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SPRAVATO® (esketamine)

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Real World Evidence – Effectiveness and Safety of SPRAVATO with Outcomes Assessed Under 12 Months

Last Updated: 06/19/2026

SUMMARY

A retrospective observational analysis of the Veterans Health Administration database found a 5.6-point reduction in the mean Patient Health Questionnaire-9 (PHQ-9) scores after completion of the SPRAVATO induction phase in veterans with treatment-resistant depression (TRD), with severe depression decreasing from 50.0% to 17.5%, and remission achieved by 11.3% of patients.¹
A real-world retrospective study reported greater improvement in PHQ-9 scores in patients with TRD who were adherent during the induction period compared with patients who were non-adherent.²
A real-world retrospective cohort study using the PremiOM™ MDD Dataset analyzed data from 163 adult patients with TRD who received SPRAVATO from March 2019 to June 2022. The study reported a prominent reduction in mean PHQ-9 score in patients treated with a longer duration of SPRAVATO (at least 3 months).³
A real-world retrospective cohort study analyzed data from 171 patients with TRD with comorbid psychiatric disorders and high exposure to psychiatric medications who received SPRAVATO from July 2019-June 2021. Significant reductions in mean PHQ-9 and Generalized Anxiety Disorder-7 (GAD-7) scores were observed from baseline (PHQ-9, 16.7; GAD-7, 12.0) to last available treatment (PHQ-9, 12.0; GAD-7, 8.7).⁴
A real-world retrospective study (INTEGRATE) analyzed data from 189 patients with major depressive disorder (MDD) who met criteria of TRD treated with SPRAVATO in Spain. Based on clinical judgment, 80.4% of patients achieved response or remission during the induction phase; 90% of patients did so during the maintenance phase. The remission rate increased from 9.5% (induction phase) to 38.3% (maintenance phase) which were generally consistent with MADRS assessments. Most adverse events (AEs) were mild or moderate and resolved on the day of administration; dissociation (50.3%) and somnolence (41.8%) were the most frequently reported AEs.⁵
The REAL-ESK study, a retrospective, observational, and multicenter analysis of patients with TRD treated with SPRAVATO across Italian mental health centers, demonstrated significant reductions in depressive symptoms.⁶
- In the cohort of 116 patients assessed at 1 and 3 months, the response and remission rates, respectively, increased from 28.4% and 11.2% at month 1 to 64.2% and 40.6% at month 3. The most common AEs were dissociation (39.7%), sedation (28.4%), and transient hypertension (10.3%).⁶
An observational, retrospective, multicenter compassionate use study in Spain in patients with TRD reported a clinically significant reduction in mean MADRS score from the baseline at all assessed time points (28, 90, and 180 days; P≤0.0001).⁷
A non-interventional, prospective study in Australia and New Zealand (October 2021 to March 2023) reported that patients with TRD had significantly improved quality of life and work productivity, with depression symptom improvement, after 16 weeks of treatment with SPRAVATO.⁸
An indirect comparison of SUSTAIN-2 and a European Observational TRD cohort (EOTC), where the choice of treatment was at the physician’s discretion (excluding SPRAVATO), found response and remission odds ratios in favor of SPRAVATO + oral antidepressant (AD) treatment at 6 months.⁹^,¹⁰

clinical studies

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

Study Design	Results
Studies Conducted in the US
Smith et al (2025)¹ conducted a retrospective observational cohort study to evaluate the effectiveness of SPRAVATO in US veterans with TRD who completed the induction phase. Data Source: Electronic health records from the Veterans Health Administration database, including demographic data, SPRAVATO treatment details, and PHQ-9 scores, were collected from March 5, 2018 to January 17, 2025. Inclusion Criteria: Adults (≥18 years) with a diagnosis of MDD, evidence of TRD (defined as ≥3 distinct ADs within a 12-month period and ≥1 MDD diagnosis), who initiated SPRAVATO treatment on or after March 5, 2019, were included. Eligible patients had to complete ≥8 SPRAVATO sessions (induction phase) during the post-index period, ≥1 PHQ-9 score recorded within 60 days prior to or on the index date and ≥1 PHQ-9 total score within 7 days after completing the induction phase.	Patient Characteristics The final cohort included 80 veterans who met all the inclusion criteria. Mean age was 47.2±12.9 years; 82.5% of patients were male, and 41.3% had a diagnosis of severe MDD. Most common mental health comorbidities included PTSD (77.5%), sleep-wake disorders (65.0%), anxiety disorder (63.8%), and substance use disorder (35.0%). Common physical comorbidities included hyperlipidemia (41.3%) and hypertension (33.8%). MDD Severity and Symptoms The mean±SD PHQ-9 score decreased from 18.8±5.6 at baseline to 13.2±6.4 after induction, reflecting a clinically meaningful reduction (>5 points) of 5.6 points. The proportion of patients with severe MDD (PHQ-9 ≥20) dropped from 50.0% at baseline to 17.5% after induction. Remission (PHQ-9 ≤4) was achieved by 11.3% of patients after induction. The percentage of those who had the most severe symptoms (PHQ-9 score of 20-27) at treatment initiation (50%) had decreased to 17.5% by the end of induction. On average, item-level symptom reductions were seen in: SI: 1.5 to 0.8 (42.2% decrease) Psychomotor retardation: 1.3 to 0.8 (40.2%) Feeling bad about oneself: 2.3 to 1.5 (33.5%) Depressed mood/hopeless: 2.4 to 1.7 (32.0%) Anhedonia: 2.5 to 1.8 (27.6%) Insomnia: 2.4 to 1.8 (26.3%) Concentration issues: 2.1 to 1.6 (26.3%) Fatigue: 2.5 to 1.8 (25.9%) Appetite changes: 1.9 to 1.5 (22.7%)
Marci et al (2024)² was a retrospective observational study that assessed the relationship between adherence to SPRAVATO treatment during induction phase and improvement in depressive symptoms (in terms of PHQ-9 score) in patients with TRD under real-world conditions. Patients were diagnosed with TRD when they had documented evidence of use of ≥2 unique ADs of adequate dose and duration at any time before the index date and in the same MDE, defined as no clean period of ≥180 days without ADs and/or MDD diagnoses between either the 2 most recent unique ADs of adequate dose and duration and the most recent AD of adequate dose and duration and the index date. Definition of Adherence: Patients were considered adherent to therapy if they completed ≥6 sessions within 30 days of ESK treatment initiation (75% of recommended doses during induction phase). Data Source: PHQ-9 data, from patients treated with SPRAVATO between 03/2019 and 06/2022, obtained from the PremiOM™ MDD Dataset Key Inclusion Criteria: Adults with TRD initiated on SPRAVATO on or after 03/2019 and with ≥1 PHQ-9 score(s) in the 6 months before and ≥1 PHQ-9 score(s) in the 6 months after the index date. The patient should have documented confirmation of undergoing ≥1 SPRAVATO treatment sessions within 30 days following the index date. Index Date: date of first SPRAVATO prescription Baseline Period: the 6-month period before and including the index date Follow-up Period: the 6-month period after the index date	Patient Characteristics Of 64 patients included in the study, 35 were adherent and 29 non-adherent. Compared to males, more females were non-adherent (19 females vs 10 males). Non-adherent patients were more likely to have a comorbidity diagnosed in the 6 months before or on index date compared to adherent patients: Anxiety disorder, 75.9% vs 48.6% Attention-deficit/hyperactivity disorder, 34.5% vs 22.9% Bipolar disorder, 24.1% vs 11.4% Hypertension, 20.7% vs 8.6% Mean (SD) PHQ-9 score at baseline: At follow-up of >0-3 months: adherent, 18.0 (6.2); non-adherent, 14.1 (6.8) At follow-up of >3-6 months: adherent, 16.7 (6.4); non-adherent, 13.2 (6.9) Mean Change in PHQ-9 Scores at 3 and 6 Months After Initiating SPRAVATO Treatment Paired mean difference (SD) in mean PHQ-9 score at >0-3 months compared to baseline: Adherent (n=28): -6.6 (7.8); 95% CI, -9.6 to -3.6; P<0.001; Cohen’s d, 0.85 Non-adherent (n=18): -3.6 (7.4); 95% CI, -7.2 to 0.1; P=0.057; Cohen’s d, 0.48 Paired mean difference (SD) in mean PHQ-9 score at >3-6 months compared to baseline: Adherent (n=28): -7.1 (6.8); 95% CI, -9.8 to -4.5; P<0.001; Cohen’s d, 1.05 Non-adherent (n=23): -4.1 (8.5); 95% CI, -7.8 to -0.5; P=0.029; Cohen’s d, 0.49 Greater improvement in PHQ-9 total scores were observed in patients who were adherent during the induction period compared with the non-adherent arm.
McInnes et al (2024)¹¹ was an EHR-based study to evaluate the effectiveness of SPRAVATO treatment in patients with MDD and TRD in a real-world setting based on changes in PHQ-9 scores over time compared to baseline. PHQ-9 scores were captured at baseline, within 30 days of SPRAVATO initiation, and within 30 days of all subsequent SPRAVATO treatment sessions. Data Source: Osmind EHR Inclusion Criteria for ESK All-comers Cohort: Adults with a diagnosis of MDD who have received ≥1 SPRAVATO treatment(s) on or after 03/05/2019 and on or before 03/31/2023. Index Date: Date of first documented SPRAVATO treatment Follow-up Period: until 06/30/2023 Subgroups: ESK-TRD cohort: Patients with documented history of use of ≥2 unique ADs in the 730 days before the index date Patients who received ≥8 treatment sessions within 42 days, thereby completing the induction phase.	Patient Characteristics Of 664 patients included in the ESK all-comers cohort, 361 were in the ESK-TRD cohort. Sociodemographic characteristics were similar between the two cohorts (mean age, 45 years; females, ~60%). The number of SPRAVATO treatments received were also consistent between the two cohorts; ~67% continued to receive SPRAVATO after the initial 8-12 treatments. Both ESK all-comers and ESK-TRD cohorts had a mean baseline PHQ-9 score of 17. Outcomes PHQ-9 scores declined significantly after the first treatment session. After 5-8 treatment sessions, the decrease was estimated to be over 4 points (b= -4.9/-4.2 for ESK-all-comers and ESK-TRD cohorts, respectively). After 13-16 treatment sessions, larger clinically significant decreases were observed (b= -5.9/-5.1 for ESK-all-comers and ESK-TRD cohorts, respectively). Changes in PHQ-9 scores were similar between the ESK all-comers cohort and the induction completers cohort, which was similar to that seen between the ESK-TRD cohort and those with TRD who completed induction. The median number of treatments to initial response was 10 and 12 for the ESK all-comers and ESK-TRD cohorts, respectively; the response rates continued to increase with time. The mean equivalent temporal interval was 70 days for the ESK all-comers cohort and 68 days for the ESK-TRD cohort. Based on survival prediction models, 85% of the ESK all-comers cohort and 75% of the ESK-TRD cohort achieved a clinical response at some point. These results suggest response rates improved with continued treatment.
McInnes et al (2024)¹² was a real-world study to primarily evaluate the effectiveness of SPRAVATO in patients with MDD and TRD based on changes over time compared to baseline in PRO scores, including PHQ-9, HRSD, BDI-II, and QIDS-SR16, and limited use of MADRS scores. The secondary objective was to evaluate comorbid diagnoses and concomitant medications in patients treated with SPRAVATO. Changes in PHQ-9, HRSD, QIDS-SR16, BDI-II, and MADRS were captured at baseline, within 30 days of SPRAVATO initiation, and within 30 days of all subsequent SPRAVATO treatment sessions. Data Source: Osmind EHR Inclusion Criteria for ESK All-comers Cohort: Adults with a diagnosis of MDD who have received ≥1 SPRAVATO treatment(s) on or after 03/05/2019 and on or before 03/31/2023. Index Date: Date of first documented SPRAVATO treatment Follow-up Period: until 06/30/2023 Subgroup: ESK-TRD cohort: Patients with documented history of use of ≥2 unique ADs in the 730 days before the index date	Patient Characteristics Of 664 patients included in the ESK all-comers cohort, 361 were in the ESK-TRD cohort. Sociodemographic characteristics were similar between the two cohorts (mean age, 45 years; females, ~60%). Outcomes Analysis of PHQ-9 Score and Other Depression Scales See study poster above for results on PHQ-9. The probability of response using other scales increased after 12 treatments. Comorbid Psychiatric Diagnoses in Patients Receiving SPRAVATO Treatment Anxiety (>70%) was the most common comorbid diagnosis, followed by trauma, stress-related disorders, and neurodevelopmental disorders (all in <30% of patients). Attention deficit hyperactivity disorders (>25%) were the most common neurodevelopmental disorders. Sleep-wake disorders were also noted in >20% of the patients. Concomitant Medications in Patients Receiving SPRAVATO Treatment Concomitant ADs (≥1) were taken by ~77% and ~85% of ESK all-comers and ESK-TRD cohorts, respectively. An augmentation agent was taken during SPRAVATO treatment by ~65% of patients in both cohorts. Additional psychiatric medication was taken by ~50% and ~40% of ESK all-comers and ESK-TRD cohorts, respectively. Benzodiazepines was the most common class of medications reported (ESK all-comers cohort, 42% and ESK-TRD cohort, 45%)
Marci et al (2023)³ was a real-world, retrospective, longitudinal, observational cohort study of data from adult patients with TRD who were treated with SPRAVATO between March 2019 and June 2022. Severity in depressive symptoms, using the PHQ-9 scale, was compared from baseline to >0-3-month and >3-6-month periods after the index date (defined as the day of SPRAVATO initiation). Remission was defined as a follow-up PHQ-9 score of <5. Data Source: The PremiOM™ MDD Dataset in the US.	Patient Characteristics A total of 163 patients (mean age, 49.5 years; female, 58.3%) were included in the analysis. Outcomes At baseline, 55.8% of patients had either moderately severe or severe depression (PHQ-9 ≥15; mean PHQ-9 score, 15), which decreased to 34.4% and 20.9% of patients in the >0-3-month and >3-6-month postindex periods, respectively. Statistically significant reductions in PHQ-9 scores compared with the baseline were reported in the >0-3-month (2.9 points; 95% CI, 1.7-4.1; P<0.001) and the >3-6-month (4.4 points; 95% CI, 3.2-5.6; P<0.001) postindex periods. The average decrease in PHQ-9 score was 3.2 points (95% CI, 2.0-4.5; P<0.001), with an effect size of 0.42, in patients with ≥1 PHQ-9 score in the baseline and the >0-3-month postindex period (n=151). The average decrease in PHQ-9 score was 4.4 points (95% CI, 3.2-5.7; P<0.001), with an effect size of 0.60, in patients with ≥1 PHQ-9 score in the baseline and the >3-6-month postindex period (n=136). The odds of a patient being in remission were 3.2 (95% CI, 1.5-7.0; P=0.003) and 4.9 (95% CI, 1.9-12.8; P=0.001) times greater in the >0-3-month and the >3-6-month postindex periods, respectively, vs the baseline. Longer duration of treatment with SPRAVATO resulted in a more pronounced reduction in PHQ-9 scores, with the largest reduction reported in patients treated with SPRAVATO for at least 3 months. Analyses of sensitivity, which did not include estimated PHQ-9 scores, revealed consistent results.
Brendle et al (2022)⁴ was a retrospective analysis of real-world evidence outcomes from 171 patients with TRD receiving SPRAVATO (July 2019-June 2022) in a private outpatient psychiatric clinic setting. Primary outcomes assessed were PHQ-9 depression scores, GAD-7 anxiety scores and SI score, item 9 on PHQ-9. Data Source: EHR system and medical charts of a REMS-certified psychiatric clinic for SPRAVATO treatment Inclusion Criteria: Adults (≥18 years old) with MDD, recurrent without psychotic features and received SPRAVATO between July 2019-June 2021. Exclusion Criteria: Patients who had received any other form of ketamine were excluded.	Patient Demographics and Characteristics The mean age of the 171 treated patients was 36 years. Most patients were White (92%), and predominantly female (60.0%), and had comorbid psychiatric diagnoses. Most patients (98%) used other psychiatric medications besides SPRAVATO with a mean (SD) of 5.8 (4.0) medications per patient, out of which there was a mean (SD) of 2.3 (2.3) ADs used per patient. Depression and Anxiety Outcomes Based on the PHQ-9 and GAD-7 scores from treatment sessions 1-28, the average PHQ-9, GAD-7 and mean SI scores decreased significantly (P<0.001) from baseline suggesting improvement in severity of depression and anxiety symptoms. The baseline mean PHQ-9 score was 16.7 (SD, 5.8) and mean GAD-7 score was 12.0 (SD, 5.8). Mean PHQ-9 and GAD-7 scores at last available SPRAVATO treatment were 12.0 (SD, 6.4) and 8.7 (SD, 5.6) showing significant reductions from baseline. There was also a significant decrease in the suicide score from a baseline of 1.09 (SD, 1.06) to 0.79 (SD, 0.94). Safety Information from REMS documents were used to account for the number of patients experiencing AEs including sedation, dissociation, and increased BP. Dissociation (73%) occurred more frequently than sedation (22%) with most symptoms presenting within the first 30 minutes of SPRAVATO administration and resolving by 2 hours. Patients were reported to be ready to leave approximately 90 minutes after dosing. Mean BP slightly decreased over time throughout each treatment session. There was 1 SAE reported in which a patient experienced prolonged dissociation, sedation, nausea, and vomiting with full resolution occurring the same day before leaving the center.
Studies Conducted Outside of the US
Molero et al (2025)⁵ was a real-world, retrospective, observational, cross-sectional study of adult (18-74 years old) patients across 37 sites in Spain with TRD, defined as non-response to ≥2 oral ADs during the current moderate to severe depressive episode (INTEGRATE study). Study Design: Patients who were initiated on SPRAVATO treatment at least 4 weeks prior to inclusion and were treated per product labeling between March and October 2023 were included. Treatment phases were defined as follows: Induction: weeks 1–4 Optimization: weeks 5-8 Maintenance: week 9 onwards Data was collected from medical records, clinical assessments (MADRS and SDS scores) and clinician's judgment to evaluate response, remission, and AEs.	Patient Demographics and Characteristics A total of 189 patients were included in the study, with a mean age of 53 years (SD, 11.6); 60.3% of patients were female, and 83.1% of patients were <65 years of age. Total 74.1% of patients received ≥2 oral ADs. All patients were receiving oral ADs at the time of treatment initiation with SPRAVATO, with 74.1% receiving 2 or more oral ADs. At study entry, patients had been on SPRAVATO for a mean of 8.3 weeks (SD, 5.1); of the 189 patients included, 90.5% (n=171) were in the optimization or maintenance phase and 9.5% (n=18) were in the induction phase. Effectiveness Of the 189 patients included, 152 (80.4%) achieved clinical response or remission during induction; 90% did so during maintenance. The remission rates across the phases were as follows: 9.5%, induction; 18.7%, optimization; 38.3%, maintenance. At the time of study visit, 29.1% and 29.6% of patients were in remission per investigator’s judgement and per the MADRS score, respectively; 45.3% of those in remission were in functional remission (SDS score ≤6). Overall, 28% of patients showed symptom improvement within 24 hours of the first dose. Safety Overall, 85.2% of patients reported ≥1 AE; most were mild (79.2%) or moderate (20.3%) in intensity. Most AEs (97.5%) resolved on the same day and required no pharmacological intervention. The most frequent AEs were as follows: dissociation (50.3%), somnolence (41.8%), dizziness (40.2%), dysgeusia (20.1%), and other psychiatric disorder (15.3%). Two SAEs were reported (SI and ductal carcinoma), and both were considered unrelated to SPRAVATO.
Gutierrez-Rojas et al (2024)⁷ was an observational, retrospective study in 9 hospitals in Spain to evaluate the efficacy, safety, and tolerability of SPRAVATO in adult patients with TRD through the compassionate use program as advised by the Spanish National Regulatory Agency of Medicinal Products. Inclusion Criteria: Eligible patients had failed to respond (<50% improvement in depressive symptoms) to ≥2 oral ADs of adequate dose and duration, and ≥1 combination or potentiation strategy with antipsychotics, lithium, mood stabilizers, or thyroid hormones and a non-pharmacological treatment. Exclusion Criteria: <18 years of age Comorbid pathologies such as untreated hypertension or previous cardiovascular disorders Inability to self-administer drug Suicidal thoughts or with a history of suicide attempt in the 6 months before the study Presence of comorbid psychotic symptoms bipolar depression.	Patient Characteristics A total of 71 patients were included, of which 70.4% (n=50) were female. The mean (SD) age was 54.6 (11.0) years. The majority (87%) of patients were treated in the outpatient setting. Mean (SD) MADRS score at baseline was 38.3 (5.9); >30% had made prior suicide attempts. Besides ADs, before treatment with SPRAVATO, patients had received mood stabilizers (32.4%), atypical antipsychotics (46.5%), ECT therapy (31.0%), or psychotherapy (46.5%) during the current MDE. Efficacy The mean duration (SD) of SPRAVATO treatment was 273.6 (181.7) days MADRS score evolution tracked from baseline to 28 days, 90 days, and 180 days showed a generalized decrease in mean (SD) scores: MADRS 28 days (n=71): 23.4 (12.9) MADRS 90 days (n=65): 16.9 (11.2) MADRS 180 days (n=53): 14.1 (11.5) Pairwise comparison of the change in MADRS score from baseline showed significant improvement (P=0.0001) across all time points. 45.1% of the patients experienced an initial response (≥50% improvement in MADRS score from baseline) within the first 15 days of treatment. Safety and Tolerability >95.0% of the patients experienced side effects; 35.2% experienced 2 side effects, and 23.9% had 1 side effect. All side effects were mild and resolved after the 60-minute observational period. The most frequent side effects were dissociative symptoms (56.3%), dizziness (36.6%), sedation (31.0%), drowsiness (28.2%), and paresthesia (28.2%).
Hopwood et al (2024)⁸ was an non-interventional, prospective, multicenter study in Australia and New Zealand (October 2021 to March 2023) evaluating the effect of SPRAVATO with a newly initiated oral AD via an early access program in patients with TRD. This study aimed to evaluate the impact of SPRAVATO on quality of life, work productivity, and depression symptom severity, assessed through AQoL-8D scores from baseline to week 16. AQoL-8D has 35 items grouped in 8 dimensions, which can be further grouped into 2 super-dimensions - “physical” and “psychosocial”. The “physical” super-dimension comprises independent living, senses, and pain dimensions, and the “psychosocial” super-dimension comprises mental health, happiness, self-worth, coping, and relationships dimensions. Secondary objectives included measuring the change in WPAI and HAM-D scores at 16 weeks from baseline. Inclusion Criterion: Adult patients with TRD who failed to respond to treatment with ≥2 ADs over an adequate duration and dosage to treat the current depressive episode.	Patient Characteristics: A total of 105 patients were included in the analysis (mean age, 38.7 years; female, 59.0%; Australian, 92.4%). Mean number (SD) of previous MDEs was 2.8 (2.3). Most common comorbidities included anxiety (72.4%) and PTSD (23.8%). 48.6% of patients received 3-5 prior lines of therapies; 28.6% received >6 lines of prior therapies. Prior medications included SSRI (76.2%), SNRI (79.0%), atypical antipsychotics (49.5%), and tricyclic ADs (35.2%), among others. Changes in Quality of Life: All dimensions of AQoL-8D showed statistically significant improvements. Primary improvements were observed in the psychosocial dimensions of happiness, mental health, and self-worth, reporting a 17.0%, 18.0%, and 19.0% decrease from baseline to week 16), respectively. Based on weighted statistical analyses, the total AQoL utility scores improved 0.14 points from baseline to week 16 (P<0.01). Changes in Depression Rating: At 16 weeks, the mean HAM-D score decreased by 8.0 points from baseline, indicating a statistically and clinically significant improvement (P<0.001). By the end of 16 weeks, the percentage of patients with severe depression decreased from 77.1% to 29.8%, moderate or severe depression decreased from 94.0% to 47.0% (39 of 84), and normal mood or mild depression increased from 6.0% to 54.0%. Work Productivity Activity Index: All measures of WPAI significantly improved after 16 weeks of treatment: Absenteeism decreased by 17.6% Employment levels increased by 3.2% Presenteeism decreased by 12.8% Overall work impairment due to depression decreased by 14.8% Activity impairment due to depression decreased by 20.4%
Martinotti et al (2022)⁶ was a real-world retrospective analysis of 116 patients with TRD treated with SPRAVATO using assessment scores from the MADRS and HAM-D-21 at baseline (T0), 1-month (T1) and 3-month (T2) follow-ups. Primary outcomes were assessed using MADRS and HAM-D-21 scale scores. Response was defined as 50% reduction from baseline in either score and remission defined as MADRS score of <10 or HAM-D-21 score of <7. Study Design: Patients were analyzed as part of an “early access programme” in Italy that supplied SPRAVATO to major centers treating TRD across the country. 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.	Patient Demographics and Characteristics The mean age of the 116 treated patients was 50 years and 52.6% of patients were female. Psychiatric comorbidities included personality disorders (15%), substance use disorder (6%), and general anxiety disorder (5%), among others. One-Month and 3-Month Treatment Outcomes A significant reduction in the MADRS score was observed at T1 (n=106; mean, 22.27±9.81; P<0.0001) and T2 (n=91; mean, 14.69±9.88; P<0.0001) compared to baseline ([T0]; mean, 35±8.53). SPRAVATO had a significant effect (P<0.0001) in reducing suicidal thoughts (MADRS item 10) at T1 (mean, 1±0.55) and T2 (mean, 0.94±0.1) compared to baseline (mean, 2.13±1.58). Compared to T0, there was an increase in clinical response (T1, 28.4%; T2, 64.2%) and remission (T1, 11.2%; T2, 40.6%) with significant improvement in both at T2 vs T1 (P<0.0001). Only 29% (early remitters) of patients in remission at T2 were also in remission at T1. 38% of patients in remission at T2 were non-responders at T1. Psychiatric Comorbidities and Add-on Therapies SPRAVATO had similar effectiveness irrespective of psychiatric comorbidities. Patients on medications other than ADs, such as antipsychotics or mood stabilizers, showed an overall lower response rate to SPRAVATO (T1, P=0.023; T2, P=0.010). Safety Dissociation (39.7%), sedation (28.4%), and transient hypertension (10.3%) were the most common side effects, whereas 27.6% of patients reported no side effects. Three patients (2.58%) discontinued because of severe side effects at T1.
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; 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; TRD, treatment-resistant depression; US, United States; WPAI, Work Productivity Activity Index.

Indirect Comparison of SUSTAIN-2 vs European Observational TRD cohort

Oliveira-Maia et al (2023 and 2023)⁹^,¹⁰ reported results of an indirect comparison between 2 studies to compare SPRAVATO efficacy data with real-world treatment (RWT) strategies⁹ (ICEBERG study) and real-world (RW) polypharmacy strategies¹⁰ for TRD.

Study Design

Two studies with similar recruitment conditions were selected⁹^,¹⁰:

The EOTC: A prospective, non-interventional, multicenter study in patients starting a new, routine treatment for TRD, in real-world clinical practice.
SUSTAIN-2: A longterm, open-label study of the safety and efficacy of SPRAVATO nasal spray plus new oral AD, including European patients.

Baseline characteristics were similar between the 2 studies. Patients who stopped prior to study termination were imputed as non-responders.⁹^,¹⁰

Treatment differences were estimated by reweighting observations (inverse probability weighting using propensity scores estimated with 17 covariates) in the EOTC using SUSTAIN-2 as a reference, resulting in an estimate of treatment effects among treated patients.⁹^,¹⁰

Response (≥50% improvement in total MADRS score) and remission (total MADRS score ≤10) at 6 months were compared with baseline. Analysis was based on observed cases.⁹^,¹⁰

Results

In the ICEBERG study, treatment with SPRAVATO (N=559) was indirectly compared vs RWT strategies (N=307)⁹ and RW polypharmacy (N=225).¹⁰

The overall logistic regressions for response and remission showed a significant odds ratio (OR; both P<0.0001) in favor of SPRAVATO vs RWT strategies.⁹ See Table: Chances of Response and Remission at Month 6 for SPRAVATO vs Real-World Treatment.

Similarly, a significant OR favoring treatment with SPRAVATO vs RW polypharmacy strategies was reported.¹⁰ See Table: Chances of Response and Remission at Month 6 for SPRAVATO vs Real-World Polypharmacy.

Results for SPRAVATO vs RWT strategies were consistent following adjustment for multiple covariates (OR [95% CI] for 6-month response: 2.61 [1.80-3.77], P<0.0001; OR [95% CI] for 6-month remission: 2.53 [1.64-3.91], P<0.0001).⁹

Chances of Response and Remission at Month 6 for SPRAVATO vs Real-World Treatment⁹

SPRAVATO + Oral AD^a vs RWT^b	Response	Remission
OR (95% CI); P value	2.76 (2.03-3.73); <0.0001	2.28 (1.62-3.20); <0.0001
RR (95% CI); P value	1.88 (1.53-2.31); <0.0001	1.85 (1.42-2.41); <0.0001
RD (95% CI); P value	0.23 (0.17-0.30); <0.0001	0.15 (0.096-0.21); <0.0001
NNT (95% CI)	5 (4-6)	7 (5-11)
Abbreviations: AD, antidepressant; ATT, rescaled average treatment effect among treated; CI, confidence interval; NNT, number needed to treat; NS, nasal spray; OR, odds ratio; RD, risk difference; RR, relative risk; RWT, real-world treatment; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. ^aGiven in combination with an SSRI or SNRI. ^bRWT data were adjusted using the ATT covariate adjustment method.

Chances of Response and Remission at Month 6 for SPRAVATO vs Real-World Polypharmacy¹⁰

SPRAVATO + Oral AD^a vs RW Polypharmacy^b	Response	Remission
OR (95% CI); P value	2.71 (1.93-3.80); <0.0001	2.11 (1.45-3.07); 0.0001
RR (95% CI); P value	1.86 (1.47-2.35); <0.0001	1.74 (1.30-2.32); 0.0002
RD (95% CI); P value	0.23 (0.16-0.30); <0.0001	0.14 (0.08-0.21); <0.0001
NNT (95% CI)	5 (4-7)	8 (5-13)
Abbreviations: AD, antidepressant; ATT, rescaled average treatment effect among treated; CI, confidence interval; NNT, number needed to treat; NS, nasal spray; OR, odds ratio; RD, risk difference; RR, relative risk; RW, real-world; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. ^aGiven in combination with an SSRI or SNRI. ^bRW polypharmacy data were adjusted using the ATT covariate adjustment method.

The following were significantly associated with a lower likelihood of achieving response: age ≥55 at major depressive disorder diagnosis; previous treatment failures with augmentation, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), or other ADs; and male gender.⁹

The following were significantly associated with a lower likelihood of achieving remission: higher baseline MADRS (≥31); previous treatment failures with augmentation or TCAs; patients with major depressive episode (MDE) lasting 52-103 weeks vs patients with MDE lasting <32 weeks; and prior history of suicidal ideation (not suicidal behavior) at baseline.⁹

Limitations

Due to the absence of a common comparator in the 2 studies, only an indirect comparison was possible. Increased compliance and motivation to continue treatment in the SUSTAIN2 clinical trial setting may have led to potential bias in favor of SPRAVATO. In addition, higher frequency of visits in SUSTAIN2 compared with the EOTC study may have led to improved outcomes. However, increased visits are also expected in realworld clinical treatment with SPRAVATO.⁹^,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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