¹Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom, ²Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Research & Innovation, Newcastle upon Tyne, United Kingdom

Background: Data from the RECOVER randomized controlled trial (RCT) conducted in the United States (NCT03887715) supports the use of implanted vagus nerve stimulation (VNS), alongside other ongoing treatments, for patients with marked difficult-to-treat depression (DTD). Reductions in depressive symptoms, an improvement in psychosocial functioning and quality of life (QoL), and a durable response are seen (summarized in this symposium by Dr Rush). This presentation will build on this by covering three areas: 1) Additional naturalistic data of VNS in DTD; 2) Expert clinical opinion regarding VNS use; and 3) Implications from VNS studies regarding how efficacy and effectiveness of treatments for DTD should be investigated.

Aims & Objectives: To present naturalistic data to compliment RCT evidence regarding the efficacy and effectiveness of VNS for DTD; Consider clinical practicalities in the use of VNS; and to reflect on study design for treatment trials in DTD.

Method: Data will be presented from the European naturalistic prospective multi-center observational study RESTORE-LIFE (NCT03320304) examining 12-month outcomes in comparison with RECOVER, and effects of VNS on both negative and positive affect as well as QoL. Data from a Delphi study of a panel of 32 international experts’ consensus views om 55 statements regarding the use of VNS for the treatment of DTD will be presented. Implications from VNS in DTD studies regarding trial duration, outcome measures and when these are assessed will be considered.

Results: RESTORE-LIFE baseline characteristics (n=147) were similar to RECOVER with regards to depression severity and impairment in QoL, and mean number of lifetime failed antidepressant treatments (medications, ECT, TMS and psychotherapies): 13.3 (8.4) in RECOVER and 15.6 (10.7) in RESTORE-LIFE. The mean percent time in partial response, response, and remission over 12 months on the clinician-rated MADRS was 41.1%, 24.5%, and 14.7% in RESTORE-LIFE and 32.9%, 18.9%, and 9.5% in RECOVER. In additional to improvements in symptoms, increased QoL and positive affect were seen in RESTORE-Life. In the Delphi study, consensus was reached by the panel on 75% of the statements covering a wide range of issues including the main goals for VNS being the long-term management of symptoms and improvement in quality of life, that the treatment is appropriate for all ages of patients and that there are few contraindications. Regarding study design, analysis of VNS data support the importance of assessing function and QoL and not just depressive symptoms, considering partial response (≥30% improvement) and not just response (≥50% improvement) or remission, and assessing outcomes over a prolonged time frame rather than at one single time point.

Discussion & Conclusions: Naturalistic outcome data of VNS in DTD supports the findings from RECOVER. VNS appears to not only decrease negative affect but increase positive affect. There is broad expert consensus regarding many aspects of patient selection and use of VNS clinically. Lessons can be learnt from the VNS dataset to help inform future studies in patients with DTD.