Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial.

Background: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomised, blinded, sham-controlled trial. Here we report post-hoc sub-group analyses from the VNS Rehab trial. We aimed to determine whether treatment effects were consistent across subgroups. Methods: VNS Rehab included 108 participants with moderate to severe arm /hand weakness, at least nine months after ischaemic stroke. They were randomised to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in iFugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. The trial was registered on ClinicalTrials.gov (NCT03131960). We explored the effect of VNS treatment by sex (n=70 males; n=38 females), age (≤ 65 or >65 years)), time from stroke (median time, 2 years) and baseline FMA-UE score (<=33 severe, >33 moderate). We assessed whether there was any interaction with treatment. No hypotheses were specified prior to this analysis and no formal adjustment was made for multiplicity. Findings: On the first day after completion of in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (p=0.001, between group difference 2.6, 95% CI 1.03 to 4.2). The between group difference was similar across all subgroups (figure). No significant treatment interactions were observed with baseline characteristics. Interpretation: Participants with moderate to severe arm and hand impairment after ischaemic stroke showed clinically meaningful improvements in motor impairment and function with rehabilitation paired with VNS compared to rehabilitation with sham VNS. The response appeared similar across pre-defined subgroups of interest.

Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

The RECOVER trial randomized 493 patients with markedly treatment-resistant major depressive disorder to treatment-as-usual with or without active vagus nerve stimulation (VNS Therapy). While the primary outcome measure did not statistically separate the treatment conditions, the field may lack optimal metrics for quantifying symptom improvement in markedly treatment-resistant patients. This study examined the impact of three factors on sensitivity to clinical improvement across the total RECOVER sample and to differences in the effectiveness of the randomized conditions, systematically varying outcome classification (remission, response, and partial response), observation period (3-12months, 6-12months, 10-12months and last observation), and depression rating scale. Effect sizes for detecting therapeutic change across the total sample and the difference in effectiveness between the randomized groups were markedly higher for partial response than response or remission classifications. Longer observation periods produced larger therapeutic effects across the sample, but the effect sizes for the randomized treatment differences were substantially higher in the final 10-12month period. The MADRS showed the least sensitivity to change across the sample and between the treatment groups. Using the partial response classification and the 10-12month observation period, a significant difference between the groups was obtained for 3 of 4 depression scales. The findings derive from a retrospective assessment of alternative outcome metrics. In a large randomized controlled trial of VNS for markedly treatment-resistant depression, the magnitude of therapeutic effects and separation of treatment groups differed as a function of outcome classification, measurement period, and rating scale.

Background Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. Objective We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. Methods Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl–Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. Findings The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. Conclusion The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial

The use of vagus nerve stimulation (VNS) to reduce or stop electroconvulsive therapy (ECT) in treatment-resistant depression seems promising. The aim of this study was to investigate the efficacy of VNS on the reduction of ECT sessions and mood stabilization. We conducted a monocentric retrospective case series of patients who suffered from treatment-resistant depression, treated with ECT and referred to our center for VNS. We investigated the number and the frequency of ECT sessions before and after VNS implantation. Secondary criteria consisted in the Montgomery Åsberg Depression Rating Scale (MADRS) score, number of medical treatments, dosage of the main treatment and length of hospital stays before and after VNS. Additionally, we sent an anonymous survey to psychiatrists and other physicians in our institution to investigate their knowledge and perception of VNS therapy to treat treatment-resistant depression. Seven patients benefited from VNS: six (86%) were female (mean age of 51.7 +/- 16.0 years at surgery), and five (71%) suffered from bipolar depression (three type I and two type II). All patients were followed up at least 2 years post-implantation (range: 27-68 months). Prior to VNS, six patients were treated by maintenance ECT. After VNS, three (43%) patients did not require maintenance ECT anymore, and three (43%) patients required less frequent ECT session with a mean 14.7 +/- 9.8 weeks between sessions after VNS vs. 2.9 +/- 0.8 weeks before VNS. At last follow-up, 4 (57%) patients had stopped ECT. Five (71%) patients implanted with VNS were good responders (50% decrease relative to baseline MADRS). According to the survey, psychiatrists had a significantly better perception and knowledge of ECT, but a worse perception and knowledge of VNS compared to other physicians. VNS is a good option for treatment-resistant depression requiring maintenance ECT dependence. Larger on-going studies will help broaden the implanted patients while strengthening psychiatrists' knowledge on this therapy.

Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.

Ever since the introduction of chemical and electrical convulsive treatment for psychiatric disorders in the 1930s and 1940s, biological techniques have been used extensively in the amelioration of a variety of psychiatric disorders. Techniques of recent vintage have included transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation (VNS). Since VNS attenuates seizures in animal models, the treatment was initially developed and approved by the FDA for treatment of drug-resistant partial-onset epilepsy. Additional data, including the known neuroanatomy of the vagus nerve, effects of VNS on monoamines and mood improvement in patients with epilepsy who were treated with VNS, provided a rationale for further investigation in patients with primary mood disorders. VNS has been administered acutely for 10 weeks to 60 patients with treatment-resistant depression. Longer-term follow-up data has been analysed for the first 30 patients. Response rates have been at least 30% in the acute study. Similar to findings in epilepsy and in contrast to the usual results of long-term medication trials, longer term data regarding symptomatic and functional outcomes of depressed patients receiving VNS continue to look promising. As opposed to electroconvulsive therapy, VNS is not associated with cognitive impairment. These results have led to approval of VNS for the treatment of resistant depression (unipolar or bipolar) in both Europe and Canada. Currently, a pivotal double-blind acute study is underway in the US.

Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis, and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation, and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis, and increasing dendritic spine density.

The aim of this study was to assess the safety and efficacy of combined active responsive neurostimulation (RNS) and vagus nerve stimulation (VNS) therapies in pediatric patients with drug-resistant epilepsy. A single-center retrospective chart review was conducted on pediatric patients implanted with the RNS System with a concomitant active VNS System (VNS+RNS) between 2015 and 2021. Patients with at least 1 month of overlapping concomitant VNS and RNS treatment were included. Patients who had an RNS device implanted after 21 years of age, those who had responsive neurostimulators implanted after their VNS was inactivated, or those in whom the VNS battery died and was not replaced before RNS System implantation were excluded. Seven pediatric VNS+RNS patients were identified, and their courses of treatment were evaluated. All patients tolerated concurrent VNS and RNS treatment well, no device-device interactions were identified, and no major treatment-related adverse effects were noted. The median follow-up after RNS System implantation was 1.2 years. By electroclinical criteria, all 7 patients achieved 75%-99% reductions in the frequency of disabling seizures after RNS System implantation. By patient and caregiver report, 2 patients (28.6%) had 75%-99% reductions in the frequency of their disabling seizures, 2 patients (28.6%) achieved 50%-74% reductions, 2 patients achieved 1%-24% reduction in frequency of disabling seizures, and 1 patient (14.3%) experienced a 1%-24% increase in seizure frequency. The available VNS magnet swipe data identified 2 patients with 75%-99% reductions in seizure frequency as measured by magnet swipes, one with 25%-49% reductions and the other with 1%-24% increases in seizure frequency as measured by magnet swipes. This study demonstrated that RNS and VNS therapies can safely be used simultaneously in pediatric patients. RNS may potentially augment the therapeutic effects of VNS treatment. Patients in whom a response to VNS has been suboptimal should still be considered for RNS therapy.

We report on two patients who experienced emergence of full manic symptoms while receiving vagal nerve stimulation (VNS). Two patients, both with a well-documented and verified history of longstanding unipolar depression, were initiated on VNS for treatment of their severe major depressive episodes. The two patients had emergence of full manic symptoms after 8 and 9months of VNS, respectively. Manic symptoms were adequately managed with standard treatments (mood stabilizer and electroconvulsive therapy) and VNS was continued in the two subjects for up to 5years without any further occurrences of manic/hypomanic episodes. These cases suggest that some patients with treatment-resistant depression may have a previously unrecognized bipolar disorder, triggered only by VNS. This report also provides evidence that VNS-induced manic switches, however serious and troubling to patients, can be managed safely, and that VNS maintenance can be continued for an extended period of time without manic relapses. Although the mechanism of action of VNS is not known, emerging evidence supports central nervous system dopaminergic and possibly cholinergic system involvement.

The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Vagus nerve stimulation (VNS) has been employed worldwide as an adjunctive therapy in drug-resistant epilepsy patients. However, the mechanisms of VNS action potentially increase the risk of obstetric complications. The study presents the long-term single-center experience with pregnancies and childbirth in women with VNS for refractory epilepsy based on prospectively collected epileptologic data and a retrospective analysis of pregnancy, childbirth, and data about long-term child development. From a group of patients with VNS implanted for refractory epilepsy between October 1999 and January 2018, all the women of childbearing age (younger than 40 years) were identified. After checking their hospital records for data about any pregnancies, the women with confirmed childbirth during active VNS stimulation and their general practitioners were interviewed based on a prepared questionnaire regarding their gynecologic history, the course of pregnancy and childbirth, gestational week, birth weight and length, any congenital anomalies of the child, and the child's psychomotor development, school performance, and somatic health problems. From the group of 257 patients implanted with VNS for refractory epilepsy, 4 women (1.5%) became pregnant and gave birth (all on polypharmacotherapy). The mean interval from VNS implantation to birth was 44.3 months. Slight seizure worsening during the last trimester was reported in one woman. In one patient, acute caesarean section was required due to placental separation. Planned birth induction and caesarean section were used in the other two women because of their seizure disorder. No malfunction of the stimulation system was detected during pregnancy or after birth. No congenital malformations were observed. The two children who were of school age at the time of this study require special schooling. The study results confirmed a high rate of obstetric interventions in patients with VNS. Although no teratogenic effect of VNS has been proven, the higher incidence of children exposed to VNS needing special education requires attention.

Vagus nerve stimulation was performed experimentally for the first time more than 150years ago. In the 1980s and 1990s, vagus nerve stimulation was shown, both in the anesthetized and in the conscious animal, to exert marked antiarrhythmic effects, particularly during acute myocardial ischemia. There is a strong rationale for a beneficial effect of augmented vagal activity in the setting of chronic heart failure. Studies in experimental models of heart failure showed that chronic vagus nerve stimulation exerts beneficial effects on left ventricular function and on survival. Vagus nerve stimulation is approved in man for refractory epilepsy and depression. The first-in-man study performed in 32 patients with chronic heart failure suggests that vagus nerve stimulation was safe and well tolerated. Six months of open-label treatment was associated with significant improvements (P<0.001) in NYHA class, quality of life, 6-min walk test, LV ejection fraction (from 22±7 to 29±8%), and LV systolic volumes (P=0.02). These improvements were maintained at 1year. Mechanisms of action may include the following: heart rate, anti-adrenergic, anti-apoptotic, and anti-inflammatory effects as well as an increase in nitric oxide. Controlled clinical trials will start soon to assess whether vagus nerve stimulation can indeed represent a new non-pharmacological approach for the treatment of symptomatic heart failure.