Vagus Nerve Stimulation: 2-Year Outcomes for Bipolar Versus Unipolar Treatment-Resistant Depression

doi:10.1016/j.biopsych.2008.04.036

Biological Psychiatry

Volume 64, Issue 6, 15 September 2008, Pages 455-460

https://doi.org/10.1016/j.biopsych.2008.04.036 Get rights and content

Background

The outcome of vagus nerve stimulation (VNS) for patients with bipolar treatment-resistant depression (TRD) has not been well characterized. This study describes the outcome of VNS for bipolar TRD patients participating in the acute and longitudinal pivotal trials and compares their outcome with unipolar TRD patients in the same trials.

Methods

Of 235 participants enrolled in the acute study, 25 (11%) were diagnosed with DSM-IV bipolar I or II disorder. A sham-controlled 12-week trial of VNS preceded 2 years of open treatment. Bipolar and unipolar subjects were compared on baseline characteristics as well as acute and long-term outcomes.

Results

At baseline, bipolar TRD was as severe as unipolar TRD but with depressive episodes of shorter duration and more failed antidepressant trials/year. Acute, 1-year, and 2-year outcomes were similar for both groups, even when the definition of response for bipolar TRD was expanded to include lack of manic symptoms.

Conclusions

Bipolar TRD is a serious condition. In this hypothesis-generating analysis, VNS short- and long-term effects on bipolar and unipolar TRD were similar. Because these analyses were post hoc, these findings should not be interpreted as warranting clinical inference regarding effectiveness of VNS in patients with bipolar depression.

Section snippets

Methods and Materials

Participants were part of a double-blind, randomized, multicenter, pivotal study assessing the safety and efficacy of VNS for TRD (3, 4). Institutional review boards at each study center approved the study; all participants provided informed consent after full explanation of the procedures.

Eligibility required that participants be diagnosed with bipolar (or unipolar) depression, in a chronic (> 2 years) or recurrent major depressive episode (MDE), and have a baseline score of ≥ 20 on the

Results

Supplement 1 provides baseline demographic data and patient characteristics. Of the 235 participants enrolled in the acute study, 25 (11%) were diagnosed with DSM-IV bipolar I (n = 12) or II (n = 13) disorder. The proportion of participants endorsing a history of antidepressant-induced mania was significantly greater among those with bipolar depression than those with unipolar depression (p < .001).The duration of treatment-resistant bipolar major depressive episodes was significantly less than

Discussion

Participants with bipolar disorder were less likely to have an episode of chronic depression, and episodes were, on average, of shorter duration. As would be expected, participants with bipolar disorder had more lifetime episodes and more episodes of antidepressant-induced mania. Although the absolute numbers of failed trials during the current episode were similar for the unipolar and bipolar cohorts, the number of failed trials/year was greater in the bipolar group, which is consistent with

References (8)

L.L. Judd et al.
The prevalence and disability of bipolar spectrum disorders in the US population: Re-analysis of the ECA database taking into account subthreshold cases
J Affect Disord
(2003)
A.J. Rush et al.
Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial
Biol Psychiatry
(2005)
A.J. Rush et al.
Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: A naturalistic study
Biol Psychiatry
(2005)
M.S. George et al.
A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression
Biol Psychiatry
(2005)

There are more references available in the full text version of this article.

Cited by (71)

Multiple sensor theory in airway mechanosensory units
2023, Respiratory Physiology and Neurobiology
Two conventional doctrines govern airway mechanosensory interpretation: One-Sensor Theory (OST) and Line-Labeled Theory (LLT). In OST, one afferent fiber connects to a single sensor. In LLT, a different type of sensor sends signals via its specific line to a particular brain region to evoke its reflex. Thus, airway slowly adapting receptors (SARs) inhibit breathing and rapidly adapting receptors (RARs) stimulate breathing. However, recent studies show many different mechanosensors connect to a single afferent fiber (Multiple-Sensor Theory, MST). That is, SARs and RARs may send different types of information through the same afferent pathway, indicating different information has been integrated at the sensory unit level. Thus, a sensory unit is not merely a transducer (textbook concept), but also a processor. MST is a conceptual shift. Data generated over last eight decades under OST require re-interpretation.
Vagus nerve stimulation: An update on a novel treatment for treatment-resistant depression
2022, Journal of the Neurological Sciences
Citation Excerpt :
A previous study by Nierenberg et al. (2008) [48] attempted to characterize the effects of VNS in bipolar TRD compared to unipolar TRD. Although the authors ultimately found that the short- and long-term treatment antidepressant effects of VNS were equivalent between groups, the study was limited by its relatively small size (total N = 235, N of participants with DSM-IV diagnosis of bipolar I or II = 25) and only two-year duration [48]. McAllister-Williams et al. (2020) [49] further advanced scientific understanding of the effect of VNS in bipolar TRD by utilizing the previously described TRD registry.
In this review, we provide an overview of essential clinical trials examining the effect of vagal nerve stimulation (VNS) in treatment-resistant depression (TRD), the applicable neuroanatomy of the vagus nerve, and the proposed mechanism of action (MOA) of VNS in TRD.
Vagal nerve stimulation (VNS) is currently the only FDA-approved neurostimulation treatment for severe treatment-resistant depression (TRD). The implanted VNS device sends electrical impulses to the left cervical vagus nerve, resulting in stimulation of afferent vagal brainstem pathways known to be associated with mood regulation. Within the last decade, several clinical trials have attempted to further elucidate this effect specifically in TRD. Early clinical trials including the D01, D02, and D03 trials showed promising evidence of the antidepressant efficacy and durability of VNS as a treatment for TRD. Later trials comparing VNS and treatment-as-usual (TAU) resulted in similar findings regarding antidepressant efficacy and durability. VNS was additionally found to be beneficial in improving quality of life and suicidality among unipolar TRD patients and depression among bipolar TRD patients. Ongoing and future studies such as the RECOVER trial continue to investigate the psychiatric benefits of VNS within the TRD population. Although the MOA of VNS in TRD is still not fully understood, recent brain imaging studies and animal studies have proven instrumental in addressing this knowledge gap.
Is vagal-nerve stimulation safe during pregnancy? A mini review
2021, Epilepsy Research
Citation Excerpt :
Vagus-nerve stimulation (VNS) is a common nerve-regulation technology (Boon et al., 2009; George et al., 2002; San-Juan et al., 2019; Starnes et al., 2019). VNS has been approved by FDA to treat refractory epilepsy and treatment-resistant depression (Ben-Menachem et al., 2013; Conway and Xiong, 2018; Howland, 2014; Morris et al., 2013; Nierenberg et al., 2008). VNS could also have therapeutic potential for other diseases of the central nervous system (Parkinson's disease, addiction, and ischemic stroke) (Farrand et al., 2017; García-Toro et al., 2011; Ma et al., 2019) and non-central nervous system (rheumatoid arthritis, inflammatory bowel disease, heart failure, and kidney disease) (Bonaz et al., 2016; Drewes et al., 2021; Hilderman and Bruchfeld, 2020; Kibleur et al., 2018; Wang et al., 2019).
Vagus-nerve stimulation (VNS) is the most common neuromodulation technique and has been approved by the FDA for treating refractory epilepsy and refractory depression. Although VNS has been used for nearly 32 years, the impact of VNS on the safety of pregnant women and neonate remains to be evaluated.
We first analyze the relationship between the vagus nerve and the reproductive system (ovary and uterus) and then determine whether harm is inflicted to the reproductive system, thereby affecting the pregnancy. A comprehensive literature search is performed on PubMed/MEDLINE database, Web of Science, and Scopus. Ten articles are included in the study, and 44 pregnancies of 38 patients are analyzed.
The vagus nerve is connected with the reproductive system, but VNS may have little effect on pregnancy. We analyze 10 articles (38 patients with 44 pregnancies) about VNS complications during pregnancy. Two of the 44 pregnancies (2/44, 4.5 %) are miscarriages, and two pregnancies have fetuses with congenital malformations (2/42, 4.8 %), which could also be attributed to polytherapy with antiepileptic drugs. The rest of the pregnant women have no postpartum complications, and their fetuses are healthy.
VNS may be relatively safe and effective for the fetus and mother during pregnancy, and turning off VNS during pregnancy is unnecessary. However, owing to the small sample size and short follow-up time in the present study, further research is needed.
Vagus nerve stimulation (VNS) therapy in patients with treatment resistant depression: A systematic review and meta-analysis
2020, Comprehensive Psychiatry
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.
Vagus nerve stimulation and depression
2019, Presse Medicale
La stimulation du nerf vague (SNV) est une option thérapeutique dans le traitement des dépressions résistantes depuis quinze ans qui reste très peu utilisée. Malgré plusieurs études cliniques attestant de son rapport bénéfice-risque favorable et son approbation par la Food Drug Administration dès 2005, la SNV n’a pas encore trouvé sa place dans nos algorithmes de prise en charge des dépressions résistantes. Ceci est particulièrement vrai en France, où seul un nombre restreint d’implantations a eu lieu dans cette indication, et ce essentiellement lors de l’année écoulée ! Les explications possibles à ce retard sont multiples : (1) les psychiatres envisagent rarement le recours aux traitements neurochirurgicaux, même lorsqu’ils sont mini-invasifs et réversibles comme la SNV, (2) les premiers essais cliniques sur la SNV pour le traitement de la dépression résistante se sont heurtés à des difficultés de méthodologie communes à toutes les recherches cliniques impliquant des systèmes de neuromodulation implantés, et ont initialement échoué à fournir des résultats clairs quant à l’efficacité de la technique, (3) la SNV requiert des équipes pluridisciplinaires réunissant des psychiatres et des neurochirurgiens, équipes qui n’existent que depuis peu. Pourtant, les études de ces vingt dernières années attribuent toutes le même profil d’efficacité thérapeutique à la SNV pour le traitement de la dépression résistante : l’effet est cumulatif et se maintient sur le long terme chez des patients pour lesquels il était précédemment difficile d’obtenir une réponse et/ou une rémission prolongée, qu’ils soient unipolaires ou bipolaires. Ainsi, la SNV semble offrir une alternative aux patients dépressifs les plus sévères. Cette revue présente la SNV comme une option thérapeutique d’intérêt pour le traitement de la dépression uni ou bipolaire, récurrente et résistante, synthétisant les données de la littérature sur l’efficacité et la tolérance de cette procédure, puis tentant de définir les profils de dépression les plus à même de bénéficier de cette thérapie innovante.
Vagus nerve stimulation (VNS) is an old, yet new, option for treatment-resistant depression. Despite several clinical trials over the last 15 years showing a consistent benefit-risk balance of the technic, VNS still struggles to find its place in our therapeutic algorithms. This is especially true in France, where only a few surgeries have been performed nationwide, all in the last year. The reasons behind this lag are manifolds; (1) psychiatrists usually do not consider surgical treatments, even when they are minimally invasive and reversible, (2) early VNS trials stumbled on methodological difficulties that are common to all invasive neurostimulation technics, and initially failed to provide strong evidence for its efficacy, and (3) VNS requires multidisciplinary teams involving psychiatrists and neurosurgeons that did not exist then. Nevertheless, studies of the past twenty years support VNS as a treatment of depression endowed with a unique efficacy profile: a long runner best at maintaining remission in hard-to-stabilize depression, even in the context of ECT withdrawal, and irrespective of whether it is unipolar or bipolar. Thus, VNS potentially addresses the unmet medical needs of some of the most severe and chronic patients with depression. This review aims at introducing VNS as a treatment option for depression, summarizing available evidence for its efficacy and tolerance, and delineating patient profiles that might benefit the most of such treatment.
Long-term effects of vagus nerve stimulation in treatment-resistant depression: A 5-year follow up case series
2015, Brain Stimulation

View all citing articles on Scopus

View full text

Brief ReportVagus Nerve Stimulation: 2-Year Outcomes for Bipolar Versus Unipolar Treatment-Resistant Depression

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

J Affect Disord

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Brief Report
Vagus Nerve Stimulation: 2-Year Outcomes for Bipolar Versus Unipolar Treatment-Resistant Depression