An Old Idea, New Data: The Vagus Nerve and Durable Recovery in Treatment-Resistant Depression

A Pathway Functional Psychiatry Has Always Valued

For years, functional and integrative psychiatry has emphasized the importance of vagal tone in mental health. We talk about heart rate variability (HRV), breathwork, the gut-brain axis, inflammation, and stress resilience. The vagus nerve sits at the center of that discussion, linking the brain with the heart, gut, and immune system in ways that directly shape mental and physical health.

Because of this, the vagus nerve has long been part of how we think about emotional regulation and recovery from mental health challenges. New data suggest that directly stimulating this nerve may offer durable remission to patients struggling with treatment-resistant depression (TRD).

The Challenge of Durability in Treatment-Resistant Depression

Patients with treatment-resistant depression have often been through numerous medication trials, years of psychotherapy, and many have even tried interventional treatments like ketamine, TMS, and ECT. Often, treatments will yield partial responses and temporary relief, with sustained recovery being far more difficult to achieve.

A recent report from the RECOVER trial examined long-term outcomes of vagus nerve stimulation (VNS) in individuals with moderate to severe treatment-resistant depression (Conway et al., 2026). It’s not news that VNS can help those suffering with depression; it has demonstrated efficacy in many prior studies (Conway et al, 2025) (Schlaepfer et al, 2008). This study, however, focused on whether benefit was durable over time.

What the RECOVER Trial Found

In the study, individuals with treatment-resistant depression received standard treatment alongside either active or sham VNS, and outcomes were tracked over two years.

Among those who experienced meaningful improvement in depressive symptoms by 12 months, approximately 80 percent maintained that benefit at 24 months. Even more compelling, a subset of patients who had not improved at 12 months went on to show meaningful improvement between 12 and 24 months.

Beyond the usual psychometric assessments like the MADRS, functional outcomes and quality of life measures also showed sustained gains. Rather than producing a rapid mood shift like ketamine, which can be powerful but not always durable, VNS appears to promote more gradual, longer-lasting changes in the underlying regulatory networks.

Why This Matters Through a Functional Psychiatry Lens

From a functional psychiatry perspective, depression is not just a “chemical imbalance.” It is multifactorial, related to factors like nutrient deficiencies, gut imbalances, inflammation, metabolic dysfunction, and autonomic imbalance.

The vagus nerve is a critical player in the stress response, inflammatory tone, and gut-brain communication. Low vagal tone is under-discussed as a dynamic seen in major depression (Böttcher et al., 2024). Functional psychiatry clinicians support vagal tone indirectly through meditation and breathwork, metabolic optimization, anti-inflammatory nutrition, microbiome work, and psychotherapy. VNS offers a more direct way to modulate that same pathway.

Clinical Implications

VNS is not a first-line treatment, and it may not be right for every person with treatment-resistant depression. The RECOVER data highlights the importance of patience, with some individuals not showing improvement until well beyond the one-year mark.

The durability factor is particularly compelling, given that many treatments, including TMS and ketamine, may only offer transient relief for many. VNS may be incorporated into a comprehensive treatment plan addressing lifestyle, nutritional, metabolic, inflammatory, and psychological factors.

Final Thoughts

Functional psychiatry has long recognized the vagus nerve as central to mental health. These recent findings reinforce that targeting this pathway, even in severe and chronic depression, can lead to meaningful and sustained change.