Vagus Nerve Stimulation - Summary of Published Research

Introduction

What follows are citations for some of the larger published studies looking at VNS. Patients and psychiatrists will often be involved in applying for funding for further assessment/ treatment, and it is helpful to be able to state what the evidence is. All of these papers should either be available through the NHS e-library, or through any NHS/ hospital library.

Overview of VNS Studies

Patient populations

So far, there have been three large studies (D-01, D-02, and D-03) which have produced a greater number of individual papers. Summaries of each of the studies are given below. It is important to recognise that many of the patients reported in the studies were also included in other studies and this is illustrated in the following series of figures. Click on the image to open a larger version; use the 'back' button in your browser to return to this page.

Figure 1. Overview of outcomes from VNS Studies (2000-2006)

 

D-01, D-02, and D-03

The following figures show which studies were included in the three major studies of VNS.

Figure 2. D-01 Studies

Figure 3. D-02 Studies

Figure 4. D-03 Studies

 

Follow-up studies of same cohort of patients

The D-01 cohort has been followed-up at two years:

Figure 5. Long-term follow-up of the D-01 cohort

The D-02 studies essentially involved the same cohort. Patients who took part in the 10-week controlled trial went on to an open follow-up study and comparisons were made of the outcomes in this group and those who were receiving treatment-as-usual. The D-02 cohort is shown below in Figure 6.

Figure 6. Long-term follow-up of the original RCT study group

 

D-01 Reports

This study took place in the USA and initially involved 30 patients. A further 30 patients were recruited into the study.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study
Rush, A. J., George, M. S., Sackeim, H. A., Marangell, L. B., Husain, M. M., Giller, C., Nahas, Z., Haines, S., Simpson, R. K., Jr. & Goodman, R.
Biological Psychiatry (2000) 47; 4: 276-286.

BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects.

METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS.

RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date.

CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome
Sackeim, H. A., Rush, A. J., George, M. S., Marangell, L. B., Husain, M. M., Nahas, Z., Johnson, C. R., Seidman, S., Giller, C., Haines, S., Simpson, R. K., Jr. & Goodman, R. R.
Neuropsychopharmacology (2001) 25; 5: 713-728.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes
Marangell, L. B., Rush, A. J., George, M. S., Sackeim, H. A., Johnson, C. R., Husain, M. M., Nahas, Z. & Lisanby, S. H.
Biological Psychiatry (2002) 51; 4: 280-287.

BACKGROUND: Vagus nerve stimulation has shown promising results in an open, acute phase pilot study of adults in a treatment-resistant major depressive episode. This open, naturalistic follow-up study was conducted to determine whether the initial promising effects were sustained, and whether changes in function would be observed. METHODS: Thirty adult outpatients in a treatment-resistant, nonpsychotic major depressive episode received an additional 9 months of vagus nerve stimulation treatment following exit from the 3-month acute study. Changes in psychotropic medications and vagus nerve stimulation stimulus parameters were allowed during this longer-term follow-up study. A priori definitions were used to define response (> or = 50% reduction in baseline Hamilton Rating Scale for Depression total score) and remission (Hamilton Rating Scale for Depression < or = 10). RESULTS: The response rate was sustained [40% (12/30) to 46% (13/28); p =.317] and the remission rate significantly increased [17% (5/30) to 29% (8/28); p =.045] with an additional 9 months of long-term vagus nerve stimulation treatment after exit from the acute study (1 year total vagus nerve stimulation treatment). Significant improvements in function between acute study exit and the 1-year follow-up assessment as measured by the Medical Outcomes Study Short Form-36 were observed. CONCLUSIONS: Longer-term vagus nerve stimulation treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status in this naturalistic follow-up study.

 

D-02 Reports

This study also took place in the USA. The first part of the study involved a 10-week randomised controlled trial (RCT) comparing response rates with patients whose VNS had not been activated. All the patients then took part in a longer-term open study and all patients received active stimulation. Response rates of those patients receiving VNS were compared with a group of patients who received similar treatment but without VNS.The papers resulting from this study include:

Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients
Carpenter, L. L., Moreno, F. A., Kling, M. A., Anderson, G. M., Regenold, W. T., Labiner, D. M. & Price, L. H.
Biological Psychiatry (2004) 56; 6: 418-426.

BACKGROUND: Vagus nerve stimulation (VNS) has shown promising antidepressant effects in treatment-resistant depression, but the mechanisms of action are not known. Cerebrospinal fluid (CSF) studies in epilepsy patients show that VNS alters concentrations of monamines and gamma-aminobutyric acid (GABA), neurotransmitter systems possibly involved in the pathogenesis of depression. METHODS: Twenty-one adults with treatment-resistant, recurrent, or chronic major depression underwent standardized lumbar puncture for collection of 12 mL CSF on three separate but identical procedure days during participation in the VNS D-02 clinical trial. All subjects remained on stable regimens of mood medications. Collections were made at baseline (2 weeks after surgical implantation but before device activation), week 12 (end of the acute-phase study), and week 24. Cerebrospinal fluid concentrations of norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined with high-performance liquid chromatography. Concentrations of GABA were assayed with mass spectrometry. RESULTS: Comparison of sham versus active VNS revealed a significant (mean 21%) VNS-associated increase in CSF HVA. Mean CSF concentrations of NE, 5-HIAA, MHPG, and GABA did not change significantly. Higher baseline HVA/5-HIAA ratio predicted worse clinical outcome. CONCLUSIONS: Although several of the CSF neurochemical effects we observed in this VNS study were similar to those described in the literature for antidepressants and electroconvulsive therapy, the results do not suggest a putative antidepressant mechanism of action for VNS.

A One-Year Comparison of Vagus Nerve Stimulation with Treatment as Usual for Treatment-Resistant Depression
George, M. S., Rush, A. J., Marangell, L. B., Sackeim, H. A., Brannan, S. K., Davis, S. M., Howland, R., Kling, M. A., Moreno, F. & Rittberg, B.
Biological Psychiatry (2005) 58; 5: 364-373.

Background
Previous reports have described the effects of vagus nerve stimulation plus treatment as usual (VNS+TAU) during open trials of patients with treatment-resistant depression (TRD). To better understand these effects on long-term outcome, we compared 12-month VNS+TAU outcomes with those of a comparable TRD group.

Methods
Admission criteria were similar for those receiving VNS+TAU (n = 205) or only TAU (n = 124). In the primary analysis, repeated-measures linear regression was used to compare the VNS+TAU group (monthly data) with the TAU group (quarterly data) according to scores of the 30-item Inventory of Depressive Symptomatology–Self-Report (IDS-SR30).

Results
The two groups had similar baseline demographic data, psychiatric and treatment histories, and degrees of treatment resistance, except that more TAU participants had at least 10 prior major depressive episodes, and the VNS+TAU group had more electroconvulsive therapy before study entry. Vagus nerve stimulation plus treatment as usual was associated with greater improvement per month in IDS-SR30 than TAU across 12 months (p < .001). Response rates according to the 24-item Hamilton Rating Scale for Depression (last observation carried forward) at 12 months were 27% for VNS+TAU and 13% for TAU (p < .011). Both groups received similar TAU (drugs and electroconvulsive therapy) during follow-up.

Conclusions
This comparison of two similar but nonrandomized TRD groups showed that VNS+TAU was associated with a greater antidepressant benefit over 12 months.

Vagus Nerve Stimulation for Treatment-Resistant Depression: A Randomized, Controlled Acute Phase Trial
Rush, A. J., Marangell, L. B., Sackeim, H. A., George, M. S., Brannan, S. K., Davis, S. M., Howland, R., Kling, M. A., Rittberg, B. R. & Burke, W. J.
Biological Psychiatry (2005) 58; 5: 347-354.

Background
Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy.

Methods
This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (?50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD24]).

Results
At 10-weeks, HRSD24 response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology – Self-Report (IDS-SR30), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events.

Conclusions
This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes
Nahas, Z., Marangell, L. B., Husain, M. M., Rush, A. J., Sackeim, H. A., Lisanby, S. H., Martinez, J. M. & George, M. S.
Journal of Clinical Psychiatry (2005) 66; 9: 1097-1104.

BACKGROUND: Vagus nerve stimulation (VNS) had antidepressant effects in an initial open, acute phase pilot study of 59 participants in a treatment-resistant major depressive episode (MDE). We examined the effects of adjunctive VNS over 24 months in this cohort.

METHOD: Adult outpatients (N = 59) with chronic or recurrent major depressive disorder or bipolar (I or II) disorder and experiencing a treatment-resistant, nonpsychotic MDE (DSM-IV criteria) received 2 years of VNS. Changes in psychotropic medications and VNS stimulus parameters were allowed only after the first 3 months. Response was defined as > or = 50% reduction from the baseline 28-item Hamilton Rating Scale for Depression (HAM-D-28) total score, and remission was defined as a HAM-D-28 score < or = 10.

RESULTS: Based on last observation carried forward analyses, HAM-D-28 response rates were 31% (18/59) after 3 months, 44% (26/59) after 1 year, and 42% (25/59) after 2 years of adjunctive VNS. Remission rates were 15% (9/59) at 3 months, 27% (16/59) at 1 year, and 22% (13/59) at 2 years. By 2 years, 2 deaths (unrelated to VNS) had occurred, 4 participants had withdrawn from the study, and 81% (48/59) were still receiving VNS. Longer-term VNS was generally well tolerated.

CONCLUSION: These results suggest that patients with chronic or recurrent, treatment-resistant depression may show long-term benefit when treated with VNS.

 

D-03 Reports

The D-03 study was a European replication of the D-02 study and used a similar protocol. So far, there have been relatively few publications, but those published/ presented include:

Schlaepfer, T., Wagner, M., Frick, C., et al (2004) First Results from the European Multicenter Trial D-03 for Vagus Nerve Stimulation in Refractory Major Depression (Poster). In XXIVth Congress of the CINP. Paris.

In Eplleptology. Vagus nerve stimulation (VNS) has been used for the treatment of refractory epilepsy. More recently it has been proposed as a putative treatment in acute and maintenance of drug resistant maior depression. Data from an open label multi-center pilat study (D01) suggest also a potential clinical usefulness. In this US study, one third of the 60 patients induded, reached a reduction of depressive symptoms of 50% or more after 3 months of chronic stimulation.

We report on data of an ongoing European trial (DO3) following the same simple design. These results are slgnlficantly better. In the first 37 patients mean HRSD-28 score fell from 32.1 to 18.3 afler three months of chronic stimulation and 46% of the patients included reached the response criterion of reduction of depressive symptoms of 50% or more as measured with the HRSD28 scale. There is a clear indicatlon, that the further improvement of depressive symptoms within a period of one year, which has been demonstrated In previous studies, can be replicated In this study too.

These data, while obtained from an open uncontrolled study only, are interesting because such an effect would be hard to explain by a placebo effect only. It will be crucial to carefully analyze study populations of the DO1 and the DO3 studies for differences. Both differences in treatment resistance, stimulation dose or both could be responsible for the difference.

Presently, the preliminary data from pilot studles including the one presented here on VNS suggest a sustained antidepressant effect In treatment resistant major depression. If these findings can be confirmed in more rigorously designed studies, VNS could become an important treatment option for a subgroup of refractory patients.

Frick, C., Brannan, S. K., Hasdemir, M., et al (2005) Time course of Depressive Symptomatology during Vagus Nerve Stimulation: Comparisons of the EU with the US results (Poster). In 44th Annual Meeting of the American College of Neuropsychopharmacolgy. Waikoloa, Hawaii.

Frick, C., Hosten, S., Kosel, M., et al (2006) Results of the European Multi-Centre study (D03) of Vagus Nerve Stimulation in treatment resistant depressive patients (Poster). In 19th Congress of the European College of Neuropsychopharmacology. Paris, France.

---- (2006) Severity of Depression during the first year of Vagus Nerve Stimulation in the group of non-responders (Poster). In 19th Congress of the European College of Neuropsychopharmacology. Paris, France.

Vagus nerve stimulation in chronic treatment-resistant depression: Preliminary findings of an open-label study
Corcoran, C. D., Thomas, P., Phillips, J. & O'Keane, V.
British Journal of Psychiatry (2006) 189; 3: 282-283.

We evaluated the efficacy and safety of vagus nerve stimulation therapy in the treatment of 11 patients with chronic treatment-resistant depression. Mood was evaluated at frequent intervals over the year following implantation. All measures of depression, including the Hamilton Rating Scale for Depression reduced significantly. The response and remission rates were 55% and 27% respectively at 1 year. Side-effects were common, and some were severe.