SUMMARY  

• The observed rates of treatment-emergent mania in SPRAVATO phase 3 studies in treatment-resistant depression (TRD) (<0.5% across studies) did not exceed the rates published in the literature with other antidepressant (AD) treatments.^1-3
  • An important confounding factor that should be considered is that, in addition to starting nasal spray medication (esketamine or placebo), all patients received a newly initiated oral AD during the treatment phase.
• In an analysis of 51 reports of patients diagnosed with major depressive disorder (MDD) and treated with an AD, the estimated overall risk of mood-switching was 3.42% per year of treatment.²
• In an international analysis of 2811 patients with a major depressive episode, 16.9% of patients had a history of AD-induced hypomania/mania.³
• There were no adverse events (AEs) of mania in phase 3 clinical studies of patients with major MDD and suicidal ideation with intent.
• Postmarketing safety data of SPRAVATO:
  • An analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database (from the first quarter of 2019 to the fourth quarter of 2023) identified 14,606 SPRAVATO-related AEs, of which 6 were cases of hypomania.⁴
  • An analysis of the European Pharmacovigilance database (EudraVigilance; from March 2019 to April 2024) identified 1637 SPRAVATO-related AEs, of which 11 were reports of mania and 7 of hypomania.⁵ 

BACKGROUND

Emergence of symptoms of hypomania or mania has been reported with the use of oral AD in patients with MDD. Emergence of such symptoms may be related to undiagnosed bipolar disorder.^2,3

Patients with bipolar disorder or related disorders (as assessed by the Mini International Neuropsychiatric Interview [MINI]) were excluded from enrollment in the SPRAVATO clinical program in TRD. The use of lithium, anticonvulsants (valproate, carbamazepine), and antipsychotics were prohibited during the studies.¹

CLINICAL DATA

Clinical Trial Data

In the phase 3 TRD clinical trial program, the observed rate of mania was <0.5%. A confounding factor was all patients initiated a newly initiated oral AD at the time of study entry.

• Across completed phase 2 and 3 studies, treatment-emergent AEs of mania were reported in 2 patients exposed to SPRAVATO plus an oral daily AD.^1,6-11
  • A severe AE of mania was reported in a 20-year-old male on day 2 of the double-blind phase in a short-term, phase 3 trial (TRANSFORM-1). The patient had received SPRAVATO 56 mg + newly initiated daily duloxetine 60 mg the previous day. This AE led to withdrawal from the study, was resolved on day 7 without treatment, and was assessed as probably related to SPRAVATO by the investigator. The investigator confirmed the patient had no prior history of bipolar disorder, no family history of bipolar disorder, and no history of drug or alcohol use prior to the visit.^1,6
  • A serious and moderately severe AE of mania was reported in a 61-year-old male, with no family history of bipolar disorder, on day 38 during the follow-up phase of a long-term, maintenance-of-effect, phase 3 study (SUSTAIN-1). The patient had received SPRAVATO 56 mg + newly initiated daily sertraline 50 mg on day 1. SPRAVATO was increased to 84 mg on day 5 and discontinued on day 26 as the patient continued into the follow-up phase. The patient experienced depressive symptoms beginning on day 32 and was hospitalized on day 35 due to worsening symptoms. At the time, the patient was on sertraline 200 mg daily, and the dose was reduced to 100 mg daily on day 37. On day 38, the patient’s depression resolved, however, a manic episode was reported the same day. Medications administered during the manic episode included sertraline, valproic acid, haloperidol, olanzapine, clonazepam, and lithium carbonate. The last dose of sertraline was on day 42 and the patient completed the follow-up phase on day 43. On day 65, the mania resolved, and the patient was discharged. This AE was assessed as not related to SPRAVATO by the investigator and possibly related to sertraline.^1,10
• The interim analysis of the long-term (up to 4.5 years) phase 3 SUSTAIN-3 study reported discontinuation of SPRAVATO in 0.3% (3/1148) of patients due to AEs related to mania.¹²

Real-World Studies

Santucci et al (2024)¹³ conducted a real-world study to evaluate the effectiveness and safety of treatment with SPRAVATO and intravenous ketamine in 45 patients with bipolar depression. Of the 22 patients who received SPRAVATO, 10 cases of mild-to-moderate hypomania were reported in 9 patients over a total follow-up period of 247 patient-months. However, 2 of those patients were initially diagnosed with unipolar depression, and this was their first hypomanic/manic episode. None required hospitalization. The authors noted that the hypomanic symptoms could have been attributed to modifications to the study drugs or other adjunctive therapies.

Martinotti et al (2022)¹⁴ conducted a retrospective, real-world, observational study (REAL-ESK study) in Italy to evaluate the effectiveness of SPRAVATO in 116 patients with unipolar and bipolar TRD. Side effects related to manic symptoms were reported in 2.6% of patients.

Postmarketing Safety Data

Food and Drug Administration Adverse Event Reporting System (FAERS)

An analysis of the FAERS database (from the first quarter of 2019 to the fourth quarter of 2023) identified 14,606 SPRAVATO-related AEs, of which 6 were reports of hypomania with a reporting odds ratio (ROR) of 12.44 (95% confidence interval [CI], 5.57-27.79); proportional reporting ratio of 12.43 (95% CI, 5.57-27.75); and Empirical Bayes Geometric Mean (EBGM) of 12.35 (the lower limit of the 95% CI for the EBGM, 5.53).⁴ Limitations of the FAERS database include the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate the incidence rates of the events.¹⁵

European Pharmacovigilance Database (EudraVigilance)

An analysis of the EudraVigilance database identified 1637 SPRAVATO-related AEs (from March 2019 to April 2024), of which 11 were cases of mania and 7 hypomania. Six (33.3%) cases were considered serious. SPRAVATO was used for TRD in 10 cases and bipolar disorder in 4 cases (no data was available for the remaining cases). The disproportionality analysis reported a higher association of symptoms of mania and hypomania with SPRAVATO compared to other drugs in the EudraVigilance database (ROR, 27.4 [95% CI, 17.2-43.7]). As this database holds similar limitations as FAERS, further well-designed observational studies are needed to reach definitive conclusions.⁵ The authors also noted the potential for manic symptoms as a result of the bipolar condition itself or with other concomitant antidepressants.¹⁶

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 09 December 2024.