vagus nerve stimulation therapy in treatment-resistant depression: a series report

Regular Article

Vagus nerve stimulation therapy in treatment-resistantdepression: A series reportGiuseppe Tisi, MD,1* Angelo Franzini, MD,2 Giuseppe Messina, MD,2 Mario Savino, MD3 andOrsola Gambini, MD1

1Department of Psychiatry, University of Milan, 2Neurological Institute ‘Carlo Besta’ and 3European Institute of Oncology,Milan, Italy

Aim: The purpose of this study was to evaluate theefficacy of vagus nerve stimulation (VNS) as a thera-peutic option for treatment-resistant depression(TRD), with follow-up periods of 1, 3 and 5 yearsafter VNS surgery.

Methods: We examined 27 consecutive patients withunipolar TRD. Depressive symptoms were evaluatedboth at baseline and at follow-up after the surgery bymeans of the 21-item Hamilton Rating Scale forDepression (HAM-D 21).

Results: The mean HAM-D preoperative score was25.6. Twenty-two patients were evaluated after 1 yearof treatment, and the mean improvement of theHAM-D score was of 10.3. Five patients (20%) wentinto complete remission (HAM-D < 7) after 1 year,six patients (22.3%) were considered responders(50% reduction of HAM-D scoring) and eightpatients had score reduction of less then 20%. Nine-teen patients were evaluated after 24–36 months: the

average improvement on the HAM-D score was of12.1 points (47.2%). One patient went into completeremission and eight patients (42.1%) were respond-ers. Up to the present date, seven patients have under-gone re-evaluation at 48–60 months from surgeryshowing an average score reduction of 14.2. Twomore patients obtained complete remission, whilefour of them did not have any improvement sincetheir last follow-up control visit.

Conclusion: VNS antidepressant was successful in20% of TRD patients, although some patientsrequired several months to obtain clinical improve-ment or remission of symptomatology. Nonethelessthis procedure can be considered as a useful option intreating TRD.

Key words: Hamilton Rating Scale for Depression,long-term follow up, remission, treatment-resistantdepression, vagus nerve stimulation.

DEPRESSION IS A disabling condition that is esti-mated to have a 20% lifetime prevalence in the

general population.1 Although a wide range of effec-tive pharmacological and non-pharmacologicalinterventions are available, a significant number ofpatients do not respond completely to therapy,2,3 andare considered resistant or refractory, defining a clini-cal condition that is called treatment-resistant depres-sion (TRD) in its broad sense.

The majority of patients that have suffered from adepressive episode often experience a recurrence ofthe disease or do not completely recover from theepisode itself.3 About one-third of depressed patientsdo not have a successful outcome with the first anti-depressant treatment,4 and up to 20% of them arestill ill 2 years after the onset of the disease.5 Ithas been estimated that 10–20% of patients do notbenefit from conventional antidepressant drugsand/or even from other non-pharmacological treat-ments, such as light-therapy, psychotherapy and elec-troconvulsive therapy (ECT).6 For these reasons, TRDis one of the major challenges for psychiatrists.

Many definitions of what is considered treatmentresistance have been formulated, the majority of

*Correspondence: Giuseppe Tisi, MD, via Di Rudinì 8, 20142 Milan,Italy. Email: [email protected] 20 May 2013; revised 22 January 2014; accepted 26January 2014.

Psychiatry and Clinical Neurosciences 2014; 68: 606–611 doi:10.1111/pcn.12166

606 © 2014 The AuthorsPsychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

mailto:[email protected]

them indicating a lack of response to a variablenumber of adequate (in terms of dosage and time)antidepressant trials and psychotherapy.

Among other neurostimulation techniques, vagusnerve stimulation (VNS) has proven to be a signifi-cant alternative option for some patients sufferingfrom TRD, and several clinical studies during the lastyears show that the clinical improvement achievedin such patients seems to be sustained over years.7–9

The rationale for the use of VNS in treating chronicdepressed patients has been based on the observationof mood improvement in implanted epilepticpatients.10 Moreover, several neuroimaging findings,both in epileptic and depressed patients, show modi-fications in brain regions that are associated withneurotransmitters that have anticonvulsant and anti-depressant actions. Functional magnetic resonanceimaging (fMRI), positron emission tomography(PET) and single-photon emission computed tomog-raphy (SPECT) studies revealed metabolic changes ofcortical limbic, paralimbic and associative regions, towhich vagus nerve projects through many differentpathways and connections, such as nucleus tractussolitarius, nucleus parabrachialis, locus coeruleus,and several other brainstem and diencephalicstructures.11,12

Previous naturalistic studies have shown clinicalimprovement in depressive symptoms after 12months of VNS active therapy. An average responserate of 29.8% and a remission rate of 17.1% havebeen reported after 1 year of VNS in a naturalisticsetting.13 Few studies reported clinical outcomes of 2or more years after the implantation.7,14

The purpose of this study was to describe the clini-cal and symptomatic outcome after VNS implanta-tion and to evaluate the efficacy of this therapeuticoption in TRD in a long-term follow-up observation.Patients were evaluated before undergoing surgeryand after follow-up periods of 1, 3 and 5 years.

METHODS

Patients

The protocol of the study was approved by the ethicscommittee of the C. Besta Neurological Institute inMilan. Patients were required to give their writteninformed consent before participating in the study.

From 2006 to 2009, 27 consecutive patients withTRD, 18 men and nine women, underwent VNS sur-gical procedure. None of these patients had depres-

sion with psychotic features, although this was notan exclusion criterion. Four of the patients hadcomorbidity with anxiety disorders (one with panicdisorder, two with generalized anxiety disorder andone with obsessive–compulsive disorder). Moreover,two of them had a concomitant pain disorder. In ourprotocol, TRD is defined as lack of response after atleast four full-dosage antidepressant trials (includ-ing serotonin reuptake inhibitors, noradrenalinereuptake inhibitors, monoamine oxidase inhibitorsand tricyclics) and at least 6 months of psycho-therapy. It is to be noticed that three patients hadbeen treated with electroconvulsive therapy (ECT) inthe past. The duration of the current depressiveepisode had to be of at least 2 years without remis-sion or response to treatment.

Exclusion criteria were age below 18 years, currentsubstance abuse, current acute psychotic or manicepisode, suicidal ideation (as shown in item 4 of theHamilton Rating Scale for Depression [HAM-D]) andany other medical condition that could contraindi-cate the surgical intervention.

Patients’ motivation for dropping out of the studyincluded consent withdrawal, death, lack of efficacyand geographical distance from the institute. Patientswere recruited from all over Italy.

Depressive symptoms were evaluated both at base-line and at follow-up after surgery by means of the21-item HAM-D (HAM-D 21). To be enrolled in thestudy, the baseline score had to be > o = 20. The pre-surgical psychiatric evaluation was performed toconfirm the diagnosis as well as the high level ofpharmacological and treatment resistance. Follow-upevaluations were performed at 1, 3 (between 24 and36 months) and 5 (48–60 months) years after thesurgery.

All patients were on antidepressants (and mood-stabilizers as augmentation therapy), which were notwithdrawn after surgery. Throughout the follow-upperiod, the dosage of antidepressant medications wasadjusted according to clinical condition, while nochange of type of antidepressant treatment wasperformed during the period under consideration.Table 1 shows the general characteristics of thepatients.

Procedure

VNS therapy is a non-pharmacological treatmentconsisted in the implantation of an electrode on theleft cervical vagus nerve. The electrode is connected to

Psychiatry and Clinical Neurosciences 2014; 68: 606–611 VNS and treatment-resistant depression 607

© 2014 The AuthorsPsychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology

a pulse generator, situated subcutaneously in the leftthoracic region, through a lead tunneled under theskin. Once programmed, the pulse generator trans-mits chronic intermittent electrical stimulation to thenerve and can be regulated by the doctor with a por-table device, without any surgical intervention.

This study is a case series of 27 patients sufferingfrom TRD. They were enrolled and they underwentsurgery at the Neurological Institute C. Besta.

The outcome measure was improvement frombaseline evaluation over time in the scores of theHAM-D 21.

Patients that had a reduction of at least 50% of theinitial score were considered responders, while remis-sion was defined as a score of 7 or lower on theHAM-D 21, no matter what the baseline score was.

Statistical analysis

Simple descriptive statistics (mean and SD) wereobtained for the patients’ demographic and epide-miological characteristics. Mean improvement in thescore (at 1, 3 and 5 years after the surgery) was ana-lyzed comparing HAM-D scores between evaluationsusing the paired t-test, and each evaluation was com-pared with the baseline score with the same method.Paired t-test was not used to analyze data concerningthe 5-year follow-up because of the small number

(seven patients): HAM-D raw score improvement wasreported, but no statistical analysis was performed.The number of patients who met the criteria forresponse and/or remission at all the end-points wasalso determined.

P-value is considered statistically significant if<0.05 (one-tailed).

RESULTSThe mean HAM-D preoperative score of the 27patients enrolled was of 25.6, with a maximum scoreof 33 and a minimum of 20. The number of patientsevaluated was 22 at 1 year (15 men, seven women),19 after 2 years (12 men, seven women) and seven at5 years (five men and two women).

The high rate of drop-outs was determined by dif-ferent factors. Half of the patients (n = 15) autono-mously abandoned the study because of a reportedlack of efficacy of the treatment, others were unableto attend to clinical evaluations because of geo-graphical distance from the institute. Four patientsdied, none of them for issues directly related todepression or to the surgery.

The mean (SD) age of the patients was 57.5 ± 14years, and the average duration of the disease was of18.5 years, with an SD of 13.3. The onset of thedisease, meaning the first depressive episode in thepatient’s life, occurred at the age of 38.8 ± 17.8years. All of the patients had a diagnosis of majordepression.

As shown in Table 2, after 1 year of treatment, themean improvement of HAM-D score was of 10.3points, reflecting a 38.9% average decrease of thebaseline score. Among the 22 patients that werere-evaluated after 1 year, six (27.3%) were consideredresponders, as they had a decrease of more than halfof the initial score. Remission was obtained in fivepatients (20%), three did not show any results in

Table 1 Characteristics of the 27 patients

Characteristics Value

Age at implantation (mean ± SD) 57.5 ± 14 yearsAge at disease onset (mean ± SD) 38.8 ± 17.8 yearsDuration of disease (mean ± SD) 18.5 ± 13.3 yearsWomen/men 9/18 (33.3%)

Table 2 Clinical outcome in observed patients

Baseline 12 months 24–36 months 48–60 months

No. of patients 27 22 19 7HAM-D improvement – 10.3 (38.9%) 12.1 (47.2%) 14.2 (55.5%)HAM-D mean 25.6 ± 4.0 15.3 ± 7.7 13.5 ± 6.0 11.4 ± 6.2Remitters – 5 (20%) 4 (21%) 2Responders – 6 (27.3%) 8 (42.1%) –

HAM-D, Hamilton Rating Scale for Depression.

608 G. Tisi et al. Psychiatry and Clinical Neurosciences 2014; 68: 606–611


terms of improvement of depressive symptoms,while six had a minimal improvement of less than10% of the score.

The second postoperative psychiatric evaluationwas performed between 24 and 36 months from thesurgery, and included 19 patients, all of whom hadundergone the testing performed at 1 year. Theaverage score improvement was of 12.1 points(47.2%) compared to the initial score and of 1.8compared to the previous follow-up end-point. Eightpatients were responders, one other patient had acomplete remission of symptoms, while eightpatients’ symptoms worsened (with an averageincrease of +4 points on HAM-D) or did not change.Of the six patients that left the study, one was aresponder.

To the present date, seven patients have been testedat the 5-year follow up (48–60 months) and none ofthem missed previous evaluations. The HAM-D 21score had a mean reduction of 14.2 points comparedto baseline. Two patients went into complete remis-sion, while five of them did not have any improve-ment (one patient’s symptoms worsened) from theirlast follow-up control.

Every follow-up evaluation (except for the last one,which is not taken into consideration in the statisticalanalysis because of the small number of patients)shows a statistically significant improvement com-pared to the baseline, while after the first year thereduction of the score is less relevant, indicating apersistence of the initial improvement rather thanany further significant increase.

The most common side-effect was occasional voicealteration/hoarseness (17/27, 63%), which was gen-erally mild, transitory and related to current intensity.Moreover none of the patients had a manic or hypo-manic episode during VNS treatment.

DISCUSSIONData collected in this study clearly show a clinicalimprovement in depressive symptoms of patientstreated with long-term VNS.

Of the six patients that were responders at 1 year,two did not undergo the subsequent evaluations,two were still responders (compared to baseline) at24–36 months, while in two cases, symptoms wors-ened. Six more patients obtained treatment responseat 24–36 months, and two of them obtained com-plete remission at 48–60 months. Patients whosesymptoms remitted at the first evaluation (n = 5) had

an HAM-D score of less than 7 also in the subsequentevaluations at 3 and 5 years, with the exclusion ofpatients who dropped out of the study before followup (n = 2). In our sample, all the patients that under-went remission maintained remission throughout allthe evaluations, while some of the responders wors-ened over time: two of them between the first and thesecond evaluation after the surgery, and one morebetween the second and the last evaluation.

The evaluations of subjects taking part in the studyrevealed that the majority of patients maintainedtheir clinical improvement over time, particularlywhen they were remitters, which means that com-plete resolution of depression is likely to be main-tained with long-term VNS. This is in line withpublished data, even though, to the best of ourknowledge, there are no studies evaluating patientsat 5 years’ follow up. In a 1-year follow-up study,Marangell et al.9 noticed that the majority of patients(91%) that were responders in the acute phase main-tained their response up to 1 year. Bajbouj et al.7

evaluated 74 patients over a follow-up period of 2years, and remarked that the proportion of patientswho fulfilled remission criteria remained constantover time. Some authors emphasized that the open-label response/remission rate increased with chronicstimulation (in a ≤24-months follow-up period)13,15

and in particular at high electrical dose parameters.14

Our data confirm this observation over a longerperiod of time, suggesting that one of the most sig-nificant advantages of VNS therapy should be thereduction of recurring episodes over time.

In a recent review, Holtzheimer et al.16 reportedthat open-label studies have shown a 30–40%response rate and a 15–17% remission rate after 3–24months of VNS. As shown in Table 2, our data areclose to these percentages, and are also in line withother authors17 who reported a sustained responsein 61–76% of patients, in a 2-year follow-up study.Sustained response is well represented also in oursample, with a significant response after 1 year main-tained over 3 years (Table 3).

It is noteworthy that all patients were on medica-tion. For this reason we are not able to estimate theefficacy of VNS therapy alone, even though pharma-cological treatment of responders was not modified.As long as the clinical situation allowed us, we didnot make changes regarding antidepressant or mood-stabilizer therapy. Moreover, George et al.18 found ahigher response rate in patients treated with com-bined therapy (pharmacotherapy and VNS) than in



those seen with treatment as usual (without VNS) ina non-randomized comparison group.

In line with published data,19 our observationsshow that VNS is a safe and well-tolerated therapy. Inour sample, the only side-effect was voice alterationor hoarseness, which presented in 17 patients andgenerally correlated to current intensity. There wasno report of other side-effects; in particular wedid not notice any negative neuropsychologicaleffect, as reported by Moreines et al.,20 nor cognitiveimpairments.21

The positive results of this study should be inter-preted taking into account two important designlimitations. The first is the small sample size, in par-ticular with respect to subjects who underwent the5-year follow up. Further studies with a larger patientpopulation are warranted, particularly over a long-term follow-up period.

The second is that neither stimulation parametersnor antidepressant treatments were controlled,although the differences in the overall numbers ofantidepressant and other psychotropic treatments didnot differ significantly over time.

Despite these limitations, these data suggest thatVNS treatment, in addition to medication, representsan important therapeutic option in those patientsthat did not have satisfactory response to conven-tional therapies, both in terms of efficacy and side-effect profile. Most importantly, the present studyshows that the meaningful treatment response, onceachieved, seems to be sustained and maintained overa long period of time, up to 5 years after the surgery.

ACKNOWLEDGMENTThe authors reported no conflict of interest.

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Table 3. Comparison of 21-item Hamilton RatingScale for Depression scores between evaluations

Evaluations Means P-value

Basal–1 year 25.6–15.3 <0.051 year–3 years 15.3–13.5 >0.05Basal–3 years 25.6–13.5 <0.05

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vagus nerve stimulation therapy in treatment-resistant depression: a series report

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