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Cited by 91Vagus Nerve Stimulation ResearchTreatment of Major DepressionTranscranial Magnetic Stimulation Studies

Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis

Open access
Wu, Chunxiao, Liu, Peihui, Fu, Huaili, Chen, Wentao, Cui, Shaoyang, Lu, Liming, Tang, Chunzhi·2018·Medicine
DOI 10.1097/md.0000000000013845PMC PMC6314717
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Abstract

Background: Transcutaneous auricular vagus nerve stimulation (taVNS), as a noninvasive intervention, has beneficial effects on major depressive disorder based on clinical observations. However, the potential benefits and clinical role of taVNS in the treatment of major depressive disorder are still uncertain and have not been systematically evaluated. Therefore, we performed a systematic review and meta-analysis to evaluate the effectiveness and safety of taVNS in treating major depressive disorder. Methods: Four electronic databases, namely, Embase, MEDLINE, the Cochrane Library and PsycINFO, were searched for all related trials published through May 1, 2018. We extracted the basic information and data of the included studies and evaluated the methodological quality with the Cochrane risk of bias tool and the nonrandomized studies-of interventions (ROBINS-I) tool. A meta-analysis of the comparative effects was conducted using the Review Manager 5.3 software. Results: A total of 423 citations from the databases were searched, and 4 studies with 222 individuals were included in the meta-analysis. The taVNS technique could decrease 24-item HAMD scores more than the sham intervention (MD: −4.23, 95% CI: −7.15, −1.31; P = .005) and was also more effective in decreasing Self-Rating Depression Scale scores ((MD: −10.34, 95% CI: −13.48, −7.20; P < .00001), Beck Depression Inventory scores (MD: −10.3, 95% CI: −18.1, −2.5; P = .01) and Self-Rating Anxiety Scale scores (MD: −6.57, 95% CI: −9.30, −3.84; P < .00001). However, there was no significant difference in the Hamilton Anxiety Rating Scale scores between the taVNS and sham taVNS groups (MD: −1.12, 95% CI: −2.56, 0.32; P = .13). No obvious adverse effects of taVNS treatment were reported in the included studies. Conclusion: The results of the analysis preliminarily demonstrated that taVNS therapy can effectively ameliorate the symptoms of major depressive disorder, providing an alternative technique for addressing depression. However, more well-designed RCTs with larger sample sizes and follow-ups are needed in future studies to confirm our findings.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis found that transcutaneous auricular vagus nerve stimulation (taVNS) reduced depressive symptom scores compared with sham taVNS in patients with major depressive disorder, with mostly mild or no adverse effects. However, the evidence was limited by only 3 included studies, mostly nonrandomized designs, and short follow-up.

Key findings

  • taVNS significantly reduced 24-item Hamilton Depression Rating Scale scores versus sham (MD: −4.23, 95% CI: −7.15 to −1.31; P = .005; 3 studies; I² = 64%).
  • taVNS significantly reduced Self-Rating Depression Scale scores (MD: −10.34, 95% CI: −13.48 to −7.20; P < .00001; 2 studies; I² = 0%) and Beck Depression Inventory scores (MD: −10.3, 95% CI: −18.1 to −2.5; P = .01; 1 study).
  • taVNS significantly reduced Self-Rating Anxiety Scale scores (MD: −6.57, 95% CI: −9.30 to −3.84; P < .00001; 2 studies; I² = 0%), but not Hamilton Anxiety Rating Scale scores (MD: −1.12, 95% CI: −2.56 to 0.32; P = .13; 2 studies; I² = 0%).
  • Adverse events were mostly mild: one study reported tinnitus in 2 taVNS patients and 3 sham patients that recovered quickly after cessation; another reported no adverse side effects. Egger’s test showed no obvious publication bias (P = .773).

Methods

  • Systematic review and meta-analysis of clinical trials comparing taVNS with placebo or non-taVNS in patients diagnosed with major depressive disorder; searches covered Embase, MEDLINE, Cochrane Library/CENTRAL, and PsycINFO through May 1, 2018.
  • Three studies (n = 222) met inclusion criteria: one randomized controlled trial and two nonrandomized controlled trials, conducted in Germany and China, with sample sizes from 37 to 160 patients and therapy duration from 2 to 4 weeks.
  • Continuous outcomes were pooled as mean differences with 95% CIs using Review Manager 5.3; fixed- or random-effects models were chosen based on I² and P-value thresholds, with subgroup/sensitivity analysis if clinical heterogeneity was present.

Limitations

  • The paper states that most included studies were non-RCTs, only one RCT with a small sample size was included, and this may have weakened the strength of the evidence.
  • The paper states that all included studies blinded patients only and did not blind therapists or outcome assessors, and that only one study reported follow-up surveys, limiting evaluation of long-term effectiveness.
  • Evident from the text: only 3 studies were quantitatively synthesized, the HAMD analysis had substantial heterogeneity (I² = 64%), and the small number of studies prevented funnel-plot assessment of publication bias; the text also inconsistently refers to “4 included studies” after stating 3 studies were included.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1097/md.0000000000013845

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    One study reported that 2 patients who underwent taVNS and 3 patients who underwent sham taVNS had mild tinnitus side effects but recovered quickly after cessation of the taVNS intervention.

    “One study reported that 2 patients who underwent taVNS and 3 patients who underwent sham taVNS had mild tinnitus side effects but recovered quickly after cessation of the taVNS intervention.[14]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Rong P Liu J Wang L Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study. J Affect Disord 2016; 195: 172– 9. 26896810 PMC4828906 source

      Not checked in the free run.

  • Findingown data

    The SAS score showed a significant difference between the taVNS group and the sham group at the end of treatment (MD: −6.57, 95% CI: −9.30, −3.84; P < .00001).

    “After combining the results, the pooled results showed that there was a significant difference between the taVNS group and the sham group at the end of treatment (MD: −6.57, 95% CI: −9.30, −3.84; P < .00001) (Fig. 6).”
    Quote in the paperSubstantial claim
  • Findingown data

    Three studies (n = 222) met the inclusion criteria and were eligible for further quantitative analyses.

    “Three studies (n = 222) met the inclusion criteria and were eligible for further quantitative analyses.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The interventions used in the control groups were all sham taVNS.

    “The interventions used in the control groups were all sham taVNS.[13–15]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Hein E Nowak M Kiess O Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study. J Neural Transm (Vienna) 2013; 120: 821– 7. 23117749 source

      Not checked in the free run.

    • cites [14] Rong P Liu J Wang L Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study. J Affect Disord 2016; 195: 172– 9. 26896810 PMC4828906 source

      Not checked in the free run.

    • cites [15] Tu Y Fang J Cao J A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder. Brain Stimul 2018; 11: 501– 8. 29398576 PMC5930128 source

      Not checked in the free run.

  • Findingown data

    The pooled SDS score differed between the taVNS group and the sham group at the end of treatment (MD: −10.34, 95% CI: −13.48, −7.20; P < .00001).

    “The pooled results of the SDS score differed between the taVNS group and the sham group at the end of treatment (MD: −10.34, 95% CI: −13.48, −7.20; P < .00001) (Fig. 3).”
    Quote in the paperSubstantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingnone given

    The population of the included studies were all major depressive disorder patients according to ICD-10 and were all in a stable stage.

    “The population of the included studies were all major depressive disorder patients according to the ICD-10 (World Health Organization 1992), and the patients were all in a stable stage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Among the 3 included studies, there was one randomized controlled trial and 2 nonrandomized controlled trials.

    “Among the 3 included studies, there was one randomized controlled trial and 2 nonrandomized controlled trials.[13–15]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Hein E Nowak M Kiess O Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study. J Neural Transm (Vienna) 2013; 120: 821– 7. 23117749

      Not checked in the free run.

    • cites [14] Rong P Liu J Wang L Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study. J Affect Disord 2016; 195: 172– 9. 26896810 PMC4828906 source

      Not checked in the free run.

    • cites [15] Tu Y Fang J Cao J A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder. Brain Stimul 2018; 11: 501– 8. 29398576 PMC5930128

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The HAMA score was lower in the taVNS group post-intervention than in the sham group (MD: −1.12, 95% CI: −2.56, 0.32; P = .13), with no significant difference between taVNS and sham taVNS.

    “The pooled results showed that the HAMA score was lower (MD: −1.12, 95% CI: −2.56, 0.32; P = .13) in the taVNS group post-intervention than in the sham group. While there were no significant differences between the taVNS and sham taVNS (Fig. 5)”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Neurostimulation such as vagus nerve stimulation, deep brain stimulation, or electroconvulsive therapy has been recommended and is effective for treatment-resistant depression.

    “Neurostimulation, such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), or electroconvulsive therapy (ECT), has been recommended and is effective for treatment-resistant depression; however, these interventions also possess a certain risk of developing infections and other potential side effects due to surgical implantation.[6–8]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Sackeim HA Rush Aj Fau-George MS George Ms Fau-Marangell LB Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001; 25: 713– 28. 11682255 source

      Not checked in the free run.

    • cites [7] Moksnes KM Ilner SO Electroconvulsive therapy—efficacy and side-effects. Tidsskrift den Norske Lægeforening Tidsskrift Praktisk Medicin Række 2010; 130: 2460– 4. 21164584

      Not checked in the free run.

    • cites [8] Saleh C Fontaine D Deep brain stimulation for psychiatric diseases: what are the risks? Curr Psychiatry Rep 2015; 17: 33. 25795265

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Transcutaneous auricular vagus nerve stimulation (taVNS), as a noninvasive method, has good efficacy in treating neuropsychiatric disorders.

    “Transcutaneous auricular vagus nerve stimulation (taVNS), as a noninvasive method, has a good efficacy in treating neuropsychiatric disorders.[9]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Shiozawa P da Silva ME de Carvalho TC Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: A systematic review. Arq Neuropsiquiatr 2014; 72: 542– 7. 25054988

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The meta-analysis analysed only one type of vagus nerve stimulation (taVNS) for treating depression and did not combine with other therapies, allowing accurate evaluation of clinical effects without other confounding factors.

    “We only analysed one type of vagus nerve stimulation (transcutaneous auricular vagus nerve stimulation) for treating depression and did not combine with other therapies, thus allowing us to evaluate the clinical effects of taVNS accurately without other confounding factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The previous systematic review involving taVNS therapy was not comprehensive and included few taVNS studies in the analysis.

    “Although this previous systematic review involved taVNS therapy, the review was not comprehensive and included few taVNS studies in the analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Zhang ZX Li CR Rong PJ Efficacy and safety of auricular therapy for depression. Med Acupunct 2016; 28: 256– 67.

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Most included studies were non-RCTs, and only one RCT with a small sample size was included, which may have weakened the strength of the evidence.

    “First, most of the included studies were non-RCTs, and only one RCT with a small sample size was included in the analysis, which may have weakened the strength of the evidence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    The attrition bias and reporting bias of the randomized controlled trial were low risk.

    “The attrition bias and reporting bias of this RCT were low risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    All included studies only blinded patients and did not blind the therapists or the outcome assessors.

    “Second, all the included studies only blinded patients and did not blind the therapists or the outcome assessors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Only one study reported follow-up surveys, which may influence the evaluation of the long-term effectiveness of taVNS in treating major depressive disorder.

    “Third, only one study reported follow-up surveys, which may influence the evaluation of the long-term effectiveness of transcutaneous auricular vagus nerve stimulation in treating major depressive disorder.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Data and relevant information were extracted by 2 reviewers independently.

    “Data and relevant information were extracted by 2 reviewers (PHL and HLF) independently.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The two non-RCT studies had a low risk of bias in selection of participants, classification of interventions, deviations, outcome assessments, and attrition, and a moderate risk of reporting selection bias.

    “The 2 non-RCT studies had a low risk of bias in the selection of the participants, classification of interventions, deviations, outcome assessments, and attrition and a moderate risk of reporting selection bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Another 2 reviewers checked the accuracy of the data and evaluated the methodological quality of the included studies according to the Cochrane risk of bias tool and the ROBINS-I bias tool.

    “Another 2 reviewers (WTC and CXW) checked for the accuracy of the data and related information and then evaluated the methodological quality of the included studies according to the Cochrane risk of bias tool and the ROBINS-I bias tool.[11,12]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Savovic J Weeks L Fau - Sterne JAC Evaluation of the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials: focus groups, online survey, proposed recommendations and their implementation. Syst Rev 2014; 3: 37. 24731537 PMC4022341 source

      Not checked in the free run.

    • cites [12] Sterne JA Hernán MA Reeves BC ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; 355: i4919. 27733354 PMC5062054 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The BDI scale mainly assesses depression patients from a psychodynamic perspective.

    “The BDI scale mainly assesses depression patients from a psychodynamic perspective.[18,19]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Wang YP Gorenstein C Psychometric properties of the Beck Depression Inventory—II: a comprehensive review. Rev Bras Psiquiatr 2013; 35: 416– 31. 24402217

      Not checked in the free run.

    • cites [19] Jackson-Koku G Beck Depression Inventory. Occup Med (Lond) 2016; 66: 174– 5. 26892598

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A portion of major depressive disorder patients may be resistant to antidepressants and may need a variety of therapies to address major depressive disorder.

    “A portion of major depressive disorder patients may be resistant to antidepressants and may need a variety of therapies to address major depressive disorder.[23,24]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] McIntyre RS Filteau MJ Martin L Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord 2014; 156: 1– 7. 24314926 source

      Not checked in the free run.

    • cites [24] Ionescu DF Rosenbaum JF Alpert JE Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci 2015; 17: 111– 26. 26246787 PMC4518696

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The taVNS technique could alleviate the symptoms of depression, providing an alternative technique for patients who suffer a stable depressive disorder and are unwilling to select other invasive therapies.

    “The taVNS technique could alleviate the symptoms of depression, providing an alternative technique for patients who suffer a stable depressive disorder and are unwilling to select other invasive therapies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The included studies' samples are representative of the broader population of patients with major depressive disorder.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The HAMD is the most frequently used and is considered the gold standard for assessing depressive symptoms.

    “The HAMD is the most frequently used and is considered the gold standard for assessing depressive symptoms that includes evaluating the mood, suicide ideation, feelings of guilt, insomnia and other somatic symptoms of depression patients.[16,17]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Trajkovic G Starcevic V Fau-Latas M Reliability of the Hamilton Rating Scale for depression: a meta-analysis over a period of 49 years. Psychiatry Res 2011; 189: 1– 9. 21276619

      Not checked in the free run.

    • cites [17] Hedlund JL Viewig BW The Hamilton rating scale for depression: a comprehensive review. J Operational Psychiatry 1979; 10: 149– 65.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vagus nerve stimulation was effective for refractory or medication-resistant depression.

    “Previous researchers demonstrated that vagus nerve stimulation was effective for refractory or medication-resistant depression.[20,21]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Berry SM Broglio K Bunker M A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl) 2013; 6: 17– 35. 23482508 PMC3590011

      Not checked in the free run.

    • cites [21] Carreno FR Frazer A Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics 2017; 14: 716– 27. 28585221 PMC5509631 source

      Not checked in the free run.

19 of 19

  • The paper relies on this without support.

    Sham taVNS is a valid control that does not produce therapeutic effects on depression.

    “The interventions used in the control groups were all sham taVNS.[13–15]”

  • The paper relies on this without support.

    The included studies' samples are representative of the broader population of patients with major depressive disorder.

    “The population of the included studies were all major depressive disorder patients according to the ICD-10 (World Health Organization 1992), and the patients were all in a stable stage.”

  • The paper relies on this without support.

    Absence of reported adverse events in the included studies indicates that taVNS is safe.

    “Another study reported that there were no adverse side effects after the taVNS intervention.[13]”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Outcome-assessment bias for non-RCTs changes from moderate to low

    Minor

    The quality assessment assigns one non-RCT a moderate risk of outcome-assessment bias, but the discussion describes both non-RCTs as low risk for outcome assessments.

  • Number of included studies changes from three to four

    Minor

    The characteristics section first says three studies were included, then says four were included.

  • Reported sample-size range is incompatible with the total

    Minor

    For three studies, if one had 160 patients and the smallest study had 37, the total must be at least 160 + 37 + 37 = 234 patients, not 222.

    Reported 222 · recomputed 234

  • HAMD study count changes from four to three

    Minor

    The HAMD subsection says four studies used the outcome but describes pooling results from three studies.

  • Blinding of patients in the RCT is described inconsistently

    Minor

    The quality assessment says the RCT did not blind participants, whereas the limitations section says all included studies blinded patients.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hedlund, 1979, The Hamilton rating scale for depression: a comprehensive review, J Operational Psychiatry, 10, 149

Cited by

Sorted by citations

Related

Authors
Wu, C., Liu, P., Fu, H., Chen, W., Cui, S., Lu, L., & Tang, C.
Affiliations
  • Medical College of Acu-Moxi and Rehabilitation
  • Guangzhou University of Chinese Medicine (CN)
Corresponding author
  • Lu, Liming
  • Tang, Chunzhi
ORCID
Venue
Medicine
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-12
Volume
97
Issue
52
Pages
e13845
ISSN
  • 0025-7974 (ISSN-L)
  • 1536-5964
DOI
10.1097/md.0000000000013845
PMC
PMC6314717
OpenAlex
W2907233789
Semantic Scholar
1b1c243ad9ef3fa30a8b8f49062523f49ded2546
Cited by
91
References
29
Citations by year
2026: 16 · 2025: 9 · 2024: 19 · 2023: 17 · 2022: 9 · 2021: 11 · 2020: 7 · 2019: 1 · 2018: 1
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Medicine (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
transcutaneous auricular vagus nerve stimulation, major depressive disorder, non-invasive neuromodulation, depression treatment, depression symptom reduction, anxiety symptoms, treatment safety, adverse effects
MeSH terms
Major Depressive Disorder, Humans, Treatment Outcome, Ear Auricle, Auriculotherapy, Vagus Nerve Stimulation

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