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, 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 vagus nerve stimulation (VNS) and esketamine (intravenous or intranasal) in patients with difficult-to-treat depression. Over 12 months, patients showed a reduction in depressive symptoms and a decreased rate of hospitalization. The need for esketamine sessions declined from 2.33/month at 6 months to 0.8 at 12 months.²
• 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.³

Clinical studies

Real World Study

Kavakbasi et al (2023)² reported outcomes from a small real-world prospective (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 (mean, 8.9 failed antidepressant trials in the current episode). Six patients were included in the analysis. There was a significant improvement in the mean Montgomery-Åsberg Depression Rating Scale total score from the baseline at the 12-month follow-up (30.9 vs 18.3). Additionally, the 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 significantly decreased from before vs after VNS (0.17 vs 0.11). However, 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 Report

Gao et al (2025)³ described the case of an 18-year-old female patient with TRD and comorbid eating disorder, in addition to generalized anxiety disorder, PTSD, and 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.

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 18 September 2025.