SUMMARY

• Phase 3 clinical trials of SPRAVATO in patients with treatment-resistant depression (TRD)^1-4 excluded patients who were nonresponsive to an adequate course of electroconvulsive therapy (ECT) in the current major depressive episode, defined as ≥7 treatments with unilateral/bilateral ECT.^5-8
• Phase 3 clinical trials of SPRAVATO in patients with moderate to severe major depressive disorder and active suicidal ideation with intent,^9,10 allowed for the inclusion of ECT nonresponders at imminent risk for suicide.^11,12 However, no subgroup analyses were performed to assess efficacy or safety in these patients.
• A multicenter, open-label study in the Netherlands evaluated SPRAVATO (28-84 mg) in 42 patients with severe TRD; 61.9% of patients had received prior ECT. At 28 days, the Montgomery-Åsberg Depression Rating Scale (MADRS) score decreased by 10.1 points (P<0.001). Prior ECT did not affect induction-phase outcomes but was linked to slight worsening during the continuation phase. No serious adverse events (AEs) occurred.¹³ 
• A retrospective study in Germany assessed SPRAVATO in 96 inpatients with TRD; 39 had prior ECT nonresponse in the current episode (ECT+) and 57 had not previously received an adequate course of ECT (ECT-). Both the ECT+ and ECT- groups exhibited significant improvement (MADRS reduction: 8.7 and 13.0 points, respectively). For the ECT+ vs ECT- group, the response rate was 21.9% vs 34.9% and the remission rate was 12.1% vs 24.4%, respectively, with no significant differences. The suicidality score decreased in both groups. No major safety concerns were reported.¹⁴ 
• A real-world, prospective study in Spain evaluating the effectiveness, tolerability, and safety of SPRAVATO in 16 patients with TRD, including 6 with prior ECT, reported no significant differences in MADRS scores between those who received prior ECT and those who did not.¹⁵
• A real-world, retrospective study in Israel evaluating the effectiveness of SPRAVATO in 62 adult patients with TRD, including 15 with prior ECT, reported that significantly more patients with prior ECT responded to treatment with SPRAVATO vs patients without prior ECT during the acute phase (8 weeks) of treatment (P<0.05).¹⁶

Clinical Data

Real-world Studies

Busz et al (2025)¹³ conducted a multicenter, openlabel, realworld cohort study in the  Netherlands within the Dutch compassionate use program to evaluate SPRAVATO among adult patients with severe TRD and to examine whether prior ECT influenced symptom trajectories during induction (0-28 days) and continuation (29-90 days) phases.

Study Design/Methods

SPRAVATO was administered twice weekly during a 4-week induction phase (dose range, 28-84 mg), followed by once weekly to every 2 weeks in the continuation phase, based on clinical response and tolerability. The primary outcome was the absolute change in the MADRS score over the first 28 and 90 days of treatment. Other outcomes included response (≥50% reduction in MADRS score), remission (MADRS ≤10), and minimal clinically important difference (MCID; ≥10-point decrease in MADRS score). Moderation by prior ECT was analyzed using linear mixed models.

Results

• Of the 42 adults (mean age, 54.8; female, 73.8%; mean baseline MADRS, 33.6) with TRD (≥2 failed antidepressant trials) enrolled, 61.9% had a history of ECT.
• Induction (0-28 days): During the 4‑week induction phase, the mean MADRS score decreased by 10.1 points (95% confidence interval [CI], 7.3-12.6; t=7.20; P<0.001), corresponding to a large effect size (Cohen’s d=1.9). Furthermore, 28.6% of patients met the response criterion, 14.3% achieved remission, and 52.4% reached the MCID threshold.
• Continuation (29-90 days): Across the continuation phase, there was no additional statistically significant decrease in the overall MADRS score. By day 90, 35.7% of patients met the response criterion, 19.0% achieved remission, and 47.6% reached MCID.
• Moderation by prior ECT: In the induction phase, prior ECT did not significantly moderate the MADRS score change (ECT × time estimate, 0.11; 95% CI, -0.12 to 0.35; P=0.338). In the continuation phase, prior ECT significantly moderated symptom trajectory (ECT × time estimate, 0.15; 95% CI, 0.05-0.24; P=0.003), with patients who received vs did not receive prior ECT showing slight daily worsening of +0.06 MADRS points (95% CI, 0.01-0.12; P=0.024) vs slight daily improvement of -0.08 MADRS points (95% CI, -0.16 to -0.01; P=0.034).
• Safety and discontinuation: Across 1121 SPRAVATO sessions, no serious AEs were reported; transient dissociation and blood pressure elevation were common and well tolerated. By day 90, 33.3% of patients had discontinued treatment (due to AEs in 3 patients, acute suicidality in 1 patient, and lack of efficacy in 10 patients).

Kavakbasi et al (2025)¹⁴ performed a retrospective, singlecenter, inpatient, real-world cohort study comparing SPRAVATO effectiveness between adult patients with TRD with prior ECT nonresponse (ECT+) and those without an adequate ECT course in the current episode (ECT-) using investigator‑rated MADRS, patient‑rated Beck’s Depression Inventory II (BDI-II), and the MADRS suicidality item.

Study Design/Methods

SPRAVATO was typically started at 56 mg and was titrated to 84 mg by approximately the third session, being administered twice weekly; oral medications and psychotherapy were continued. Outcomes of interest were changes in depression severity and suicidal ideations, response rates, and remission rates. A factorial analysis of variance (ANOVA) model was used, with prior ECT status as a covariate.

Results

• Among the 96 inpatients (mean age, 47.0 years; women, 52.1%) with TRD (ECT+, n=39; ECT-, n=57), the mean MADRS score and BDI-II scores at baseline were 32.6 and 37.6, respectively, and 58.3% of patients had ≥1 psychiatric comorbidity
• Depression severity: The MADRS score improved significantly overall (F=27.389; P<0.001), with no significant time × ECT interaction (F=2.166; P=0.143) among ECT+ patients. ECT+ patients had a higher overall MADRS score (F=10.386; P=0.002).
• Mean changes in MADRS scores: The ECT+ group showed an MADRS score improvement of 8.7 points (from 37.3 to 28.6; P=0.001), while the ECT- group showed an MADRS score improvement of 13.0 points (from 34.7 to 21.7; P<0.001).
• Mean changes in BDI-II scores: The BDI-II score decreased by 8.8 points in the ECT+ group (P=0.010) and by 14.6 points in the ECT- group (P<0.001). History of ECT non-response did not impact changes in BDI-II over time (P=0.124).
• Response and remission: In the ECT+ vs ECT- group, the response rate was 21.9% vs 34.9% (P=0.167) and the remission rate was 12.1% vs 24.4% (P=0.141).
• Suicidality: Suicidal ideation decreased significantly in both groups (F=17.196; P<0.001). Baseline was higher in the ECT+ group by 0.7 points (P=0.017); the follow-up difference was not significant. History of ECT non-response did not influence changes in suicidality during the treatment course (P=0.457).
• Safety: No deaths were noted, but there was 1 suicide attempt. Treatment discontinuation was reported in 9.4% of patients, primarily due to intolerable dissociations (n=4), sedation and dizziness (n=1), discontinuation against medical advice (n=2), switch to ECT due to worsening of depression (n=1) and discontinuation due to subjective inefficiency of treatment (n=1).

Vendrell-Serres et al (2024)¹⁵ conducted a single-center, real-world, prospective study in Spain from February 2020 to November 2022 to evaluate the effectiveness, tolerability, and safety of SPRAVATO in adult patients with TRD enrolled in an expanded use program prior to commercial availability of SPRAVATO. To be eligible for treatment, patients were required to have failed ≥2 oral antidepressants during the current episode, ≥1 combination/augmentation treatment, and have refused or failed ≥1 nonpharmacological treatment, such as ECT. The study also explored the effect of prior ECT on treatment response.

Study Design/Methods

• SPRAVATO (dose range, 28 mg to 84 mg) was administered twice-weekly in the 4-week induction phase, followed by once-weekly to every 2 weeks in the 6-month maintenance phase, based on individual clinical response and tolerability. The follow-up period was up to 4 months.
• Depressive symptoms using the MADRS were assessed at baseline (T1), and after 48 hours (T2), 8 days (T3), 15 days (T4), 22 days (T5), 29 days (T6), 2 months (T7), 3 months (T8), and 4 months (T9).
• Response was defined as ≥50% reduction in the baseline MADRS score, and remission was defined as a MADRS score of ≤12.

Results

• 16 patients were included (mean age, 53.1 years; age range, 27 to 71 years; female, 56.3%; mean baseline MADRS score, 36.7), of which 6 (37.5%) were treated with prior ECT.
• The mean MADRS scores at T1, T6, and T9 were 26.7, 19.1, and 16.0, respectively (P<0.00001).
• At the end of the induction phase, 50.5% of patients responded, while 31.3% remitted at the end of the study.
• Mixed model analysis of the influence of prior ECT on MADRS scores reported no significant differences between patients who previously received ECT and those who did not (coefficient, -1.75; CI, -6.88 to 3.37; P=0.503).
• Two patients discontinued treatment prematurely due to a worsening of depressive symptoms.
• AEs included dissociation (37.5%), sleepiness (25.0%), nausea (18.8%), anxiety (12.5%), blurry vision, paresthesia, high blood pressure and headache, and metallic taste (6.25% each).
• All AEs were mild and did not require treatment, except for 1 moderate case of high blood pressure and headache, which was treated with captopril 25 mg.
• No AEs were specified for the group of patients who had prior ECT.

Dvorak et al (2024)¹⁶ conducted a single-center, real-world, retrospective study in Israel from January 2021 to January 2023 to evaluate the effectiveness of SPRAVATO in adult patients with TRD, including the influence of prior ECT on SPRAVATO treatment.

Study Design/Methods

• The recommended dosing of SPRAVATO was administered twice weekly during the first 4-8 weeks of treatment, followed by weekly in the maintenance phase for 4 weeks, and then continued once every two weeks for at least 6 months.
• Assessments were made using the Quick Inventory of Depressive Symptomatology (QIDS) score at baseline, weekly during the acute phase, and monthly during the maintenance phase (4-6 months).
• In the acute phase, response was defined as a 30% improvement in the baseline QIDS score; partial response, a 9-30% improvement; nonresponse, a <9% improvement.
• In the maintenance phase, response was defined as >45% improvement in the baseline QIDS score; partial response, 25-45% improvement; nonresponse, <25% improvement.

Results

• 62 patients were included (mean age, 43.2 years; female, 54.1%), in which 15 received prior ECT.
• In the acute phase, 22 patients (35.5%) were responders, 17 patients (27.4%) were partial responders, and 23 patients (37.1%) were non-responders.
• In the maintenance phase, 17 patients (51.5%) were responders, 11 patients (33.3%) were partial responders, and 5 patients (15.2%) were non-responders; 33 patients completed the maintenance phase.
• QIDS scores significantly decreased from the baseline in the acute and maintenance phases (baseline, 22.73±4.8; acute phase, 16.55±6.5; and maintenance phase, 12.15±6.37; P<0.001).
• During the acute phase, significantly more patients with prior ECT responded to treatment with SPRAVATO vs patients without prior ECT (53.3% vs 31.8%; P<0.05).

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 December 2025.

This response excludes case reports.^17-22