Depression is currently the leading cause of disability worldwide1 and one-third of patients with depression will not respond to medication treatment.2 With this rate of treatment-resistant depression (TRD) there is increasing use and research in the field of neurostimulation, which remains the refuge of choice for people with refractory symptoms.
The common element linking neurostimulation techniques is the direct excitation of neural cells via electric or magnetic currents, and either via direct contact with the nervous system or from outside the head. Historically, direct cellular simulation is quite prevalent in medicine, from pacemaker implantation to cochlear implants; however, the use of such techniques for mental illness has been hampered by several factors ranging from technologic limitations to societal stigma. This article reviews the practice of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS) in TRD. See Table 1 for an overview and direct comparison of the three modalities discussed.
Comparison of Neurostimulation Techniques for Use in Treatment-Resistant Depression
ECT has been a long-standing treatment option for TRD since its initial use in 1937 and remains the gold standard of neurostimulation treatments today.3 ECT involves the application of an electrical current to create a therapeutic seizure in a patient under the effect of anesthesia and muscle relaxant, with the supervision of a multidisciplinary team. Generally, treatments are given 2 to 3 times a week, taking on average between 6 and 12 treatments for full effect, although variations in protocols have been described through the years.3
In TRD, ECT is around 60% effective for reduction in symptoms and there is evidence to suggest that ECT may be even more effective, with up to 80% to 90% in symptom reduction, as a first-line treatment.4 Response rates are higher in patients with psychotic depression and in the elderly,5 as well as in patients with psychomotor retardation and a family history of depression.6 The longer the depressive episode continues, the less likely ECT is to be effective.7 ECT is not only indicated in TRD but also in several other psychiatric disorders, including bipolar disorder (mania, depressed, and mixed episodes), treatment-resistant schizophrenia, schizoaffective disorder, and catatonia.
Despite the great effect ECT has on TRD, side effects, unclear mechanism of action, and stigma have hindered its use. Although common side effects include headache, nausea, and muscle soreness, cognitive side effects have been the most concerning to people who consider ECT treatment, with short-term memory impairment being of greatest concern.3 The field continues to research ways to decrease cognitive impairment including alterations in pulse width and electrode placement. The use of ultra-brief pulse width and unilateral electrode placement has been shown to be as effective as the traditional-brief pulse width bitemporal electrode placement, with significant reduction in cognitive side effects;8–10 however, it does take more treatments to achieve the same effect.11 Spacing out treatments from 2 to 3 times a week may have a slightly slower effect, but can also decrease cognitive side effects.12 In severe cases in which a rapid response is needed, bitemporal ECT should be considered first, but in all other cases a trial of unilateral ECT is primarily used to minimize adverse events.
There are several theories on the mechanism of action of ECT: the monoamine transmitter theory (enhances dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid neurotransmission);13–15 the neuroendocrine theory (activation of the hypothalamic-pituitary-adrenal axis);16 the anticonvulsant theory (elevation of the seizure threshold stabilizing mood);17 and the neurotrophic theory (enhanced neurogenesis, neurotrophic signaling, and functional connectivity).18–20 This is an area that continues to be studied in an effort to focus on ECT's effectiveness and to decrease side effects.
If ECT has been helpful, efforts must be made to sustain effects as it is not curative. Maintenance ECT, treatment at less frequent intervals, is effective for relapse prevention of depression and with greater efficacy if combined with antidepressant medication treatment.21 Patients who have a change in antidepressants after ECT have a significantly lower readmission rate after 1 year than those kept on the same antidepressant.22 Also, cognitive-behavioral group therapy in combination with antidepressants has shown a significant difference in sustaining response after successful ECT than does medication alone.23
ECT is widely used in the US in both private and public settings. Inpatient use has decreased markedly due to a decline in the percentage of hospitals conducting ECT (from 14.8% to 10.6% between 1993 and 2009).24 Inpatients from poorer areas or who are publicly insured or uninsured are less likely to receive care from hospitals conducting ECT.24 Due to lesser use of ECT in hospitals where they are treated, depressed African-American inpatients continue to be far less likely than white people to receive the treatment.25
With costs of approximately $1,000 to $1,500 per treatment, ECT is covered by insurance companies, with some requiring prior authorization. When compared with TMS, ECT is the more cost-effective option for TRD given the estimated lower effectiveness of TMS and need for more treatments.26 In a 2011 meta-analysis, depression remission rates were reported as 38% for TMS versus 58.8% for ECT;27 however, the risk of adverse effects associated with TMS is lower.26
Although ECT remains a beneficial option for TRD, there are still several areas for improvement in the side-effect profile and true understanding of its mechanism of action. Decreasing stigma through patient, public, and professional education also remains an area for growth. Due to these factors and the need for ECT to be conducted in a specialized setting with anesthesia and muscle relaxation, its generalizability and widespread use for TRD is somewhat limited. Thus, attention has shifted to other brain stimulation methods as outlined below.
Transcranial Magnetic Stimulation
TMS was initially reported as a potential treatment for depression in 1996.28 Repetitive TMS (rTMS) is now US Food and Drug Administration (FDA)-approved for the treatment of major depressive disorder (MDD) after failure of a single antidepressant trial. It is a promising treatment for depression, although uncertainty remains regarding its promise of efficacy to all users.29 The advantages of TMS include the lack of need for anesthesia and a surgical implant.
rTMS belongs to the family of noninvasive brain stimulation treatments that focus on function of integrated neuronal networks. Indeed, most psychiatric disorders present with abnormal neural function, but grossly normal morphology; thus, treatments focus on optimizing functional connectivity between different areas of the brain. TMS directs high field strength-magnetic pulses to chosen brain locations, most commonly the dorsolateral prefrontal cortex (DLPFC) in an excitatory fashion. Repetitive administration ensures that the changes in cortical excitability outlast the treatment.30 Inhibitory low-frequency rTMS targeting the orbitofrontal cortex is promising for obsessive-compulsive disorder (OCD) and posttraumatic stress disorder,31,32 even auditory hallucinations, and a small body of evidence points to potential efficacy in depressive disorders.
TMS resulted from the evolution of transcranial electric stimulation, a technique available since the mid-1980s, which had the disadvantage of causing pain.33 Already established as a possible treatment option for conditions such as dystonia, Parkinson's disease, pain, and strokes in neurology, TMS was hailed as a treatment that would rival the effects of ECT for depressive disorders, but have less adverse effects. As animal data suggested,34 TMS can produce changes in cyclic adenosine monophosphate and cause decreased immobility in forced swimming tests. The main issue with TMS in clinical practice, however, is that its efficacy is not fully predictable.30 Clinical experience with rTMS confirms its ease of use; for instance, no changes in neuropsychologic function were detected in a study of 68 users who received approximately 24,000 (cumulative) pulses of TMS.35
Over the past few years, the aim has been to determine what parameters of TMS to use and how to optimize function and safety. TMS is delivered via magnetic coils placed tangentially to the scalp. Coils are available in different shapes such as circular, figure-of-8, and H-shaped. Electric current transforms to a magnetic field in the coil and can penetrate the skull and brain tissue unimpeded. The shape of the coil determines the pattern of the electric field produced. At frequencies higher than 5 Hz, the effect of TMS is excitatory. Multiple other factors affect the success of TMS treatment and have contributed to heterogeneity in results reported in the literature including duration of treatment courses (3–6 weeks), duration of sessions and number of pulses used, intensity of stimulation, unilateral versus bilateral administration, and concomitant use of medications.29 Protocols range from daily to 3 or 5 times per week. The most agreed upon protocols involve multiple sessions of high-frequency rTMS applied to the left DLPFC. Patients can receive TMS on an outpatient basis, with no need for anesthesia or sedation. The cost per treatment varies per provider, generally $300 to $500, with some insurance companies starting to provide reimbursement.
In general, younger patients, those with less resistance to standard depression treatments (including medications) and those with more acute depressive episodes, are more likely to benefit from TMS.36 However, these characteristics overlap with less resistance in depression, making patient selection challenging and casting doubt on whether rTMS could be beneficial for people with more advanced TRD. More research is needed in this area; the answer may rely on TMS being an adjunct, rather than a primary treatment, but even in that framework, the timing and synergy of selected treatment combinations is also not fully understood.
Adverse events related to rTMS may include headache, seizure activity,37 and induction of manic symptoms (although mania was not reported in systematic meta-analyses, only in case reports). As the adverse effects of rTMS are generally less than those of ECT, one case series examined whether rTMS can be used as maintenance treatment after ECT, with positive results.38 Although purely exploratory, this study represents an intriguing and promising way of combining neurostimulation techniques for optimal outcomes.
The mechanism of action by which rTMS decreases depressive symptoms is not fully understood. In the immediate aftermath of administration, rTMS synchronizes brain waves to the stimulation frequency. It is thus thought that rTMS may relieve depression by resetting intrinsic cerebral rhythm39 that could be disrupted in depression, although newer evidence points to a neuroprotective effect and a promotion of neuroplasticity via protection from oxidative injury and a beneficial effect on brain-derived neurotrophic factor.40,41
In depressive disorders, abnormalities in connections in the DLPFC, subgenual cingulate, insula, and thalamus are known to be related to the development of depressive symptoms.42,43 However, as the DLPFC is the only easily accessible area for rTMS, stimulating other areas for depression treatment has not been studied. Thus, efficacy of rTMS may depend on how well the DLPFC activates other areas.44 Cerebral blood flow ratio of the DLPFC to the ventromedial prefrontal cortex correlates with response to treatment.45 Additionally, pretreatment anterior cingulate activity correlates with good response to TMS.46
In summary, rTMS can be considered as fairly efficacious for the treatment of mild-to-moderate depression, but not always a reliable method of treating TRD because correlates of successful treatment are still under study. It can be viewed as an adjunct to pharmacologic treatment or a substitute to ECT if medical conditions are prohibitive. Advantages, including outpatient use, ease of administration, and relative low cost compared to psychiatric inpatient treatments, make it an attractive option for an expanding field of study.
Deep Brain Stimulation
Even though it is the most invasive of the treatments available for depression, DBS represents a major advance in the field of psychiatry. DBS is a neurosurgical brain stimulation technique that has been FDA-approved in Parkinson's disease, essential tremor, dystonia, and OCD and is experimentally used to treat MDD.47
As a surgical procedure, DBS involves subcortically implanting an electrode connected to a stimulator that targets a part of the brain involved with the illness being treated. The specific target area is found using stereotactic imaging techniques while the patient is awake under local anesthesia as to evaluate the effect of stimulation. Then under general anesthesia, the pulse generator is placed under the clavicle and connected to the electrode. The effect of continuous stimulation on depression is observed over time, often with subtle, gradual improvement over the course of treatment. Programming of the stimulator is required to fine-tune clinical improvement and affect/mood regulation with DBS is a flexible, dynamic process. A possible downside is the need for frequent visits over a longer period of time than compared with other illnesses to achieve sustained results.48,49
Stimulation brain targets studied for depression include the nucleus accumbens, the inferior thalamic peduncle, the subcallosal cingulate gyrus, the ventral capsule/ventral striatum, and the lateral habenula.49 Findings suggest that DBS may be 71% more effective than sham treatment and about 1 of 3 patients with TRD can benefit from the treatment.50 Response and remission rates with DBS have varied in the literature and also may be affected by electrode site placement.
Although the mechanism of action is unclear, there are several theories; electrophysiologic (both neuronal excitation and inhibition) and neurotransmitter modulation (increase in serotonin) likely explain the acute effects of DBS, and plasticity and neurogenesis possibly explain the chronic effects.47
The most studied site for DBS in TRD is at the subcallosal cingulate gyrus. A 2013 review51 reported outcome data from six centers totaling 67 patients with response and remission rates after 24 weeks to 6 months of 41% to 66% and 18% to 50%, respectively. With longer follow-up studies of 2 to 6 years, response and remission rates increased to 64% to 92% and 42% to 58%.51 Two more recent studies at this site showed the response and remission rate at 25% and 33% to 50% in a total of 10 patients.52,53
In another study with longitudinal follow up, DBS was applied to the nucleus accumbens and found response and remission rates of 50% and 30%, respectively, in 10 patients at 12 months54 and 45% and 9%, respectively, at 2 years in 11 patients.55 Although a more recent study found no responders or remitters after 4 months in four patients, there was a decrease in Hamilton Depression Rating Scale scores.56
Similar response rates have also been described at the ventral capsule/ventral striatum target. A study from 2010 of 17 patients reported response and remission rates of 53% and 35%, respectively, at 3 months, 47% and 29%, respectively, at 6 months, 53% and 41%, respectively, at 12 months, and 71% and 35%, respectively, at the last follow-up.57
Only single case reports have been published for the inferior thalamic peduncle and lateral habenula targets, both resulting in antidepressant effects.58,59
Side effects and serious adverse events have been reported with DBS including worsening depression, suicide attempts, and completed suicide60; events related to the surgical procedure (bleeding, infection, stroke, scarring, seizure, lead displacement, dysphagia, pain); and events related to parameter changes (psychotic symptoms, agitation, transient increase in anxiety, muscle cramps, vision/eye movement problems, headache, paresthesia, disequilibrium, erythema, increased sweating).48,55
Historically, psychosurgical procedures such as lobotomy evoke dark memories. To avoid this stigma in DBS, the consensus for neurosurgery for psychiatric disorders published consensus guidelines that recommend all procedures that are still in an investigational stage should be performed based upon a scientific protocol by a multidisciplinary team under ethical and regulatory oversight by the institutional review board.61
Advantages of DBS include reversibility, adjustability, titratability, and continual targeted stimulation without evidence of cognitive side effects as in ECT.51,62 However, DBS is an invasive procedure and is generally restricted to treatment refractory patients in a study environment due to lack of FDA approval and randomized control trials. It is also a costly treatment not covered by insurance, ranging from $200,000 to $250,000 just for the surgery and device itself, not to mention the cost of battery replacement and parameter setting sessions.63 There are certain future challenges that include establishing the optimal target site for electrode placement, forming stimulation parameters, and having higher caliber studies with larger sample sizes to further establish efficacy.
Obstacles to Use of Neurostimulation Techniques
Stigma about using brain stimulation techniques remains prominent in public opinion, and most of it, unsurprisingly, surrounds ECT as other neurostimulation techniques have not been as available or widely used for a sustained amount of time. In general, stigma surrounding mental illness stems from vague fears and misperceptions, but stigma surrounding ECT relates specifically to how treatments were conducted in their infancy—forcefully, without anesthesia or muscle relaxant and in what was perceived as an overall fairly inhumane manner. Public image of ECT remains influenced by these depictions, whether in the media or literature. Although the way ECT is practiced is now vastly different, perception has minimally changed.
A closer look at fears surrounding ECT, and neurostimulation in general, suggests that potential patients may fear severe adverse effects, permanent damage, irreversible memory loss, and being institutionalized. Patients who undergo ECT, in contrast, typically have a positive outlook and marked relief. It is noted that most information about ECT is from first-hand accounts and typically positive (for an excellent review on the topic of ECT depiction and stigma, see Dowman et al.64). But, fear is only one factor impeding neurostimulation use; lack of knowledge and negative attitudes of health professionals are also prominent reasons for lack of ECT use. Limited access to ECT as a treatment option often results in low referral rates and underuse. Surveys from various countries indicate wide cultural divergence regarding the usefulness of ECT65,66 as well as the limited teaching about ECT, even in psychiatry residency programs across the US and Canada.
Ironically, the idea that only the most severe of cases warrant ECT is perpetuated by both the public and medical professionals, and this constitutes a major hurdle to using neurostimulation early enough in the course of TRD treatment; as patient desperation, symptom severity, and physician frustration may primarily drive treatment choice, the opportunity for a judicious combination of integrative treatment may be missed. Better teaching and debunking myths about usefulness of neurostimulation techniques would be immensely useful in improving access/referrals to these options.
Conclusions and Future Directions
Neurostimulation for the treatment of TRD is an expanding field driven by the need for better efficacy, safety, and tolerability of treatments of depression. The neurostimluation techniques covered in this article include the three most studied modalities and can be added to available TRD treatments such as pharmacotherapy and psychotherapy for optimal outcomes. However, ECT, TMS, and DBS have shown variable success in the treatment of TRD, with ECT still the gold standard and most efficacious. This may be due to the heterogeneity of people with TRD, side-effect profiles, stigma, accessibility, cost, and lack of knowledge of both the brain mechanisms of action and targeted areas for TRD.
Several factors may contribute to challenges of implementation of neurostimulation techniques in TRD. TRD is often a chronic disease and the course of treatment needs to be dynamically adjusted to illness fluctuations. As neurostimulation techniques generally require several visits and extended protocols, and possibly consultations and external referrals, the addition of such treatments to the chronic picture of TRD may be subject to delays. When encountering treatment resistance in a patient with depression, it is highly recommended that clinicians consider neurostimulation early, and not as a last resort, as longer durations of depressive symptoms correlate with poorer treatment regardless of chosen modality.
The field of neurostimulation continues to grow including other modalities such as variations on TMS (deep and synchronized TMS), vagal nerve stimulation, magnetic seizure therapy, transcranial direct current stimulation, and noninvasive focal deep brain stimulation to further current treatment options. Additional research is needed to gauge each treatment's overall effectiveness in TRD in addition to those more established modalities.
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Comparison of Neurostimulation Techniques for Use in Treatment-Resistant Depression
||Approved (“gold standard”)
||Approved after failure of one antidepressant
||Not approved (investigational)
|Type of intervention
||Convulsion (under general anesthesia)
||MDD, bipolar disorder, schizoaffective disorder, schizophrenia, catatonia
||MDD, investigational in medical conditions (pain, dystonia, Parkinson's disease, stroke) and other psychiatric conditions (OCD, PTSD)
||Parkinson's disease, essential tremor, dystonia, OCD, investigational in MDD
|Efficacy in TRD
||Still unclear (additional studies needed)
||Still unclear (additional studies needed)
||Anesthetic effects, headache, nausea, muscle soreness, affects cognitive abilities
||Headache, potential seizures, mania induction
||Suicide, events related to surgical procedure, events related to stimulus parameter changes
||$1,000–$1,500 per treatment
||$300–$500 per treatment
||$200,000–$250,000 for surgery and device (additional cost for battery replacement and parameter setting)