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SPRAVATO® (esketamine)
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SPRAVATO - Adverse Event - Suicidal Ideation and Behavior in Treatment-Resistant Depression Clinical Trials

Last Updated: 03/24/2026

summary

  • Antidepressants (AD) increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. 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. SPRAVATO nasal spray is not approved for use in pediatrics.1,2
  • The Columbia-Suicide Severity Rating Scale (C-SSRS) was used to prospectively assess potential suicidal ideation and behavior in the SPRAVATO clinical trial program in patients with treatment-resistant depression (TRD). Patients with suicidal ideation were not excluded; however, patients with suicidal behavior in the past year and suicidal ideation with some intent to act in the previous 6 months were excluded.3-6
  • Across all phase 27 and phase 3 studies3-5,8-10 for TRD, suicidal ideation, assessed by C-SSRS, showed a decrease from baseline to endpoint in the SPRAVATO treatment groups. There was no evidence of association between SPRAVATO and increased risk of treatment-emergent suicidal ideation and behavior.11 See CLINICAL TRIAL DATA
  • There have been 3 completed suicides reported in the SPRAVATO clinical program for TRD.6,11,12 See Serious Adverse Events of Completed Suicide in Clinical Studies
  • Overall, across phase 27 and 3,3-5,8-10 suicidality-related AEs were uncommon, and most of the reported cases were those of suicidal ideation. Clinical review of suicidality-related treatment-emergent adverse events (TEAE) indicated that most of these events were likely associated with the underlying disease in the patient population studied.12 
  • 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. 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.13-16 
  • 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 adverse events.17 
  • In an analysis of postmarketing safety data using the FAERS database (from the first quarter of 2019 to the fourth quarter of 2023), 720 cases of suicidal ideation (reporting odds ratio [ROR], 52.93), 205 cases of suicide attempt (ROR, 18.55), 16 cases of self-injurious ideation (ROR, 22.51), 9 cases of suicidal depression (ROR, 11.53), and 3 cases of suicide threat (ROR, 28.22) were reported.18 

PRODUCT LABELING

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.19

BACKGROUND

The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess potential suicidal ideation and behavior during the SPRAVATO clinical trial program. It is a clinical interview providing a summary of both suicidal ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present.12

clinical Trial data

The overall incidence of TEAEs of suicidality in completed phase 3 studies is summarized in Table: Treatment-Emergent Adverse Events of Suicidality in Phase 3 Studies in TRD


Treatment-Emergent Adverse Events of Suicidality in Phase 3 and 4 Studies in TRD5,8-10,12,20a
Study
SPRAVATO (28 mg, 56 mg, or 84 mg) + AD
(%, n/N)
AD+PBO
(%, n/N)
Pooled TRANSFORM-1/2
0.9 (3/346)
0.9 (2/222)
TRANSFORM-3
1.4 (1/72)
-
SUSTAIN-1
   IND Phase
1.1 (5/437)
N/A
   OP Phase
0.2 (1/455)
-
   MA Phase
2.0 (3/152)
0.7 (1/145)
SUSTAIN-2
   IND Phase
2.4 (19/779)
N/A
   OP/MA
3.8 (23/603)
N/A
SUSTAIN-3
2.7 (31/1148)
N/A
Phase 4 Monotherapy study
2.2 (5/226)
1.2 (3/250)
Abbreviations: AD, oral antidepressant; IND, induction; MA, maintenance; N/A, not applicable; OP, optimization; PBO, placebo.aTEAEs of suicidality includes completed suicide, depression suicidal, intentional overdose, intentional self-injury, multiple drug overdose intentional, poisoning deliberate, self-injurious behaviour, self-injurious ideation, suicidal behaviour, suicidal ideation, suicide attempt. Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.Note: TRANSFORM-1 and TRANSFORM-2 were short-term, double-blind, 4-week studies in patients <65 years of age who received treatment twice a week (TRANSFORM-1 was fixed-dose and TRANSFORM-2 was flexible-dose); the table reports pooled results from both studies; TRANSFORM-3 was a short-term, double-blind, flexible-dose, 4-week study in patients ≥65 years who received treatment twice a week.
SUSTAIN-1 was a long-term, randomized withdrawal study to assess the efficacy of flexibly-dosed SPRAVATO+AD compared with AD+PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO+AD. Patients received treatment twice a week during the initial 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (optimization phase was the following 12 weeks followed by the maintenance phase).
SUSTAIN-2 was an open-label, flexibly-dosed study to evaluate the long-term safety of SPRAVATO+AD. Patients received treatment twice a week for the first 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (48-week optimization/maintenance phase). Note: no comparator data is available based on the open-label design.SUSTAIN‑3 was a phase 3, long‑term, open‑label extension study designed to assess the ongoing safety and efficacy of treatment with SPRAVATO+AD. Participants entered a 4‑week induction period (when applicable), followed by an extended optimization/maintenance phase with flexible treatment duration. Note: no comparator data is available based on the open-label and single‑arm study design. Phase 4 Monotherapy study consisted of a 4-week double-blind period followed by a 3-month OL period. Patients were randomized to SPRAVATO 56 mg or 84 mg or placebo. During the OL period, all patients received SPRAVATO, including those who had previously received placebo. Use of adjunctive antidepressants and antipsychotics was allowed during the OL treatment phase.

Postbaseline Suicidal Ideation based on C-SSRS in SPRAVATO Combination Studies

Prior to screening, between 25% and 37% of patients across phase 3 studies/treatment groups had a lifetime history of suicidal ideation, and 14% to 19% had a lifetime history of suicidal behavior.12 During the double-blind period of phase 3 clinical trials of SPRAVATO in TRD,3-5,8,9 the proportion of patients with no suicidal ideation at baseline who went on to report suicidal ideation at any time point postbaseline was similar in the SPRAVATO+AD group and in the AD+PBO group.11 See Table: Postbaseline Reported Treatment-Emergent Suicidal Ideation (Based On C-SSRS) in Patients with No Ideation at Baseline


Postbaseline Reported Treatment-Emergent Suicidal Ideation (Based on C-SSRS) in Patients with No Ideation or Behavior at Baseline5,8-11a
Study
SPRAVATO (28 mg, 56 mg, or 84 mg) + AD
(%, n/N)
AD+PBO
(%, n/N)
Pooled TRANSFORM-1/2
10.2 (26/254)
12.3 (20/162)
TRANSFORM-3
13.8 (8/58)
16.7 (9/54)
SUSTAIN-1
   IND Phase
11.3 (41/362)
N/A
   OP Phase
5.7 (22/387)
-
   MA Phase
2.4 (3/126)
 4.5 (6/133)
SUSTAIN-2
   IND Phase
11.1 (71/637)
N/A
   OP/MA
11.6 (59/509)
N/A
SUSTAIN-3
1.0 (11/1148)
N/A
Abbreviations: AD, oral antidepressant; IND, induction; MA, maintenance; N/A; not applicable; OP, optimization; PBO, placebo.
aFor each study, each subject is counted only once in the above table, based on the most severe postbaseline C-SSRS category
Note: TRANSFORM-1 and TRANSFORM-2 were short-term, double-blind, 4-week studies in patients <65 years of age who received treatment twice a week (1 was fixed-dose and 2 was flexible-dose); the table reports pooled results from both studies; TRANSFORM-3 was a short-term, double-blind, flexible-dose, 4-week study in patients ≥65 years who received treatment twice a week.
SUSTAIN-1 was a long-term, randomized withdrawal study to assess the efficacy of flexibly-dosed SPRAVATO+AD compared with AD+PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO+AD. Patients received treatment twice a week during the initial 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (optimization phase was the following 12 weeks followed by the maintenance phase).
SUSTAIN-2 was an open-label, flexibly-dosed study to evaluate the long-term safety of SPRAVATO+AD. Patients received treatment twice a week for the first 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (48-week optimization/maintenance phase). Note: No comparator data is available based on the open-label design.SUSTAIN‑3 was a phase 3, long‑term, open‑label extension study designed to assess the ongoing safety and efficacy of treatment with SPRAVATO+AD. Participants entered a 4‑week induction period (when applicable), followed by an extended optimization/maintenance phase with flexible treatment duration. Note: no comparator data is available based on the open-label and single‑arm study design.

Postbaseline Suicidal Ideation based on C-SSRS in SPRAVATO Monotherapy Study

At screening, 46% (174/378) of patients reported a lifetime history of suicidal ideation, and 24.1% (91/378) reported a lifetime history of suicidal behavior.20 In the double-blind phase, treatment‑emergent suicidal ideation occurred in 6.7% (7/105) of patients treated with 56 mg SPRAVATO and 6.6% (8/121) of those receiving 84 mg, compared with 9.6% (24/250) of patients in the placebo arm.20 During the open-label phase 10% (44/441) of patients experienced treatment-emergent suicidal ideation.21 

Postbaseline Suicidal Behavior Based on C-SSRS in SPRAVATO Combination Studies

In patients who did not have suicidal ideation or behavior at baseline across the phase 3 trials, 5 patients treated with SPRAVATO+AD were assessed to have suicidal behavior at any time postbaseline:11

  • In SUSTAIN-1: 1 (0.3%) patient in the open label IND phase5,11
  • In SUSTAIN-2 (open label study): 2 (0.3%) patients in IND phase and 2 (0.4%) patients in the OP/MA phase9,11

In patients who had suicidal ideation at baseline, 5 were observed to have postbaseline suicidal behavior:

  • In the 2 short-term studies in patients <65 years of age: 1 (1.2%) patient3,4,12
  • In the long-term safety study: 2 (1.6%) patients in the IND phase and 2 (2.2%) patients during the OP/MA phase,9,12

All patients who reported suicidal behavior during the phase 3 trials based on C-SSRS had a lifetime history of suicidal ideation or suicidal behavior.12

Postbaseline Suicidal Behavior Based on C-SSRS in SPRAVATO Monotherapy Study

Suicidal behavior occurred in two patients during the double‑blind phase, with one case in each SPRAVATO dosage group (56 mg and 84 mg).20 In the open‑label phase, suicidal behavior was reported in one patient who had suicidal ideation at baseline.21 

SAEs of Completed Suicides in Clinical Studies

Although death by suicide is always tragic, in the SPRAVATO TRD development program, the suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22-1.00) completed suicides per 100 patient-years reported in a different study in a TRD population.22,23 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.24,25

There have been 3 completed suicides in the SPRAVATO clinical program for TRD, including in an ongoing phase 3 trial.6,11, 12 See Table: Serious Adverse Events of Completed Suicides in Clinical Studies of SPRAVATO in TRD


Serious Adverse Events of Completed Suicides in Clinical Studies of SPRAVATO in TRD11,12
Study
Age (years) /Gender
Narrative
Investigator’s Assessment of Relationship to SPRAVATO
SYNAPSE
(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 open-label phase he received 4 doses of SPRAVATO 56 mg.12
Not related
SUSTAIN-2
(Phase 3, long-term, open label safety trial)
55; female
Died due to suicide (ie, overdosed with zolpidem and oxazepam) on day 188, 12 days after receiving the last dose of SPRAVATO 84 mg.9 Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide.12,24
Not related
SUSTAIN-3
(Long-term, open-label safety extension trial)
48; male
Died due to a 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.26 
Not related

McIntyre et al (2024)27 conducted a secondary safety and tolerability analysis of the ESCAPE-TRD28 study, a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO (n=334) vs quetiapine extended-release (QUE-XR; n=336) for the treatment of TRD. Treatment-emergent suicidal ideation was reported in 5 patients (1.5%) in the SPRAVATO group and 7 patients (2.1%) in the QUE-XR group. Treatment-emergent suicide attempts were reported in 2 patients (0.6%) in the SPRAVATO group and 1 patient (0.3%) in the QUE-XR group.

postmarketing safety data

SPRAVATO REMS and Janssen US-GMS Database

Sancora et al (2025)13 evaluated safety information 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 2024.14 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.13,15,16 

EudraVigilance Database

Ammendolia et al (2025)17 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 SPRAVATO‑related 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. Within the serious cases, there were 17 completed suicides (6.4%), 26 cases of suicidal ideation (9.8%), and 14 cases of suicide attempt (5%). 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=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. When compared to fluoxetine, there were significant increased potential risks with SPRAVATO use in 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 case reports, 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)

Liu et al (2024),18 using data from the FAERS database, conducted an analysis of 14,606 SPRAVATO-related AEs reported in 6887 patients between the first quarter of 2019 and the fourth quarter of 2023. See Table: Suicide-related Adverse Events


Suicide-related Adverse Events18 
Adverse Event
n
Reporting Odds Ratio
(95% CI)
Proportional Reporting Ratio
(95% CI)
Empirical Bayes Geometric Mean
(EBGM)
Suicidal ideation
720
52.93
(48.95-57.23)
47.50
(44.28-50.96)
46.18
(42.71)
Suicidal attempt
205
18.55
(16.13-21.33)
18.03
(15.74-20.65)
17.84
(15.51)
Self-injurious ideation
16
22.51
(13.73-36.88)
22.46
(13.72-36.76)
22.17
(13.53)
Suicidal depression
9
11.53
(5.98-22.23)
11.52
(5.98-22.18)
11.45
(5.94)
Suicide threat
3
28.22
(9.01-88.39)
28.21
(9.01-88.31)
27.75
(8.86)

Limitations of the FAERS database are similar to the above Eudravigilance database.29 

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 21 January 2026.

 

References

Show
1 Center for Drug Evaluation and Research. Summary Review. NDA 211243 - SPRAVATO (esketamine) - Reference ID: 4398871. 2019- [cited 2024 April 15]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000SumR.pdf
2 United States Food & Drug Administration. Suicidality in children and adolescents being treated with antidepressant medications. 2018- [cited 2024 April 15]. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications
3 Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.  
4 Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.  
5 Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.  
6 European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). SPRAVATO assessment report. Procedure No. EMEA/H/C/004535/0000. 2019- [cited 2025 September 08]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf
7 Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: results of a double-blind, doubly-randomized, placebo-controlled study. JAMA Psychiatry. 2018;75(2):139-148.  
8 Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141.  
9 Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891.  
10 Zaki N, Chen L, Lane R, et al. Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study. Int J Neuropsychopharmacol. 2025;28(6):pyaf027.  
11 Hough D. Esketamine. United States Food & Drug Administration February 2019 presentation- [cited 2025 April 16]. Available from: https://web.archive.org/web/20191215093404/https://www.fda.gov/media/121379/download
12 Data on File. Esketamine. Integrated Summary of Safety - TRD. Janssen Research & Development, LLC. EDMS-ERI-155147726, 1.0; 2018.  
13 Sanacora G, Ahmed M, Brown B, et al. Real-world safety of esketamine nasal spray: a comprehensive analysis almost 5 years after first approval. Am J Psychiatry. 2025;182(10):913-921.  
14 Sanacora G, Ahmed M, Brown B, et al. Supplement to: Real-world safety of esketamine nasal spray: a comprehensive analysis almost 5 years after first approval. Am J Psychiatry. 2025;182(10):913-921.  
15 Kern DM, Canuso CM, Daly E, et al. Suicide-specific mortality among patients with treatment-resistant major depressive disorder, major depressive disorder with prior suicidal ideation or suicide attempts, or major depressive disorder alone. Brain Behav. 2023;13(8).  
16 Bergfeld IO, Mantione M, Figee M, et al. Treatment-resistant depression and suicidality. J Affect Disorders. 2018;235:362-367.  
17 Ammendolia I, Mannucci C, Esposito E, et al. Safety profile and suicidality associated with the use of esketamine in the treatment of major depressive disorder in european countries: an eudravigilance database analysis. Pharmaceuticals (Basel). 2025;18(5):702.  
18 Liu R, Liu C, Feng D, et al. Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database. Front Pharmacol. 2024;15:1414703.  
19 SPRAVATO (esketamine) nasal spray [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf
20 Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression a randomized clinical trial. JAMA Psychiatry. 2025;82 (9):877-887.  
21 Janik A, Qiu X, Lane R, et al. Supplement to: Esketamine monotherapy in adults with treatment-resistant depression a randomized clinical trial. JAMA Psychiatry. 2025;82(9):877-887.  
22 Bergfeld IO, Mantione M, Figee M, et al. Treatment-resistant depression and suicidality. J Affect Discord. 2018;235:362-367.  
23 Drevets WC, Singh J, Hough D, et al. Letter to the editor: Comment on a word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(10):856-857.  
24 Data on File. Esketamine. Clinical Study Report ESKETINTRD3004. Janssen Research & Development, LLC. EDMS-ERI-146551506; 2018.  
25 Data on File. Esketamine. Clinical Study Report ESKETINTRD3002. Janssen Research & Development, LLC. EDMS-ERI-149600979.; 2018.  
26 Zaki N, Chen L, Lane R, et al. Supplement to: Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study. Int J Neuropsychopharmacol. 2025;28(6):pyaf027.  
27 McIntyre RS, Bitter I, Buyze J. Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression. Eur Neuropsychopharmacol. 2024;85:58-65.  
28 Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389(14):1298-1309.  
29 FDA Adverse Event Reporting System (FAERS) Public Dashboard. Accessed 2025-09-08. Available via: https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard