CORRESPONDENCE
Efficacy and Safety of Transcranial Direct Current
Stimulation in Major Depression
To the Editor:
ver the last years, a novel neuromodulation technique—
O transcranial direct current stimulation (tDCS)— has been
investigated for noninvasive and painless modulation of
human brain activity through the scalp, in particular of the dorso-
lateral prefrontal cortex (DLPFC). Transcranial direct current stimu-
lation delivers weak direct currents (1–2 mA) through sponge elec-
trodes on the scalp (1), differently from transcranial magnetic
stimulation (TMS), which involves magnetic fields to induce electri-
cal stimulating currents into the cortex. Part of the delivered current
enters the skull, modulating the activity of cortical neurons and
leading to polarity-dependent changes in cortical excitability. Two
electrodes—an anode and a cathode—are generally placed on the
scalp, allowing current to flow throughout the brain between the
two sites and polarization to occur over a relatively wide cortical
area. Even though focality of stimulation is lower with tDCS than
TMS, potential advantages of tDCS include its portability, safety,
and reduced costs. In addition, both cathodal and anodal tDCS—
the two modalities of action of the technique— cannot be discrim-
inated by the patient from each other and versus sham stimulation,
which might be of interest for planning sham-controlled trials.
In terms of mechanisms of action, electrophysiological data sug-
gest that tDCS might strengthen synaptic connections through a
mechanism similar to long-term potentiation, modulate neu-
rotransmitter systems, and promote brain derived neurotrophic
factor– dependent synaptic plasticity (1,2). In addition, changes in
resting membrane potential, spontaneous neuronal firing rates,
cerebral blood flow, and metabolism have been reported (1–3).
Given that the modulatory effects of tDCS over the cortex can be
long-lasting, its action on cognitive and emotional functions has
started to be investigated in healthy subjects and neurologic (e.g.,
stroke rehabilitation) and psychiatric disorders (i.e., major depres-
sion [MD]) (4). Despite preliminary encouraging results in the field
of depressive disorders, it needs to be stressed that tDCS is currently
an investigational therapy and lacks formal approval for the treat-
ment of these conditions by the US Food and Drug Administration
and European Medicines Agency as well as guidelines defining
optimal parameters of stimulation in terms of safety and efficacy.
Major depression has been associated with alterations of corti-
cal activity and excitability (5–7), particularly in prefrontal areas.
Hence, it is reasonable to hypothesize that altering this pathologi-
cal state with techniques of brain stimulation or modulation might
offer a therapeutic target. Taken as a whole, relatively few studies
with tDCS have been published in the treatment of MD. Among
these, three studies have examined the effect of the technique in a
double-blind, sham-controlled design in depressed patients, and
the remainder have examined patients with treatment-resistant
depression (TRD) in open-label conditions. A pivotal 2-week, dou-
ble-blind, sham-controlled tDCS study (anodal modality over the
DLPFC, 2 mA for 20 min) in MD patients reported a mean symptom
improvement of 40% compared with 10% in the sham group (8). In
terms of safety, tDCS was well-tolerated with minor side-effects.
More recently, the same group conducted a 2-week, parallel-group,
double-blind randomized clinical trial with 40 drug-free patients
with MD with two active modalities of tDCS versus sham and found
the active stimulation over the DLPFC of largest benefit with an
overall good tolerability. Of note, antidepressant effects were main-
tained for 1 month after the end of treatment (9). A subsequent
case-report showed only modest improvement of depressive
0006-3223/$36.00
symptoms with 4 weeks of augmentative anodal tDCS over DLPFC
in a patient with TRD (10). Subsequently, however, an open-label
trial with tDCS over the DLPFC for 5 days found a significant im-
provement of depressive symptoms with favorable tolerability in
14 patients with TRD and high suicide risk (11). A recent double-
blind, sham-controlled trial conducted with 40 depressed subjects
reported a significant improvement of depression scores over 10
tDCS sessions (anodal stimulation centered over the left DLPFC,
with the cathode placed on the lateral aspect of the contralateral
orbit) with only minor side-effects, despite no between-group dif-
ference in the five-session, sham-controlled phase (12). A recent
study assessing differential efficacy of tDCS in unipolar (n ⫽ 14)
versus bipolar (n ⫽ 14) depressed subjects in a twice-daily, 5-day
open treatment (anodal electrode placed on the left prefrontal
cortex and cathodal on the right) found similar rates of improve-
ment in both groups with no adverse effect (13). Finally, in a recent
blind-rater trial, 23 patients with TRD were treated with augmenta-
tive tDCS for 5 days, two sessions/day. A significant reduction in
rating scales scores was observed at the study end point, support-
ing the efficacy and good tolerability of tDCS with clinical benefit
being progressive and extended to the first week of follow-up (14).
To date, few studies on the safety of tDCS have been published
(15,16), and information needs to be derived from the aforemen-
tioned clinical trials—which, taken as a whole, report a favorable
tolerability, also in light of the minimum level of invasiveness of the
technique. On one hand, it seems that the main reported problem
might be a transient skin reaction below the stimulating electrode,
which can rarely become a small burn. In addition, transient head-
ache, skin itching, and redness have been reported. On the other
hand, safety concerns for the operators have not been reported.
On the basis of these findings, there is no sufficient evidence to
support tDCS as a recommended therapeutic modality for depres-
sion. However, a growing body of evidence with double-blind,
sham-controlled trials, in particular, represent a first specific step in
this direction and encourage further studies in this area. As for TMS,
additional investigation is required to clarify optimal parameters of
stimulation (e.g., duration of treatment, electrode placement), clin-
ical target (i.e., MD or TRD), treatment modality (i.e., monotherapy
or augmentation), duration of benefit, and patient characteristics
that might condition response to tDCS. Nevertheless, the imple-
mentation of novel neuromodulatory techniques with minimal lev-
els of invasiveness and minor side effects in the field of psychiatric
treatments provides further confirmation of the pathophysiologi-
cal acquisitions in this area as well as the presence of a “third way” of
treatments besides psychotropic drugs and psychotherapy.
Bernardo Dell’Ossoa*
Alberto Priorib
A. Carlo Altamuraa
a
Department of Psychiatry, Fondazione IRCCS Cà Granda, Ospedale Maggiore
Policlinico; bCenter for Neurostimulation, Fondazione IRCCS Cà Granda, Ospedale
Maggiore Policlinico, University of Milan, Italy
*Corresponding author E-mail: bernardo.dellosso@unimi.it.
Dr. Alberto Priori is president and a shareholder of the company Newronika s.r.l., Mi-
lano, and reports his patent pending “Process for Reducing Neuromuscular Fatigue Caused
by Exercise,”—patent number: WO2008155114 (A1). All other authors report no biomedical
financial interests or potential conflicts of interest.
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