Vagus Nerve Stimulation in Difficult-to-Treat Depression: When Does It Work Best?

Gus Alva, MD, discussed vagus nerve stimulation (VNS) as an underutilized but clinically important neuromodulation option in the stepwise management of difficult-to-treat depression, from the 2026 Southern California Psychiatry conference.

Alva described the current landscape of interventional options for difficult-to-treat depression as broader than many clinicians appreciate, encompassing IV ketamine, intranasal esketamine, repetitive transcranial magnetic stimulation, deep brain stimulation, and VNS. He argued that VNS occupies a distinct and underappreciated position within this continuum, and that its consideration should not be reserved exclusively for patients with the highest degree of chronicity or treatment failure. He proposed that patients who have not responded adequately to 4 or more treatment modalities—including psychotherapy, medications, augmentation, IV or intranasal ketamine, and electroconvulsive therapy—are appropriate candidates for VNS evaluation.¹

Alva acknowledged that VNS differs from other neuromodulation modalities in its onset profile, noting that clinical benefit tends to accrue gradually over time rather than emerging acutely. He emphasized, however, that once established, VNS provides continuous stimulation 24 hours a day, 7 days a week—a characteristic he identified as uniquely valuable for patients seeking sustained, nonepisodic intervention. He also addressed a common misconception regarding the outpatient use of VNS, clarifying that outpatient programming and personalized device titration are feasible when clinicians work with appropriate device support, specifically referencing coordination with LivaNova (the manufacturer) to optimize individualized stimulation parameters.

Alva then briefly previewed additional session content on sleep disorders, framing sleep as a critical and frequently underaddressed dimension of psychiatric and neurological health. He highlighted the glymphatic system—the process by which interstitial fluid comingles with cerebrospinal fluid to clear metabolic waste products including beta-amyloid during sleep—as a key mechanistic reason why sleep quality carries long-term neurological significance beyond daytime functioning.²

Dr Alva is a board-certified psychiatrist and the Mood Disorders Section Editor for Psychiatric Times.

References

1. Conway CR, Aaronson ST, Sackeim HA, et al. Vagus nerve stimulation in treatment-resistant depression: a one-year, randomized, sham-controlled trial. Brain Stimul. 2025;18(3):676–689.

2. Jessen NA, Munk AS, Lundgaard I, et al. The glymphatic system: a beginner's guide. Neurochem Res. 2015;40(12):2583–2599.