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 RESEARCH ARTICLE

Advances in brain stimulation for depression

Anna Wani, MD

University of Texas Southwestern Medical Center, Dallas, TX, USA

Kenneth Trevino, PhD

University of Texas Southwestern Medical Center, Dallas, TX, USA

Paige Marnell, MD

University of Texas Southwestern Medical Center, Dallas, TX, USA

Mustafa M. Husain, MD

University of Texas Southwestern Medical Center, Dallas, TX, USA

BACKGROUND: Major depressive disorder is a common and debilitating psychiatric disorder that negatively impacts a large portion of the population. Although a range of antidepressant treatments have been developed, many patients are unable to obtain an adequate therapeutic response despite completing several antidepressant medication trials. As a result, neurostimulation treatment modalities have been developed as potential alternatives. This article provides an overview of advances in neurostimulation for treating depression.

METHODS: We conducted a comprehensive review of the neurostimulation literature to identify recent findings involving the description and rationale, efficacy, and side effects of vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and deep brain stimulation (DBS).

RESULTS: VNS and TMS are the newest neurostimulation modalities that have been approved by the FDA for treating depression. VNS is approved for patients with treatment-resistant depression (TRD), while TMS has demonstrated efficacy only for milder forms of TRD. Despite demonstrated efficacy, further research is needed to address certain limitations and/or determine how best to utilize these forms of neurostimulation. Investigational forms of neurostimulation include MST and DBS. Although MST and DBS have demonstrated promise as a depression treatment, research is still being conducted to determine and/or enhance their antidepressant properties.

CONCLUSIONS: Although electroconvulsive therapy remains the primary and most effective treatment option for patients with severe TRD, there have been considerable gains in the field of neurostimulation. Many of the neurostimulation techniques described in this review represent promising treatment alternatives for patients with TRD.

KEYWORDS: treatment-resistant depression, magnetic seizure therapy, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, neurostimulation

ANNALS OF CLINICAL PSYCHIATRY 2013;25(3):217-224

  INTRODUCTION

Major depressive disorder

Major depressive disorder (MDD) is one of the most common and debilitating psychiatric disorders, which negatively impacts various aspects of an individual’s life, including family, social network, occupational function, and overall level of functioning.1,2 Approximately 35.1 million adults in the United States will be diagnosed with MDD in their lifetime.3 MDD is the fourth leading cause of disability and is predicted to be the second most disabling disease across all countries by 2020.4 The debilitating nature of MDD is highlighted by the estimated annual loss of $30 to $55 billion in depression-related medical and productivity costs.5-7 Although a broad range of antidepressant treatments have been developed, reflecting an increase in our understanding of depression, a significant number of individuals diagnosed with MDD remain unable to achieve or maintain a satisfactory response to multiple antidepressant treatments.8

Treatment-resistant depression

Patients who continue to experience MDD, despite completing multiple antidepressant trials, are commonly referred to as experiencing treatment-resistant depression (TRD). Although there is some variability in the number and type of treatment failures that constitute the presence of TRD, in general, patients who fail to respond to at least 2 adequate trials of antidepressant medications from different drug classes are considered to have some degree of treatment resistance.9-15 In addition, various TRD staging models have been designed as a means of measuring TRD severity.14,16-18 A comprehensive review of the various TRD staging models that have been proposed is beyond the scope of this review. However, all TRD staging models consider only failed antidepressant medication trials that are of adequate dose and duration.

Approximately 15% of patients treated for MDD continue to experience depression or are categorized as having TRD.10 The prevalence rate for patients who fail to obtain a complete remission of their depressive symptoms has been reported at 60% to 70%.19-21 Due to the significant number of patients who fail to respond to antidepressant medication, various neurostimulation treatment modalities have been developed as potential alternatives.

Electroconvulsive therapy

Electroconvulsive therapy (ECT), which was introduced in 1938, is one of the most frequently used forms of neurostimulation for patients experiencing TRD. The process of administering ECT in North America involves the use of general anesthesia and muscle relaxants, which have been incorporated in order to eliminate or minimize seizure-related side effects or discomfort. After patients are fully anesthetized, a mild electrical current is administered to a specific area of the brain with the intent of inducing a therapeutic seizure. Regarding the efficacy of ECT, response rates of 80% to 90% have been reported,22 and response rates are as high as 50% to 60% among patients who have demonstrated some degree of treatment resistance.22 The long-standing and well-established electrode placement and administration of ECT have resulted in greater antidepressant efficacy; however, the limitations of ECT still include a high rate of relapse and a risk of experiencing specific cognitive side effects. Studies of ECT have reported relapse rates that exceed 50%, with the majority of these patients relapsing within months after the completion of treatment.23 Regarding the cognitive side effects of ECT, patients can experiencing anterograde and/or retrograde amnesia following treatment.24 Due to the stagnancy of ECT described above and the significant number of patients who fail to respond to antidepressant medication, there is a need to develop additional forms of neurostimulation for the treatment of MDD.

The purpose of this review is to summarize the various forms of neurostimulation treatment modalities that have been developed for the treatment of depression. This summary includes a description of the antidepressant efficacy and side effects of vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, and deep brain stimulation.

Vagus nerve stimulation therapy

The first neurostimulation treatment for depression developed and approved after the introduction of ECT was vagus nerve stimulation (VNS) therapy. This form of neurostimulation involves implanting a small pulse generator that is designed to provide a brief intermittent electrical current to the left vagus nerve. This pulse generator is implanted subcutaneously in the left chest wall, and an attached lead is wrapped around the left vagus nerve via a small incision in the neck.25,26 After implantation, the pulse generator can then be activated and adjusted with the use of a programming wand that is held over the device.

Although the exact mechanisms by which VNS therapy works are unknown, its antidepressant effect is likely related to the neuroanatomic makeup and pathways of the vagus nerve. Because the vagus nerve is predominately comprised of afferent fibers, which bring information to the brain, stimulation of the vagus nerve can activate attached structures that have been implicated in depression.26,27 Many of the afferent cells that make up the vagus nerve project to the nucleus tractus solitaries, which directly projects to several areas in the brainstem, limbic, and cortical areas, as well as indirectly to the locus coeruleus (LC) and parabrachial nucleus (PB). The LC and PB connect to the amygdala and the bed nucleus of the stria terminalis, which are areas that have been implicated in mood regulation.28

Research using positron emission tomography (PET) imaging has indicated that stimulation of the vagus nerve affects the limbic system in a manner similar to antidepressant medication.29,30 VNS has been shown to enhance transmission of norepinephrine in the LC and serotonin in the dorsal raphe nucleus, which are neurochemical changes that correspond with the theorized antidepressant mechanisms of psychotropic medication.28,31 VNS has also been shown to alter the concentration of serotonin, norepinephrine, γ-aminobutyric acid (GABA), and glutamate, which are neurotransmitters that have been implicated in mood disorder.28,31,32

Efficacy of VNS for depression. VNS was originally developed as a treatment for intractable seizures; however, after demonstrating antidepressant properties, VNS was also studied as a potential treatment for depression.26,27,33 The pilot study was a multicenter, open-label trial designed to examine the safety and efficacy of VNS for treating depression. This study included 59 patients with unipolar or bipolar depression who were currently experiencing a major depressive episode (MDE). In this study, a response was defined as a reduction in baseline scores of ≥50% on the 28-item Hamilton Depression Rating Scale (HRSD28), and remission was defined as a score of <10 on the same measure. During the acute phase of this trial, 30.5% of the patients experienced a response to VNS and 15.3% experienced remission. The Clinical Global Impression (CGI) assessments showed that 37.3% of patients were much improved, 5.1% of patients were minimally worse, and the remaining 57.6% of participants were minimally improved or unchanged. Of the first 30 patients treated with VNS, the response rate increased from 40% to 46%, and the remission rate increased from 17% to 29% with another 9 months of VNS therapy. This demonstrated that the efficacy of VNS therapy for the treatment of depression may be enhanced with a longer duration of treatment.34

After the promising results of the initial VNS trial for the treatment of depression, a large-scale efficacy trial was conducted, which included 235 patients classified as having TRD. This study was a double-blind multicenter clinical trial, which was designed to assess the safety and efficacy of both an acute (12 weeks postimplantation) and long-term (12 months postimplantation) course of VNS. Following implantation and recovery, patients received a fixed stimulation dose for a period of 8 weeks, during which stimulation parameters could be adjusted only in response to severe side effects. Response was defined as a >50% decrease of HRSD24 scores from baseline, and remission was defined as an HRSD score of <9. At the end of the acute phase, no significant difference was demonstrated between the sham and active treatment groups. However, during the long-term open-label treatment phase, a response rate of 29.8% and a remission rate of 17.1% were observed. In comparison with a control group of TRD patients who received treatment as usual (12.5% response), VNS demonstrated greater antidepressant efficacy, which supports its therapeutic application as a long-term treatment for TRD.35 Based on these findings, VNS received FDA approval in 2005 as an adjunctive long-term treatment for patients age >18 with TRD.25

Safety of VNS for depression. The side effects associated with VNS therapy can be categorized as either surgery/implant- or stimulation-related. In association with the surgical procedure, the most common side effects were incision pain (36%), voice alteration (33%), incision site reaction (29%), and pain around the device generator or leads (23%). Most of these side effects resolved within the first month after surgery. The most common side effects related to the stimulation of the vagus nerve itself were voice alteration (55%) and an increase in cough (24%). Voice alteration was thought to be a result of the transference of current to the recurrent laryngeal nerve, which innervates the vocal cords. Most of the side effects due to VNS resolved as tolerance to the stimulation developed; however, voice alteration persisted in some cases. Another way to mitigate side effects was to alter the stimulation parameters in order to build tolerance.25,26

Transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive form of neurostimulation that was first developed as a neurophysiological probe to test the central motor system.36 However, as its potential for changing synaptic connectivity and activity became apparent, interest in TMS began to shift toward its potential clinical application. The process of administering TMS involves passing an electrical current through a coil, which produces a pulsating magnetic field that passes unimpeded through the scalp. The strength of this field is of sufficient intensity to depolarize neurons and, with repeated application, modulate cortical excitability in a controlled manner without inducing a seizure.37,38

The focal nature of the magnetic field generated by TMS allows specific cortical regions to be targeted with minimal impact on surrounding cortical areas.39,40 TMS can be administered in a variety of forms based on the number and pattern of TMS stimulations (ie, magnetic pulses) delivered during a session. Repetitive TMS (rTMS) is the most common form of TMS used to treat depression and is typically administered at a high frequency over the left dorsolateral prefrontal cortex (DLPFC), a cortical area found to be underactive in patients with MDD.41,42

Efficacy of rTMS for depression. The antidepressant properties associated with rTMS have been well documented in the psychiatric literature. A recent meta-analysis, which included 34 randomized controlled trials of rTMS, found a statistically significant reduction in depressive symptoms with this form of treatment. Although the decrease in depressive symptoms secondary to rTMS was statistically significant independent of whether the patients were concurrently on antidepressants, those patients who were not taking any antidepressant medications had a greater decrease in depressive symptoms than those who were taking antidepressant medications.43

Two large-scale multicenter studies were instrumental in establishing the efficacy of rTMS. The first utilized a double-blind randomized controlled study design and had a sample size of 301 patients diagnosed with MDD.44 Active rTMS treatment, which targeted the DLPFC, was administered 5 days a week for 6 weeks (30 total sessions), with an additional 3-week taper phase. Each treatment session lasted 37.5 minutes, with stimulation provided at a rate of 10 magnetic pulses per second, at 120% magnetic field intensity relative to the patient’s observed resting motor threshold (MT). The outcome measures for this study included the Montgomery-Åsberg Depression Rating Scale, HRSD17, and HRSD24. The results of this study indicated that active treatment was significantly more effective than sham rTMS in response rate (50% reduction in scale score) at both week 4 and week 6 of the treatment. At 6 weeks, the active TMS group was about twice as likely to have achieved remission compared with the sham TMS group (MADRS, 14.2% vs 5.2%; HRSD17: 15.5% vs 7.1%; HRSD24: 17.4% vs 8.2%). Based on the HRSD17, the remission rate for patients who completed 6 weeks of treatment with TMS alone (15.5%) further increased to 22.6% after 9 weeks, which included a 3-week taper phase.44

The second study randomized 190 moderately treatment-resistant, antidepressant-free patients to either active or sham treatment.45 The treatments were provided for a 3-week fixed period, 5 times a week for 40 minutes, at 120% magnetic field intensity relative to the patient’s observed resting MT, at 10 pulses per second for 4 seconds, with an interval for 26 seconds. After the 3-week period, the patients were divided into 3 groups based on response: remitters (HRSD24 score <3 once or score of 10 on 2 consecutive assessments), responders (>30% reduction in HRSD24 score from baseline), and nonresponders (<30% reduction in HRSD24 score from baseline). Those who remitted were tapered off rTMS and maintained on medication. Those who were responders continued to receive treatment for an additional 3 weeks, and nonresponders were transferred to 3 weeks of open-label treatment. Fourteen percent of the active group and 5% of the sham group remitted in the blinded phase, with a 30% remission rate in the unblended phase.43

The accumulating evidence over the past few years has consistently demonstrated the efficacy of rTMS in the treatment of MDD. In December 2008, rTMS was FDA approved as a treatment for MDD in adults who have failed to improve despite prior antidepressant medication above the minimally effective dose during the current episode.36

Safety of TMS for depression. rTMS has consistently demonstrated high tolerability and a minimal side effect profile. In studies for TMS, the treatment was well tolerated with low dropout (discontinuation) rates. In a study of 301 patients, the dropout rate “due to side effects” from active TMS was 4.5% at week 4.44 The most serious side effect associated with rTMS involves the potential risk of inducing a seizure. Although a seizure can occur during rTMS, it is considered a relatively rare event, with fewer than 13 documented cases of TMS-related seizure.46 Furthermore, many of these documented cases involved patients who had a neurologic disorder or were taking medication that lowered their seizure threshold. As a result, many of the patients who experienced a TMS-induced seizure were likely not appropriate candidates for TMS. An additional cause of TMS-induced seizure involves treating patients outside of recommended stimulation guidelines, for example, providing too short an interval (ie, time delay) between magnetic pulses or stimulating at too high an intensity. Given this information, it is important to consider a patient’s medical history in conjunction with following recommended treatment guidelines for rTMS.

The most common side effects associated with rTMS are headache (32%), pain at the site of stimulation (35%), and muscle twitching (20.6%).44,45 These side effects can be reduced by increasing the intensity and decreasing the frequency of rTMS delivery. Another concern in relation to rTMS involves the potential of hearing loss due to the high peak pressure of the coil during stimulation. However, this problem can be avoided with consistent and proper use of earplugs during rTMS sessions. There have also been documented cases in which TMS has induced hypomania or mania; however, this has been a rare occurrence.46

Magnetic seizure therapy

Magnetic seizure therapy (MST) is an investigational form of neurostimulation that has demonstrated promise as a potential alternative to ECT. MST, which is administered under similar conditions as ECT (eg, use of general anesthesia and muscle relaxants), uses rTMS to deliver a rapidly alternating magnetic field in order to induce a seizure.47 The possibility of using rTMS to induce a seizure was first documented in 1989.48 The rationale for investigating the therapeutic application of MST over ECT includes the advantage of greater localization during stimulation, which is essential to reduce the cognitive side effects associated with ECT. The increased localization achieved with MST is a result of the lack of impedance experienced as the magnetic stimulus passes through the skull.33,49

Efficacy of MST for depression. The first patient to be treated with MST was a 20-year-old woman who experienced a 3-year episode of major depression and had failed multiple medication trials. A total of 4 MST treatment sessions were administered, which resulted in a decrease in her depressive symptoms, reflected by a decrease in her HRSD24 score from 20 to 13. Based on this case study, which demonstrated proof of concept, additional MST trials have been conducted.

The first efficacy trials of MST compared 10 depressed patients who received MST with 10 matched patients who were treated with ECT.50 In this study, patients received a series of 10 to 12 treatments, administered over a period of 3 to 4 weeks. The results of this trial indicated a significant decrease from baseline depressive symptom severity scores for both MST and ECT; however, ECT patients were found to have a significantly higher decrease compared with patients treated with MST.

The need to improve the antidepressant efficacy of MST is an essential factor in its potential role as an alternative to ECT. Although increasing the output of stimulation relative to a patient’s seizure threshold may increase the efficacy of MST, until recently this has not been possible due to technological limitations.51 A recently published open-label, randomly assigned clinical trial of MST was able to increase the output of stimulation during treatment, which was equivalent to approximately 3 times the seizure threshold in ECT.52 This study treated a total of 20 depressed patients with an average score at baseline on the HRSD28 of 30.7 and 25.8 for the MST and ECT groups, respectively. The average posttreatment score on the HRSD24 was 18.3 for the MST group and 13.9 for the ECT group, scores that were significantly lower for both treatment groups. Although these results are insufficient to support FDA approval, they are sufficient to support the continued research and development of MST as a potential treatment for depression.

Safety of MST for depression. Although few randomized controlled trials comparing MST and ECT have been conducted, preliminary findings have supported the tolerability and safety of MST. One of the first clinical trials of MST in depression used a within-subject, blinded, randomized controlled study design to compare the acute neuropsychological effects of MST and ECT.53 In this study, 10 patients who were diagnosed with MDD and referred for ECT received 2 initial treatments of MST before being switched to standard ECT. During this study, no serious adverse events were noted, and MST was found to be well tolerated by all study patients. Subjective side effects were found to be much lower following MST compared with ECT. Patients were also found to have quicker reorientation with MST vs ECT, which was demonstrated by measures of retrograde amnesia and category fluency.

MST has been associated with a significantly shorter recovery time and reduced confusion following treatment.52,54,55 Achieving a faster reorientation time with MST is a significant finding, given that time to reorientation has been identified as a predictor of long-term cognitive side effects.24 Overall, MST is a well-tolerated form of neurostimulation that has the potential for providing a superior neuropsychological side effect profile compared with ECT. However, other risks that accompany the administration of general anesthesia and induction of a seizure are the same as ECT.49

Deep brain stimulation

Deep brain stimulation (DBS) is an investigational form of neurostimulation currently being evaluated as a potential treatment for depression. DBS was first approved by the FDA for essential tremor in 1997 and for Parkinson’s disease in 2002.56 It involves implanting electrodes unilaterally or bilaterally in specific areas of the brain, which are connected to a programmable pulse generator implanted in the chest wall.57 The pulse generator can be programmed to deliver electrical impulses at variable frequencies and intensities with the use of a small handheld programming device.

The antidepressant efficacy of DBS is based on the theory that chronic depression may be the result of hyperactivity in the subgenual cingulate region of the brain (Brodmann area 25).57 As such, DBS is intended to decrease the activity in this region of the brain to help alleviate a patient’s depressive symptoms. In addition, many patients treated with DBS for motor disorders have experienced changes in their mood during stimulation.58-60 Although promising results regarding the antidepressant properties of DBS have been reported, the invasive and investigational nature of DBS limits current trials to patients with severe TRD.58

Efficacy of DBS for depression. In one of the pilot studies that examined DBS for MDD, 6 patients received targeted DBS bilaterally at Brodmann area 25. Response was defined as a >50% decrease in HRSD17, and remission was an HRSD17 score of <8. Four of the 6 patients attained sustained remission, and a decrease in blood flow in Brodmann area 25 also was noted by PET scanning.57 An extended open-label trial of DBS, which included 20 patients diagnosed with MDD, also demonstrated the long-term efficacy of DBS. In this trial, response was defined as a >50% decrease in HRSD17 and remission as an HRSD17 score of <8. At the last follow-up, which was 3 to 6 years after implantation, the average response rate was 64.3%, and remission rates were 42.9% at the last follow-up visit. Another notable correlation in this study was that when patients had battery depletion of the DBS device, a clinical correlation of decline in mood was noted over the previous 4 to 6 weeks. Improvement of mood was noted 2 to 4 weeks after battery replacement.61

Safety of DBS for depression. The side effects of DBS were mainly related to the surgical implant procedure required for treatment. Three of the first 6 patients experienced hardware infections, which resulted in prolonged courses of antibiotics and surgeries to explant the electrodes. Only 1 of the 3 patients opted for a reinsertion of hardware.57 Surgeries also were required for battery replacement. Apart from the surgical complications, the other relevant adverse events during the course of this study were that 4 of 20 patients were admitted for worsening depression. At the end of the study, 2 patients committed suicide; these patients had been part of the group admitted for depression.61

  DISCUSSION

Various forms of neurostimulation have been developed that represent potential treatment alternatives for patients with TRD. The 2 newest forms of neurostimulation that have received FDA approved for the treatment of depression are VNS and TMS. The antidepressant properties of VNS have been well documented; however, the availability of this form of neurostimulation remains limited due to its financial cost and invasive nature. In comparison, TMS is considered a noninvasive form of neurostimulation that has demonstrated efficacy for milder forms of TRD. Despite demonstrated efficacy, additional research is needed to address certain limitations and/or determine the future direction of these forms of neurostimulation.

At this time, MST and DBS are forms of neurostimulation that are approved only for investigational use. The side effect profile of MST is significantly lower than that of ECT; however, the efficacy of MST still requires additional research. Further investigation of the treatment parameters or improvements in technology may help to enhance the antidepressant efficacy of MST. DBS is another promising form of neurostimulation currently being investigated as a potential treatment option for patients with well-established, documented TRD. The major limitation of DBS involves the implant procedure, which requires invasive surgery. Due to the invasive nature of DBS, this form of neurostimulation will likely be reserved for the most severe types of TRD. The future direction of DBS will involve evaluating the benefits of stimulating other areas of the brain associated with depression, such as the ventral capsule, subcallosal gyrus, and nucleus accumbens.

A limitation of this review involves the exclusion of transcranial direct current stimulation (tDCS), one of the newest forms of neurostimulation being investigated as a treatment for depression. This form of neurostimulation involves passing a mild, depolarizing current between 2 electrodes placed on the scalp, which passes through the skull and stimulates underlying brain tissue.62-64 Although tDCS is a relatively new form of neurostimulation for depression, preliminary trials have demonstrated promising results.62-64 In addition, tDCS is considered a noninvasive form of neurostimulation that is easy to administer. The role of tDCS in the treatment of depression will become more apparent as its antidepressant properties are established through future clinical trials.

  CONCLUSIONS

Treatment-resistant depression is a serious and significant public health concern that affects individuals with depression and society as a whole. Due to the significant number of patients who fail to respond to antidepressant medication, various forms of neurostimulation have been developed as potential treatment alternatives. Although VNS and TMS currently are available, and MST and DBS have demonstrated promise as future treatment options, certain limitations must be considered before pursuing these potential treatments. It is also essential to establish that a patient is treatment resistant before considering VNS or DBS, due to their invasive nature. Despite gains in the field of neurostimulation, ECT remains the primary treatment option for patients with TRD due to its high efficacy and established safety. However, the forms of neurostimulation described in this review represent promising treatment alternatives for patients with TRD.

DISCLOSURES: Dr. Trevino receives grant/research support from the National Institute of Mental Health (T32 Fellowship MH67543-08). Drs. Wani and Marnell report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Husain receives grant/research support from Alkermes, Brainsway, Cyberonics, MagStim, NARSAD, the National Institute on Aging, the National Institute on Drug Abuse, the National Institute of Health, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, NeoSync, the Stanley Foundation, and St. Jude Medical (ANS).

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CORRESPONDENCE: Mustafa M. Husain, MD University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, TX 75235-8898 USA E-MAIL: mustafa.husain@utsouthwestern.edu