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Compr Psychiatry. 2019 Dec 12;98:152156. doi: 10.1016/j.comppsych.2019.152156. [Epub ahead of print]

Vagus nerve stimulation (VNS) therapy in patients with treatment resistant depression: A systematic review and meta-analysis.

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Amygdala Limited, Letchworth Garden City SG6 2AA, UK. Electronic address:
Independent Statistician, Sainte-Anne, Guadeloupe, France. Electronic address:
Symmetron Limited, London, UK. Electronic address:
Mtech Access Limited, Bicester, Oxfordshire OX26 4PP, UK. Electronic address:
Department of Psychiatry, UNC School of Medicine, Chapel Hill, NC, USA. Electronic address:



Vagus nerve stimulation (VNS) therapy is approved for treatment-resistant depression (TRD). A recent 5-year comparative study prompted this review of its impact in this very severe population. Previous systematic literature reviews (SLR) cited concerns in terms of missing studies or patient duplication.


This SLR addressed these criticisms, assessed all outcomes of longer-term adjunctive VNS in all studies, irrespective of TRD severity, comparing where feasible with treatment-as-usual (TAU). We searched for adult VNS+TAU studies (January 1, 2000 to June 24, 2019). Comparative and single-arm studies were eligible. All reported efficacy, safety and quality of life (QOL) outcomes were assessed. Where possible, meta-analysis was used to calculate overall pooled effect estimates across studies at several time points.


Of 22 identified studies, there were two randomized controlled (RCT), sixteen single-arm and four non-randomized comparative studies. Numerous depression-specific, safety and QOL measures were reported. Meta-analysis was possible for three efficacy [Montgomery-Asberg Depression Rating Scale, Clinician Global Impression-Improvement, Hamilton Rating Scale for Depression] and three safety [serious adverse events, study drop-outs and all-cause mortality] but no QOL measures. Data beyond 2 years was not poolable. Analyses demonstrated that antidepressant benefits improved to 24 months and safety issues were minimal. Heterogeneity was high and statistically significant.


Despite limitations in the evidence base, our comprehensive summary of VNS+TAU outcomes suggests that this treatment provides improving benefit and hope for this very hard-to-treat chronic population. More comparative TRD studies should describe safety and QOL.


Long-term outcomes; Meta-analysis; Systematic review; Treatment resistant depression; Vagus nerve stimulation (VNS) therapy

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Conflict of interest statement

Declaration of competing interest J Bottomley, C LeReun, A Diamantopoulos and S Mitchell have received consultancy payments from LivaNova. B Gaynes has received consultation payments from LivaNova addressing models of treatment resistant depression.

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