A Prospective, Multi-center Randomized, Controlled, Blinded Trial of Vagus Verve Stimulation for Difficult to Treat Depression: the RECOVER Trial

Abstract

Abstract Introduction: Therapeutic Vagus Nerve Stimulation (VNS) has been FDA-approved for treatment-resistant depression (TRD). In 2007, the US Centers for Medicare and Medicaid Services (CMS) issued a non-coverage decision, making access difficult for patients. In 2019, CMS requested a “coverage with evidence development trial” to determine potential VNS efficacy in the US Medicare TRD population. This trial, RECOVER, is co-sponsored by CMS and the device maker (LivaNova) to assess VNS efficacy over 12 months is large, multi-centered (N=71, US sites), randomized, and placebo-controlled. Methods: Inclusion criteria include: ≥18 years old, diagnosis of Major Depressive Disorder (MDD) or Major Depressive Episode (MDE) in bipolar disorder, chronic (2 years) or recurrent (≥ 4 MDEs), failure of four medical record-verified AD treatments in the current MDE, a score of ≥ 22 on the Montgomery Asberg Depression Rating Scale (MADRS). Exclusion criteria include: substance use and psychotic disorders, acute suicidal ideation/intention, severe personality disorder. All subjects undergo VNS implantation then randomized to active treatment (device on) or sham (implanted, not activated) for 12 months. Depression ratings are performed by blinded, offsite raters. The trial’s primary measure is number of months in response (active –vs- placebo). Results: 480 patients enrolled; subject mean age is 54.0, 34.6 mean MADRS, mean age of onset is 20.9, and 20.4 years of lifetime MDE. Average failed lifetime ADs is 14.1, with many receiving aggressive treatments: ECT (41.9%), TMS (46.7%), and ketamine (21.3%). Many report psychiatric hospitalizations (64.0%); attempted suicide (43.8%). To date, 222 patients (including 40 early terminated) have completed the trial’s first year. Conclusions: RECOVER is the largest prospective, randomized, device-based, placebo-controlled MDD trial ever undertaken; enrolling severe TRD patients not studied in most MDD clinical trials. It will provide a thorough understanding of the nature of VNS response (e.g., onset of response and potential baseline outcome predictors). Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Treatment-Resistant Depression, Vagus Nerve Stimulation, Difficult to Treat Depression, Major Depressive Disorder