Vagus nerve stimulation in chronic treatment-resistant depression: Preliminary findings of an open-label study

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

INTRODUCTION

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INTRODUCTION

Major depressive disorder is one of the leading causes of morbidityin the world (Ustun et al, 2004). Chronicity, where thereis ongoing unremitted major depression for at least a 2-yearperiod, occurs in approximately 2.1% of the world populationand is associated with severe impairment in psychosocial functioning(Scott, 2000). Vagus nerve stimulation therapy has been foundto be an effective treatment for the management of resistantepilepsy and to be efficacious in some trials involving individualswith treatment-resistant depression (George et al, 2000). Theaim of this study was to evaluate the safety and efficacy ofvagus nerve stimulation therapy in 11 patients with chronictreatment-resistant depression.

METHOD

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METHOD

Participants and setting
Patients were recruited from Beaumont Hospital, Dublin. Thiscentre was part of the European safety and efficacy study forvagus nerve stimulation therapy in treatment-resistant depression(D-03). Patients were eligible for inclusion if they fulfilledcriteria for major depressive disorder, suffered from a chronic(>2 years) current episode, scored $≥$ 20 on the Hamilton RatingScale for Depression (HRSD; Hamilton, 1960) and had failed to respond to antidepressants from at least two different categories.Major depressive disorder was diagnosed using the StructuredClinical Interview for DSM-IV (First et al, 1996), and wasmeasured using multiple scales including the HRSD and the Inventoryof Depressive Symptomatology - Subjective Rating (Rush et al, 1986). Ethical approval was obtained locally. All patients gave fullyinformed written consent and were made aware of all potentialcomplications.

Surgical procedure
The neurosurgical team, led by J. P. implanted the NeuroCybernetic Prosthesis system (Cyberonics Europe, Belgium) surgically.This procedure involves the subcutaneous implantation, undergeneral anaesthetic, of a pacemaker-like device into the leftaxillary area of the chest, with a bipolar lead tracking fromthere to the cervical vagus nerve. The device operates by discharginga small fixed electrical signal of 30 s duration every 5 minto the vagus nerve.

Study design
There were two periods under study: an acute phase (12 weeks),commencing from 2 weeks after implantation, and a long-termphase of stimulation administration (40 weeks). For the first2 weeks of the acute phase vagus stimulation was adjusted,and thereafter remained fixed until week 12. Participants wereevaluated at weekly or 2-weekly intervals during this phase, and thereafter had follow-up evaluation at 6, 9 and 12 months.A combined total of five antidepressants and mood stabiliserswere allowed as long as the individual had been stable on thesemedications for 4 weeks before the initial visit. Patientswere considered protocol violators if their antidepressant medicationswere changed during the acute phase. However, alterations in psychotropic medication were allowed during the long-term phase.

Statistical analysis
One-way analysis of variance of outcome measures over time wasperformed. Posthoc analysis was used to examine differencesin scores over the specific time points. Response was definedas a $≥$ 50% decrease in the HRSD from the baseline HRSD scores.Remission was defined as HRSD score <10.

RESULTS

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RESULTS

All participants were White, with a mean age of 43 (s. d.=8.72)years, and 73% were female. Overall, patients had a long historyof depression with a mean length of illness of 20 (s. d.=8.34)years. They had a median episode duration of 46 months; only2 had not had a previous episode. Electroconvulsive therapy(ECT) had been received by 55%.

Clinical outcomes
All measures of depression were statistically reduced at 1 yearcompared with baseline (Table 1). There was one responderat 3 months, two responders at 6 months and 6 responders at 1 year. Three patients had remitted (defined as HRSD-24<10)by 1 year. Covarying for medications added during the studyperiod did not result in any loss of statistical significance(F (39,4)=6.5, P<0.001).

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Table 1 Mean (s.d.) scores on Hamilton Rating Scale for Depression (HRSD–24), Montgomery–Åsberg Depression Rating Scale (MADRS) and Inventory of Depressive Symptomatology – Subjective Rating (IDS–SR) for II patients at 0, 3, 6 and 12 months after vagus nerve stimulation therapy

There were several serious adverse events. Patient 1, a treatment non-responder, died by suicide at 9 months following implantation,but had not revealed this intention verbally. Patient 2 experienceda number of recurrences of pulmonary emboli that first occurredfollowing surgery unrelated to the vagus nerve stimulationtherapy. Patients 3 and 4 developed vocal cord palsies of mixedduration following surgery; the palsy of patient 3 lasted forapproximately 2 months, and that of patient 4 approximately6 months. There was a consequent delay in initiating treatment(i. e. the device was not switched on) until symptom resolution.Both patients made a full recovery from the palsy.

DISCUSSION

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DISCUSSION

This study suggests that vagus nerve stimulation may be an effective treatment for some individuals suffering from chronic treatment-resistant depression. The response rates for the acute phase of the studywere disappointing, in that only one patient responded after3 months. By 1 year, 55% of the sample had responded to treatment,suggesting that long-term follow-up is required to realisethe therapeutic potential of vagus nerve stimulation treatment.The placebo response in these patients was typically poor andso probably does not account for the response rate (Stewart et al, 1993).

There was a striking number of adverse events in this study.It could be reasonably argued that the suicide was unrelatedto the treatment, except insofar as treatment was ineffective,seeing that patient 1 left a suicide note explaining her intentionbefore treatment to kill herself if the therapy did not cureher depression. It is more likely that the pulmonary embolithat were experienced by patient 2 were related to her canceror antipsychotic medication, rather than the vagus nerve stimulation.The vocal cord palsies experienced by patients 3 and 4 (18%of the sample) would appear to be an idiosyncratic finding:although this is a direct consequence of the surgical procedure,it usually only occurs in 1% of cases both internationally (George et al, 2000), and within the study hospital, where 50 such procedures areperformed annually.

The findings from our trial are in keeping with previous observationsof a response rate of 40% over a period of at least 1 yearwith vagus nerve stimulation treatment for major depressivedisorder, suggesting that adequate time should be allowed beforeconclusions can be reached about clinical efficacy (Marangell et al, 2002).

Current physical treatment approaches to resistant depressioninclude ECT (Folkerts et al, 1997) and psychosurgery (Bridges et al, 1994).ECT has a high incidence of reported adverse side-effects (UK ECT Review Group, 2003). Psychosurgery by its very nature will always be a treatmentof last resort. It has been reported that 63% of patients receivingpsychosurgery in the UK for resistant depression are markedlyimproved as a result (Royal College of Psychiatrists, 2002).Deep brain stimulation therapy has been reported to be effectivein 4 out of 6 cases of resistant depression (Mayberg et al, 2005).

Limitations
The main limitations of this study were that it was an openstudy, and patients were not randomised to active or sham treatment.It was not possible for raters to be masked because of surgicalscarring. In addition, the sample size was small. Medicationchanges were allowed during the long-term phase of the study,possibly impacting on the findings, although we controlled forthis statistically.

REFERENCES

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