Long-term efficacy and safety of vagus nerve stimulation in treatment-resistant depression: A systematic review (Rosson, 2025)

Rosson, Stella, Bresolin, Nicola, D'Amico, Alberto, Denaro, Luca, Landi, Andrea, Sambataro, Fabio, Pigato, Giorgio,

In Journal of Affective Disorders 1 February 2026 394 Part A

Available online at this link

Background Vagus Nerve Stimulation (VNS) is an approved neuromodulation treatment for individuals with Treatment-Resistant Depression (TRD). Although early efficacy and safety have been documented, a comprehensive review of long-term outcomes is needed.

Methods We performed a systematic review following the PRISMA guidelines on Pubmed, Scopus, PsychINFO, ClinicalTrials.gov for longitudinal studies that reported response, remission, retention rates, and other efficacy and safety outcomes, in individuals with TRD treated with VNS over 2 or more years. We appraised the evidence using Newcastle-Ottawa Scale, JBI, GRADE.

Results We included 10 cohort studies and 8 case series, totaling more than 900 cases and 300 controls. They were mainly middle-aged, female, and white, with more than 4 failed antidepressant trials. Response rates ranged from 28 % to 57 % in larger cohorts, 42 % to 100 % in smaller cohorts, remission rates 19 %–39 % in larger cohorts, 21 %–100 % in smaller cohorts. Retention rates were 61 %–81 % in larger cohorts, 26 %–100 % in smaller cohorts. Common side effects were stimulation-related, such as voice alteration and local pain; treatment-emergent mania was rare. Functioning, quality of life, and suicidality were reported less consistently. Average NOS quality was 6/9, JBI 7/10, certainty of evidence very low.

Conclusions Despite the suboptimal quality and certainty of evidence, VNS provided sustained therapeutic benefits in a significant share of patients with severe TRD, with limited safety concerns, in the long term. Our study confirms that VNS is a viable option for individuals with chronic or recurrent depression who do not improve with other treatments.