Journal of Psychiatric Research 47 (2013) 1e7

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Journal of Psychiatric Research

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Review

Clinical utility of transcranial direct current stimulation (tDCS) for treating major
depression: A systematic review and meta-analysis of randomized, double-blind
and sham-controlled trials
Marcelo T. Berlim a, b, c, *, Frederique Van den Eynde a, b, Z. Jeff Daskalakis d, e
a
Neuromodulation Research Clinic, Douglas Mental Health University Institute, Montréal, Québec, Canada
b
McGill University, Montréal, Québec, Canada
c
Depressive Disorders Program, Douglas Mental Health University Institute, Montréal, Québec, Canada
d
Brain Stimulation Treatment and Research Program, Centre for Addiction and Mental Health, Ontario, Canada
e
University of Toronto, Ontario, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Objective: tDCS is a promising novel therapeutic intervention for major depression (MD). However,
Received 4 August 2012 clinical trials to date have reported conflicting results concerning its efficacy, which likely resulted from
Received in revised form low statistical power. Thus, we carried out a systematic review and meta-analysis on randomized,
26 September 2012
double-blind and controlled trials of tDCS in MD with a focus on clinically relevant outcomes, namely
Accepted 27 September 2012
response and remission rates.
Method: We searched the literature for English language randomized, double-blind and sham-controlled
Keywords:
trials (RCTs) on tDCS for treating MD from 1998 through July 2012 using MEDLINE, EMBASE, PsycINFO,
Transcranial direct current stimulation
tDCS
Cochrane Central Register of Controlled Trials and SCOPUS. We also consulted the Web of Science’s
Major depression Citations Index Expanded for the selected RCTs up to July 2012. The main outcome measures were
Response response and remission rates. We used a random-effects model and Odds Ratios (OR).
Remission Results: Data were obtained from 6 RCTs that included a total of 200 subjects with MD. After an average of
Meta-analysis 10.8
3.76 tDCS sessions, no significant difference was found between active and sham tDCS in terms of
Systematic review both response (23.3% [24/103] vs. 12.4% [12/97], respectively; OR ¼ 1.97; 95% CI ¼ 0.85e4.57; p ¼ 0.11)
and remission (12.2% [12/98] vs. 5.4% [5/92], respectively; OR ¼ 2.13; 95% CI ¼ 0.64e7.06; p ¼ 0.22). Also,
no differences between mean baseline depression scores and dropout rates in the active and sham tDCS
groups were found. Furthermore, sensitivity analyses excluding RCTs that involved less than 10 treat-
ment sessions or stimulus intensity of less than 2 mA did not alter the findings. However, tDCS used as
monotherapy was associated with higher response rates when compared to sham tDCS (p ¼ 0.043).
Finally, the risk of publication bias in this meta-analysis was found to be low.
Conclusions: The clinical utility of tDCS as a treatment for MD remains unclear when clinically relevant
outcomes such as response and remission rates are considered. Future studies should include larger and
more representative samples, investigate how tDCS compares to other therapeutic neuromodulation
techniques, as well as identify optimal stimulation parameters.
Ó 2012 Elsevier Ltd. All rights reserved.

Transcranial direct current stimulation (tDCS) is a non-invasive
and safe neuromodulation technique in which a weak electrical
current is applied to the cerebral cortex via two scalp electrodes
(Brunoni et al., 2011a; Fregni and Pascual-Leone, 2007; Miranda
et al., 2006), resulting in lasting changes in neuronal excitability
in underlying cortical regions (Arul-Anandam and Loo, 2009;
* Corresponding author. Douglas Mental Health University Institute, 6875 LaSalle
Blvd., FBC-3 Pavilion, Montréal, Québec, Canada H4H 1R3.
E-mail addresses: nrc.douglas@me.com, marcelo.berlim@mcgill.ca (M.T. Berlim).
Brunoni et al., 2012, 2011b) depending on the polarity of the
stimulation. More specifically, anodal tDCS typically leads to an
excitatory effect through neuronal depolarization, while the
converse applies to cathodal tDCS (i.e., reduced neuronal firing
secondary to hyperpolarization) (Stagg and Nitsche, 2011; Zaghi
et al., 2010). Compared to other more established neuro-
modulation techniques such as repetitive transcranial magnetic
stimulation (rTMS) (George and Aston-Jones, 2010; Rosa and
Lisanby, 2012), tDCS offers several practical advantages including
its high portability, low cost, ease of administration, favorable side

0022-3956/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jpsychires.2012.09.025
2 M.T. Berlim et al. / Journal of Psychiatric Research 47 (2013) 1e7
effects profile, and associated reliable sham condition (Been et al.,
2007; Fregni and Pascual-Leone, 2007; Murphy et al., 2009).
Encouraging evidence from both open-label and randomized,
double-blind controlled trials (RCTs) have suggested that tDCS has
antidepressant effects (Boggio et al., 2008; Dell’osso et al., 2011;
Ferrucci and Bortolomasi, 2009; Loo et al., 2012). Furthermore,
preliminary data have demonstrated its potential to enhance some
aspects of cognitive functioning in both depressed subjects (e.g.,
inhibitory control (Boggio et al., 2007)), working memory (Fregni
et al., 2006b) and healthy volunteers (e.g., planning ability
(Dockery et al., 2009), declarative memory (Javadi and Walsh,
2011)). The most common tDCS protocol for major depression
(MD) involves anodal stimulation of the left dorsolateral prefrontal
cortex (DLPFC), and cathodal inhibition of the contralateral DLPFC
or the supra-orbital region (Brunoni et al., 2012). Furthermore,
stimulation parameters typically involve direct currents of 1e2 mA
administered for up to 20 min per session (Nitsche et al., 2008).
Although tDCS has been recently proposed as a promising novel
treatment for MD (Fregni et al., 2005), its clinical utility remains
unclear as RCTs published to date have produced conflicting results.
For example, Loo et al. (2010) and Palm et al. (2012) have shown
active tDCS to be no superior to sham tDCS for MD, whereas Fregni
et al. (2006a) and Boggio et al. (2008) have reported that active
tDCS produced significantly higher rates of clinical improvement in
depressed subjects when compared to sham tDCS.
A plausible explanation for these discrepant findings is the lack
of statistical power in some RCTs (Maxwell et al., 2008). Therefore,
the use of meta-analytical approaches could be helpful in exam-
ining this issue by allowing the integration of findings from
multiple studies and the more accurate estimation of the treatment
effects of tDCS (Huf et al., 2011).
Recently, Kalu et al. (2012) have conducted the first meta-
analysis on tDCS for MD and have shown that this neuro-
modulation technique is significantly more effective than sham
tDCS in reducing depressive symptoms according to scores on
standard depression scales (i.e., Hedges’ g ¼ 0.74; 95% CI ¼ 0.21e
1.27; p ¼ 0.006). However, the clinical magnitude of these re-
ported changes in depressive symptomatology is difficult to inter-
pret, especially in light of current recommendations on the
assessment of treatment efficacy in MD that advocate the use of
more clinically relevant outcomes such as response and remission
rates (Rush et al., 2006). Furthermore, the study by Kalu et al.
(2012) lacked relevant information regarding some of its key
methodological aspects (e.g., search syntaxes and outputs, reasons
for excluding studies), and this, in turn, might limit its replicability.
Therefore, to summarize the best available evidence on the use
of tDCS for treating MD (taking into consideration the potential
limitations of the previous meta-analysis), we carried out
a systematic review and meta-analysis of randomized, double-
blind and sham-controlled trials with a focus on response and
remission rates. Furthermore, we assessed the integrity of blinding
in the included RCTs on tDCS, as well as its overall acceptability
compared to sham tDCS.
1. Methodology of the literature review
1.1. Search strategy
We identified articles for inclusion in this meta-analysis by:
- Screening the bibliographies of the meta-analysis by Kalu et al.
(2012) as well as of all included RCTs;
- Searching MEDLINE, EMBASE, PsycINFO, the Cochrane Central
Register of Controlled Trials (CENTRAL) and SCOPUS from July
1, 1998 (when Priori et al. (1998) published their seminal paper
on tDCS using contemporary stimulation parameters) until
August 20, 2012;
- Consulting the Web of Science’s Citations Index Expanded for
all included RCTs in order to identify published articles that
have prospectively cited them up to August 20, 2012.
The search procedures (including syntaxes, parameters, and
results) are described in detail in the Supplemental Data.
1.2. Study selection
Candidate studies (judged on the basis of their title and abstract)
had to satisfy the following criteria (Higgins and Green, 2008):
- Study validity: Random allocation; double-blind (i.e., patients
and clinical raters blinded to treatment conditions); sham-
controlled; parallel or crossover design (with only data from
the initial randomization being used for the latter to avoid
carryover effects); 5 subjects with MD randomized per study
arm;
- Sample characteristics: Subjects aged 18e75 years with a diag-
nosis of primary major depressive episode (unipolar or bipolar)
according to the Diagnostic and Statistical Manual of Mental
Disorders or the International Classification of Diseases
criteria;
- Treatment characteristics: Anodal tDCS at 1 mA given for 5
sessions over the left DLPFC, either as a monotherapy or as an
augmentation strategy for MD;
- Publication-related: Articles written in English.
Studies were excluded if they:
- Enrolled subjects with “narrow” diagnoses (e.g., postpartum
depression) or secondary MD (e.g., vascular depression);
- Started tDCS at the same time as a new antidepressant
medication;
- Did not report rates of response to treatment and/or remission.
1.3. Data extraction
Data were recorded in a structured fashion as follows:
- Sample characteristics e Mean age, gender, treatment strategy
used (i.e., augmentation or monotherapy), presence of
treatment-resistant MD;
- tDCS-related e Stimulation intensity (mA, duration of session,
electrode size), number of treatment sessions, sham strategy;
- Primary outcome measure e Number of responders to treat-
ment based on the RCTs’ primary efficacy measure (defined as
a 50% reduction in post-treatment scores on the Hamilton
Depression Rating Scale [HAM-D] (Hamilton, 1960) or on the
MontgomeryeAsberg Depression Rating Scale [MADRS]
(Montgomery and Asberg, 1979) at study end;
- Secondary outcome measure e Number of remitters based on
the RCTs’ primary efficacy measure (e.g., 17-item or 21-item
HAM-D scores 7 or 8, respectively, or MADRS scores 6)
at study end;
- Integrity of blinding e Was determined by comparing the
number of subjects in the active and sham tDCS groups who
were able to correctly guess their treatment allocation at
stimulation period end;
- Acceptability of treatment e Overall dropout rates for active and
sham tDCS groups at study end.
 M.T. Berlim et al. / Journal of Psychiatric Research 47 (2013) 1e7 3

1.4. Data synthesis and analyses 2.2. Included RCTs: main characteristics

Analyses were performed using Comprehensive Meta-Analyses
Version 2.0 (Biostat, Englewood, NJ, USA), and IBM SPSS Version
20 (IBM Corporation, Chicago, IL, USA).
We used a random-effects model because it was assumed that
the true treatment effects had likely varied between the included
RCTs (Riley et al., 2011). If provided, intention-to-treat data, using
a method such as “last observation carried forward”, were
preferred over data from completers (Fergusson et al., 2002). The
efficacy of tDCS for MD as well as its acceptability and the integrity
of blinding were investigated with Odds Ratios (OR) (Borenstein
et al., 2009). Also, to rule out the presence of baseline differ-
ences in depressive symptoms between active and sham tDCS
groups, we computed the pooled standardized mean difference
(SMD) of subjects’ baseline scores on the HAM-D or the MADRS.
We also conducted sensitivity analyses to determine the potential
impact of treatment strategy (i.e., tDCS as a monotherapy vs.
augmentation), total number of sessions (5 vs. 10), and electrical
current (1 vs. 2 mA) on effect size estimates for response and
remission rates.
Heterogeneity was assessed using the Q statistics and I2
(Cooper et al., 2009). Values of p < 0.10 for the former and >35%
for the latter were deemed as indicative of study heterogeneity
(Borenstein et al., 2009). Finally, we used Funnel Plots, Egger’s
Regression Intercept (Egger et al., 1997) and Duval and Tweedie’s
(2000) Trim & Fill procedure to test for the presence of publica-
tion bias (Borenstein et al., 2009; Cooper et al., 2009).
2. Results
Overall, 6 RCTs were included in our meta-analysis, totaling 200
subjects with MD, of whom 103 were randomized to active tDCS
(mean age ¼ 49.9
4.07 years; 49% females), and 97 were
randomized to sham tDCS (mean age ¼ 49.7
4.9 years; 60.9%
females). The mean number of tDCS sessions delivered was
10.8
3.76. Also, enrolled subjects had some degree of treatment-
resistant depressive illness as indexed by the mean number of failed
antidepressants in the current episode (2.36
1.19). The main
characteristics of the included RCTs are described on Tables 1 and 2.
2.3. Response rates
Data relating to response rates were available from all 6 RCTs.
Overall, 24 (out of 103; 23.2%) and 12 (out of 97; 12.4%) subjects
receiving active tDCS or sham tDCS were classified as responders to
treatment, respectively. The pooled OR was 1.97 (95% CI ¼ 0.85e
4.56; z ¼ 1.59; p ¼ 0.11), indicating no significant difference in
outcome for active tDCS (Fig. 1).
Heterogeneity between RCTs did not exceed that expected by
chance (df ¼ 5; Q5 ¼ 5.4, p ¼ 0.37; I2 ¼ 7.5), implying that the
variance among the effect sizes was no greater than expected by
sampling error. Additionally, the associated Funnel Plot was
reasonably symmetrical (please refer to the Supplemental Data).
Publication bias was assessed more conservatively Egger’s regres-
sion intercept, which was 0.92 (df ¼ 4; t ¼ 0.66; two-tailed
p ¼ 0.55), suggesting a low risk of publication bias. Furthermore,
in the Duval and Tweedie’s Trim & Fill procedure, none of the RCTs
was trimmed and filled on the opposite side of zero.

2.1. Literature search 2.4. Remission rates

Of the 6 RCTs included in the previous meta-analysis on tDCS
for MD, 5 were selected for the present investigation (Boggio
et al., 2008; Fregni et al., 2006a; Loo et al., 2012, 2010; Palm
et al., 2012). Also, we retrieved 37 references (after discarding
duplicates) from MEDLINE, PsycINFO, EMBASE, CENTRAL and
SCOPUS and 71 references (after discarding duplicates) from the
Web of Science’s Citations Index Expanded. Of these, 1 met our
eligibility criteria (Blumberger et al., 2012). Please refer to the
Supplemental Data for a detailed description of the study selec-
tion procedure.
Data relating to remission rates were available from 5 RCTs.
Overall, there was no significant difference between active and
sham tDCS in terms of remitters at study end (12.2% [12/98] vs. 5.4%
[5/92], respectively). The pooled OR was 2.13 (95% CI ¼ 0.64e7.06;
z ¼ 1.24; p ¼ 0.22) (Fig. 2).
Heterogeneity between RCTs did not exceed that expected by
chance (df ¼ 4; Q4 ¼ 1.96, p ¼ 0.74; I2 ¼ 0). The associated Funnel
Plot was reasonably symmetrical (please refer to the Supplemental
Data), and Egger’s regression intercept was 0.24 (df ¼ 3; t ¼ 0.27;
two-tailed p ¼ 0.8), also suggesting a low risk of publication bias.

Table 1
Included randomized, double-blind and sham-controlled trials on tDCS for major depression: main characteristics.

Study Active tDCS Sham tDCS Primary diagnosis Treatment strategy TRDa

n Age
SD (yrs) Female/male (n) n Age
SD (yrs) Female/male (n)

Fregni et al., 2006a, 2006b 5 N/A N/A 5 N/A N/A All with MDDb Monotherapy N/A
Boggio et al., 2008 21 51.6
7.7 14/7 19 46.4
6.45 13/6 All with MDDb Monotherapy 1.65
1.2
Loo et al., 2010 20 48.95 11/9 20 45.6
12.45 11/9 All with MDDb Mixedc 1.3
1.6
Blumberger et al., 2012 13 45.3
11.6 3/10 11 49.7
9.4 10/1 All with MDDb Augmentation 4.2
2.3
Loo et al., 2012 33 47.8
12.5 14/17 31 48.6
12.6 14/15 86.5% with MDDb Mixede 1.75
1.9
and 13.5% with BDd
Palm et al., 2012 11 56
12 6/5 11 58
12 8/3 90.1% with MDDb Augmentation 2.9
1.6
and 9.9% with BDd
a
Level of treatment-resistant depression as indexed by the number of failed antidepressants in the current major depressive episode.
b
Major depressive disorder.
c
Augmentation strategy in 35% and 65% of the subjects receiving active and sham tDCS, respectively; monotherapy in 65% and 35% of the subjects receiving active and sham
tDCS, respectively.
d
Bipolar depression.
e
Augmentation strategy in 71% and 72.5% of the subjects receiving active and sham tDCS, respectively; monotherapy in 29% and 27.5% of the subjects receiving active and
sham tDCS, respectively.
4 M.T. Berlim et al. / Journal of Psychiatric Research 47 (2013) 1e7

Table 2
tDCS treatment parameters.

Study Anode placement Cathode placement Electrode Current Session Number of

size (cm2) (mA) duration (min) sessions
Fregni et al., 2006a, 2006b Left DLPFCa Right supra-orbital area 35 1 20 5
Boggio et al., 2008 Left DLPFCa Right supra-orbital area 35 2 20 10
& occipital region
Loo et al., 2010 Left DLPFCa Right supra-orbital area 35 1 20 10c
Blumberger et al., 2012 Left DLPFCa Right DLPFCb 35 2 20 15
Loo et al., 2012 Left DLPFCa Right supra-orbital area 35 2 20 15
Palm et al., 2012 Left DLPFCa Right supra-orbital area 35 1e2d 20 10
a
Left dorsolateral prefrontal cortex (F3) as determined by the 10e20 EEG Electrode Placement System.
b
Right dorsolateral prefrontal cortex (F4) as determined by the 10e20 EEG Electrode Placement System.
c
5 sessions under double-blind treatment (active vs. sham tDCS) and 5 additional sessions with single-blind active tDCS.
d
The first 10 patients received 1 mA and the following 12 received 2 mA.

Moreover, no RCT was trimmed in the Duval and Tweedie’s Trim & (5 vs. 10) or the electrical current used (1 vs. 2 mA) were not
Fill procedure, thus reinforcing the low risk of publication bias. associated with differential efficacy results (i.e., their difference was
not statistically significant). For the associated Forrest Plots please
2.5. Active tDCS vs. sham tDCS: baseline depression severity refer to the Supplemental Data.

No differences on mean baseline depression scores for active vs. 3. Discussion

sham tDCS groups were found (SMD ¼ 0.06; z ¼ 0.43, p ¼ 0.66),
thus ruling out illness severity at baseline as a confounding factor.
For the associated Forrest Plot please refer to the Supplemental
Data.
2.6. Acceptability of tDCS treatment
Overall, no difference was observed between active and sham
tDCS groups in terms of dropout rates at study end (4.8% [5/103] vs.
5.1% [5/97], respectively; OR ¼ 0.89; 95% CI ¼ 0.26e3.08; z ¼ 0.18,
p ¼ 0.86) (Fig. 3).
2.7. Integrity of blinding
Four RCTs reported data on integrity of blinding (Blumberger
et al., 2012; Loo et al., 2012, 2010; Palm et al., 2012). Overall, no
difference was observed between active and sham tDCS groups
(with 44.1% [30/68] vs. 53.7% [36/67] of patients correctly guessing,
at study end, their treatment allocation, respectively; OR ¼ 0.67;
95% CI ¼ 0.26e1.7; z ¼ 0.82, p ¼ 0.41). For the associated Forrest
Plot please refer to the Supplemental Data.
2.8. Sensitivity analyses
The use of active tDCS as a monotherapy for MD was signifi-
cantly more effective than sham tDCS in terms of response (but not
remission) rates (OR ¼ 7.54, 95% CI ¼ 1.63e34.8, z ¼ 2.59, p ¼ 0.01;
Q ¼ 4.1, df ¼ 1, p ¼ 0.043). Finally, the number of sessions delivered
This is the first meta-analysis assessing the efficacy of tDCS for
MD using clinically meaningful outcomes such as response and
remission rates. Our results show that this neuromodulation
technique is not more effective than sham tDCS. Indeed, following
a mean of 10.8
3.76 sessions, only 23.2% and 12.2% of depressed
subjects receiving active tDCS were responders and remitters
(versus 12.4% and 5.4% with sham tDCS), respectively. Furthermore,
we did not find significant differences on dropout rates, blinding
integrity as well as on baseline depressive symptomatology
between active and sham tDCS groups. Therefore, the clinical utility
of tDCS as a treatment for MD remains unclear.
Our main results clearly contrast with those previously reported
in the initial sham-controlled trials (Boggio et al., 2008; Fregni et al.,
2006a), and in the meta-analysis by Kalu et al. (2012). Regarding
the latter, the discrepancy likely results from the selection of
alternative treatment outcomes (i.e., percentage change from
baseline to endpoint in depression scales vs. response/remission
rates). Nevertheless, it is important to stress that, despite the
encouraging initial results from RCTs, the statistical power to test
the summary effects in this meta-analysis was substantially higher
than that of any of the primary studies (Borenstein et al., 2009).
Interestingly, we have also shown, based on sensitivity analyses,
that higher stimulus intensity (1 mA vs. 2 mA) and the delivery of
more tDCS sessions (5 vs. 10) were not associated with an
optimization of the antidepressant effects of tDCS. Although
certainly preliminary, these analyses point to the fact that no
individually described tDCS protocol could be seen as paradigmatic,

Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper Active Sham Relative
ratio limit limit Z-Value p-Value tDCS tDCS weight
Fregni et al, 2006 33.000 1.064 1023.555 1.995 0.046 4/5 0/5 5.79
Boggio et al, 2008 5.231 0.947 28.906 1.897 0.058 8 / 21 2 / 19 21.60
Loo et al, 2010 1.714 0.400 7.340 0.726 0.468 6 / 20 4 / 20 28.73
Blumberger et al, 2012 0.833 0.046 15.086 -0.123 0.902 1 / 13 1 / 11 8.06
Loo et al, 2012 0.931 0.212 4.097 -0.095 0.925 4 / 33 4 / 31 27.81
Palm et al, 2012 1.000 0.055 18.304 0.000 1.000 1 / 11 1 / 11 8.00
1.974 0.854 4.566 1.591 0.112 24 / 103 12 / 97
0.01 0.1 1 10 100

Favours Sham tDCS Favours Active tDCS

Fig. 1. Meta-analysis of active vs. sham tDCS for major depression: response rates.
 M.T. Berlim et al. / Journal of Psychiatric Research 47 (2013) 1e7 5

Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper Active Sham Relative
ratio limit limit Z-Value p-Value tDCS tDCS weight
Boggio et al, 2008 13.000 0.668 252.980 1.694 0.090 5 / 21 0/ 19 16.28
Loo et al, 2010 1.889 0.385 9.271 0.784 0.433 5 / 20 3/ 20 56.68
Blumberger et al,2012 0.840 0.015 46.086 -0.085 0.932 1 / 13 1/ 11 8.94
Loo et al, 2012 0.938 0.018 48.786 -0.032 0.975 1 / 33 1/ 31 9.19
Palm et al, 2012 1.000 0.018 55.267 0.000 1.000 1 / 11 1/ 11 8.91
2.131 0.643 7.059 1.238 0.216 12 / 98 5/ 92
0.01 0.1 1 10 100

Favours Sham tDCS Favours Active tDCS

Fig. 2. Meta-analysis of active vs. sham tDCS for major depression: remission rates.

and that further improvements in the efficacy of this technique
might involve the manipulation of stimulation parameters likely
yet to be identified.
The included RCTs did not differ in obvious ways regarding
sample characteristics but did differ in permitting concurrent use of
antidepressants during tDCS treatment. In the two studies report-
ing greater efficacy of tDCS (Boggio et al., 2008; Fregni et al., 2006a),
participants were not taking medication prior to and during the
neuromodulation treatment, whereas most participants continued
on antidepressants in the other RCTs (Blumberger et al., 2012; Loo
et al., 2012, 2010; Palm et al., 2012). Our results, although explor-
atory, concur with the notion that active tDCS is more effective
when used as a monotherapy for MD. Two possible explanations for
this finding are that the concomitant use of certain medications
(e.g., anticonvulsants (Nitsche and Paulusi, 2011)) may have nega-
tively influenced the efficacy of tDCS and/or that the potential for
further improvement in the augmentation trials may have been
limited by the fact that participants were already receiving treat-
ment for MD; nevertheless, regarding the second possibility, it is
clear that participants were still significantly depressed at baseline.
A possible related confounder is the fact that Loo et al. (2012, 2010)
have included subjects who were both off medication or receiving
stable pharmacological regimens and this might have limited their
ability to detect clinically relevant effects of tDCS.
As the therapeutic use of tDCS involves several variables, it is
conceivable that the optimum protocol is yet to be determined.
Accordingly, future studies should investigate new ways of
enhancing its antidepressant effects, such as the identification of
more clinically relevant stimulation parameters or electrode
montages. For example, Loo et al. (2012) have recently suggested
that stronger and more lasting benefits may be derived from the
extension of tDCS treatment to 6 weeks, but this has not yet been
tested in a sham-controlled trial. Also, alternative electrode shapes,
sizes and placements have been recently proposed, including
a concentric-ring configuration (Datta et al., 2009), and a fronto-
extracephalic montage in which the cathode is placed over the
right upper arm. The latter, in particular, has been hypothesized to
result in a more widespread pattern of cortical activation compared
to the standard bi-frontal montage, and could be thus associated
with more significant antidepressant effects (Martin et al., 2011).
Furthermore, it is unclear whether higher stimulus intensities (e.g.,
>2 mA) or longer duration of individual tDCS sessions (e.g.,
>20 min) using 35 cm2 electrodes are safe and tolerable, and
whether this approach is a more effective treatment for MD
(Nitsche and Paulusi, 2011). These variations in stimulation
parameters warrant further systematic study. In addition, novel
brain targets for tDCS might be associated with more significant
clinical effects (Brunoni et al., 2012), and the use of electrophysio-
logical and/or neuroimaging assessments might open new avenues
for optimized tDCS application in the treatment of MD (Keeser
et al., 2011; Pena-Gomez et al., 2011). Furthermore, there is
a need for RCTs directly comparing tDCS with other neuro-
modulation techniques (particularly rTMS) as well as specific
studies in subjects with bipolar and unipolar MD. Finally, future
studies should clarify whether the antidepressant efficacy of tDCS is
influenced by the concurrent use of psychotropic medications.
3.1. Limitations
First, the included RCTs enrolled a relatively small number of
depressed subjects. Second, the most commonly used strategy for
locating the DLPFC (i.e., the 10e20 International System of Elec-
trode Placement (Munday, 2005)), might not be optimal (DaSilva
et al., 2011), and future studies could likely benefit from neuro-
navigation approaches (Schonfeldt-Lecuona et al., 2010). Third, we
have only examined the efficacy of tDCS at study end; thus, we were
unable to estimate the stability of its medium- to long-term anti-
depressant effects and/or its cost-effectiveness. This is especially
relevant considering the time-consuming nature of tDCS. Fourth,
owing to the relatively small number of trials, we could not assess

Study name Statistics for each study Odds ratio and 95% CI
Odds Low er Upper Activ e Sham Relativ e
ratio limit limit Z-Value p-Value tDCS tDCS w eight
Fregni et al, 2006 1.000 0.016 62.300 0.000 1.000 1/ 5 1/ 5 8.98
Boggio et al, 2008 0.902 0.017 47.815 -0.051 0.960 1 / 21 1 / 19 9.73
Loo et al, 2010 0.317 0.012 8.260 -0.691 0.490 0 / 20 1 / 20 14.42
Blumberger et al, 2012 0.259 0.010 7.034 -0.802 0.423 0 / 13 1 / 11 14.07
Loo et al, 2012 0.935 0.124 7.082 -0.065 0.949 2 / 33 2 / 31 37.41
Palm et al, 2012 6.053 0.258 142.040 1.118 0.263 2 / 11 0 / 11 15.39
0.893 0.259 3.079 -0.179 0.858 5 / 103 5 / 97
0.01 0.1 1 10 100

Favours Sham tDCS Favours Active tDCS

Fig. 3. Meta-analysis of active vs. sham tDCS for major depression: dropout rates.
6 M.T. Berlim et al. / Journal of Psychiatric Research 47 (2013) 1e7
whether tDCS is differentially effective in unipolar and bipolar
depression. Fifth, the analyses were limited by “missing data”, as
we could not obtain data from all RCTs. Finally, meta-analyses have
been often criticized for combining heterogeneous studies, for the
potential of publication bias, and for the inclusion of poor-quality
trials (Borenstein et al., 2009). In the present study, however,
these concerns were addressed by the comprehensive systematic
review of the literature and the use of stringent inclusion criteria,
and by the objective examination of both publication bias and study
heterogeneity. In particular, the lack of significant heterogeneity
among the included RCTs shows that our results are reliable overall
(Higgins and Green, 2008).
4. Conclusion
The current meta-analysis, which included 200 depressed
subjects, shows that the clinical utility of tDCS as treatment for MD
remains unclear and that there is e at present e insufficient
evidence to support the notion that tDCS is superior to placebo in
achieving response and/or remission in subjects with MD. Future
research should focus on the investigation of larger and more
representative samples, on the potential differential efficacy of
tDCS in subtypes of MD, and on how it compares to other thera-
peutic neuromodulation approaches. Also, further studies should
focus on the search for optimal stimulation parameters for tDCS as
well as on the investigation of its neurobiological underpinnings.
Role of the funding source
We received no funding for this study.
Contributors
None.
Conflict of interest
Drs Berlim and Van den Eynde report no conflicts of interest. Dr
Daskalakis received external funding through Neuronetics and
Brainsway Inc, Aspect Medical and a travel allowance through
Pfizer and Merck. Dr Daskalakis has also received speaker funding
through Sepracor Inc and served on the advisory board for
Hoffmann-La Roche Limited.
Acknowledgment
None.
Appendix A. Supplementary material
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.jpsychires.2012.09.025.
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