Effects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study

doi:10.1016/j.biopsych.2005.05.024

Biological Psychiatry

Volume 58, Issue 5, 1 September 2005, Pages 355-363

https://doi.org/10.1016/j.biopsych.2005.05.024 Get rights and content

Background

The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established.

Methods

This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted.

Results

The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD₂₄) scores (average improvement, .45 points [SE = .05] per month (p < .001). At exit, HRSD₂₄ response rate was 27.2% (55/202); remission rate (HRSD₂₄ ≤ 9) was 15.8% (32/202). Montgomery Äsberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events.

Conclusions

These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.

Section snippets

Study Overview

For entry into this naturalistic phase, participants had to have completed the acute phase randomized comparison of sham versus active VNS (10 weeks of either sham or active VNS delivered after 2 weeks of recovery from device implantation) (Rush et al 2000, Rush et al 2003, Rush et al 2004a, Rush et al 1996, Rush et al 2002, Rush et al 2004b, Rush et al 2005). The IRB approvals and informed consents obtained at the beginning of the 12-week acute study (Rush et al 2000, Rush et al 2003, Rush et

Sample Development

The evaluable (n = 205) sample was developed from the implanted/randomized sample (n = 235). Of these 235 participants, two participants were not included in this analysis of the 12-month outcomes (one because of suicide during the acute phase; one because of device explantation secondary to infection during the acute phase). The remaining 233 participants formed the 12-month safety sample.

Of these 233 participants, 28 were not evaluable for efficacy. Three participants had HRSD₂₄ scores <18

Discussion

This 12-month study (n = 205) of VNS used as an adjunct to other antidepressant treatments in patients with treatment-resistant, chronic or recurrent mood disorders revealed statistically significant reductions in depressive symptoms. The primary repeated measures linear regression analysis of the evaluable sample revealed a statistically significant reduction over time in both the HRSD₂₄ total scores and the IDS-SR₃₀ total scores.

The clinical relevance of the symptom reduction was demonstrated

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A previous review was updated by a systematic literature search to identify studies that (a) compared vmHRV in clinically depressed children/adolescents with non-depressed controls and (b) reported associations between vmHRV and depression severity.
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Vagus Nerve Stimulation (VNS) therapy is widely understood to provide clinically meaningful improvements in seizure control to patients with drug-resistant epilepsy, and has been a staple in the clinical armamentaria available to epileptologists for over 25 years. Despite the long history of evidence-based reviews by neurology professional societies, there is still evidence of a practice gap in VNS titration and dosing that aims to maximize clinical benefit. Recent retrospective analyses have strongly argued for a more consistent application of a population-wide target dose of VNS, and further argued the importance of quickly achieving this target dose to hasten the onset of clinical benefits; however, these analyses failed to provide evidence for practical implementation. Herein, we describe a randomized controlled trial assessing the impact of titrating VNS according to three different protocols to achieve the target dose of 1.5 mA at 500µsec, for a 20-Hz signal frequency. The study was registered as NCT02385526 on March 11, 2015. Sixty-two patients were randomized into treatment groups that followed different titration protocols. One protocol (Group A) was designed to align with currently accepted professional guidance for VNS titration and the manufacturer’s labeling for VNS in epilepsy (Heck et al., 2002), while the other two protocols were derived from VNS applications in other therapeutic areas. Group A participants were most likely to achieve the target dose parameters in 12 weeks or less (81.8%), with a median time-until-achievement of the target dose of 8.1 weeks, while less than 60% of patients in other groups were able to achieve the same endpoint. Participants in all groups experienced low levels of transient tolerability concerns and adverse events, suggesting titration to the target dose in 12 weeks or less following the Group A protocol is generally acceptable to most patients. These findings indicate that patients receiving VNS for epilepsy can achieve the manufacturer-recommended dose range in 12 weeks or less. A wider implementation of the approach will likely improve the clinical impact of VNS on seizure control and prevent undertreatment.
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Antidepressant pharmacotherapy has been shown to decrease the neural response to sad faces, measured using functional magnetic resonance imaging (Fu et al., 2004). Since vagus nerve stimulation can be effective for some cases of treatment-resistant depression (Rush et al., 2005; Nemeroff et al., 2006; Aaronson et al., 2013), our findings suggest that one possible mechanism of action could be through attenuating emotional biases, particularly towards sadness, which may help play a role in alleviating depressive symptoms. Indeed, a relevant avenue for further research would be to investigate whether this reduced emotional bias mediates the beneficial effect of tVNS on depression.
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Original articleEffects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study

Background

Methods

Results

Conclusions

Section snippets

Study Overview

Sample Development

Discussion

Psychiatr Clin North Am

Biol Psychiatry

Psychiatry Res

Control Clin Trials

Biol Psychiatry

Neuropsychopharmacology

Seizure

Effectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disordersResults of a 2-year observational algorithm study

J Clin Psychiatry

Practice guideline for the treatment of patients with major depressive disorder (revision)

Am J Psychiatry

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1Acute and continuation treatment of major depressive disorder

World J Biol Psychiatry

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures

Epilepsia

COSTARTCoding Symbols for Thesaurus of Adverse Reaction Terms

Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study

Epilepsia

Medication compliance

The burden of recurrent depressionCauses, consequences, and future prospects

J Clin Psychiatry

ECDEU Assessment Manual for Psychopharmacology. Publication No. 76–338

A rating scale for depression

J Neurol Neurosurg Psychiatry

Development of a rating scale for primary depressive illness

Br J Soc Clin Psychol

Original article
Effects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study