Does Rexulti (brexpiprazole) increase the risk of seizure?

Rexulti (Brexpiprazole) and Seizure Risk

Yes, brexpiprazole (Rexulti) can cause seizures, and like other antipsychotic drugs, the risk is greatest in patients with a history of seizures or conditions that lower the seizure threshold. 1

FDA-Labeled Warning

The FDA drug label explicitly states that brexpiprazole may cause seizures, with risk being greatest in patients with a history of seizures or with conditions that lower the seizure threshold 1. Importantly, conditions that lower seizure threshold may be more prevalent in older patients 1.

Mechanism and Context

• Brexpiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors 2
• Like all antipsychotic medications, it carries inherent seizure risk, though the exact mechanism remains incompletely understood 1

Clinical Evidence on Antipsychotic-Related Seizures

• Among antipsychotics generally, medium-to-high potency first-generation antipsychotics carry the highest seizure risk (2.5-fold increased risk in affective disorders), while second-generation agents like amisulpride, aripiprazole, and risperidone show lower risk profiles 3
• Drug-induced seizures account for approximately 6.1% of first-occurring seizures, with antipsychotics being among the commonly implicated medication classes 4

High-Risk Patient Populations

Use brexpiprazole with extreme caution or consider alternatives in patients with:

• History of epilepsy or prior seizures 1, 4
• Elderly age (conditions lowering seizure threshold are more prevalent) 1
• Concurrent neurological diseases 4
• Impaired liver or kidney function (affects drug metabolism and excretion) 4
• Polypharmacy, especially with other CNS-active medications 4
• Fever or acute illness 4
• Blood-brain barrier dysfunction 4

Clinical Management Approach

For patients requiring brexpiprazole who have seizure risk factors:

• Ensure any existing anticonvulsant medications are optimized before initiating brexpiprazole 5
• Start at the lowest effective dose and titrate slowly 1
• Monitor closely for any changes in seizure frequency or new-onset seizure activity 5
• Educate patients and caregivers about seizure warning signs 1

If seizures occur during brexpiprazole treatment:

• Discontinue brexpiprazole immediately and evaluate for alternative causes 1
• Consider switching to an antipsychotic with lower seizure potential if continued antipsychotic treatment is necessary 3

Important Caveats

• The sedative effects of brexpiprazole (somnolence reported in 4-5% of patients) may mask early signs of increased seizure activity, making vigilant monitoring essential 1
• Brexpiprazole can cause additional risk factors for seizures including body temperature dysregulation, which may lower seizure threshold further 1
• The combination of somnolence, orthostatic hypotension, and motor instability increases fall risk, which is particularly concerning in patients who may experience seizures 1