Repetitive Transcranial Magnetic Stimulation Is as
Effective as Electroconvulsive Therapy in the
Treatment of Nondelusional Major Depressive Disorder:
An Open Study
Leon Grunhaus, Pinhas N. Dannon, Shaul Schreiber, Ornah H. Dolberg,
Revital Amiaz, Reuven Ziv, and Eli Lefkifker
Background: Repetitive transcranial magnetic stimula-
tion (rTMS), a new method for the stimulation of the
central nervous system, is being proposed as a potential
new treatment in patients with major depressive disorder
(MDD). We tested the hypothesis that rTMS would be as
effective as electroconvulsive therapy (ECT) in patients
Methods: Forty patients with MDD referred for ECT
were randomly assigned to either ECT or rTMS. Repetitive
transcranial magnetic stimulation was performed at 90%
power of the motor threshold. The stimulation frequency
was 10 Hz for either 2 sec (first eight patients) or 6 sec
(final 12 patients) for 20 trains. Patients were treated for
up to 20 treatment days. Electroconvulsive therapy was
performed according to standard protocols.
Results: Overall patients responded best to ECT (?2?
3.8, p ? .05). Patients with MDD and psychosis re-
sponded significantly better to ECT (?2? 9.2, p ? .01),
whereas MDD patients without psychosis responded sim-
ilarly to both treatments (?2? 0.0, ns). The analysis of
variance with repeated measures of clinical variables for
the whole sample revealed significant treatment effects for
both groups; however, interaction between group and
treatment was seen only for the Global Assessment of
Function and the Sleep assessment. When the psychosis–
nonpsychosis grouping was considered, patients with psy-
chosis responded dramatically better to ECT in all assess-
ments, whereas those without psychosis responded
similarly to both treatments.
Conclusions: Overall ECT was a more potent treatment
for patients with MDD, this being particularly evident in
patients with MDD and psychosis; however, in patients
with MDD without psychosis the effects of rTMS were
similar to those of ECT. The results we report are
encouraging and support an important role for rTMS in
the treatment of severe MDD; however, additional blinded
studies are needed to precisely define this role. Biol
Psychiatry 2000;47:314–324 © 2000 Society of Biologi-
Key Words: TMS, ECT, MDD, transcranial magnetic
stimulation, electroconvulsive therapy
noninvasive and almost painless stimulation of the central
nervous system (CNS). In TMS a relatively small coil is
applied to the scalp while a powerful and rapidly alternat-
ing electrical current is passed through the coil wire. This
produces a magnetic field that passes unimpeded through
the scalp and in turn induces ionic flow in neuronal tissue
(Barker 1991). Transcranial magnetic stimulation applied
over the motor cortex, for example, will induce a con-
tralateral muscular-evoked potential (MEP) that can be
used for measurements of nerve conduction. Initially TMS
was used in the study of nerve conduction and cognitive
function (Hallet and Cohen 1989); however, antidepres-
sant effects in patients with mood disorders were soon
reported (Conca et al 1996; Grisaru et al 1994; Hoflich et
al 1993; Kolbinger et al 1995).
The development of stimulators capable of delivering
stimulation frequencies of up to 60 Hz (repetitive trans-
cranial magnetic stimulation [rTMS]) increased the poten-
tial clinical applications of rTMS. Three recently pub-
lished studies (Figiel et al 1998; George et al 1997;
Pascual-Leone et al 1996) involving stimulation of the left
dorsolateral prefrontal cortex (LDLPFC) suggest that
rTMS may have significant antidepressant properties.
George et al (1997) reported on a 2-week placebo-
controlled crossover trial of real and sham rTMS in 12
ranscranial magnetic stimulation (TMS) was intro-
duced by Barker et al in 1985 as a new method for
From the Psychiatry Division, Sheba Medical Center, Ramat Gan, Israel.
Address reprint requests to Leon Grunhaus, MD, Chair Psychiatry Division, Sheba
Medical Center, Ramat Gan, Israel 52621.
Received February 3, 1999; revised June 1, 1999; revised August 20, 1999;
accepted September 17, 1999.
© 2000 Society of Biological Psychiatry0006-3223/00/$20.00
patients with major depressive disorder (MDD). In that
study significant, albeit mild, antidepressant effects for
rTMS were found. Pascual-Leone et al reported on the
effects of 1 week of either sham or real rTMS over several
brain regions in 17 patients with MDD with psychotic
features. They found very significant effects of 1 week of
rTMS applied over the LDLPFC. Figiel et al, in the largest
open study published so far, reported a 42% overall
response rate to rTMS in refractory depressed patients
treated with rTMS.
Electroconvulsive therapy (ECT) is considered the most
powerful antidepressant treatment. Patients referred for
ECT usually suffer from medication resistant MDD, have
delusions or hallucinations or intense suicidal thoughts, or
are very ill in general (American 1990). Electroconvulsive
therapy is a safe and reliable procedure; however, it
requires anesthesia, muscular relaxation, and the induction
of a CNS seizure, and memory disturbances may compli-
cate its course. A treatment that could provide a similar
kind of relief while being less invasive is sorely needed.
Repetitive transcranial magnetic stimulation has been
advanced as a potential nonconvulsive substitute for ECT
(Belmaker and Fleishman 1995; George and Wasserman
1994; Zyss 1994), although Sackeim has argued against
this hypothesis (Sackeim 1994). Studies in laboratory
animals, in both behavioral and biochemical models, have
shown that TMS shares some of the effects of electrocon-
vulsive shock (Ben-Sachar et al 1997; Fleischmann et al
1994, 1995, 1996, 1999; Zyss et al 1997), particularly
seizure inhibition and seizure shortening. The decrease in
seizure length is one of the well-established effects of ECT
in humans (Abrams 1992). These similarities between the
effects of electroconvulsive shock, ECT, and TMS on
seizures provided the basis for our study comparing ECT
and rTMS in severe depression. Our results suggest that
rTMS is as effective as ECT in the treatment of patients
with MDD without psychosis; however, it appears to be
ineffective in patients with MDD with psychotic features.
Methods and Materials
Patients included in this study were both inpatients and outpa-
tients with MDD referred for ECT. Reasons for referral included
nonresponse to antidepressant treatment and/or the diagnosis of
psychotic MDD. Patients were considered for inclusion in this
protocol if they met the following criteria: age over 18; a
DSM-IV diagnosis of MDD; a 17-item Hamilton Rating Scale
for Depression (HRSD) score of ?18; no personal or first-degree
relative history of seizure; and no medical, neurological, or
neurosurgical disorder that would preclude the administration of
ECT or rTMS (Pascual-Leone et al 1993; Wasserman 1998).
Patients with additional axis-I diagnoses were excluded from the
study. All protocols were approved both by the Sheba Medical
Center and the Ministry of Health Human Research Committee.
Patients signed an informed consent before inclusion in the
study. All patients were assessed with standard clinical, psychi-
atric, and laboratory examinations (complete blood count, blood
chemistry, and thyroid indices). All patients were assessed at
baseline with a battery of rating scales that included a DSM-IV
checklist, a previous history of depressive illness form, the
17-item HRSD, the Brief Psychiatric Rating Scale (BPRS), the
Global Depression Scale (GDR), the Global Assessment of
Function Scale (GAS), the Pittsburgh Sleep Quality Index
(PSQI), and the Mini Mental State Examination (MMS). Addi-
tionally, the adequacy of the antidepressant treatment was
assessed by clinical interview with a modified Michigan Ade-
quacy of Treatment Scale (MATS; Grunhaus and Remen 1993).
Ratings were repeated weekly for 4 weeks in both groups,
whereas in the ECT group they were also performed in the final
week of ECT treatment. All ratings were performed by the same
research assistant, who was not blind to the treatment method.
Raters were trained by the senior investigator through live
clinical interviews. Clinical ratings were confirmed with nurses’
observations in the units or collateral reports by family members.
Patients were randomly allocated to either the rTMS or the ECT
group according to an a priori generated list.
Demographics and baseline clinical variables are described in
Table 1. No differences in age, gender distribution, baseline
severity, proportion of psychotic patients, length of episode,
proportion of patients receiving ECT in previous episodes, and
proportion of patients having been treated properly (as assessed
with the MATS) were identified. Most patients were inpatients;
they were equally distributed between the ECT and rTMS
groups. No difference between the groups was identified at the
baseline clinical ratings.
Electroconvulsive therapy was performed according to approved
protocols at Sheba Medical Center. Electroconvulsive therapy
equipment consisted of a MECTA (Lake Oswego, OR) SR-1
machine that delivers a brief-pulse bidirectional current. In brief,
the methods include:
1. Titration of electrical charge during the first ECT treat-
ment using the methods of limits (Sackeim et al 1987,
1993)—although seizure duration was assessed both by
the cuff method and electroencephalographic (EEG) mea-
surements, we used the motor response of the leg to
determine seizure length.
2. Subsequent ECT treatments were performed at 2.5 times
the threshold energy and charge was titrated upward every
second or third treatment to maintain a seizure length of
3. Electrode placement was initially right unilateral (D’Iglia
position; all patients were right-handed) in all patients, and
patients could be switched to bilateral electrode placement
if improvement (HRSD decrease of ?30%) was not
observed by the sixth treatment.
4. All patients received 100% oxygenation during the proce-
dure and anesthesia with methohexital (1 mg/kg) and
muscle relaxation with succinylcholine (1 mg/kg).
rTMS Is as Effective as ECT315
5. Post-ECT monitoring according to established anesthesia
procedures was performed. ECT treatments were given
Psychotropic medications were continued during the course of
ECT according to physicians preference; however, they remained
stable across the course of ECT. The use of benzodiazepines was
limited to ?3 mg of lorazepam equivalents a day and were held the
night before the ECT. We were interested in testing the efficacy of
rTMS in the context of an average ECT practice. Additional
with antidepressants (six patients), antidepressants alone (five pa-
tients), and neuroleptics and anticonvulsants (one patient). Four
patients did not receive any additional medications.
Patients treated with ECT received a mean of 9.6 treatments
(range 7 to 14). Patients responding to ECT had mean seizure
duration similar to that of those patients unresponsive to ECT
(clinical seizure in responders 42 ? 24.2 vs. in nonresponders
26 ? 6.1, t ? ?1.3, ns; EEG seizure in responders 66.2 ? 26.8
vs. 47.4 ? 13.9 in nonresponders, t ? 1.9, ns). Twelve patients
received unilateral ECT for the whole course of ECT, whereas
eight patients were switched to bilateral electrode placement
because of insufficient response to ECT. Response rates were
similar in both groups.
We used MAGSTIM (New York) rapid equipment with four
booster modules. Motor threshold (MT) over the left motor
cortex (area controlling the abductor pollicis brevis [APB]) was
determined by electromyographic method, looking for the lowest
machine power output that would provide in five of 10 stimula-
tions an MEP of at least 50 ?V. Motor threshold was determined
daily in all cases. Stimulations were given at 90% MT with
continuous electromyographic monitoring. Repetitive transcra-
nial magnetic stimulation was administered over the LDLPC.
Placement of the electrode over the LDLPFC was determined
following the method of Pascual-Leone et al (1996): placing the
coil 5 cm forward, and in a 45° angle from the vertex, from the
best spot for the APB control. We used a 10-cm wingspan
figure-eight coil cooled in ice for the rTMS administration.
During stimulation the coil was held with the handle towards the
back of the head and at a 45° angle. Repetitive transcranial
magnetic stimulation was administered five times a week for 4
weeks (for a total of 20 stimulations). Although limiting the time
period for administration of rTMS while leaving the length of the
ECT at the discretion of the clinician may introduce a bias
against rTMS, our human use approval required this limitation.
To the first eight patients we administered 20 trains of rTMS at
10 Hz for 2 sec (total of 400 magnetic pulses per treatment day).
To the final 12 patients we administered 20 trains of rTMS at 10
Hz for 6 sec (total of 1200 magnetic pulses per treatment day).
This was the first rTMS protocol performed at our center, so the
authors opted for a more cautious approach at the outset of the
study. All psychiatric medications were discontinued before the
administration of rTMS; clonazepam (1–2 mg/day, given in
twice-daily doses) was started in all patients to decrease anxiety,
provide relief of severe insomnia, and have an additional
protective element regarding seizures. Patients who did not
respond to the course of rTMS were offered a course of ECT.
The response to ECT of rTMS nonresponders will be the subject
of another communication.
The statistical analyses were performed for the whole sample
(N ? 40), psychotic patients (n ? 19), and nonpsychotic patients
only (n ? 21). This study was considered preliminary, so power
Table 1. Demographics and Baseline Assessments—All Samples
X ? SD
(N ? 20)
X ? SD
(N ? 20)
Duration of episode (months)
MATS (?1, ?2)
Previous ECT (N/Y)
Axis II (N/Y)
63.6 ? 15.0
6.9 ? 7.9
2.4 ? 3.05
28.4 ? 9.3
39.5 ? 12.7
31.0 ? 8.5
2.6 ? 0.6
25.9 ? 4.1
12.5 ? 4.4
58.4 ? 15.7
8.3 ? 7.4
2.3 ? 2.85
25.8 ? 6.1
37.8 ? 8.3
34.1 ? 11.7
2.4 ? 0.7
24.8 ? 4.1
11.7 ? 5.7
ECT ? electroconvulsive therapy, rTMS ? repetitive transcranial magnetic stimulation, CI ? confidence interval, HRSD ?
Hamilton Rating Scale, BPRS ? Brief Psychiatric Rating Scale, GAS? Global Assessment of Function Scale, GDR ? Global
Depression Scale, MMS ? Mini Mental State Examination, PSQI ? Pittsburgh Sleep Quality Index, MATS ? Michigan
Adequacy of Treatment Scale.
aChi-square with continuity correction.
bN ? 35 (n ? 16 ECT group, n ? 19 rTMS group).
cN ? 39 (n ? 19 ECT group, n ? 20 rTMS group).
316L. Grunhaus et al
calculations to determine the minimal sample needed to detect a
difference between the groups were not done (Cohen and Cohen
1975). In general, to detect mean differences of .3 with a power
of 80%, over 50 patients are required. The main hypothesis was
tested with analysis of variance (ANOVA) with repeated mea-
sures, with additional post hoc analysis performed with two-
sample t tests and chi-squares. Time points taken into consider-
ation for the analysis were baseline, week 2, and end of treatment
(week 4 for the rTMS group and the week when the clinician
considered that the ECT course had ended for the ECT group).
Response to treatment was categorized using a dual definition.
Patients were considered to be responders to treatment if the final
HRSD had decreased to ?50% or more from baseline and the
final GAS of ?60. A repeated-measures ANOVA of the HRSD
[group effect F(1,18) ? 0.36, ns; treatment effect F(2,36) ?
18.9, p ? .001; interaction F(2,2) ? 2.0, ns] and BPRS ratings
[group effect F(1,18) ? 0.99, ns; treatment effect F(2,36) ? 6.9,
p ? .01; interaction F(2,2) ? 1.3, ns] was performed comparing
the rTMS patients treated with 400 daily stimulations with those
treated with 1200 daily stimulations. No difference in HRSD or
BPRS ratings was found. We therefore pooled the sample.
Results are presented first for the whole sample, then
for the nonpsychotic patients, and finally for the psy-
Figure 1. Hamilton Rating Scale for Depression (HRSD) ratings at baseline, 2 weeks into the treatment, and the end of the treatment
for the repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) groups for the whole sample and for
the psychotic and nonpsychotic groups.
rTMS Is as Effective as ECT 317
chotic patients in Figures 1–5. In Figure 1 we can see
that HRSD ratings for the whole sample are not signif-
icantly different between the groups, although the
interaction between time and group was almost signif-
icant (p ? .1). In nonpsychotic patients the HRSD
decreased similarly in both groups (significant treat-
ment effect); however, in patients with psychosis the
improvement is strikingly better with ECT than with
rTMS (significant time and treatment effects, and of the
interaction). In Figures 2–5 we observe that the effects
of ECT and rTMS on the BPRS, GAS, GDR, and PSQI
closely mimic the effects on the HRSD.
The cognitive effects of both treatments were explored
with the MMS. No difference between the groups (ECT
baseline 25.9 ? 4.1, ECT end of treatment 24.5 ? 7.6;
rTMS baseline 24.8 ? 4.1, rTMS end of treatment 26.3 ?
3.9, repeated measures ANOVA [group effect F(1,29) ?
0.1, ns; time effect F(2,58) ? 1.3, ns; interaction F(2,2) ?
2.3, ns]) was observed. The analysis was also performed
for the psychotic–nonpsychotic groups with similar
To explore further the clinical effects of these treatment
modalities we defined the overall response rate using the
previously described definitions (see Methods and Mate-
Figure 2. Brief Psychiatric Rating Scale (BPRS) ratings at baseline, 2 weeks into the treatment, and the end of the treatment for the
repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) groups for the whole sample and for the
psychotic and nonpsychotic groups.
318 L. Grunhaus et al
rials). We compared the response at week 4 for patients
treated with rTMS and at the end of treatment for patients
treated with ECT. When the whole sample is considered,
ECT-treated patients responded significantly better than
patients treated with rTMS (ECT group responders 16 of
20; rTMS group responders 9 of 20; ?2? 3.8, p ? .05).
For the patients with psychosis this difference is striking,
with all patients treated with ECT responding and only
two of the rTMS-treated patients responding (ECT group
responders 10 of 10; rTMS group responders 2 of 9; ?2?
9.2, p ? .01). In the group of nonpsychotic patients this
difference disappears and patients respond to both inter-
ventions (ECT group responders 6 of 10; rTMS group
responders 7 of 11; ?2? 0.02, ns).
A repeated-measures ANOVA using the responder–non-
responder groupings was used to compare the HRSD ratings
of both groups at week 2 and at the end of the treatment. The
ANOVA was significantly different for time effect
[F(1,18) ? 7.3, p ? .01], group effect [F(1,18) ? 172.4, p ?
.001], and interaction [F(1,1) ? 6.2, p ? .02]. The group
means for the responders were 16.8 ? 11.0 at week 2 and
nonresponders were 21.7 ? 4.5 at week 2 and 21.4 ? 4.1 at
the end of the treatment.
Figure 3. Global Assessment of Function Scale (GAS) ratings at baseline, 2 weeks into the treatment, and the end of the treatment for
the repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) groups for the whole sample and for the
psychotic and nonpsychotic groups.
rTMS Is as Effective as ECT319
To compare whether the clinical response was as
sound in those patients responding to each treatment
modality we compared the final HRSD and GAS ratings
for those patients responding to either treatment modal-
ity. Twenty-five patients were included in this analysis
(ECT group n ? 16, rTMS-treated group n ? 9). The
final HRSD ratings (ECT group 7.6 ? 4.8; rTMS group
8.6 ? 4.1; t ? ?0.5, ns) and GAS ratings (ECT group
68.8 ? 16.9; rTMS group 67.2 ? 10.6; t ? 0.24, ns)
were similar in both groups.
The side-effect profile of rTMS was considerably
mild. Five patients in the rTMS complained of mild
headache, which responded to analgesics. In one pa-
tient, and only during one of the treatment sessions, we
noted that 20 msec following each magnetic pulse an
MEP discharge was observed. This patient was being
stimulated with 2-sec trains. The patient was receiving
2 mg of clonazepam. In this case spread was controlled
by decreasing stimulation power by 10%. As in other
cases the MT of this patient was determined daily. On
the day of this event MT was identical to that obtained
on the previous day. The course of treatment in the ECT
group was as expected: all patients concluded the
Figure 4. Global Depression Scale (GDR) ratings at baseline, 2 weeks into the treatment, and the end of the treatment for the repetitive
transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) groups for the whole sample and for the psychotic and
320L. Grunhaus et al
The findings of this study support the following
1. Some measures of clinical response (?2? 3.8, p ?
.05), but not others (ANOVA with repeated mea-
sures, ns), suggest that patients treated with ECT
had a more consistent antidepressant treatment re-
sponse than those treated with rTMS.
2. Electroconvulsive therapy is clearly superior to
rTMS in patients with MDD and psychosis, as
shown both by categorical analysis and in almost all
clinical variables tested.
3. The response to rTMS was similar to that ob-
served with ECT in patients with MDD without
4. In those patients who responded to either treatment
modality, the depth of the clinical response, as
measured by the final clinical ratings, was similar in
5. Repetitive transcranial magnetic stimulation was
well tolerated, with only minor side effects de-
Figure 5. Pittsburgh Sleep Quality Index (PSQI) at baseline, 2 weeks into the treatment, and the end of the treatment for the repetitive
transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) groups for the whole sample and for the psychotic and
rTMS Is as Effective as ECT 321
scribed. Older patients tolerated the procedure as
well as their younger counterparts.
6. The data presented strongly suggest that continuing
rTMS for 4 weeks increased the efficacy of this
treatment. On the other hand, it also suggests that if
there was minimal improvement by 2 weeks the
additional weeks of treatment provided little added
7. Although it was not formally tested, there were no
age differences in treatment response. Older patients
responded as well as younger ones. In this regard
our study differs from that of Figiel et al 1998. The
response of older patients to rTMS will be the
subject of another communication.
However, our conclusions need to be tempered because of
1. Absence of a sham group: Our treatment groups did
not include a sham comparison because of the
ethical concerns of including severely ill hospital-
ized patients in a sham protocol. The lack of a sham
control may constitute a problem in rTMS studies.
The placebo components of this treatment (daily
contact, popular beliefs on the effects of magnets,
etc.) could be powerful. Similar psychological is-
sues, however, could be in effect in the ECT-treated
patients in whom an aversion to the treatment may
constitute a strong factor for an “escape into health.”
2. Nonblind assessments: Our raters were not blind to
treatment allocation; however, patient ratings were
always corroborated with nurses’ observations in the
units and/or collateral information from relatives.
3. Use of two treatment paradigms: The first eight
patients were treated with only 400 stimulations per
treatment day, whereas the final 12 patients received
1200 stimulations per treatment day. The indications
for lower and higher frequency paradigms should be
4. Patients in the ECT group were allowed psycho-
tropics as indicated by their treating physicians,
whereas rTMS patients were restricted to clonaz-
epam only. It is unclear whether clonazepam may
impact negatively on rTMS. However, these patients
are severely ill, with significant agitation and or
insomnia. It is very difficult to totally avoid addi-
tional medications particularly during the first week
The basic concept of this study was to compare
rTMS and ECT as ECT is done in regular treatment
facilities. Whether this was a bias against rTMS
cannot be determined from this study.
The suggestion that rTMS may have a role in the
treatment of MDD originated with the works by Pascual-
Leone et al, George et al, and Figiel et al. Pascual-Leone
et al (1996) reported that rTMS (90% MT, 10 Hz for 10
sec, 20 trains/day for a total of 2000 pulses/day) over the
LDLPFC had antidepressant effects in 11 of 17 outpatients
with recurrent unipolar MDD with psychosis who “had
been resistant to medications, despite combinations and
high dosage” (p. 233). The protocol described in the study
by Pascual-Leone et al differs from standard psychiatric
treatment protocols because patients received rTMS for 5
days over the various brain regions (real vs. sham rTMS
over LDLPFC, rightdorsolateral
[RDLPFC], and vertex) and remained free from additional
treatment for the rest of the month. For the whole 5-month
period of the study the patients received only 5 days of an
active treatment, rTMS over the LDLPFC. Thus, although
from a diagnostic point of view the patients met criteria for
MDD with psychotic features, the clinical severity, how-
ever, must have been significantly lower than that of the
cases we are reporting, most of our sample being inpa-
tients referred for ECT. Whether the more intense stimu-
lation paradigm used by Pascual-Leone et al was a factor
in the outcome needs to be considered.
George et al (1997) reported on 12 patients with
recurrent MDD treated with rTMS in a randomized cross-
over real-versus-sham comparison. The authors described
a significant, albeit mild, effect of real LDLPFC rTMS on
depression ratings (80% MT at 20 Hz, for 2 sec, 20 trains
for a total of 800 pulses/day). Figiel et al (1998), in the
largest rTMS study published so far, reported on an open
trial of LDLPFC rTMS administered for 5 days (110% MT
at 10 Hz, for 5 sec, 10 trains for a total of 500 pulses/day),
finding a 43% response rate. Figiel et al noted that older
patients, particularly those with late-onset depression, and
patients with psychosis responded poorly. The main dif-
ference between the George et al and Figiel et al studies
and ours relates to the length of the treatment period. We
extended our protocol to 20 stimulation days (4 weeks) in
consideration of the fact that on average it takes between
six and eight ECT treatments to reach therapeutic results
(Grunhaus et al, unpublished observations). From our
results it is quite clear that the 4-week paradigm we used
provided additional improvement on depression ratings.
Whether higher frequency TMS (rTMS) with a figure-
eight coil over the LDLPFC is superior to TMS at lower
frequencies with a round coil and over other brain areas,
especially the RDLPFC, is unknown. Studies have shown
antidepressant response to TMS administered at low stim-
ulation frequencies (?1 Hz) with a round coil over the
vertex, or the RDLPFC position (Conca et al 1996; Grisaru
et al 1994; Hoflich et al 1993; Klein et al 1999; Kolbinger
et al 1995). Grisaru et al (1998) have reported that
treatment with rTMS at 20 Hz over the LDLPFC may
worsen the clinical course of manic patients, whereas a
322 L. Grunhaus et al
similar stimulation paradigm over the RDLPFC seems to
lead to clinical improvement.
The support for the application of rTMS pulses over the
LDLPFC was derived from the evidence accumulated over
the past 10 years pointing towards involvement of the
fronto–limbic–subcortical circuits in MDD (Cummings
1993; Drevets et al 1997; George et al 1994), particularly
in the LDLPFC. Most brain-imaging studies (Baxter et al
1989; Bench et al 1993; Bonne et al 1996; Martinot et al
1990; Mayberg et al 1991) suggest decreased cerebral
blood flow (CBF) or decreased metabolic rates (Baxter et
al 1989; Martinot et al 1990) in the LDLPFC and other
frontal areas in MDD. Drevets et al (1992), however,
reported increased CBF in the left prefrontal cortex using
15O–positron emission tomography (15O-PET). It is un-
clear whether these changes are state related or demon-
strate a more stable, trait type of abnormality. Drevets et al
(1997) proposed that changes seen in the subgenual
portion of the left prefrontal cortex of patients with either
familial bipolar or unipolar depressive disorder (seen with
PET scans and with magnetic resonance imaging) are
either an “abnormality of brain development or a degen-
erative change resulting from recurrent illness” (p. 826).
The neurophysiological responses to rTMS are pleo-
morphic and may depend on a significant number of
parameters. Type of coil (figure eight and round), coil
location, size of the coil, stimulation frequency, number of
magnetic pulses, metabolic state of the brain, and brain
circuitry affected, all influence response to rTMS. The
magnetic pulses stimulate both cortico-cortical connec-
tions and corticofugal fibers (George and Wasserman
1994; George et al 1995). The cortico-cortical activation is
not limited to local neuronal networks. Distant activation
following rTMS has been demonstrated. Pulse-dependent
increases in CBF measured with15O-labeled H20, as seen
in parietal regions after TMS stimulation on the orbito-
frontal cortex (Paus et al 1997), or the EEG activation seen
in the contralateral motor cortex following rTMS demon-
strate cortical reactivity and connectivity (Illmoniemi et al
1997). Thus, TMS applied to a rather limited area of the
brain (the LDLPFC) could lead to activation or inhibition
of much broader areas through both cortico-cortical and
cortico–basal ganglia connections.
It is evident from this discussion that the variables
affecting the interactions between rTMS and the brain are
multiple and may involve a significant amount of individ-
ual phenotypic variability. Patients may require different
stimulation paradigms according to their neurophysiolog-
ical status. For example, increased CBF or metabolic rates
may require low-frequency stimulations, whereas de-
creased CBF or metabolic rates may require higher fre-
quency stimulation paradigms (McCann et al 1998). Thus,
clinical response could depended on a large number of
variables that we are just beginning to understand. We
propose that state of brain function, type of coil, coil
location, stimulation paradigm, and diagnosis are factors
that need to be considered when exploring the therapeutic
response to TMS.
The suggestion that rTMS may have effects similar to
those seen with ECT in the treatment of MDD without
psychosis is very exciting; however, it needs to be tem-
pered by the paucity of clinical data and the novelty of
rTMS as a treatment. Electroconvulsive therapy is cur-
rently used very late in the treatment algorithms of MDD;
TMS, with its much less invasive profile and possibly
milder side-effect profile could become a much earlier
alternative for patients with MDD without psychosis.
However, additional blinded studies are needed before this
suggestion becomes a specific clinical recommendation.
This study was made possible by an Established Investigator Award of
NARSAD to Leon Grunhaus, MD.
Elisheba Noy and Lital Shemer were in charge of the data collection
and data analysis. Their diligent work was invaluable to the success of
Partial results from this study were presented at the 1998 Biological
Psychiatry Meeting in Toronto.
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