The expanding evidence base for rTMS treatment of depression

Mark S. George, Joseph J. Taylor, and E. Baron Shor


Transcranial magnetic stimulation (TMS) is perhaps the most popular of the new brain stimulation techniques because its clinical effects are produced without the need for a craniotomy [as with deep brain stimulation (DBS)] or seizure induction [as with electroconvulsive therapy (ECT)]. As a focal, noninvasive form of brain stimulation, TMS produces limited side effects and can be used as either a therapy or a research tool (e.g., to measure how excitable the brain is or to produce a temporary lesion) [1–3]. TMS uses an electromagnetic coil on the scalp to create an extremely potent (near 1.5 T) but brief (ms) magnetic field. This magnetic field enters the surface of the brain without interference from the skin, muscle, and bone. In the brain, the magnetic pulse encounters nerve cells and induces electrical current to flow. Thus, the magnetic field created from electrical energy in the coil passes through the skull and is converted back into electrical energy in the brain [4]. It is for this reason that TMS is sometimes called ‘electrodeless electrical stimulation’. Brief history The idea of using TMS, or something akin to it, to alter neural function goes back to at least the early 1900s. In 1902 Pollacsek and Beer, psychiatrists working down the street from Sigmund Freud in Vienna, filed a patent to treat depression and neuroses with an electromagnetic device that looks surprisingly like today’s TMS machines [5]. The modern TMS era began in 1985 when Barker et al. [6,7], working in Sheffield, England, created a focal electromagnetic device with sufficient power to induce currents in the spine. They quickly realized that their device could also directly and non-invasively stimulate the human brain, launching the modern TMS era.

Seizure Risk

Repetitive TMS or rTMS can create behaviors not seen with single pulses, including the potential risk of causing an unintended seizure. Worldwide, out of the 300 000 or more treatment or research sessions in the history of TMS, approximately 20 seizures have occurred [8]. In the United States, since market introduction of the NeuroStar TMS Therapy system in October 2008, seven seizures have been reported out of 250 000 NeuroStar TMS treatment sessions in over 8000 patients. In five of the seven seizures, patients had concurrent use of medications that may have altered seizure threshold. The estimated risk of seizure under ordinary clinical use is approximately one in 30 000 treatments (0.003% of treatments) or one in 1000 patients (0.1% of patients) (M. Demitrack, Neuronetics, personal communication). This risk is less than or comparable to the risk of seizure associated with antidepressant medications [9,10]. All TMS seizures have occurred during stimulation, rather than later, and have been self-limited with no sequelae. rTMS seizures are more likely to occur with certain combinations of TMS intensity, frequency, duration and interstimulus interval [11,12].


In 2008, the NeuroStar TMS Therapy system (Neuronetics, Inc., Malvern, PA, USA) received Food and Drug Administration (FDA) clearance for the treatment of adult patients with Major Depressive Disorder (MDD) who have failed to receive satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode. FDA clearance was based on a large, multisite, sham-controlled randomized study that showed that daily prefrontal TMS was a well-tolerated and effective treatment for certain patients with major depression. The observed effect sizes in both the original study population (N ¼ 301, [13]) and in the subset of patients who met the FDA approved indication for use of the NeuroStar TMS Therapy system (N ¼ 164, [14]) are of similar or greater magnitude than those observed with the majority of currently approved antidepressant medication treatments. George et al. in a 190 patient National Institute of Mental Health-sponsored multisite, randomized controlled trial [called optimised TMS (OPT-TMS)] demonstrated that rTMS, as drug-free monotherapy, produced statistically significant antidepressant effects with a remission rate four times that of sham patients [15]. This study provided industryindependent class I evidence of safety and efficacy in a well-studied and carefully controlled cohort. Recently, two additional publications resulted from this trial. McDonald et al. [16& ] reported on an openlabel extension phase. They found that 43 of 141 (30.5%) patients who enrolled in the open-phase study eventually met criteria for remission. Some patients took up to 6 weeks to fully remit [16& ]. Most recently Mantovani [17& ] reported on the 3-month durability of the TMS antidepressant response in this trial. Of the 50 patients who remitted and agreed to participate in follow-up, at 3 months, 29 of 50 (58%) were classified as in remission [Hamilton depression rating scale (HDRS)-24  10], two of 50 (4%) as partial responders (30%  HDRS24 reduction <50% from baseline), and one of 50 (2%) met criteria for relapse [17& ]. Several other recent studies describe the effectiveness of TMS in modern clinical practice. The first was a multisite observational study in 307 real-world patients receiving Neurostar TMS in clinical practice settings [18&&]. With an acute course of TMS treatments [average 28.3 (SD: 10.1) treatment sessions], symptom severity ratings decreased significantly. With categorical outcomes, 58% of the participants were responders of the primary outcome measure, and 37% had reached remission, with similar findings on the secondary measures. Given that over half of the participants met criteria for resistance to two or more antidepressant trials in the current episode, outcomes were stratified by level of treatment resistance (<2 vs. 2 treatment failures); response and KEY POINTS TMS is an exciting research tool and is FDA approved for treating depression. Repeated daily prefrontal TMS has acute antidepressant effects similar to medications or ECT, with few side effects. More research on the fundamental neurobiological effects of brain electrical stimulation will help these new techniques continue to improve and evolve. Mood and anxiety disorders 14 Volume 26 Number 1 January 2013 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. remission rates were similar between groups (e.g., 59.4 vs. 56.8% response for low vs. high levels of resistance; 39.9 vs. 34.9% remission rates). Connolly et al. [19& ] reported data from the first 100 patients treated at their university-based TMS clinical service following FDA approval. Their cohort was also treatment resistant, with a mean of 3.4 failed adequate antidepressant trials in the current episode. Thirty-one individuals had received prior lifetime ECT, and 60% had a history of psychiatric hospitalization. The clinical global impression-investigator response rate was 50.6% and the remission rate was 24.7% at 6 weeks. The HDRS response and remission rates were 41.2 and 35.3%, respectively. Forty-two patients (49%) entered 6 months of maintenance TMS treatment. Sixty-two percent (26/42 patients) maintained their responder status at the last assessment during the maintenance treatment. These data from care-seeking patients suggest that TMS, unlike many therapies in medicine, does not suffer from an efficacy/effectiveness gap between clinical trials and clinical treatments.

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