(esketamine)
Connect with us
Connect with us
This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.
SPRAVATO® (esketamine)
Medical Information
SPRAVATO - Serious Adverse Event - Death
Last Updated: 10/27/2025
SUMMARY
- A total of 15 deaths were reported in the SPRAVATO clinical trial program for treatment-resistant depression (TRD) and the clinical trial program for major depressive disorder (MDD) in patients with active suicidal ideation and intent.1
- 4 Study investigators assessed these deaths as either unrelated or doubtfully related to SPRAVATO. - Four of the deaths that occurred in the TRD development program were due to cardiovascular events or physical trauma resulting from accidents. One death was due to COVID-19-related pneumonia, 2 deaths due to COVID-19 infection, 2 deaths due to pneumonia, and 2 deaths due to unknown causes.1-4
- Three deaths in the SPRAVATO TRD development program were due to suicides, all occurring during open-label treatment. After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO.5
-9 - A death by suicide was reported in a patient previously treated with SPRAVATO in the follow-up phase of a trial in patients with MDD with active suicidal ideation and intent.2
, 10 Postmarketing safety data collected from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) program and Janssen US Global Medical Safety (US-GMS) database between 5 March 2019 and 5 January 2024, reported 228 deaths, of which 70 deaths were due to suicide. No deaths were attributed to SPRAVATO by the GMS medical team; however, not all cases could be adequately assessed.11 ,12 - In an analysis of postmarketing safety data for SPRAVATO (first quarter of 2004 to second quarter of 2023) from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, 218 deaths were reported, of which 83 were due to suicide. Limitations of the database preclude the ability to demonstrate causality.13
,14
CLINICAL trial DATA
Details of the deaths during SPRAVATO clinical trials can be found in the Table: Serious Adverse Events of Death. There were a total of 4 deaths by suicide. After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO. Additionally, safety data was reviewed every 6 months by an Independent Data Monitoring Committee (IDMC) to ensure the continuing safety of the patients enrolled in the phase 3 trials.6
Table: Serious Adverse Events of Death presents additional details regarding the deaths.
| Study | Age (years) /Gender | Narrative | Investigator’s Assessment of Relationship to SPRAVATO |
|---|---|---|---|
| TRANSFORM-2 (TRD; phase 3, short-term, double-blind trial) | 41; male | Experienced multiple injuries following a road traffic accident on day 16 of the double-blind phase (approximately 28 hours after receiving the last dose of SPRAVATO 84 mg) and subsequently died.16 | Not related |
| SUSTAIN-2 (TRD; phase 3, up to 1 year, open label safety trial) | 60; male | Died from acute cardiac and respiratory failure on day 113 of treatment with SPRAVATO 56 mg (event reported 5 days after last dose). Patient had medical history of hypertension and vein surgery.8 | Doubtful |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 73; female | Died from myocardial infarction 6 days after a dose of SPRAVATO 84 mg. Patient had medical history of controlled hypertension and hyperlipidemia.4 | Doubtful |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 59; male | Died from accidental polytrauma to the head, abdomen, and brain due to being hit by an automobile while riding a bicycle. Patient died on day 364 of the optimization/maintenance phase, 6 days after the last dose of SPRAVATO 56 mg.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 66; male | Died from COVID-19-related pneumonia 13 days after the last dose of SPRAVATO 84 mg.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 62; male | Died from pneumonia on day 1279 of treatment 13 days after the last dose of SPRAVATO 84 mg.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 60; male | Died from COVID-19 infection on day 1062 of treatment 24 days after the last dose of SPRAVATO 84 mg.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 60; male | Died from COVID-19 infection on day 1149 of treatment 15 days after the last dose of SPRAVATO 84 mg.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 58; male | Cause of death was unknown. The patient was found dead on day 1245 of treatment 8 days after the last dose of SPRAVATO 56 mg. The homeowner who reported the death to the investigator stated that the death was not a suicide. The investigator confirmed the patient was divorced and lived alone for some time, without active contact with his family. Prior to his death, the patient was drinking more, his diabetes was poorly controlled, and his depressed mood and suicidal ideation were not improving.4 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 66; female | Died from pneumonia on day 1968 of treatment 65 days after the last dose of SPRAVATO 28 mg.4 | Not related |
| ESCAPE-TRD (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 55; female | Cause of death was unknown. The patient died on the day of her last SPRAVATO 84 mg dose (day 64 of treatment). She had a medical history of hypertension and Type 2 diabetes. Her clinician cited pulmonary thromboembolism as a probable cause of death with hypertension as a risk factor.17 | Not related |
| Deaths due to suicide | |||
| SYNAPSE (TRD; Phase 2 Adjunctive Trial) | 41; male | Died due to suicide on day 45, 20 days after receiving the last dose of study medication during the follow-up phase of the study. During the 2- week double-blind treatment phase, the patient was in the placebo/ SPRAVATO 14-mg group, and during the OL phase he received 4 doses of SPRAVATO 56 mg.18 | Not related |
| SUSTAIN-2 (TRD; phase 3, long-term, open label safety trial) | 55; female | Died as a result of suicide (i.e., overdosed with zolpidem and oxazepam) on day 188, 12 days after receiving the last dose of SPRAVATO 84 mg.8 Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide.6,18 | Not related |
| SUSTAIN-3 (TRD; long-term, open-label safety extension trial) | 48; male | Died due to suicide on day 26 of the induction phase. The patient had been receiving SPRAVATO 84 mg with the last dose administered 4 days prior to the event.18 | Not related |
| ASPIRE-1 (MDD with active suicidal ideation and intent; phase 3, short-term, double-blind trial) | 53; female | Died due to suicide during the follow-up phase. The last dose of SPRAVATO 84 mg was received 3 days prior to the event. The investigator considered MDD, TRD with chronic passive and active suicidal ideation, and a history of 5 suicide attempts as the risk factors.2,10 | Not related |
| Abbreviations: COVID-19, coronavirus disease; MDD, major depressive disorder; TRD, treatment-resistant depression. | |||
Safety information was collected from SPRAVATO REMS patient monitoring forms completed by REMS 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 2024.11,12 Of the 1,486,213 administrations of SPRAVATO among 58,483 patients, 228 deaths were reported. The fatal cases included, 83 deaths not otherwise specified, 70 deaths by suicide, 6 overdose, 5 myocardial infarctions, 4 COVID-19 infections, 3 cases each of accidental overdoses, cardiac arrests, cerebrovascular accidents, diabetes mellitus, drug abuse, postprocedural complications, sepsis, and 2 cases each of multiple organ dysfunction syndrome, neoplasm malignant, road traffic accidents, and toxicity to various agents.
Additionally, there was 1 death each due to accident at work, alcohol abuse, alcohol use, aortic aneurysm, arteriosclerosis, brain injury, brain neoplasm malignant, Candida infection, cerebral hemorrhage, electrolyte imbalance, failure to thrive, fall, hallucination (auditory), hepatic cirrhosis, intentional overdose, intestinal obstruction, intestinal perforation, lung neoplasm malignant, multimorbidity, Parkinson’s disease, pneumonia, pulmonary embolism, substance abuse, cardiac disorder with sepsis and COVID-19, cardiovascular disorder with multiple organ dysfunction syndrome and cerebrovascular accident, toxicity to various agents with accidental overdose, hip fracture with gall, pneumonia with multiple organ dysfunction syndrome, suspected suicide with alcohol use, overdose with brain injury, and substance abuse with accidental overdose.
No deaths were attributed to SPRAVATO by the GMS medical team, however, not all cases could be adequately assessed. The approximate incidence of death was 0.6 per 100 patients-years, which was lower than the reported range of 0.79-4.6 per 100 patient-years among TRD patients not receiving SPRAVATO.11,19
An analysis of the FAERS database (first quarter of 2004 to second quarter of 2023) identified a total of 218 deaths reported for SPRAVATO. There were 57 deaths in females, 120 deaths in males, and 41 of unknown gender. Deaths by suicide were reported in 38 females and 45 males.13
The authors noted that confounding factors that may have affected results include age, gender, concomitant treatments, underlying conditions, and lifestyle. In addition, there may have been duplicate reports and inaccurate or incomplete data (e.g., medical history). Therefore, causality cannot be inferred.13,14 Although most reports were from the US, not all were reported within the US. The analysis was not limited to SPRAVATO nasal spray and could have included other formulations of SPRAVATO.13
Literature Search
A literature search of MEDLINE®
References
| 1 | |
| 2 | |
| 3 | |
| 4 | |
| 5 | |
| 6 | |
| 7 | |
| 8 | |
| 9 | |
| 10 | |
| 11 | |
| 12 | |
| 13 | |
| 14 | |
| 15 | |
| 16 | |
| 17 | |
| 18 | |
| 19 | |
| 20 |