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SPRAVATO® (esketamine)

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Real World Evidence – Effectiveness and Safety of SPRAVATO Therapy

Last Updated: 11/07/2024

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.
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.⁴
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).⁵
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%.⁶
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).⁷
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).⁸
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.⁹
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.¹⁰
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).¹¹
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.¹²
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.¹³
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.¹⁴^,¹⁵
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, 2024, was consistent with the established safety profile of SPRAVATO and did not identify new safety signals.¹⁶ 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.¹⁷^-¹⁹

REAL-WORLD EFFECTIVENESS AND SAFETY DATA

SPRAVATO Real-World Effectiveness and Safety Study Summaries

Study Design	Results
Treatment-Resistant Depression
Studies Conducted in the United States
Marton T, Joshi K, Zhdanava M, et al. Real-world clinical effectiveness of esketamine nasal spray based on the Montgomery-Åsberg Depression Rating Scale (MADRS) among patients with treatment-resistant depression in the United States. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA.
Real-world, retrospective study to evaluate the effectiveness of SPRAVATO in patients with TRD based on MADRS data and compare findings to trial results.¹ 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 T, Joshi K, Zhdanava M, et al. Response and remission on esketamine nasal spray in patients with treatment-resistant depression overall and among TMS-naive subgroup. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA. Marton T, Joshi K, Zhdanava M, et al. Clinical effectiveness and persistence on esketamine nasal spray in patients with treatment-resistant depression overall and TMS-naive subgroup. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA.
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%.
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.⁴ 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.
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.⁶ 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.⁷ 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.²⁰ 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.²¹ 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 2022.⁵ 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.⁸ 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 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 United States
Samalin L, Mekaoui L, Rothärmel M, et al. Use of esketamine nasal spray in patients with treatment-resistant depression in routine practice: a real-world French study. Dépress Anxiety. 2024;2024(1):7262794.
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).¹⁰ 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 Characteristics¹⁰ 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. The median number (IQR) of lines of treatment before SPRAVATO initiation was 6 (4-9); 88.5% of patients received ≥3 lines of treatment. 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% For patients <65 years of age, 93.7% (119 of 127) initiated with SPRAVATO 56 mg, with 80.7% (n=96) titrating to SPRAVATO 84 mg. For patients ≥65 years of age, 92.6% (25 of 27) initiated with SPRAVATO 28 mg, with 88.0% (n=22) titrating to SPRAVATO 56 mg, and then 72.7% (n=16) titrating to SPRAVATO 84 mg. 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. Reasons for discontinuations (after a median time, weeks) were: Unsatisfactory effect: 52.0% (5.4 weeks) In accordance to the Summary of Product Characteristics: 26.4% (28.9 weeks) Patient demand: 24.8% (9.6 weeks) Adverse Events: 8.8% (10.6 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%), blood pressure 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), suicidal ideation (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 blood pressure (n=6), somnolence (n=5), dissociation (n=4), vertigo (n=4), suicidal ideation (n=2), and suicide attempt (n=1). 1 fatality occurred of unknown cause and was considered unrelated to SPRAVATO.
Gutiérrez-Rojas L, Vendrell-Serres J, Ramos-Quiroga JA, et al. Compassionate use of esketamine intranasal in patients with severe major depressive disorder resistant to the treatment. [Published online ahead of print August 7, 2024]. J Psychopharmacol. doi:10.1177/02698811241267837.
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 Products¹¹ 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 M, Scott EM, Codyre D, et al. A real-world study examining the impact of esketamine nasal spray in people living with major depressive disorder in Australia and New Zealand. Psychiatry Res Commun. 2024;4(3):100177.
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.¹² 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 major depressive episodes 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 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.⁹ 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.
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 2023.¹³ 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); 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-D, Hamilton Depression Rating Scale; 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; PTSD, post-traumatic stress disorder; q, quarter; QIDS-SR16, Quick Inventory of Depressive Symptomatology-16; REMS, Risk Evaluation and Mitigation Strategies; rTMS, repetitive transcranial magnetic stimulation; TMS, transcranial magnetic stimulation; SAE, serious adverse event; SD, standard deviation; SE, standard error; SI, suicidal ideation; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TMS, transcranial magnetic stimulation; TRD, treatment-resistant depression; WPAI, Work Productivity Activity Index.

Indirect Comparison of SUSTAIN-2 vs European Observational TRD cohort

Oliveira-Maia et al (2023 and 2023)¹⁴^,¹⁵ reported results of an indirect comparison between 2 studies to compare SPRAVATO efficacy data with real-world treatment (RWT) strategies¹⁴ (ICEBERG study) and real-world (RW) polypharmacy strategies¹⁵ for TRD.

Study Design

Two studies with similar recruitment conditions were selected¹⁴^,¹⁵:

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.¹⁴^,¹⁵

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.¹⁴^,¹⁵

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.¹⁴^,¹⁵

Results

In the ICEBERG study, treatment with SPRAVATO (N=559) was indirectly compared vs RWT strategies (N=307)¹⁴ and RW polypharmacy (N=225).¹⁵

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.¹⁴ 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.¹⁵ 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).¹⁴

Chances of Response and Remission at Month 6 for SPRAVATO vs Real-World Treatment¹⁴

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 Polypharmacy¹⁵

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.¹⁴

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.¹⁴

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.¹⁴^,¹⁵

POSTMARKETING SAFETY DATABASES

REMS Database

5-year REMS Data

Safety data of interest were gathered from REMS patient enrollment and monitoring forms completed by certified US healthcare settings and pharmacies from March 5, 2019, to January 5, 2024. In 58,483 patients who received at least 1 SPRAVATO treatment session, 61.1% were female with a mean age (SD) of 43.4 (14.7). Of these patients, 44,908 (76.8%) reported ≥1 adverse event of special interest (AESI). Sedation, dissociation, and increased BP (defined as post-administration BP increase of ≥20 mmHg or a value ≥180 mmHg for systolic, or ≥15 mmHg or a value of ≥105 mmHg for diastolic, compared with values prior to administration) were reported by 36,190 (61.9%), 38,410 (65.7%), 6,818 (11.7%) patients, respectively. In 1,486,213 treatment sessions, sedation, dissociation, and increased BP were reported in 515,367 (34.7%), 608,746 (41.0%), and 13,510 (0.9%) of treatment sessions, respectively.¹⁶

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. The rate of increased BP dropped from 1.6% during the first session to below 1% by the end of the induction phase. The percentage of patients experiencing ≥1 AESI was similar between males (76.9%) and females (76.8%). Although the rates of sedation and dissociation were consistent across sexes and age groups, an increased proportion of males vs females (13.4% vs 10.6%) experienced increased BP. Increased BP was also more common in patients aged 25-55 years and >55 years (11.7% and 12.9%, respectively) vs patients <25 years old (6.8%).¹⁶

Serious AEs (SAEs) were defined as any event that leads to hospitalization, disability or permanent damage, death, a life-threatening condition, or any event that may jeopardize the patient or may require intervention to prevent one of these outcomes. SAEs were reported by 1.6% of patients and in <0.1% of treatment sessions. Of 2,096 SAEs reported, vomiting (7.5%), increased BP (6.8%), and nausea (6.7%) were the most frequent (≥5%); 4.1% of events were unevaluable. The occurrence rate of SAEs was similar for males (1.5%) and females (1.6%); younger patients experienced a slightly lower rate compared to other age groups: <25 years, 1.1%; 25-55 years old, 1.5%; and >55 years, 1.9%.¹⁶

AESIs reported as SAEs during the overall evaluation period (per the REMS patient monitoring form) are illustrated in Table: Summary of AESIs Associated With Reports of SAEs.

Summary of AESIs Associated With Reports of SAEs¹⁶

n (%)	SAEs^a,b(N=2096)
Sedation	26 (1.2)
Dissociation	83 (4.0)
Increased BP	142 (6.8)
Abbreviations: AE, adverse event; AESI, adverse event of special interest; BP, blood pressure; MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event. ^aTotal number of events reported. ^bSAEs are coded using MedDRA version 22.0.

Based on the REMS patient monitoring form, <0.1% of patients across all treatment sessions reported SAEs that were life-threatening, resulted in death, caused disability or permanent damage; 0.3% resulted in hospitalization; 0.5% were not specified; and 0.8% were considered important medical events.¹⁶

FDA Adverse Event Reporting System

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹⁷ 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 SAEs, 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 SAEs was higher in patients receiving SPRAVATO 84 mg compared to patients receiving SPRAVATO 56 mg. Females were also more likely to suffer from SPRAVATO-related SAEs 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.¹⁷

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).²² 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.¹⁸

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.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 09 September 2024. This response does not include studies reporting <30 patients treated with SPRAVATO.

References

Show

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2	Marton T, Joshi K, Zhdanava M, et al. Response and remission on esketamine nasal spray in patients with treatment-resistant depression overall and among TMS-naive subgroup. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA.
3	Marton T, Joshi K, Zhdanava M, et al. Clinical effectiveness and persistence on esketamine nasal spray in patients with treatment-resistant depression overall and TMS-naive subgroup. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA.
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