What antipsychotics, excluding risperidone (Risperdal) and aripiprazole (Abilify), have a low seizure threshold?

Antipsychotics with Low Seizure Threshold

Clozapine has the highest risk of lowering seizure threshold among all antipsychotics, with approximately 5% incidence of seizures at high doses, followed by chlorpromazine and other low-potency first-generation antipsychotics. 1, 2

Seizure Risk by Antipsychotic Class

First-Generation Antipsychotics with High Seizure Risk:

• Chlorpromazine appears to have the greatest risk of seizure provocation among first-generation antipsychotics 2
• Low-to-medium potency first-generation antipsychotics (chlorpromazine, zuclopenthixol, flupenthixol, pericyazine, promazine, thioridazine) have an incidence rate of seizures of 49.4 per 10,000 person-years 3
• Medium-to-high potency first-generation antipsychotics (haloperidol, prochlorperazine, trifluoperazine) have an incidence rate of seizures of 59.1 per 10,000 person-years 3
• Thioridazine has been associated with increased seizure risk (adjusted odds ratio 1.78) 1

Second-Generation Antipsychotics with High Seizure Risk:

• Clozapine has the highest seizure risk among second-generation antipsychotics, with approximately 3-5% of patients experiencing seizures 1, 2
• The risk for seizures with clozapine increases as the dose increases, especially if dosage changes are made rapidly 1
• Olanzapine and quetiapine have been shown to have epileptogenic properties in clinical use 4
• In patients with dementia, olanzapine/quetiapine use was associated with an increased risk of seizures (adjusted odds ratio 2.37) 3
• Clozapine has shown epileptogenic properties in electroconvulsive therapy studies 4

Factors That Increase Seizure Risk

• Rapid dose titration of antipsychotics 5
• Elevated blood plasma levels of antipsychotics 5
• History of seizure activity 2
• Concurrent use of other drugs that lower seizure threshold 2
• Slow drug metabolism 2
• Drug-drug interactions 2
• Underlying conditions like dementia significantly increase seizure risk with antipsychotic use 3

Clinical Recommendations

• To minimize seizure risk, start with a small dose of antipsychotic, titrate slowly, monitor serum levels, and maintain the minimal effective dose 5
• For patients with epilepsy or seizure risk factors, avoid clozapine if possible 2, 5
• For patients with Parkinson's disease who need antipsychotics, quetiapine is recommended as first-line (which has lower seizure risk than many alternatives) 6
• In patients with dementia, amisulpride, aripiprazole, risperidone, or sulpiride appear to have lower seizure risk (adjusted odds ratio 0.92) compared to other antipsychotics 3

Summary of Antipsychotics by Seizure Risk

Highest Risk:

• Clozapine (5% incidence of seizures at high doses) 1, 2
• Chlorpromazine and other low-potency first-generation antipsychotics 2, 3
• Olanzapine 3, 4
• Zuclopenthixol 4

Moderate Risk:

• Quetiapine 3
• Medium-to-high potency first-generation antipsychotics (haloperidol, prochlorperazine, trifluoperazine) 3

Lower Risk (excluding risperidone and aripiprazole as per question):

• Amisulpride 3
• Sulpiride 3
• Haloperidol (though still has some risk) 2
• Fluphenazine 2
• Pimozide 2
• Trifluoperazine 2

Remember that all antipsychotics can potentially lower seizure threshold to some degree, but the risk varies significantly between medications 2, 5.