Right Prefrontal Repetitive Transcranial Magnetic Stimulation
in Obsessive-Compulsive Disorder:
A Double-Blind, Placebo-Controlled Study
Pino Alonso, M.D.
Patients were randomly assigned to 18 sessions of
Jesús Pujol, M.D., Ph.D.
real (N=10) or sham (N=8) rTMS. Treatments lasted 20 minutes,and the frequency was 1 Hz for both conditions, but the inten-
Narcís Cardoner, M.D.
sity was 110% of motor threshold for real rTMS and 20% for the
Luisa Benlloch, M.D.
Joan Deus, Ph.D.
No significant changes in OCD were detected in either
José M. Menchón, M.D., Ph.D.
group after treatment. Two patients who received real rTMS,
Antoni Capdevila, M.D., Ph.D.
with checking compulsions, and one receiving sham treatment,
Julio Vallejo, M.D., Ph.D.
with sexual/religious obsessions, were considered responders.
Low-frequency rTMS of the right prefrontal cor-
The efficacy of repetitive transcranial magnetic
tex failed to produce significant improvement of OCD and was
stimulation (rTMS) of the right prefrontal cortex for patients
not significantly different from sham treatment. Further studies
with obsessive-compulsive disorder (OCD) was studied under
are indicated to assess the efficacy of rTMS in OCD and to clarify
double-blind, placebo-controlled conditions.
the optimal stimulation characteristics.
(Am J Psychiatry 2001; 158:1143–1145)
Repetitive transcranial magnetic stimulation (rTMS) and 46 but also influencing areas 6, 8, 10, 44, and 45. Three-di-
has been proposed as therapeutic for different psychiatric
mensional magnetic resonance imaging (MRI) models were used
disorders, mainly depression, although the stimulation
to establish the proper position of the coil. The MRI anatomicalreferences were transposed to the patient’s head by using mea-
characteristics are still controversial (1–3). Concerning ob-
sured distances from the sulci scalp projection to external head
sessive-compulsive disorder (OCD), Greenberg et al. (4)
landmarks. The sulci position was permanently marked for each
reported a significant reduction in compulsions during
patient by using an individualized cap.
and 8 hours after a single session of right prefrontal rTMS.
The patients received 18 sessions (three sessions per week for 6
This study was designed to assess whether prolonged
weeks), at a frequency of 1 Hz; each session lasted 20 minutes. Forreal rTMS, the intensity was 110% of the motor threshold. Motor
stimulation of the right prefrontal cortex at low frequency
threshold was determined over the right motor cortex by finding
would produce significant improvement in a group of
the minimum intensity that produced a visible motor response in
OCD patients under double-blind, placebo-controlled
the left thumb. Although high-intensity stimulation at low fre-
quency has recently shown antidepressant effects with a lowerrisk of seizure induction (5), large numbers of sessions have rarelybeen tested in terms of safety. Consequently, we decided to ad-
minister rTMS three times per week instead of the more usualdaily rate.
The study participants were 18 right-handed outpatients (12
female; mean age=35.2 years, SD=12.1) who met the DSM-IV cri-
For sham treatment the coil was placed over the same area,
teria for OCD. Five of them were unmedicated, and the rest had
perpendicular to the scalp. Patients received 18 sessions at 1 Hz,
been receiving stable pharmacological treatment for 12 weeks:
albeit with an intensity of 20% of the motor threshold. The rTMS
fluoxetine, 80 mg/day (N=5), or clomipramine, 225 mg/day, com-
was performed by a trained technician blind to the expected ef-
bined with fluvoxamine, 300 mg/day (N=8) (Table 1). No patient
fects of each treatment condition. He was told which stimulation
met the DSM-IV criteria for any other axis I disorder. Individuals
characteristics should be applied to each subject by one of the in-
with a history of seizure or head trauma were not included. All pa-
vestigators (J.P.), who determined the threshold.
tients gave written informed consent after complete description
Assessments were performed at baseline and weekly until 10
weeks after rTMS by a psychiatrist (P.A.), also blind to treatment
The subjects were randomly assigned to real or sham rTMS and
conditions. The Yale-Brown Obsessive Compulsive Scale (6) and
were blind to the expected effects of each condition. The rTMS
the Hamilton Depression Rating Scale (7) were used.
was performed by using a Magstim Rapid stimulator (Magstim
We used a 2×8 factorial design (two groups, eight time points)
Company, Ltd., Whitland, U.K.). The brain target was the right
with repeated measurements on the second factor (groups: real
dorsolateral prefrontal cortex. To encompass this relatively wide
rTMS, sham rTMS; times: baseline, six weekly assessments, final
area, we used a 70-mm circular coil. Its distal end was positioned
10-week assessment). We predicted that real rTMS would induce
flat over the cortex superior to the inferior frontal sulcus and an-
significantly greater improvement in OCD than would sham
terior to the precentral sulcus, centered over Brodmann areas 9
TABLE 1. Demographic and Clinical Characteristics of Patients With Obsessive-Compulsive Disorder (OCD) Who Received
Real or Sham Repetitive Transcranial Magnetic Stimulation (rTMS)
Sexual and religious obsessions Clomipramine,
Sexual and religious obsessions Fluoxetine
Sexual and religious obsessions Clomipramine,
pulsive Scale (U=35.5, p=0.68) or Hamilton depressionscale (U=35.0, p=0.65) (Mann-Whitney U test). For the to-
All patients completed the study. Only one patient, who
tal score on the Yale-Brown scale, two-factor analysis of
received real rTMS, reported mild headache. There were
variance (ANOVA) showed no significant effect for group
no seizures, neurological complications, or complaints
(F=0.07, df=1, 16, p=0.80) or time (F=1.31, df=7, 112, p=
0.25) and no significant group-by-time interaction (F=
Baseline and 10-week scores on the clinical measures
0.52, df=7, 112, p=0.81). Similar results were obtained for
are presented in Table 1. At baseline there was no signifi-
the obsession and compulsion subscales.
cant difference between the groups receiving real and
For the Hamilton depression scale, ANOVA also showed
sham rTMS in scores on the Yale-Brown Obsessive Com-
no significant group effect (F=0.38, df=1, 16, p=0.54), time
effect, (F=0.49, df=7, 112, p=0.84), or group-by-time inter-
tients in the group receiving real rTMS were checkers
Two patients who received real rTMS, both checkers,
Further investigation involving larger groups of patients
were considered responders, defined as having a global re-
should be performed to clarify whether rTMS could be a
duction in Yale-Brown Obsessive Compulsive Scale score
useful therapy in OCD and determine the optimal stimu-
greater than 40%. This criterion was also met by a patient
lation characteristics for its delivery.
with sexual/religious obsessions in the group receivingsham treatment. Improvement appeared following the 5th
Received May 23, 2000; revisions received Oct. 18, 2000, and Jan.
11, 2001; accepted Feb. 1, 2001. From the Obsessive-Compulsive Dis-order Clinical and Research Unit, Department of Psychiatry, BellvitgeUniversity Hospital, Barcelona, Spain; and the Magnetic Resonance
Center of Pedralbes, Barcelona, Spain. Address reprint requests to Dr.
Vallejo, Servicio de Psiquiatría, Ciudad Sanitaria y Universitaria de
Among the patients in this study, low-frequency right
Bellvitge, c/o Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barce-
prefrontal rTMS failed to produce significant improve-
lona, Spain; [email protected]
ment in OCD or any difference from sham rTMS.
Supported in part by grant FIS 00/0226 from the Spanish Ministerio
de Sanidad y Consumo and by grant 1999FI-00726 to Dr. Alonso from
Differences induced by rTMS in the first hours, which
were the main findings of Greenberg et al. (4), were not as-
The authors thank Joan Pau Soto for technical assistance and Ger-
sessed. Furthermore, our stimulation characteristics dif-
ald Fannon, Ph.D., for revision of the manuscript.
fered from those used by Greenberg et al.: we used a circu-lar coil, the frequency was 1 Hz, and the intensity was
Thirteen of our patients had previously undergone un-
1. George MS, Lisanby SH, Sackeim HA: Transcranial magnetic
stimulation: applications in neuropsychiatry. Arch Gen Psychi-
successful pharmacological treatment for OCD, even
combined clomipramine and fluvoxamine therapy, and
2. Reid PD, Shajahan PM, Glabus MF, Ebmeier KP: Transcranial
can therefore be considered to have resistant OCD. This
magnetic stimulation in depression. Br J Psychiatry 1998; 173:
point may have contributed to our negative results.
The selection of the right prefrontal cortex as the target
3. Pascual-Leone A, Rubio B, Pallardó F, Català MD: Rapid-rate
cortical region for stimulation might also explain our find-
transcranial magnetic stimulation of left dorsolateral prefron-tal cortex in drug-resistant depression. Lancet 1996; 348:233–
ings. Our choice was based on the fact that rTMS of this
area was associated in the study of Greenberg et al. (4)
4. Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer
with significant reduction of compulsions. Furthermore,
TE, Altemus M, Wassermann EM, Post RM, Murphy DL: Effect of
rTMS has recently demonstrated remote effects, with left
prefrontal repetitive transcranial magnetic stimulation in ob-
prefrontal stimulation inducing changes in cerebral perfu-
sessive-compulsive disorder: a preliminary study. Am J Psychia-try 1997; 154:867–869
sion in the bilateral anterior cingulate and orbitofrontal
5. Klein E, Kreinin I, Chistyakov A, Koren D, Mecz L, Marmur S,
cortex (8). The prefrontal cortex may be a starting point to
Ben-Sachar D, Feinsod M: Therapeutic efficacy of right prefron-
induce remote stimulation of regions consistently in-
tal slow repetitive transcranial magnetic stimulation in major
volved in OCD, such as the anterior cingulate and orbito-
depression: a double-blind controlled study. Arch Gen Psychia-
frontal cortex, that cannot be directly stimulated with cur-
6. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann
RL, Hill CL, Heninger GR, Charney DS: The Yale-Brown Obses-
Although no significant differences between treatment
sive Compulsive Scale, I: development, use, and reliability.
groups were detected, the patients treated with real rTMS
had a somewhat greater reduction in obsessions. Our neg-
7. Hamilton M: A rating scale for depression. J Neurol Neurosurg
ative findings may be related to type II error, since a mini-
mum of 27 subjects in each treatment condition would
8. George MS, Stallings LE, Speer AM, Nahas Z, Spicer KM, Vincent
DJ, Bohning DE, Cheng KT, Molloy M, Teneback CC, Risch SC:
have been necessary to reach an 80% power (alpha=0.05).
Prefrontal repetitive transcranial magnetic stimulation (rTMS)
Although the small group size did not allow us to study
changes relative perfusion locally and remotely. Human Psy-
OCD subtypes, the fact that both of the responding pa-
FOGLIO ILLUSTRATIVO: INFORMAZIONI PER L’UTILIZZATORE Tyrosin TU t.o.p. Sospensione iniettabile Legga attentamente questo foglio prima di usare questo medicinale. Conservi questo foglio. Potrebbe aver bisogno di leggerlo di nuovo. Se avesse qualsiasi dubbio, si rivolga al medico. Se uno qualsiasi degli effetti collaterali peggiorasse, o se notasse la comparsa di un qualsi
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