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

ConditionDepression - Major Depressive Disorder
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-60
SponsorElisabeth Balint

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Inpatient psychiatric admission at Privatklinik Meiringen

Clinical primary diagnosis of at least a moderate depressive episode

Beck Depression Inventory-II (BDI-II) score of at least 20 at admission

Age between 18 and 60 years

Disqualifiers

Active substance use disorder / addiction

Current psychosis

Bipolar disorder

Borderline personality disorder

Trial design

Design model

Parallel

Treatments tested in this trial

  • Slow-Paced Breathing

    Behavioral

    Guided slow-paced breathing technique with prolonged exhalation (4 seconds inhalation, 6 seconds exhalation, resulting in 6 breaths per minute) to stimulate the vagus nerve. Conducted for 20 minutes, 3 times daily, 5 days per week over a period of 4 weeks in a seated position, accompanied by daily protocol logging. Administered in addition to standard inpatient psychiatric care.

  • Transcutaneous Auricular Vagus Nerve Stimulation (tVNS)

    Device

    Electrical nerve stimulation using a CE-certified class IIa medical device (tVNS® by tVNS Technologies GmbH). Stimulation is applied via custom ear electrodes to the cymba conchae of the left outer ear canal to transcutaneously activate vagal afferents. Parameters: 25 Hz frequency, 250 µs pulse duration, 28 s ON / 32 s OFF cycle, intensity adjusted individually between 0.1 and 5.0 mA below pain threshold. Administered for 20 minutes, 3 times daily, 5 days per week over 4 weeks as an add-on to standard inpatient care.

  • Sham Auricular Electrical Stimulation

    Device

    Sham sensory control using identical stimulation parameters (25 Hz, 250 µs pulses, 28 s ON / 32 s OFF) and device setup as active tVNS, but the stimulation electrode is attached to the left earlobe, a region devoid of vagal innervation. Conducted for 20 minutes, 3 times daily, 5 days per week for 4 weeks in addition to standard inpatient care.

  • Treatment as Usual (TAU)

    Other intervention

    Standard multimodal inpatient psychiatric and psychotherapeutic treatment program including medication, psychotherapy, and clinical ward routine, accompanied by daily logging of relaxation exercises.

Treatment groups

160 Participants
are divided into 4 treatment groups
Group A: Slow-Paced BreathingExperimental treatment 1 intervention
Group B: Transcutaneous Auricular Vagus Nerve Stimulation (tVNS)Active comparator 1 intervention
Group C: Sham Auricular StimulationSham comparator 1 intervention
Group D: Treatment as Usual (TAU)Other 1 intervention

Trial outcomes

Primary outcomes

1

Change From Baseline in Beck Depression Inventory-II (BDI-II) Score at Week 4

The Beck Depression Inventory-II (BDI-II) is a 21-item self-report instrument used to measure the severity of depressive symptoms. Each item is scored on a 4-point scale ranging from 0 to 3, yielding a total score from 0 to 63 points. Higher scores indicate greater severity of depression (0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression). The change in the total score from baseline (Week 0) to completion of the 4-week intervention period will be analyzed.

Time frame
Baseline (Week 0) and post-intervention (Week 4)

Secondary outcomes

1

Change From Baseline in Hamilton Depression Rating Scale (HAMD) Score at Week 4

The Hamilton Depression Rating Scale (HAMD) is a clinician-rated assessment tool used to quantify the severity of depressive symptoms in patients diagnosed with depression. The scale rates various depressive symptoms (including mood, feelings of guilt, suicide ideation, insomnia, anxiety, and somatic symptoms). Higher total scores reflect greater symptom severity. The change from baseline (Week 0) to completion of the 4-week intervention period will be analyzed.

Time frame
Baseline (Week 0) and Week 4 (post-intervention)
2

Change From Baseline in Brief Symptom Checklist (BSCL) Score at Week 4 and 16

The Brief Symptom Checklist (BSCL) is a validated self-report questionnaire assessing current subjective psychological distress and psychiatric symptom burden across multiple dimensions (e.g., somatization, depression, anxiety). Items are rated on a 5-point Likert scale (0 = not at all, to 4 = extremely), with higher scores reflecting higher levels of subjective psychological distress. Changes from baseline to Week 4 and the 3-month follow-up (Week 16) will be evaluated.

Time frame
Baseline (Week 0), Week 4 (post-intervention), and Week 16 (3-month follow-up)
3

Change From Baseline in General Self-Efficacy Scale (SWE) Score at Week 4 and Week 16

The General Self-Efficacy Scale (SWE / Selbstwirksamkeitserwartung) is a self-report instrument assessing optimistic self-beliefs and confidence in coping with a variety of difficult demands and life challenges. Higher total scores indicate a greater perceived sense of personal self-efficacy and competence. Changes from baseline to Week 4 and the 3-month follow-up (Week 16) will be evaluated.

Time frame
Baseline (Week 0), Week 4 (post-intervention), and Week 16 (3-month follow-up)
4

Change From Baseline in Heart Rate Variability (HRV) Parameters at Week 4

Heart rate variability will be measured using 24-hour ambulatory ECG recordings analyzed via Kubios HRV software. Evaluated autonomic regulation parameters include time-domain metrics: standard deviation of normal-to-normal intervals (SDNN, in ms) and root mean square of successive differences (RMSSD, in ms); and frequency-domain metrics: low-frequency power (LF, in ms²), high-frequency power (HF, in ms²), and total power (in ms²). Higher RMSSD and HF power reflect increased parasympathetic (vagal) tone. Change from baseline to post-intervention (Week 4) will be evaluated.

Time frame
Baseline (Week 0) and Week 4 (post-intervention)

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Elisabeth Balint

Lead sponsor

Privatklinik Meiringen

Sponsor institution

Source ClinicalTrials.gov

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