Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review articleTranscranial direct current stimulation for the treatment of major depressive disorder: A summary of preclinical, clinical and translational findings
Highlights
► tDCS is a novel brain stimulation tool increasingly used in neuropsychiatry. ► tDCS is based on polarity-effects of DCs in changing cortical excitability. ► Advantages of tDCS are: portability, easiness of use and low rate of side effects. ► tDCS clinical trials in depression have shown promising results. ► We update the main findings and challenges of tDCS as a treatment for depression.
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.
Section snippets
Historical remarks
Reports of brain stimulation through electric currents have existed since the Ancient time; with observations by Greek and Roman physicians that the electric “torpedo fish” delivered electric discharges that could relieve headache (Largus, 1529). After the introduction of the electric battery in the 18th century, some physicians started to use these galvanic batteries to perform electric brain stimulation in selected subjects (Zago et al., 2008), although these interventions were uncontrolled
Technical aspects and mechanisms of action
tDCS devices are essentially composed by four main components: electrodes (usually one anode and one cathode), power supply (usually 9 V batteries), an amperemeter (for measurement of the intensity of the electric current) and a potentiometer (to allow adjustment of the electric current). One electrode is necessarily placed over the scalp, above the cortical area aimed to be stimulated. The other electrode can be also positioned over the scalp, or, alternatively, on an extra-cephalic position
Putative mechanisms of action
Among several biological hypotheses for explaining MDD, one specially appealing to the field of neuromodulation is the neural system hypothesis, which understands depression as a condition related to dysfunction in several cortical and subcortical areas, specially (as shown by neuroimaging and EEG studies) the dorsolateral and ventromedial areas of the prefrontal cortex (PFC), the amygdala and the hippocampus (Campbell et al., 2004, Hamilton et al., 2008), which are associated with symptoms
Clinical studies
From 2006 onwards, at least 19 clinical studies with different methodologies (such as case reports; open-label trials; randomized, controlled trials; and meta-analysis) have been published exploring tDCS effects on depression (Table 1). We further discuss their main findings and limitations.
Future directions
Although the abovementioned results are promising, there are important issues related to tDCS clinical research. We discuss three of them.
Conclusion
tDCS has a wide range of potential applications, including treatment of major depressive disorder, as preclinical and clinical studies showed that it elicits potent neuromodulatory effects. tDCS has some interesting, unique aspects such as noninvasiveness and low rate of side effects, being a putative substitutive/augmentative agent for antidepressant drugs, and low-cost and portability, making it suitable for use in clinical practice.
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