Repetitive Transcranial Magnetic Stimulation versus
Electroconvulsive Therapy for Major Depression:
Preliminary Results of a Randomized Trial
Philip G. Janicak, Sheila M. Dowd, Brian Martis, Danesh Alam, Dennis Beedle,
Jack Krasuski, Mary Jane Strong, Rajiv Sharma, Cherise Rosen, and Marlos Viana
Background: Many severely depressed patients do not
benefit from or tolerate existing treatments. Repetitive
transcranial magnetic stimulation (rTMS) has been re-
ported to benefit depression. We compared rTMS to
electroconvulsive therapy (ECT) in severely ill, depressed
Methods: Twenty-five patients with a major depression
(unipolar or bipolar) deemed clinically appropriate for ECT
were randomly assigned to rTMS (10–20 treatments, 10 Hz,
110% motor threshold applied to the left dorsolateral pre-
frontal cortex for a total of 10,000–20,000 stimulations) or a
course of bitemporal ECT (4–12 treatments). The primary
outcome measure was the 24-item Hamilton Depression
Rating Scale (HDRS). The Brief Psychiatric Rating Scale
(BPRS), Young Mania Rating Scale (YMS), and Clinical
Global Impression scale (CGI) were secondary measures.
Minimal rescue medications were utilized.
Results: Mean percent improvement on the baseline
HDRS score did not significantly differ between the two
treatments (i.e., 55% for the rTMS group vs. 64% for the
ECT group [p ? ns]). With response defined as a 50%
reduction from baseline and a final score ? 8 on the
HDRS, there was also no significant difference between
the two groups. We did not observe any differences
between groups on the secondary measures.
Conclusions: A 2–4 week randomized, prospective trial
comparing rTMS to ECT produced comparable therapeu-
tic effects in severely depressed patients. Biol Psychiatry
Key Words: rTMS, ECT, major depression, randomized
care facilities worldwide (World Health Organization 2000).
Major depressive disorder (MDD) is associated with substan-
tial personal and societal costs, owing to issues such as
suicide, lost productivity, and the high rates of health service
utilization (Janicak et al 2001; Sturm and Wells 1995).
Since the 1950s, antidepressants have been the primary
treatment approach for depressive disorders, and electro-
convulsive therapy (ECT) has remained an option for
patients refractory or intolerant to pharmacotherapy (Jani-
cak et al 2001). Although there is strong support for
antidepressant efficacy (Janicak et al 1985, 1989), a
substantial number of depressed patients do not benefit
from or cannot tolerate psychopharmacotherapy or ECT
(Janicak and Martis 1999). Furthermore, ECT has well-
documented side effects, including short-term antero-
grade, retrograde, and autobiographical memory deficits;
is costly; often requires hospitalization; and is associated
with substantial social stigma (Fink 1997; Janicak et al
1991). Given the pervasive nature of depression and the
need for more effective, safer, and more socially accept-
able therapeutic strategies, alternative approaches are be-
ing investigated, including repetitive transcranial magnetic
stimulation (rTMS) (Martis and Janicak 2000; Gates et al
1992; Hufnagel et al 1993), vagal nerve stimulation (Rush
et al 2000), and bright-light therapy (Terman et al 2001).
Repetitive TMS utilizes an electrical current that passes
through a metal coil applied to the scalp to produce
fluctuating magnetic pulses (George et al 1998a). Unlike
electrical stimulation, these magnetic pulses enter the
brain painlessly and unimpeded, causing neuronal depo-
larization in a localized area under the coil and possibly
distal effects as well (Barker et al 1987; Lisanby et al
2000a). Early observations in which this technique was
used as a neurophysiological probe indicated that some
neurology patients experienced mood elevation (Lisanby
et al 2000a). The subsequent therapeutic application of
epression is a common and serious illness afflicting
10% of all patients seeking treatment at primary health
From the Department of Psychiatry, University of Illinois at Chicago, Chicago,
Address reprint requests to Philip G. Janicak, M.D., University of Illinois at
Chicago, Department of Psychiatry, 1601 W. Taylor Street, Chicago IL 60612.
Received July 30, 2001; revised November 12, 2001; accepted November 21, 2001.
© 2002 Society of Biological Psychiatry0006-3223/02/$22.00
transcranial magnetic stimulation (TMS) for depression
has produced encouraging preliminary results (Beedle et al
1998; Hallet and Cohen 1989). Furthermore, both human
and animal studies have observed a number of similar
effects induced by rTMS, ECT (or electroconvulsive
shock), and antidepressants on the endocrine system, sleep
parameters, and in certain behavioral and biochemical
measures, all of which are associated with potential
antidepressant properties (Keck et al 2001; Krystal et al
2000; Lisanby et al 2000b; Szuba et al 2000).
Concurrent with these observations, several studies
have explored the potential antidepressant effects of rTMS
in humans. To date, much of the literature has centered on
comparisons of rTMS to sham rTMS. Although there are
significant methodological questions to be resolved (Loo
et al 2000; Lisanby et al 2001a), and not all reports have
been positive (e.g., Loo et al 1999; Padberg et al 1999),
most studies observed that patients treated with rTMS had
a significantly better result than those receiving sham
rTMS (George et al 1997, 2000; Kimbrell et al 1999; Klein
et al 1999; Nahas et al 1998; Pascual-Leone et al 1996).
Furthermore, although the literature reveals uncertainty as
to what constitutes optimal rTMS parameters for the
treatment of depression, we believe the existing data
provide reasonable direction, and our choice of parameters
for the present study reflects this literature (see Table 1 for
a description of the parameters).
The relative efficacy of rTMS versus sham rTMS has also
been studied in patients with drug treatment–resistant depres-
sion (TRD), albeit variably defined (Avery 1999; Berman et
al 2000; Figiel et al 1998; Greer 1998; Hoflich et al 1993;
Loo et al 1999; Nahas et al 1998; Padberg et al 1999;
Pascual-Leone et al 1996). Overall, the majority of studies
have reported a positive outcome with rTMS for TRD (see
Martis and Janicak 2000 for review).
There have also been favorable preliminary results in
comparisons of rTMS to ECT for a more severely ill, often
drug-resistant, heterogeneous group of patients typically
seen in clinical practice (Grunhaus et al 2000; Pridmore et
al 2000). The aim of the present study was to extend these
findings by comparing the efficacy of rTMS to ECT for
patients with major depression for whom ECT would be
considered appropriate in a general clinical setting. The
issues that differentiated this study from earlier compari-
sons were the use of more aggressive rTMS parameters;
administering ECT with bitemporal electrode placement;
and minimizing the use of concurrent medication.
Methods and Materials
Eligible subjects were between the ages of 18 to 75 years, met the
Structured Clinical Interview for Diagnosis (SCID)-derived
DSM-IV criteria (American Psychiatric Association 1994) for
major depression (unipolar or bipolar) and were deemed clini-
cally appropriate for a course of ECT by their treating psychia-
trist. The severity of depression and/or lack of adequate response
to or intolerance of pharmacotherapy were important factors in
making this decision (American Psychiatric Association 1990).
All subjects enrolled in the study had a chronic illness, scored
greater than twenty on the Hamilton Rating Depression Scale
(HDRS; Hamilton 1960), and had multiple medication trials.
Twenty-five subjects (age range, 18–66) diagnosed with a
depressive episode (unipolar or bipolar) were randomized to
rTMS or ECT (see Table 2). One subject randomized to ECT
withdrew from the study after receiving only three treatments
and before any clinical effect or assessment. Only one patient
crossed over from ECT to rTMS, achieving a 60% reduction on
the HDRS with rTMS versus only a 36% reduction with ECT
(Levy et al 2000). This patient, however, inadvertently received
low-energy right unilateral RUL-ECT. One subject withdrew
from rTMS treatment following four sessions and before any
clinical effect or assessment. Therefore all analyses related to
treatment response are based on 22 subjects.
Table 1. ECT and rTMS Administration Parameters
● ECT treatment parameters
● Monday, Wednesday, Friday treatment schedule
● MECTA SR1 or Thymatron™ DGx device
● Bitemporal stimulus electrode placement
● 100% oxygenation
● Methohexitol (1 mg/kg)
● Succinylcholine (1 mg/kg)
● Minimal rescue medications were used. Those medications
included sedative–hypnotics (e.g., zolpidem 5–20 mg q.h.s.,
p.r.n.) and occasionally lorazepam (1–2 mg p.o. p.r.n.) for anxiety
● 3–12 bitemporal ECT treatments
● If subjects meet response criteria at treatment 3 through 12, study is
● If subjects do not meet response criteria by the 12th treatment they
are offered the option to cross over to rTMS
● rTMS treatment parameters:
● Monday through Friday daily treatment schedule
● Magstim Super Rapid™ device with double 70mm coil (Magstim
Company US, LLC: New York, NY)
● Left dorsolateral, prefrontal cortex; 110% MT; 10 Hz frequency
● Twenty trains of 50 stimulations per train, each 5 sec in duration
(i.e., 1000 stimulations per session; total of 10,000–20,000
stimulations per course).
● 20, 30-sec, inter-train intervals
● Minimal rescue medications (e.g., anxiolytic, sedative–hypnotic)
as described above
● To avoid any potential hearing impairment patients also wore
earplugs during the procedure
● 10–20 rTMS treatment sessions
● If subjects meet response criteria at treatment 10 or 15, their study
participation is completed
● If subjects do not meet criteria by session 20, they are offered the
option to cross over to ECT
ECT, electroconvulsive therapy; rTMS, repetitive transcranial magnetic stim-
ulation; MT, motor threshold.
660 P.G. Janicak et al
Following a description of all procedures, subjects provided
informed consent as approved by the University of Illinois at
Chicago, Alexian Brothers Hospital, and the University of
Chicago’s Institutional Review Boards. Patients were excluded if
they had any serious medical conditions that would preclude a
course of ECT or rTMS or a history of clinically significant
substance or alcohol abuse/dependency within the previous 3
months. Females who were pregnant or of childbearing potential
not on acceptable contraception were also excluded because of
unknown risks to the fetus. Subjects were also excluded if they
had intracranial metallic or magnetic implants or a pacemaker.
Subjects were randomly assigned to either the ECT or rTMS
treatment arm. Following the initial randomized treatment trial,
subjects who did not meet response criteria could crossover to
the alternative arm. Using the Magstim Super Rapid™ device,
rTMS was administered as a U.S. Food and Drug Administra-
tion–approved investigational procedure at the Psychiatric Clin-
ical Research Center at the University of Illinois at Chicago.
Electroconvulsive therapy was administered at three sites: the
University of Illinois clinical psychiatric unit, Alexian Brothers
Hospital, and the University of Chicago. Table 1 lists the
schedules and treatment parameters for both ECT and rTMS
There were no differences between the rTMS and ECT
treatment groups in terms of age, number of previous hospital-
izations, age at first episode, length of episode, length of
medication washout, and baseline symptoms (see Table 3). There
were also no differences in the history of ECT treatment
(Fisher’s Exact Test; p ? ns) and the gender distribution
(Fisher’s Exact Test; p ? ns) between the two groups.
In rTMS, motor threshold (MT) was determined by using the
right first dorsal interosseous (FDI) as the target muscle (Was-
sermann et al 1996). Mapping studies have found that the
greatest responses for FDI stimulation are derived from coil
(center) placement in a lateral–sagittal orientation at a point 2 cm
behind and 4 cm to the left of the nasion–inion line. Therefore,
our point of stimulation began in approximately this region. The
stimulator was set at 1 Hz, a low intensity, and methodically
moved across the left frontal–parietal region of the cranium
centered at the above-indicated point until the motor cortex for
the FDI was located. Up to 10 single pulses were given at each
level of intensity. Beginning at 60% intensity, it was increased by
2% and the procedure repeated until FDI MT was achieved,
which was defined as the stimulus intensity that reliably pro-
duces visibly observable right FDI muscle contractions. The
point of prefrontal cortex magnetic stimulation was determined
by moving the coil 5 cm anteriorly from the point of MT
determination. The site was then marked for reference with an
indelible skin marker.
Stimulus parameters for ECT were determined by the use of
preselected dosage methods when using the MECTA SR 1
device and the age-adjusted method when using the Thyma-
tron™ DGx device as described in the manufacturers’ instruction
manuals. Dosing was adjusted during the treatment based on
seizure duration, side effects, and response. Patients recently
tapered from benzodiazepines or anticonvulsants were started at
lower stimulus intensity, owing to the possibility of prolonged
initial seizures. Motor and electroencephalogram (EEG) seizure
durations were generally quite robust. The mean length of seizure
duration as measured by EEG recording was 48.93 (13.26) sec
with a minimum of 29 sec and a maximum of 74 sec.
Before treatment, 20 of the 22 subjects completed a brief
medication washout (mean number of days ? 4 ? 3). There were
Table 2. Clinical Characteristics of the Sample
Number of subjects
Mean no. of treatments (SD)
n ? 13
n ? 9
2.5 (1.1)Mean no. of treatment weeks (SD)
rTMS, repetitive transcranial magnetic stimulation; ECT, electroconvulsive
therapy; M, male; F, female.
Table 3. Mean Demographic Information for the Entire Sample
Number previous hospitalizations
Age at first episode
Length of episode in weeks
Length of medication washout in days
CGI baseline severity of illness
rTMS, repetitive transcranial magnetic stimulation; ECT, electroconvulsive therapy; HDRS, Hamilton Depression Rating Scale; YMS, Young Mania Rating Scale;
BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression Scale.
rTMS vs. ECT661
no differences between groups in medications received before
washout. No patients were receiving depot neuroleptics, and
those previously treated with fluoxetine had not received that
medication for at least 1 month before starting the trial. Ratings
were administered at baseline and weekly throughout the course
of ECT/rTMS. Assessments included the 24-item HDRS, the
Brief Psychiatric Rating Scale (BPRS; Overall and Gorham
1962), the Young Mania Rating Scale (YMS; Young et al 1978),
and the Clinical Global Impression scale (CGI; Guy 1976).
Response was defined “a priori” as a 50% decrease in HDRS
score from baseline and a total HDRS score of 8 or less. Raters
were first trained during formal educational seminars, then
co-rated with an experienced rater, and finally conducted super-
vised interviews. The intra-class coefficient among raters for the
HDRS was 0.958. Given the experimental nature of the proce-
dure, data were collected on all adverse events associated with
the rTMS procedures (i.e., seizure activity, psychiatric side
effects, and local skin irritation) through an open-ended
Every attempt was made to minimize the use of concomitant
rescue medications. Total avoidance of adjunctive medications in
severely depressed patients receiving ECT or rTMS is not always
possible owing to significant sleeplessness, anxiety, apprehen-
sion, and psychosis. Anxiolytics (primarily lorazepam or zolpi-
dem) were used sparingly, provided only on a p.r.n. basis, and an
attempt was made to slowly taper their use. In all cases, those
subjects who received anxiolytics did so from the outset of the
trial. Three subjects received clonazepam during the study,
because they had been receiving it before admission. Early in the
study, three of the ECT subjects with psychosis also received
rescue antipsychotic medication for at least part of the treatment
course. This was stopped for all subsequent ECT subjects, and
the rTMS subjects did not receive any antipsychotic medication.
Clinical improvement was computed in several ways. A paired
samples t test comparing baseline to end-of-treatment ratings was
computed for each group. A continuous measure of improvement
was obtained by computing percent change on the rating scale
total scores ((pretreatment ? posttreatment)/pretreatment). Ad-
ditional nonparametric tests were also run to further explore the
results. In addition, a categorization of responders or nonre-
sponders was based on whether a subject achieved at least a 50%
reduction from baseline and a total score of ?8 on the final
HDRS rating. All p values are two-tailed. Pearson correlations
were used to examine the relationship between continuous
The data analyses of response to treatment included all
subjects who completed the study (n ? 22). We computed
a paired samples t test comparing baseline and end-of-
treatment HDRS total within each group. Both the rTMS
and ECT groups evidenced significant improvement
[t(12) ? 4.7, p ? .000, and t(8) ? 5.0, p ? .001,
respectively]. Further, based on percent change scores
comparing baseline to end-of-treatment, there were no
significant differences between the ECT and rTMS groups
[t(20) ? .587, p ? .564] (see Table 4). Thus, both groups
evidenced a significant decrease in the baseline HDRS at
the end of treatment and the decrease was not significantly
different between the two groups. Given the present
sample size, a difference of 1.3 SD between the two
groups would be detected, if present with power 0.81 (2
sided test, alpha ? 0.05).
We also employed a rigorous a priori response criteria,
defined as a ?50% decrease from baseline HDRS and a
total final score ? 8. Utilizing both of these response
criteria, we found no significant difference in response
rates between the treatment groups (Fisher’s Exact Test;
p ? ns) (see Table 5).
Within each group, a paired samples t test comparing
baseline BPRS total score to end-of-treatment total score
evidenced significant improvement in those subjects
treated with rTMS [t(12) ? 3.47, p ? .005 and ECT t(8) ?
2.9, p ? .019]. A paired samples t test comparing baseline
YMS to end-of-treatment scores found no significant
change in the rTMS [t(12) ? .353, p ? .730] or in the ECT
[t(8) ? ?1.08, p ? .310] groups. The mean score on the
CGI improvement item averaged a score of 2 (much
improved) for both the rTMS and ECT groups.
Analyses of change scores on our secondary measures
(i.e., BPRS, YMS, and CGI) found no significant differ-
ences between the treatment groups [BPRS t(20) ?
?1.08, p ? . 292; YMS t(9.5) ? ?0.935, p ? . 373; and
CGI t(19) ? ?0.051; p ? . 960] (see Table 6). All of the
Table 4. Mean HDRS Scores and Percent Change
(n ? 13)
(n ? 9)
(n ? 22)
32.2 (6.8) 13.9 (11.1)55% (36)
31.4 (8.5)10.9 (9.5)64% (30)
31.9 (7.4) 12.8 (10.4)59% (33)
HDRS, Hamilton Depression Rating Scale; rTMS, repetitive transcranial
magnetic stimulation; ECT, electroconvulsive therapy.
Table 5. Number of Subjects Who Achieved a ?50%
Reduction from Baseline and a Final HDRS Score of ?8 by
?50%; ?8 Response rate
rTMS (n ? 13)
ECT (n ? 9)
Fisher’s Exact test; p ? ns.
HDRS, Hamilton Depression Rating Scale; rTMS, repetitive transcranial
magnetic stimulation; ECT, electro convulsive therapy.
662 P.G. Janicak et al
qualitative statements above hold when based on nonpara-
A post hoc examination of the subjects who responded
to rTMS (n ? 6) revealed a significant correlation between
the number of treatments to achieve response (defined as
a ?50% improvement and a score of ?8 on the HDRS)
and age [r(4) ? .90, p ? .05]. By contrast, in the ECT
responder’s group (n ? 5) there was no correlation
between the number of treatments to achieve the same
response criteria and age [r(3) ? .046, p ? ns].
Data comparing treatment response in psychotic pa-
tients were not analyzed owing to the small number (i.e.,
three in the rTMS group and five in the ECT group) and
because three of the five subjects in the ECT group
received antipsychotic medication during the study.
In general, the utilization of rescue medications during
the study was minimal and did not differ between the two
treatment groups (see Table 7).
There were no significant adverse events (e.g., seizures)
and generally only mild side effects were reported in the
rTMS group. Facial twitching was noted in six subjects
during the stimulus train period. Six of the rTMS subjects
evidenced erythema at the site of coil placement. Subjec-
tively, various effects localized to the stimulation site were
reported, including mild pain or discomfort (n ? 6),
feelings of warmth (n ? 3), a tapping sensation (“like a
hammer”) (n ? 2), and headache (n ? 1). One subject
reported moderate pain at the site of the coil placement,
and a topical anesthetic was applied for several treatments,
but eventually this subject was able to continue treatments
without the anesthetic. Four subjects described a sense of
nervousness or anxiety before and during the treatments.
Conversely, one subject described that rTMS was like
“meditation” and was calming and relaxing. There were no
serious or unexpected adverse events associated with ECT.
Adverse effects with bitemporal ECT included short-term
memory impairment, drowsiness shortly after treatment,
and postictal and anesthesia-induced confusion.
Our 2–4 week preliminary trial found that rTMS produced
comparable antidepressant efficacy to bitemporal ECT in
22 patients with a major depressive episode (see Figure 1).
Although there was a steeper initial drop in HDRS scores
in the ECT group, an analysis of the mean change scores
from baseline to week 1 showed no significant difference
between the ECT and rTMS groups [t(19) ? ?1.7, p ?
.099]. Using a conservative a priori response criteria (i.e.,
?50% decrease from baseline HDRS and ?8 score on the
final HDRS), we failed to show a difference between the
two groups. We also calculated percent improvement from
baseline rating scores on the 24-item HDRS and found no
significant group differences between rTMS and bitempo-
ral ECT. Additionally, on our secondary measures of
response (BPRS, YMS, and CGI scale), there were no
significant differences between the two treatment groups,
with both evidencing significant improvements (i.e.,
BPRS and CGI) or no change (i.e., YMS).
Of interest, an exploratory analysis on rTMS responders
found a correlation between age and the number of
treatments needed to achieve response. Although predic-
Table 6. Mean Scores on Secondary Measures of Response
rTMS (n ? 13)
ECT (n ? 9)
2.5 (3.0) 2.1 (1.0)
3 (3.50) 2 (1.62)
t test; p ? ns.
BPRS, Brief Psychiatric Rating Scale; YMS, Young Mania Rating Scale; CGI,
Clinical Global Improvement Scale; rTMS, repetitive transcranial magnetic stim-
ulation; ECT, electroconvulsive therapy.
Table 7. Use of Rescue Medications by Group
Anxiolytics Sedative–hypnotics Antipsychotics
Week 1 (n ? 13)
Week 2 (n ? 11)
Week 3 (n ? 9)
Week 4 (n ? 6)
Week 1 (n ? 9)
Week 2 (n ? 7)
Week 3 (n ? 2)
Week 4 (n ? 1)
rTMS, repetitive transcranial magnetic stimulation; ECT, electroconvulsive
Figure 1. Hamilton Depression Rating Scale (HDRS) ratings at
baseline, week 1, and at end of treatment. rTMS, repetitive trans-
cranial magnetic stimulation; ECT, electroconvulsive therapy.
rTMS vs. ECT 663
tive conclusions cannot be made from such a correlation,
these findings may relate to the study by Figiel et al (1998)
that reported that older age was associated with poorer
rTMS outcome. Sixteen of 28 of the younger subjects
responded, and only 5 out of the 22 subjects over the age
of 65 responded (i.e., a 60% decrease and a score of 16 or
less on the HDRS, and a moderate score on the CGI). In
their study, however, only five rTMS sessions were given.
Overall, we observed a 55% improvement from the
baseline HDRS score in the rTMS group. Our results are
consistent with the two earlier reports comparing rTMS to
ECT, albeit with varying designs.
In an open study design, Grunhaus et al (2000) ran-
domly assigned 40 patients with MDD to either rTMS or
right unilateral, nondominant ECT. Subjects with insuffi-
cient response could be switched to bilateral ECT admin-
istration. The authors concluded that ECT was more
effective than rTMS for patients with MDD and psychosis.
In the nonpsychotic group, however, the therapeutic ef-
fects of rTMS were similar to those of ECT. Of note, the
psychotically depressed patients receiving ECT also re-
ceived antidepressants and/or antipsychotics, whereas the
rTMS patients did not. In addition, stimulus intensity with
rTMS (i.e., 90% of MT) was lower than those reported to
be most effective by George et al (1998a).
Pridmore et al (2000) randomly assigned 32 patients
with MDD who failed to respond to at least one course of
medication to rTMS or unilateral, nondominant ECT.
Although the ECT group had a significantly greater
percent improvement on the Beck Depression Inventory
(BDI) (69% vs. 46%), blind raters found that on the HDRS
the rate of remission (i.e., a total final score of ?8) and
percent improvement over the course of treatment were
the same for subjects receiving either ECT or rTMS. Of
note, an equal number of subjects in both groups received
concurrent medication, but no other information was
Thus, Grunhaus et al (2000) reported a 40% improve-
ment, and Pridmore et al (2000) found a 56% improve-
ment on the HDRS. Our findings approximate the upper
end of this range and are comparable to sham-controlled
studies in which the range in percent improvement has
been reported to be 18% (George et al 1997) to 51%
(Epstein et al 1998).
The absence of a placebo control or sham rTMS group
is an important limitation to this study. Because this was a
pilot study designed to involve subjects with more severe
depression, we did not feel that a placebo arm was justified
at this time. Given the severity and chronicity of illness
and the prior exposure to multiple treatments without
adequate resolution of symptoms in our sample, we also
think it less likely to observe a placebo response in such a
patient group. Thase (1999), in a review of the use of
clinical trials reported that placebo response rates are
likely to approach zero in severe depression (e.g., psychot-
ic). Further, there remains considerable debate about what
constitutes an appropriate sham TMS control. For exam-
ple, Lisanby et al (2001a), comparing the effects of active
rTMS to four types of sham TMS on motor evoked
potentials (MEPs) in human subjects, reported cortical
stimulation in the range of 48%–76% with the sham
In addition, although bias is inherent with the use of
unblinded assessments, the raters in the study did undergo
rigorous training and had a very high intraclass correlation
on the HDRS reliability analysis. Again, the goal of this
study was to collect preliminary data examining the
potential benefits of rTMS relative to standard ECT
treatments. Based on this experience, a larger study is
planned to address these issues.
Grunhaus et al (2000) reported that ECT was more
effective than rTMS in depressed patients with psychosis.
In the sample of the present study, three out of five
psychotic subjects treated with ECT received antipsy-
chotic medication versus none of the three psychotic
rTMS subjects (Table 7). The three rTMS psychotic
subjects had a mean percent change from the baseline
HDRS score of 78% versus the five psychotic subjects in
the ECT group, who averaged a 70% improvement. In
turn, the nine nonpsychotic subjects in the rTMS group
averaged a 47% improvement on the HDRS versus the
four nonpsychotic subjects in the ECT group, who aver-
aged a 56% improvement.
In the present study, the subjects assigned to rTMS did
not report any severe adverse events and none dropped out
of the trial because of side effects. Unlike a recent report
that described a switch to mania following rTMS treat-
ment (Ornah et al 2001), none of our subjects, including
the three bipolar depressed subjects, exhibited a change in
manic symptoms as evidenced by ratings on the YMS.
None of the mild to moderate side effects were persistent,
and these generally responded to minimal intervention.
This is consistent with other studies that found relatively
mild adverse effects (Grunhaus et al 2000; Pridmore et al
2000). In turn, the ECT group did not experience any
serious adverse events, and no subject dropped out be-
cause of side effects.
This pilot project also included an examination of select
components of cognition designed to assess potential
changes in functioning in the rTMS group. These data
were collected primarily for safety purposes. Thus, we
only obtained information on the cognitive effects of
rTMS and do not have comparable information for the
ECT group. Results of this preliminary investigation have
been presented in abstract form (Martis et al 2000).
All attempts were made to reduce the risk for seizure by
664 P.G. Janicak et al
using rTMS stimulus parameters promulgated in the
guidelines published by the International Workshop on the
Safety of rTMS (Wassermann 1998). Although the opti-
mal parameters for rTMS have not yet been established,
we chose parameters based on current research tempered
by these safety guidelines. Thus, for coil placement, most
studies with positive outcomes in depression have used
stimulation over the left dorsolateral prefrontal cortex
(DLPFC) (Figiel et al 1998; George et al 1997; Greer et al
1998; Nahas et al 1998; Pascual-Leone et al 1996;).
Although the optimal frequency of stimulation continues
to be studied, higher frequencies (e.g., ?1–20 Hz) appear
to be more efficacious over the left DLPFC. There is a
smaller database, however, which indicates that right
DLPFC coil placement and lower frequencies (e.g.,
?1Hz) may also be efficacious. Based on recent imaging
studies, George et al (1998a, 2000), Nahas et al (2000) and
Kozel et al (2000) have hypothesized that using higher
intensities, as determined by MT, may have more robust
effects (as the magnetic field declines logarithmically with
distance from the coil); however, intensities greater than
120% of MT have generally been avoided because of the
potential to increase seizure risk (Wassermann 1998). The
number of stimulations delivered is determined by the
frequency (Hz) plus stimulation train duration. In this
context, one safety issue is the intertrain interval, which
has typically been 20–50 sec in duration (George et al
2000; Grunhaus et al 2000; Janicak et al 2000; Pridmore et
al 2000). Although the number of stimulations has varied
across studies, most positive trials deliver between 8000
and 20,000 stimulations per treatment course.
Although our rTMS stimulus parameters were more
aggressive than many of the previous studies, they did not
produce a seizure or other serious adverse events. In a
similar vein we attempted to maximize efficacy with
bitemporal ECT (Sackeim et al 2000). This differs from
the Grunhaus et al (2000) and Pridmore et al (2000)
studies, wherein treatment was initiated with unilateral
nondominant ECT; however, eight subjects in the Grun-
haus study were subsequently switched to bitemporal
Repetitive transcranial magnetic stimulation may be a
viable intermediate strategy between antidepressants and
ECT or may augment medication or ECT treatment
(Conca et al 1996; Grunhaus et al 2000; Lisanby et al
2001c; Martis and Janicak 2000; Pridmore et al 2000;
Sackeim 2000). Magnetic stimulation with more aggres-
sive treatment parameters is also being studied as a
possible alternative to electrically induced seizures. The
potential benefit may be less cognitive disruption (Lisanby
et al 2001b, 2001d).
Our preliminary data indicate that rTMS may be an
alternative to ECT for at least some patients with more
severe depression. Even if only a proportion of subjects
responds to this alternative intervention, there are distinct
advantages to rTMS. Compared to ECT, rTMS appears to
have a potentially lower adverse effect profile, including
fewer cognitive adverse effects (Little et al 2000); is easier
to administer; and more cost effective (e.g., no need for
anesthesia induction or operating room recovery monitor-
ing). An additional important social benefit is that rTMS
may engender less stigma than ECT. We believe that the
positive preliminary results in three reported comparison
trials (i.e.; Grunhaus et al 2000; Pridmore 2000; and our
data) warrant further investigation with advancing designs
and larger subject sample size. To that end, as noted
earlier, we plan to conduct a larger, more rigorously
This project was supported in part by the Department of Psychiatry,
the Campus Research Board (598-224), and the National Institutes of
Health–funded General Clinical Research Center (1 MO1 RR 13987-01),
all at University of Illinois at Chicago. Dr. Martis was supported in part
by an Eleanor B. Pillsbury Fellowship Grant. Dr. Alam is supported in
part by an Eleanor B. Pillsbury Fellowship Grant.
We would like to acknowledge the contributions of Eileen Martin,
Ph.D., Anthony D’Agostino, M.D., Gregory Teas, M.D., Emil Coccaro,
M.D., Larry Goldman, M.D., and Francis McMahon, M.D.
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