The Brain's Delicate Balance: Excitation vs. Inhibition
Seizures occur due to an imbalance in the brain's electrical activity, resulting from either excessive excitatory stimulation or inadequate inhibitory influences [1.3.2]. The primary inhibitory neurotransmitter is gamma-aminobutyric acid (GABA), while glutamate is the main excitatory one [1.3.2]. Many medications can disrupt this balance, lowering the seizure threshold and making a seizure more likely, even in individuals without a history of epilepsy [1.4.3]. This phenomenon is known as a drug-induced seizure (DIS) [1.3.4]. The mechanisms are varied and can include direct antagonism of GABA receptors, potentiation of excitatory NMDA receptors, or alterations in ion channel function [1.3.4].
Common Classes of Medications That Can Trigger Seizures
Several categories of widely used medications contain drugs known to have proconvulsant effects. It is important to note that risk is often dose-dependent and heightened by certain patient-specific factors [1.4.2].
Antidepressants This is one of the most frequently implicated classes in drug-induced seizures [1.4.4].
- Bupropion (Wellbutrin, Zyban): This medication is clearly associated with a dose-dependent seizure risk [1.2.3, 1.4.2]. In one study, it was the leading cause of drug-induced seizures reported to a poison control system [1.5.4]. The immediate-release (IR) formulation carries a higher risk than sustained or extended-release versions [1.8.1].
- Tricyclic Antidepressants (TCAs): Drugs like clomipramine and amitriptyline are known to lower the seizure threshold, particularly in overdose situations, but also at therapeutic doses [1.8.1, 1.8.2].
- SSRIs and SNRIs: While generally considered safer, with some studies suggesting they may even have anticonvulsant effects at therapeutic doses, seizures are still possible, especially in overdose or with high doses [1.8.1, 1.8.3]. Venlafaxine has emerged as a common cause in some reports [1.5.4].
Antibiotics Certain antibiotics can cause neurotoxicity and induce seizures, often by interfering with GABA receptors [1.7.2, 1.7.3].
- β-Lactams (Penicillins, Cephalosporins, Carbapenems): These are frequently associated with seizures [1.7.3]. Penicillin, cefazolin, and imipenem are notable examples [1.2.2, 1.7.3]. The risk is higher in patients with renal insufficiency, as the drugs can accumulate in the body [1.7.3].
- Fluoroquinolones: This class of antibiotics can also cause seizures, possibly by antagonizing GABA receptors [1.3.4].
Pain Medications
- Tramadol (Ultram): This centrally acting analgesic is a significant cause of drug-induced seizures, even at therapeutic doses [1.4.2, 1.13.1]. It is more likely to cause seizures than other opioids [1.13.1]. The risk is amplified when combined with other drugs that lower the seizure threshold, such as antidepressants [1.13.3].
- Opioids: While all opioids can lower the seizure threshold, tramadol is a particular concern [1.2.3, 1.9.1]. The metabolite of meperidine (Demerol) is also known to be a proconvulsant [1.3.4].
- NSAIDs: Seizures have been reported with nonsteroidal anti-inflammatory drugs, though this is more common after overdose [1.2.2].
Over-the-Counter (OTC) Medications
- Antihistamines: First-generation antihistamines, particularly diphenhydramine (the active ingredient in Benadryl), are a common trigger [1.2.4]. Taking higher than recommended doses can lead to serious adverse effects including seizures, coma, and death [1.11.1]. In one study, diphenhydramine was the second leading cause of drug-induced seizures [1.5.4].
Comparison of Seizure Risk in Common Medication Classes
| Medication Class | High-Risk Examples | Lower-Risk Examples | Primary Mechanism (if known) |
|---|---|---|---|
| Antidepressants | Bupropion (IR), Clomipramine, Maprotiline [1.8.1, 1.8.3] | Sertraline, Fluoxetine (at therapeutic doses) [1.8.1] | Varies; NMDA agonism, GABA antagonism [1.3.4] |
| Antibiotics | Penicillins, Cefazolin, Imipenem [1.2.2, 1.7.3] | Doxycycline [1.7.3] | GABA antagonism [1.7.2] |
| Pain Relievers | Tramadol, Meperidine [1.3.4, 1.13.1] | Paracetamol, Ibuprofen (at therapeutic doses) [1.2.3] | Opioid and monoaminergic effects (Tramadol) [1.13.1] |
| Antipsychotics | Clozapine, Chlorpromazine [1.8.1] | Aripiprazole, Risperidone [1.8.1] | Varies; NMDA agonism (Clozapine) [1.3.4] |
| Stimulants | Methylphenidate (historically cautioned, but recent large studies suggest no increased risk at therapeutic doses) [1.10.1, 1.10.2] | Atomoxetine [1.8.1] | Lowering convulsive threshold [1.2.2] |
Risk Factors and Management
Certain factors can increase an individual's susceptibility to drug-induced seizures. These include a personal or family history of seizures, pre-existing CNS disorders, impaired kidney or liver function, high doses of medication, polypharmacy, and abrupt withdrawal from sedatives like benzodiazepines or alcohol [1.4.1, 1.4.2, 1.14.2].
If a drug-induced seizure occurs, the primary management step is to discontinue the offending agent if possible [1.2.2]. Most of these seizures are self-limited [1.3.2]. For prolonged or recurrent seizures (status epilepticus), benzodiazepines are the first-line treatment, followed by second-line agents like barbiturates or propofol [1.6.1, 1.6.2].
Conclusion
While many medications are essential for treating various conditions, it is vital for both clinicians and patients to be aware of their potential to induce seizures. From common antidepressants and pain relievers to antibiotics and OTC allergy pills, the list of potential culprits is extensive. Understanding the risks, recognizing susceptible individuals, and knowing the signs of a drug-induced seizure are key to ensuring medication safety. Always consult a healthcare professional before starting or stopping any medication, especially if you have a history of seizures or other neurological conditions.
For further reading, MedLink provides a comprehensive overview of drug-induced seizures: MedLink Neurology [1.2.2]
