SUMMARY

• A real-world retrospective study reported greater improvement in Patient Health Questionnaire-9 (PHQ-9) scores in patients with treatment-resistant depression (TRD) who were adherent during the induction period compared with patients who were non-adherent.¹
• 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).²
• 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%.³
• A retrospective analysis of the Mindful Health Solutions 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).⁴
• 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).⁵
• The REAL-ESK study, a retrospective, observational, and multicenter analysis of 116 patients with TRD from Italy who were treated with SPRAVATO, found significant reductions in depressive symptoms at 1-month and 3-month follow-ups compared to baseline. Response and remission rates increased from month 1 (28.4% and 11.2%, respectively) to month 3 (64.2% and 40.6%, respectively). The most common adverse events (AEs) were dissociation, sedation, and transient hypertension.⁶
• The safety profile from a real-world SPRAVATO Temporary Authorization for Use (ATU) program in France in 66 patients with TRD who lacked a therapeutic alternative was consistent with SPRAVATO phase 3 clinical trials.⁷
• The ESKALE study, a retrospective analysis of real-world clinical practice in France, found that there was a greater reduction in the mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score from treatment initiation and a higher number of responders in the cohort of patients who initiated SPRAVATO + antidepressant (AD) post-launch compared with the cohorts that initiated treatment during and post ATUc.⁸
• A descriptive retrospective multicenter compassionate use study in Spain in 24 patients with TRD found that 60% of patients responded to SPRAVATO nasal spray plus an AD and 30% remitted.⁹
• A real-world retrospective study analyzed physician-reported data from 94 patients with depression, including patients with TRD and major depressive disorder 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.¹⁰
• 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 + AD treatment at 6 months.^11,12
• Postmarketing safety data from the US Risk Evaluation and Mitigation Strategies (REMS) and SPRAVATO global medical safety database from March 5, 2019, to January 5, 2023, did not identify new safety signals.¹³ 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. Another analysis using the FDA Adverse Event Reporting System (FAERS) was also conducted to identify safety signals.¹⁴
• See Table: SPRAVATO Real-World Effectiveness and Safety Study Summaries below for details.

REAL-WORLD EFFECTIVENESS AND SAFETY DATA

SPRAVATO Real-World Effectiveness and Safety Summaries

Study Design	Results
Treatment-Resistant Depression
Marci CD, Joshi K, Severtson SG, et al. The association between adherence to esketamine nasal spray therapy dosing regimen and changes in depressive symptoms among patients with treatment-resistant depression in the United States. Poster presented at the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; May 28-31, 2024; Miami Beach, FL.
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.1 Patients were diagnosed with TRD when they had documented evidence of use of ≥2 unique antidepressants 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 antidepressants and/or MDD diagnoses between either the 2 most recent unique antidepressants of adequate dose and duration and the most recent antidepressant 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.
Clemens K, Zhdanava M, Teeple A, et al. Real-world change in depressive symptoms among patients with treatment-resistant depression initiated on esketamine nasal spray. Poster presented at Psych Congress Elevate; May 30-June 2, 2024; Las Vegas, NV.
Retrospective observational study of real-world SPRAVATO use evaluating the effectiveness of SPRAVATO treatment in US patients with TRD.3 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 J, Zhdanava M, Joshi K, et al. Clinical effectiveness of esketamine for treatment-resistant depression: a real-world study of patients in Mindful Health Solutions clinics. Poster presented at: Psych Congress Elevate; May 30-June 2, 2024; Las Vegas, NV.
Retrospective observational study to assess the effectiveness of SPRAVATO for TRD in real-world conditions.4 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.
McInnes LA, Joshi K, Kane G, et al. Impact of duration of esketamine nasal spray treatment on change in depression symptoms in real-world patients. Poster presented at the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; May 28-31, 2024; Miami Beach, FL.
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.15 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 LA, Joshi K, Kane G, et al. A retrospective study of real-world outcomes for esketamine Nasal spray among patients with treatment-resistant depression. Poster presented at the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; May 28-31, 2024; Miami Beach, FL.
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.16 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 CD, Karkare S, Jha MK, et al. Change in depressive symptoms following esketamine initiation among patients with treatment-resistant depression in a real-world setting. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 9-10, 2023; Colorado Springs, CO
Real-world, retrospective, longitudinal, observational cohort study of data from adult patients with TRD who were treated with SPRAVATO between March 2019 and June 2022.2 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 M, Ahuja S, Valle MD, et al. Safety and effectiveness of intranasal esketamine for treatment-resistant depression: a real-world retrospective study. J Comp Eff Res. 2022;11(18):1323-1336.
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.5 Primary outcomes assessed were PHQ-9 depression scores, GAD-7 anxiety scores and SI score, item 9 on PHQ-9. Data Source: electronic health record system and medical charts of a REMS-certified psychiatric clinic for SPRAVATO treatment Inclusion Criteria: Adults (≥18 years old) with major depressive disorder, 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 serious AE reported in which a patient experienced prolonged dissociation, sedation, nausea, and vomiting with full resolution occurring the same day before leaving the center.
Martinotti G, Vita A, Fagiolini A. Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study). J Affect Disord. 2022;319:646-654.
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.6 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 selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor 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. 3 patients (2.58%) discontinued because of severe side effects at T1.
Samalin L, Rothärmel M, Mekaoui L, et al. Esketamine nasal spray in patients with treatment-resistant depression: the real-world experience in the French cohort early-access programme. Int J Psychiatry Clin. 2022;26(4):352-362.
Real-world study in France in adult patients with TRD who received SPRAVATO nasal spray.7 Data Source: ATUc program authorized by the French National ANSM to address adult patients with TRD lacking a therapeutic alternative. Note that SPRAVATO has since been approved.	Patient Demographics and Characteristics The mean age of the 66 treated patients was 52.5 years and the majority were female (62.1%); the mean MADRS total score was 32.9. Since the start of the current depressive episode, all 66 patients were prescribed ≥2 ADs from 2 different classes (mean [SD], 4.2 [2.1]). 54 (81.8%) patients were prescribed ≥1 antipsychotic as part of a potentiation regimen. 21 (31.8%) patients were prescribed repetitive TMS sessions. 28 (42.4%) patients were prescribed ECT sessions (median ECT sessions was 17). ECT had been considered at the time of treatment request in all treated patients (N=66) but could not be performed efficiently in 39% as they were resistant. For the others, 53% refused ECT, 3% had no access, and 5% were contraindicated. Efficacy Of the 49 patients with a completed treatment initiation form and available data, treatment was initiated in a complete hospitalization setting in 27 (55.1%) patients and in day hospitalization in 22 (44.9%) for treatment administration purposes. SPRAVATO was initiated with AD monotherapy in 16 (28.1%) patients, AD plus augmentation therapy in 9 (15.8%), combination therapy with 2 ADs in 17 (29.8%), and combination therapy plus augmentation in 15 (26.3%). In 47 patients with cumulative data, the median treatment exposure time to SPRAVATO was 30.0 (range, 10-148) days. The mean (SD) duration of monitoring following SPRAVATO administration was 123.3 minutes (25.4), performed mainly by nurses. MADRS total score reporting was not mandatory but at least 2 scores were reported during the induction period for 46 patients. Of the 46 patients, 25 had scores at the end of induction. Mean MADRS total scores decreased from a baseline score 30.9 to a score of 19.5 by week 4. 22 (47.8%) achieved response (decrease of ≥50% in the MADRS total score) at least once after treatment initiation (median time to response, 18.5 [range, 2-77] days; SPRAVATO 56 mg, 68.2%; SPRAVATO 84 mg, 31.8%). 17 achieved remission (MADRS total score ≤12) at least once after treatment initiation (median time to remission, 21 [range, 2-46] days; SPRAVATO 56 mg, 70.6%; SPRAVATO 84 mg, 29.4%). 17 patients discontinued treatment due to lack of efficacy (SPRAVATO 56 mg, 58.8%; SPRAVATO 84 mg, 41.2%) Most patients were using 56 mg of SPRAVATO at the time of response and remission. 4 weeks following treatment, patients had a 31.6% probability of achieving remission. Using Kaplan-Meier analysis, this increased to 60.3% after 8 weeks. Safety There were 201 medically confirmed AEs reported in 51 patients. 187 AEs were non-serious and 14 were considered serious 8 discontinued due to AEs. AEs (including SAEs) in ≥10% of patients were dissociation (n=19; 28.8%), sedation (n=17; 25.8%), somnolence (n=17; 25.8%), dizziness (n=14; 21.2%), anxiety (n=11; 16.7%), increased BP (n=10; 15.2%; 1 patient required nicardipine and another hydrochlorothiazide), nausea (n=7; 10.6%), and derealization (n=7; 10.6%). All AEs associated with SPRAVATO were transient and self-limiting, and occurred on the day of administration. Overall, 13 patients experienced increased BP or hypertension after administration. 24 patients discontinued after a median time from treatment initiation of 28 days (range, 15-132 days). There were no new safety signals during the ATUc compared with the phase 3 clinical trials, no deaths, and no cases of dependence.
Samalin L, Bukowski N, Codet MA, et al. A descriptive study of treatment-resistant depression patients treated by esketamine: ESKALE study interim analysis. Poster presented at: Journées Neurosciences Psychiatrie Neurologie (JNPN); July 1-2, 2021; Paris, France.
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).8 Study Design: This interim analysis collected data from medical records of patients who had been included in the study from June 26, 2020, to January 11, 2021, and treated with SPRAVATO and an AD between October 29, 2019, and March 1, 2021. Patients were included in 1 of 3 cohorts depending upon treatment initiation date. Number of Patients Treated with SPRAVATO Overall and per Cohort	Patient Demographics and Characteristics The mean age of the 62 treated patients was 49.2 years and the majority were female (67.7%). The median time in years from first diagnosis of depression was 9.3 (range, 3.8-20.9 years). Mean MADRS total score (SD) at baseline was 31.8 (7.3). The mean number of lines of treatment at the time of SPRAVATO initiation ranged from 3.2 to 5.2 across the 3 cohorts. Patients were on a numerically greater number and variety of drugs compared to previous depressive episodes at the time of SPRAVATO initiation. In the current depressive episode, a higher number of patients had received neurostimulation (ECT, 73.9%; rTMS, 60.8%) in the ATUc (46.2%) and post-ATU (46.2%) cohorts compared to post launch (15%). Efficacy There was a greater reduction in the mean MADRS total score from treatment initiation and a higher number of responders (defined as ≥50% improvement in MADRS total score) in the post launch cohort compared with the other 2 cohorts. Change in MADRS From Initiation (A) and Percentage of Responders (B) The odds for recording SPRAVATO responders at 1 week was 8-fold higher in patients who had 2 previously well-conducted treatment lines (n=11) in comparison to those with ≥3 (n=22) lines (P=0.027). Those with prior treatment with neurostimulation had a 4.5-fold higher likelihood of a non-satisfactory outcome (P=0.014). Safety There were 321 AEs in 39 patients; the majority (60%) were mild in severity. The most common AEs were ineffective therapeutic drug (33.9%), dissociative disorder (32%), somnolence (21%), and sedation (16%).
Fuertes-Saiz A, Benito A, Mora-Marin R. Compassionate use of intranasal esketamine in treatment resistant depression: a descriptive multicentric study of the Levante area in Spain. Poster presented at: 20th World Psychiatric Association; March 10-13, 2021; Virtual Congress.
Retrospective multicenter study in 8 hospitals in Spain where compassionate use of SPRAVATO was approved by the Spanish Medicines and Health Products Agency for use in conjunction with an AD in patients with TRD.9 The HAM-D-17, MADRS and visual analogue scale for depression were measured at baseline and at 3 and 6 months. To compare different depression rating scales, t-scores were calculated and a mixed linear general model for repeated measures was used for mean comparison at different time points. Inclusion criterion: Eligible patients had failed to respond to 2 or more “proper AD trials”, 1 augmentation or potentiation strategy and a non-pharmacological treatment such as ECT.	Patient Characteristics A total of 24 patients were included, of which 66.7% (n=16) were female. The mean age was 53.4 years. Approximately 42% (n=10) had already received treatment with ECT. Efficacy A statistically significant decrease in the mean depression t-scores (F [1,8], 227.6; P<0.001) was observed when comparing baseline (mean, 59.15; SE, 2.52) to 3-month scores (mean, 41.10; SE, 3.07; P<0.001) and baseline to 6-month scores (mean, 36.99; SE, 4.27; P<0.001). Response was achieved in 60% (n=12) and remission in 30% (n=6) of patients. The authors did not define response and remission criteria. Safety 2 patients discontinued treatment due to no therapeutic effect after 6 months of treatment. Feelings of dizziness, dissociative symptoms, irritability, and tiredness were each reported by 4% (n=1) of individuals, with no reported adverse effects in the remainder of patients; the investigators did not report the timing of AE occurrences.
Treatment-Resistant Depression and Major Depressive Disorder with Suicidal Ideation
Jha M, Teeple A, Joshi K, et al. Effectiveness of esketamine as a treatment for depression: a real-world survey of disease improvement. Poster presented at: Neuroscience Education Institute (NEI) Congress; November 9-12, 2023; Colorado Springs, CO.
Retrospective analysis of real-world data from 94 patients with depression who were treated with SPRAVATO between July 2022 and February 2023.10 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; ANSM, Agency for Medicines and Health Product Safety; ATU, Temporary Authorization for Use; ATUc; Temporary Authorization for Use (cohort); 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-D-21/17, Hamilton Rating Scale for Depression-21/17; HRSD, Hamilton Rating Scale for Depression; 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; PHQ-9, Patient Health Questionnaire-9; OR, odds ratio; PRO, patient-reported outcome; q, quarter; QIDS-SR16, Quick Inventory of Depressive Symptomatology-16; REMS, Risk Evaluation and Mitigation Strategies; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; SE, standard error; SI, suicidal ideation; TMS, transcranial magnetic stimulation; TRD, treatment-resistant depression.

Indirect Comparison of SUSTAIN-2 vs European Observational TRD cohort

Rive et al (2021)¹¹ and Morrens et al (2021)¹² reported on results of an indirect comparison between 2 studies to compare SPRAVATO efficacy data with specific real-world treatment strategies for TRD.

Study Design

Two studies with similar recruitment conditions were selected:

• The EOTC: A prospective, non-interventional, multicenter study in patients starting a new, routine treatment for TRD, in real-world clinical practice. Data were stratified into 3 groups:
  • Monotherapy (1 AD).
  • Combination therapy (≥2 AD).
  • Augmentation therapy (≥1 augmentation medication plus ≥1 AD).
• 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. Subjects who stopped prior to study termination were imputed as non-responders.

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.

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

Results

The overall logistic regressions for response and remission showed a significant odds ratio (OR; both P<0.0001) in favor of SPRAVATO + AD (see Table: Likelihood for Response for SPRAVATO [SUSTAIN-2] vs RWT [EOTC] and Table: Likelihood for Remission for SPRAVATO [SUSTAIN-2] vs RWT [EOTC]). Results were consistent following adjustment for multiple covariates and several sensitivity analyses.

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

The following were significantly associated with a lower likelihood of achieving remission: higher baseline MADRS (≥31); previous treatment failures with augmentation or TCAs.

Limitations and Bias

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.

POSTMARKETING SAFETY DATABASES

REMS Database

4-year REMS Data

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies from March 5, 2019, to January 5, 2023.¹³ Results from this analysis showed that in 34,110 patients who had received at least 1 SPRAVATO treatment session, 21,956 (64.4%) reported sedation, 22,953 (67.3%) reported dissociation, and 4,120 (12.1%) reported increased BP (defined as either an increase of ≥20 mm Hg before administration to ≥180 mm Hg [systolic] after administration and/or ≥15 mm Hg before administration to ≥105 mm Hg [diastolic] after administration, or if values before administration were missing, ≥180 mm Hg [systolic] and/or ≥105 mm Hg [diastolic] were used). In the 815,172 treatment sessions, sedation, dissociation, and increased BP were reported in 36.6%, 42.3%, and 1.0% of treatment sessions. The majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period. There were 1,580 serious AEs with increased BP, dizziness, nausea, and vomiting being the most frequently (≥5%) reported; 4.9% of events were non-evaluable, in that key information was missing (eg, lack of information regarding onset of event relative to drug exposure, key patient characteristics, medical and medication history) and a meaningful medical assessment could not be made.

In a separate search of the SPRAVATO global medical safety database, which included AEs reported from the REMS, there were 440,369 cases from the REMS reporting a total of 658,360 AEs within the same time frame. Among those cases, 2,437 (0.4%) were reported as serious. There were 147 fatal cases in 147 unique patients with 160 reported fatal events. Of the 147 cases, 136 cased reported only 1 fatal event which included 67 deaths not otherwise specified, 45 completed suicide, 3 overdose, 2 coronavirus disease 2019 (COVID-19) infection, 2 road traffic accidents, and 1 death each due aortic aneurysm, arteriosclerosis, Candida infection, cerebrovascular accident, diabetes mellitus, drug abuse, electrolyte imbalance, failure to thrive, hepatic cirrhosis, intestinal obstruction, intestinal perforation, multimorbidity, myocardial infarction, neoplasm malignant, post procedural complication, pulmonary embolism, and sepsis. Eleven remaining fatal cases which reported more than 1 fatal event: Cardiac disorder, sepsis, and COVID-19; cardiovascular disorder, multiple organ dysfunction syndrome, and cerebrovascular accident; toxicity to various agents and accidental overdose; hip fracture and gall; hallucination auditory and completed suicide; pneumonia and multiple organ dysfunction syndrome; toxicity to various agents and completed suicide; suspected suicide and alcohol use; overdose and brain injury; organ failure and COVID-19; and substance abuse and accidental overdose. The majority of deaths were assessed by Global Medical Safety as not related to SPRAVATO treatment.¹³

5-year REMS Data (A Focus on the First 12 Treatment Sessions)

The 5-year REMS database analysis (March 5, 2019 to January 5, 2024) included 58,483 patients who had ≥1 SPRAVATO treatment sessions.¹⁷ At the first treatment session, 65.2% of patients were aged between 18 and 49 years and 61.1% were female.¹⁷ A more in-depth analysis of the first 12 treatment sessions found that the cumulative rates of SPRAVATO TEAEs of interest in sessions 1-8, which included 58,471 patients, were 55.8% for sedation, 61.2% for dissociation, and 6.2% for increased BP.¹⁷ In sessions 9-12, which included 43,908 patients, the rates of TEAEs were 46.2% for sedation, 51.2% for dissociation, and 2.8% for increased BP.¹⁷

The decrease in the rate of TEAEs of interest from sessions 1-8 to sessions 9-12 across both dose levels is depicted in Table: TEAEs of Interest by Dose Level and Treatment Session.

SAEs (as determined by the reporter) during the overall evaluation period are illustrated in Table: Summary of AEs of Interest Associated With Reports of SAEs by Treatment Session.

The most common SAEs (≥0.1%) in the first 12 treatment sessions were dissociation, dizziness, hypertension, nausea, vomiting and increased BP.¹⁷

Based on the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice (ICP-CGP) criteria, ≤0.4% of patients across all treatment phases reported SAEs resulting in hospitalization (sessions 1-8 and 9-12, 0.1%), death (sessions 1-8, <0.1%), a life-threatening event (sessions 1-8 and 9-12, <0.1%), or an important medical event (sessions 1-8, 0.4%; sessions 9-12, 0.1%).¹⁷

FDA Adverse Event Reporting System

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹⁴ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval. If the proportion of AEs of interest was greater in cases vs non-cases, then this was considered a disproportionality signal. AEs were classified into 4 categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

There was a total of 2,274 SPRAVATO-related AEs in 962 patients with 389 serious AEs, including 22 deaths. The most frequently reported AEs (≥5%) were dissociation (n=212, 9.32%), sedation (n=173, 7.6%), and drug ineffective (n=119, 5.23%). The top 3 AEs in the expected AEs with signal category based on reporting odds ratio (listed in descending order) were dissociation (n=212), sedation (n=173), and feeling drunk (n=20); in the expected AEs without a signal category were vertigo (n=5), vision blurred (n=8), and tremor (n=9); in the disease-related AEs category were self-injurious ideation (n=5), SI (n=64), and depression (n=65); and in the unexpected AEs category were dissociative disorder (n=4), autoscopy (n=6), and drug monitoring procedure not performed (n=4). The frequency of serious AEs was higher in patients receiving SPRAVATO 84 mg compared to patients receiving SPRAVATO 56 mg. Females were also more likely to suffer from serious SPRAVATO-related AEs compared to males. A sensitivity analysis using venlafaxine as a comparator for disease-related AEs identified the following signals: self-injurious ideation, SI, emotional disorder, depression, crying, and depressed mood.¹⁴

Limitations of the FAERS includes: the database contains duplicate, incomplete, and/or unverified AEs, making causality difficult to prove; AE reports are voluntary and unsolicited (which generally leads to under-reporting of AEs for most drugs) and, therefore, AE rates cannot be determined; FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).¹⁸ Other considerations include: the increasing AE trends for SPRAVATO over the first year are expected due to the low initial SPRAVATO usage following approval, partly due to REMS requirements for certifying treatment centers; expected AEs such as dissociation and sedation are solicited and reported via the REMS at every SPRAVATO treatment session triggering multiple reports in FAERS; use of venlafaxine as a control for sensitivity analyses may not be appropriate since the TRD population indicated for SPRAVATO likely possess a significantly greater burden of disease.

Another analysis conducted using the FAERS database for 5061 SPRAVATO-related AEs from the first quarter of 2019 to the first quarter of 2023 reported that apart from the AEs mentioned in its labeling, this study identified additional potential signals, including flashback, tachyphylaxis, and autoscopy.¹⁹

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 07 November 2023.