Summary

• Patients with a current or past history of seizures, with the exception of uncomplicated childhood febrile seizures, were excluded from the SPRAVATO nasal spray phase 3 trials and, therefore, there is no systematically collected data on SPRAVATO treatment in this population.^1-7
  • The primary reason for exclusion was to avoid confounding the safety signal.⁸
• Two patients had an adverse event of seizure in the phase 3 treatment-resistant depression clinical program.
  • A 37-year-old male patient in the maintenance-of-effect study¹, without a prior history of seizures or head injury and on SPRAVATO 56 mg and venlafaxine XR 75 mg, had serious adverse events of simple partial seizures and autonomic nervous system imbalance on day 5 of the induction phase. The patient was not on any other concomitant medications and the investigator considered both events very likely related to SPRAVATO and doubtfully related to venlafaxine XR. Both drugs were discontinued, and the patient had a complete recovery 2.5 hours postdose. The patient was withdrawn from the study on day 7.⁹
  • A 52-year-old female patient in the long-term safety study,⁷ with a history of shakes in the limbs/muscular spasm, but no prior history of seizures or loss of consciousness, had a nonserious adverse event of generalized tonic-clonic seizure on day 278 while on SPRAVATO 56 mg once weekly and sertraline 150 mg daily (considered by the investigator as possibly related to both drugs). The patient was also on concomitant paracetamol, clomipramine, lormetazepam, and clonazepam. The seizure occurred prior to receiving her dose and subsequently the patient was not dosed with SPRAVATO (last dose of SPRAVATO received on day 267). The patient was treated with valproic acid and lorazepam, with event resolution on the same day. The patient discontinued SPRAVATO and continued to receive sertraline 150 mg and clonazepam in the follow-up phase of the study.⁹
• An analysis conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) database for 5132 SPRAVATO-related adverse drug events from the first quarter of 2019 to the second quarter of 2023 reported the occurrence of 7 cases of psychogenic seizure, classified under the system organ class of nervous system disorders, with a reporting odds ratio (95% confidence interval [CI]) of 48.22 (22.75-102.19); proportional reporting ratio (chi-squared), 48.19 (314.91); empirical Bayesian geometric mean (EBGM; the lower limit of the 95% CI for the EBGM), 46.94 (25.04); and information component (IC; the lower limit of the 95% CI for the IC), 5.55 (3.88).¹⁰
  • The results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.¹¹ 

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 November 2024.