DURABILITY OF VAGUS NERVE STIMULATION TREATMENT-RESISTANT DEPRESSION: NEW, MORE COMPREHENSIVE FINDINGS FROM THE RECOVER TRIAL

Patients with markedly treatment-resistant major depression (TRD) have low likelihood of benefiting from antidepressant treatments and high likelihood of rapid relapse if benefit is obtained. Hence, in the management markedly treatment-resistant MDD there are two very high thresholds to surmount: obtaining initial acute benefit and sustaining this benefit over time. Vagus Nerve Stimulation (VNS) of the left cervical vagus nerve, using a surgically-implanted pulse generator and electrical lead attached to the vagus nerve, received FDA approval for markedly TRD in 2005. Older studies of VNS demonstrated that patients with TRD who responded to VNS sustained response (60-70%). Subsequent studies using registry data also demonstrated high sustained antidepressant benefit.

Methods

The RECOVER VNS trial is the largest, prospective, device-based trial ever conducted in psychiatry, with 84 sites targeting 500 unipolar and 500 bipolar TRD participants. The goal of RECOVER is to characterize change in depressive symptoms, function, and quality of life (QoL) in a cohort of largely Medicare TRD patients. Here we report on the unipolar cohort, which has completed two years of the trial. Year one is tripleblinded, with blinded, offsite raters, blinded on site raters, and the patients themselves blinded. After year one, all participants become open-label and all devices were activated. The focus of this presentation is to report on the durability of benefits in those patients who were assigned to active VNS in year one total time spanning September 2019 to April 2025.

Participants

Adults with moderate-severe MDD with ≥4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (N=214).

Interventions

VNS and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, ketamine/esketamine) were characterized over the 12-month extension.

Main Outcomes and Measures

The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression–Improvement (CGII) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in patients without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori.

Results

Most patients with substantial benefit maintained their benefit (18-month median=78.8%; 24-month median=79.0% across 5 measures), as did patients with at least a meaningful benefit at 12 months (18-month median=83.1%; 24-month median=81.3% across 7 measures). Furthermore, many patients with no meaningful benefit at 12 months achieved it at 18 (median=30.6%) and 24 (median=37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatry modalities.

Conclusions and Relevance

Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of patients continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. These data add to the literature supporting the long-term durability of benefit of VNS in markedly TRD.

References

McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. Oct 2023;22(3):394–412. doi:10.1002/wps.21120 Sackeim HA, Brannan SK, Rush AJ, George MS, Marangell LB, Allen J. Durability of antidepressant response to vagus nerve stimulation (VNS). Int J Neuropsychopharmacol. Dec 2007;10(6):817–26. doi:10.1017/S1461145706007425