Dataset Information

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.

ABSTRACT:

Purpose

The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population.

Methods

A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described.

Results

Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life.

Limitations

Most comparisons of VNS+TAU and TAU were derived from observational, open label studies.

Conclusion

The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.

SUBMITTER: Sackeim HA

PROVIDER: S-EPMC7751788 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.

Sackeim Harold A HA Dibué Maxine M Bunker Mark T MT Rush A John AJ

Neuropsychiatric disease and treatment 20201214

<h4>Purpose</h4>The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population.<h4>Methods</h4>A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are describe ...[more]

PMID: 33364761

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Project description:BackgroundDepressive illness is associated with significant adverse consequences for patients and their families, and for society. Clinical challenges are encountered in the management of patients suffering from depression whether they are designated difficult-to-treat or treatment-resistant. Prospective serial depression treatment trials have shown that less than 40% of patients with major depressive disorder remit with an initial pharmacotherapy trial, and a progressively smaller proportion of patients remit with each subsequent trial. For patients who suffer from difficult-to-treat depression (DTD), treatments should focus on patient-centred symptom control, patient functioning, and improving patient quality of life. Among the treatment options for patients with DTD is Vagus Nerve Stimulation (VNS) Therapy. VNS Therapy involves intermittent electrical stimulation of the left cervical vagus nerve and has been shown to be efficacious for long-term management of patients with DTD.MethodsRESTORE-LIFE is a prospective, observational, multi-site, global post-market study intended to assess short-, mid-, and long-term effectiveness and efficiency outcomes in a 'real-world' setting among patients with DTD treated with adjunctive VNS Therapy. A minimum of 500 patients will be implanted with a VNS Therapy System at up to 80 global sites. Eligible patients will participate in a baseline visit between 1 and 6 weeks before device implant and will be followed for a minimum of 36 months and a maximum of 60 months. The diagnosis of depression and comorbid disorders will be determined using the Mini-International Neuropsychiatric Interview (MINI). The primary endpoint is response rate, defined as a decrease of ≥50% in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to 12 months post-implant.DiscussionA standardized approach in the management of DTD may not be appropriate for the treatment of such a complex heterogenous patient population. This study has been designed to evaluate whether VNS Therapy meaningfully improves and sustains clinical and depressive symptom outcomes in patients with DTD. This study will investigate the durability of VNS response in DTD and utility of VNS for long-term disease management of DTD. In addition, the study results will potentially clarify clinical, functional, and health economic questions in a real-world patient population with DTD.Trial registrationClinicalTrials.gov NCT03320304. Registered 25 October 2017.

Project description:Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated "ON" and nonstimulated "OFF" periods and between responder (R) and nonresponder (NR) patients. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during "ON" and "OFF" periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients. Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity. Impact statement Electroencephalography (EEG) desynchronization has been proposed to be a mechanism for antiepileptic effect of vagus nerve stimulation (VNS). We measured interictal EEG time-series synchronization during stimulated (ON) and nonstimulated (OFF) periods in epileptic patients treated by VNS. Phase lag index differences between ON and OFF periods were measured in delta, theta, and beta bands only in responder patients. To our knowledge, our study is the first to statistically correlate interictal cortical desynchronization during ON periods with reduction in seizure frequency. Our result supports the hypothesis that the antiseizure effect of VNS is mediated by cortical desynchronization.

Dataset Information

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.

Purpose

Methods

Results

Limitations

Conclusion

Publications

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.

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