Characteristics Associated With Antiepileptic Drug-Induced Psychotic Disorders

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Patients taking levetiracetam should be monitored for AIPD.

Patients with epilepsy have higher rates of comorbid mental illness and an increased risk of psychotic disorders. In fact, a 2014 meta-analysis found an 8-fold risk of psychosis in this population compared with controls.1 In up to 8.4% of patients, antiepileptic drugs (AED) may be the source of psychotic illness.2

Despite this established association, clear diagnostic criteria for AED-induced psychotic disorder (AIPD) have not been defined and clinical characteristics and long-term outcomes have not been adequately explored in research on patients affected by AIPD.

Noting that this lack of clarity can lead to inappropriate and even harmful treatment that can actually worsen patients’ epilepsy, researchers at the University of Melbourne in Australia and Sun Yat-sen University in China aimed to identify factors that may differentiate AIPD from non-AED-related psychosis.3 They compared hospital records spanning a period of approximately 22.5 years pertaining to patients with AIPD and those with psychotic disorders not induced by AEDs. The analysis focused on data specific to epilepsy, its treatment, psychotic symptoms, and outcomes of the psychotic episodes.

Epilepsy diagnoses were based on criteria defined by the International League Against Epilepsy (ILAE), and psychotic disorders were diagnosed based on the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Additionally, the association between patients’ psychotic disorder and epilepsy were established per ILAE recommendations: Epilepsy-related psychotic disorders were classified as psychosis of epilepsy, which included interictal psychosis of epilepsy, postictal psychosis, and AIPD.

Of 2630 total patients with epilepsy, 98 (3.7%) were found to have psychotic disorders, of which 14 (14.3%) were determined to have AIPD. Comparisons between the AIPD and non-AIPD groups revealed the following results:

  • More females than males in the AIPD group (76.9% vs 41.7%; P < .05)
  • Higher rates of use of levetiracetam in the AIPD group (84.6% vs 20.2%, P < .01), and higher rates of carbamazepine use in the non-AIPD group (15.4% in AIPD vs 44.0% in non-AIPD, P < .05).
  • Higher rates of structural/metabolic epilepsy in the AIPD group (84.6% vs 56.0%, P < .05)
  • Higher rates of temporal lobe involvement in the AIPD group [69.2% vs 38.1%, odds ratio (OR) 4.063, P < .05]
  • More common disorganized behaviors and thinking in the AIPD group (100% vs 72.6% and 76.9% vs 64.3%, respectively; P < .05)
  • Shorter duration of psychotic episodes in the AIPD group (less than 1 week in 42.9% of AIPD patients vs 22.6% of non-AIPD patients (P < .05)
  • Lower number of patients taking continuous antipsychotic medication in the AIPD group (15.4% vs 66.7%, P < .01)
  • None of the AIPD patients demonstrated a chronic course of psychosis, compared with 40.5% of the non-AIPD patients

Multivariate logistic regression linked 4 factors with AIPD: female gender, temporal lobe involvement, current levetiracetam use, and a negative association with carbamazepine. In 11 of the 14 AIPD patients, symptoms resolved upon cessation of the culprit AED, and the other 3 patients recovered after the AED dosage was reduced.

Despite the small sample size and retrospective study design, these findings suggest that in patients with epilepsy who develop symptoms of psychosis – especially related to abnormal behaviors and disorganized thinking and speech – AIPD should be considered as a potential diagnosis. Additionally, the “current usage of levetiracetam should raise the strong suspicion of AIPD” in such cases, according to the authors.

Disclosures: Ziya Chen was supported by the Australian and New Zealand Association of Neurologists (ANZAN) Bayer Asia Pacific Region Neurology Educational Grant.


  1. Clancy MJ, Clarke MC, Connor DJ, Cannon M, Cotter DR. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014 Mar 13;14:75.
  2. Piedad J, Rickards H, Besag FM, Cavanna AE. Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations. CNS Drugs. 2012 Apr 1;26(4):319-35.
  3. Chen Z, Lusicic A, O’Brien TJ, Velakoulis D, Adams SJ, Kwan P. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain. 2016 Aug 8; doi:0.1093/brain/aww196.