What medications reduce the seizure threshold?

From the Guidelines

Medications that reduce seizure threshold include bupropion, tramadol, and other drugs such as antipsychotics, antidepressants, stimulants, antibiotics, analgesics, immunosuppressants, and certain anesthetics. These medications lower the seizure threshold through various mechanisms, including altering neurotransmitter balance, affecting ion channels, or causing direct neurotoxicity, as seen with bupropion which has a 0.1% seizure risk among those receiving the drug for smoking cessation 1. The risk is dose-dependent and increases with higher doses, rapid titration, or when combining multiple threshold-lowering medications. Some of the key medications that reduce seizure threshold are:

• Antipsychotics (particularly clozapine, chlorpromazine, and olanzapine)
• Antidepressants (especially bupropion, tricyclic antidepressants like amitriptyline, and SSRIs like fluoxetine)
• Stimulants (methylphenidate, amphetamines)
• Antibiotics (imipenem, ciprofloxacin, metronidazole)
• Analgesics (tramadol, meperidine)
• Immunosuppressants (cyclosporine, tacrolimus)
• Certain anesthetics (propofol, etomidate)
• Other medications include theophylline, baclofen, and lithium. Tramadol, for example, lowers the seizure threshold and can interact with certain medications to cause serotonin syndrome, a potentially fatal reaction 1. Patients with pre-existing seizure disorders, brain injuries, or electrolyte abnormalities are at higher risk. When prescribing these medications to at-risk patients, start with lower doses, titrate slowly, monitor closely, and consider alternative medications when possible. If these medications are necessary, concurrent use of anti-seizure medications may be appropriate in high-risk individuals.

From the FDA Drug Label

• Drugs that lower seizure threshold: Dose bupropion hydrochloride extended-release tablets (XL) with caution. ( 5.3,7.3) The following is a list of meds that may reduce seizure threshold mentioned in the label:

• Bupropion itself, as it requires caution when dosing due to its potential to lower seizure threshold 2 Note that the label does not provide a comprehensive list of medications that reduce seizure threshold, only that bupropion should be dosed with caution in this context.

From the Research

Medications that Reduce Seizure Threshold

The following medications have been identified as reducing the seizure threshold:

• Antipsychotic medications, including:
  • First-generation antipsychotics: chlorpromazine, molindone, haloperidol, fluphenazine, pimozide, and trifluoperazine 3
  • Second-generation antipsychotics: clozapine, risperidone 3, 4
• Antidepressant medications, including:
  • Maprotiline and clomipramine, which have a relatively high seizurogenic potential 4
  • Phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine, and trazodone, which exhibit a relatively low risk 4
  • Bupropion, which can lower the seizure threshold, particularly at high doses 5
• Other medications, including:
  • Vortioxetine, which has a unique mechanism of action and may lower the seizure threshold 5
  • Vilazodone, which has a relatively low risk of lowering the seizure threshold 5

Factors that Increase the Risk of Seizure Induction

The following factors can increase the risk of seizure induction when taking medications that reduce the seizure threshold:

• History of seizure activity 3, 4
• Concurrent use of other drugs that lower seizure threshold 3, 4
• Rapid dose titration 3, 4
• Slow drug metabolism 3
• Metabolic factors 3
• Drug-drug interactions 3, 6

Clinical Implications

The use of medications that reduce the seizure threshold should be carefully evaluated in patients with a history of seizure activity or other risk factors. Clinicians should be aware of the potential for drug-drug interactions and adjust doses accordingly 6. Additionally, patients should be monitored closely for signs of seizure activity, particularly when initiating or adjusting medications that reduce the seizure threshold.