Slow-Paced Breathing and Electrical Vagus Nerve Stimulation as Add-on Treatments for Depression

Registry record from ClinicalTrials.gov (NCT07844733). This is a study registration, not published results. Lead sponsor: Elisabeth Balint. Recruitment status: NOT_YET_RECRUITING. Phase: NA. Study type: INTERVENTIONAL. Enrollment: 160 participants (ESTIMATED). Conditions: Depression - Major Depressive Disorder. Interventions: BEHAVIORAL: Slow-Paced Breathing; DEVICE: Transcutaneous Auricular Vagus Nerve Stimulation (tVNS); DEVICE: Sham Auricular Electrical Stimulation; OTHER: Treatment as Usual (TAU). Primary outcome measures: Change From Baseline in Beck Depression Inventory-II (BDI-II) Score at Week 4 , Baseline (Week 0) and post-intervention (Week 4). Brief summary: Depression is a common mental health condition, and standard psychiatric therapies do not always lead to satisfactory recovery. As a result, there is an urgent need for effective, complementary treatments. The vagus nerve is the main component of the parasympathetic nervous system, which regulates bodily rest and calms inflammatory responses. In clinical depression, vagus nerve activity is often reduced, and low-grade inflammation is frequently observed. While electrical stimulation of the vagus nerve via surgically implanted devices has been shown to reduce depressive symptoms, its invasive nature carries risks. Non-invasive alternatives-such as slow-paced breathing exercises or gentle transcutaneous electrical stimulation at the outer ear-offer promising ways to stimulate this nerve safely without surgery. The main purpose of this clinical study is to evaluate whether slow-paced breathing is an effective add-on therapy to reduce depressive symptoms in hospitalized patients compared to standard multimodal psychiatric treatment. Additionally, the study investigates whether the effects of slow-paced breathing are comparable to transcutaneous auricular vagus nerve stimulation (tVNS) and whether they differ from a sham (placebo) stimulation. A total of 160 adult inpatients with at least a moderate depressive episode will be randomly assigned to one of four groups during their hospital stay: Group 1 (Slow-Paced Breathing): Participants practice a guided, slow-paced breathing technique (inhaling for 4 seconds, exhaling for 6 seconds) for 20 minutes, 3 times daily, 5 days per week over 4 weeks. Group 2 (Electrical Vagus Nerve Stimulation): Participants receive non-invasive electrical stimulation to the outer ear canal using a certified medical device (tVNS) for 20 minutes, 3 times daily, 5 days per week over 4 weeks. Group 3 (Sham Stimulation): Participants receive identical-looking electrical stimulation applied to the earlobe (an area lacking vagal nerve fibers) on the same schedule, serving as an active control. Participants do not know whether they receive active or sham stimulation. Group 4 (Treatment as Usual): Participants receive the standard multimodal inpatient psychiatric treatment program alone, alongside daily logging of relaxation and mindfulness activities. All participants continue to receive standard psychiatric care. Depressive symptoms are assessed using the Beck Depression Inventory-II (BDI-II) and the Hamilton Depression Rating Scale. In addition, heart rate variability (HRV) via a 24-hour recording and blood inflammatory markers (such as IL-6 and CRP) are measured before and after the 4-week intervention period to explore the physiological mechanisms of vagus activation. A follow-up questionnaire is completed after 3 months to assess long-term outcomes.