Drug-Induced Seizures: Considerations for Underlying Molecular Mechanisms

Area of Science:

• Pharmacology
• Neuroscience
• Drug Safety

Background:

• Drug-induced seizures (DIS) represent a critical safety liability across diverse therapeutic classes, including antidepressants, antipsychotics, antibiotics, and analgesics.
• Current understanding of DIS molecular mechanisms remains limited, hindering effective risk assessment and mitigation strategies during drug development.
• DIS etiology involves disruptions in inhibitory (e.g., gamma-aminobutyric acid) or excitatory (e.g., glutamate) neurotransmission, leading to neuronal hyperexcitability.

Purpose of the Study:

• To review and discuss key molecular mechanisms implicated in drug-induced seizures (DIS).
• To highlight the importance of understanding DIS mechanisms for improving drug safety testing and development.
• To examine species-specific susceptibility differences and clinical sign interpretation in DIS risk evaluation.

Main Methods:

• Literature review and synthesis of identified molecular mechanisms associated with drug-induced seizures (DIS).
• Analysis of species-specific susceptibility data for DIS, comparing beagle dogs, rodents, cynomolgus monkeys, and Göttingen minipigs.
• Evaluation of clinical signs, including tremors and convulsions, in the context of electroencephalographic (EEG) activity for DIS assessment.

Main Results:

• Identified various molecular mechanisms contributing to DIS across different drug classes.
• Demonstrated significant species differences in DIS susceptibility, with canines exhibiting higher susceptibility than rodents, monkeys, and minipigs.
• Distinguished between physiological tremors and pathological epileptiform activity, emphasizing the need for careful clinical sign interpretation in DIS evaluation.

Conclusions:

• A deeper understanding of DIS molecular mechanisms can facilitate the application of in vivo and in vitro models for risk characterization and mitigation.
• Species-specific susceptibility data are critical for appropriate non-clinical species selection in DIS risk assessment.
• Accurate interpretation of clinical signs, differentiating tremors from seizure activity, is essential for robust DIS risk evaluation during drug development.