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Neuro Endocrinol Lett 2007; 28(1):33–38
ORIGINAL ARTICLE
Neuroendocrinology Letters Volume 28 No. 1 2007
The effect of repetitive transcranial magnetic
stimulation (rTMS) add on serotonin reuptake
inhibitors in patients with panic disorder:
A randomized, double blind sham controlled study
Ján P, Richard Z, Martin B, Jiří H, Miloslav K,
Tomáš N & Beata P
Prague Psychiatric Center, 3rd Faculty of Medicine, Charles University in Prague, Center of
Neuropsychiatric Studies, Prague, Czech Republic
Head of the Prague Psychiatric Center: Prof. Cyril Höschl, MD., DSc.
Correspondence to: Ján Praško MD.
Prague Psychiatric Center,
Ústavní 91, 181 03 Prague 8, Czech Republic
FAX: +420266003366
EM AIL: prasko@pcp.lf3.cuni.cz
Submitted: August 5, 2006 Accepted: August 12, 2006
Key words: panic disorder; repetitive transcranial magnetic stimulation; rTMS;
antidepressants
Neuroendocrinol Lett 2007; 28(1):33–38 PMID: 17277734 NEL280107A01 © 2007 Neuroendocrinology Letters www.nel.edu
Abstract BACKGROUND: Transcranial magnetic stimulation (rTMS) can modulate cortical
activity. The goal of our study was to assess whether rTMS would facilitate effect of
serotonin reuptake inhibitors in patients with panic disorder.
METHODS: Fifteen patients suffering from panic disorder resistant to serotonin
reuptake inhibitor (SRI) therapy were randomly assigned to either active or to
sham rTMS. The aim of the study was to compare the 2 and 4 weeks efficacy of the
10 sessions 1 Hz rTMS with sham rTMS add on SRI therapy. We use 1 Hz, 30 min-
utes rTMS, 110% of motor threshold administered over the right dorso-lateral
prefrontal cortex (DLPFC). The same time schedule was used for sham administra-
tion. Fifteen patients finished the study. Psychopathology was assessed using the
rating scales CGI, HAMA, PDSS and BAI before the treatment, immediately after
the experimental treatment and 2 weeks after the experimental treatment by an
independent reviewer.
RESULTS: Both groups improved during the study period but the treatment effect
did not differ between groups in any of the instruments.
CONCLUSION: Low frequency rTMS administered over the right dorso-lateral
prefrontal cortex after 10 sessions did not differ from sham rTMS add on serotonin
reuptake inhibitors in patients with panic disorder.
34
Copyright © 2007 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Ján Praško, Richard Záleský, Martin Bareš, Jiří Horáček, Miloslav Kopeček, Tomáš Novák & Beata Pašková
Introduction
Panic disorder is chronic psychiatric disorder. Only
approx. 25% patients reach full remission after drug
therapy over four years follow up (Katschnig et al.,
1995). One way to increase proportion of patients with
full remission is cognitive behavioral therapy. This
kind of therapy is effective but is not available to all
patients. So another therapeutic modality in patients
with panic disorder are tested. Repetitive transcranial
magnetic stimulation (shortly rTMS) is based on the
electromagnetic field induction (duration of 100–200 ms,
2T intensity) using the coil placed over the skull. The ef-
fect is neuronal depolarisation within the depth of 2cm
(depending on distance of coil from underlying cortex)
from head surface (George, et al., 1999). Mechanism of
action of TMS in neuropsychiatric disorders is not yet
fully known. It was observed that low frequency TMS
reduced cerebral glucose metabolism in cortical and sub-
cortical regions immediately after application as revealed
by PET and SPECT imaging studies (Speer et al., 2003)
. Nevertheless, there are completely opposite findings
(Stallings et al., 1997, Kimbrell et al., 1999). Studies using
high frequency TMS as treatment of depression disorders
coupled with SPECT mapping of cerebral activity and
rCBF showed increased rCBF in the site of stimulation
(over the left dorso-lateral prefrontal cortex – LDPFC)
as well as changes in remote regions (Catafau et al., 2001,
Nahas et al., 2001). Prefrontal rTMS can affect memory
(Pascual-Leone et al. 1996), mood (George et al. 1996)
in healthy individuals and may act as an antidepressants
(Pacual-Leone at al. 1996). There are only few studies
using rTMS in panic disorder.
One case report described application of low frequency
rTMS (1Hz) over the righ dorso-lateral prefrontal cortex
in patient with panic disorder resulting in a marked
improvement, maintained for 4 weeks (Zwanger et al.,
2002). Second small case-series presented a modest and
partial symptom improvement in three patients with
panic disorder but improvement did not seem to be clini-
cally relevant (Garcia-Toro et al., 2002). This finding is
in agreement with our study where we found correlation
of symptomatology with regional metabolic changes in
patients with panic disorder in rest conditions (Paskova
et al., 2003). Positive correlation between severity of
symptoms and intensity of 18FDG PET uptake in right
fronto-temporal area were detected. These areas seem to
be possible candidate locations for rTMS. Positive cor-
relation between metabolism and intensity of symptoms
suggested further application of low frequency rTMS,
which decrease metabolism in the area of administra-
tion.
The general aims of our randomized, double blind,
sham controlled rTMS study was to assess the therapeu-
tic effect the low frequency rTMS add to SRI in patienst
with panic disorder. Null hypothesis was:
rTMS will have no impact on the symptomatology
in the patients with panic disorder
•
Alternative hypothesis was:
rTMS will have significant impact on the symp-
tomatology of panic disorder comparing with
sham rTMS.
Methods
Subjects
Fifteen patients with panic disorder according to
ICD-10 research diagnostic criteria for panic disorder
or for panic disorder with agoraphobia; treated with
SRIs minimaly for 6 weeks before the study and did not
respond to this medication, were randomly allocated to
active rTMS or sham rTMS after initial assessment.
Including criteria:
ICD-10 research critaria for panic disorder or for
panic disorder with agoraphobia
Non-responders on SRIs (at least 6 weeks treatment)
Age 18–45 years
Written informal consensus
Excluding criteria:
Major depressive disorder
Risk of suicidality
17-item HAMD more than 16
Organic psychiatric disorder
Psychotic disorder in history
Abusus of alcohol or other drugs
Serious somatic disease
Patients using non-prescribed medication
Gravidity or lactation
Epilepsy or pathological EEG
Patients with implantats of pacemakers
Including criteria were confirmed with 2 independent
raters.
Criteria for exclusion during the study (drop out):
Fulfilling the excluding criteria
Patient do not collaborate
Decision of researcher in the case of health prob-
lems of patients
The study was designed as a double-blind, therefore
rTMS was performed by a psychiatrist trained in rTMS
application and rating was provided by another trained
psychiatrist blind to rTMS therapy. Patients were ran-
domly assigned to the two treatment groups:
1st group – treated with active rTMS
2nd group – treated with sham rTMS
Technical devices
Magstim Super Rapid stimulator (Whitland, UK)
with an air cooled, figure-eight 70-mm coil was used for
10 sessions (5 sessions per week for 2 weeks) The fre-
quency of 1Hz rTMS at 110% of motor threshold (MT)
was administered over the right DLPFC for 30 min., with
•
a,
b,
c,
d,
a,
b,
c,
d,
e,
f,
g,
h,
i,
j,
k,
a,
b,
c,
•
•
35
Neuroendocrinology Letters Vol.28 No.1, 2007 • Article available online: http://node.nel.edu
The effect of rTMS add on serotonin reuptake inhibitors in patients with panic disorder
the total number of 1 800 pulses per session. The right
DPLFC stimulation site was defined as the region 5 cm
rostral in the same sagittal plane as the optimal site for
MT production in the left abductor pollicis brevis. MT
was assessed as the lowest strength of TMS needed to
elicit 5 or more electromyographic responses (EMG,
Neurosign 400 equipment) ≥50 V within ten trials. The
sham stimulation was defined with a coil diverted by
90 degrees over the same area and same intensity and
design as real rTMS.
Ratings
General psychopathology was assessed by Clini-
cal Global Impression (CGI – Guy 1976); anxiety was
objectively measured with HAMA – Hamilton Rating
Scale for Anxiety (Hamilton 1959) and self report BAI
– Beck Anxiety Inventory (Beck a Emery 1985). Severity
of symptomatology was measured with PDSS – Panic
Disorder Severity Scale (Shear et al 1997). Rating scales
were administered the day before first rTMS administra-
tion (week 0), then after 2 weeks (after 10 stimulation)
(week 2) and after 4 weeks (2 weeks after last stimulation)
(week 4).
Ethical issues
Investigation was carried out in accordance with the
latest version of the Declaration of Helsinki and the writ-
ten informed consent was obtained from all subjects after
the nature of the procedures had been fully explained.
The local ethic Committee of Prague Psychiatric Center
and Mental Hospital Bohnice approved this project.
Statistics
All data are presented as the mean and SD. Patient’s
demographic and baseline clinical characteristics were
compared between treatment groups and analyzed using
the two-sample t-test or the Mann-Whitney U test and
chi-square test or Fisher’s exact test for continuous and
categorical variables, respectively. Results were analyzed
using non-parametric repeated measure analysis of
variance (Friedman’s test with post hoc Wilcoxon signed
rank test with a Bonferroni correction for multiple
comparisons) and Mann-Whitney U-tests for intra- and
inter-group comparisons respectively. Results were con-
sidered significant if p<0.05. Statistical computing was
performed with Statsoft Statistica version 7.0 software.
RESULTS
Description of the patient groups
There were thirty three patient referred to the Prague
Psychiatric centre for resistant panic disorder. Twenty
one of them fulfilled the diagnostic including criteria
to the study but only fifteen signed informed consensus
(Table 2). Fifteen patients was randomized to two study
groups. The patients had been receiving stable pharma-
cological treatment (antidepressants) for 6 weeks before
study enrollment and during the study.
There were no statistically significant differences
between the active and sham groups in terms of de-
mographic characteristics such as age, marital status,
duration of the disorder and dose of antidepressant
medication (calculated to the paroxetine equivalents:
paroxetine 20 mg = citalopram 20 mg or fluoxetine 20 mg,
or sertralin 50 mg or venlafaxin 75 mg). The groups sig-
nificantly differed in education; more patients from the
sham group finished secondary school than from rTMS
group. The demographic and medication baseline data
of completers are presented in the Table 3.
There were no statistically significant differences
between the active and sham groups in the average
scores of psychopathology rating scales of CGI, HAMA,
Table 1. Time table for using the measures.
Measurements Week 0 Week 2 Week 4
ICD-10 X
MINI X
CGI-S XXX
PDSS XXX
HAMA XXX
BAI XXX
ICD-10 = The International Classification of Disorders, 10th revision
MINI = Mini-International Neuropsychiatric Interview
CGI-S = Clinical Global Impression-Severity
PDSS = Panic Disorder Severity Scale
HAMA = Hamilton Anxiety Rating Scale
BAI = Beck Anxiety Inventory
Table 2. Patients included and excluded from the study.
Patients referred to the PCP 33
Including diagnostic criteria reached 21
Signed informed consensus 15
Completers 15
Table 3. Demographic data.
rTMS Sham Statistics
number 7 8
age 33.7±9.2 33.8±12.2 UTT: n.s.
gender; male : female 1:6 3:5 chi2: n.s.
education:
basic : secondary : university 5: 1: 1 1 : 6 : 1 chi2:
p< 0.05
single : married 2 : 5 2:6 FET: n.s.
antidepressant medication
(equivalent of paroxetine)
20.0±1.6
mg
22.5±17.5
mg UTT: n.s.
duration of disorder
(years) 9.9±6.1 9.1±6.9 UTT: n.s.
UTT – unpaired t-test; FET - Fischer’s exact test,
chi2 – Chi-square test with Yates’ correction
36
Copyright © 2007 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Ján Praško, Richard Záleský, Martin Bareš, Jiří Horáček, Miloslav Kopeček, Tomáš Novák & Beata Pašková
PDSS and BAI. The baseline data from rating scales are
presented in the Table 4.
Pharmacotherapy
All patients followed with medication (SSRIs) which
they used before without any change during the study.
The average doses of antidepressant medication given on
Table 3. The mean doses (unpaired t-test) of the psycho-
pharmacs not differ between groups.
Rating scales
CGI – severity
There were not significant differences in the sever-
ity scores of Clinical Global Impression (CGI) in both
groups at the beginning (see Table 5). Severity scores
dropped significantly in both groups during the treat-
ment, but the differences between the groups after two
week of treatment and after another two weeks were not
significant (Mann Whitney U test: n.s.). Only one patient
from rTMS and 2 patients from sham rTMS groups
reached the score 2 immediately after treatment.
HAMA
HAMA is an objective rating scale for measuring
general symptoms of anxiety (not solely focused on panic
symptoms). At the beginning there were not significant
differences in the severity of HAMA scores between the
two groups. During the tretment statistically significant
decrease of total HAMA scores occurred in sham group
but not in rTMS group. However, no significant differ-
ence in mean total scores was found between two groups
after two week of treatment and after another two weeks
(Mann Whitney U test: n.s (p=0.054) – see Table 5).
There were 3 patients from rTMS group and 2 patients
from sham rTMS group who reached the 50% decrease
of the HAMA score after treatment.
PDSS
Panic Disorder Severity Scale (PDSS) is an instrument
for specific assessment of panic disorder. It is the most
sensitive instrument for this disorder. There were not
significant differences in the severity scores of PDSS in
both groups at the beginning (see Table 5). At the end of
Table 4. The rating scales before the treatment.
rTMS sham Statistics
test: p-value
mean SD mean SD
CGI – S 5.286 0.7559 4.625 1.188 MW: n.s.
HAMA 21.43 4.791 21.13 5.111 MW: n.s.
PDSS 17.86 3.338 16.25 4.464 MW: n.s.
BAI 34.86 10.07 25.38 14.21 MW: n.s.
MW = Mann-Whitney U test
Table 5. Mean scores in rating scales during the treatment.
rTMS sham Statistics
test: p-value
mean SD mean SD
CGI – S
Week 0 5.286 0.7559 4.625 1.188 n.s.
Week 2 4.143 1.345 3.75 1.488 n.s.
Week 4 3.714 0.488 2.75 1.165 n.s.
HAMA
Week 0 21.43 4.791 21.13 5.111 n.s.
Week 2 18.43 11.41 13.13 6.175 n.s.
Week 4 15.86 4.914 10.75 3.845 n.s. (p=0.054)
PDSS
Week 0 17.86 3.338 16.25 4.464 n.s.
Week 2 14.57 4.429 10.75 6.431 n.s.
Week 4 11.71 4.071 8.25 4.95 n.s.
BAI
Week 0 34.86 10.07 25.38 14.21 n.s.
Week 2 24.14 11.57 15.63 7.891 n.s.
Week 4 23.86 10.43 14.5 6.164 n.s. (p=0.072)
37
Neuroendocrinology Letters Vol.28 No.1, 2007 • Article available online: http://node.nel.edu
The effect of rTMS add on serotonin reuptake inhibitors in patients with panic disorder
treatment there was a significant decrease in total PDSS
scores in both groups. The difference between the groups
was not statistically significant in week 2 and week 4
(Mann Whitney U test: n.s.). No one from rTMS group
and 2 patients from sham rTMS group reached the 50%
decrease of the PDSS score after treatment.
BAI
There were no significant differences in the severity
of Beck Anxiety Inventory (BAI) scores between the
two groups at the beginning. Time path of BAI scores
is similar to that of HAMA. Statistically significant
decrease of total scores during the treatment occurred
in sham group but not in rTMS group. However, the
difference in the mean BAI total scores between the two
treatment groups was not statistically significant in week
2 and week 4 (Mann Whitney U test: n.s (p=0.072) – see
Table 5). There were 2 patients from rTMS group and 1
patient from sham rTMS group who reached the 50%
decrease of the BAI score after treatment.
Tolerability and safety
There were no seizures, headaches, neurological and
cognitive difficulties occurred.
Discussion
According to our hypotheses, the study has con-
firmed the null hypothesis – low frequency rTMS of
right dorsolateral prefrontal cortex had no significant
impact on the symptomatology in the patients suffering
with the panic disorder who did not respond to SSRIs.
There were sligthly better results in sham rTMS group.
But no significant differences between treatment groups
were detected. However the two groups were too small
to generalize these results. Our negative findings may be
related to type II error. Also we treated chronic patients
suffering with panic disorder in this study. There was
relatively long mean previous duration (9 years) of the
disorder in these patients. The question is how can rTMS
work in less chronic patients? How do patients respond
without any medication? Another question is wheather
the place of stimulation, duration and low frequency
of rTMS is optimal for patients with panic disorder?
Some studies indicated that for rTMS efficacy are very
important parameters of intensity, number of pulses or
number of sessions (Gerson et al., 2003). Some rTMS
studies in patients with depression showed that 10 ses-
sions could be insufficient even in therapy in patients
with depression (Gerson et al., 2003). Maybe for rTMS
effect in patients with panic disorder is necessary rTMS
therapy longer than 10 sessions. Another question is, if
the place of stimulation and low frequency of stimula-
tion are optimal for panic disorder patients? In our case
study (Zalesky et al., 2004) we presented patient with
panic disorder and agoraphobia which was treated with
high-frequency rTMS administered over the left dorso-
lateral prefrontal cortex for 2 weeks. After the treatment
there was an improvement in the scores of rating scales.
However the symptoms have worsened again after the
end of the treatment. This could indicate insufficient
duration of the therapy. Another case study described
effective high-frequency rTMS over the left frontal
cortex after the failure of low frequency rTMS over right
frontal cortex (Guaiana et al., 2005). That suggests that
high-frequency rTMS and application over the left-
frontal cortex could be effective. Choice of the place and
low frequency in our study was done according results
of hypermetabolism in panic patients on PET in this
region (Paskova et al., 2003). According the Hoffman
and Cavus (2002) hypothesis the low frequency rTMS
reduces hypermetabolism and hyperexcitability in the
brain regions. Functional neuroimaging studies (Shin et
al., 1997) suggest that patients with posttraumatic stress
disorder have the similar right-sided frontal activation
as our patients with panic disorder. Grisaru et al. (1998)
reported a pilot study of 10 patients with posttraumatic
stress disorder who received slow rTMS to both the left
and right motor cortex. Their symptoms improved for
1–7 days after the trial. That was not the case in our study
with panic disorder patients. Maybe we should consider
the possible indirect propagated effect of slow rTMS.
Neuroimaging data for patients with depression and
epilepsy, for instance, have suggested that greater sup-
pressive effect of 1 Hz rTMS are obtained in the cortical
region contralateral to that being stimulated (Speer et al.,
2000). If indirect effect of rTMS are distinct from direct
effects, this finding would be important in designing
intervention studies based on known cortical patterns of
pathological activation. Further studies in this area need
to be undertaken.
Conclusion
Low frequency rTMS administered over the right
dorso-lateral prefrontal cortex during 10 sessions did
not differ from sham rTMS in facilitating the effect of
SRIs in patients with panic disorder in our study. Further
studies are indicated to assess the efficacy of rTMS in
panic disorder and to clarify the optimal stimulation
characteristics.
Acknowledgement
Supported by the project n. MŠMT ČR 1M0517 and
the Internal Grant Agency (IGA) of Ministry of Health:
NF 7565-3
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