Vagus Nerve Stimulation
The use of VNS for chronic or recurrent depression (uni or bipolar) was approved in 2005 by the FDA, for patients that have failed to respond to at least four antidepressant trials ().
Stimulating the vagus nerve to treat mood disorders was supported by several lines of evidence. Beneficial effects on mood were seen in epileptic patients that used VNS (Elger et al, 2000
; Harden et al, 2000
). Also, VNS is successfully used for epilepsy and there is evidence of beneficial effects of anticonvulsants as mood stabilizers and antidepressants (Goodwin and Jamison, 2007
). In addition, ECT is also hypothesized to act, in part, through its anticonvulsant properties (Sackeim, 1999
). Effects on different neurotransmitters (Ben-Menachem et al, 1995
) and imaging findings (Henry et al, 1998
) also favor this indication of VNS.
The mechanism of action is not fully understood, but stimulation is intended to enter the brain through the primary afferent pathways of the nerve that connect to the nucleus tractus solitarius and from it to many brain areas, including the forebrain, largely through the parabrachial nucleus and the locus ceruleus (Crawley, 1985
; Frisina et al, 2009
; Momose-Sato and Sato, 2011
). VNS does, for instance, enhance cortical inhibition and affect hippocampal plasticity (Zuo et al, 2007
). Interestingly, ECT has also been demonstrated to increase cortical inhibition (Bajbouj et al, 2006
Side effects include hoarseness, cough, and neck or jaw pain.
The first VNS implant for depression was performed in July 1998 at the Medical University of South Carolina in Charleston (Rush et al, 2000
), a decade after the first human epilepsy implant (Penry and Dean, 1990
). The left vagus is used based on the knowledge that right vagus is closely associated with the cardiac atria and the left vagus with cardiac ventricular function. This is supported by the lack of cardiac effects of left VNS although stimulation parameters could also be a possible explanation. The first pilot study included 30 patients with resistant major depression (uni and bipolar) and VNS showed response in 40% after 10 weeks, an encouraging result given the degree of resistance of the sample.
The only published double-blind, randomized, controlled study (Rush et al, 2005a
) studied 235 outpatients with depression (unipolar, n
=210 and bipolar, n
=25) and the effects of acute (10 weeks) treatment with VNS. The groups did not significantly differ in response rates (active=15.2% and sham=10.0%). This well-controlled study found no supporting evidence for acute antidepressant benefits of VNS. A parallel but not randomized group receiving ‘treatment as usual' was followed for 12 months and compared in an open-label fashion with the VNS group (George et al, 2005
). After 1 year, response rate for the VNS group was 27 and 13% for the treatment as usual group (statistically significant). The latter study was the basis for FDA approval of VNS for resistant depression (Rush et al, 2005b
There are some published studies dealing with long-term follow-up on the benefits of VNS. Schlaepfer et al (2008b)
, in an open study, report that after a remission and response rate of 37 and 17% in the first 3 months, a sustained response (no relapse in 1 year) of 44% was observed. Nahas et al (2005)
report a response rate of 42% (25/59) after 2 years. Also, Sackeim et al (2007a)
analyzed the durability of response to VNS. In a pilot and a pivotal study, they classified the outcomes as early responders (50% reduction in symptom scores within 3 months), later responders (same reduction within 12 months) and non-responders. In the pilot study, 72.2% and 61.1% of early responders (n
=18) were responders at 12 and 24 months, respectively; 78.8% of late responders (n
=14) were responders at 24 months. In the pivotal trial, of early responders (n
=30), 63.3% and 76.7% maintained response at 12 and 24 months, respectively; of late responders (n
=40), 65.0% maintained response at 24 months.
A recent naturalistic study (Bajbouj et al, 2010
) assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. After 2 years, response rate was 53.1% (26/49) and remission was 38.9% (19/49). Important to note is that two patients committed suicide during the study; no other deaths were reported. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.
All these results should be contrasted with naturalistic outcomes reported in the literature for patients with treatment-resistant depression receiving treatment as usual which. In a naturalistic outcome, Dunner et al (2006)
found a response rate of 11% (13/112) in 12 months and 18% (19/103) in 24 months. Only 5 out of the 13 responders at 12 months were still responders at 24 months. A similar thing was observed with remission, being 3.6% (4/112) at 12 months and 7.8% (8/103) at 24 months. Similarly, only one of the four remitters remained a remitter at 24 months.
For bipolar disorder, a pilot prospective, open-label, study of nine rapid-cycling bipolar patients (excluded from larger trials) found evidence of benefit over 12 months (Marangell et al, 2008
Deep Brain Stimulation
Direct electrical stimulation of the brain was tried in the 1960s (Heath, 1963
), but modern DBS started in the 1980s with works on movement disorders (Leiphart and Valone, 2010
DBS, although more invasive than the other techniques, is arguably the most focal way of treating mood disorders available (Butson and McIntyre, 2006
). An area in the millimeter range is usually used for stimulation. Different brain regions have been tried, some based on beneficial effects on depression while treating other primary disorder (eg, Parkinson or obsessive–compulsive disorder), and some based on hypothetical pathways related to mood symptoms. Animal work on DBS is largely focused on exploring the mechanisms of action (Hamani et al, 2010
). A number of regions have been proposed with DBS to treat depression, with some degree of overlap in the circuits that they modulate (for a review, see Hauptman et al, 2008
Most of the studies used stimulation of the subgenual cingulate, the ventral anterior internal capsule (ventral capsule/ventral striatum (VC/VS)) and the nucleus accumbens. There are also case reports of stimulation of the inferior thalamic peduncle and lateral habenula (). These will be briefly discussed.
Targets for deep brain stimulation (DBS).
The subgenual cingulate cortex.
The subgenual cingulate cortex (more specifically, the white matter of Brodmann's area 25). Is a region connected to the nucleus accumbens and limbic cortical loop. It is also connected to orbitofrontal, dorsomedial prefrontal, dorsolateral prefrontal, and dorsal cingulate cortices. Increases in blood flow are seen in this area during induced sadness (Vago et al, 2011
). Early studies have implicated the subgenual cingulate cortex (Cg25) in acute sadness and antidepressant effects (Mayberg et al, 1999
; Seminowicz et al, 2004
) and a decrease in Cg25 activity has been associated with immediate clinical response to a number of antidepressant treatments including serotonin reuptake inhibitors (Mayberg et al, 2000
), ECT (Nobler et al, 2001
), TMS (Mottaghy et al, 2002
), and ablative surgery (Dougherty et al, 2003
). DBS has been thought as an instrument to functionally inhibit the activity in this region. Mayberg et al (2005)
, implanted DBS electrodes in the bilateral subgenual cingulate cortex in six patients with treatment-resistant depression. Chronic stimulation at 130
Hz resulted in a significant response and remission of depression in four of the six patients at 6 months; in the two remaining patients, one experienced a significant reduction in depression over the first 4 months that fluctuated over time and remained submaximal, and the other patient had no response. A subsequent extension report came from this group with 20 implanted patients. In all, 12/20 patients had a reduction of at least 50% in the 17-item Hamilton Rating Scale for Depression (HRSD-17) score and 7 patients met criteria for remission (HRSD-17
7). PET studies of some responders showed widespread changes in cortical and limbic metabolic activity, including increased activity in lateral prefrontal cortex and Cg25WM, but a reduction in Cg25 grey matter (Lozano et al, 2008
This group recently published an extended follow-up of these patients. After an initial 12-month study of DBS, patients were seen annually and at a last follow-up visit. The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3–6 years), the average response rate was 64.3%, two patients died by suicide during depressive relapses (Kennedy et al, 2011
Ventral anterior internal capsule.
A region that has been a DBS target for treating depression is the same used for the treatment of OCD patients (Nuttin et al, 1999
) that got better from depressive symptoms, the ventral anterior internal capsule (VC/VS). In this case, the nucleus accumbens is not the target. Malone et al (2009)
attempted bilateral VC/VS DBS in 15 patients with treatment-resistant depression. They found that the proportion of patients with at least 50% reduction in HRSD-24 was 47% at 3 months, 40% at 6 months, and 53% at last follow-up, while remission rates with HRSD-24 were 20% at 6 months and 40% at last follow-up.
The nucleus accumbens/VS are regions that have long been regarded as part of the circuitry associated with depression and drug addiction (Monk et al, 2008
; Thomas et al, 2000
). The first case report of DBS implant in this region was for a patient with OCD and major depression. Stimulation of the bilateral NAC and ventral caudate at 130
Hz resulted in significant relief from depression and anxiety, with a remission at 6 months (Aouizerate et al, 2004
). Subsequently, three patients had bilateral implantation (Schlaepfer et al, 2008a
) with improvement in anhedonia and depression. In addition to other effects, there was an increases in the metabolism of dorsolateral and dorsomedial prefrontal cortices. Metabolism of the ventral and ventrolateral medial prefrontal cortex, shown in previous studies to be hyperactive in depression, was decreased. In an extension of this study (Bewernick et al, 2010
), 10 patients with refractory depression received bilateral stimulation to the nucleus accumbens, 5 (50%) of which had a response associated also with a reduction in anxiety after 12 months.
Inferior thalamic peduncle.
The inferior thalamic peduncle, is a bundle of fibers connecting the thalamus to the orbitofrontal cortex and aids the inhibition of input of irrelevant stimuli, providing selective attention. Velasco et al (2005)
identified this region as a potential target to treat depression. This region, along with the orbitofrontal cortex is hyperactive in depression and reverts with pharmacological treatment. The first case treated with DBS implanted in this site was a 49-year-old woman with severe TRD and multiple hospitalizations (Jimenez et al, 2005
) that improved with the treatment. Patient maintained remission scores during 8 months of active stimulation without antidepressant medication. When stimulation was turned off, fluctuations on depression scores were observed and disappeared when the device was again turned on by month 20. Borderline personality disorder and bulimia were also present and may complicate generalization of conclusions.
Finally, the last region tested so far as a DBS target for depression is the lateral habenula (Sartorius and Henn, 2007
), a region implicated in reward processing and emotional decision making. This region is located in the diencephalon, behind the thalamus and consists of a group of nerve cells neighboring the pineal gland. It is traditionally divided in a lateral part (limbic) and a medial part (motor). The putative use of this region is based on animal work showing that when the lateral habenula is inhibited by electrical stimulation in rats, norepinephrine in the hippocampus/prefrontal cortex increases, as does serotonin in the striatal circuits. Reduced depressive behaviors were observed in an animal model following lesions of the lateral habenula, and this effect was thought to be mediated through increased dorsal raphe serotonin (Yang et al, 2008
). On the other hand, DBS of the lateral habenula has been reported to attenuate positive reward-associated reinforcement. The first case report reached remission after about 20 weeks of stimulation and had a relapse a couple of days after the DBS unit was switched to off because of an incidental bicycle accident. The patient achieved remission again after 12 weeks of high voltage (10.5
V) stimulation (Sartorius et al, 2010
). Intracranial hemorrhage is the most common surgical complication (Binder et al, 2003
). It has been reported to be around 1–2% in large series of patients with implants for the treatment of Parkinson. Hemorrhage can be small and asymptomatic or can result in severe neurological deficit. No severe hemorrhagic complications were published so far for patients treated DBS for depression (Blomstedt et al, 2011
). Side effects such as depression and suicide ideation have been reported, but usually associated with misplacement of electrodes (Berney et al, 2002
; Bezerra et al, 1999
Side effects/complications in depressive implanted patients included: dysphagia, swollen eye, pain, erythema, anxiety increase, sweating, disequilibrium, hypomania, paresthesia, agitation, headache, lead dislodgement, psychotic symptoms, muscle cramps, affection of vision (with nucleus accumbens stimulation); seizure (one case in 20 implanted), infections, perioperative pain, worsening of mood (with subgenual cingulate cortex stimulation); on hypomanic episode (out of 15 implanted with VC/VS stimulation). No complications were reported in the cases with DBS in the inferior thalamic peduncle or lateral habenula (Blomstedt et al, 2011
The most appropriate target, optimal stimulation parameters, and long-term effects and efficacy remain uncertain. What is clear is that large-scale trials must be conducted to adequately assess the safety and efficacy of stimulation for depression. Data from such studies will provide information regarding optimal target localization, stimulation parameters, and adverse effects. Also important will be the illumination of the mechanism of action. Although DBS is often thought of as a ‘virtual lesion', recent evidence demonstrates that the effects of DBS can be subtler and may modulate information flow rather than halt it. For example, studies in Parkinson's disease indicate that DBS of the subthalamic nucleus appears to exert its therapeutic action by suppressing pathological oscillations in a specific frequency range (Eusebio et al, 2011
). According to McIntyre et al (2004)
, the general hypothesis to explain the mechanism of high-frequency DBS stimulation are depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments, these investigators suggest that stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS. In addition, computational modeling of frequency-specific action of DBS suggests it may act by regularizing pathological patterns of activity within thalamic/basal ganglia circuits (Dorval et al, 2009
). While oscillatory abnormalities in depression are incompletely understood, such modeling work may ultimately inform the appropriate targets and dosing paradigms for application in mood disorders.
Surgical ablative approaches were tried in the past to treat neurological and psychiatric disorders and have undergone a renaissance in recent years. Ablations guided some of the DBS electrode positioning for movement disorders (Benabid et al, 1991
) and provided the rationale for some DBS approaches for psychiatric disorders (Leiphart and Valone, 2010
The advances that were made in neurosurgical techniques, in particular the development of stereotactic operation, have dramatically improved the accuracy, making it possible to place tiny lesions with high precision. These lesions have minimal side effects in individual brain regions, their substructures or fiber tracts of the projection pathways (Juckel et al, 2009
). Techniques relevant to the treatment of depression are cingulotomy and limbic leucotomy.
Cingulotomy uses thermocoagulation to perform a bilateral lesion (about 1
cm wide and extend dorsally 2
cm into the callosum) of the cingulum. The aim is to interrupt the thalamo–fronto–cortical pathways and thus relieve anxiety (Cosgrove and Rauch, 2003
). Limbic leucotomy combines the cingulotomy with subcaudate tractotomy (lesion of the white substance) anterior to the head of the caudate nucleus. It destroys fiber strands between the prefrontal cortex and the limbic system (connections between the prefrontal cortex and the hippocampus, amygdala, thalamus, and hypothalamus) and leads to a secondary degeneration of the dorsomedial thalamic nucleus.
Therapeutic effects usually take long (about 1 year) to manifest after the surgery. The most common side effect is spontaneous seizures (1–2% of patients). It should be kept in mind that these techniques have the characteristic of being irreversible and more studies are needed define its place in the clinical setting.