Focal Brain Stimulation For Treatment–Resistant Depression: Transcranial Magnetic Stimulation, Vagus-Nerve Stimulation, and Deep-Brain Stimulation

Paul E. Holtzheimer III, MD and David H. Avery, MD

Dr. Holtzheimer is assistant professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Emory University in Atlanta, Georgia.

Dr. Avery is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at University of Washington School of Medicine in Seattle, Washington.

Disclosure: The authors report no financial, academic, or other interest in any organization that may pose a conflict of interest. Drs. Holtzheimer and Avery are currently co-investigators in a multi-site study of repetitive transcranial magnetic stimulation sponsored by Neuronetics, Inc.

Funding/support: This work was supported in part by the National Institute of Mental Health, grant no. R01 MH062154 awarded to Dr. Avery.

Please direct all correspondence to: David H. Avery, MD, Department of Psychiatry and Behavioral Sciences, Harborview Medical Center, 325 Ninth Ave, Box 359896, Seattle, WA 98104; Tel: 206-731-4527; Fax: 206-731-8615; E-mail: [email protected].

 

Abstract

There is an increased interest in focal brain stimulation as a potential treatment for depression. This is largely due to an attempt to find treatments for depression that have efficacy similar to electroconvulsive therapy (ECT) but are not associated with the same limitations as ECT. This article describes three techniques for focal brain stimulation: transcranial magnetic stimulation, vagus-nerve stimulation, and deep-brain stimulation. It also discusses the data supporting their use in treatment-resistant depression.

Introduction

Major depression is a common and disabling illness associated with increased mortality, both from suicide and nonsuicidal causes.^1,2 Fortunately, most depressed patients will respond adequately to medications and/or psychotherapy; however, there are a number of patients who do not respond to or cannot tolerate antidepressant treatments.

Electroconvulsive therapy (ECT) is a reasonable treatment option for treatment-resistant depression (TRD). With ECT, electricity is delivered to the cortex through scalp electrodes applied over frontal and/or temporal cortical regions. A generalized cortical seizure is produced, and the patient is kept paralyzed and unconscious during the treatment to prevent harm from a tonic-clonic seizure. Response rates with ECT, even in treatment-resistant patients, can be as high as 50% to 90%.^2-5 ECT also reduces suicide attempt rates and has been shown to reduce overall mortality rates in depressed patients over a 3-year follow-up.^1,3 Despite its potential benefits, ECT still has significant risks and side effects including post-ictal confusion, transient memory disturbance, and cardiopulmonary complications.^6-8 These risks, as well as societal stigmatization, have significantly limited the use of ECT, and many patients (and often their healthcare providers) are reluctant to accept this treatment.

Given the efficacy of ECT, which provides generalized electrical stimulation to the brain, there is a growing interest in identifying techniques for focally stimulating the brain. Focal brain stimulation might possibly achieve antidepressant efficacy equivalent, or nearly equivalent, to that seen with ECT, without the associated cognitive and anesthesia risks.

Transcranial magnetic stimulation (TMS), vagus-nerve stimulation (VNS), and deep-brain stimulation (DBS) are three established techniques for achieving focal brain stimulation. These techniques have been investigated as potential treatments for depression (Table).^9-13 This article will describe these techniques and discuss the data supporting their safety and efficacy in treating depression.

Transcranial Magnetic Stimulation

When TMS is administered, an electrical current is passed through an electromagnetic coil placed on the scalp. A brief, rapidly changing magnetic field is created, inducing a small electrical current within the underlying cortex. The area of stimulation is relatively focal, and covers about a 2–4 cm diameter region of cortex when using a “figure-of-eightâ€? coil; the region of stimulation is broader when using a less focal circular coil.¹⁴ TMS effectively depolarizes cortical neurons within the area of stimulation. For example, a TMS pulse applied over the motor cortex results in contraction of the contralateral muscle. Single-pulse TMS is established as a diagnostic and research tool in humans.¹⁵

Repetitive TMS (rTMS), in which repeated electrical pulses are generated in the cortex, is a more recent development of TMS technology, and is associated with unique neurophysiologic effects. For example, high frequency (“fastâ€?) rTMS, defined as >1 Hz stimulation, has been shown to cause an increase in motor cortical excitability that persists beyond the end of stimulation.¹⁶ Conversely, low frequency (“slowâ€?) rTMS, defined as £1 Hz stimulation, has been shown to decrease motor cortical excitability.¹⁷ rTMS has been used to map brain functions such as speech, vision, movement, and attention, and has been extensively studied as a potential treatment for depression. There is no need for anesthesia when giving non-convulsive rTMS, and it can be given on an outpatient basis.

In interpreting rTMS studies in depression, it is important to recognize the variability in treatment parameters possible with rTMS, and to recognize that different parameters and parameter combinations may have differential neurophysiological effects. For example, stimulation frequency can be either slow or fast, with varying effects on motor cortical excitability as described above. However, fast rTMS can be given at different frequencies (eg, 5 Hz, 10 Hz, or 20 Hz), and there is some evidence that different types of “fastâ€? rTMS (eg, 10 Hz versus 20 Hz) may exert different physiologic effects.¹⁸

Stimulation intensity can also be varied. Typically, intensity is expressed as a percentage of the subject’s motor threshold (MT) for the abductor pollicis brevis or first dorsal interosseous muscle. Some rTMS studies have used subthreshold stimulation (eg, 80% MT), while others have used threshold or suprathreshold stimulation (100% to 110% MT).

In addition to stimulation frequency and intensity, rTMS parameters can vary by train duration (length of a “burstâ€? of pulses at a given frequency), number of trains per session, number of treatment sessions, intertrain interval, and stimulation location (eg, which part of the cortex is targeted). The neurophysiologic effects of rTMS most likely represent an interaction of all of these parameters; for example, the risk that rTMS will induce a generalized seizure is at least partially determined by an interaction of intensity with frequency and train duration.¹⁹

Given this potential variability in rTMS parameters, it is perhaps not surprising that treatment studies of rTMS in depression have varied considerably in parameter selection. This may in part explain the variability in treatment response between studies (discussed below), although patient factors likely play a role as well. The data supporting rTMS as a treatment for depression are reviewed below, and the factors potentially affecting treatment response are discussed in more detail.

Open and Early Controlled Studies

Hoflich and colleagues²⁰ first reported modest antidepressant effects of rTMS in one of two patients. Since that time, several open and controlled studies have been conducted. The earliest of these stimulated various cortical sites (eg, vertex and motor cortex) using very slow rTMS (0.02–0.5 Hz) at intensities 80% to 130% MT for five or fewer sessions. These studies generally showed very modest improvements in depression ratings (see Burt and colleagues²¹ for a review). Most subsequent studies applied rTMS to the left dorsolateral prefrontal cortex (DLPFC), based on evidence that this region appeared to be functionally involved in mood regulation and depression.^22,23 These studies also used fast rTMS and showed more substantial improvements in depression.^24-26 For example, Epstein and colleagues²⁷ found a 56% response rate in 32 medication-resistant patients treated with five sessions of 10 Hz, left DLPFC rTMS at 110% MT intensity. Additionally, open studies of slow (0.5–1 Hz) rTMS applied to the right DLPFC found mean decreases in Hamilton Rating Scale for Depression scores of 31% to 42%.^28,29

While these early studies did not definitively demonstrate antidepressant effects for rTMS, they did help define which rTMS parameters were likely to be therapeutic. It appeared from these data that high-frequency rTMS applied to the left DLPFC likely resulted in antidepressant effects; it was also suggested that low-frequency rTMS applied to the right DLPFC might be effective as well.

 

High-Frequency, Left DLPFC rTMS

The vast majority of sham-controlled studies of rTMS in TRD have investigated high-frequency (5–20 Hz) rTMS applied to the left DLPFC. These studies have used a range of intensities (from sub- to supra-threshold) and various treatment durations (5–20 treatment sessions). A number of meta-analyses have evaluated these studies, each analysis using somewhat different inclusion/exclusion criteria and statistical methods. These analyses agreed that high-frequency (³5 Hz), left DLPFC rTMS given for at least 10 daily sessions results in statistically significant antidepressant effects.^21,30-32 Kozel and colleagues³¹ also demonstrated that, while publication bias for rTMS studies likely existed, 20–55 similarly-sized negative studies would be needed to make the mean effect size for rTMS statistically nonsignificant. Given that published and ongoing rTMS depression studies throughout the world are tracked by the International Society for Transcranial Stimulation,⁹ it is extremely unlikely that this many negative studies of rTMS have been conducted but not reported. Therefore, it is reasonable to conclude that high-frequency, left DLPFC rTMS, given for at least 10 sessions, does indeed have statistically significant antidepressant effects.

Despite this, it remains unclear whether high-frequency, left DLPFC rTMS can produce clinically meaningful effects. Every meta-analysis of rTMS has cautioned that, while rTMS may have statistically significant effects, the degree of antidepressant response in these studies is modest at best.^20,30-32 Indeed, Holtzheimer and colleagues³⁰ showed that the average response rate across all studies using high-frequency, left DLPFC rTMS was 18% for active rTMS and 2% for sham rTMS. While this difference in response rates between active and sham rTMS is of similar magnitude as for many antidepressant studies, the response rate for actively-treated patients is still quite low.

One explanation for this low response rate is simply that rTMS does not produce clinically significant antidepressant effects. However, the response rate across studies varies widely, and most studies of rTMS have described some subjects with rather dramatic responses to rTMS treatment. Therefore, another explanation for the low response rate across studies is that patient and treatment factors can significantly influence response to rTMS.

Patient factors that influence response to rTMS likely include degree of treatment resistance, duration of current depressive episode, presence of psychosis, and age. Patients with TRD generally have low response rates to all antidepressant treatments, including ECT.^5,33 Therefore, treatment response expectations for rTMS should be lower when studying treatment-resistant patients. Duration of current depressive episode may also decrease likelihood of antidepressant response^5,34,35; patients with depressive episodes longer than 4 years may be unlikely to respond to rTMS.³⁴ As well, patients with psychotic features may not respond well to rTMS treatment,³⁶ and older patients may not respond as well to rTMS as younger patients.^37,38

Treatment factors which may influence antidepressant response to high-frequency, left DLFPC rTMS likely include number of treatment sessions and stimulation intensity. The majority of studies of rTMS in depression have treated with 10 or fewer daily sessions. Additionally, many of these studies have used subthreshold stimulation intensity. One analysis of the rTMS literature found that studies using more treatment sessions (>10) and higher treatment intensities (>100% MT) demonstrated greater antidepressant response rates.³⁹ More recent studies also suggest that subthreshold intensity rTMS may not be as effective in treating depression.^40,41 A recently completed sham-controlled study of rTMS in our center investigated 15 sessions of 10 Hz, 110% MT, left DLPFC rTMS in 68 patients with TRD.⁴² Response rates were 31% for active rTMS and 6% for sham rTMS; remission rates were 20% for active rTMS and 3% for sham rTMS. Therefore, by treating with more than 10 treatment sessions at suprathreshold stimulation intensities, it may be possible to increase the antidepressant response rate to rTMS.

Additional evidence for the clinical efficacy of high-frequency, left DLPFC rTMS comes from comparisons of rTMS with ECT. Four open-label studies have directly compared rTMS to ECT in treatment-resistant depressed patients.^36,43-45 While one of these studies showed ECT to be superior to rTMS in treating patients with psychotic depression,³⁶ these studies generally showed no difference in antidepressant response between rTMS and ECT in nonpsychotic depressed patients. Of note, all of these studies used more than 10 treatment sessions. While these studies were not powered to demonstrate statistical equivalence between the two treatments, they are still suggestive that rTMS can have antidepressant effects at least similar to ECT in some patients. However, important caveats in interpreting these studies are that there was no sham control and that ECT parameters were not consistently optimized (although ECT response rates were quite similar to those often seen in treatment-resistant patients).

In summary, current data support the conclusion that high-frequency, left DLPFC rTMS produces statistically significant antidepressant effects. While the clinical significance of these effects has not yet been conclusively demonstrated, studies comparing rTMS to ECT and a recent sham-controlled study using higher intensity stimulation over 15 sessions suggest that high-frequency, left DLPFC rTMS may indeed have clinically relevant antidepressant effects. Larger, more definitive trials are needed to confirm this.

Low-Frequency, Right DLPFC rTMS

A small number of open studies suggest low-frequency, right DLPFC rTMS may also have antidepressant effects.^28,29,46 Three sham-controlled studies have also shown statistically significant antidepressant effects for low-frequency, right-sided rTMS. Klein and colleagues⁴⁷ treated 67 patients with 10 sessions of 1 Hz, right DLPFC rTMS and found a 49% response rate in the active rTMS group and a 25% response rate in the sham rTMS group. Notably, inclusion in this study was not limited to TRD Patients, perhaps explaining the relatively larger sham and rTMS response rates seen. Fitzgerald and colleagues⁴⁸ compared 10 Hz, left DLPFC rTMS to 1 Hz, right DLPFC rTMS to sham rTMS in 60 patients with TRD; all patients received 10 sessions of double-blind treatment. Both active rTMS conditions were superior to sham stimulation, and there was no significant difference between the two active groups. Kaufmann and colleagues⁴⁹ randomized 12 patients with TRD to receive 10 sessions of active or sham 1 Hz rTMS to the right DLPFC. Four of seven patients (57%) in the active rTMS group met both response and remission criteria. Two of five patients (40%) in the sham group met response criteria and one of five patients (20%) met remission criteria. Active rTMS patients showed a statistically significant reduction in depression ratings from baseline to the final treatment session; sham-treated patients showed no significant change in depression ratings.

In summary, a limited database supports antidepressant efficacy for low-frequency (1 Hz), right DLPFC rTMS in TRD. More research is needed to determine whether this form of rTMS truly has statistically and clinically significant antidepressant effects. Additionally, it will be important to determine whether certain patients are more likely to respond to specific forms of rTMS.

Low-Frequency, Left DLPFC rTMS

A few small studies have investigated low-frequency, left DLPFC stimulation. Padberg and colleagues⁵⁰ compared five sessions of low-frequency, left DLPFC rTMS with high-frequency, left DLPFC rTMS and sham rTMS. In this study, modest but statistically significant antidepressant effects were found with low-frequency, left DLPFC rTMS but not with high-frequency, left DLPFC or sham rTMS; shorter treatment duration (only five sessions) may have confounded these results. Kimbrell and colleagues⁵¹ found statistically significant antidepressant effects with 10 sessions of 80% MT 1 Hz, left DLPFC rTMS, but not with 20 Hz, left DLPFC or sham rTMS. Of note, this study used subthreshold stimulation intensity which (as discussed above) may be less effective than higher stimulation intensities. Rosenberg and colleagues⁵² randomized 15 patients with posttraumatic stress disorder and major depression to receive 1 Hz or 5 Hz left DLPFC rTMS. Response rates in the 1 Hz and 5 Hz groups were 67% and 83% respectively, and there was no statistically significant difference between the two conditions. However, the lack of a sham control group in this study limits the conclusions that can be drawn. In summary, the database for low-frequency, left DLPFC rTMS is suggestive of antidepressant effects, but is inconclusive.

Other rTMS Treatment Parameters

Several investigators have explored the effects of various rTMS parameter combinations in patients with depression. Loo and colleagues⁵³ randomized 19 depressed patients to receive sham stimulation or high-frequency (15 Hz) rTMS applied to both the right and left DLPFC. All patients improved, but there was no statistical difference between active and sham treated patients. Hausmann and colleagues⁵⁴ randomized 38 patients to receive (1) high-frequency, left DLPFC rTMS; (2) a combination of high-frequency left and low-frequency right DLPFC rTMS; or (3) sham rTMS. At the beginning of the study, all patients were also started on antidepressant medications. There was no significant difference in antidepressant response between the three groups, but these results were confounded by the “add-onâ€? nature of the trial and the use of heterogeneous medication regimens. Conca and colleagues⁵⁵ compared the antidepressant effects of (1) high-frequency, left DLPFC rTMS plus low-frequency, right DLPFC rTMS; (2) high-frequency, left DLPFC rTMS plus low-frequency, left DLPFC rTMS; and (3) high-frequency, left DLPFC rTMS alone. No significant difference in antidepressant response was seen between the groups.

A few investigators have also explored using TMS to induce generalized seizures as a potential treatment for depression (similar to ECT)—a technique called magnetic seizure therapy (MST). While no definitive results have been reported, there is some evidence that MST results in antidepressant effects with fewer cognitive side effects than ECT.^56,57 It is unclear whether MST is more or less efficacious than nonconvulsive TMS.

These studies highlight the variability in TMS parameters. They also suggest that other treatment parameters may have antidepressant effects. However, the data are too sparse to draw firm conclusions regarding the relative efficacy of TMS given these parameters.

rTMS Side Effects and Safety

Studies of rTMS have shown it to be safe and well-tolerated.³⁰ Despite extensive neuropsychological testing, rTMS has consistently proven to have no negative cognitive side effects.^58,59 While transient auditory threshold increases have been reported with rTMS,⁵⁸ this can be eliminated with the use of foam earplugs. Some patients report a mild headache during and/or following rTMS, but this is typically short-lived and easily treated with over-the-counter analgesics.

The most concerning risk of rTMS is a generalized seizure. Several reports have shown that high frequency rTMS can induce a generalized seizure in epileptic and nonepileptic individuals.¹⁹ Low-frequency rTMS does not appear to increase the risk of seizure.¹⁹ Factors which increase the risk of seizure with rTMS include other risk factors for seizure in the patient (eg, history of epilepsy, proconvulsant medications), increased rTMS intensity, higher stimulation frequencies, and short intertrain intervals.¹⁹ Safety guidelines have been published to help investigators better control the risk of seizure with rTMS.¹⁹ No seizure has been reported with rTMS used according to these guidelines.

Use of rTMS in Special Populations

Geriatric Patients

One open study of rTMS in depressed patients found that older patients had a much lower response rate than younger patients.³⁸ A double-blind, sham-controlled study³⁸ in elderly patients with TRD also failed to show statistically significant antidepressant effects for rTMS. Interestingly, despite the absence of antidepressant effects in this study, active rTMS was associated with statistically significant improvements in cognitive function.⁶⁰ A more recent study of rTMS for post-stroke depression (mean patient age=64.8 years) demonstrated statistically significant antidepressant effects for rTMS.⁶¹ One explanation for the mixed results for rTMS in older persons may be greater prefrontal atrophy in older age. Since the induced current from rTMS drops off rapidly with increasing distance from the TMS coil,⁶² patients with prefrontal atrophy may need higher stimulation intensities to achieve the same degree of cortical stimulation as patients without atrophy. One open study in older patients with depression showed that greater scalp-cortical distance at the prefrontal cortex relative to the motor cortex (rather than absolute scalp-cortical distance at the prefrontal cortex) negatively correlated with antidepressant response.⁶³

Bipolar Depression

A number of studies of rTMS for depression have included patients with bipolar depression. While many of these patients have shown clinical improvements with rTMS, the numbers of patients in each study were too small to draw definitive conclusions about the relative efficacy and safety of rTMS in bipolar depression. Two small, sham-controlled studies have specifically investigated high-frequency, left DLPFC rTMS in patients with bipolar depression. One showed a modest, but statistically significant benefit for rTMS over sham.⁶⁴ The other showed no statistically significant difference in antidepressant response between the active and sham rTMS groups.⁶⁵ Interestingly, several investigators have reported the development of mania in patients receiving rTMS (some without a prior diagnosis of bipolar disorder).^66-69 More research is clearly needed to identify whether rTMS is a safe and efficacious treatment for bipolar depression.

Children and Adolescents

To date there are no published trials of rTMS in children or adolescents. Walter and colleagues⁷⁰ collated all known cases of rTMS use in children and adolescents and identified only one center that had treated seven younger patients with a variety of diagnoses (three with unipolar depression, one with bipolar depression, and three with schizophrenia). Clinical improvement was seen in all patients except one with unipolar depression and one with bipolar depression. To date, the safety and efficacy of rTMS in younger persons is unknown.

Pregnancy

Nahas and colleagues⁷¹ reported a single case of a depressed pregnant woman who was successfully treated during her second trimester with rTMS. No apparent adverse effects for the patient or fetus were identified. Still, the safety of TMS and rTMS during pregnancy has not yet been established.

Review of rTMS Studies: Limitations

An important limitation of all rTMS studies to date is small sample size. Only two studies of rTMS in depression have included more than 30 patients per treatment arm.^42,47 Additionally, the clinical significance of rTMS has yet to be proven. Heterogeneity of patient and treatment parameters in the rTMS literature limit firm conclusions as to which patients will best respond to which types of treatment. Larger trials using optimized rTMS are needed to better clarify these issues.

In relation, the optimal parameters for rTMS as a treatment for depression are unknown. While active rTMS appears to have greater antidepressant properties than sham rTMS, the overall antidepressant response rate to rTMS is relatively low compared to other antidepressant treatments. However, high-frequency, left DLPFC rTMS is the only type of rTMS that has been extensively studied, and the majority of these studies have used 10 or fewer treatment sessions and treatment intensities at or below motor threshold. For high-frequency, left DLPFC rTMS, it appears that higher intensities, longer treatment courses, and greater total number of pulses may be more effective.³⁹ It is possible that other types of rTMS (eg, low-frequency, right DLPFC or combination left-right rTMS) may be more effective for some patients. More research is needed to further optimize treatment parameters for rTMS.

Another limitation of rTMS treatment studies to date is the difficulty in finding a completely adequate sham condition. Sham TMS is often given by rotating the coil away from the scalp at either 45 or 90 degrees such that the focus of stimulation is away from the cortex. However, such sham stimulation induces less of a scalp sensation than active TMS. As well, sham stimulation at 45 degrees may induce some activity in the cortex and may therefore be partially active.⁷²

The mechanism of action of rTMS is largely unknown. Preclinical studies suggest rTMS may induce physiological and behavioral effects in animals similar to those elicited with established antidepressant treatments.^73,74 Imaging data also suggest rTMS alters functioning of cortical and subcortical brain regions implicated in the pathophysiology of depression.^75,76 Still, an important limitation of TMS is that it can only directly stimulate cortical regions close to the coil—deeper brain structures involved in the pathophysiology of depression cannot be directly targeted.

Summary

Multiple studies have investigated TMS as a treatment for TRD. The strongest database supports antidepressant effects for high-frequency, left DLPFC rTMS. Further, there is evidence that optimization of patient factors and treatment parameters may improve response rates to this type of rTMS. A smaller, but compelling database supports the antidepressant efficacy of low-frequency, right DLPFC rTMS. Other studies suggest antidepressant effects with other combinations of rTMS parameters, but the available data are quite limited. If proven efficacious, rTMS would provide an important treatment option for patients with TRD. Given that it is associated with relatively few side effects and can be given on an outpatient basis, rTMS might provide an alternative to some patients who might otherwise be referred for electroconvulsive therapy (ECT). In sum, more research is needed to better clarify the antidepressant effects of rTMS and to better identify which patient and treatment factors are most predictive of antidepressant response.

Vagus-Nerve Stimulation

In VNS administration, an electrical stimulator is connected to a patient’s left vagus nerve and attached to a programmable pulse generator implanted subcutaneously in the patient’s chest. The stimulator can be programmed to deliver electrical pulses to the nerve at various frequencies and currents. Typically, stimulation parameters are 0.25 milliampules, 20–30 Hz, 250–500 microsecond pulse width, and an on/off cycle of 30 seconds on every 3–5 minutes. VNS is an established treatment for treatment-resistant epilepsy.¹⁰ Based on mood improvements reported by epileptic patients receiving VNS, it has also been suggested as a treatment for depression.¹¹ This idea is further supported by data that many anticonvulsant agents can have antidepressant effects,⁷⁷ and by evidence that the anticonvulsant effects of ECT may be associated with its antidepressant effects.⁷⁸

One open study and one double-blind study have shown antidepressant efficacy for VNS in epilepsy patients with comorbid depression.^79,80 A single open study investigated VNS in 60 non-epileptic patients with profound TRD, many of whom had previously failed ECT.¹² One patient improved during the 2-week, single-blind, no treatment recovery period following implantation surgery. Of the remaining 59 patients, response and remission rates after 10 weeks of treatment were 31% and 15% respectively. These results suggested VNS might have clinically meaningful antidepressant effects in treatment-resistant patients. However, a large, sham-controlled study failed to show a statistically significant difference between sham and active VNS.¹¹

Despite the negative findings of the sham-controlled study, there is evidence that VNS may still be a useful treatment for some patients with TRD. First, for the 59 patients enrolled in the open study of VNS, response and remission rates increased to 45% and 27% at 1 year postsurgery, and were 44% and 22% at 2 years postsurgery.¹³ Second, 1-year response and remission rates for VNS-treated patients enrolled in the sham-controlled study were 30% and 17% respectively.⁸¹ The 1-year response and remission rates in a large group of demographically-comparable, treatment-resistant depressed patients were 13% and 7% respectively.⁸¹ The 1-year response rate was significantly greater in the VNS group, and the greater remission rate trended towards significance.

Side effects of VNS surgery and treatment are generally mild.⁸² Surgical complications are rare, with incision pain being the most commonly reported adverse event. Common side effects of treatment include voice hoarseness and coughing. In general, VNS appears to be well-tolerated and acceptable to patients.

The potential mechanism of action of VNS in treating epilepsy and depression is currently unknown. Imaging studies suggest that VNS alters functioning of cortical and subcortical brain regions known to be involved in mood regulation and depression.⁸³ However, as with TMS, VNS cannot directly modulate the functioning of many brain regions implicated in the pathophysiology of depression.

In summary, VNS is a relatively safe, well-tolerated treatment that may have efficacy in TRD. Current efficacy data are mixed, with a large, sham-controlled study finding no statistically significant acute antidepressant effects. However, long-term follow-up data suggest response and remission may increase over time in VNS-treated patients, and that these increases may be statistically and perhaps clinically significant compared to treatment-as-usual. More research is needed to clarify what role VNS may play in the treatment of TRD.

Deep-Brain Stimulation

With DBS, a small electrical stimulator is implanted into a defined brain location, often a subcortical area, and connected to a programmable subcutaneous pulse generator. Bilateral DBS of the subthalamus or globus pallidus is a relatively new, but generally accepted treatment for treatment-resistant Parkinson’s disease.⁸⁴

To date, there are no published reports of DBS for TRD, although at least one study is currently underway.⁸⁵ Several lines of evidence support the investigation of DBS as a treatment for depression. First, DBS has been clearly associated with significant mood changes in patients with Parkinson’s disease^86,87; thus, direct modulation of mood with DBS is possible. Second, functional imaging studies clearly implicate certain deep brain regions in the pathophysiology of depression, such as the amygdala and anterior cingulate cortex.^76,88 Function in these regions could be directly modulated with DBS; as discussed above, this is not possible with either TMS or VNS. Third, two small case series have reported potential benefit from bilateral internal capsule DBS in patients with severe, treatment-resistant obsessive-compulsive disorder.^85,89

Side effects of DBS surgery and treatment can include intracranial hemorrhage, delirium, mood changes (including depression and mania), and movement disorders.⁹⁰ It is important to recognize that these effects were seen in patients with Parkinson’s disease treated with DBS. It is not yet clear what side effects may occur in non-Parkinsonian patients that undergo DBS surgery and long-term treatment.

In summary, DBS is an innovative technique for directly altering the function of deep brain structures that has shown efficacy in treating treatment-resistant Parkinson’s disease. While DBS has not yet shown efficacy in depressed patients, such investigations are warranted.

Conclusion

Over the last several years, focal brain stimulation techniques have been increasingly investigated as potential treatments for TRD. The largest and most convincing database supports antidepressant efficacy for high-frequency, left DLPFC rTMS. A smaller database supports efficacy for low-frequency, right DLPFC rTMS. A more mixed database supports the use of other combinations of rTMS parameters in treating depression. While the clinical significance of rTMS has yet to be established, the data suggest that careful attention to relevant patient and treatment factors may improve antidepressant response rates. It is currently unclear whether VNS has statistically or clinically significant antidepressant effects, but long-term follow-up data with treatment-resistant patients suggest this technique may be a useful treatment. DBS has not yet been studied as a treatment for TRD, but such investigations appear warranted. Taken together, these techniques offer an exciting new approach to the treatment of TRD, and may improve our understanding of the basic neurobiology of depression and antidepressant treatments. PP

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