DEPRESSION AND ANXIETY 00:1–8 (2016)

Research Article
A STUDY OF THE PATTERN OF RESPONSE TO rTMS
TREATMENT IN DEPRESSION
Paul B. Fitzgerald, M.B.B.S., M.P.M., Ph.D., FRANZCP,1 ∗ Kate E. Hoy, B.B.N.Sc. (Hons.),
D.Psych. (Clin. Neuro.),1 Rodney J. Anderson, B.Sc. (Hons.), G.Dip.Psych.,1 and
Zafiris J. Daskalakis, M.D., Ph.D., FRCP (C)2

Background: Considerable research has demonstrated the efficacy of repetitive

transcranial magnetic stimulation (rTMS) treatment in patients with depres-
sion. However, limited research has described the pattern of response to rTMS
treatment or explored possible predictors of the likelihood of treatment response.
Methods: Data from 11 clinical trials (n = 1,132) was pooled and we described
the pattern of response to rTMS, rate of response, and remission as well as po-
tential clinical and demographic predictors of response. Results: There was a
bimodal pattern of response to rTMS with the response-associated peak at 57%
reduction in depression rating scale scores. About 46% of patients achieved re-
sponse criteria, with 31% completing rTMS treatment in remission. A greater
likelihood of response was seen for patients who had less severe depression at
baseline, a shorter duration of the current episode, and recurrent rather than
single episode of depression. Greater response was also seen in patients treated at
higher stimulation intensity. Conclusions: A meaningful percentage (>40%)
of patients respond to a course of rTMS treatment. Response does vary with a
number of clinical and demographic variables but none of these variables exert a
sufficiently strong influence on response rates to warrant using these criteria to
exclude patients from treatment. Depression and Anxiety 00:1–8, 2016. 
C

2016 Wiley Periodicals, Inc.

Key words: brain stimulation; depression; treatment resistance; treatment;

clinical trials

1 MonashAlfred Psychiatry Research Centre, The Alfred and
Monash University, Central Clinical School, Melbourne, Victo-
ria, Australia
2 Temerty Centre for Therapeutic Brain Intervention and the
Campbell Family Mental Health Research Institute, Centre for
Addiction and Mental Health, University of Toronto, Toronto,
Ontario, Canada
Contract grant sponsor: National Health and Medical Research
Council (NHMRC); Contract grant numbers: 1041890, 1078567
(Practitioner Fellowship grant to PBF), 1082894 (Career Develop-
ment Fellowship to KEH); Contract grant sponsor: Alfred Health.
∗ Correspondence
to: Paul B. Fitzgerald, Monash Alfred Psychia-
try Research Centre, First Floor, Old Baker Building, The Alfred,
Commercial Road, Melbourne, Victoria 3004, Australia
E-mail: paul.fitzgerald@monash.edu
INTRODUCTION
Repetitive transcranial magnetic stimulation (rTMS)
treatment is an increasingly available treatment for pa-
tients with Major Depressive Disorder (MDD) and espe-
cially Treatment Resistant Depression (TRD). Evidence
for the efficacy of rTMS in this population has come
from a large number of randomized controlled trials in-
cluding several larger multisite trials (for example [1,2]).
These trials have predominately investigated the effi-
cacy of high-frequency rTMS (usually 10 Hz) applied to
the left dorsolateral prefrontal cortex (DLPFC). There
Received for publication 12 November 2015; Revised 8 March 2016;
Accepted 13 March 2016
DOI 10.1002/da.22503
Published online in Wiley Online Library
(wileyonlinelibrary.com).


C 2016 Wiley Periodicals, Inc.
2 Fitzgerald et al.
are several meta-analyses confirming the efficacy of this
technique (for example [3]).
Although less numerous, studies have also demon-
strated the efficacy of low-frequency rTMS (1 Hz) ap-
plied to the right DLPFC.[4, 5] There is meta-analytic
support for this approach[6] and for its equivalence to
the high-frequency approach.[7] Finally, there is also sup-
port for sequential bilateral forms of rTMS combining
high-frequency rTMS applied to the left DLPFC and
low-frequency stimulation applied to the right DLPFC
with some studies demonstrating evidence for enhanced
efficacy compared to unilateral stimulation[8] whereas
others do not. Therefore, all three forms of rTMS treat-
ment for depression (high-frequency left rTMS, low-
frequency right rTMS, and bilateral rTMS) have been
shown to significantly improve TRD and to have com-
parable rates of efficacy.
Although a large number of studies have investigated
the efficacy of rTMS in relation to categorical outcomes
(i.e., response and remission) we still know little about
the pattern of response. For example, whether treatment
response is likely to be “all or none” or whether there
are degrees of response. Such knowledge would be of
considerable clinical use in the provision of information
to patients contemplating rTMS treatment. There are
also uncertainties about whether illness or social demo-
graphic variables can predict clinical response.
AIMS OF THE STUDY
The aims of the study, therefore, were to analyze the
pattern of clinical response and potential predictors of
response to rTMS treatment for depression via pooled
primary data from a series of clinical trials that we have
conducted over the last 15 years.
METHOD
STUDY DESIGN
For the purpose of this study we pooled data from 11 separate
clinical trials, nine of which have already been described in published
papers.[5, 9–16] Several trials were sham controlled and for these stud-
ies only the data from the active treatment groups were included. Data
for analysis were only included where these were consistently collected
across all or a significant majority of studies. Data were only included
from subjects receiving active treatment. Seven studies used the 17-
item Hamilton Depression Rating Scale (HAMD)[17] as the primary
outcome measure and in four the Montgomery Asberg rating scale
(MADRS)[18] was used instead. Response rates were defined as a 50%
reduction in scores on either the HAMD or MADRS from baseline to
the end of acute rTMS treatment using a last observation carried for-
ward method. Where available, data were recorded on medication use
at the time of treatment, past antidepressant use, illness duration, age
of illness onset, and number of past episodes of depression. The left
and/or right hand side resting motor threshold level measured prior
to treatment onset was also included in analysis.
Subjects. The full analysis included 1,132 subjects ranging from
an age of 18–89 years (mean 46.2, SD 13.6). There were 711 female
(62.8%) and 419 male (37.1%) subjects. Thirty-two percent of patients
had been diagnosed with a single episode of MDD, 53% of patients
with a recurrence of MDD, 13% with bipolar affective disorder, and
Depression and Anxiety
1.7% with schizoaffective disorder. At the time of rTMS treatment
80.1% of patients were receiving treatment with an antidepressant,
41% with an antipsychotic, and 31.6% with a mood stabilizer.
TMS Treatment. The type of rTMS utilized varied across the
different clinical trials. A total of 29.9% of patients received treatment
with high-frequency left-sided rTMS (4 or 5 s trains of 10 Hz stimula-
tion); 45.4% received treatment with low-frequency right-sided rTMS
(mostly 1Hz stimulation); and 25% of subjects received sequential bi-
lateral rTMS (mostly 1 Hz stimulation applied to the right followed
by 10 Hz stimulation applied to the left prefrontal cortex). Of the 514
patients who received low-frequency right-sided stimulation, 120 re-
ceived stimulation with a priming protocol (6 Hz subthreshold trains
prior to 1 Hz stimulation). Of the 276 patients who received bilateral
stimulation, 84 received treatment with bilateral low-frequency (1 Hz)
stimulation.
Data Analysis. Kernel density estimation was used to explore
the distribution of the degree of improvement in the primary clinical
measure. Using the R statistical language,[19] a Gaussian kernel was
utilized and a bandwidth determined using factor 1.06. Hartigan’s dip
test[20] was utilized to test for any statistically significant deviation from
a unimodal distribution, using the “diptest” package[21] in R.
All subsequent analysis was conducted using SPSS 22.0 (SPSS for
Windows. 22.0 Chicago: SPSS; 2013). The percentage of responders
was calculated and the relationship between response and potential
predictive variables analyzed with independent samples t-tests and chi-
squared analyses. To analyze potential predictors of clinical response,
we excluded subjects who had not undergone a single clinical assess-
ment after their baseline study measure. Therefore, all subjects in this
analysis had undertaken a minimum of one and in most cases at least
2 weeks of rTMS treatment. Two comparisons were then made of
responder to nonresponder. In the first, the traditional definition of
response was used (>50% reduction in scores on the relevant depres-
sion rating scale). In the second, we used a cutoff to define response
based on plotting the distribution of response rates (Fig. 1): the cutoff
from this analysis was set at 20%. To explore the relationship between
age and response, response rates and change in depression rating scale
Figure 1. This figure shows the distribution plot of the degree of
clinical response (percentage change in depression rating scale
score) for all subjects in the sample. A bandwidth of 9.32 has
been used. The small dashed line (on the left) indicating the first
peak is at a 5% change. The dashed line is at a 57% change. The
trough (dotted line) is at 19%.
 Research Article: rTMS in Depression
Figure 2. This shows the proportion of responders, nonresponders, and partial responders (who achieve a reduction of between 25 and
50% of their depression rating scale score) in the full sample.
scores were also compared between subjects younger and older than
65 years.
RESULTS
PATTERN OF RESPONSE
For the total sample there were 498 (44%) responders
and 634 (56%) nonresponders. Excluding subjects who
did not have a postbaseline assessment, these numbers
were 498 (46.8%) responders and 566 (53.2%) nonre-
sponders. Of the nonresponders in both analyses, 218
were considered partial responders (Fig. 2). Of the 1,064
patients who had at least one postbaseline assessment,
334 (31.4%) achieved remission status by the end of
treatment.
Figure 1 shows the distribution of response across the
sample. Visual inspection of the probability distribution
plot reveals a bimodal distribution, suggesting the exis-
3
tence of two subpopulations in the data. Supporting this
suggestion, the results of Hartigan’s dip test[20] showed
a significant deviation (D = 0.027, P < .0001) from a
unimodal distribution, indicating at least, a bimodal dis-
tribution. One subpopulation experienced relatively lit-
tle improvement in depression scores over the course
of treatment whereas the second subpopulation experi-
enced a significant clinical response (peak at 57% reduc-
tion in depression scores, see Fig. 3). A cutoff between
these two peaks was taken at 20% (dotted line in Fig. 1
is at 19%) for use in the secondary analysis of predictors
of response to treatment.
To investigate if the bimodal distribution of response,
identified in the overall sample, generalized across the
individual studies that composed the sample, kernel
density estimation was utilized. Despite the heterogene-
ity of the study designs included in the overall sample,
a bimodal distribution is also observed in most of the
individual studies (see Fig. 4).
Depression and Anxiety
4 Fitzgerald et al.

Figure 3. This figure shows the trajectory of change in rating scale scores for patients considered responders and nonresponders from
start (BL) to end of rTMS treatment (error bars showing the standard deviation).

RELATIONSHIP OF CLINICAL AND
DEMOGRAPHIC VARIABLES TO RESPONSE
The comparison of responders and nonresponders
(based on a 50% reduction in depression scores) on
the demographic and clinical variables is presented in
Table 1. Responders had lower baseline depression rat-
ing scale scores (P < .001) than nonresponders, a mean
shorter illness duration (P < .001) and a later age of de-
pression onset (P = .02).
Responders were significantly older than nonrespon-
ders (P = .005). There was no difference in change
in depression rating scale scores, or the percentage of
patients achieving response criteria, between patients
aged >65 (45.4%) and <65 (47.0%).
There was a significant difference in the percentage
of responders falling into each diagnostic category: Re-
sponse was less likely for patients with a single compared
to repeated episode of depression or bipolar disorder.
Response was more common for patients receiving an
antidepressant at the time of treatment: 47.8% of medi-
cated and only 36.6% of unmedicated patients responded
(P < .005). Response was also more common in patients
taking a mood stabilizer (52.7 vs. 43.8%, P < .02). There
was no difference in rates of response in patients taking
an antipsychotic medication.
Response rates were higher in patients with no co-
morbidity (54.1%) than in those with a comorbid anx-
iety diagnosis (panic disorder 35.0%, PTSD 47.8%,
GAD 47.3%; P < .005). In regards to TMS treat-
ment type, response was highest for patients receiving
unilateral right-sided rTMS (47.5%) and bilateral
rTMS (54%) and lowest for left-sided rTMS (39.2%;
P < .05).
In regards to TMS stimulation intensity (100, 110, and
120% across different trials), there was a significantly
greater response rate in patients who received treatment
in trials where stimulation was applied at 110 and 120%
of the RMT (51.6 and 44.4%) than at 100% of the RMT
(28.7%). The mean change in depression rating scale
score was significantly different across the three groups
(F (2, 1061) = 3.3, P < .001) with significant differences
between the 100 and 110% groups (P = .002) and 100
and 120% groups (P < .05) but not the 110 and 120%
groups.
The analysis of response and nonresponse was re-
peated using the 20% cutoff. By this definition, 70.5% of
patients who had at least one postbaseline assessment and
66.2% of the total sample met response criteria. None of
the analyses differed from those in the primary compar-
isons under than the relationship of age and response,

Depression and Anxiety

 Research Article: rTMS in Depression 5

Figure 4. Distribution plot for the degree of clinical response across individual studies. Studies published to date are referenced here:
Study a,[9] Study b,[12] Study c,[10] Study d,[16] Study f,[11] Study g,[15] Study h,[5] Study i,[13] Study j.[14] Data from studies e and k are
not yet published.

which was not significant in this secondary analysis
(P = .06 compared to .001).
DISCUSSION
The primary finding from this study is that response to
rTMS treatment appears to fall on a bimodal distribution
with individuals receiving treatment having a likelihood
of around 40–45% of achieving clinical response. Al-
though there is a group of “partial responders” to treat-
ment, the majority of patients receiving rTMS are likely
to have relatively no change in depressive symptoms or a
substantial one. The majority of patients achieving clini-
cal response had end of treatment depression scores close
to or below remission levels.
We are aware of only one previous study that has used
these methods to investigate the pattern of response to
rTMS treatment and that was in a much smaller sam-
ple and with a less standard form of rTMS (applied to
dorsomedial prefrontal cortex).[22] Establishing the ex-
istence of a bimodal distribution pattern of response
has two main implications. First, it allows clinicians to
provide accurate information to patients in regards
to both the likelihood of response and what this is
likely to be. We have also provided a robust estimate of
response rates given that these rates have come from
pooling outcome data from over 1,000 patients treated
in a series of variable clinical trials. Third, these results
support an approach of defining “responder” and “non-
responder” groups based on the pattern of clinical re-
sponse rather than a priori criteria, for the purpose of the
analysis of predictors of outcome as although not clearly
delineated, these groups appear to have some degree of
meaningful difference.

Depression and Anxiety

6 Fitzgerald et al.

TABLE 1. Demographic and baseline clinical variables

Responders Non responders

Mean SD Mean SD t/χ 2 Significance
Age 47.7 13.0 45.1 14.0 3.2 .001
Sex (M/F) 189/309 202/357 0.18 .67
Diagnosis (number of subjects) MDD—single episode 121 208 21.9 .000
MDD—relapse 287 277
BPAD 78 65

Number of failed antidepressant trials 5.7 9.0 6.1 6.5 0.48 .49
Age of illness onset 28.7 13.8 26.1 14.0 2.4 .02
Number of episodes 5.5 5.9 5.0 6.1 1.0 .32
Illness duration (years) 9.7 13.7 15.3 15.2 −3.7 .000
Baseline HAMD/MADRS 21.6 7.2 23.7 8.5 −4.3 .000
Left-sided resting motor threshold 48.9 17.2 48.3 15.4 0.39 .71
Right-sided resting motor threshold 52.9 14.2 53.7 11.7 −0.5 .62
Concurrently taking antidepressant medication (yes/no) 421/70 437/121 9.7 .002
Concurrently taking mood stabilizer medication (yes/no) 176/289 154/351 5.8 .02
Concurrently taking antipsychotic medication (yes/no) 203/232 279/325 0.02 .88

Comorbid diagnoses (number of subjects) Panic disorder 36 67 18.9 .002

PTSD 22 67
GAD 86 98
Type of TMS Left-sided 121 188 13.1 .02
Right-sided 232 256
Bilateral 132 132

MDD, major depressive disorder; BPAD, bipolar affective disorder; OCD, obsessive-compulsive disorder; GAD, generalized anxiety disorder;
HAMD, Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory.

Our analysis of predictors of response produced some
unpredicted, as well as some less surprising, results. The
relationship of illness duration to response is at least par-
tially consistent with previous research, which has gen-
erally identified less treatment-resistant patients as be-
ing more likely to respond to treatment (for example
[1, 23, 24]). We did not, however, find any difference in
response rates based on the number of failed antidepres-
sant medication trials. This may be explained by the high
number of failed trials (a mean of 5.8 ± 7.6) across the
board in our sample. rTMS response may well be better
in patients who have failed only one or two medications
but there is less likely to be differences in response rates
between, for example, patients who have failed five or
six medications so that the effect of number of medica-
tion trials does not necessarily appear apparent given the
degree of treatment resistance in our sample.
One of the more surprising findings, however, was
that the responder group was significantly older than
the nonresponder group (although only for the anal-
ysis based on the traditional definition of response).
Although the mean difference in age between responders
and nonresponders was small, the direction of this effect
was counter to that previously seen in the literature,[25]
especially in early rTMS studies. These studies proposed
a poorer response to rTMS in the elderly related to age
related greater increases in the scalp to cortex distance
in prefrontal brain regions than in motor cortex.[26] This
difference was proposed to lead to an “under dosing” of
the brain in more elderly subjects (and hence poorer re-
sponse) and some studies compensated for this by adjust-
ing stimulation intensity based on measures of scalp to
cortex distance.[1] However, it is possible that this issue
was only meaningful in early rTMS studies that were
using subthreshold stimulation intensities. The use of
higher intensities in most of the studies we have included
here may well have overcome this as an issue—above a
certain intensity level the vast majority of subjects, young
or old, may well get sufficient stimulation to the cor-
tex. One previous analysis suggested that the intensity
adjustment required to compensate for greater scalp to
cortex differences in prefrontal regions is of the order of
3–13.5%[27] : This is well within the range of the increase
of average stimulation intensity used in clinical rTMS
trials over the last 15 years. In this context it is certainly
interesting that we found greater responses in subjects
receiving treatment at higher intensities.
Given that this factor does not seem relevant, why
were responders older? The answer to this may lie in
looking at several of the other factors, especially illness
duration and recurrence of depression. There was clearly
a better response in patients with recurrent rather than
single episodes of depression and patients with shorter
illness duration. Patients with recurrent episodic depres-
sion would seem likely to be somewhat older than those
presenting with a single episode continuing over time
until they present for rTMS treatment.
The difference in response rates seen in patients re-
ceiving antidepressants and mood stabilizers at the time
of rTMS treatment was somewhat surprising and has not

Depression and Anxiety

 Research Article: rTMS in Depression
been reported previously as far as we are aware. Recent
meta-analyses have been inconsistent in the analysis of
whether rTMS is equally effective in medicated or un-
medicated patients[3, 28] and few studies have contrasted
these groups. All of the studies included in this analysis
required patients to have failed at least two medication
trials prior to undertaking rTMS and in none of the
trials were patients taken off medication prior to partic-
ipation. Therefore, the medication-free patients in this
sample were patients who had given up on medication
treatment usually after multiple failed trials. In this con-
text, they may be somewhat different from a subgroup of
the medicated patients who have received partial benefit
from medication treatment prior to rTMS. In this con-
text, they could be considered more treatment resistant
or less able to tolerate biomedical interventions.
The differences in response rates seen in the patient
groups receiving different forms of rTMS is also worthy
of note. A considerable body of research has explored
differences in response to left- versus right-sided rTMS
and differences between unilateral and bilateral treat-
ment (see meta-analysis summaries in [7, 29]). In fact,
data from quite a number of these studies is included
in this current analysis. Previous studies have failed to
find significant differences in response between left- and
right-sided rTMS.[7] It is possible that the greater re-
sponse to right-sided treatment seen here reflects a sub-
population of patients receiving priming stimulation on
the right, which we have previously shown to be better
than the standard right-sided treatment approach.[16] It
is less clear why bilateral treatment is associated with a
high response rate. A series of comparative trials that
we have conducted and included in this analysis have
failed to demonstrate differences in response between
bilateral treatment and either left- or right-sided unilat-
eral rTMS, as recently summarized in a meta-analysis
showing no differences between uni- and bilateral re-
sponse rates.[29] However, in one study included here,
bilateral stimulation was associated with a very high
response rate[14] and other reports have described im-
proved outcomes with bilateral stimulation compared to
unilateral.[8] Given the lack of blinding in the current
comparison, we do not feel that it justifies a shift from
unilateral to bilateral stimulation is the primary approach
to rTMS treatment.
It is also worthy of comment that the results question
whether a 50% cutoff is an appropriate determinant of
response for the purpose of studies exploring predictors.
Our data would argue that this produces groups that do
not reflect the clinical profile of changes in outcomes
with rTMS treatment. Twenty percent gives a better
approximation of the differences in response between the
groups and may be a better level to use in future studies,
for example those looking for genetic or neuroimaging
markers of response.
In conclusion, a sizeable proportion of patients (4–5
out of 10) appear likely to respond to rTMS treatment.
Improved outcomes of treatment are to be expected in
patients who are less ill at commencement of treatment,
7
have a shorter illness duration, and an episodic rather
than continuous illness course. There appears to be a
relationship with concurrent antidepressant and mood
stabilizer medication treatment that warrants further in-
vestigation and improved responses were seen where
higher stimulation intensities were used. It is notable
that although we uncovered and confirmed a number
of variables which influence clinical response, none of
these variables appear to have such a strong relation-
ship to clinical response to justify using them to base
decisions on whether patients should undertake treat-
ment or not. rTMS is an effective and useful clinical
treatment for patients with depression although ques-
tions remain as to the most effective way to apply this
intervention.
Conflict of interest. PBF has received equipment
for research from Cervel Neurotech, Medtronic Ltd.,
MagVenture A/S and Brainsway Ltd., and funds for re-
search from Cervel Neurotech. In the last 5 years, ZJD
received research and equipment in-kind support for an
investigator-initiated study through Brainsway Inc. ZJD
has also served on the advisory board for Hoffmann-La
Roche Limited and Merck and received speaker support
from Sepracor and Eli Lilly. KEH and RJA reported
no biomedical financial interests or potential conflicts of
interest.
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