Original article/article original
Safety 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

https://doi.org/10.1016/j.neucli.2006.08.006Get rights and content

Abstract

Depression is a common and debilitating illness, for which alternative treatments are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and relatively painless experimental technique of altering brain physiology. The authors critically review the evidence for the efficacy, safety and tolerability of rTMS in the treatment of depression based on published data over the last decade. They also discuss studies which have examined relevant clinical, demographic, methodological, and technical parameters that might be implicated in optimizing the antidepressant efficacy of this technique. rTMS depression trials conducted through early 2006 are included in this review, which focuses mainly on the results of published sham-controlled studies, literature reviews and meta-analyses. Trials published so far have been characterized by the use of a great variety of stimulation parameters, study designs, questionable sham controls, small sample sizes and heterogeneously depressed populations, all of which have made comparisons between studies difficult. Meta-analyses of 2-week rTMS sham-controlled studies support, for the most part, the antidepressant effects of rTMS which are statistically superior to sham. However, the degree of clinical improvement remains small, although greater efficacy has been shown with longer treatment courses and predictors of response to rTMS are progressively being identified. rTMS is a promising antidepressant treatment with overall minor adverse effects. Because the clinical efficacy of rTMS as an antidepressant remains questionable, further systematic, large-scale multicenter studies comparing rTMS to a sham and/or to an antidepressant medication along with more stringent stimulation parameters are warranted in order to identify patient populations most likely to benefit and treatment parameters most likely to optimize its antidepressant efficacy.

Résumé

La dépression est une affection fréquente aux lourdes conséquences, pour laquelle il est urgent de trouver des thérapeutiques alternatives. La stimulation magnétique transcrânienne répétitive (SMTr) est une technique expérimentale non-invasive et relativement indolore permettant de modifier la physiologie cérébrale. Les auteurs examinent de façon critique les données disponibles sur les dix dernières années au sujet de l'efficacité, la sécurité et la tolérance de la SMTr. Ils discutent aussi les études qui ont examiné les paramètres cliniques, démographiques, méthodologiques et techniques susceptibles de contribuer à l'optimisation de l'efficacité antidépressive de cette technique. Les essais thérapeutiques dans la dépression conduits jusqu'au début 2006 sont inclus dans cette revue qui se focalise principalement sur les études contrôlées (vs. stimulation simulée), les revues de la littérature et les méta-analyses. Elle démontre une grande diversité de paramètres de stimulation, de designs expérimentaux, de techniques discutables de stimulation simulée, de tailles d'échantillons et de populations de patients déprimés, rendant les comparaisons difficiles. La plupart des méta-analyses des études contrôlées vs. stimulation simulée sur deux semaines concluent à une supériorité statistiquement significative de l'effet antidépresseur de la SMTr comparée à la stimulation simulée. Cependant l'ampleur de l'amélioration clinique reste faible, bien qu'émerge progressivement l'observation d'une plus grande efficacité avec la prolongation de la durée du traitement et l'identification de prédicteurs de la réponse. La SMTr est un traitement antidépresseur prometteur avec des effets secondaires globalement mineurs. La question de l'efficacité clinique de la SMTr restant ouverte, il est nécessaire de réaliser de nouvelles études systématiques multicentriques et à large échelle, comparant stimulation active avec stimulation simulée ou avec traitement antidépresseur, en recourant à des paramètres de stimulations plus exigeants, ce afin d'identifier les populations de patients les plus susceptibles de bénéficier de ce traitement et les paramètres de traitements pertinents pour l'optimisation de l'efficacité antidépressive.

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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