Adverse Events of SPRAVATO - Suicidal Ideation and Behavior in Clinical Trials of Major Depressive Disorder and Active Suicidal Ideation with Intent

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
• Postmarketing safety data collected from the Janssen US Global Medical Safety (US-GMS) database, which included data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) program between 5 March 2019 and 5 January 2024, reported suicidal ideation in 11.2% (447/3985) of cases, with an incidence of 1.8% (70/3985) for death by suicide.^7,8 
• Postmarketing EudraVigilance data collected between 1 January 2019 to 31 December 2024, identified a total of 751 individual case safety reports (ICSRs) with 17 completed suicides, 26 cases of suicidal ideation, and 14 suicide attempts among serious SPRAVATO-related AEs.⁹ 
• 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.¹⁰ 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.¹¹

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

SPRAVATO REMS and Janssen US-GMS Database

Safety information was collected from SPRAVATO REMS patient monitoring forms completed by certified US healthcare settings and pharmacies, as well as reports submitted to the Janssen US-GMS database (which includes AEs submitted from REMS and other sources) between 5 March 2019 and 5 January 2024.^7,8  There were 2096 serious adverse events reported from REMS data, of which 3.6% (n=76) involved suicidal ideation. A total of 3985 serious adverse events were reported in the US-GMS Database. Of these, suicidal ideation was reported in 11.2% (n=447) of events. There were 131 cases of fatal or life-threatening suicidality-related events that were further categorized into death by suicide (n=70), suicidal ideation (n=30), suicide attempt (n=21), accidental overdose (n=3), intentional overdose (n=3), toxicity due to various agents (n=2), intentional self-injury (n=1), and suspected suicide (n=1). Latency data was available in 52 of the 70 patients who died by suicide, and in half (n=26) of patients, suicide reportedly occurred within 1 week of the most recent dose. The rate of deaths by suicide was 0.18 per 100 patient-years. Comparatively, a real-word retrospective study and a meta-analysis including 28 studies found rates of 0.14 and 0.47 per 100 patient-years, respectively.^7,12,13 

EudraVigilance Database

Ammendolia et al (2025)⁹ conducted an analysis of the EudraVigilance database, which includes reports from countries in the European Economic Area and the United Kingdom, identified 751 ICSRs of SPRAVATOrelated adverse reactions from 1 January 2019 to 31 December 2024. Of the total reported cases, 265 (35.3%) were classified as serious, with 27 of these cases attributed to death. Among the serious cases, there were 17 completed suicides (6.4%), 26 cases of suicidal ideation (9.8%), and 14 cases of suicide attempt (5.3%). Additional analyses were performed to examine differences in suicide-related outcomes by sex, age, and other antidepressant use. Comparisons between males and females showed a higher incidence of suicidal ideation in females (65.4% [n=17] vs 34.6% [n=9]; P=not significant (NS)) and suicide attempt (78.6% [n=11] vs 21.4% [n=3]; P=NS), whereas completed suicide was more common among males (70.6% [n=12] vs 29.4% [n=5]; P=0.005). Although suicidal AEs occurred more frequently in patients aged 18-64 than in those 65-85, no significant differences were found. There were significant increased potential risks with SPRAVATO use compared to fluoxetine for suicidal ideation (ROR, 2.94; 95% CI, 1.75-4.94) and completed suicide (ROR, 8.05; 95% CI, 3.55-18.3). Similar findings were observed in comparison between SPRAVATO and venlafaxine for suicidal ideation (ROR, 5.25; 95% CI, 3.15-8.73) and completed suicide (ROR, 10.58; 95% CI, 5.08–22.04).  

Limitations of the EudraVigilance database include the absence of denominators, the possibility of missed or duplicate cases, variability in the quality of information provided, and the inability to infer causality. Patients who received SPRAVATO may have had more severe depression than those who received SSRIs, and suicidality may be a result of the disease.

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹⁰ 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.¹⁰ Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).¹⁴

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).¹¹

Limitations of the FAERS database are similar to the above Eudravigilance database.¹⁵ 

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 01 April 2026.