Psychiatria Danubina, 2017; Vol. 29, No.

1, pp 31-38 Original paper

© Medicinska naklada - Zagreb, Croatia

EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE

rTMS IN TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD):
A PROSPECTIVE COHORT STUDY IN CROATIA
Igor Filipcic1,2,3, Zeljko Milovac1, Strahimir Sucic1, Tomislav Gajsak1, Ivona Simunovic Filipcic4,
Ena Ivezic1, Vjekoslav Aljinovic1, Ivana Orgulan1, Sandra Zecevic Penic1 & Zarko Bajic5
1
Psychiatric Hospital “Sveti Ivan”, Zagreb, Croatia
2
Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
3
School of Medicine, University of Zagreb, Zagreb, Croatia
4
Department of Psychological Medicine, University Hospital Center Zagreb, Zagreb, Croatia
5
Biometrika Healthcare Research, Zagreb, Croatia

received: 1.12.2016; revised: 17.1.2017; accepted: 23.1.2017

SUMMARY
Background: An increasing body of research suggest that repetitive Transcranial Magnetic Stimulation (rTMS) is effective and
safe treatment option for patients with major depressive disorder (MDD). The Psychiatric Hospital “Sveti Ivan“has the first TMS
laboratory with rTMS and deep TMS (dTMS) in Croatia. The objective of this study was to assess the efficacy, safety and tolerability
of augmentative rTMS treatment vs standard treatment in Croatian patients with major depressive disorder (MDD).
Subjects and methods: Total of 93 MDD patients were enrolled; 41 of them were treated by augmentative rTMS and 52 were
treated by standard (psychopharmacotherapy and psychotherapy) therapy only. We delivered rTMS to the left dorsolateral
prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration), 3000 pulses per session using a figure-eight coil,
minimum of 20 sessions during four weeks. Our key outcome was the change in Hamilton Depression Scale (HAM-D17) result from
baseline to 4th week. Our secondary outcomes were changes in Hamilton Anxiety (HAM-A) and WHOQOL-BREF scales.
Results: After four weeks the changes of HAM-D17 and HAM-A results were significantly different between the group of patients
treated by augmentative rTMS (48% and 53% decrease, respectively) and the group of patients treated by the standard therapy alone
(24% and 30% decrease) (P=0.004, P=0.007). Absolute benefit increase defined as the difference between rates of remission (HAM-
D17 ≤7) in rTMS and control group was 33% (P=0.001). Number of patients needed to treat with rTMS in order to achieve
remission in one patient was NNT=3. In a group of patients treated with augmentative rTMS 21/41 (51%), and in control group
17/52 (33%) were responders (P=0.071).
Conclusions: It seems that augmentative treatment with rTMS is more effective on depression and anxiety symptoms than
standard therapy in MDD with equal safety and tolerability. Randomized, controlled studies are required to verify this finding.

Key words: repetitive transcranial magnetic stimulation (rTMS) - major depressive disorder (MDD) - anxiety

* * * * *

INTRODUCTION magnetic induction. The TMS coil device modulates the

electrical activity of the brain using a magnetic field.
Depression is now the leading cause of disability Depressive disorder rTMS treatment usually involves
worldwide and it is a major contributor to the overall one of three protocols: high frequencies rTMS (HF
global burden of disease (WHO 2016). Clinical res- rTMS) protocol, which is applied to the left dorsolateral
ponse cannot be achieved to antidepressant pharmaco- prefrontal cortex (DLPFC); low frequency rTMS (LF
therapy or psychotherapy in more than 30% of patients rTMS) protocol applied to the right DLPFC and bila-
(Rush et al. 2003). Patients which have been diagnosed teral HF / LF rTMS.
with a major depressive disorder (MDD), but who fail to The selection of DLPFC as a cortical target for
experience sufficient response after adequate rounds of rTMS application is based on pathophysiological chan-
pharmacotherapy or psychotherapy are called treatment- ges. Functional images of the brain in depressed patients
resistant depression (TRD) patients. showed a decrease in cortical blood flow, glucose and
With the development of neuroscience, technology oxygen consumption in the left frontal region (Kennedy
and psychiatry, we are now able to treat TRDs with et al. 1997), reflecting a hypometabolic state, accom-
repetitive transcranial magnetic stimulation (rTMS). It panied by hypermetabolism in the right prefrontal areas
is safe and efficacious, noninvasive brain stimulation (Bench et al. 1995). DLPFC is synaptically connected to
treatment for medication resistant MDD (Liu et al. the limbic system which takes part in the regulation of
2014). Repetitive transcranial magnetic stimulation mood (striatum, thalamus and anterior cingulate cortex)
(rTMS) is a neurostimulation and neuromodulation (Paus et al. 2001). It is believed that rTMS over the
technique. It is based on the principle of electro- DLPFC modulates brain network involved in the

31
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER(MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

regulation of mood and affects various neurotrans- SUBJECTS AND METHODS

mitters. Lan and colleagues (2016) described the
structural changes in the brain (gray matter volume Study design
increased by 3.5-11.2%) in patients with a depressive
disorder after rTMS treatment (Lan et al. 2016). Four This prospective cohort study was done during 2016
regions in which they detect these changes were: left at Psychiatric Hospital Sveti Ivan, Zagreb, Croatia. The
anterior cingulate cortex, the left insula, left superior study protocol was approved by the Ethics Committee
temporal gyrus and the right angular gyrus. Increase in of Psychiatric Hospital Sveti Ivan. Informed consent
the volume of the left anterior cingulate cortex was obtained from all patients. The study complied with
correlated with improvement of depression severity World Medical Association Declaration of Helsinki
(Lan et al. 2016). 2013 (World Medical Association 2013).
The first attempts at treating depressive disorder
with rTMS are shown in a study by George and Subjects
colleagues in 1995 after which numerous papers were The targeted population was patients of both sexes,
published on this topic (George et al. 1995). A large diagnosed with major depressive disorder (ICD-10: F32
number of randomized controlled trials (RCTs) and and F33) who were treated in a psychiatric hospital as
meta-analyses supported the antidepressant effect of outpatients, in daily hospital or who were hospitalized.
TMS in patients with MDD when it was used in daily Inclusion criteria were: ICD-10 and DSM-V major
sessions over several weeks directed to the dorsolateral depression disorder, single or recurrent episode,
prefrontal cortex (DLPFC). Two large, multicenter, treatment resistant depression (according to the Croatian
randomized controlled trials showed superior anti- clinical guidelines for treatment of depressive disorder,
depressant efficacy of rTMS over sham rTMS. In the Mihaljevic et al. 2013) and ages between 20 and 70.
study by O’Reardon and colleagues, in 2007, 301 Exclusion criteria were previous treatment with TMS,
patients with TRD were treated with placebo or active feromagnetic material close to the head, cardiac
rTMS over the left frontal cortex (DLPFC). After 6 pacemaker, and implanted electronic device, history of
weeks, patients in the active TMS group were about uncontrolled epilepsy, suicidal ideation. We chose a
twice as likely to achieve remission compared to consecutive sample of patients by the order of their
patients in the placebo group (MADRS: 14.2% versus arrival at the exam during the enrollment period.
5.2%, HAMD 17: 15.5% versus 7.1%, HAMD 24,
17.4% versus 8.2%). Antidepressant effects were Needed sample size
greater in TRD patients with less medication resistance
(O’Reardon et al. 2007). In 2008, with the support of Power analysis was performed before the start of the
this and other similar research FDA (Food and drug enrollment. A sample size of 68 achieves 80% power at
administration) approved rTMS device for clinical p<0.05 to detect a standardized effect size f≥0.20 which
treatment of TRDs. Another multicenter study involving corresponds to partial eta squared of η2=0.04 of the
a larger number of patients was the study by George and repeated measures analysis of variance within-between
colleagues in 2010. It was conducted on 190 patients interaction. Expecting up to 15% of respondents lost to
with MDD who were not taking their medications. A follow up, the initially needed sample size was
protocol of 10 Hz in the left prefrontal cortex with determined to be n=80 with equal sizes of two study
motor threshold to 120% (3000 pulses per session) was groups. Power analysis was done in PASS 14 Power
Analysis and Sample Size Software (2015) (NCSS,
applied through three weeks of daily treatment.
LLC, Kaysville, Utah, USA).
Remission was achieved in 14.1% of patients of the
active group compared to 5.1% in the placebo group
(George et al. 2010). Outcomes
In a meta-analysis which studied the clinical Our key outcome was the change in Hamilton
response, remission, and the rate of discontinuation of Depression Scale (HAM-D17) result from baseline to
therapy during treatment with HF rTMS, data were 4th week. HAM-D17 is a gold standard measure of the
involved from 29 randomized controlled trials with a severity of depressive symptoms (Hamilton 1960, Bodo
total of 1371 patients (Berlim et al. 2014). After an et al. 2016). Our secondary outcomes were the pro-
average of 13 sessions, clinical response was 29.3% and portion of patients experiencing remission of symptoms
remission 18.6%, three times more than among those defined as HAM-D17 score ≤7, proportion of patients
who received placebo therapy (Berlim et al. 2014). experiencing a positive response to treatment defined as
The Psychiatric Hospital “Sveti Ivan“ is the first the reduction in total score of >50% (Cusin et al. 2009),
hospital in Croatia to perform rTMS in therapeutic changes in results of Hamilton Anxiety Scale (HAM-
purposes. The objective of this study was to examine the A14) (Hamilton 1959) and four dimensions of The
efficacy, safety and tolerability of HF rTMS in treat- World Health Organization Quality of Life question-
ment of MDD in Croatian patients. naire (WHOQOL-BREF) (World Health Organization

32
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER (MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

1993). HAM-A14 is originally clinician based ques- and number of somatic illnesses were controlled as
tionnaire (Thomson 2015). The four WHOQOL-BREF covariates. Partial eta squared (η2) was given as the
dimensions were: physical health (items 3,4,10,15, standardized effect size. Statistical data analysis was
16,17,18), psychological health (items 5,6,7,11,19,26), done by NCSS 10 Statistical Software (2015) (NCSS,
social relationship (items 20,21,22) and environment LLC. Kaysville, Utah, USA).
(items 8,9,12,13,14,23,24,25) (World Health Organiza-
tion 1996). HAM-D17 and HAM-A14 were admini- RESULTS
stered by experienced and trained clinical rates, psychia-
trists at baseline and after four weeks. WHOQOL-BREF Total sample of 93 patients were enrolled; 41 of
was administered by patients themselves. them allocated to the rTMS treatment, and 52 allocated
to the standard treatment (Figure 1). Two study groups
Independent variable were comparable in terms of sex, age, work status,
Our independent variable was treatment with aug- diagnosis, existence of psychotic symptoms and psycho-
mentative rTMS and standard therapy versus treatment tropic medication (Table 1). However, there were
with standard therapy (psychopharmacotherapy and several potentially clinically relevant differences bet-
psychotherapy) alone. Patients were allocated in the ween two groups that we tried to control by multivariate
study groups accordingly to their subjective preferences analysis. Patients in rTMS group were better educated,
and physician estimated tolerability based on initial more often in a relationship, with somewhat longer
mapping procedure. We delivered rTMS to the left duration of primary psychiatric illness and less
dorsolateral prefrontal cortex at 120% motor threshold psychiatric comorbidities.
(10 Hz, 4-second train duration), 3000 pulses per
session for a minimum of 4 weeks using a figure-eight Assumptions of ANCOVA
coil. Each patient received a minimum of 20 sessions.
Hamilton Depression Scale at baseline and at 4th
All patients continued taking psychopharmacotherapy
week in both group did not significantly deviate from
during their HF rTMS treatment.
the theoretically expected normal distribution (in rTMS
group: Shapiro-Wilk statistic =0.99, df=40, p=0.851; in
Possible confounders control group: Shapiro-Wilk statistic =0.97, df=49,
Possible confounders whose effect we tried to p=0.281). Only the distribution of HAM-D17 in rTMS
control by multivariate analysis were sex, age, group at 4th week follow up may be considered mode-
education, marital status, work status, diagnosis, rately skewed (0.56). Other three distributions were
existence of psychotic symptoms, duration of primary approximately symmetrical with skewness <0.32. At
psychiatric illness, hospitalization or treatment in daily baseline, mean and median were the same in control
hospital or outpatients, severity of MDD at enrollment group and irrelevantly different in rTMS group
measured by the Clinical Global Impression-Severity (mean=17, median=18) what indicates that distributions
(CGI-S) scale, number of previous psychiatric hospi- were symmetrical. At 4th week follow up, mean and
talizations, number of psychiatric comorbidities, and median were the same in control group, and irrelevantly
number of somatic illnesses. different in rTMS group (mean=9, median=8). In
control group we detected 2 (3.8%) outliers in the
Statistical analysis baseline HAM-D17 measurement with z>2.58, and 1
(2.0%) in 4th week follow-up. In HAM-A14, in control
The level of statistical significance was set at group, we detected 1 (2.2%) outlier at baseline and 2
p<0.05, and we gave all confidence intervals at 95% (4.3%) at 4th week follow-up. All secondary outcomes
level. In all instances, we used two-tailed tests. Diffe- were approximately normally distributed except HAM-
rences between baseline measurement and the measure- A14 in rTMS group. Skewness of this distribution was
ment at 4th week follow-up were expressed as absolute 1.09, and kurtosis was 0.30. In all cases Levene’s test of
and relative changes. The main statistical data analysis equality of error variances did not indicate significant
was done by analysis of covariance. Normality of heterogeneity.
univariate distributions were tested by Shapiro-Wilk
test, and analysis of skewness and kurtosis. Outliers
Main results
were defined as the cases with standardized values
z>2.58. As the sensitivity analysis we repeated the After four weeks, Hamilton Depression Scale and Ha-
analysis with and without removal of outliers. milton Anxiety Scale results were statistically signifi-
Homogeneity of variances was tested by Levene’s test. cantly different between the group of patients treated by
Age, education, marital status, work status, diagnosis, rTMS and standard therapy (48% and 53% decrease,
psychotic symptoms, mode of treatment, number of respectively) and the control group treated by the stan-
psychiatric hospitalizations, Clinical global impression - dard therapy only (24% and 30% decrease), after adjust-
severity (CGI-S), number of psychiatric comorbidities, ment for HAM-D17, HAM-A14 and WHOQOL-BREF

33
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER(MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

Table 1. Participants´ baseline characteristics and psychotropic medication used during the trial
Control (n=52) rTMS (n=41)
Sex
male 18 (34.6) 15 (36.6)
female 34 (65.4) 26 (53.4)
Age (years), median (IQR) 55 (49-61) 53 (42-61)
Education
primary 5 (9.6) 1 (2.4)
secondary 37 (71.2) 25 (61.0)
university 10 (19.2) 15 (36.6)
Marital status
in a relationship 26 (50.0) 24 (58.5)
single 26 (50.0) 17 (41.5)
Work status
employed 24 (46.2) 16 (39.0)
unemployed 9 (17.3) 12 (29.3)
retired 19 (36.5) 13 (31.7)
CLINICAL CHARACTERISTICS
Diagnosis
depressive episode (F32) 9 (17.3) 9 (22.0)
recurrent depressive disorder (F33) 43 (82.7) 32 (78.0)
Psychotic symptoms 10 (19.2) 8 (19.5)
Duration of illness (years), median (IQR)* 3 (1-10) 5 (0-11)
Mode of treatment
outpatients 0 (0.0) 21 (51.2)
daily hospital 12 (23.1) 3 (7.3)
hospitalized 40 (76.9) 17 (41.5)
Number of psychiatric hospitalizations, median (IQR) 2 (1-6) 3 (1-7)
Clinical global impression - severity (CGI-S)
up to moderately ill 31 (59.6) 21 (51.2)
significantly ill 13 (25.0) 18 (43.9)
severely or very severely ill 8 (15.4) 2 (4.9)
Number of psychiatric comorbidities
none 14 (26.9) 10 (24.4)
one 23 (44.2) 26 (63.4)
two or more 15 (28.8) 5 (12.2)
Number of somatic illnesses
none 19 (36.5) 16 (39.0)
one 12 (23.1) 9 (22.0)
two 6 (11.5) 9 (22.0)
three or more 15 (28.8) 7 (17.1)
PSYCHOTROPIC MEDICATION
Anxiolytics 41 (78.8) 31 (75.6)
SSRI 16 (30.7) 12 (29.2)
SNRI 20 (38.4) 14 (34.1)
NaSSA 19 (36.5) 9 (21.9)
DNRI 3 (5.7) 2 (4.8)
SARI 6 (11.5) 3 (7.3)
Other antidepressants 6 (11.5) 6 (14.6)
Overall 2nd generation antidepressants 38 (73.0) 34 (82.9)
Data are presented as number (percentage) of participants if not stated otherwise
Abbreviations: IQR = interquartile range; SSRI = selective serotonin reuptake inhibitors;
SNRI = serotonin and norepinephrine reuptake inhibitors; NaSSA = noradrenergic and specific serotonergic antidepressants;
DNRI = norepinephrine-dopamine reuptake inhibitors; SARI = serotonin antagonist and reuptake inhibitors
* Duration of primary psychiatric diagnosis

34
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER (MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

baseline values as well as for patients age, education, of remission (HAM-D17 ≤7) in rTMS and control group
marital status, work status, diagnosis, psychotic was ABI=33%. Relative benefit increase was
symptoms, mode of treatment, number of psychiatric RBI=201%. Number of patients needed to treat with
hospitalizations, Clinical global impression - severity rTMS in order to achieve remission in one patient was
(CGI-S), number of psychiatric comorbidities, and NNT=3. In a group of patients treated with augmen-
number of somatic illnesses (Table 2). Proportion of tative rTMS 21/41 (51%), and in control group 17/52
patients achieving remission defined as HAM-D17 ≤7 (33%) were responders (a decrease in HAM-D scores of
points was significantly and clinically relevantly higher at least 50%) (P=0.071). We have not observed signi-
in rTMS than in control group (Table 2). Absolute ficant differences in changes of WHOQOL-BREF four
benefit increase defined as the difference between rates dimensions.

Table 2. Differences in depression, anxiety and quality of life indicators from baseline to 4 weeks later
Control (n=52) rTMS (n=41)
Baseline After 4 weeks ∆ ∆% Baseline After 4 weeks ∆ ∆% P Effect
HAM-D17 18 (6.8) 13 (6.5) -4.9 24% 17 (5.7) 9 (6.0) -8.1 48% 0.004 0.10
Remission (≤7), n (%) 4 (7.7) 12 (23.1) 15.4 200% 1 (2.4) 20 (48.8) 46.4 1933% 0.001 0.13
Response (>50%) 17 (32.7) 21 (51.2) 18.5 57% 0.071 0.19
HAM-A14 22 (10.8) 15 (8.0) -6.7 30% 21 (8.6) 10 (7.7) -11.3 53% 0.007 0.09
WHO BREF
Physical 46 (19.4) 43 (25.1) -3.1 7% 40 (16.6) 43 (18.4) 2.5 6% 0.504 0.01
Psychological 44 (21.6) 49 (18.3) 5.0 11% 36 (19.7) 45 (20.1) 9.0 25% 0.872 0.00
Social 49 (24.3) 52 (23.7) 3.2 6% 46 (23.5) 50 (21.2) 3.4 7% 0.423 0.01
Environment 57 (17.8) 62 (17.6) 5.4 9% 61 (15.0) 65 (17.5) 3.8 6% 0.276 0.02
Data are presented as mean (standard deviation) if not stated otherwise
Abbreviations: HAM-D17 = Hamilton Depression Scale; HAM-A14 = Hamilton Anxiety Scale; WHO BREF = World
Health Organization Quality of Life Brief Questionnaire dimensions; ∆ = absolute difference between the baseline and
measurement after 4 weeks; ∆% = relative difference calculated as absolute difference divided by the baseline value;
P = analysis of covariance, statistical significance of the difference at 4th week follow up adjusted for baseline values of all
outcomes and for age, education, marital status, work status, diagnosis, psychotic symptoms, mode of treatment, number of
psychiatric hospitalizations; for Remission and Response Pearson Chi-Square; Clinical global impression - severity (CGI-S),
number of psychiatric comorbidities, number of somatic illnesses, Effect = partial eta squared (η2) given as the standardized
effect size for numeric variables; Cramer’s V given for categorical variables

Figure 1. Study flow

35
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER(MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

Figure 2. HAM-D17 at baseline and at 4th week follow up; error bars represent 95% confidence intervals

Figure 3. HAM-A14 at baseline and at 4th week follow up; error bars represent 95% confidence intervals

DISCUSSION Although our study was not randomized and our

control condition was not sham coil, the results are
Our study showed that HF rTMS was more effective similar to first meta-analysis exploring the efficacy of
and equally tolerable as the standard procedure in MDD augmentative rTMS for TRD (Liu et al. 2014). In that
in Croatian patients. meta-analysis seven RCTs were included. Results from
The efficacy of HF rTMS of the left DLPFC in de- six RCTs showed that as a whole, 68/146 (46.6%) and
pression is broadly documented (Lefaucher et al. 2014), 15/84 (22.1%) subjects in the active or sham rTMS
although results from different studies vary with regard groups were classified as responders, respectively. Also,
to the level of this efficacy (e.g., Loo et al. 1999, Rumi in meta-analysis by Fitzgerald et al. (2016) which
et al. 2005). In our study after four weeks of treatment studied the rate of clinical response and remission, and
with augmentative rTMS in MDD patients, a significant the demographic and clinical predictors of response to
decrease (48%) in scores on the Hamilton depression rTMS from 11 clinical trials, remission rate was 31%,
rating scale HAM-D (from 17 to 9) (Figure 2) was and the rate of clinical response was 46%. The results
observed, as well as significant decrease (53%) on from our study showed that in a group of patients
HAM-A (from 21 to 10) (Figure 3). Although not sta- treated with rTMS in combination with medication
tistically significant, we noticed indicative improve- 21/41 (51.2%) were responders (a decrease in HAM-D
ment in quality of life, particularly with regard to their scores of at least 50%) and 21/41 (51.2%) remitters
psychological health (25%). After 4 weeks of treat- (scores in HAM-D of 7 or less).
ment, control group of patients with MDD showed Antidepressants are first line in the treatment of major
decrease (24%) in scores on the Hamilton depression depressive disorder, and all of our patients were treated
rating scale HAM-D (from 18 to 13) and decrease with these drugs prior to TMS therapy. In our study, both
(30%) on HAM-A (from 22 to 15) (Figures 2 and 3). groups received psychotropic medication in adequate and
Patients in the group treated with augmentative rTMS comparable doses but TMS group showed significantly
compared to patients in control group have larger de- greater decrease in HAM-D score HAM-A scores. Earlier
crease in HAM-D 17: 48% versus 24%, and in HAM-A studies have shown that rTMS hastens the response to
14: 53% versus 30%. antidepressant drugs in patients with major depressive

36
 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
Sandra Zecevic Penic & Zarko Bajic: EFFICACY, SAFETY AND TOLERABILITY OF AUGMENTATIVE rTMS IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER (MDD): A PROSPECTIVE COHORT STUDY IN CROATIA Psychiatria Danubina, 2017; Vol. 29, No. 1, pp 31-38

disorder (Rossini et al. 2005). Also, after the failure of analysis. Third, the outcome assessment was not done
medications, rTMS significantly increases the effect of independently and blindly. The effect of this bias was
antidepressants (Liu et al. 2014). More specifically, most likely against the null hypothesis. Future studies
rTMS accelerated the onset of action and augmented the with independent outcome assessment are needed in
response to amitriptyline (Rumi at al. 2005), and as an order to verify our findings.
add-on strategy of clinical significance in combination
with escitalopram in patients with major depression resis- CONCLUSION
tant to non-tricyclic antidepressants (Bretlau et al. 2008).
In this study, we observed some improvement in It seems that augmentative treatment with HF rTMS
quality of life of patients, particularly in psychological is more effective on depression and anxiety symptoms
health, but it was not statistically significant. Some than standard therapy in MDD with equal safety and
other studies described statistically significant improve- tolerability. Randomized, controlled studies are required
ments in quality of life after four week treatment. Solva- to verify this finding.
son et al. (2014) observed statistically significant impro-
vement in both functional status and QOL ((SF-36) and
(Q-LES-Q)) outcomes in patients treated with active Acknowledgements:
TMS compared with sham TMS during the acute phase
Authors wish to acknowledge the work of all patients,
of the randomized, sham-controlled trial (Solvason et al. physicians, and medical nurses who took part in the
2014). Janicak and colleagues (2013) informed of data collection.
significant improvement in functional status on a broad The study was funded by Psychiatric Hospital Sveti
range of mental health and physical health domains on Ivan, Zagreb, Croatia.
the SF-36 following acute TMS treatment). Similarly,
statistically significant improvement in patient-reported Conflict of interest: None to declare.
QOL was observed on all domains of the EQ-5D and on
the General Health Perception and Health Index scores. Contribution of individual authors:
Berlim et al. (2011) found significant increase in the Igor Filipcic was involved with study design, data
WHOQOL BREF scores for the global, physical and collection, data interpretation, and manuscript
psychological QOL domains from baseline to week four preparation.
in naturalistic trial, on 15 TRD patients. Zeljko Milovac participated in the writing and multiple
edits of the manuscript drafts and data collection.
Several clinical trials have confirmed the safety of Strahimir Sucic, Tomislav Gajsak, Vjekoslav Aljinovic,
rTMS. Induction of seizure is the most severe adverse Ivana Orgulan and Sandra Zecevic Penic partici-
effect, but given the small number of cases of seizures pated in data collection.
caused by rTMS, it is clear that the risk is extremely low Ivona Simunovic Filipcic and Ena Ivezic reviewed the
(Del Osso et al. 2011). More often there are minor side manuscript drafts.
effects in the sense of discomfort during the stimulation, Zarko Bajic performed the statistical analyses and
data interpretation
local pain, pain in the neck, transient hearing changes
and headaches after stimulation (Del Osso et al. 2011).
In our study only few patients receiving rTMS reported References
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 Igor Filipcic, Zeljko Milovac, Strahimir Sucic, Tomislav Gajsak, Ivona Simunovic Filipcic, Ena Ivezic, Vjekoslav Aljinovic, Ivana Orgulan,
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Correspondence:
Igor Filipcic, MD, PhD
Psychiatric Hospital “Sveti Ivan”
Jankomir 11, pp68, HR-10 090 Zagreb, Croatia
E-mail: igor.filipcic@pbsvi.hr

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