VAGUS NERVE STIMULATION FOR TREATMENT-RESISTANT DEPRESSION
The aim of this report is to review the most up-to-date secondary evidence on the effectiveness and safety of vagus (or vagal) nerve stimulation in patients with treatment-resistant depression (TRD).
Depression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms.1 Depression is the most common mental disorder in community settings, and is a major cause of disability across the world.2 Worldwide, depression is the 4th leading cause of disability, with a prevalence of 2.3-3.2% in men and 4.5-9.3% in women.3 It is estimated that by 2020 major depression disorder (MDD) will be the second most disabling condition in the world.4 The disability is characterized by a chronic or recurrent course, reduced daily activities and high rates of mortality secondary to suicide or indirectly due to increased mortality when depression co-occurs with general medical conditions (e.g. myocardial infarction). The average age of the first episode of a major depression occurs in the mid-20s and although the first episode may occur at any time, from early childhood through to old age, a substantial proportion of people have their first depression in childhood or adolescence.5 In the national survey of child and adolescent mental health6, 10% of 5-15 year olds had a mental disorder including 4% with emotional disorder (anxiety and depression) and 0.9% with depression. Surveys in the UK have found a surprisingly high prevalence of depression in GP practice attendees ranging from 3.5% in Aberdeen7 to 5.6% in Southern England.8
Despite the considerable efforts made over the past decades regarding pharmacological therapies there is a large proportion of patients with depression who still do not respond to the currently available treatments.9 Between 20 and 40% of patients with MDD do not show substantial clinical improvement on their first treatment with antidepressant medication.10,11 Therapeutic strategies used for TRD are multiple and sometimes include varying combinations of different agents, psychotherapy and electro-convulsive therapy (ECT).12
Vagus nerve stimulation (VNS) involves implantation of a battery-powered pulse generator under the skin of the upper left chest. A wired tunnelled under the skin is connected to the left vagus nerve. Parameters (such as pulse width and frequency, current intensity and on/off cycles) can be programmed into the pulse generator using a programming wand. At any time additional stimulation can be applied or the device turned off. The battery life of the generator is estimated as 8-12 years, but will depend on the level and frequency of electrical stimulation used.13
Individual funding requests for VNS for depression have been received by commissioners and this report aims at reviewing the most up to date secondary evidence to assist these commissioning decisions.
The most up-to-date secondary research was identified and assessed in the following stages:
- searches initially undertaken for a report on mapping the use and secondary evidence on neurostimulators were updated (to December 2009); the full search strategy can be found in the previous report;14
- search results were screened by an information specialist and secondary evidence considered relevant was selected based on population and intervention characteristics;
- references were further assessed for relevance by a reviewer; systematic reviews, economic analyses, clinical guidelines and NICE guidelines, evaluating VNS in patients with depression were selected;
- most recent publications obtainable within the time frame of this report were selected for appraisal;
- quality was assessed by one reviewer using the main categories from the CASP checklist for systematic reviews;15
- data considered important in the context of this report was extracted and summarised.
4. Selected secondary evidence
Seven papers were identified as potentially relevant secondary evidence on VNS in patients with TRD. Of these the most recent obtainable publications were selected. References to papers that were not assessed are provided in section 7.
The secondary evidence discussed in this report consists of:
- A systematic review (Daban C et al. 2008)16
- Technology Evaluation Center (TEC) assessment17
- The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) report13
Detailed information on the characteristics of the included secondary evidence is tabulated in Table 1. All the three studies addressed similar questions. Daban C et al 2008 is the most recent and appears to be well conducted. All the three studies did not assessed quality of included studies. In all the three studies, searches could have possibly missed some relevant studies, because the authors included only studies published in English language and EMBASE was not searched. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA), Issues in Emerging Health Technologies report13 was based on a rapid overview of evidence and was not reported in sufficient detail to allow quality assessment.
Searches could have possibly missed some relevant studies, because, the authors included only studies published in English language and EMBASE was not searched the authors included only studies published in English language and only MEDLINE was searched, thus searches could have possibly missed some relevant studies not reported in sufficient detail to allow quality assessment.
Quality assessment of included studies
There was some overlap in relation to number of included studies among the three secondary evidences reviewed in this report. The most recent study18 included one randomised control trial, one non-randomised comparative study, and 16 case-series studies. Based on these studies the following were reported:
4.1.1 Randomised controlled trial
The RCT was a placebo-sham randomized trial designed to evaluate patients at 12 weeks after VNS implantation. The principal outcome for the trial was a 50% improvement in the HRSD-24. Results are shown in Table 2.
- there were 15% of patients in the VNS group that showed a 50% improvement in HRSD-24, whereas 10% of the patients in the sham control group showed 50% improvement (p=0.25),
- the Inventory of Depressive Symptomatology Self-Report (IDS-SR) was considered a secondary outcome, and showed a difference in outcome that was statistically significant in favour of VNS (17% versus 7.3%, p=0.03),
- all other outcomes assessed in the trial did not show statistically significant differences between groups.
4.1.2 Non-randomised comparative study
An observational study comparing patients participating in the RCT and a separately recruited control group evaluated VNS therapy up to 1 year.
- 27% of VNS patients achieved a 50% improvement in HRSD versus 13% of control patients (last observation carry-forward [LOCF] analysis, p=0.011);
- additional reanalyses of these same data to evaluate persistence of response show that among those who achieve a response at 3 or 12 months, 60-75% of such patients are judged to remain a responder at 1 year later.
The authors concluded that in the context of relatively low overall response rates, these data do not provide evidence of efficacy.
- the percentage of responders on the basis of Hamilton Depression Rating Scale (HDRS) ranged from 29% to 40%;
- the percentage of remitters ranged from 17% to 29%;
- one study found improvements relative to baseline in executive functions, motor speed and psychomotor function;
- the only double-blind randomised controlled found no significance difference between VNS and sham.
- one study reported that the response rate was sustained after nine months of VNS: 40% to 46% (p = 0.317); and at 12 months, the remission rate significantly increased from 17% to 29% (p = 0.045);
- the responders at 3 months (n = 12) largely maintained their response, with 91% (10/11) of the patients still being responders to VNS at 12 months. Among the non-responders at 3 months (n = 18), 18% were considered as responders at 12 months;
- improvement of depressive symptoms was also seen in another study; changes in response and remission status from 3 months to 12 months were statistically significant for the HDRS24;
- the only two-year follow-up study with a relatively large sample (n = 59), showed that the majority of antidepressant effects of the VNS were seen in the acute phase (i.e. in the first 3 months) although additional improvements occurred by 12 months and were largely sustained at 24 months;
- another long-term study that compared patients receiving their treatment as usual (TAU) to patients receiving both TAU and VNS (for 12 months); showed that 27% of the VNS + TAU were responders at 12 months, with only 13% of the patients receiving their TAU (p < 0.011);
- one study that reported comparisons between patients receiving VNS plus ECT and patients receiving VNS alone; showed that both groups had comparable improvements on their HDRS scores, suggesting that ECT does not affect the VNS therapy and vice versa;
- one study showed evidence of higher rates of response (58%) and remission (36%) at the end of the study, after one year of VNS therapy;
- three single cases showed VNS have maintained antidepressant effects for up to 45 months;
- secondary clinical outcomes revealed ongoing clinical benefit, such as significant improvements in the mental component, vitality, social function, emotional role and mental health Medical Outcome Study 36-Item Short Form Survey Instrument (MOS SF-36) scores.
- VNS therapy may have an antidepressant effects in patients with TRD responding in the short- and long-term
- The RCT reviewed report weak evidence that does not demonstrate efficacy
- Results need to be regarded with some caution due to methodological shortcomings and quality of included studies
- Thus, the available evidence does not permit conclusion regarding the effect of VNS
4.2 Safety and tolerability
- incision pain related to the implantation was the most reported adverse event and generally resolved after a couple of weeks;
- other major adverse effects reported were cough or throat, discomfort when the actual stimulation is taking place. Other adverse effects include headache, shortness of breath, difficulty in swallowing, indigestion, nausea, general pain and neck pain.
- one case-series study reported ten serious or clinically significant adverse events, including two patients with worsening depression and one patient with a myocardial infarction;
- in the six short-term studies, only three patients discontinued the study due to adverse events, including one patient who committed suicide
- one case-series study reported that 3 patients met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSMIV) criteria of mania while receiving VNS;
- The long-term studies side effects were generally the same as those reported in short-term studies - typically mild and restricted to the time of stimulation.
Safety - summary
- The adverse events, although not permanent, are numerous and cannot be ignored
- Side effects were generally similar in both short- and long-term studies
5. Cost/ economic information
No specific studies were conducted for economic evaluation. However, economic evaluation of VNS for TRD depression was reported in two conference posters.23,24 These studies suggests that VNS would result in very significant cost-reductions (hospitalizations, medication, ETC, etc), over 17000 Euros after 18 months of VNS.
The reviewed secondary evidence suggests that VNS therapy may have an antidepressant effects in patients with TRD responding in the short- and long-term. However, evidence base is still limited and it is difficult to draw any firm conclusions. The only RCT included in the studies reported weak evidence that does not demonstrate efficacy. These results were based mainly on observational, often uncontrolled studies which are subject to a number of limitations. Not controlling for placebo effects and natural history of disease make it difficult to infer efficacy from these studies. It is possible that much or all of the improvement reflected a placebo response or spontaneous remission. VNS may be associated with placebo effect due to its invasive nature.
There are also several issues regarding indications for the use of VNS:
- VNS can be used to solve the problem of compliance that is associated with antidepressants;25
- VNS does not pass through the placenta and is safe for the pregnancy and for the infant and allows a sustained remission of depression;26
- The impact of VNS on patients' use of antidepressants and other medications has not been determined.27
VNS may be seen as a promising new form of treatment for TRD. However, the high cost of the device, the invasive nature of the treatment, numerous reported adverse effects, and the absence of a clear effect may limit use. There is a need for well conducted randomized controlled trials to confirm antidepressant effects observed in the observational studies.
6.1 Limitations of this report
This report did not undertake to systematically review primary studies on the effectiveness of VNS in depression. Searches were aimed at identifying systematic reviews and only the most recent obtainable publications were discussed.
7. Evidence not reviewed in this report
- Aggressive Research Intelligence Facility (ARIF). Vagal nerve stimulation for depression. 2005. Birmingham, Department of Public Health, Epidemiology, and Biostatistics, University of Birmingham. http://www.arif.bham.ac.uk/archive/vagal-nerve-stimulation-severe-depression.shtml
- HAYES Inc. Vagus nerve stimulation for depression. Lansdale, PA: HAYES, Inc,. 2005.
- Alberta Heritage Foundation for Medical Research. Vagus nerve stimulation. Edmonton: Alberta Heritage Foundation for Medical Research (AHFMR). 2000. Alberta Heritage Foundation for Medical Research (AHFMR).
- Blue Cross Blue Shield Association. Vagus nerve stimulation for treatment-resistant depression. Chicago IL: Blue Cross Blue Shield Association (BCBS). 2005. Blue Cross Blue Shield Association (BCBS).
1 National Institute of Health and Clinical Excellence. Depression: the treatment and management of depression in adults. National Clinical Practice Guideline 90. 2009.
2 Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289(23):3095-3105.
3 Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289(23):3095-3105.
4 Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997; 349(9064):1498-1504.
5 Fava M, Kendler KS. Major depressive disorder. Neuron 2000; 28(2):335-341.
6 Meltzer H, Gatward R, Goodman R, Ford T. The Mental Health of Children and Adolescents in Great Britain. The report of a survey carried out in 1999 by Social Survey Division of the Office for National Statistics on behalf of the Department of Health, the Scottish Health. London: Executive and the National Assemby for Wales:The Stationery Office; 2000.
7 Eagles JM, Wileman SM, Cameron IM, Howie FL, Lawton K, Gray DA, et al. Seasonal affective disorder among primary care attenders and a community sample in Aberdeen. Br J Psychiatry 1999; 175:472-475.
8 Thompson C, Thompson S, Smith R. Prevalence of seasonal affective disorder in primary care; a comparison of the seasonal health questionnaire and the seasonal pattern assessment questionnaire. J Affect Disord 2004; 78(3):219-226.
9 Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review. J Affect Disord 2008; 110(1-2):1-15.
10 Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996; 19(2):179-200.
11 Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry 2001; 62 Suppl 16:10-17.
12 Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review. J Affect Disord 2008; 110(1-2):1-15.
13 Topfer L, Hailey D. Vagus Nerve Stimulation (VNS) for Treatment-Resistant Depression. Issues in Emerging Health Technologies 2001;(25).
14 Malottki K, Fry-Smith A, Moore D. Mapping the evidence base and use of neurostimulators (interim report). Report number 70. Birmingham, UK: Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham; 2008.
15 Critical Appraisal Skill Programme (CASP). CASP Systematic Reviews Checklist. 2009.
16 Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review. J Affect Disord 2008; 110(1-2):1-15.
17 Blue Cross Blue Shield Association. Vagus Nerve Stimulation for Treatment-Resistant Depression. Chicago, IL: Technology Evaluation Center, Blue Cross Blue Shield Association; 2006.
18 Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of Vagus Nerve Stimulation in treatment-resistant depression. A systematic review. J Affect Disord 2008; 110(1-2):1-15.
19 Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001; 25(5):713-728.
20 Marangell LB, Rush AJ, George MS, Sackeim HA, Johnson CR, Husain MM, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes. Biol Psychiatry 2002; 51(4):280-287.
21 Nahas Z, Marangell LB, Husain MM, Rush AJ, Sackeim HA, Lisanby SH, et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry 2005; 66(9):1097-1104.
22 Nahas Z, Marangell LB, Husain MM, Rush AJ, Sackeim HA, Lisanby SH, et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry 2005; 66(9):1097-1104.
23 Annemans L, Sorel RVdAH, Buschman R, Welkenhuyen J, Verstappen D. Impact of VNS therapy on cost of care in chronic or recurrent depressive patients resistant to treatment. The ECNP Congress, Vienna, Austria; 2007
24 Sperling W, Verstappen D. Vagus nerve stimulation: clinical and socio-economic aspects of a new method treating depression. The ECNP Congress, Vienna, Austria; 2007
25 Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001; 25(5):713-728.
26 Husain MM, Stegman D, Trevino K. Pregnancy and delivery while receiving vagus nerve stimulation for the treatment of major depression: a case report. Ann Gen Psychiatry 2005; 4:16.
27 Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000; 47(4):276-286.