Antipsychotics and Seizure Risk in Patients with Brain Tumors: Mechanisms, Modifiers, and Clinical Insights

PURPOSE OF REVIEW: Neuropsychiatric symptoms including agitation, delirium, and psychosis are common in patients with primary or metastatic brain tumors and frequently necessitate antipsychotic treatment. Brain tumors create a hyperexcitable cortical environment characterized by glutamatergic excess, impaired inhibitory signaling, peritumoral edema, network disruption, and treatment-related neurotoxicity, all of which lower seizure threshold. Emerging data further implicates impaired astrocytic glutamate regulation, neuroligin-3-mediated neuron-glioma synaptic signaling, and IDH-mutant-associated oncometabolite accumulation as contributors to cortical instability. Neuropsychiatric symptoms often localize to frontal and temporal networks that are also highly epileptogenic, amplifying vulnerability. Brain tumor-related epilepsy further compounds this risk through recurrent seizures, interictal dysfunction, and antiseizure medication effects that contribute to cognitive and behavioral disturbance. RECENT FINDINGS: In general psychiatric populations, second-generation antipsychotics have low intrinsic seizure liability. However, these data largely exclude patients with structural brain disease. In neuro-oncology, seizure risk is context-dependent and reflects the interaction of tumor biology, antiseizure medication exposure, metabolic instability, and dynamic treatment effects. Clozapine and low-potency first-generation antipsychotics confer the greatest seizure risk, whereas risperidone and aripiprazole are associated with lower risk. Commonly used antiseizure medications, particularly levetiracetam, may exacerbate irritability and behavioral dysregulation, increasing the need for antipsychotic treatment within an already unstable neurophysiologic environment. This review synthesizes evidence on tumor-associated hyperexcitability, antipsychotic-specific seizure liability, and clinical modifiers of risk in brain tumor populations. We propose a seizure-informed, interdisciplinary framework that integrates tumor biology, antiseizure medication selection, and psychiatric indication to guide antipsychotic prescribing in neuro-oncology.