The potential mechanisms by which medications affect the seizure threshold are neurotransmitter changes (e.g., dopamine blockade, gaba aminobutyric acid (GABA) inhibition, alpha adrenoceptor down-regulation), cerebral neuronal effects (e.g., chloride influx inhibition), cerebral cortex irritation, and changes in cerebral blood flow.

Seizures can be caused by acute neurologic dysfunction or temporary metabolic abnormalities. Medications are a cause of provoked seizures. Opioid analgesics, some penicillin derivative antibiotics, and antineoplastic agents are examples of medications other than psychotropics that can provoke seizures. In many patients with epilepsy, a cause cannot be identified and is presumed to be a genetic predisposition.

The relationship between psychotropic medications and seizures is complicated. Psychiatric disease is more frequent among people with epilepsy. Effects of individual medications on seizure threshold vary but generally psychotropic drugs reduce seizure threshold.

Patient factors predisposing to increased risk of seizures with offending medications are shown in the table.

The seizure incidence rates with antidepressants and antipsychotics range from 0.1 to 1.5% at therapeutic doses. This is slightly higher than the 0.07–0.09% incidence of first unprovoked seizure in the general population [1]. In overdose situations, the risk increases significantly.

Medication-induced seizures are dose related. They usually occur within several weeks of medication initiation or dosage increase.

Almost all antipsychotics decrease the seizure threshold. Lower potency agents may be generally higher risk than high potency agents. But there are individual variations between agents. Chlorpromazine and clozapine carry the highest risk among typical and atypical agents, respectively [2]. There may be an increased risk overall with atypical versus typical agents [3].

As with all agents, risk with clozapine increases with dose and is about 4% over 600 mg/day. The serum level is a more accurate predictor of seizure risk and levels >1300 ng/mL carry a substantial risk of seizures [4].

Among antidepressants, tricyclic antidepressants (TCAs) decrease seizure threshold and increase seizure risk [5]. The risk with selective serotonin reuptake inhibitors (SSRIs) is considered to be no higher than in the general population. Bupropion, a dopamine and norepinephrine reuptake inhibitor, increases seizure risk slightly with a rate of 0.36% [6] at doses over 300 mg/day; risk is comparable to tricyclic antidepressants. Risk with bupropion can be minimized by using sustained or extended release formulations and lowest effective doses. Monoamine oxidase inhibitors do not appear to increase seizure risk at therapeutic doses.