Transcranial direct current stimulation for the treatment of major depressive disorder: A summary of preclinical, clinical and translational findings

Abstract

Major depressive disorder (MDD) is a common psychiatric illness, with 6–12% lifetime prevalence. It is also among the five most disabling diseases worldwide. Current pharmacological treatments, although relatively effective, present important side effects that lead to treatment discontinuation. Therefore, novel treatment options for MDD are needed. Here, we discuss the recent advancements of one new neuromodulatory technique – transcranial direct current stimulation (tDCS) – that has undergone intensive research over the past decade with promising results. tDCS is based on the application of weak, direct electric current over the scalp, leading to cortical hypo- or hyper-polarization according to the specified parameters. Recent studies have shown that tDCS is able to induce potent changes in cortical excitability as well as to elicit long-lasting changes in brain activity. Moreover, tDCS is a technique with a low rate of reported side effects, relatively easy to apply and less expensive than other neuromodulatory techniques — appealing characteristics for clinical use. In the past years, 4 of 6 phase II clinical trials and one recent meta-analysis have shown positive results in ameliorating depression symptoms. tDCS has some interesting, unique aspects such as noninvasiveness and low rate of adverse effects, being a putative substitutive/augmentative agent for antidepressant drugs, and low-cost and portability, making it suitable for use in clinical practice. Still, further phase II and phase III trials are needed as to better clarify tDCS role in the therapeutic arsenal of MDD.

Introduction

Major depressive disorder (MDD) is a severe, chronic and prevalent psychiatric illness, with community-based surveys showing a lifetime prevalence ranging from 6 to 12%, and an annual prevalence of 3–11% worldwide (Andrade et al., 2003, Kessler et al., 2005, Waraich et al., 2004). It is expected to be the second most disabling condition by 2020 (Murray and Lopez, 1997). In addition, nearly 80% of patients relapse after one antidepressant treatment (Anderson et al., 2008) and almost 33% of patients fail to achieve remission after two or more antidepressant trials — a condition named treatment-resistant depression (Berlim and Turecki, 2007). Moreover, antidepressant side effects such as weight gain; sexual dysfunction and somnolence can significantly decrease patient compliance of maintenance treatment in MDD (Brunoni et al., 2009, Zajecka, 2000). Therefore, the development of new therapeutic interventions for the treatment of this psychiatric illness is needed.

In fact, one field under intensive investigation is neuromodulation. From electroconvulsive therapy (ECT) to novel clinical and preclinical techniques, such as transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and transcranial direct current stimulation (tDCS), these techniques aim to develop novel non-pharmacological interventions for the treatment of neuropsychiatric disorders. Neuromodulation can be either invasive, for instance, Deep Brain Stimulation (DBS), a technique that implants electrodes in subcortical areas aiming the treatment of conditions such as Parkinson's disease and, more recently, MDD (George and Aston-Jones, 2010); or non-invasive, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) (Fig. 1).

RTMS uses a coil positioned over the scalp as to generate a potent, pulsatile electromagnetic field (up to 3 T), secondarily inducing an electric current flow inside the brain. Conversely, tDCS is based on the application of weak (0.5–2 mA), direct electric current into the brain through relatively large electrodes placed over the scalp (George and Aston-Jones, 2010). For MDD, rTMS has been more investigated than tDCS hitherto, with dozens of phase-II trials and at least two phase-III trials showing its efficacy — in fact, rTMS has been ultimately approved for the treatment of MDD by regulatory agencies and is being increasingly used worldwide (Brunoni et al., 2010). Nevertheless, this technique has some drawbacks, such as (1) cost: application of rTMS usually costs US$ 300.00 per session, which is expensive in most settings (Simpson et al., 2009); (2) clinical applicability: rTMS is a non-portable device that can be used only in hospital and/or ambulatory settings, obligating patients to perform daily visits to the clinic; (3) availability: rTMS is a relatively expensive device applied only by trained physicians. These issues greatly limit rTMS availability (Priori et al., 2009). One possible solution is developing handheld rTMS devices, which are in fact currently under investigation (George and Aston-Jones, 2010). Another solution would be a device that combines the non-pharmacological advantages of rTMS with low-cost, easiness of use and portability; in fact, these characteristics are present in tDCS devices. Currently, tDCS research on MDD has experimented significant advancement, with some clinical trial showing promising results (Boggio et al., 2008a, Brunoni et al., 2011b, Ferrucci et al., 2009b, Fregni et al., 2006a). The aim of this review is, therefore, to summarize the main aspects and challenges of tDCS as a novel treatment for major depression.