Concomitant Use of SPRAVATO With Somatic Treatments

Summary

• Across all phase 3 studies in the treatment-resistant depression (TRD) clinical trial program, patients were prohibited from using concomitant somatic treatments that included electroconvulsive therapy (ECT), vagal nerve stimulation (VNS), deep brain stimulation, or transcranial magnetic stimulation.¹
• A small real-world prospective study (except for 1 patient who was included retrospectively) evaluated the outcomes of add-on VNS and esketamine (intravenous or intranasal) in patients with difficult-to-treat depression. Over 12 months, patients showed a reduction in depressive symptoms (30.9 to 18.3) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score and a decreased rate of hospitalization.²
• A case series described 4 adults with severe TRD who received concomitant ECT and SPRAVATO. Over 24 weeks, patients demonstrated a 37-83% reduction in depressive symptom severity, as measured by the MADRS, with no reported relapses. Adverse events were mild to moderate and transient, with no serious safety concerns reported.³
• A case report described an 18-year-old female with TRD who was treated with SPRAVATO alongside weekly ECT. The patient experienced relapses following treatment discontinuation or missed doses. SPRAVATO was reinitiated after residential treatment, and weekly dosing was continued for over 2 years during which the patient remained relatively stable.⁴
• A case report described a 29-year-old female with TRD and high-risk suicidal ideation who received SPRAVATO in combination with accelerated intermittent theta-burst stimulation (iTBS). The patient demonstrated improvements in depressive symptoms and suicidal ideation during the acute treatment course, with further improvement noted at the 2-week follow-up.⁵
• A case report described a 62-year-old female with TRD who experienced loss of response during maintenance SPRAVATO treatment. Adjunctive transcutaneous auricular VNS was initiated while SPRAVATO was continued. Following VNS initiation, depressive symptoms progressively improved (MADRS decreased 37 to 3) and the patient achieved sustained remission, with complete functional recovery (Sheehan Disability Scale decreased 30 to 0).⁶

Clinical studies

Real-World Study with VNS

Kavakbasi et al (2023)² reported outcomes from a small real-world prospective (except for 1 patient who was included retrospectively) study evaluating the outcomes of add-on VNS and esketamine (intravenous or intranasal) in patients with difficult-to-treat depression (mean, 8.9 failed antidepressant trials in the current episode). Six patients were included in the analysis.

• Mean MADRS total score decreased from baseline to the 12-month follow-up (30.9 vs 18.3).
• Mean number of esketamine sessions per month decreased from 2.33 at 6 months to 1.14 at 9 months and 0.8 at 12 months, and the mean number of hospitalizations per month decreased from before vs after VNS (0.17 vs 0.11).
• The study had several limitations, including a small sample size, a lack of information in terms of which patients received the different formulations of esketamine, and the absence of a control group.

Case Series/Reports

Use with ECT

López-Rodríguez et al (2026)³ described a case series of 4 adults (50-72 years of age) with severe TRD who had demonstrated a partial response (defined as a 25% to 49% reduction in MADRS score from baseline) or waning benefit with ECT or SPRAVATO administered independently. During acute treatment, patients received concomitant bilateral ECT (2-3 sessions/week) and SPRAVATO (28-84 mg; twice weekly during induction) on non-ECT days, with treatment schedules adjusted over the 24-week follow-up period based on effectiveness and tolerabilty. Two patients received combination therapy following a partial response to ECT or SPRAVATO monotherapy (Cases 1 and 2, respectively), whereas 2 patients (Cases 3 and 4) receiving maintenance ECT were administered SPRAVATO after experiencing relapse despite ongoing treatment.

• All patients with TRD who had inadequate response to prior antidepressants, augmentation strategies, psychotherapy, and/or ECT experienced further improvement after combined SPRAVATO and ECT treatment, with sustained improvements in mood, functioning, and/or social engagement.
• Concomitant ECT and SPRAVATO treatment was associated with decreases in MADRS total scores from 36 to 18 (50% reduction) in Case 1, 35 to 22 (37% reduction) in Case 2, 42 to 16 (62% reduction) in Case 3, and 36 to 6 (83% reduction) in Case 4.
• Functional improvement, measured on the Global Assessment of Functioning, was observed in all four cases (pre vs post): 35 vs 65 in Case 1, 40 vs 70 in Case 2, 30 vs 60 in Case 3, and 45 vs 72 in Case 4.
• Adverse events were transient and mild to moderate in severity, and consisted primarily of dissociation or postictal confusion, attributed to SPRAVATO and ECT, respectively.

Gao et al (2025)⁴ described the case of an 18-year-old female patient with TRD and comorbid eating disorder, in addition to generalized anxiety disorder, post-traumatic stress disorder (PTSD), and borderline personality disorder (BPD), who was treated with SPRAVATO.

• In addition to psychotherapy, the patient was previously treated with antidepressants, adjunctive antipsychotics, lithium, lamotrigine, several series of ECT, and ketamine as an infusion and a compounded intranasal spray. After trials with ketamine, she was prescribed SPRAVATO.
• In addition to weekly ECT, she initially received SPRAVATO twice weekly for 4 weeks and then weekly thereafter.
  • Adding esketamine to weekly ECT appeared to be more beneficial than ECT alone for a short period.
  • The patient experienced a relapse, with a serious suicide attempt, after stopping treatment.
• SPRAVATO was restarted following residential treatment for her eating disorder (56 mg for the first session, increased to 84 mg for subsequent sessions [twice weekly for 4 weeks]). The patient missed her second weekly SPRAVATO session and experienced a relapse, resulting in hospitalization.
• During hospitalization, SPRAVATO was resumed twice a week for 2 weeks and then once weekly. The patient’s mood has remained relatively stable with ongoing weekly SPRAVATO treatment for more than 2 years.

Use with iTBS

Chang et al (2026)⁵ described the case of a 29-year-old female with TRD, admitted for severe worsening of depressive symptoms, and high-risk suicidal ideation despite previous treatment with multiple antidepressants. The patient subsequently underwent structured psychotherapy, including cognitive behavioral therapy, and a course of repetitive transcranial magnetic stimulation (rTMS; 30+ sessions); however, clinically significant depressive symptoms and suicidal ideation persisted.

• The patient received a single dose of SPRAVATO 84 mg in combination with a 4-day accelerated iTBS protocol (iTBS was started before SPRAVATO) targeting the left dorsolateral prefrontal cortex.
• During the acute treatment course, depressive symptoms improved from baseline, with Patient Health Questionnaire-9 (PHQ-9) scores decreasing from 15 to 11, Hamilton Depression Rating Scale (HAM-D) scores decreasing from 27 to 20, and Beck Depression Inventory (BDI) scores decreasing from 41 to 28.
• At the 2-week follow-up, the clinical condition of the patient remained stable, with further improvements in PHQ-9 (8), HAM-D (17), and BDI (23) scores. The patient also reported improvement in suicidal ideation.
• The patient experienced transient dissociation following SPRAVATO administration, which resolved within approximately 2 hours without additional intervention. No headache, chest pain, neurological symptoms, serious adverse events, or unexpected complications were reported during treatment.

Use with VNS

Sierra et al (2026)⁶ described a case of a 62-year-old female with a 22-year history of recurrent major depressive disorder who also had TRD and had experienced approximately 20 depressive episodes. Previous treatments included multiple antidepressants, augmentation strategies, and cognitive behavioral therapy, with persistent functional impairment that prevented employment for more than 10 years.

• SPRAVATO was initiated at 56 mg twice weekly during induction and escalated to 84 mg based on clinical response and tolerability. During maintenance treatment, SPRAVATO was administered every 2 weeks.
• MADRS total scores were reduced from baseline by 62.2% at week 2, 78.4% at week 4, and 89.2% at week 6. However, symptom recurrence occurred by week 10 despite dose optimization.
• Adjunctive transcutaneous auricular VNS was initiated at week 14 while maintenance SPRAVATO treatment was continued. Stimulation was administered once daily for 30 minutes to the left tragus using a CE-certified device, with treatment intensity individualized according to tolerability. On days when both treatments were scheduled, VNS was administered immediately before SPRAVATO.
• Following VNS initiation, depressive symptoms progressively improved, with MADRS reductions from baseline of 62.2% at week 14, 73.0% at week 18, 83.8% at week 22, 86.5% at week 34, and 91.9% at week 46.
• At the final assessment, the patient achieved sustained remission (MADRS, 37 to 3), complete functional recovery (Sheehan Disability Scale, 30 to 0), improvement in patient-reported depressive symptoms (Patient Health Questionnaire-9, 22 to 4), and improved health-related quality of life (EuroQol 5-Dimension 5-Level, 65 to 96).
• No relapse or clinically significant adverse events were reported following VNS initiation.

Literature Search

• A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 August 2026.