summary

• In clinical trials of patients with major depressive disorder (MDD) and active suicidal ideation with intent (ASPIRE-I and -II), adverse events (AEs) potentially related to suicidality during the double-blind (DB) phase were reported in 7.5% (17/227) of patients treated with SPRAVATO + standard of care (SOC) and 7.6% (17/225) of patients who were SOC + placebo (PBO).^1,2
• Of the 452 patients in the ASPIRE trials, 1 death due to suicide was reported in a patient previously treated with SPRAVATO during the follow-up phase of ASPIRE-I. Study investigators assessed the death as unrelated to SPRAVATO.^3,4 See Serious Adverse Event of Death by Suicide in ASPIRE-I.
• Per the antidepressant class Boxed Warning, monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes.⁵
  • Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO and/or the concomitant oral AD, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.⁵
  • SPRAVATO nasal spray is not approved for use in pediatrics.⁶
• In postmarketing safety data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) and the SPRAVATO global medical safety database from 5 March 2019 to 5 January 2023, suicidal ideation was reported in 10.2% (249/2437) of serious adverse events (SAEs) and 47 deaths were reported due to suicides.⁷
• In an analysis of postmarketing safety data (March 2019 to first quarter 2020) using the Food and Drug Administration Adverse Event Reporting System (FAERS), suicidal ideation (n=64), suicidal attempt (n=6), and death by suicide (n=11) were reported as disease-related AEs.⁸ In another recent analysis using the FAERS database (first quarter of 2019 to the first quarter of 2023), suicidal ideation (n=456) and suicide attempt (n=140) were reported under SPRAVATO-related AEs.⁹

clinical data

Baseline Severity of Suicidality of Patients in ASPIRE-I and ASPIRE-II

The Clinical Global Impression of Severity of Suicidality- Revised Version (CGI-SS-R) summarizes the clinician’s overall impression of severity of suicidality on a 7-point scale from 0 (normal, not at all suicidal) to 6 (among the most extremely suicidal patients. Scores were based on answers to the following question: “Considering your total clinical experience with suicidal patients and all information now available to you, how suicidal is this patient at this time?” The majority of patients were rated as moderately to severely suicidal at baseline.^3,4

Treatment-Emergent Adverse Events Potentially Related to Suicidality in ASPIRE I and II:

The incidence of TEAEs potentially related to suicidality in completed phase 3 studies in patients with major depressive disorder (MDD) and active suicidal ideation with intent is summarized in Table: Treatment-Emergent Adverse Events Potentially Related to Suicidality in ASPIRE-I and ASPIRE-II.

Serious Adverse Event of Death by Suicide in SPRAVATO Clinical Studies in Patients with Major Depressive Disorder (MDD) and Active Suicidal Ideation with Intent

Of the 452 patients in the clinical program, 1 death due to suicide was reported in a patient previously treated with SPRAVATO during the follow-up phase of the ASPIRE-1 trial.³ See table: Serious Adverse Event of Death by Suicide in ASPIRE-I.

Postmarketing Safety Data

REMS Database

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies and a separate SPRAVATO global medical safety database (which includes AEs reported from the REMS) from 5 March 2019 to 5 January 2023.⁷ Of the 2,437 SAEs, suicidal ideation was reported in 10.2% (N=249) of cases. There were 47 (0.14%) deaths due to suicide among the 34,110 patients treated. For comparison, the rate of death by suicide was estimated to be 0.95% in a similar real-world epidemiological study of patients with TRD (n = 15,013) who were treated for an average of 4.2 years.¹⁰

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.⁸ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval. If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into four categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

There was a total of 2274 SPRAVATO-related AEs in 962 patients with 389 serious AEs. Suicidal ideation, suicide attempt, and death by suicide were identified as disease-related adverse events (see Table: Suicide-related Adverse Events).

The authors noted that 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.⁸ Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).¹¹

Another analysis conducted using the FAERS database for 5061 SPRAVATO-related AEs from the first quarter of 2019 to the first quarter of 2023 reported the occurrence of suicidal ideation and suicide attempts (see Table: Suicide-related Adverse Events).⁹

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 14 May 2024.