Review
Neuropsychobiology 2011;64:170–181 Received: November 9, 2010
DOI: 10.1159/000325225
The Application of Vagus Nerve
Stimulation and Deep Brain Stimulation
in Depression
Pavel Mohr a–c Mabel Rodriguez a, c Anna Slavíčková b–d Jan Hanka a–c
a
 Prague Psychiatric Center, b 3rd Faculty of Medicine, Charles University Prague, c Center of Neuropsychiatric
Studies, and d Neurological Clinic, Thomayer University Hospital, Prague, Czech Republic
Key Words
Depression ⴢ Vagus nerve stimulation ⴢ Deep brain
stimulation
Abstract
Despite the progress in the pharmacotherapy of depression,
there is a substantial proportion of treatment-resistant pa-
tients. Recently, reversible invasive stimulation methods, i.e.
vagus nerve stimulation (VNS) and deep brain stimulation
(DBS), have been introduced into the management of treat-
ment-resistant depression (TRD). VNS has already received
regulatory approval for TRD. This paper reviews the available
clinical evidence and neurobiology of VNS and DBS in TRD.
The principle of VNS is a stimulation of the left cervical vagus
nerve with a programmable neurostimulator. VNS was ex-
amined in 4 clinical trials with 355 patients. VNS demonstrat-
ed steadily increasing improvement with full benefit after
6–12 months, sustained up to 2 years. Patients who respond-
ed best had a low-to-moderate antidepressant resistance.
However, the primary results of the only controlled trial were
negative. DBS involves stereotactical implantation of elec-
trodes powered by a pulse generator into the specific brain
regions. For depression, the targeted areas are the subtha-
lamic nucleus, internal globus pallidus, ventral internal cap-
sule/ventral striatum, the subgenual cingulated region, and
© 2011 S. Karger AG, Basel
0302–282X/11/0643–0170$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Accepted after revision: January 23, 2011
Published online: July 29, 2011
the nucleus accumbens. Antidepressant effects of DBS were
examined in case series with a total number of 50 TRD pa-
tients. Stimulation of different brain regions resulted in a re-
duction of depressive symptoms. The clinical data on the use
of VNS and DBS in TRD are encouraging. The major contribu-
tion of the methods is a novel approach that allows for pre-
cise targeting of the specific brain areas, nuclei and circuits
implicated in the etiopathogenesis of neuropsychiatric dis-
orders. For clinical practice, it is necessary to identify patients
who may best benefit from VNS or DBS.
Copyright © 2011 S. Karger AG, Basel
Introduction
Depression with its serious medical, social and eco-
nomic consequences represents a major burden to the pa-
tients, their families and the society. One-year prevalence
of major depressive disorder (MDD) found in the US pop-
ulation sample was 6.6% and the lifetime prevalence was
16.2% [1]. In a large European epidemiological project,
the 12-month prevalence of depression was 3.9% (2.6%
for males and 5.0% for females) and the observed lifetime
prevalence was 12.8% (8.9% males, 16.5% females) [2].
Depression is among the leading causes of disability; the
WHO ranks it as a number one cause indexed by the
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Pavel Mohr, MD, PhD
Prague Psychiatric Center
Ustavni 91
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CZ–181 03 Praha 8 (Czech Republic)
Tel. +420 266 003 360, E-Mail mohr @ pcp.lf3.cuni.cz
‘years lost due to disability’ across the world, in both low-
and middle-income countries [3]. The WHO projects
that, according to the measure ‘disability-adjusted life
year’, depression will rise from number 3 among the 10
leading causes of burden of diseases in 2004 to the global
top position in 2030. The financial costs of depression in
2000 were USD 83.1 billion per year in the US [4] and over
GBP 9 billion in the UK [5].
Despite the progress in the pharmacotherapy of
depression, there is still a substantial and growing pro-
portion of patients who are not responding to available
antidepressants, do not tolerate drug therapy, are partial
responders, display residual symptoms, or are labeled
as treatment resistant. Treatment-resistant depression
(TRD) affects from 15% up to one third of depressive pa-
tients [6, 7]. TRD is defined as an episode of depression
that does not respond to 1 or typically 2 or more adequate
treatment trials. TRD is not a nosological entity, and
most likely does not share a common etiology and patho-
physiological mechanisms [8]. Treatment-refractory pa-
tients are quite a heterogeneous group not responding or
not tolerating treatment due to different reasons. In ad-
dition to the recommended pharmacological strategies
how to overcome treatment resistance (e.g. switch to a
different class of antidepressant, augmentation, or com-
bination) [6], other therapeutic options, nonpharmaco-
logical interventions, are tested [8].
Modern stimulatory methods were introduced into
psychiatry in the 20th century: ‘shock therapy’, insulin-
induced coma, Metrazol-induced convulsion, electro-
convulsive therapy (ECT), and nonspecific and targeted
psychosurgery [9, 10]. The renewed interest in stimula-
tory methods came along with the safer interventions
allowing for precise targeting of key structures and with
a better understanding of underlying neurobiological
mechanisms of psychiatric disorders. In addition to the
traditional ECT, repetitive transcranial magnetic thera-
py, magnetic seizure therapy, vagus nerve stimulation
(VNS), and deep brain stimulation (DBS) have become
alternative nonpharmacological treatment options for
many psychiatric patients. Other experimental proce-
dures, such as epidural prefrontal cortical stimulation,
are under investigation [11].
VNS and DBS were adopted from neurology. The ra-
tionale behind the first use of VNS and DBS in affective
disorders was originally based on anecdotal observations
and case reports of neurological patients who improved
independently of seizure reduction. Additional lines of
reasoning stem from the administration of anticonvul-
sants and induced seizures (ECT) in the therapy of mood
VNS and DBS in Depression
disorders. In this paper, we review the current state of the
clinical evidence, the neurobiological basis, and evaluate
the potential for clinical application of VNS and DBS in
depression.
Vagus Nerve Stimulation
VNS has been available for treatment-resistant epilep-
sy since the 1990s; for depression, it was first registered in
Europe and in Canada in 2001, and in the US in 2005.
VNS is approved for patients with chronic or recurrent
depression who failed to respond to at least 4 antidepres-
sant interventions, but patients are not required to have
failed to respond to ECT [12].
Principles of VNS
The term ‘vagus nerve stimulation’ generally refers to
several different techniques used to stimulate the vagus
nerve [13]. In animal studies, the vagus may be accessed
via the abdomen and diaphragm. VNS in humans speci-
fies stimulation of the ascending fibers of the left cervical
vagus nerve using a programmable neurostimulator,
pacemaker-like device, implanted in the left chest wall.
The battery-powered stimulator delivers electrical im-
pulses through a subcutaneous bipolar lead. The elec-
trode is wrapped around the left vagus nerve in the neck,
near the carotid artery. Implantation is usually an outpa-
tient procedure under local anesthesia requiring two
small incisions and is typically performed by a neuro-
surgeon. The neurostimulator programming wand with
software and a portable computer provide telemetric
communication with the pulse generator that enables de-
vice programming and data retrieval. Stimulator settings
are programmed to deliver intermittent stimulation with
a current of 0.25–3.0 mA, a frequency of 20–50 Hz, and a
pulse width of 500 ns for 30–90 s every 5–10 min. Each
patient is given a magnet that, when held over the pulse
generator, turns stimulation off. When the magnet is re-
moved, stimulation resumes [13].
The device is turned on after the recovery postimplan-
tation period, in most cases after 2 weeks. In the reviewed
studies, stimulation parameters were adjusted gradually
over the course of the next 2 weeks with increasing inten-
sity (increments of 0.25 mA output current) to the max-
imal level that could be comfortably tolerated by the
patient. Additional adjustments (increase or decrease)
during long-term follow-up can be made according to ef-
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Neuropsychobiology 2011;64:170–181 171
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ficacy and safety. The frequency of visits is initially once
a week, biweekly during the acute phase and monthly in
the chronic phase. In the course of VNS therapy, con-
comitant treatment with antidepressants, mood stabiliz-
ers, or other psychotropic drugs is permitted. Patients
with VNS can be administrated ECT when the stimulator
is turned off. The duration of therapy depends on the bat-
tery life (several years, depending on the settings); the
stimulator is replaceable.
Neurobiology of VNS
The exact mechanism of antidepressant action of VNS
is not fully understood. Hypotheses are based on the neu-
robiology of the vagus nerve and its effects on brain func-
tions implicated in mood control [14, 15]. The vagus nerve
is a mixed nerve composed of about 80% afferent fibers.
Antidepressant effects are attributed partially to the pro-
jection of afferent fibers to the nucleus tractus solitarius
that relays incoming sensory information to the brain
through an automatic feedback loop, direct projections to
the reticular formation in the medulla, and ascending pro-
jections to the forebrain via the parabrachial nucleus and
the locus coeruleus. The locus coeruleus is the site of many
norepinephrine-containing neurons that have important
connections to the amygdala, hypothalamus, insula, thal-
amus, orbitofrontal cortex, and other limbic regions re-
sponsible for mood and anxiety regulation [14–16].
Both human and animal studies indicate that VNS
evokes changes in neurotransmitters implicated in the
pathophysiology of depression, i.e. serotonin, norepi-
nephrine, GABA, and glutamate [17–21]. Neuroimaging
studies with SPECT, PET, and functional MRI demon-
strate that VNS induces changes in regional cerebral
blood flow (rCBF) similar to those seen with antidepres-
sants [22–24]; either in the amygdala or in the hippocam-
pus or parahippocampus [14].
Hypothesized antidepressant action is further sup-
ported by the findings from animal studies. Acute VNS
in rats increased the expression of brain-derived neuro-
trophic factor and fibroblast growth factor in the hippo-
campus and cerebral cortex, decreased the abundance of
nerve growth factor mRNA in the hippocampus, and in-
creased the norepinephrine concentration in the prefron-
tal cortex [25]. Similarly, chronic VNS increased neuro-
nal plasticity and brain-derived neurotrophic factor ac-
tivity in rats’ hippocampus [26]. However, no changes in
brain-derived neurotrophic factor concentrations follow-
ing VNS were found in patients [27].
172 Neuropsychobiology 2011;64:170–181
Clinical Trials of VNS in Depression
In a study sample of 20 adult epilepsy patients who un-
derwent VNS implantation and 20 patients with no
intervention, mood was assessed at baseline and after 3
months [28]. In addition to the reduction of seizure fre-
quency, the VNS group showed a significant improve-
ment in depression rating scales across time. However, no
change was detected in anxiety measure and the groups
did not differ significantly in mood improvement. Simi-
lar results, i.e. mood improvement independent of seizure
control, were observed in 11 patients receiving VNS for
epilepsy [29]. In the Czech case series of 3 TRD patients,
VNS was found to be well tolerated, with a gradual onset
of action and fluctuating course of depression over the
long-term follow-up of 4–6 years [30]. Besides anecdotal
and case reports, efficacy of VNS in treatment of depres-
sion was investigated in a total of 4 study samples (ta-
ble 1). All the trials, referred to under code labeling from
a device manufacturer (D01–D04), were add-on and in-
cluded treatment-resistant patients.
The first open trial examined 30 patients who failed
to respond to 62 antidepressant medication treatments
from different classes during the current episode [31].
VNS efficacy was evaluated during a 10-week active stim-
ulation with a follow-up of 10 months. As a concomitant
therapy, antidepressants and/or mood stabilizers at a sta-
ble dosage from baseline throughout a 12-week active
period were allowed. Study results demonstrated that a
baseline 28-item Hamilton Rating Scale for Depression
(HRSD28) score of 38.0 8 5.5 significantly decreased at
the acute study exit (23.0 8 10.8). Similar improvement
over time was reported for the Montgomery-Asberg
Depression Rating Scale (MADRS) scores (33.8 8 5.6
and 20.1 8 12.2, respectively). Response rates, defined as
650% reduction in baseline scores, were 40% for both
HRSD and the Clinical Global Impressions-Improve-
ment and 50% for the MADRS. No patient discontinued
due to adverse events. The most frequently reported
events were hoarseness, throat pain, headache, shortness
of breath, general pain, neck pain, and abnormal wound
healing.
Investigators continued with subject enrollment over
time and the original study sample doubled in size; 60
patients had implanted VNS. Reassessments of the total
study group were performed at 10 weeks [32] and 24
months [33]. Data from the 10-week evaluation of 59 pa-
tients showed a 30.5% response rate for HRSD28, 34.0%
for MADRS, and 37.3% for Clinical Global Impressions.
Voice alteration or hoarseness was the most common side
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Table 1. Add-on studies of VNS in TRD

Study Reference Number Duration of Results

active treatment

D01 Rush et al. [31], 2000 30 10 weeks Response rates

(open, pilot) HRSD: 40%
MADRS: 50%
Sackeim et al. [32], 2001 59 10 weeks Response rates
HRSD: 31%
MADRS: 34%
Nahas et al. [33], 2005 59 24 months Response rate
HRSD: 42%
Remission rate
HRSD: 22%
D02 Rush et al. [36], 2005 222 10 weeks Response rates (HRSD)
(double-blind acute (112 active, 110 sham) Active: 15%
phase plus open-label Sham: 10% (n.s.)
follow-up) Response rates (IDS-SR)
Active: 17%
Sham: 7% (p < 0.03)
Rush et al. [37], 2005 205 12 months Response rates
HRSD: 27%
MADRS: 28%
Remission rate
HRSD: 16%
D03 Schlaepfer et al. [34], 2008 74 12 months Response rate
(open-label) HRSD: 53%
Remission rate
HRSD: 33%
Bajbouj et al. [35], 2010 49 24 months Response rate
HRSD: 53%
Remission rate
HRSD: 39%

D04 George et al. [38], 2005 205 (VNS + TAU)a 12 months Improvement (IDS-SR)
(open, comparative) 124 (TAU) VNS+TAU > TAU
Response rate (HRSD)
VNS+TAU: 27%
TAU: 13% (p < 0.01)

IDS-SR = Inventory of Depressive Symptomatology – Self-Report; n.s. = not significant.

a Study sample from D02.

effect. The 2-year outcome analysis demonstrated in-
creasing improvement reaching the maximum at 1 year,
which was maintained for the rest of the follow-up [32].
Analysis of the primary treatment outcome detected that
the HRSD28 response rate at 3 months was 31%, after 1
year 44%, and at the endpoint of 2 years 42%. Remission
rates were 15, 27, and 22%, respectively. Side effects di-
minished over time, with a low dropout rate; at the end-
point, 90% of patients had their device still implanted and
81% activated.
The European D03 study [34, 35] was an open-label
add-on trial with 74 TRD patients, using a design identi-
cal to that in the US D01 trial. European patients were
more frequently diagnosed with recurrent unipolar de-
pression, had more lifetime episodes of depression, less
treatment trials and a marginally lower score in HRSD28,
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but not in MADRS. Response rates (HRSD28) increased
from 37% after 3 months to 53%, which is the rate that
was sustained up to 2 years (53.1%). Remission rates were
17, 33, and 38.9%, respectively. The most common side
effects were voice alteration, coughing, and pain. Of the
total sample of 74 patients who had VNS implanted, 60
patients (81.1%) were evaluated at the end of the 12-month
period and 49 (66.2%) at the 2-year endpoint. Of the 24
patients who terminated prematurely, 8 (33.3%) met re-
sponse criteria, and 2 patients committed suicide.
A double-blind trial compared active stimulation ver-
sus sham in 235 subjects with a DSM-IV diagnosis of
MDD (unipolar or bipolar) who had been in the current
episode of depression for a minimum of 2 years or who
had had at least 4 lifetime depressive episodes [36]. All
participants were implanted with a VNS device and ran-
domized 1:1 to active or inactive (sham) stimulation. Af-
ter a 2-week recovery period following the surgical pro-
cedure, patients with an HRSD24 score 618 entered the
acute phase. The active group had stimulation parame-
ters adjusted over the first 2 weeks and subsequently fixed
for the remaining 8 weeks of the study. The primary out-
come measure was response, i.e. a 650% reduction of the
total HRSD24 score. However, study results failed to de-
tect a significant difference between the response rate to
active and sham stimulation (15 vs. 10%, respectively;
p = 0.251). Of the secondary measures, only subjective
self-report of depression (Inventory of Depressive Symp-
tomatology) yielded statistical difference favoring active
intervention (response rates: 17 vs. 7.3%, respectively; p =
0.032). Two patients from the active group did not com-
plete the study because of adverse events; one due to in-
fection related to implantation and the second commit-
ted suicide. The most frequently reported side effects
were voice alterations, cough, dyspnea, dysphagia, neck
pain, paresthesia, vomiting, laryngismus, and dyspepsia.
Following the acute phase of the original study, all pa-
tients could enter a 12-month open extension trial [37].
The subjects who previously received sham treatment
were eligible if their HRSD24 score was 618. The analysis
demonstrated a significant reduction of depressive symp-
toms in the primary outcome measure: the mean rate of
improvement in the HRSD24 score was 0.45 points (SE =
0.05) per month (p = 0.001). The response rate at the end-
point was 27.2% and the remission rate (HRSD24 ^9) was
15.8%. Similar results were shown for secondary mea-
sures, i.e. MADRS and Clinical Global Impressions: re-
sponse rates were 28.2 and 34%, respectively. The most
common side effects included voice alteration, dyspnea,
and neck pain.
174 Neuropsychobiology 2011;64:170–181
The study sample (n = 205) from the extension trial
[37] was used for a retrospective, nonrandomized com-
parison of combined VNS plus ‘treatment as usual’ (TAU)
intervention versus TAU alone (n = 124) after 12 months
of stimulation [38]. Combined intervention was found to
be more effective on both primary (Inventory of Depres-
sive Symptomatology-Self-Report; p ! 0.001) and second-
ary measures: HRSD24 response rates were 27% for VNS
+ TAU versus 13% for TAU (p ! 0.01).
Evaluation of the VNS Data
Slower onset of antidepressant action suggests that
VNS is not suitable for acute treatment of TRD [39]. Given
the fact that full benefit is observed after 6–12 months of
stimulation with sustained efficacy up to 2 years, VNS
may be indicated for long-term control of symptoms of
depression. VNS proved to be effective in reducing severe,
persistent symptoms and in reducing exacerbations of de-
pression. Patients who respond best to VNS are those with
a low-to-moderate, but not extreme antidepressant resis-
tance and patients with a lower number of unsuccessful
drug trials during the current mood episode. For example,
in the study D01, patients who never received ECT were
found to be 4 times more likely to respond to VNS; none
of the 13 patients who had failed to respond to more than
7 adequate antidepressant trials in the current episode re-
sponded, compared to 39% of the rest of the patients [32].
The number of female subjects in the VNS trials (63–
68%) approximately represents the clinical population.
Although no additional analysis of efficacy or tolerability
according to gender was performed, examination of pre-
dictors of outcome in the D01 study found that gender was
not a prognostic factor of response [32]. No further infor-
mation was provided on the efficacy and safety in elderly
patients. The median age of stimulated subjects was 47–48
years, and inclusion criteria set the upper age limit to 70
years in the US studies and 80 years in the European trial.
The oldest patient was 78 at the time of implantation; no
specific age-related complications were reported [35].
Whereas VNS in epilepsy is labeled for use in children
from 12 years of age, its use for treatment of mood disor-
ders in children and adolescents has not been studied.
Post hoc analysis of the controlled D02 trial examin-
ing a small subpopulation (n = 25) of patients with bipolar
I and II disorder [40] suggested that VNS may also be
effective in bipolar disorder. Index episodes of bipolar
depression were as severe as unipolar depression but of
shorter duration; nevertheless, acute and long-term (12-
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and 24-month) outcomes were similar. Rapid-cycling bi-
polar patients were unvaryingly excluded from the re-
viewed studies; the first data on the application of VNS
in this difficult-to-treat population was reported by
Marangell et al. [41]. The results from 9 outpatients
with treatment-resistant rapid-cycling bipolar disorder
showed that VNS can over the course of 1 year produce
significant improvement in the global measure of illness,
as well as in specific symptom domains. The pilot data
need further replication. The rate of stimulation-induced
switch to mania or hypomania in the VNS trials was low
(2–3 per study), mostly in patients with bipolar disorder
or a history of drug-induced switch. From the clinical
point of view, the switch can be considered as an indirect
evidence of antidepressant activity. The manic symptoms
usually subsided with adjustment of stimulation param-
eters. The number of suicide attempts (3–5% per study)
was higher than expected in a population of treatment-
resistant patients [35]; nonetheless, it should be noted that
more than 50% of patients who attempted suicide had a
prior history of at least one suicide attempt.
Overall, VNS is safe and well tolerated. VNS had no
deleterious cognitive effects [42], improved sleep archi-
tecture [43] and in one case report was found to be safe
in pregnancy [44].
Negative results of the only controlled trial with VNS
in primary outcome measure are intriguing and require
closer scrutiny. Since the open trials have shown addition-
al improvement in symptoms beyond 12 weeks, the dou-
ble-blind study may not have been of adequate duration.
Moreover, the patients may have been underdosed (vary-
ing dosages of concomitant medication), or the study was
not sufficiently powered to detect a smaller amount of
benefit. Finally, the comparable rate of objectively mea-
sured improvement between active and sham stimulation
may indicate a strong placebo effect of the procedure.
Deep Brain Stimulation
The main clinical use of DBS is in neurological condi-
tions, essential tremor, motor symptoms in Parkinson’s
disease, dystonia, epilepsy, and chronic pain [45, 46]. In
psychiatry, DBS has been examined first in the treatment
of refractory obsessive-compulsive disorder (OCD) and
Tourette syndrome, and more recently in major depression
[47]. In 2009, DBS was approved for treatment of otherwise
intractable OCD in Europe and the US FDA approved the
administration of DBS under the Humanitarian Device
Exemption program for chronic and severe OCD [48].
VNS and DBS in Depression
Principles of DBS
DBS is a surgical procedure that involves stereotactic-
al implantation of electrodes into the targeted brain re-
gions. The electrodes are powered via leads by a subcuta-
neously placed pulse generator. During a surgical proce-
dure, a pulse generator is being implanted subcutaneous-
ly in the chest, near the clavicle [45, 46, 49]. The generator
sends electric impulses via 1 or 2 leads tunneled under the
scalp to the anchoring points in the skull. The anchoring
points are attached to the electrodes stereotactically im-
planted into the brain. The paired electrodes include up
to 5 platinum/iridium contact areas that usually spread
sequentially to cover additional parts of the targeted ana-
tomical site. Stereotactical techniques using neuroimag-
ing methods, a surgical navigation computer, together
with stereotactic brain atlases enable to aim any intracra-
nial structure within millimeter precision [45].
Programmable contact sites on the leads allow for the
adjustment of stimulation in different anatomical re-
gions. Stimulation parameters are set and modulated by
the portable device that programs the pulse generator.
Self-programming devices also allow patients to activate
and deactivate the stimulation. The settings may vary
greatly, with a pulse width between 60 and 450 ␮s, volt-
age between 0 and 10.5 V, and pulse frequency from 2 to
250 Hz. Stimulation can be either continuous or inter-
mittent.
Currently, there is no standardized procedure for ac-
tive stimulation onset, setting adjustment, or frequency
of visits for depressive patients. The postoperative recov-
ery phase with stimulation turned off can thus last from
1 up to 4 weeks. Adjustment of stimulation parameters in
the acute phase is typically gradual, at least once a week,
with increasing intensity while observing for immediate
response. Chronic stimulation parameters are set on the
basis of positive mood effects and absence of adverse ef-
fects. The frequency of visits during the chronic phase is
once a month or less, depending on the protocol. As in
the VNS, duration of stimulation is limited by the battery
life.
Neurobiology of DBS
Similarly to VNS, the precise mechanism of action
remains largely unknown [45]. DBS induces an electrical
field in the brain tissue that attenuates exponentially
with the distance from the electrode. Originally, inhibi-
tory effects of DBS mediated by depolarization blockade,
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Table 2. Case series of DBS in TRD

Target area Reference Number Duration of follow-up Results

Subgenual cingulate gyrus Mayberg et al. [62], 2005 6 6 months Response rate
HRSD: 67%
Remission rate
HRSD: 50%
Lozano et al. [63], 2008 20 12 months Response rate
HRSD: 55%
Remission rate
HRSD: 35%
Kennedy et al. [80], 2011 20 36–72 months Response rates (HRSD)
Year 3: 75%
Last follow-up: 64%
Remission rates (HRSD)
Year 3: 50%
Last follow-up: 43%
Ventral capsule/ventral striatum Malone et al. [64], 2009 15 6–51 months Response rates
(mean 23.5 months) HRSD: 53%
MADRS: 53%
Remission rate
HRSD: 40%
MADRS: 30%
Malone [65], 2010 17 14–67 months Response rate
(mean 37.4 months) MADRS: 71%
Remission rate
MADRS: 35%
Anterior limb of capsula interna Gabriëls et al. [69], 2007 3 6 months Response rate
MADRS: 100%
Remission rate
MADRS: 66.6%
Nucleus accumbens Schlaepfer et al. [70], 2008 3 ‘several months’ (on/off) Improvement
HRSD (p < 0.01)
MADRS (p = 0.03)
Bewernick et al. [71], 2010 10 12 months Response rate
HRSD: 50%

synaptic inhibition, and synaptic depression were as-
sumed. However, an excitatory response to high-fre-
quency DBS has also been found [50]. The most likely
explanation is a stimulation-induced modulation of im-
paired network activity. DBS is not producing a lesion; it
may rather alter complex firing patterns of the neurons
in the region and thus modify activity in the neuronal
circuits. Gray matter and neurons have different respon-
siveness, as well as myelinated and unmyelinated fibers.
Moreover, effects on glia may also play an important role
and the therapeutic effects of DBS differ across the target
points [51].
The targeted brain structures for Parkinson’s disease
are subthalamic nuclei, for dystonia the globus pallidus
internus, for cluster headache the ipsilateral ventroposte-
rior hypothalamus, for OCD the anterior limb of the cap-
sula interna, and for depression the subthalamic nucleus,
internal globus pallidus, ventral internal capsule/ventral
striatum, subgenual cingulate region, nucleus accumbens
(NA), inferior thalamic peduncle, and the lateral haben-
ula [47, 52]. There are several physiological methods for
verification of the anatomical target, including micro-
electrode and semi-microelectrode recording of the
spontaneous and evoked electrical activity, or macro-
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stimulation. Alternatively, preoperative diffusion tensor
imaging for connectivity-based cortical mapping was
suggested for more precise targeting of the key structures
within the anterior cingulate cortex [53].
Clinical Trials of DBS in Depression
Introduction of DBS into psychiatry was based on the
first anecdotal cases reporting stimulation-provoked
mood changes, depression and mania in patients without
psychiatric history. Antidepressant effects following the
stimulation of the globus pallidus internus and subtha-
lamic nuclei in several subjects with movement disorders
were documented with the depression rating scales [54,
55]. In a case series of 27 patients with Parkinson’s dis-
ease, a significant improvement of mood at 5 weeks and
3 months after surgery and stimulation of the bilateral
subthalamic nucleus was demonstrated [56]. However,
the antidepressant effect was lost at 6, 12, and 18 months,
and the HRSD score was similar to the control group. In
a case report of a female patient with comorbid MDD and
borderline personality disorder and bulimia, who under-
went DBS in the inferior thalamic penduncle under a
double-blind protocol (alternating on and off stimula-
tion), depressive symptoms significantly diminished and
neurocognitive performance improved during active
stimulation [57, 58]. Reduction of depression symptoms
in a patient with comorbid OCD and MDD was found
after implantation of electrodes into the ventral caudate
nucleus, when the tip of the electrode stimulated the NA
[59, 60]. Interestingly, a similar case report of OCD-de-
pression comorbidity, where the electrode did not reach
the NA, described worsening of depression symptoms af-
ter active stimulation and the patient required reintro-
duction of antidepressant medication [60]. A complete
remission of severe TRD was reported in a 64-year-old
female patient after bilateral stimulation of the lateral ha-
benula, the site of interaction of the serotonergic,
noradrenergic, and dopaminergic systems [61].
Pilot data from nondepressed patients and individual
case vignettes were subsequently examined in several
case series of patients with TRD; the total number of sub-
jects in published reports on case series is now 50 (ta-
ble 2).
In an open study of 6 TRD patients, Mayberg et al. [62]
implanted DBS bilaterally in the white matter fibers con-
necting to the Brodman area 25 in the subgenual cingu-
late gyrus and used chronic high-frequency stimulation.
All 6 patients reported acute improvement following
VNS and DBS in Depression
stimulation. After 2 months, 2 subjects demonstrated a
more than 50% decrease in the HRSD score. At 6 months
of DBS, 4 subjects out of 6 achieved response and 3 remis-
sion of MDD (HRSD score ^8). At 1 month of DBS, rCBF
was decreased in the stimulated area and adjacent orbital
frontal cortex. Responders had an additional reduction in
rCBF of the medial cortex, and an increase in CBF to dor-
sal prefrontal anterior cingulate and parietal cortices, un-
like nonresponders.
The original study sample was expanded to include a
total of 20 patients followed up for up to 3–6 years [63,
80]. The results indicate progressive improvement from
week 1 (40% of patients responded, 1 in remission) to 6
months when a plateau was reached (60% responders,
35% remitters). Long-term follow-up indicates a fluctuat-
ing course that is difficult to interpret. Response rates
between year 1 and 2 decreased from 62.5% to 46.2% and
increased up to 75% at year 3 and 64.3% at the last follow-
up visit (observed cases). Similarly, remission rates after
1, 2, and 3 years were 18.8, 15.4, and 50%, respectively
[80]. PET scans (using 18FDG) confirmed metabolic
changes in the specific cortical and limbic regions impli-
cated in the pathogenesis of depression [62]. DBS was well
tolerated; however, 2 patients died by suicide during de-
pressive relapses, 2 other patients made suicide attempts
and one died from causes unrelated to depression [80].
Most frequently reported adverse events were periopera-
tive headache and wound infections (both n = 4); 3 pa-
tients had their hardware removed with 1 subsequent re-
implantation. One patient experienced a generalized sei-
zure at the evening of surgery.
A different stimulation area for TRD, i.e. ventral cap-
sule/ventral striatum, was targeted in a multicenter study
reported by Malone and colleagues [64, 65]. The ventral
capsule/ventral striatum region is traditionally stimulat-
ed in OCD; in addition, it also has a pathophysiological
role in depression [66, 67]. Moreover, stimulation of the
ventral capsule/ventral striatum resulted in a PET-mea-
sured reduction of subgenual cingulate activity, other-
wise hyperactive in depression [68]. Fifteen or 17 [65]
chronic refractory patients were followed for a minimum
of 6 months up to 4 years. Both continuous and categori-
cal primary efficacy measures (HRSD, MADRS, Global
Assessment of Functioning) demonstrated statistically
significant improvement. In the total study sample of 17
patients, the response rate for the MADRS (650% reduc-
tion) was 53% at 3 months, 47% at 6 months, 53% at 12
months, and 71% at the last follow-up (range from 14 to
67 months; mean 37.4 months). Remission rates accord-
ing to the MADRS were: 35, 29, 41, and 35%, respectively.
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There were a total of 25 serious adverse events reported
in 6 patients. Four of them were DBS-related: 1 case of
occipital pain, 1 case of a lead fracture, and 2 incidents of
hypomania.
A case series of 3 subjects with TRD reported clini-
cally significant improvement after 6 months of bilateral
DBS in the ventral part of the anterior limb of the internal
capsule [69]. All 3 patients, who previously failed to re-
spond to years of pharmacotherapy, psychotherapy, and
ECT, yielded 650% reduction in severity of depression
on the MADRS and 2 of them achieved remission. Qual-
ity of life improved as well.
Schlaepfer with collaborators [70, 71] selected to target
the reward system, presumably impaired in depression
[72–74]. In an account of 3 severely depressed patients
who failed to respond to psychotherapy, pharmacothera-
py, and ECT trials, DBS stimulated the NA in a double-
blind manner, alternating voltage from 0 to 4 V. Immedi-
ately after switching the stimulation on, 2 out of 3 patients
reported spontaneously increased exploratory motiva-
tion, consistent with the role of NA in the reward-seeking
behavior. Clinical assessments in all 3 subjects (using
HRSD and MADRS) demonstrated significant improve-
ment when the stimulator was on and immediate worsen-
ing during periods when it was turned off. A negative
correlation between stimulation and depression rating
scores was found (increased stimulation resulted in score
reduction). No side effects were reported. PET imaging
using 18FDG showed significant metabolic activation in
the bilateral ventral striatum (including NA), the bilat-
eral dorsolateral and dorsomedial prefrontal cortex, the
cingulate cortex, and the bilateral amygdala. Decreased
metabolism after stimulation was detected in the ventro-
medial and ventrolateral prefrontal cortex, dorsal cau-
date nucleus, and thalamus.
Long-term stimulation of the NA over the course of at
least 12 months in an extended sample yielded positive
response (defined as 50% reduction in the HRSD score)
in 5 out of 10 refractory patients [71]. Moreover, second-
ary analyses demonstrated reduction of anxiety symp-
toms in responders and an increased level of positive (‘he-
donic’) activities in the total sample. Functional imaging
assessment of 7 patients with PET revealed decreased
metabolic activity in the prefrontal subregions (orbital
prefrontal cortex, subgenual and posterior cingulate cor-
tices, thalamus, and caudate nucleus) and an increase in
the precentral gyrus. In contrast to the previous report
[70], long-term DBS did not induce an increase in NA
metabolism, suggesting thus different effects of acute and
chronic stimulation. It may be of interest that the origi-
178 Neuropsychobiology 2011;64:170–181
nally planned sham-controlled design had to be changed
by the authors to open-label. The reason was rapid and
massive worsening of depressive symptoms during off
phases or accidental discontinuation of stimulation.
Evaluation of the DBS Data
Data from a small set of patients suggest an antide-
pressant effect of DBS in different brain regions. Numer-
ous stimulation targets producing similar effects plus a
small number of subjects make it difficult to draw any
definite conclusions. Initial mood improvement, ob-
served immediately after implantation without electrical
stimulation, suggests a possible placebo effect. However,
in a controlled paradigm (on/off comparison), active
stimulation was clearly separated from inactive interven-
tion.
A small number of depressed patients treated with
DBS does not allow for any detailed analysis of efficacy
and safety according to gender or to examine effects in
elderly patients. The proportion of females in study sam-
ples varied from 40 to 73%, the mean age from 46 to 49
years. The oldest patient with provided age was 66 years
at the time of implantation [70]. Almost all subjects were
diagnosed with unipolar major depression, reports iden-
tified 1 patient with bipolar I [64] and 1 patient with bi-
polar II [62, 63] disorder. A stimulation-induced switch
to hypomania that resolved after parameter modifica-
tion was registered in a patient with bipolar I disorder
[64] and in 2 patients from a German case series [71].
Previously, there have been reports on series of sui-
cides in patients successfully treated with DBS of the sub-
thalamic nucleus for movement disorders [75–77]. An in-
ternational multicenter retrospective survey of 5,311 Par-
kinson’s disease patients treated with DBS found a rate of
completed suicides of 0.45% and a rate of suicide attempts
of 0.90% [76]. The authors identified postoperative de-
pression, a history of impulse control disorder, and some
demographic factors (being single, younger age at onset,
history of suicide attempt) as risk factors associated with
suicide risk. A second retrospective analysis of a sample
of 200 patients confirmed postoperative depression and
impaired impulse control, but not other demographic or
clinical characteristics as predictors of suicide attempt
[77]. In addition, in an animal study high-frequency
stimulation of the subthalamic nucleus resulted in a de-
crease in the neighboring serotonin neurons and sub-
sequent depressive-like behavior in rats [78]. This effect
was reversible with antidepressant modulating serotonin
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neurotransmission. It should be noted that suicide behav-
ior in depressed patients with DBS was observed with the
stimulation of different brain regions: 2 patients with in-
creased suicidality (13.3% of the study sample) after stim-
ulation of the ventral capsule/striatum [64], 1 completed
and 1 attempted suicide (20% of the sample) after stimu-
lation of the NA [71], two deaths by suicide and two sui-
cidal attempts (40% of the sample) following stimulation
of the subgenual cingulum [80]. Although no general
conclusions can be drawn at this point, a relatively high
rate of suicidal behavior in a small set of patients warrants
caution.
Neuropsychological assessment of 6 patients from the
Mayberg sample found improvement in several cognitive
measures from baseline, not attributable to the antide-
pressant effect [62, 79]. Likewise, no deleterious effects on
cognition were reported in a subset of patients from the
Malone study [64].
Conclusions
The data on the use of VNS and DBS in the treatment
of depression are encouraging. Whereas VNS has been
approved for TRD, DBS still remains an experimental in-
tervention. The major contribution of the methods is a
novel approach, an alternative to the current antidepres-
sant modalities, with assured compliance. Invasive stim-
ulatory procedures allow for precise targeting of the spe-
cific brain areas, nuclei and circuits implicated in the
etiopathogenesis of neuropsychiatric disorders and may
thus replace traditional psychosurgery.
Nevertheless, several issues need to be clarified prior
to the general embracement and implementation of the
methods into therapeutic algorithms. First, in order to
unequivocally assess pros and cons, more controlled data
with higher statistical power are needed. The review evi-
dences that, despite the apparent methodological diffi-
culties, such research is feasible. For obvious reasons, in-
vasive therapeutic methods will not become a first-line
choice. Thus, it is essential to identify potential respond-
ers, patients who may best profit from VNS or DBS. An-
other key aspect is economics, the cost of the devices that
is considerable. Cost-benefit analyses will be necessary to
assess the true value of VNS and DBS.
Finally, new therapeutic approaches also present new
ethical challenges and dilemmas. In addition to the his-
torically negative perception of psychosurgery, consider-
ations concerning availability, or alternatively fear of in-
discriminating use of invasive stimulation methods in
psychiatry may be of concern. Moreover, new philosoph-
ical questions regarding personality ‘integrity’, ‘manipu-
lation’ or ‘control’ of mental functions may arise.
Acknowledgements
This study was supported by the research projects CNS
1M0517, MZ0PCP2005, and GACR 309/09/H072.

References
1 Kessler RC, Berglund P, Demler O, Jin R, Ko-
retz D, Merikangas KR, Rush AJ, Walters EE,
Wang PS: The epidemiology of major depres-
sive disorder: results from the National
Comorbidity Survey Replication (NCS-R).
JAMA 2003;289:3095–3105.
2 The ESEMeD/MHDEA 2000 Investigators:
Prevalence of mental disorders in Europe:
results from the European Study of the Epi-
demiology of Mental Disorders (ESEMeD)
project. Acta Psychiatr Scand 2004: 109
(suppl 420):21–27.
3 WHO: The Global Burden of Disease: 2004
Update. Geneva, WHO Press, 2008.
4 Greenberg PE, Kessler RC, Birnbaum HG,
Leong SA, Lowe SW, Berglund PA, Corey-
Lisle PK: The economic burden of depression
in the United States: how did it change be-
tween 1990 and 2000? J Clin Psychiatry 2003;
64:1465–1475.
5 Thomas CM, Morris S: Cost of depression
among adults in England in 2000. Br J Psy-
chiatry 2003;183:514–519.
6 Souery D, Papakostas GI, Trivedi MH: Treat-
ment-resistant depression. J Clin Psychiatry
2006;67(suppl 6):16–22.
7 Berlim MT, Turecki G: Definition, assess-
ment, and staging of treatment-resistant re-
fractory major depression: a review of cur-
rent concepts and methods. Can J Psychiatry
2007;52:46–54.
8 Mathew SJ: Treatment-resistant depression:
recent developments and future directions.
Depress Anxiety 2008;25:989–992.
9 Jarema M: A few facts from the history of se-
lected biological treatment methods in psy-
chiatry. Neuroendocrinol Lett 2008; 29
(suppl 1):5–9.
10 Andrade P, Noblesse LH, Temel Y, Acker-
mans L, Lim LW, Steinbusch HW, Visser-
Vandewalle V: Neurostimulatory and abla-
tive treatment options in major depressive
disorder: a systematic review. Acta Neuro-
chir 2010;152:565–577.
11 Nahas Z, Anderson BS, Borckardt J, Arana
AB, George MS, Reeves ST, Takacs I: Bilat-
eral epidural prefrontal cortical stimulation
for treatment-resistant depression. Biol Psy-
chiatry 2010;67:101–109.
12 http://www.accessdata.fda.gov/scripts/cdrh/
c f d o c s /c f t o p i c / p m a / p m a . c f m? n u m =
p970003s050 (accessed November 7, 2010).
13 Schachter SC, Schmidt D: Vagus Nerve Stim-
ulation, ed 3. London, Dunitz, 2003.
198.143.41.65 - 7/19/2015 10:44:12 PM

VNS and DBS in Depression Neuropsychobiology 2011;64:170–181 179

Downloaded by:
14 Nemeroff CB, Mayberg HS, Krahl SE, Mc-
Namara J, Frazer A, Henry TR, George MS,
Charney DS, Brannan SK: VNS therapy in
treatment-resistant depression: clinical evi-
dence and putative neurobiological mecha-
nisms. Neuropsychopharmacology 2006; 31:
1345–1355.
15 George MS, Sackeim HA, Rush AJ, Ma-
rangell LB, Nahas Z, Husain MM, Lisanby
S, Burt T, Goldman J, Ballenger JC: Vagus
nerve stimulation: a new tool for brain re-
search and therapy. Biol Psychiatry 2000;47:
287–295.
16 Henry TR: Therapeutic mechanisms of va-
gus nerve stimulation. Neurology 2002;
59(suppl 4):S3–S14.
17 Dorr AE, Debonnel G: Effect of vagus nerve
stimulation on serotonergic and noradrener-
gic transmission. J Pharmacol Exp Ther
2006;318:890–898.
18 Manta S, Dong J, Debonnel G, Blier P: En-
hancement of the function of rat serotonin
and norepinephrine neurons by sustained
vagus nerve stimulation. J Psychiatry Neuro-
sci 2009;34:272–280.
19 Krahl SE, Clark KB, Smith DC, Browning
RA: Locus coeruleus lesions suppress the sei-
zure-attenuating effects of vagus nerve stim-
ulation. Epilepsia 1998;39:709–174.
20 Ben-Menachem E, Hamberger A, Hedner T,
Hammond EJ, Uthman BM, Slater J, Treig T,
Stefan H, Ramsay RE, Wernicke JF: Effects of
vagus nerve stimulation on amino acids and
other metabolites in the CSF of patients with
partial seizures. Epilepsy Res 1995; 20: 221–
227.
21 Walker BR, Easton A, Gale K: Regulation of
limbic motor seizures by GABA and gluta-
mate transmission in nucleus tractus soli-
tarius. Epilepsia 1999;40:1051–1057.
22 Henry TR, Bakay RA, Votaw JR, Pennell PB,
Epstein CM, Faber TL, Grafton ST, Hoffman
JM: Brain blood flow alterations induced by
therapeutic vagus nerve stimulation in par-
tial epilepsy. 1. Acute effects at high and low
levels of stimulation. Epilepsia 1998;39:983–
890.
23 Zobel A, Joe A, Freymann N, Clusmann H,
Schramm J, Reinhardt M, Biersack HJ, Maier
W, Broich K: Changes in regional cerebral
blood flow by therapeutic vagus nerve stim-
ulation in depression: an exploratory ap-
proach. Psychiatry Res 2005;139:165–179.
24 Conway CR, Sheline YI, Chibnall JT, George
MS, Fletcher JW, Mintun MA: Cerebral
blood flow changes during vagus nerve stim-
ulation for depression. Psychiatry Res 2006;
146:179–184.
25 Follesa P, Biggio F, Gorini G, Caria S, Talani
G, Dazzi L, Puligheddu M, Marrosu F, Biggio
G: Vagus nerve stimulation increases nor-
epinephrine concentration and the gene ex-
pression of BDNF and bFGF in the rat brain.
Brain Res 2007;1179:28–34.
180 Neuropsychobiology 2011;64:170–181
26 Biggio F, Gorini G, Utzeri C, Olla P, Marrosu
F, Mocchetti I, Follesa P: Chronic vagus
nerve stimulation induces neuronal plastic-
ity in the rat hippocampus. Int J Neuropsy-
chopharmacol 2009;12:1209–1221.
27 Lang UE, Bajbouj M, Gallinat J, Hellweg
R: Brain-derived neurotrophic factor serum
concentrations in depressive patients dur-
ing vagus nerve stimulation and repetitive
transcranial magnetic stimulation. Psycho-
pharmacology 2006;187:56–59.
28 Harden CL, Pulver MC, Ravdin LD, Nikolov
B, Halper JP, Labar DR: A pilot study of
mood in epilepsy patients treated with vagus
nerve stimulation. Epilepsy Behav 2000; 1:
93–99.
29 Elger G, Hoppe C, Falkai P, Rush AJ, Elger
CE: Vagus nerve stimulation is associated
with mood improvements in epilepsy pa-
tients. Epilepsy Res 2000;42:203–210.
30 Bares M, Mohr P, Hendrychova Y, Kopecek
M, Mohapl M: Vagus nerve stimulation
(VNS) in the treatment of resistant depres-
sive disorder – One-year experiences. Psy-
chiatrie 2006;10:13–15.
31 Rush AJ, George MS, Sackeim HA, Ma-
rangell LB, Husain MM, Giller C, Nahas Z,
Haines S, Simpson RK Jr, Goodman R: Vagus
nerve stimulation (VNS) for treatment-resis-
tant depressions: a multicenter study. Biol
Psychiatry 2000;47:276–286.
32 Sackeim HA, Rush AJ, George MS, Ma-
rangell LB, Husain MM, Nahas Z, Johnson
CR, Seidman S, Giller C, Haines S, Simpson
RK Jr, Goodman RR: Vagus nerve stimula-
tion (VNS) for treatment-resistant depres-
sion: efficacy, side effects, and predictors of
outcome. Neuropsychopharmacology 2001;
25:713–728.
33 Nahas Z, Marangell LB, Husain MM, Rush
AJ, Sackeim HA, Lisanby SH, Martinez JM,
George MS: Two-year outcome of vagus
nerve stimulation (VNS) for treatment of
major depressive episodes. J Clin Psychiatry
2005;66:1097–1104.
34 Schlaepfer TE, Frick C, Zobel A, Maier W,
Heuser I, Bajbouj M, O’Keane V, Corcoran C,
Adolfsson R, Trimble M, Rau H, Hoff HJ,
Padberg F, Müller-Siecheneder F, Audenaert
K, Van den Abbeele D, Stanga Z, Hasdemir
M: Vagus nerve stimulation for depression:
efficacy and safety in a European study. Psy-
chol Med 2008;38:651–661.
35 Bajbouj M, Merkl A, Schlaepfer TE, Frick C,
Zobel A, Maier W, O’Keane V, Corcoran C,
Adolfsson R, Trimble M, Rau H, Hoff HJ,
Padberg F, Müller-Siecheneder F, Audenaert
K, van den Abbeele D, Matthews K, Christ-
mas D, Eljamel S, Heuser I: Two-year out-
come of vagus nerve stimulation in treat-
ment-resistant depression. J Clin Psycho-
pharmacol 2010;30:273–281.
36 Rush AJ, Marangell LB, Sackeim HA, George
MS, Brannan SK, Davis SM, Howland R,
Kling MA, Rittberg BR, Burke WJ, Rapaport
MH, Zajecka J, Nierenberg AA, Husain MM,
Ginsberg D, Cooke RG: Vagus nerve stimu-
lation for treatment-resistant depression: a
randomized, controlled acute phase trial.
Biol Psychiatry 2005; 58:347–354.
37 Rush AJ, Sackeim HA, Marangell LB, George
MS, Brannan SK, Davis SM, Lavori P, How-
land R, Kling MA, Rittberg B, Carpenter L,
Ninan P, Moreno F, Schwartz T, Conway C,
Burke M, Barry JJ: Effects of 12 months of
vagus nerve stimulation in treatment-resis-
tant depression: a naturalistic study. Biol
Psychiatry 2005;58:355–363.
38 George MS, Rush AJ, Marangell LB, Sackeim
HA, Brannan SK, Davis SM, Howland R,
Kling MA, Moreno F, Rittberg B, Dunner D,
Schwartz T, Carpenter L, Burke M, Ninan P,
Goodnick P: A one-year comparison of va-
gus nerve stimulation with treatment as usu-
al for treatment-resistant depression. Biol
Psychiatry 2005;58:364–373.
39 Rush AJ, Siefert SE: Clinical issues in consid-
ering vagus nerve stimulation for treatment-
resistant depression. Exp Neurol 2009; 219:
36–43.
40 Nierenberg AA, Alpert JE, Gardner-Schus-
ter EE, Seay S, Mischoulon D: Vagus nerve
stimulation: 2-year outcomes for bipolar ver-
sus unipolar treatment-resistant depression.
Biol Psychiatry 2008; 64:455–460.
41 Marangell LB, Suppes T, Zboyan HA, Pra-
shad SJ, Fischer G, Snow D, Sureddi S, Allen
JC: A 1-year pilot study of vagus nerve stimu-
lation in treatment-resistant rapid-cycling
bipolar disorder. J Clin Psychiatry 2008; 69:
183–189.
42 Sackeim HA, Keilp JG, Rush AJ, George MS,
Marangell LB, Dormer JS, Burt T, Lisanby
SH, Husain M, Cullum CM, Oliver N, Zboy-
an H: The effects of vagus nerve stimulation
on cognitive performance in patients with
treatment-resistant depression. Neuropsy-
chiatry Neuropsychol Behav Neurol 2001;14:
53–62.
43 Armitage R, Husain M, Hoffmann R, Rush
AJ: The effects of vagus nerve stimulation on
sleep EEG in depression: a preliminary re-
port. J Psychosom Res 2003;54:475–482.
44 Husain MM, Stegman D, Trevino K: Preg-
nancy and delivery while receiving vagus
nerve stimulation for the treatment of major
depression: a case report. Ann Gen Psychia-
try 2005;4:16.
45 Greenberg BD, Rezai AR: Mechanisms and
the current state of deep brain stimulation in
neuropsychiatry. CNS Spectr 2003; 8: 522–
526.
46 Hardesty DE, Sackeim HA: Deep brain stim-
ulation in movement and psychiatric disor-
ders. Biol Psychiatry 2007; 61:831–835.
47 Mohr P: Deep brain stimulation in psychia-
try. Neuro Endocrinol Lett 2008; 29(suppl
1):123–132.
198.143.41.65 - 7/19/2015 10:44:12 PM
Mohr /Rodriguez /Slavíčková /Hanka
Downloaded by:
48 Kuhn J, Gaebel W, Klosterkoetter J, Woopen
C: Deep brain stimulation as a new therapeu-
tic approach in therapy-resistant mental
disorders: ethical aspects of investigational
treatment. Eur Arch Psychiatry Clin Neuro-
sci 2009;259(suppl 2):135–141.
49 Marangell LB, Martinez M, Jurdi RA, Zboy-
an H: Neurostimulation therapies in depres-
sion: a review of new modalities. Acta Psy-
chiatr Scand 2007;116:174–181.
50 McIntyre CC, Savasta M, Kerkerian-Le Goff
L, Vitek JL: Uncovering the mechanism(s) of
action of deep brain stimulation: activation,
inhibition, or both. Clin Neurophysiol 2004;
115:1239–1248.
51 Perlmutter JS, Mink JW: Deep brain stimula-
tion. Annu Rev Neurosci 2006;29:229–257.
52 Hauptman JS, DeSalles AAF, Espinoza R, Se-
drak M, Ishida W: Potential surgical targets
for deep brain stimulation in treatment-re-
sistant depression. Neurosurg Focus 2008;
25:E3.
53 Johansen-Berg H, Gutman DA, Behrens TE,
Matthews PM, Rushworth MF, Katz E, Lo-
zano AM, Mayberg HS: Anatomical con-
nectivity of the subgenual cingulate region
targeted with deep brain stimulation for
treatment-resistant depression. Cereb Cor-
tex 2008;18:1374–1383.
54 Castelli L, Perozzo P, Zibetti M, Crivelli B,
Morabito U, Lanotte M, Cossa F, Bergamas-
co B, Lopiano L: Chronic deep brain stimula-
tion of the subthalamic nucleus for Parkin-
son’s disease: effects on cognition, mood,
anxiety and personality traits. Eur Neurol
2006;55:136–144.
55 Kosel M, Sturm V, Frick C, Lenartz D,
Zeidler G, Brodesser D, Schlaepfer TE: Mood
improvement after deep brain stimulation of
the internal globus pallidus for tardive dys-
kinesia in a patient suffering from major de-
pression. J Psychiatr Res 2007;41:801–803.
56 Wang X, Chang C, Geng N, Li N, Wang J, Ma
J, Xue W, Zhao W, Wu H, Wang P, Gao G:
Long-term effects of bilateral deep brain
stimulation of the subthalamic nucleus on
depression in patients with Parkinson’s dis-
ease. Parkinsonism Relat Disord 2009; 15:
587–591.
57 Jiménez F, Velasco F, Salin-Pascual R,
Hernández JA, Velasco M, Criales JL, Nico-
lini H: A patient with a resistant major de-
pression disorder treated with deep brain
stimulation in the inferior thalamic pedun-
cle. Neurosurgery 2005;57:585–593.
58 Jiménez F, Velasco F, Salin-Pascual R, Velas-
co M, Nicolini H, Velasco AL, Castro G:
Neuromodulation of the inferior thalamic
peduncle for major depression and obsessive
compulsive disorder. Acta Neurochir 2007;
97:393–398.
VNS and DBS in Depression
59 Aouizerate B, Cuny E, Martin-Guehl C,
Guehl D, Amieva H, Benazzouz A, Fabri-
goule C, Allard M, Rougier A, Bioulac B, Ti-
gnol J, Burbaud P: Deep brain stimulation of
the ventral caudate nucleus in the treatment
of obsessive-compulsive disorder and major
depression. Case Report. J Neurosurg 2004;
101:682–686.
60 Aouizerate B, Cuny E, Bardinet E, Yelnik J,
Martin-Guehl C, Rotge JY, Rougier A, Biou-
lac B, Tignol J, Mallet L, Burbaud P, Guehl D:
Distinct striatal targets in treating obsessive-
compulsive disorder and major depression. J
Neurosurg 2009;111:775–779.
61 Sartorius A, Kiening KL, Kirsch P, von Gall
CC, Haberkorn U, Unterberg AW, Henn FA,
Meyer-Lindenberg A: Remission of major
depression under deep brain stimulation of
the lateral habenula in a therapy-refractory
patient. Biol Psychiatry 2010; 67:e9–e11.
62 Mayberg HS, Lozano AM, Voon V, McNeely
HE, Seminowicz D, Hamani C, Schwalb
JM, Kennedy SH: Deep brain stimulation for
treatment-resistant depression. Neuron
2005;45:651–660.
63 Lozano AM, Mayberg HS, Giacobbe P, Ha-
mani C, Craddock RC, Kennedy SH: Subcal-
losal cingulate gyrus deep brain stimulation
for treatment-resistant depression. Biol Psy-
chiatry 2008;64:461–467.
64 Malone DA, Dougherty DD, Rezai AR, Car-
penter LL, Friehs GM, Eskandar EN, Rauch
SL, Rasmussen SA, Machado AG, Kubu CS,
Tyrka AR, Price LH, Stypulkowski PH,
Giftakis JE, Rise MT, Malloy PF, Salloway
SP, Greenberg BD: Deep brain stimulation
of the ventral capsule/ventral striatum for
treatment resistant depression. Biol Psychia-
try 2009;65:267–275.
65 Malone DA Jr: Use of deep brain stimulation
in treatment-resistant depression. Cleve Clin
J Med 2010;77(suppl 3):S77–S80.
66 Rauch SL: Neuroimaging and neurocircuitry
models pertaining to the neurosurgical
treatment of psychiatric disorders. Neuro-
surg Clin N Am 2003;14:213–223.
67 Epstein J, Pan H, Kocsis JH, Yang Y, Butler T,
Chusid J, Hochberg H, Murrough J, Stroh-
mayer E, Stern E, Silbersweig DA: Lack of
ventral striatal response to positive stimuli
in depressed versus normal subjects. Am J
Psychiatry 2006;163:1784–1790.
68 Mayberg HS. Targeted electrode-based mod-
ulation of neural circuits for depression. J
Clin Invest 2009;119:717–725.
69 Gabriëls L, Cosyns P, Nuttin B: Deep brain
stimulation in treatment-refractory major
depression: preliminary results in three pa-
tients. Eur Psychiatry 2007;22(suppl 1):264.
70 Schlaepfer TE, Cohen MX, Frick C, Kosel M,
Brodesser D, Axmacher N, Joe AY, Kreft M,
Lenartz D, Sturm V: Deep brain stimulation
to reward circuitry alleviates anhedonia in
refractory major depression. Neuropsycho-
pharmacology 2008;33:368–377.
Neuropsychobiology 2011;64:170–181
71 Bewernick BH, Hurlemann R, Matusch, A,
Kayser S, Grubert C, Hadrysiewicz B, Ax-
macher N, Lemke M, Cooper-Mahkorn D,
Cohen MX, Brockmann H, Lenartz D,
Sturm V, Schlaepfer TE: Nucleus accumbens
deep brain stimulation decreases ratings of
depression and anxiety in treatment-resis-
tant depression. Biol Psychiatry 2010; 67:
110–116.
72 Tremblay LK, Naranjo CA, Graham SJ,
Herrmann N, Mayberg HS, Hevenor S,
Busto UE: Functional neuroanatomical sub-
strates of altered reward processing in major
depressive disorder revealed by a dopami-
nergic probe. Arch Gen Psychiatry 2005; 62:
1228–1236.
73 Nestler EJ, Carlezon WA Jr: The mesolimbic
dopamine reward circuit in depression. Biol
Psychiatry 2006;59:1151–1159.
74 Gorwood P: Neurobiological mechanisms of
anhedonia. Dialogues Clin Neurosci 2008;
10:291–299.
75 Burkhard PR, Vingerhoets FJ, Berney A, Bo-
gousslavsky J, Villemure JG, Ghika J: Suicide
after successful deep brain stimulation for
movement disorders. Neurology 2004; 63:
2170–2172.
76 Voon V, Krack P, Lang AE, Lozano AM, Du-
jardin K, Schüpbach M, D’Ambrosia J, Tho-
bois S, Tamma F, Herzog J, Speelman JD,
Samanta J, Kubu C, Rossignol H, Poon Y-Y,
Saint-Cyr JA, Ardouin C, Moro E: A multi-
centre study on suicide outcomes following
subthalamic stimulation for Parkinson’ dis-
ease. Brain 2008;131:2720–2728.
77 Soulas T, Gurruchaga J-M, Palfi S, Cesaro P,
Nguyen J-P, Fenolon G: Attempted and com-
pleted suicides after subthalamic nucleus
stimulation for Parkinson’s disease. J Neurol
Neurosurg Neuropsychiatry 2008; 79: 952–
954.
78 Temel Y, Boothman LJ, Blokland A, Magill
PJ, Steinbusch HW, Visser-Vandewalle V,
Sharp T: Inhibition of 5-HT neuron activity
and induction of depressive-like behavior by
high-frequency stimulation of the subtha-
lamic nucleus. Proc Natl Acad Sci USA 2007;
104:17087–17092.
79 McNeely HE, Mayberg HS, Lozano AM,
Kennedy SH: Neuropsychological impact of
Cg25 deep brain stimulation for treatment-
resistant depression: preliminary results
over 12 months. J Nerv Ment Dis 2008; 196:
405–410.
80 Kennedy SH, Giacobbe P, Rizvi SJ, Placenza
FM, Nishikawa Y, Mayberg HS, Lozano AM:
Deep brain stimulation for treatment-resis-
tant depression: follow-up after 3 to 6 years.
Am J Psychiatry 2011;168:502–510.
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