Titration of vagus nerve stimulation for difficult-to-treat depression and onset of response: Early insights from the RESTORE-LIFE study

The RESTORE-LIFE study ( ClinicalTrials.gov NCT03320304 ) is a global, prospective, multi-center, observational study, which assesses the long-term effectiveness and safety of vagus nerve stimulation (VNS) as an adjunctive treatment in difficult-to-treat depression (DTD). Data on the impact of stimulation parameters on clinical outcome are limited. The study is ongoing, however titration of stimulation parameters and their association with clinical response was analyzed in the first 100 patients (mean age 50.0, range 22–79) reaching 12 months follow-up. Daily charge delivered was compared in 12-month responders vs. non-responders to VNS. Regression models were employed to investigate the relationship between VNS dosing parameters and mean MADRS reduction. The probability of reaching an output current of 1.0 mA and 1.5 mA was 93 % and 70 % at 6 months and 95 % and 81 % at 12 months respectively. By month 12, there was a trend towards higher daily charge delivered in non-responders than in responders ( p = 0.0798 for median). Older age (>65, p = 0.001) as well as high baseline MADRS ( p < 0.001) were significantly predictive for mean MADRS reduction, whereas stimulation parameters at 12 months were not. The majority of patients reached a current output of at least 1.5 mA, which is considered to be well within the therapeutic range. The daily charge delivered was higher in non-responders, possibly because physicians tended to increase the duty cycle in those who did not respond. Demographics typically associated with difficulty to treat (older age and higher baseline MADRS) were associated with greater MADRS reduction. • After 12 months, there was a trend towards higher daily charge delivered in non-responders than in responders (p=0.0798). • Older age and high baseline MADRS were predictive for mean MADRS reduction, stimulation parameters at 12 months were not. • The majority of patients had reached a current output of at least 1.5 mA. • The overall percentage of stimulation-related side-effects in the long-term course (47%) was lower than reported previously. • The study demonstrated long-term effectiveness of VNS with a cumulative response rate of 52.8% after 12 months.