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SPRAVATO® (esketamine)

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Real World Evidence – Effectiveness and Safety of SPRAVATO With Outcomes Over 12+ Months

Last Updated: 06/19/2026

SUMMARY

A retrospective analysis of the Mindful Health Solutions (MHS) database observed clinically meaningful improvement in Montgomery-Åsberg Depression Rating Scale (MADRS; mean reduction of ≥6 points) scores within 4 weeks of treatment with SPRAVATO in patients with TRD, including a subgroup with moderate-to-severe depression (baseline MADRS score ≥28).¹
Retrospective analyses of the MHS database with a transcranial magnetic stimulation (TMS)-naïve subgroup of patients with TRD indicated that while prior TMS experience does not affect the response² and remission² or effectiveness³ of SPRAVATO, TMS-naïve patients may improve faster than those previously receiving TMS.
Real-world analyses of the Komodo database found that the median time to substantial clinical improvement (PHQ-9 reduction of ≥6 among those with baseline score ≥6) was 4.4 months. Per Kaplan-Meier analyses, the probability of achieving this improvement at 12 months was 71%.⁴
A retrospective analysis of the MHS database observed clinically meaningful improvement in the PHQ-9 (mean reduction of ≥3 points) after 32 treatment sessions with SPRAVATO in patients with TRD, including a subgroup with comorbid anxiety and a subgroup with more severe baseline depression (PHQ-9 ≥10).⁵
In a cohort of 78 patients assessed at 6 and 12 months (REAL-ESK study), 76.2% of patients were responders/remitters at 6 months and of those who continued treatment to 12 months (n=19), 78.9% of patients were responders/remitters. Overall, 71.8% and 42% of patients reported ≥1 AE at 6 months and 12 months, respectively.⁶
The ESKALE study, a retrospective analysis of real-world clinical practice in France, reported that during the 12-month follow-up period, 64.6% (93/144) of patients achieved a clinical response after a median of 3.1 weeks of treatment with SPRAVATO.⁷
A real-world retrospective study analyzed physician-reported data from 94 patients with depression, including patients with TRD and MDD with suicidal ideation, who received SPRAVATO from July 2022 to February 2023. A majority of prescribers (80%) reported high satisfaction with SPRAVATO to reach patient treatment goals.⁸
Postmarketing safety data from the US Risk Evaluation and Mitigation Strategies (REMS) and US cases from the Janssen Global Medical Safety database (US-GMS) from 5 March 2019 to 5 January 2024, was consistent with the established safety profile of SPRAVATO and did not identify new safety signals.⁹ Sedation and dissociation were the most commonly reported AEs; the majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period. Other analyses using the FDA Adverse Event Reporting System (FAERS) were also conducted to identify safety signals.¹⁰

clinical studies

Studies have been conducted to evaluate the real-world safety and efficacy of SPRAVATO in patients with TRD. Outcomes following treatment with SPRAVATO over 12+ months have been summarized below in Table: SPRAVATO Real-World Effectiveness and Safety Study Summaries with Outcomes At 12+ Months

SPRAVATO Real-World Effectiveness and Safety Study Summaries with Outcomes Over 12+ Months

Study Design	Results
Studies Conducted in the US
Marton et al (2024)¹ conducted a real-world, retrospective study to evaluate the effectiveness of SPRAVATO in patients with TRD based on MADRS data and compare findings to trial results. MADRS scores were collected from 05/02/2018 to 01/15/2024 or the end of treatment in 4-week intervals. Data Source: De-identified patient data (including demographic information, SPRAVATO treatment details, and MADRS scores) from MHS clinics collected between the prespecified index date range. Index Date: Date of initiation of SPRAVATO treatment Inclusion Criteria: Adults with TRD who initiated SPRAVATO between 03/05/2019 and end of data and had ≥1 baseline MADRS score Subgroup: Patients with moderate-to-severe depression (MADRS score ≥28) Outcome Measures: Response was defined as a MADRS score decrease from baseline by ≥50% Remission was defined as a MADRS score <12	Patient Characteristics The overall cohort included 853 patients, of which 727 (85.2%) had a baseline MADRS score ≥28. Mean age of the overall cohort at the index date was 43.8 years and of the baseline MADRS score ≥28 subgroup was 43.6 years; 57.3% and 57.4% of patients were females in the overall cohort and in the subgroup, respectively. Mean Change from Baseline MADRS Score Mean duration of follow-up: overall cohort, 12.9 months; baseline MADRS score ≥28 subgroup, 12.3 months Mean number of SPRAVATO sessions: overall cohort, 26.2; baseline MADRS score ≥28 subgroup, 26.4 Mean decrease in MADRS scores from baseline in the overall cohort and the baseline MADRS score ≥28 subgroup was, respectively: After 4 weeks: 6.8 points (95% CI, -7.7 to -6.0; P<0.001) and 7.7 points (95% CI, -8.7 to -6.7; P<0.001) After 8 weeks: 12.9 points (95% CI, -13.8 to -11.9; P<0.001) and 13.5 points (95% CI, -14.6 to -12.5; P<0.001) After 28 weeks: 15.5 points (95% CI, -17.4 to -13.3; P<0.001) and 18.7 points (95% CI, -20.5 to -17.0; P<0.001) After 52 weeks: 17.7 points (95% CI, -20.3 to -15.4; P<0.001) and 19.6 points (95% CI, -22.3 to -17.1; P<0.001) Time to Response and Remission in the Subgroup (Baseline MADRS Score ≥28) at 12 Months After the Index Date The probability of response was 79.4%, and the median time to response was 3.7 months. The probability of remission was 52.7%, and the median time to remission was 10.2 months.
Marton et al (2024)² and Marton et al (2024)³ were retrospective observational studies that used PHQ-9 scores to evaluate response and remission² to SPRAVATO and effectiveness and persistence³ of treatment with SPRAVATO in patients with TRD, with or without exposure to previous TMS therapy. Data Source²^,³: De-identified patient data (including demographic information, SPRAVATO and TMS treatment details, and PHQ-9 scores) from MHS clinics collected between 05/02/2018 and 01/15/2024 Inclusion Criteria²^,³: Adults with TRD who initiated SPRAVATO between 03/05/2019 and end of data and had ≥1 baseline PHQ-9 score Index Date²^,³: Date of initiation of SPRAVATO treatment Subgroup²^,³: TMS-naïve patients (without a history of TMS treatment before or on the index date) Outcome Measures: Response was defined as PHQ-9 score decrease from baseline by ≥50% and was assessed among patients with a baseline PHQ-9 score ≥10.² Remission was defined as PHQ-9 score <5 and was assessed among patients with a baseline PHQ-9 score ≥5.² Persistence was defined as absence of gaps >60 days between consecutive SPRAVATO treatment sessions or the end of follow-up; discontinuation date was the date of the last treatment session before the >60-day gap.³	Patient Characteristics²^,³ Overall cohort included 911 patients, of which 512 (56.2%) were TMS-naïve Average age of the overall cohort at the index date was 43.7 years, and that of the TMS-naïve subgroup was 42.6 years; 56.6% and 54.3% of patients were females in the overall cohort and TMS-naïve subgroup, respectively. Mean duration of follow-up: overall cohort, 12.8 months; TMS-naïve subgroup, 12.5 months Mean number of SPRAVATO sessions: overall cohort, 24.9; TMS-naïve subgroup, 23.8 Response and Remission Outcomes² Probability of achieving response 12 months after index date: overall cohort, 69.6%; TMS-naïve subgroup, 75.4% Median time to response: overall cohort, 3.6 months; TMS-naïve subgroup, 2.5 months Probability of achieving remission 12 months after index date: overall cohort, 37.3%; TMS-naïve subgroup, 44.3% Median time to remission: overall cohort, not reached; TMS-naïve subgroup, 15.1 months Effectiveness Over Time and Persistence³ Mean decrease in PHQ-9 scores from baseline in the overall cohort and the TMS-naïve subgroup was, respectively: After 8 sessions: 4.0 points (95% CI, -4.4 to -3.5; P<0.001) and 4.4 points (95% CI, -5.1 to -3.8; P<0.001) After 12 sessions: 4.6 points (95% CI, -5.0 to -4.0; P<0.001) and 4.9 points (95% CI, -5.7 to -4.3; P<0.001) After 28 sessions: 5.7 points (95% CI, -6.6 to -5.0; P<0.001) and 5.8 points (95% CI, -6.9 to -4.9; P<0.001) After 52 sessions: 5.9 points (95% CI, -7.5 to -4.3; P<0.001) and 6.0 points (95% CI, -8.1 to -3.6; P<0.001) The median persistent time on SPRAVATO in the overall cohort was 7.2 months, and in the TMS-naïve subgroup was 7.5 months. The persistence rate of SPRAVATO at 12 months in the overall cohort was 37.0%, and in the TMS-naïve subgroup was 36.3%.
Clemens et al (2024)⁴ was a retrospective observational study of real-world SPRAVATO use evaluating the effectiveness of SPRAVATO treatment in US patients with TRD. TRD was defined by the receipt of ≥2 unique ADs of adequate dose and duration in the same MDE during which SPRAVATO was initiated. Data Source: De-identified closed health insurance claims data from Komodo Research Database and PHQ-9 scores from Komodo Clinical Observations Database (01/2016-06/2023) Key Inclusion Criteria: Adults with ≥1 diagnosis of MDD and evidence of TRD before index date who initiated SPRAVATO treatment during the intake period (03/05/2019-end of data). Patients were expected to have ≥1 PHQ-9 score(s) during the baseline period or on the index date and during the follow-up period while still on SPRAVATO treatment (for up to 30 days after the last SPRAVATO claim). Index Date: Date of SPRAVATO initiation Baseline Period: 12 months prior to index date Follow-up Period: index date to date of final data availability or end of continuous healthcare insurance eligibility Subgroup: Patients with moderate-to-severe depression (PHQ-9 ≥10)	Patient Characteristics In the overall cohort (N=103), the mean age of patients was 41.5 years; 65.0% were females. Of the 103 patients, 80 had a baseline PHQ-9 score ≥10 (mean age, 41.0 years; females 66.3%). Mean baseline PHQ-9 in the overall cohort was 15.1 and 18.1 in the subgroup. Reduction in Depression Severity The mean follow-up period and mean number of ESK sessions were 17.0 months and 19.7 in the overall group and 15.7 months and 21.7 in the subgroup, respectively. The reduction in mean PHQ-9 score from baseline to follow-up was statistically significant in the overall cohort (mean difference, -3.93; 95% CI, -5.11 to -2.72; P<0.001) as well as in the subgroup with baseline PHQ-9 ≥10 (mean difference, -5.36; 95% CI, -6.73 to -4.13; P<0.001). The decline was more substantial in patients who completed the ESK induction phase. From baseline to follow-up, proportion of patients with moderately severe to severe depression significantly reduced from 55.3% to 30.1% in the overall cohort (OR, 0.35; 95% CI, 0.24-0.51; P <0.001) and from 71.3% to 38.8% in the subgroup (OR, 0.26; 95% CI, 0.16-0.42; P<0.001). Time to Substantial Clinical Improvement Per Kaplan-Meier analyses, the probability of achieving substantial clinical improvement (PHQ-9 reduction of ≥6 among those with baseline score ≥6) at 12 months following SPRAVATO initiation was 71.0% and 81.8% in the overall cohort and subgroup, respectively. Median time to substantial clinical improvement was 4.4 months in the overall cohort and 2.8 months in the subgroup.
Guo et al (2024)⁵ conducted a retrospective observational study to assess the effectiveness of SPRAVATO for TRD in real-world conditions. Data Source: De-identified patient data (including demographic information, SPRAVATO treatment details, and PHQ-9 scores) from MHS clinics collected between 05/02/2018 and 01/15/2024 Inclusion Criteria: Adults with TRD who initiated SPRAVATO between 03/05/2019 and end of data at a MHS clinic and had ≥1 baseline PHQ-9 score Index Date: Date of initiation of SPRAVATO treatment Subgroups: Patients with comorbid anxiety diagnosed before or on the index date Patients with moderate-to-severe depression (baseline PHQ-9 score ≥10)	Patient Characteristics PHQ-9 score analysis (overall ESK cohort, N=911; comorbid anxiety subgroup, n=624; baseline PHQ-9 score ≥10 subgroup 2, n=773). Average age of the overall ESK cohort at index date was 43.7 years; 56.6% of patients were females. Overall ESK Cohort Mean duration of follow-up: 12.8 months Mean number of ESK sessions: 24.9 Mean baseline PHQ-9: 16.3 Mean reduction in PHQ-9 score after 8 sessions (induction completion): 4.0 (95% CI, -4.4 to -3.5; P<0.001) Mean reduction in PHQ-9 score after 32 sessions: 6.1 (95% CI, -6.9 to -5.2; P<0.001) Percentage of patients with severe depression at baseline vs after 8 sessions vs after 32 sessions: 32.2% vs 17.5% vs 9.5% Comorbid Anxiety Subgroup Mean duration of follow-up: 13.8 months Mean number of ESK sessions: 26.2 Mean baseline PHQ-9: 16.3 Mean reduction in PHQ-9 score after 8 sessions (induction completion): 3.8 (95% CI, -4.3 to -3.4; P<0.001) Mean reduction in PHQ-9 score after 32 sessions: 5.9 (95% CI, -7.1 to -4.8; P<0.001) Percentage of patients with severe depression at baseline vs after 8 sessions vs after 32 sessions: 31.9% vs 17.3% vs 10.3% Baseline PHQ-9 Score ≥10 Subgroup Mean duration of follow-up: 12.9 months Mean number of ESK sessions: 26.3 Mean baseline PHQ-9: 18.1 Mean reduction in PHQ-9 score after 8 sessions (induction completion): 4.5 (95% CI, -4.9 to -4.0; P<0.001) Mean reduction in PHQ-9 score after 32 sessions: 7.0 points (95% CI, -7.8 to -6.1; P<0.001) Percentage of patients with severe depression at baseline vs after 8 sessions vs after 32 sessions: 37.9% vs 19.3% vs 9.8%. Continued improvement was seen in the overall cohort as well as in the subgroups over the 32 treatment sessions.
Studies Conducted Outside of the US
Rosso et al (2025)⁶ was a real-world, retrospective analysis (REAL-ESK) of 78 adult patients with TRD treated with SPRAVATO, using assessment scores from MADRS and HAM-A at baseline (T0) and at the 6-month (T1) and 12-month (T2) follow-up. Response was defined as a 50% reduction from baseline in the MADRS score, and remission was defined as MADRS score <10. Inclusion Criteria Adults (≥18 years old) with TRD No response to ≥2 different ADs. Being treated with SSRI/SNRI for which SPRAVATO was considered appropriate. Exclusion Criteria Patients with comorbid organic pathologies (untreated arterial hypertension or previous cerebrovascular disorders) that were considered contraindications for SPRAVATO. Diagnosis of bipolar disorder or psychotic disorders	Patient Demographics and Characteristics The mean (±SD) age was 51.8 (±12.6) years; 55.1% of patients were female. The mean duration of the current MDE was 15.6 months; the average number of previous episodes was 5.2. Six-Month and Twelve-Month Treatment Outcomes At 6 months, 63 patients continued SPRAVATO treatment; of those patients, 48 (76.2%) of were responders/remitters. Among 15 non-responders at 6 months, 4 showed improvement at 12 months. Between 6 and 12 months, 44 patients discontinued, mainly due to clinical remission (63.6%) and unknown reasons (29.5%) Of the 19 patients that continued treatment for 12 months, 15 (78.9%) were responders/remitters. The mean (±SD) MADRS score significantly decreased from baseline (34.9±9.9) to 6 months (11.7±9.5; P<0.001) and remained stable at 12 months (11.6±9.9). The mean (±SD) HAM-A score also declined from baseline (34.1±8.4) to 6 months (13.8±10.3) and further to 12 months (11.0±9.8; P<0.001). Factors associated with better outcomes at 6 months included a shorter episode current MDE duration (12.1 vs 21.3; P=0.003), fewer psychiatric comorbidities (35.4% vs 73.3%; P=0.010). Psychiatric comorbidities were present in 47.4% of patients and included anxiety disorders (29.7%), personality disorders (21.7%), OCD and PTSD (16.2% each), and others. Most patients experienced treatment failure in ≥3 prior AD treatments and many were receiving combination of treatment: 46.3% on combinations of ADs and/or 46.2% antipsychotics, and/or 57.7% on mood stabilizers. Safety At 6 months, 71.8% of patients reported at least 1 AE, most commonly sedation (31.7%) and dissociation (28.6%). At 12 months, AEs were reported by 42% of patients who continued treatment.
Samalin et al (2024)⁷ was a real-world retrospective study of adult (≥18 years old) patients in France with moderate to severe TRD, defined as non-responsive to ≥2 oral ADs (ESKALE study). Study Design: Patients who initiated on SPRAVATO from October 2019 to July 2021 were included and data was collected over a 12-month period after SPRAVATO initiation up to June 2022.	Patient Demographics and Characteristics A total of 157 patients were included, in which 112 (71.3%) completed the 12-month follow-up. The mean (SD) age of the patients was 49.1 (15.8) years, and 66.2% were female; 82.8% were <65 years of age. Mean MADRS total score (SD) at baseline was 32.1 (7.7) in 144 evaluable patients. Concomitant treatments during SPRAVATO initiation: AD(s): 93.6% (SNRI, 65.0% and SSRI, 57.3%) Potentiation strategy: 63.1% (second-generation antipsychotics, 36.3%; lithium, 25.5%; and antiepileptics, 21.7%) No ADs: 6.4% The overall treatment period lasted a median duration of (IQR) 19.4 (4.4-40.1) weeks, with 77.7% (n=122) of patients reaching the first maintenance phase at 5-8 weeks. 37.6% of patients permanently discontinued SPRAVATO during a 6-month treatment period, while 79.6% stopped during the follow-up phase after a median period (IQR) of 13.1 (4.1-26.1) weeks. Effectiveness Of the 144 (91.7%) patients included in the response analysis, 93 (64.6%) reached a clinical response (defined as ≥50% improvement in MADRS total score from treatment initiation) during the 12-month follow-up period (after a median time [IQR], 3.1 [1.1-5.7] weeks). The Kaplan-Meier estimation of the median time to response in the overall population was 5.7 weeks (95% CI, 4.1-8.4). Of the patients still receiving SPRAVATO at the end of the 1-month induction phase (n=127), 40.2% of patients achieved a clinical response, with 19.7% in remission from MDE. Among patients still receiving SPRAVATO at month 3, 56.2% achieved a clinical response, and 43.8% were in remission from MDE. Of the 92 (73.6%) patients who permanently discontinued SPRAVATO and had an available MADRS score, 45.7% and 35.9% achieved response and remission, respectively. Safety Over the study period, 66.2% (n=104) of the patients reported ≥1 AE, including dissociation (34.4%), somnolence (15.9%), vertigo (15.9%), sedation (14.6%), BP increase (14.0%), and anxiety (14.0%). 57.3% of all patients experienced AEs related to SPRAVATO use, according to the clinician’s judgment. One (0.6%) patient-reported SPRAVATO dependence of moderate severity. Of the 26 patients who experienced ≥1 serious event, 21 (13.4%) had a psychiatric disorder, including worsening depression (n=10), SI (n=5), mental disorder (n=2), and suicidal attempt (n=1). There was one case each of anhedonia, anxiety, confusional state, and flat affect. AEs leading to permanent discontinuation of SPRAVATO was seen in 13.4% of patients (n=21) patients, including increased BP (n=6), somnolence (n=5), dissociation (n=4), vertigo (n=4), SI (n=2), and suicide attempt (n=1). One fatality occurred of unknown cause and was considered unrelated to SPRAVATO.
Treatment-Resistant Depression and Major Depressive Disorder with Suicidal Ideation
Jha et al (2023)⁸ was a retrospective analysis of real-world data from 94 patients with depression who were treated with SPRAVATO between July 2022 and February 2023. Treatment with SPRAVATO was analyzed for its market availability, improvement in disease state and daily functioning (analyzed by the CGI-I), depression severity (analyzed by the CGI-S), and satisfaction of the physician with the medication. Data Source: the Adelphi Real World Depression Disease Specific Programme XII [DSP™]	Patient Characteristics A total of 108 eligible physicians (who treated at least 10 patients with depression per week) provided information on 94 patients (mean age, 44.3 years; male, 47%) with depression, including TRD or MDSI, who were treated with SPRAVATO (n=9 for 1-30 days; n=85 for >30 days). Of all the patients, ≥30% were receiving SPRAVATO for >2 years. Outcomes The physician-reported CGI-I score showed “much improved” or “very much improved” status in 88%, 60%, 73%, 77%, and 63% of patients after 0-3 months, 3-6 months, 6-12 months, 1-2 years, and >2 years of SPRAVATO treatment, respectively. Physicians believed improvement in depressive symptoms occurred in 100% of patients in the 1- to 30-day group vs 98% in the >30-day group; the remaining 2% of patients in the >30-day group neither improved nor worsened in condition severity since initiation. The assessment of CGI-S scores showed that depressive symptoms improved or maintained in 77% and 22% of patients in the 1- to 30-day group vs 65% and 33% of patients in the >30-day group, respectively. The CGI-S score showed a mean improvement of 1.2 points in the 1- to 30-day group vs 0.9 in the >30-day group. For patients in the >30-day group, better social functioning was reported in 62% of patients; better quality of life, 53% of patients; increased ability to work, 41% of patients; ability to meet their own basic needs, 37% of patients; and improved overall general health, 34% of patients. SPRAVATO treatment was “available without restrictions” for 12% of patients; “available with restrictions”, 43% of patients; and “not routinely available”, 45% of patients. Most physicians (80%) reported high satisfaction (score, 4 or 5) with the achievement of patient treatment goals with SPRAVATO. Similarly, 80% of physicians responded “no” when asked whether patients faced insurance-related delays in receiving SPRAVATO treatment.
Abbreviations: AD, antidepressant; AE, adverse event; AQoL-8D, Australian Quality of Life-8 dimension; BDI-II, Beck’s Depression Inventory II; BP, blood pressure; CGI-I, Clinician Global Impression of Improvement; CGI-S, Clinician Global Impression of Severity; CI, confidence interval; ECT, electroconvulsive therapy; EHR, electronic health record; ESK, esketamine; GAD-7, Generalized Anxiety Disorder-7; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HAM-D-21, Hamilton Rating Scale for Depression-21; HRSD, Hamilton Rating Scale for Depression; IQR, interquartile range; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; MDE, major depressive episode; MDSI, major depressive disorder with suicidal ideation; MHS, Mindful Health Solutions; OCD, obsessive-compulsive disorder; OR, odds ratio; PHQ-9, Patient Health Questionnaire-9; PRO, patient-reported outcome; PTSD, post-traumatic stress disorder; QIDS-SR16, Quick Inventory of Depressive Symptomatology-16; REMS, Risk Evaluation and Mitigation Strategies; SAE, serious adverse event; SD, standard deviation; SDS, Sheehan Disability Scale; SI, suicidal ideation; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TMS, transcranial magnetic stimulation; TRD, treatment-resistant depression; US, United States; WPAI, Work Productivity Activity Index.

POSTMARKETING SAFETY DATABASES

REMS and US-GMS Database

~5-Year of Safety Data

Safety data of interest were gathered from REMS patient enrollment and monitoring forms completed by certified US healthcare settings and pharmacies from 5 March 2019 to 5 January 2024. Of the 58,483 patients who received at least one SPRAVATO treatment session, 44,908 (76.8%) reported ≥1 adverse event of special interest (AESI). Sedation, dissociation, and increased BP (defined as a BP increase at 40 min after administration of ≥20 mmHg or a value of ≥180 mmHg for systolic BP and/or a BP increase of ≥15 mmHg or a value of ≥105 mmHg for diastolic BP, compared to values prior to administration) were reported by 61.9%, 65.7%, and 11.7% of patients, respectively. Among 1,486,213 treatment sessions, sedation, dissociation, and increased BP were reported in 34.7%, 41.0%, and 0.9% sessions, respectively.⁹

Sedation and dissociation rates decreased during the induction phase (sessions 1-8) and remained consistent in the early (sessions 9-12) and late (sessions ≥13) maintenance phases. Median resolution time for sedation and dissociation was 70 minutes and 60 minutes, respectively. Sedation and dissociation rates were similar across age subgroups.⁹

The rate of increased BP dropped from 1.6 events per 100 administrations during the first session to 0.9 events per 100 administrations in the early maintenance phase. Increased BP was more common in patients aged 25-55 years and those aged >55 years (11.7% and 12.9%, respectively) vs patients aged <25 years (6.8%).⁹^,¹¹

An SAE was defined as any event that led to hospitalization, disability or permanent damage, death, a life-threatening condition or any event that could jeopardize the patient or require intervention to prevent the aforementioned outcomes. SAEs were reported by 1.6% of patients and in <0.1% of treatment sessions.⁹

Based on the US-GMS database, which gathers data from the REMS as well as other sources, 2742 serious cases and 3985 serious adverse events were identified. The most common SAEs (≥2%) were suicidal ideation (11.2%), hospitalization (4.8%), hypertension (4.3%), vomiting (3.5%), nausea (2.9%), death (2.7%), and dissociation (2.2%).⁹

There were 131 fatal and life-threatening suicidality-related events reported to GMS, of which 70 were deaths due to suicide. A total of 228 deaths were reported, which resulted in an estimated incidence of 0.6 per 100 patient-years. No deaths were considered by the GMS medical team to be related to SPRAVATO; however, some cases could not be adequately assessed.⁹

FDA Adverse Event Reporting System

A recent pharmacovigilance analysis was conducted using the FAERS database for 14,606 SPRAVATO-related AEs in 6887 patients from the first quarter of 2019 to the fourth quarter of 2023. The study reported that apart from the AEs mentioned in its labeling, the study identified additional potential signals, including impaired hand-eye coordination, feelings of worthlessness, agoraphobia, feeling of guilt, inappropriate affect, and increased therapeutic response. (See Table: Summary of High-Intensity AE Signals from FAERS Analysis).¹⁰

Summary of High-Intensity AE Signals from FAERS Analysis¹⁰

AE	n	ROR	PRR	EBGM
Dissociation	1093	2257.80	1899.64	876.86
Dissociative disorder	57	510.92	506.70	386.60
Sedation	688	172.68	155.53	142.05
Flashback	9	127.48	127.31	118.14
Morbid thoughts	17	107.45	107.19	100.63
Abbreviations: AE, adverse event; EBGM, Empirical Bayes Geometric Mean; PRR, Proportional Reporting Ratio; ROR, Reporting Odds Ratio.

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.¹² Although most reports were from the US, not all were reported within the US.¹⁰

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 19 August 2025. This response does not include studies reporting <50 patients treated with SPRAVATO.

This response contains general safety findings and does not include literature pertaining to use in other comorbid or psychiatric conditions. For specific adverse events of concern or use in other conditions, please contact 1-800-526-7736 or access jnjmedicalconnect.com

References

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11	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.
12	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

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