Original article/article originalSafety and efficacy of repetitive transcranial magnetic stimulation in the treatment of depression: a critical appraisal of the last 10 yearsSécurité et efficacité de la stimulation magnétique transcrânienne répétitive dans le traitement de la dépression : une évaluation critique des dix dernières années
Introduction
Major depression is one of the most prevalent psychiatric disorders and it represents a major public health concern given its association with a considerably high level of morbidity and mortality leading to tremendous economic costs to society [86]. Despite the availability of a wide array of antidepressant medications, along with electroconvulsive therapy (ECT) and psychotherapy, a substantial number of depressed patients (50–60%) respond only partially or not at all to at least one trial of an antidepressant medication [127]. In addition, close to 20% of these patients are refractory to any antidepressant medication [47].
Alternative therapeutic options which are safe and effective are therefore urgently needed, particularly for patients with treatment-resistant depression. Among these, a promising new approach to treat depression is repetitive transcranial magnetic stimulation (rTMS).
rTMS, a powerful research tool, is a non-invasive and relatively painless experimental technique of selective stimulation of the cerebral cortex, which was initially introduced in a single-pulse form (TMS) by Barker in 1985 to investigate cortical functions and nerve conduction [4].
It involves the application to the scalp of an insulated metal coil through which passes a rapidly alternating electrical current which, in turn, generates a brief and pulsed magnetic field (1.5–2.0 Tesla) perpendicular to that current. The generated magnetic field unimpededly crosses the soft tissues and the skull and, in turn, induces electrical currents of sufficient intensity to result in localized depolarization of superficial cortical neurons [5], [25], [39], [45] with the generation of propagating action potentials, leading to local and remote effects on cortical and subcortical neuronal circuitry, metabolism, neurotransmitter release as well as induction of gene expression [41], [43], [52], [76], [130].
rTMS has relatively few side effects if safety guidelines are adequately followed [133]. It has been investigated as a less invasive alternative to ECT in the treatment of neuropsychiatric disorders, particularly depressive disorders, though the neurobiological underpinnings of its putative antidepressant effects are still poorly understood.
A number of neuropsychological and functional neuroimaging studies have suggested a differential role for the left and right hemispheres in the regulation of mood and behavior and have found asymmetric cortical excitability to be implicated in the pathophysiology of depression, with lower excitability and metabolic hypoactivity in the left prefrontal cortex compared to higher right frontal cortical excitability [6], [87], [124].
High (≥ 3–5 Hz) and low (≤ 1 Hz) frequency rTMS have been found to have opposite effects on cortical excitability [13], [27], [106], [120], [126], with low-frequency rTMS generally leading to decreased cortical excitability as well as reduced regional metabolism and blood flow [13], [132], and high-frequency rTMS increasing cortical excitability along with increased regional cerebral blood flow [15], [126], [131].
A recent study by Li et al. (2004) [75], which involved direct stimulation of the left prefrontal cortex with 1 Hz rTMS interleaved with functional magnetic resonance imaging (fMRI), demonstrated that rTMS, in addition to its enhancing effects on the prefrontal cortex also indirectly activates subcortical structures involved in the pathophysiology of depression via fronto-cingulate-subcortical neuronal circuits, such as the anterior cingulate gyrus, putamen, hippocampus, and thalamus [34], [69], [111], [123], [131].
Other studies, which have used positron emission tomography (PET) have also confirmed rTMS-induced dose-dependent changes in regional cortical blood flow and metabolism as well as in areas remote from the site of stimulation [33], [108], [109].
Wassermann et al. (1998) [134] found that transcranial magnetic stimulation applied to one primary motor cortex results in a reduced response to stimulation in the contralateral motor cortex, thus demonstrating a transcallosal propagating effect of TMS across well-defined neuronal circuits with possible alterations of neurotransmitter release at a distance.
For example, it has been demonstrated in several animal and human studies that prefrontal rTMS may induce the release of dopamine in mesostriatal and mesolimbic regions, at least acutely [110], [128], and may even increase and normalize serum brain-derived neurotrophic factor (BDNF) levels of patients suffering from depression [135].
In this article, our aim is to present a critical appraisal of the safety, tolerability and efficacy of rTMS as a treatment for depression, based on the results of a relatively large number of clinical trials published in the last 10 years, most of which have been included in a growing number of reviews and meta-analyses. We also discuss the clinical, demographic, and technical parameters which stand out as potential positive predictors of response to rTMS and which may have an important impact on optimizing the efficacy of this technique.
Section snippets
Efficacy studies
Following the modest antidepressant effects of an early open trial of low-frequency single-pulse TMS applied to the vertex [58], there has been, in the last decade, a progressively growing number of rTMS depression studies, both open and sham-controlled, which have explored the putative effectiveness of this technique as an antidepressant.
These studies have involved different methodological designs, various stimulation parameters (frequency, intensity, stimulation site, number of stimuli,
Sham-controlled studies
Sham-controlled rTMS depression studies published so far can be broadly categorized into studies with concomitant pharmacotherapy (including antidepressant medications) and studies without associated medications, except for the use of some anxiolytic agents. These studies are summarized in Table 1, Table 2, respectively. For the sake of clarity, studies comparing high- or low-frequency rTMS with a sham condition were grouped in the same table, irrespective of whether they involved
Comparison studies
Aside from studies which have compared active rTMS to a sham control with or without concomitant pharmacotherapy, several trials have directly compared active rTMS with ECT, rTMS at different stimulus frequencies and/or intensities, and rTMS as add-on therapy to recently introduced antidepressant drugs, mostly versus a sham control.
To date, only one study has directly compared active rTMS to an antidepressant medication in depressed patients suffering from Parkinson's disease [35].
Most of these
Studies of rTMS as add-on to antidepressants
Most rTMS depression studies have assessed the safety and efficacy of this approach as an adjunctive treatment for medication-resistant patients receiving concomitant antidepressant pharmacotherapy. Other add-on studies have included non-resistant depressed subjects in order to investigate the enhancing effects of combining rTMS to an antidepressant medication started simultaneously with the former, in comparison to a sham rTMS control with that same antidepressant [62], [112], [118], [119].
Meta-analyses
Given the contradictory results and small sample sizes in most of the trials that were conducted to date, meta-analyses were published to evaluate the clinical efficacy of rTMS in depression. These included different numbers of sham-controlled studies (between five and twenty-three), while adopting a variety of inclusion criteria defined for the analysis [1], [12], [18], [59], [74], [90], [91], [94].
According to five of the six published meta-analyses which are discussed separately in the
Clinical and demographic factors
So far, there have been limited data in the literature on which clinical and demographic factors might predict better therapeutic response to rTMS in depression.
Some studies suggested that patients with psychotic depression tend to have a low response rate to rTMS, while the absence of psychotic symptoms in depression might lead to better treatment outcomes [48], [49]. However, this suggestion cannot be confirmed because the majority of rTMS depression studies have excluded patients with
Safety and tolerability
The majority of studies which have used rTMS to treat depressed patients within a range of stimulation parameters defined according to Wassermann's [133] safety guidelines have not been associated with major adverse effects.
In a recent review of the literature on the safety of rTMS to non-motor areas (including the prefrontal cortex), Machii et al. (2006) [88] found that tension-type headaches were the most common adverse effect (20–25%) followed by neck pain, these generally occurring after
Conclusion
rTMS is a promising antidepressant treatment with overall minor adverse effects and there is now growing interest in the use of this technique for the treatment of neuropsychiatric disorders, particularly depression. Actually, some countries like Canada and Israel have formally approved its use as a therapeutic modality for the treatment of depression.
In our personal experience, this technique has been relatively welcomed by patients, in part because of its relatively painless and non-invasive
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2017, NeuroImageCitation Excerpt :It allows for focused, non-invasive stimulation of cortical brain areas using rapidly switched extracranial magnetic fields. Repetitive TMS (rTMS) is a variant applying trains of electromagnetic pulses to the brain for up to 20 min (Rossi et al., 2009), which results in depolarization of cortical neurons and subsequent behavioral changes (Barker et al., 1985; Rachid and Bertschy, 2006). Although the precise mechanisms of rTMS treatment effects are still unclear, rTMS is an FDA-approved treatment in treatment resistant major depressive disorder (MDD) (George et al., 2010; Janicak et al., 2010).
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2014, Clinical NeurophysiologyCitation Excerpt :Another question is to determine the additive and potentiating antidepressant effect of rTMS in patients receiving antidepressant drugs. Among all publications on rTMS in depression, most of them involved patients concomitantly receiving rTMS and pharmacological treatments, as highlighted in a previous review (Rachid and Bertschy, 2006). In fact, antidepressant medication is not interrupted in the majority of published studies assessing rTMS effects, and there is no controlled data regarding the administered drugs, including dosages and time of administration.
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2012, International Review of NeurobiologyEffects of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex on the attentional processing of emotional information in major depression: A pilot study
2011, Psychiatry ResearchCitation Excerpt :These results are discussed in more detail in the following. In line with several previous reports (Avery et al., 2006; Rachid and Bertschy, 2006; Bortolomasi et al., 2007; Herwig et al., 2007; O'Reardon, 2007), this study was able to demonstrate a mean reduction in scores on the HAMD scale of 43.8% after 2 weeks of rTMS treatment. For more than half of our depressive patient sample (64%) this implicated a reduction of more than 50% of their scores, with beneficial effects of rTMS treatment also reported on self-report measures of depressive symptoms (i.e., a mean change of 21.7% on the BDI).