Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial.

Abstract

Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy.
To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230).
Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed.
There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS.
Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Full text

Page 1

Although the use of weak electrical currents to stimulate the brain
has been described for centuries in the history of medicine, it has
been reintroduced with higher intensity currents since 2000 as
‘transcranial direct current stimulation’ (tDCS).1It involves
passing a weak, depolarising current through the brain. This shifts
the resting membrane potential,
depolarising the soma of pyramidal cells, whereas cathodal
stimulation results in hyperpolarisation.2The effects of tDCS on
neuronal excitability have now been demonstrated in numerous
neuroimaging and physiological studies, providing a sound
neurobiological basis for its use for neuromodulation in patient
populations.1,3
Increased understanding of the effects of tDCS has been
accompanied by application in clinical trials exploring its
therapeutic potential in neurology and, more recently, psychiatry.1
Its potential role in depression has generated particular interest.
Prior to 2000, early stimulation trials used relatively low current
intensities (0.02–0.5mA)with
stimulation technique. As a result, outcomes were highly
variable.3,4Since then, the development of commercial equipment
enabling the reliable delivery of currents in the 1–2mA range has
led to renewed interest in tDCS in clinical research. Since 2000,
three sham-controlled trials investigating the efficacy of tDCS
for treating depression have reported encouraging results. Fregni
et al5(n=10, tDCS given at 1mA, 20min per session, 5 sessions
on alternate days) and Boggio et al6(n=40, 2mA, 20min, 10
sessions on consecutive weekdays) both found tDCS more
effective than a sham control. In Loo et al7(n=40, 1mA,
20min, 5 sessions on alternate days followed by 5 further active
treatments) clinically meaningful improvement was seen with
active tDCS over 10 sessions of treatment, but differences
with anodalstimulation
considerablevariabilityin
failed to reach statistical significance over the initial 5-session
sham-controlled comparison period.
This present study further tested the efficacy of tDCS in
individuals with current depression, administering stimulation
at 2mA, for 20min in 15 daily sessions, with a further 15 sessions
on an open-label basis (registered at www.clinicaltrials.gov:
NCT00763230). Acute and cumulative neuropsychological effects
were also assessed with a detailed battery of tests chosen to
specifically assess verbal memory and executive function.
Method
Participants
The study was approved by the human research ethics committee
of the University of New South Wales and was conducted at the
Black Dog Research Institute in Sydney. Recruitment began in
September 2008 and the final 1-month follow-up was conducted
in February 2011. The trial was closed after the intended sample
size was reached (including an additional two participants who
had already been screened as suitable and consented at the time
of the decision to close the study). The sample size was estimated
from the results of Fregni et al,5the only published study of tDCS
given in the 1–2mA range in February 2007, and our pilot data in
nine participants. From changes in responses to the Hamilton
Rating Scale for Depression reported in Fregni et al5(60% mean
reduction in the active group, 10% mean reduction in the sham
group), assuming a baseline depression score of 20 (with a
standard deviation of 7.5), a sample size of 10 participants per
group (a total of 20 for the study) would have been required to
detect an effect of the same magnitude with 80% power and
a=0.05. Our pilot data from the first nine participants of the
study described in Loo et al7showed a 4.5-point difference in
52
Transcranial direct current stimulation
for depression: 3-week, randomised,
sham-controlled trial{
Colleen K. Loo, Angelo Alonzo, Donel Martin, Philip B. Mitchell, Veronica Galvez
and Perminder Sachdev
Background
Preliminary evidence suggests transcranial direct current
stimulation (tDCS) has antidepressant efficacy.
Aims
To further investigate the efficacy of tDCS in a double-blind,
sham-controlled trial (registered at www.clinicaltrials.gov:
NCT00763230).
Method
Sixty-four participants with current depression received
active or sham anodal tDCS to the left prefrontal cortex
(2mA, 15 sessions over 3 weeks), followed by a 3-week
open-label active treatment phase. Mood and
neuropsychological effects were assessed.
Results
There was significantly greater improvement in mood after
active than after sham treatment (P50.05), although no
difference in responder rates (13% in both groups). Attention
and working memory improved after a single session of
active but not sham tDCS (P50.05). There was no decline in
neuropsychological functioning after 3–6 weeks of active
stimulation. One participant with bipolar disorder became
hypomanic after active tDCS.
Conclusions
Findings confirm earlier reports of the antidepressant efficacy
and safety of tDCS. Vigilance for mood switching is advised
when administering tDCS to individuals with bipolar
disorder.
Declaration of interest
None.
The British Journal of Psychiatry (2012)
200, 52–59. doi: 10.1192/bjp.bp.111.097634
{See pp. 10–11, this issue.

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depression scores between active (n=4) and sham (n=5) tDCS
treatment over a 1.5-week sham-controlled study period, with
tDCS given at 1mA for 20min. As the present study involved
tDCS at 2mA on consecutive weekdays, with sham and active
treatment compared over a 15-session, 3-week study period, we
estimated there would be at least a six-point difference between
active and sham groups in depression scores at the end of the
sham-controlled treatment phase. Using end of treatment mean
scores of 17.3 (active group) and 23.3 (sham group), and a
s.d.=8.2, based on our pilot data, the power analysis indicated
that 31 participants per group (total sample 62) would be required
to detect this effect with 80% power and a=0.05.
Sixty-four participants with a DSM-IV8major depressive
episode and with a score of 520 on the Montgomery–A˚sberg
Depression Rating Scale (MADRS)9gave informed written
consent and were enrolled as out-patients. Diagnosis was based
on a structured assessment using the Mini-International Neuro-
psychiatric Interview (MINI)10and confirmed in a clinical
interview by a study psychiatrist (C.K.L.). Exclusion criteria were
other Axis I disorders, alcohol misuse, drug dependence or
misuse, neurological disorders, electronic or metal implants,
history of heart disease, neurological disorders, failure to respond
to electroconvulsive therapy in the current depressive episode,
pregnancy and concurrent treatment with medications that have
been shown to alter effects of tDCS (benzodiazepines, anti-
convulsants, dextromethorphan and pseudoephedrine).11,12Treat-
ment resistance was assessed for the current episode of depression
as the number of failed adequate courses of antidepressant
medications, and also according to the Maudsley Staging system.13
During the study, participants were either medication free or
remained on antidepressant medications (to which they had failed
to respond after an adequate treatment trial). For clinical and
ethical reasons, participants were not required to withdraw from
these medications if they or their treating clinicians had concerns
about possible deterioration as a consequence of medication
withdrawal. Any concurrent antidepressant medications were
continued at stable doses, which had not been altered for at least
4 weeks prior to study entry.
Study design
Participants were stratified by gender and age and randomly
assigned by a computer-generated random sequence to active
(n=33) or sham (n=31) treatment over a 3-week masked
treatment phase. After being screened and signing consent,
participants were enrolled and allocated to treatment groups by
research staff who were not involved in mood ratings. The
treatment assignment was indicated by a code on study treatment
sheets, which were concealed from raters. Active or sham tDCS
was administered every weekday (15 treatments in total), with
participants and ratersmasked
participants were then offered an additional 3 weeks of open-label
active tDCS, also administered every weekday. Participants who
met the criterion for response (50% improvement in MADRS
score from baseline) were eligible to receive further sessions of
tDCS on a weekly basis, over the 1-month follow-up period. After
both the sham-controlled and open-label phases, participants were
asked to guess their group allocation in the sham-controlled phase
to assess integrity of the masking. Participants and raters were
unmasked after the 6-week trial duration or at trial exit for
participants who withdrew before trial completion.
togroupallocation. All
Treatment with tDCS
The tDCS was administered by an Eldith DC-stimulator
(NeuroConn GmbH, Germany) with the anode over the left
dorsolateral prefrontal cortex, identified as pF3 on the inter-
national 10/20 EEG (electroencephalogram) system, and the
cathode placed over the lateral aspect of the contralateral orbit,
at the F8 position (10/20 system). Conductive rubber electrodes
(765=35cm2) covered by sponges soaked in saline were used
and held in place by a band. Stimulation was given at 2mA for
20min, with a gradual ramp up and ramp down of the current
over 30s. For sham stimulation, a 1mA current was applied for
30s giving an initial sensation of tDCS while minimising
stimulatory effects. Ramp up and ramp down was over 10s. The
safety procedure utilised during stimulation was as previously
described in Loo et al.14
Assessment of mood and cognition
The primary outcome measure for mood evaluation was the
MADRS. Participants were evaluated at baseline, after sessions 8,
15, 23 and 30, and at 1 week and 1 month after trial completion.
Each participant was rated by the same psychiatrist or
psychologist throughout the study using the MADRS, Inventory
of Depressive Symptomatology (IDS)15and Clinical Global
Impression – Severity of Illness (CGI-S)16scale. The clinician-rated
Quick Inventory of Depressive Symptomatology (QIDS-C)17score
was also calculated as a subset of scores derived from the IDS.
At the same time points, participants rated their mood using
the self-rated version of the QIDS (QIDS-SR).17At baseline,
participants were also rated using the CORE Measure of Psycho-
motor Disturbance (CORE)18as a possible predictor of response.
Neuropsychological functioning was assessed at baseline, and
after the sham-controlled (post-session 15) and open-label
(post-session 30) phases using the following tests: Rey Auditory
Verbal Learning Test (RAVLT),19Digit Span Forwards and
Backwards,20Stroop Test,21Controlled Oral Word Association
Test (COWAT)22and Letter–Number Sequencing.23Immediate
effects of tDCS on processing speed were also assessed at treatment
sessions 1 and 15 (tested immediately before and after
stimulation) using the Symbol Digit Modalities Test (SDMT),24
and simple and choice reaction-time tests. Alternative test versions
were used on different testing occasions for the RAVLT, COWAT
and SDMT.
Statistical analysis
The two treatment groups were analysed for differences in
demographic and clinical variables at baseline using w2-tests for
categorical variables and t-tests for continuous variables (Table
1). Statistical tests were two-tailed. Intention-to-treat last-
observation-carried-forward scores were used for the analyses
below. Only those participants with at least one post-baseline
rating were included in the analyses.
To test the effect of condition on mood over the course of
treatment, for each depression rating, a 262 mixed between–
within ANCOVA covarying for baseline CORE scores was
conducted with the between-groups factor being condition (active
v. sham tDCS) and the within-participants factor being time
(baseline and post-session 15). Analyses tested for main effects
of condition and time as well as the condition6time interaction.
Baseline CORE ratings were correlated (Pearson’s correlation)
with the percentage change in MADRS scores over the 15 active
treatment sessions (i.e. sessions 1–15 for active group, 16–30 for
sham group) to examine whether CORE scores predicted
response.
The number needed to treat (NNT) to obtain one responder
to active treatment was calculated for active v. sham tDCS over
the 3-week sham-controlled period. In a further exploratory
53
Transcranial direct current stimulation in depression

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Loo et al
analysis, the NNT to obtain a responder was also calculated for 6
weeks of active tDCS (i.e. tDCS received in the active group over
the sham-controlled and open-label phases) v. 3 weeks of sham
tDCS.
Scores from neuropsychological tests examining changes over
the first 15 sessions (active or sham), and scores from tests
administered immediately before and after sessions 1 and 15
(active or sham) were also analysed with a mixed between–within
ANOVA testing for main effects of condition and time as well as
condition6time interactions. In addition, neuropsychological
tests scores were separately analysed for participants who received
30 active treatments (i.e. active group), examining for a main
effect of time across the 30 sessions using a repeated measures
ANCOVA controlling for the percentage change in MADRS scores
over the same period.
To test the integrity of masking, a w2-test was used to test for
an association between participants’ group allocation in the sham-
controlled phase and whether they guessed their treatment was
‘active’ or ‘sham’.
Results
Participants
The only significant difference between the active and sham
groups at baseline was higher CORE scores for the active group
(Table 1). In total, 58 participants completed the 15-session
sham-controlled phase with 52 participants going on to complete
the open-label phase (Fig. 1). In total 13/31 participants (active
group) and 10/29 participants (group initially assigned to sham
treatment) received further sessions of tDCS (given weekly)
during the 1-month follow-up period.
Mood outcomes
There were significant main effects of time over the sham-
controlled phase for all mood outcome measures indicating that
scores were significantly lower at the end of the sham-controlled
phase compared with baseline (Table 2). The only main effect of
group was found in the QIDS-SR with higher scores for the sham
group.
A significant interaction between group and time was found in
MADRS scores (the primary outcome measure), with simple
effects indicating that there was a greater decrease in scores from
baseline to the end of the sham-controlled phase in the active
group (Fig. 2) (effect size: 0.49). However, the same interaction
only trended towards significance in QIDS-C scores and did not
reach significance in the remaining mood outcome measures.
Over the sham-controlled phase, four participants in both the
active and sham groups met the criterion for response. No
participants in either group met the criterion for remission
(MADRS score 510). By the end of the additional open-label
phase, 15 participants in the active group and 12 participants in
the sham group met the criterion for response. At 1-week
follow-up the proportion of responders was 16/26 (active group)
and 6/26 (sham group). At 1-month follow-up there were 13/20
(active group) and 7/23 (sham group) responders. The NNT was
16.7 for the 3-week active–sham comparison. The NNT for 6
weeks’ active tDCS compared with 3 weeks’ sham stimulation
was 2.6. There was no significant correlation between CORE
scores and percentage change in MADRS scores over the 3-week
active treatment period.
Neuropsychological functioning –
sham v. active tDCS
Over the sham-controlled phase, a significant main effect of time
was found for Stroop Interference, indicating that participants
were quicker in performing the task at the end of the sham-
controlled phase compared with baseline. However, there was no
interaction between group and time (Table 3).
Analyses of participants’
immediately before and after the first (tDCS 1) and final (tDCS
15) sessions in the sham-controlled phase, showed a significant
effect of time only at the first tDCS session. In addition, there
was a significant interaction between time and group with simple
effects revealing that there was no difference between pre- and
performanceinthe SDMT
54
Table 1
Comparison of demographic and clinical variables at study entry for sham and active groups
ShamActive Test statistic
n
Mean s.d.
n
Means.d. d.f.
F
w2
P
Categorical variables
Gender, male/female
Melancholic/non-melancholic
Concurrent antidepressant medication, yes/no
Bipolar diagnosis, yes/no
Edinburgh Handedness Inventory, right/left
15/14a
15/14a
21/8a
4/25a
25/4a
17/14a
16/15a
22/9a
4/27a
28/2a
1
1
1
1
1
0.06
0.00
0.02
0.01
0.82
0.81
0.99
0.90
0.92
0.37
Continuous variables
Age, years
Age at onset, year
Duration of current episode, months
Duration of all previous episodes, months
Antidepressants failed current episode, n: mean
Total lifetime failed antidepressants, n: mean
Maudsley Staging parameters
Baseline MADRS score
Baseline IDS score
Baseline QIDS-C score
Baseline CGI score
Baseline CORE score
Baseline QIDS-SR score
48.6
28.2
55.6
82.3
1.79
2.79
6.93
29.5
35.7
14.9
4.28
3.71
16.0
12.6
12.5
65
93.2
2.14
3.36
2.51
4.96
7.37
2.48
0.53
2.61
3.26
47.8
28.3
33.8
54.9
1.71
3.13
6.65
30.4
36.6
15.3
4.45
6.40
14.6
12.5
12.6
56.2
65.5
1.62
2.63
2.11
6.02
9.63
3.50
0.62
5.51
4.69
1,58
1,58
1,58
1,58
1,58
1,58
1,58
1,58
1,57
1,58
1,58
1,42
1,57
0.23
0.25
1.39
1.33
0.17
0.43
0.48
0.63
0.41
0.59
1.17
2.40
1.36
0.82
0.98
0.17
0.19
0.87
0.67
0.63
0.53
0.69
0.56
0.25
0.02
0.18
MADRS, Montgomery–A˚sberg Depression Rating Scale; IDS, Inventory of Depressive Symptomatology; QIDS-C, Quick Inventory of Depressive Symptomatology (Clinician-rated);
CGI, Clinician Global Impression; CORE, CORE Measure of Psychomotor Disturbance; QIDS-SR, Quick Inventory of Depressive Symptomatology (Self-Report).
a. Actual tally recorded.

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Transcranial direct current stimulation in depression
55
Table 2
Mood ratings over sham-controlled period (first 15 treatment sessions): sham v. activea
Baseline
Post-session 15
Test statistics
Sham (n=31)
Active (n=33)
Sham (n=29)
Active (n=31)
Sham v. active
Time effects
Time6group interaction
Scale
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM
d.f.
F
P
F
P
F
P
MADRS
29.7
1.03
29.9
1.00
24.9
1.41
20.6
1.36
55
2.09
0.15
25.00
50.01
4.68
0.04
IDS
36.4
1.61
35.6
1.58
29.8
1.68
25.2
1.65
54
1.83
0.18
18.60
50.01
2.23
0.14
QIDS-C
15.1
0.58
15.0
0.57
12.7
0.73
10.7
0.71
55
2.56
0.12
13.00
50.01
2.77
0.10
CGI
4.34
0.10
4.35
0.10
3.93
0.14
3.70
0.14
55
0.52
0.48
8.77
0.01
1.27
0.27
QIDS-SR
16.2
0.79
14.0
0.79
12.5
0.89
10.3
0.89
53
4.23
50.05
16.00
50.01
50.01
0.98
SEM, standard error of the mean; MADRS, Montgomery–A˚sberg Depression Rating Scale; IDS, Inventory of Depressive Symptomatology; QIDS-C, Quick Inventory of Depressive Symptomatology (Clinician-rated); CGI, Clinician Global Impression; QIDS-SR, Quick
Inventory of Depressive Symptomatology (Self-Report).
a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score.
Allocated to sham (n=31)
Received intervention
as assigned (n=31)
Lost to follow-up (n=5)
Discontinued in masked phase
(n=3)
– Too busy
– Headache after first session
– Personal reasons
Discontinued in open phase
(n=2)
– Surgery
– Became hypomanic
Analysed at end masked phase
(n=29)
Excluded from analysis (n=2)
– Did not have a rating
after baseline
Allocated to active (n=33)
Received intervention
as assigned (n=33)
Lost to follow-up (n=7)
Discontinued in masked phase
(n=3)
– Too unwell
– No improvement
– Difficulty travelling
Discontinued in open phase
(n=4)
– Too busy
– Switched to a different trial
– Difficulty travelling
– Side-effects from mood
stabiliser and direct
current stimulation
Analysed at end masked phase
(n=31)
Excluded from analysis (n=2)
– Did not have a rating
after baseline
Excluded (n=279)
Did not meet inclusion
criteria (n=269)
Changed mind (n=10)
Assessed for eligibility
(n=343)
Randomised
(n=64)
Fig. 1
through the trial.
Consort diagram showing progress of participants
..........................
<
0
0
<
<
0
<
0
<
0
<
0
<
0
35 –
30 –
25 –
20 –
15 –
10 –
5 –
0 –
Baseline81523 30
1-month
follow-up
1-week
follow-up
Number of treatment sessions completed
Montgomery–A˚sberg Depression Rating Scale
Fig. 2
scores for active and sham treatment groups over the masked
(first 15 sessions) and open-label (sessions 16–30) study phases,
and at follow-up, with standard error bars.
Mean Montgomery–A ˚sberg Depression Rating Scale

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Loo et al
56
Table 3
Cognitive test results over 15-session masked period: sham v. activea
Baseline
Post-session 15
Test statistics
Sham
Active
Sham
Active
Sham v. active
Time effects
Time6group interaction
Measure
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM
d.f.
F
P
F
P
F
P
RAVLT
Total
52.4
2.15
56.5
2.33
52.4
2.33
56.0
2.25
54
1.53
0.22
0.00
0.96
0.08
0.78
Delay
10.6
0.66
11.8
0.64
10.1
0.63
11.9
0.61
54
2.82
0.10
0.58
0.45
0.88
0.35
Digit Span
Forwards
10.6
0.54
10.3
0.52
11.1
0.48
10.4
0.46
54
0.52
0.48
1.16
0.29
0.67
0.42
Backwards
6.89
0.51
7.43
0.49
7.20
0.58
7.35
0.55
54
0.22
0.64
0.01
0.92
0.47
0.50
Letter–Number Sequencing
11.8
0.58
10.6
0.55
12.3
0.63
11.4
0.60
54
1.78
0.19
0.00
0.93
0.23
0.63
COWAT, letter: total
42.1
2.42
40.2
2.28
45.6
2.53
40.0
2.39
51
1.25
0.27
3.00
0.09
2.49
0.12
Stroop, interference: s
26.6
2.56
30.6
2.51
22.7
1.89
24.4
1.85
49
0.87
0.36
5.24
0.03
0.80
0.73
SEM, standard error of the mean; RAVLT, Rey Auditory Verbal Learning Task; COWAT, Controlled Oral Word Association Test. a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score and percentage change in Montgomery–A˚sberg Depression Rating Scale score over the sham-controlled period.
Table 4
Cognitive tests results immediately before and after direct current stimulation sessions 1 and 15: sham vs. activea
Pre-direct current stimulation
Post-direct current stimulation
Test statistics
Sham
Active
Sham
Active
Sham v. active
Time effects
Time6group interaction
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM
d.f.
F
P
F
P
F
P
Session 1
Symbol Digit Modalities Test
50.4
2.03
46.5
1.99
50.1
1.80
50.7
1.77
54
0.37
0.54
10.1
50.01
10.0
50.01
Simple reaction time, ms
289
22.0
307
21.0
294
21.0
327
20.0
53
0.88
0.35
3.31
0.08
0.39
0.53
Choice reaction time, ms
670
26.0
643
25.0
644
23.0
641
22.0
51
0.22
0.64
0.32
0.58
0.62
0.43
Session 15
Symbol Digit Modalities Test
52.3
2.53
51.4
2.39
53.7
2.23
53.3
2.11
54
0.04
0.84
2.90
0.09
0.08
0.79
Simple reaction time, ms
288
11.0
281
10.0
305
16.0
302
15.0
54
0.11
0.75
0.08
0.79
0.04
0.84
Choice reaction time, ms
659
27.0
648
26.0
648
24.0
633
24.0
51
0.14
0.71
0.47
0.50
0.06
0.81
SEM, standard error of the mean. a. All analyses control for baseline CORE Measure of Psychomotor Disturbance score.

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Transcranial direct current stimulation in depression
post-tDCS scores for the sham group, whereas scores in the active
group significantly improved following tDCS (Table 4).
Effects of 6 weeks of active tDCS on
neuropsychological test performance
In the active group (the only group to receive 6 weeks of
active tDCS), there was a trend for main effect of time on the
Letter–Number Sequencing Task, suggesting higher scores at 6
weeks compared with baseline (F=3.46, d.f.=28, P=0.07). No
significant differences over time were found within the other
measures: RAVLT total (F=0.12, d.f.=28, P=0.73), RAVLT delay
(F=0.41, d.f.=28, P=0.53), Digit Span Forwards (F=1.02,
d.f.=28, P=0.32), Digit Span Backwards (F=0.01, d.f.=28,
P=0.93), Stroop Interference (F=0.24, d.f.=26, P=0.63) and
COWAT (F=1.72, d.f.=27, P=0.2).
Adverse outcomes and side-effects
During the sham-controlled phase, side-effects occurring during
active treatment were skin redness (objectively observed) at the
anode and/or cathode site (n=30), tingling at anode and/or
cathode site (n=26), itching at anode and/or cathode site
(n=23), burning/heating sensation at anode and/or cathode site
(n=14), headache (n=12), dizziness/light-headedness (n=10),
fatigue (n=7), nausea (n=3), blurred vision (n=3), pain at
anode and/or cathode site (n=2), pulsing sensation at anode
and/or cathode site (n=2), neck soreness (n=1), visual effects
when eyes closed (n=1), seeing dots in the periphery (n=1),
giddiness (n=1), flaky skin (n=1), watery eyes (n=1), a feeling
of being ‘spaced out’ (n=1) and shakiness (n=1). In addition,
one participant experienced transient hypomania in the open
phase and was subsequently withdrawn from the trial. Side-effects
occurring during sham treatment were skin redness at anode and/
or cathode site (n=29), tingling at anode and/or cathode site
(n=27), itchiness at anode and/or cathode site (n=22), headache
(n=10), burning/heating sensation at anode and/or cathode site
(n=7), dizziness/light-headedness (n=6), fatigue (n=4), pulsing
sensation at anode and/or cathode site (n=2), right ear ache
(n=1), ringing in ears (n=1), nausea (n=1), twitching of right
arm (n=1), stiffness in neck and shoulders (n=1), tingling on
neck (n=1), tingling on tongue (n=1), a ‘funny feeling’ in head
(n=1), facial numbness (n=1) and reflux (n=1). All side-effects
were transient and mostly ranged from mild to moderate in
intensity.
Integrity of masking
When asked to guess their treatment assignment, correct
responses were made by 14/24 participants in the active group
and 16/25 participants in the sham group. The w2-test indicated
no significant difference between groups in the likelihood of
active/sham guesses (w2=2.45, d.f.=1, P=0.12).
Discussion
Efficacy
This study reports the largest sample of individuals with current
depression treated hitherto in a randomised controlled trial of
tDCS. It used treatment parameters that exceeded those of
previous trials, in an attempt to optimise efficacy. Overall, this
study confirmed previous reports of significant antidepressant
effects with tDCS, with the active treatment group showing
significantly greater improvement compared with the sham group
over the 3-week study period on the primary outcome measure
(change in MADRS). However, results over the 3 weeks were
clinically modest, with only a 28% decline in MADRS scores after
active stimulation, a small proportion of responders (which did
not differ between active and sham treatment groups) and
active–sham differences failing to reach significance on the other
mood rating scales. The antidepressant effects measured in this
study did not appear as robust as those previously reported in
the sham-controlled trials of Fregni et al5(60% improvement after
5 sessions/1.5 weeks) and Boggio et al6(43% improvement after
10 sessions, 2 weeks), despite the use of tDCS at higher stimulus
intensities, over a longer treatment period and with more
stimulation sessions. These results in the active treatment group
are comparable though, to those reported in our earlier trial of
tDCS (37% improvement after 10 sessions/3.5 weeks)7and a
recent open-label trial of tDCS (18% improvement in unipolar
depression after 10 sessions/1 week).25
The studies above did not differ obviously in sample
characteristics but did differ in permitting concurrent anti-
depressant medication during tDCS. In the two trials with greater
response, participants were free of medications prior to and
during the trial (clarified in a personal communication from
F. Fregni, March 2011),5,6whereas in others7,25and in this study,
participants continued on antidepressant medication. Although
participants in these latter trials were still significantly depressed
at the time of commencing tDCS, the potential for further
improvement with a physical treatment may have been limited
compared with individuals not already receiving some treatment.
A meta-analysis of trials of transcranial magnetic stimulation
(TMS), anothernon-convulsive
depression, found greater efficacy when TMS was given as a
monotherapy thanwhen it
pharmacotherapy.26
The trials above also differed in stimulus intensity and session
frequency. Recent trials (Boggio et al,6this trial, Brunoni et al25)
increased both stimulus intensity (2mA) and session frequency
(daily or twice daily) in an attempt to optimise outcomes,
however, results are not clearly superior to trials that used 1mA
and second daily treatments.5,7
stimulation has been shown to affect the duration of after effects,27
the influence of stimulus intensity and session frequency on
efficacy are as yet unknown. In a recent study of tDCS to the
motor cortex, we found that daily stimulation sessions led to
greater cumulative changes in cortical excitability than second
daily stimulation, over a given stimulation period (1 week), when
all other parameters were kept constant.28In a similar experiment,
we did not find any difference in outcomes (cortical excitability)
between gradual increase of stimulus intensity from 1mA to
2mA over five sessions conducted on consecutive weekdays, and
maintaining stimulation intensity at 2mA for all five session
(details available from the authors on request). The effects of these
variations in stimulus parameters on cortical effects warrant
further systematic study.
Although results after 3 weeks of daily tDCS were modest, the
number of responders after 6 weeks of treatment was much more
encouraging, and comparable with outcomes from a recent large
study of 6 weeks of TMS given on an open-label basis to
participants with pharmacotherapy-resistant depression (42.4%
responders).29The response rate was superior to that reported
for antidepressant medication in individuals who had failed a first
courseof medication inthe
Alternatives to Relieve Depression (STAR*D) study (28.5%).30
This suggests that tDCS has meaningful antidepressant efficacy,
including in those individuals resistant to pharmacotherapy.
Comparison of MADRS outcomes and response rates between
participants who received 3 and 6 weeks of active treatment
stimulatory treatmentfor
wasaddedtopre-existing
Although the duration of
large Sequenced Treatment
57

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Loo et al
suggest that further and more lasting benefit may be derived from
extension of the treatment period to 6 weeks. Whether this is
related to the number of treatments received (i.e. 30 v. 15) or
the overall duration of the treatment course (6 weeks rather than
3 weeks) cannot be determined from this study. Interpretation of
these outcomes is limited by the fact that treatment in the second
3 weeks of the study was administered under open-label
conditions.
Cognitive effects
Tests for acute cognitive effects following the first tDCS session
showed improvement on the SDMT in the active tDCS group
relative to the sham group. This finding suggests that tDCS may
enhance acute attention and working memory in people with
depression, in line with the acute attention-enhancing effects found
following equivalent stimulation in individuals post-stroke.31
Consistent with our previous study,7neuropsychological tests
after 3 weeks (15 sessions) of active tDCS did not show any
changes in performance across multiple cognitive domains. These
results demonstrate that multiple tDCS sessions are safe and not
associated with any adverse cognitive outcomes. Previously, Fregni
et al32showed that five daily tDCS sessions enhanced performance
on the Digit Span Forwards and Backwards test, a finding we
failed to replicate in a larger sample.7Similarly, in the current
study no improvement was found on these same measures after
either 15 or 30 active tDCS sessions. This suggests that multiple
tDCS sessions do not have cumulative cognitive enhancing effects
independent of mood effects. Nonetheless, the use of more
sensitive neurocognitive measures may help elucidate potential
cognitive-enhancing effects of multiple tDCS treatments in future
studies.
Limitations and strengths
A limitation of this study is that most participants were on
antidepressant medications concurrently with tDCS. This was
allowed in the study design for several reasons: ethical and
scientific concerns that withdrawal of medications may have
caused clinical deterioration prior to study entry; no evidence
for safety issues with concurrent use of antidepressants and tDCS;
and also because the continuation of medication while tDCS is
introduced is likely to be the approach used if tDCS is eventually
undertaken in clinical practice. Nevertheless, it means that the
effects of tDCS could not be assessed independently of the
presence of medications, which would be scientifically preferable.
It is unlikely that the continuation of medications would have
enhanced antidepressant effects, as these were medications to
which participants had already failed to respond, and doses were
stable for at least 4 weeks prior to study entry and during the
study. On the contrary, this factor may have limited the scope
of further antidepressant effects with tDCS, as discussed above.
Strengths of the study include the relatively large sample size,
extension of tDCS stimulation to 30 sessions over 6 weeks, careful
methodology with good participant adherence to the study
protocol and detailed neuropsychological testing.
Implications
In conclusion, this trial studied tDCS at stimulation parameters
beyond those previously used in depression and confirmed earlier
reports of the antidepressant efficacy and safety of tDCS. The
evidence to date suggests that tDCS is a potentially useful treatment
for depression, and that treatment should be given for longer than
3 weeks for an adequate response.
Funding
This study was supported by an Australian National Health and Medical Research (NHMRC)
council research grant number 510142.
Acknowledgements
The authors thank Dusan Hadzi-Pavlovic for advice on statistical analysis, Michael Player,
Jessica Cheung, Dr Aparna Menon, Vincent Chan, Joshua Garfield and Manasi Kogekar
for assistance with data collection and processing, Professsor Walter Paulus and Dr
Michael Nitsche for advice on tDCS, and Natalie Katalinic for assistance with manuscript
preparation.
Colleen K. Loo, MB BS, MD, FRANZCP, School of Psychiatry, University of New South
Wales, Sydney, St George Hospital, South Eastern Sydney Illawarra Health and Black
Dog Institute, Sydney, Australia; Angelo Alonzo, BA, BSc (Hons), PhD, Donel
Martin, MClinNeuroPsych, PhD, Philip B. Mitchell, AM, MB BS, MD, FRCPsych,
FRANZCP, School of Psychiatry, University of New South Wales and Black Dog
Institute, Sydney, Australia; Veronica Galvez, MD, School of Psychiatry, University of
New South Wales, Sydney, Black Dog Institute, Sydney, and Mood Disorders Clinical
and Research Unit, Psychiatry Department, Bellvitge University Hospital &
Neuroscience Group, IDIBELL (Bellvitge Biomedical Research Institute) L’Hospitalet de
Llobregat, Barcelona, Spain; Perminder Sachdev, MB BS, MD, PhD, FRANZCP,
School of Psychiatry, University of New South Wales and Neuropsychiatric Institute,
Prince of Wales Hospital, Randwick, Sydney, Australia
Correspondence: Colleen Loo, Level 2, James Laws House, St George Hospital,
Kogarah, NSW 2217, Australia. Email: colleen.loo@unsw.edu.au
First received 6 Jun 2011, final revision 9 Oct 2011, accepted 26 Oct 2011
References
1 Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al.
Transcranial direct current stimulation: state of the art 2008. Brain Stimul
2008; 1: 206–23.
2 Bindman LJ, Lippold OC, Redfearn JW. The action of brief polarizing currents
on the cerebral cortex of the rat (1) during current flow and (2) in the
production of long-lasting after-effects. J Physiol 1964; 172: 369–82.
3 Arul-Anandam AP, Loo C. Transcranial direct current stimulation: a new tool
for the treatment of depression? J Affect Disord 2009; 117: 137–45.
4 Nitsche MA, Boggio PS, Fregni F, Pascual-Leone A. Treatment of depression
with transcranial direct current stimulation (tDCS): a review. Exp Neurol
2009; 219: 14–9.
5 Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP,
Pascual-Leone A. Treatment of major depression with transcranial
direct current stimulation. Bipolar Disord 2006; 8: 203–4.
6 Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA,
Pascual-Leone A, et al. A randomized, double-blind clinical trial on the
efficacy of cortical direct current stimulation for the treatment of major
depression. Int J Neuropsychopharmacol 2008; 11: 249–54.
7 Loo CK, Sachdev P, Martin D, Pigot M, Alonzo A, Malhi GS, et al. A double-
blind, sham-controlled trial of transcranial direct current stimulation for the
treatment of depression. Int J Neuropsychopharmacol 2010; 13: 61–9.
8 American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders (4th edn) (DSM-IV). APA, 1994.
9 Montgomery SA, A ˚sberg M. A new depression scale designed to be sensitive
to change. Br J Psychiatry 1979; 134: 382–9.
10 Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al.
The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development
and validation of a structured diagnostic psychiatric interview for DSM-IV and
ICD-10. J Clin Psychiatry 1998; 59 (suppl 20): 22–33.
11 Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to
the mechanisms of transcranial DC-stimulation-induced after-effects of
human motor cortex excitability. Brain 2002; 125: 2238–47.
12 Nitsche MA, Liebetanz D, Schlitterlau A, Henschke U, Fricke K, Frommann K,
et al. GABAergic modulation of DC stimulation-induced motor cortex
excitability shifts in humans. Eur J Neurosci 2004; 19: 2720–6.
13 Fekadu A, Wooderson SC, Markopoulou K, Cleare AJ. The Maudsley Staging
Method for treatment-resistant depression: prediction of longer-term
outcome and persistence of symptoms. J Clin Psychiatry 2009; 70: 952–7.
14 Loo CK, Martin DM, Alonzo A, Gandevia S, Mitchell PB, Sachdev P. Avoiding
skin burns with transcranial direct current stimulation: preliminary
considerations. Int J Neuropsychopharmacol 2011; 14: 1–2.
58

Page 8

Transcranial direct current stimulation in depression
15 Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of
Depressive Symptomatology (IDS): psychometric properties. Psychol Med
1996; 26: 477–86.
16 Guy W. Clinical global impressions. In Assessment Manual for
Psychopharmacology – Revised: 218–22. National Insitute of Mental Health,
1976.
17 Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The
16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician
rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in
patients with chronic major depression. Biol Psychiatry 2003; 54: 573–83.
18 Parker G, Hadzi-Pavlovic D, Boyce P, Wilhelm K, Brodaty H, Mitchell P, et al.
Classifying depression by mental state signs. Br J Psychiatry 1990; 157:
55–65.
19 Rey A. L’Examen Clinique en Psychologie [in French]. Presses Universitaires
de France, 1964.
20 Wechsler D. WAIS-R Manual. Psychological Corporation, 1981.
21 Spreen O, Strauss E. A Compendium of Neuropsychological Tests (2nd edn).
Oxford University Press, 1998.
22 Benton AL, Hamsher KD. Multilingual Aphasia Examination. AJA Associates,
1989.
23 Wechsler D. Wechsler Adult Intelligence Scale – Administration and Scoring
Manual (3rd edn). The Psychological Corporation, 1997.
24 Smith A. Symbol Digit Modalities Test. Western Psychological Services, 1991.
25 Brunoni AR, Ferrucci R, Bortolomasi M, Vergari M, Tadini L, Boggio PS, et al.
Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar
depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:
96–101.
26 Slotema CW, Blom JD, Hoek HW, Sommer IE. Should we expand the toolbox
of psychiatric treatment methods to include repetitive transcranial magnetic
stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric
disorders. J Clin Psychiatry 2010; 71: 873–84.
27 Nitsche MA, Paulus W. Sustained excitability elevations induced by
transcranial DC motor cortex stimulation in humans. Neurology 2001; 57:
1899–901.
28 Alonzo A, Brassil J, Taylor J, Martin D, Loo CK. Daily transcranial direct
current stimulation (tDCS) leads to greater increases in cortical excitability
than second daily tDCS. Brain Stimul 2011; May 25 (Epub ahead of print).
29 Avery DH, Isenberg KE, Sampson SM, Janicak PG, Lisanby SH, Maixner DF, et
al. Transcranial magnetic stimulation in the acute treatment of major
depressive disorder: clinical response in an open-label extension trial. J Clin
Psychiatry 2008; 69: 441–51.
30 Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D,
et al. Acute and longer-term outcomes in depressed outpatients requiring
one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:
1905–17.
31 Kang EK, Baek MJ, Kim S, Paik NJ. Non-invasive cortical stimulation improves
post-stroke attention decline. Restor Neurol Neurosci 2009; 27: 645–50.
32 Fregni F, Boggio PS, Nitsche MA, Rigonatti SP, Pascual-Leone A. Cognitive
effects of repeated sessions of transcranial direct current stimulation in
patients with depression. Depress Anxiety 2006; 23: 482–4.
59
The butterfly
Shabbir Amanullah
As adults, we consider ourselves capable of interpreting, at least to some extent, the behaviour of children. Many a text has
been written about childhood behaviour and its interpretation. We use strategies to reinforce or root out certain behaviours.
However, we often fail to grasp the immense strength of a child’s imagination. On Canada Day we were at a park, waiting
for the fireworks display to begin at sundown. It was a warm day and children were running around the place. There was
the usual popcorn, fizzy drinks, ice cream, lobster (exclusive to Prince Edward Island), balloons and, of course, face
painting. While sitting beside a fence with a few friends, we saw a child coming towards us. She was beaming and seemed
extremely content. She had a butterfly painted on her face. It was in three different colours and covered her face entirely.
Thinking that she had come to show us all that she ‘acquired’ at the fair so far, we commented on the different things she
had with her. In a typically childish way, she explained how she got them. Then, as she was about to leave, I said, ‘You have
a pretty butterfly painted on your face’. She looked at me in stunned silence and then replied in a huff ‘I am the butterfly!’
We fail to comprehend the extent, depth and importance of the child’s imagination by assuming we ‘know’.
The British Journal of Psychiatry (2012)
200, 59. doi: 10.1192/bjp.bp.111.099622
extra