case studies indicate that newer antiepileptic drugs (AEDs) might also trigger HE, whether used alone or alongside VPA. This study investigated the risk factors of HE linked to 10 AEDs using data from the FDA Adverse Event Reporting System (FAERS), focusing on VPA co-administration effects.Methods: FAERS reports from the first quarter of 2013 to the third quarter of 2024 were examined for ten frequently prescribed antiepileptic drugs (AEDs): VPA, perampanel (PER), phenytoin (PHT), carbamazepine (CBZ), topiramate (TPM), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXA), clonazepam (CZP), and zonisamide (ZNS). Hepatic event (HE) signals were evaluated using reporting odds ratios (ROR). A multivariate logistic regression analysis was conducted to assess risk factors (age, gender, indication, drug combinations). Particular attention was given to the effects of VPA in combination with LEV, TPM, olanzapine (OLZ), or quetiapine (QTP) on the risk of HE.Results: A total of 1,456 HE-related events were identified, with 93.06% of these events linked to AEDs. VPA had the highest association with HE (ROR=122.14, 95% CI: 110.16-135.41), followed by PER, which was independent of VPA (ROR=52.62). Eight additional AEDs also indicated positive associations, mainly influenced by VPA (such as TPM and LEV). Identified risk factors for HE included age (with a lower risk observed in minors, OR = 0.61, 95% CI [0.50-0.76]) and clinical indication (with a lower risk in psychiatric disorders, OR = 0.74, 95% CI [0.62-0.89]). The combination of VPA+TPM significantly raised the risk of HE (OR=3.38, 95% CI[2.25-5.06]) without negatively impacting outcomes. Furthermore, combinations of antipsychotic medications with VPA also indicated an increased risk of HE (OLZ+VPA: OR = 1.65, 95% CI [1.18-2.30], QTP+VPA: OR = 1.95, 95% CI [1.39-2.75]).Conclusions: This research underscores the possible danger of HE related to AEDs, with a particular focus on the risks tied to VPA and PER when used alone, as well as VPA in conjunction with TPM, OLZ, or QTP. It emphasizes the need to monitor ammonia levels in patients on AEDs, particularly those on polypharmacy.
Keywords: Hyperammonemic encephalopathy, antiepileptic drugs, sodium valproate, Perampanel, Topiramate, olanzapine, quetiapine
Received: 09 Sep 2024; Accepted: 02 Jun 2025.
Copyright: © 2025 Shan, Wang, Liu, Chen, Li, Guo, Fu and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: min jin Guo, Department of Clinical Pharmacy, the 960 Hospital, Shandong Jinan, China 250031, Jinan, China
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