Understanding the Seizure Threshold
The seizure threshold refers to the balance between excitatory and inhibitory forces in the brain [1.3.3]. Excitatory signals, primarily driven by the neurotransmitter glutamate, promote neuronal firing, while inhibitory signals, largely mediated by gamma-aminobutyric acid (GABA), suppress it [1.9.3]. When this delicate balance is disrupted—either by reducing inhibition or increasing excitation—the brain becomes more susceptible to the abnormal, synchronized electrical activity that characterizes a seizure. Numerous factors can influence this threshold, including genetics, sleep deprivation, metabolic disturbances, and, significantly, various medications [1.3.3]. While some individuals have a naturally lower threshold, such as those with epilepsy, certain drugs can lower it even in people with no prior history of seizures.
Key Medication Classes That Lower Seizure Threshold
A wide range of medications across several therapeutic classes has been identified as having the potential to lower the seizure threshold. The risk is often dose-dependent and is elevated in patients with pre-existing conditions like a history of head trauma, brain tumors, or stroke [1.3.4, 1.4.1].
Antidepressants
This class is frequently associated with altering seizure risk.
- Bupropion: This antidepressant is well-known for lowering the seizure threshold, particularly at doses exceeding 450 mg/day or with immediate-release formulations [1.4.1, 1.4.2]. The risk is significant enough that it is contraindicated in patients with seizure disorders or conditions that predispose them to seizures, like eating disorders [1.4.3].
- Tricyclic Antidepressants (TCAs): Drugs like amitriptyline, imipramine, and clomipramine can induce seizures, especially at high doses or in overdose [1.4.1, 1.4.2]. Their mechanism may involve the blockade of GABA-A receptors, which reduces inhibitory signals in the brain [1.4.1]. Maprotiline and clomipramine, in particular, have a relatively high potential to cause seizures [1.3.5].
- SSRIs and SNRIs: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally considered safer and may even have anticonvulsant properties at therapeutic doses [1.3.2, 1.4.4]. However, at toxic doses or in the context of serotonin syndrome, they can lead to seizures [1.4.1].
Antipsychotics
Nearly all antipsychotics carry some risk of lowering the seizure threshold, though the degree varies.
- Clozapine: Among antipsychotics, clozapine has the highest and most-documented risk, which is dose-dependent. The incidence of seizures can be as high as 10% with this medication [1.3.2]. Doses above 600 mg/day significantly increase this risk [1.4.1].
- First-Generation (Typical) Antipsychotics: Low-potency agents like chlorpromazine and medium-to-high potency agents like haloperidol are also known to lower the seizure threshold [1.3.4, 1.3.5].
- Other Second-Generation (Atypical) Antipsychotics: Olanzapine also carries a notable risk and has been reported to cause EEG changes [1.3.2]. In contrast, risperidone appears to have a lower risk, even at higher doses [1.3.2].
Antibiotics
Certain antibiotics are known to have proconvulsive effects, often by interfering with GABAergic inhibition.
- Carbapenems: Imipenem has the most significant association with seizures within this class, especially at high doses or in patients with renal impairment [1.5.3, 1.5.4]. Its structure allows it to inhibit GABA receptors [1.5.3]. Meropenem and doripenem are considered to have a lower risk [1.5.3].
- Fluoroquinolones: This class, including ciprofloxacin and levofloxacin, can cause seizures by inhibiting GABA receptors [1.5.4, 1.9.4]. The risk is higher in patients with pre-existing CNS conditions or renal failure [1.5.4].
- Penicillins and Cephalosporins: High doses of penicillins and certain cephalosporins (like cefepime) can be neurotoxic and lead to seizures, particularly in patients with kidney disease [1.5.3, 1.5.4].
- Isoniazid: Used to treat tuberculosis, isoniazid can cause seizures by interfering with the synthesis of GABA [1.9.3, 1.9.4].
Analgesics (Pain Medications)
Several pain relievers can increase seizure susceptibility.
- Tramadol: This centrally-acting opioid analgesic consistently appears on lists of drugs that lower the seizure threshold [1.6.3, 1.6.5]. The risk is heightened when combined with other medications like antidepressants [1.10.3].
- Meperidine (Demerol): This opioid has a metabolite, normeperidine, which is a CNS stimulant that can provoke seizures, especially with long-term use or in patients with renal dysfunction [1.6.2, 1.6.4].
- Tapentadol: Similar to tramadol, this analgesic also carries a seizure risk [1.2.5].
Other Notable Medications
- Anesthetics: Certain anesthetics like lidocaine, bupivacaine, and propofol can lower the seizure threshold [1.6.3]. Some, like ketamine, can be proconvulsant or anticonvulsant depending on the dose [1.8.2].
- Theophylline: This bronchodilator, used for asthma and COPD, is known to lower the seizure threshold [1.3.3, 1.4.2].
- Stimulants: Amphetamines and methylphenidate can worsen existing seizure disorders, possibly through increased catecholamine release [1.4.1].
- Immunosuppressants: Cyclosporine and tacrolimus, used to prevent organ transplant rejection, have also been linked to an increased risk of seizures [1.4.2].
Comparison of Medications by Seizure Risk
| Medication Class | High-Risk Examples | Moderate-Risk Examples | Lower-Risk Examples | Mechanism Notes |
|---|---|---|---|---|
| Antidepressants | Bupropion, Clomipramine, Maprotiline [1.3.2, 1.4.5] | Amitriptyline, Imipramine (at high doses) [1.2.2] | SSRIs/SNRIs (at therapeutic doses) [1.3.2] | GABA-A receptor blockade (TCAs); Dopamine/Norepinephrine reuptake inhibition (Bupropion) [1.4.1] |
| Antipsychotics | Clozapine [1.3.2, 1.4.1] | Olanzapine, Chlorpromazine [1.3.5] | Risperidone, Quetiapine [1.3.2, 1.7.2] | Varies; may involve effects on GABA and glutamate systems [1.7.4]. |
| Antibiotics | Imipenem, Fluoroquinolones (e.g., Ciprofloxacin) [1.5.3, 1.5.4] | High-dose Penicillins, Cefepime [1.5.4] | Meropenem, Doripenem [1.5.3] | Primarily through GABA receptor inhibition [1.5.3, 1.9.4]. |
| Analgesics | Tramadol, Meperidine [1.6.2, 1.6.4] | Tapentadol [1.2.5] | Most NSAIDs (at therapeutic doses) | Serotonergic and noradrenergic effects (Tramadol); active metabolite accumulation (Meperidine) [1.10.3]. |
Conclusion
A significant number of commonly prescribed medications have the potential to lower the seizure threshold, thereby increasing the risk of a first-time seizure or exacerbating an existing seizure disorder. The drugs with the highest propensity include the antidepressant bupropion, the antipsychotic clozapine, the antibiotic imipenem, and the analgesic tramadol [1.2.2, 1.2.5]. The risk is not uniform and is influenced by the specific drug, its dosage, the route of administration, and patient-specific factors such as age, renal function, and underlying neurological conditions [1.10.2]. Healthcare providers must weigh the benefits of prescribing these medications against the potential seizure risk, especially in vulnerable populations. Slow dose titration and careful monitoring are essential strategies to mitigate this risk [1.3.4].
For more information, consult authoritative sources such as the Epilepsy Foundation.
