Transcript Slayt 1 - e-Psikiyatri

Transcranial Magnetic
Stimulation in
Psychiatric Disorders
Oguz Tan,
Memory Center, Istanbul, Turkey
Transcranial Magnetic Stimulation
in Psychiatric Disorders
Oguz Tan, Memory Center, Istanbul, Turkey
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Objectives: It was aimed to review the literature about the
clinical use of repetitive transcranial magnetic stimulation
(rTMS) therapy in psychiatric disorders.
Methods: A medline research was done concerning rTMS
use in mood disorders, anxiety disorders, psychotic
disorders, and substance use disorders.
Results: Application of rTMS in depressive patients usually
lead to a significant clinical improvement. Findings about the
use of rTMS in manic episodes, anxiety disorders, psychotic
disorders, and substance use disorders are limited.
Coclusion: rTMS is probably a useful therapeutic tool in
depressive disorders. Further research is needed to clarify
the role of rTMS in pasychiatric disorders other than
depression.
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Repetitive transcranial magnetic stimulation in the
treatment of depression has been intensely studied.
Since 1993 until recently, approximately 70 studies
evaluating clinical efficacy of rTMS in depression have
been published.
Most data support an antidepressant effect of highfrequency rTMS administered to the left prefrontal
cortex, although most patients enrolled in the studies
had treatment-resistant and severe depression.
Side-effect profile of rTMS is much more favorable than
ECT or pharmacotherapy. The only serious side-effect of
rTMS is seizure that have occured very rarely.
An important reference is:
www.ists.unibe.ch
This site contains:
The Avery-George-Holtzheimer Database of rTMS
Depression Studies
UPDATED as of 11/22/2004
SHAM-CONTROLLED
STUDIES
33 sham-controlled studies have been conducted since
1993 until June, 2005. 19 out of these studies found
that rTMS were superior when compared to sham
stimulation. However, in some studies, the benefit from
rTMS was modest.
SHAM-CONTROLLED STUDIES
1996
Pascual-Leone A, Rubio B, Pallardo F, Catala MD
 Rapid-rate transcranial magnetic stimulation of left dorsolateral
prefrontal cortex in drug-resistant depression. Lancet 348:233-7.
 17 patients. Medication-resistant. Cross-over study.
Non medication-free.
Psychotic depression..
Left DLPFC
10 Hz
Intensity 90 percent MT
5 sessions with active rTMS (cross-over to the other group and five
more sessions)
Total pulses 10.000
Different cortical areas (vertex stimulation, right DLPFC) stimulation
were stimulated.
 HAMD decreased from 25.2 to 13.8 after 5 sessions (45 percent
decrease in depression)
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SHAM-CONTROLLED STUDIES
1997
George MS, Wassermann EM, Kimbrell TA, et al
 Mood improvement following daily left prefrontal repetitive
transcranial magnetic stimulation in patients with depression: a
placebo-controlled crossover trial. Am J Psychiatry 154:1752-6.
 24 patients. Not medication-resistant. Cross-over study.
Some patients are medication-free.
Left DLPFC
20 Hz
Intensity 80 percent MT
10 sessions
Total pulses 8.000
 rTMS superior to Sham, but small decrease in depression rating.
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SHAM-CONTROLLED STUDIES
1999
Avery DH, Claypoole K, Robinson L, et al
 Repetitive transcranial magnetic stimulation in the treatment of
medication-resistant depression: preliminary data. J Nerv Ment Dis
187:114-7.
 6 patients. Medication-resistant.
Not medication-free.
Left DLPFC
10 Hz
Intensity 80 percent MT
10 sessions
Total pulses 10.000
 Slight improvement in rTMS group compared with sham. No
decrement in neuropsychological tests with rTMS.
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SHAM-CONTROLLED STUDIES
1999
Klein E, Kreinin I, Chistyakov A, et al
 Therapeutic efficacy of right prefrontal slow repetitive transcranial
magnetic stimulation in major depression: a double-blind controlled
study. Arch Gen Psychiatry 56:315-20.
70 patients. Not medication-resistant.
Not medication-free.
Right DLPFC
1 Hz
Intensity 110 percent MT
10 sessions
Total pulses 1200
 HAM-D decreased from 25.8 to 13.7 with rTMS and 25.3 to 19.7
with sham. Three dropouts (1 rTMS, 2 sham). Of rTMS patients, 49%
were responders (w/ >50% decrease in HAM-D); of sham patients, 25%
were responders.
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SHAM-CONTROLLED STUDIES
1999
Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Gandevia S
 Double-blind controlled investigation of transcranial magnetic
stimulation for the treatment of resistant major depression. Am J
Psychiatry 156:946-8.
 18 patients. Medication-resistant.
Not-medication-free.
Left DLPFC
10 Hz
Intensity 110 percent MT
10 sessions of real or sham rTMS, then permitted up to 20 sessions
of real rTMS
Total pulses 15.000
 With rTMS significant decreases in HAMD after 10 sessions, but not
different from sham. With rTMS, 44.9% decrease from baseline at one
month follow-up.
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SHAM-CONTROLLED STUDIES
1999
Padberg F, Zwanzger P, Thoma H, et al
 Repetitive transcranial magnetic stimulation (rTMS) in
pharmacotherapy-refractory major depression: comparative study of
fast, slow and sham rTMS. Psychiatry Res 88:163-71.
 18 patients. Medication-resistant.
Some patients are medication-free.
Left DLPFC
10 Hz or 0.3 Hz
Intensity 90 percent MT
5 sessions
Total pulses 1250
 Not clinically meaningful antidepressant efficacy. Improvement in
verbal memory scores after fast rTMS, with no change after slow rTMS,
and a trend toward poorer scores after sham.
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SHAM-CONTROLLED STUDIES
1999
Kimbrell TA, Little JT, Dunn RT, et al
 Frequency dependence of antidepressant response to left prefrontal
repetitive transcranial magnetic stimulation (rTMS) as a function of baseline
cerebral glucose metabolism. Biol Psychiatry 46:1603-13.
 26 patients. Medication-resistance NA.
Some patients medication-free.
Left DLPFC
20 Hz or 1 Hz
Intensity 90 percent MT
10 sessions
Total pulses 8000
 2/13 responded (greater than 50% response) There was a negative
correlation between the degree of antidepressant response after 1 Hz
compared to 20 Hz. Better response to 20 hz was associated with the degree
of baseline hypometabolism measured by PET, whereas 1 Hz rTMS tended
to be associated with baseline hypermetabolism. 1/10 responded in 20 Hz
group. 0/3 responded in sham group. Antidepressant response to rTMS
might vary as as a function of stimulation frequency and may depend on
pretreatment cerebral metabolism.
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SHAM-CONTROLLED STUDIES
1999
Stikhina N, Lyskov EB, Lomarev MP, Aleksanian ZA, Mikhailov VO,
Medvedev SV
 Transcranial magnetic stimulation in neurotic depression. Zh Nevrol
Psikhiatr Im S S Korsakova 99:26-9.
 29 patients. Medication-resistance NA.
Medication-free or not NA. All patients received psychotherapy.
Left frontal
40 Hz
Intensity 0.015 Tesla
10 sessions
Total pulses 480.000
 TMS significantly better than control condition.
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SHAM-CONTROLLED STUDIES
2000
Berman RM, Narasimhan M, Sanacora G, et al
 A randomized clinical trial of repetitive transcranial magnetic
stimulation in the treatment of major depression. Biol Psychiatry
47:332-7.
 20 patients. Medication-resistant.
Medication-free.
Left DLPFC
20 Hz
Intensity 80 percent MT
10 sessions
Total pulses 8000
 In rTMS group, 1/10 responded (decrease in HAM-D from 48 to 7);
in sham group 0/10 responded. Statistically significant but clinically
modest reductions of depressive symptoms.
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SHAM-CONTROLLED STUDIES
2000
Eschweiler GW, Wegerer C, Schlotter W, et al
 Left prefrontal activation predicts therapeutic effects of repetitive
transcranial magnetic stimulation (rTMS) in major depression.
Psychiatry Res 99:161-72.
 12 patients. Not medication-resistant.
Medication-free or not NA
Left DLPFC
10 Hz
Intensity 90 percent MT
Crossover study. 4 weeks’ duration consisting of two periods of 5
days with rTMS separated by 9 days of no stimulation
Total pulses 20.000
 rTMS significantly better than sham, also used near infrared
spectroscopy. Absence of a task-related increase of total hemoglobin
concentrations at the stimulation site, but not at other locations, before
the first active rTMS significantly predicted the clinical response to
active rTMS.
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SHAM-CONTROLLED STUDIES
2000
George MS, Nahas Z, Molloy M, et al
 A controlled trial of daily left prefrontal cortex TMS for treating
depression. Biol Psychiatry 48:962-70.
 30 patients. Medication-resistant.
Medication-free
Left DLPFC
5 Hz or 20 Hz or sham
Intensity 100 percent MT
10 sessions
Total pulses 16.000
 6/10 responded (greater than 50% decrease in HAMD). 3/10
responded to 20Hz. 0/10 responded to sham.
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SHAM-CONTROLLED STUDIES
2001
Garcia-Toro M, Mayol A, Arnillas H, et al
 Modest adjunctive benefit with transcranial magnetic stimulation in
medication-resistant depression. J Affect Disord 64:271-5.
 40 patients. Medication-resistant.
Not medication-free
Left DLPFC
20 Hz
10 sessions
Intensity 90 percent MT
Total pulses 12.000
 rTMS added to current antidepressant treatments. 5/17 (29%) of patients
initially randomized to rTMS were responders (>50% decrease in HDRS). 15
sham non-responders crossed over to receive active 90% MT rTMS; 4/14
(29%) patients that completed 4 weeks of treatment were responders. The 9
non-responders were treated with 10 additional sessions of 110% MT rTMS;
3/9 (33%) were responders. Real, but not sham HF-rTMS, was associated
with a significant decrease in the Hamilton Depression Rating Scale, but only
twelve patients decreased more than 50%
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SHAM-CONTROLLED STUDIES
2001
Szuba MP, O'Reardon JP, Rai AS, et al
 Acute mood and thyroid stimulating hormone effects of transcranial
magnetic stimulation in major depression. Biol Psychiatry 50:22-7.
 14 patients. Medication-resistance NA.
Medication-free NA
Left DLPFC
10 Hz
Number of sessions NA
Intensity 100 percent MT
Total pulses NA
 No efficacy data presented. Patients receiving active TMS showed
greater mood improvements with acute sessions of TMS than patients
receiving sham. Subjects are a subset of a larger study evaluation
twice daily versus once daily rTMS. The change in TSH from pre- to
post-rTMS was significantly different between active and sham
sessions
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SHAM-CONTROLLED STUDIES
2001
Manes F, Jorge R, Morcuende M, Yamada T, Paradiso S, Robinson
RG
 A controlled study of repetitive transcranial magnetic stimulation as
a treatment of depression in the elderly. Int Psychogeriatr 13:225-31.
 20 patients. Medication-resistant.
Medication-free.
Left DLPFC
20 Hz
5 sessions.
Intensity 80 percent MT
Total pulses 4000
 Studied patients >50 years old (mean age 60.7 years, SD 9.8
years). Neuropsychological testing used MMSE (minimental state
examination); no significant difference between groups pre- or posttreatment. 6 responders (3 to rTMS and 3 to sham) had significantly
greater frontal lobe volume than non-responders.
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SHAM-CONTROLLED STUDIES
2001
Garcia-Toro M, Pascual-Leone A, Romera M, et al
 Prefrontal repetitive transcranial magnetic stimulation as add on
treatment in depression. J Neurol Neurosurg Psychiatry 71:546-8.
 28 patients. 16 medication-resistant (a single trial of drug), 12 had not
received medication fort he present depressive episode.
Patients were started on sertraline.
Left DLPFC
20 Hz
10 sessions.
Intensity 90 percent MT
Total pulses 12.000
 rTMS did not add efficacy over the use of standard antidepressant
medication. Studied rTMS versus sham as add-on treatment to sertraline for
a major depressive episode. All but two patients received benzodiazepines.
Differences in response at 2 weeks in HDRS and BDI, but not at 4 weeks (2
weeks after last treatment). Non-responders to sham were crossed over to
receive 90% MT rTMS with identical parameters. Non-responders to active
90% MT rTMS crossed over to receive 110% MT rTMS.
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SHAM-CONTROLLED STUDIES
2001
Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T,
Sackeim HA
 Augmentation of sertraline antidepressant treatment with
transcranial magnetic stimulation. Biol Psychiatry 49:81S.
 36 patients. 61 percent of patients were medication-resistant.
Not medication-free.
10 Hz over the left DLPFC or 1 Hz the right DLPFC or sham
10 sessions.
Intensity 110 percent MT
Total pulses 16.000
 Compared 10 Hz left DLPFC rTMS to 1 Hz right DLPFC rTMS to
sham rTMS, all as add-on therapy to sertraline 50 mg. Remission in the
active TMS group combined was 25% vs. 8% in the sham group (NS).
Degree of medication resistance negatively correlated with response
and remission.
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SHAM-CONTROLLED STUDIES
2002
Dolberg OT, Dannon PN, Schreiber S, Grunhaus L
 Transcranial magnetic stimulation in patients with bipolar
depression: a double blind, controlled study. Bipolar Disord 4:94-5.
 20 patients. Medication-resistance NA.
Medication-free NA
Left DLPFC
Frequency (Hz) NA
10 sessions
Intensity NA
Total pulses NA
 Preliminary report. Response or remission rate NA. Depression
decreased 29 percent in the active TMS group, 20 percent in the sham
group.
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SHAM-CONTROLLED STUDIES
2002
Padberg F, Zwanzger P, Keck ME, et al
Repetitive transcranial magnetic stimulation (rTMS) in major depression:
relation between efficacy and stimulation intensity.
Neuropsychopharmacology 27:638-45.
 31 patients. Drug-resistant.
Not medication-free.
Left DLPFC
10 Hz
10 sessions.
Intensity: 100 percent MT or 90 percent MT or sham
Total pulses 15.000
MADRS scores: 4% decrease with sham, 15% decrease with 90% MT
rTMS, 33% decrease with 100% rTMS.
 3/10 responders (>50% decr in HAMD) and 2/10 partial responders (>25%
decr HAMD) with 100% MT rTMS, 2/10 responders and 1/10 partial
responder with 90% MT rTMS, 0/10 responders and 2/10 partial responders
with sham rTMS.
 Patients receiving rTMS had substantially fewer days in the hospital posttreatment (43 days for 100% MT rTMS, 61 days for 90% MT rTMS, 135 days
for sham rTMS). Improvement of depressive symptoms after rTMS
significantly increased with stimulation intensity across the three groups.
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SHAM-CONTROLLED STUDIES
2002
Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Feingold A,
Berman RM
 Lack of a therapeutic effect of a 2-week sub-threshold transcranial
magnetic stimulation course for treatment-resistant depression.
Psychiatry Res 113:245-54.
 21 patients. Medication-resistant.
Not medication-free.
Left DLPFC
20 Hz
10 sessions.
Intensity: 80 percent MT or sham
Total pulses 8000
 No statistically significant difference between rTMS- and shamtreated patients. Authors suggest this may relate to subthreshold rTMS
intensity.
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SHAM-CONTROLLED STUDIES
2003
Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter J
 Antidepressant efficacy of two different rTMS procedures High
frequency over left versus low frequency over right prefrontal cortex
compared with sham stimulation. Eur Arch Psychiatry Clin Neurosci
253:103-9.
 30 patients. Medication-resistance NA
Not medication-free.
20 Hz over the left DLPFC (90 percent MT) or 1 Hz the right DLPFC
(110 percent MT) or sham
10 sessions.
Total pulses 8000 over the left or 1200 over the right
 Patients were started on an antidepressant medication 2 weeks
before rTMS, which was used as an add-on treatment. Differences
between the rTMS procedures regarding depressive symptoms could
not be found.
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SHAM-CONTROLLED STUDIES
2003
Loo CK, Mitchell PB, Croker VM, et al
 Double-blind controlled investigation of bilateral prefrontal
transcranial magnetic stimulation for the treatment of resistant major
depression. Psychol Med 33:33-40.
 19 patients. Drug-resistant.
Not medication-free.
Bilateral DLPFC
15 Hz
15 sessions.
Intensity 90 percent MT
Total pulses 27.000
 No significant difference between the two groups. 2 responders in
the rTMS groups, 1 responder in the sham group. 6 sham patients
crossed over to rTMS; 1 patient in this group responded.
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SHAM-CONTROLLED STUDIES
2003
Nahas Z, Kozel FA, Li X, Anderson B, George MS
 Left prefrontal transcranial magnetic stimulation (TMS) treatment of
depression in bipolar affective disorder: a pilot study of acute safety
and efficacy. Bipolar Disord 5:40-7.
 23 patients. Drug-resistance NA
Not medication-free.
Left DLPFC
5 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 16.000
 No significant difference between rTMS and sham in decrease in
HAMD or response rate. No patients developed mania or hypomania
during the study.
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SHAM-CONTROLLED STUDIES
2003
Herwig U, Lampe Y, Juengling FD, et al
 Add-on rTMS for treatment of depression: a pilot study using stereotaxic
coil-navigation according to PET data. J Psychiatr Res 37:267-75.
 25 patients. Some patients are drug-resistant.
Not medication-free.
6 parients were given left DLPFC, 6 right, 6 sham (parietooccipital)
15 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 30.000
 Real stimulation improved depression moderately but significantly better
compared to sham. In the real condition, four out of 13 patients responded,
whereas none responded to sham. Left vs. right prefrontal location of
stimulation guided by PET-identified prefrontal hypometabolism (when
present). 11 of 25 patients had right prefrontal hypometabolism at baseline. 1
of 25 had left prefrontal hypometabolism at baseline. 13 of 25 had left=right
metabolism at baseline or no imaging data available. There was no evidence
that using baseline prefrontal hypometabolism to guide treatment location
was beneficial. Treatment groups were combined for analyses.
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SHAM-CONTROLLED STUDIES
2003
Nahas Z, Kozel FA, Li X, Anderson B, George MS
 Left prefrontal transcranial magnetic stimulation (TMS) treatment of
depression in bipolar affective disorder: a pilot study of acute safety
and efficacy. Bipolar Disord 5:40-7.
 23 patients. Medication-resistance NA.
Not medication-free.
Left DLPFC
5 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 16.000
 No significant difference between rTMS and sham in decrease in
HAMD or response rate. But a trend for greater improvement in daily
subjective mood ratings. No patients developed mania or hypomania
during the study.
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SHAM-CONTROLLED STUDIES
2003
Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A,
Kulkarni J
 Transcranial magnetic stimulation in the treatment of depression: a
double-blind, placebo-controlled trial. Arch Gen Psychiatry 60:1002-8.
 60 patients. Medication-resistance NA.
Not medication-free.
3 groups:
1-10 Hz left DLPFC
2-1 Hz right DLPFC
3-Sham
10 sessions.
Intensity 100 percent MT
Total pulses 3000 or 10.000
 Compares 10 Hz LPF stim with 1 Hz RPF stim with sham. Initial trial was
with 10 sessions: 14-15% decr in MADRS in both rTMS groups (1/20
patients in LPF group with >50% decr), 1% decr in sham (significant
difference between the treatment and sham groups, but not significant
difference between the treatment groups). 15 patients with >20% decr in
MADRS by 10 sessions went on to receive a total of 20 open rTMS
sessions: 40% decr in MADRS in LPF group (4/8 patients with decr >50%),
57% decr in RPF group (4/7 patients with decr >50%). Baseline
psychomotor agitation predicted succesful response to treatment.
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SHAM-CONTROLLED STUDIES
2004
Hausmann A, Kemmler G, Walpoth M, et al
 No benefit derived from repetitive transcranial magnetic stimulation in
depression: a prospective, single centre, randomised, double blind, sham
controlled "add on" trial. J Neurol Neurosurg Psychiatry 75:320-2.
 41 patients. Medication resistance NA.
They were medication-free, medication started at the start of rTMS.
Group 1: 20 Hz over the left DLPFC and subsequent sham 1 Hz over
the right DLPFC
Group 2: simulataneous bilateral active stimulation (20 Hz over the left
DLPFC, 1 Hz over the right DLPFC)
Group 3: bilateral sham stimulation
Intensity 100 percent motor threshold in the 20 Hz group, 120 in the 1
Hz group
10 sessions
Total pulses 20.000-26.000
 No significant differences between the groups. 20 Hz LPF and the
combined 20 Hz LPF/1 Hz RPF active rTMS groups were combined for
efficacy analyses. Unknown if patients were treatment-resistant at
baseline. The results suggest that rTMS as an "add on" strategy, applied in
a unilateral and a bilateral stimulation paradigm, does not exert an
additional antidepressant effect.
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SHAM-CONTROLLED STUDIES
2004
Jorge RE, Robinson RG, Tateno A, et al
 Repetitive transcranial magnetic stimulation as treatment of
poststroke depression: a preliminary study. Biol Psychiatry 55:398-405.
 20 patients. Drug-resistant.
Medication-free.
Left DLPFC
10 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 10.000
 3 patients in the active rTMS group responded and one patient
remitted, no patients in the sham group responded. 38 percent
decrease in depression in the active rTMS group, 13 percent in the
sham group.
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SHAM-CONTROLLED STUDIES
2004
Holtzheimer PE, 3rd, Russo J, Claypoole KH, Roy-Byrne P, Avery
DH
 Shorter duration of depressive episode may predict response to
repetitive transcranial magnetic stimulation. Depress Anxiety 19:24-30.
 15 patients. Drug-resistant.
Medication-free.
Left DLPFC
10 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 16.000
 No significant difference between rTMS and sham; however, a
significant negative correlation between length of current depressive
episode and response to rTMS was found. Non-responders to sham
were allowed to receive active rTMS. Patients with a current episode
shorter than 4 years showed a 52% reduction in mean HAM-D whereas
those with a current episode longer than 10 years showed only a 6%
decrease.

SHAM-CONTROLLED STUDIES
2004
Kauffmann CD, Cheema MA, Miller BE
 Slow right prefrontal transcranial magnetic stimulation as a
treatment for medication-resistant depression: a double-blind, placebocontrolled study. Depress Anxiety 19:59-62.
 12 patients. Drug-resistant.
Not medication-free.
Right DLPFC
10 Hz
10 sessions.
Intensity 110 percent MT
Total pulses 1200
 No significant difference between the groups. However, the active
TMS group showed a significant reduction in HAMD over time whereas
the sham group did not. Active TMS responders relapsed in 2-3
months. Sham responders relapsed in 2 weeks.

SHAM-CONTROLLED STUDIES
2004
Mosimann UP, Schmitt W, Greenberg BD, et al
 Repetitive transcranial magnetic stimulation: a putative add-on
treatment for major depression in elderly patients. Psychiatry Res
126:123-33.
 24 elderly patients (mean age 62 years). Drug-resistant.
Not medication-free.
Left DLPFC
20 Hz
10 sessions.
Intensity 100 percent MT
Total pulses 16.000
 No additional antidepressant effect of active rTMS.


SHAM-CONTROLLED STUDIES
2004
Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J,
Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA.
 Repetitive transcranial magnetic stimulation is as effective as fluoxetine
in the treatment of depression in patients with Parkinson's disease. J
Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4.
 42 patients. Not medication-resistant.
Not medication-free.
15 Hz
10 sessions.
Group 1: active rTMS and placebo drug treatment
Group 2: sham rTMS and fluoxetine 20 mg/day.
 Depression scores were improved to the same extent in both groups
after two weeks of treatment (HDRS 38% for group 1, 41% for group 2). At
week 8 there was a tendency for worse motor UPDRS (Unified Parkinson’s
Disease Rating Scale) scores in group 2. ADL (Acitivities of Daily Living)
showed improvement at week 8 only in group 1. MMSE (Minimental State
Examination) improved in both groups after treatment, but faster in group 1
than in group 2. There were fewer adverse effects in group 1 than in group
2. rTMS has the same antidepressant efficacy as fluoxetine and may have
the additional advantage of some motor improvement and earlier cognitive
improvement, with fewer adverse effects.
SHAM-CONTROLLED STUDIES
2004
Koerselman F, Laman D, van Duijn H, van Duijn M, Willems M
 A 3-month, follow-up, randomized, placebo-controlled study of
repetitive transcranial magnetic stimulation in depression. J Clin
Psychiatry 65(10):1323-1328.
 55 patients. Drug-resistance NA.
Not medication-free.
Left DLPFC
20 Hz
10 sessions.
Intensity 80 percent MT
Total pulses 8000
 No difference between active and 45 deg sham TMS after 2 weeks
of treatment. However, at 12 weeks, the active TMS group was
significantly less depressed than the sham group.
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SHAM-CONTROLLED STUDIES
2005
Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO,
Mansur C, Myczkowski
 ML, Moreno RA, Marcolin MA. Biol Psychiatry. 2005 Jan 15;57(2):162-6.
 Transcranial magnetic stimulation accelerates the antidepressant effect
of amitriptyline in severe depression: a double-blind placebo-controlled
study.
 46 patients
All patients were concomitantly taking amitriptyline (mean dose 110
mg/day).
Left DLPFC
5 Hz
20 sessions
Intensity 120 percent MT
Total pulses 25.000
 rTMS had a significantly faster response to amitriptyline. There was a
significant decrease in HAM-D/17 scores, already after the first week of
treatment compared with sham. The decrease in HAM-D/17 scores in the
rTMS group was significantly superior compared with the sham group
throughout the study (p < .001 at fourth week).

rTMS versus ECT
Since 2000 until today, 7 studies comparing rTMS
with ECT and some case reports have been
publishes. In non-psychotic depression, it was
found that the efficacy of rTMS was nearly equal to
that of ECT, with a much more favorable side-effect
profile.
rTMS versus ECT
2000
Grunhaus L, Dannon PN, Schreiber S, et al
 Repetitive transcranial magnetic stimulation is as effective as
electroconvulsive therapy in the treatment of nondelusional major
depressive disorder: an open study. Biol Psychiatry 47:314-24.
 40 patients referred for ECT
rTMS group medication-free.
Left DLPFC
10 Hz
Intensity 90 percent MT
20 sessions
Total pulses 8000
 7/16 responded to rTMS;12/18 to ECT. Among nonpsychotic
depressed 5/8 responded to rTMS; 5/10 to ECT. Among psychotically
depressed, only 2/8 responded to rTMS; 7/8 to ECT.

rTMS versus ECT
2000
Pridmore S.
 Substitution of rapid transcranial magnetic stimulation treatments for
electroconvulsive therapy treatments in a course of electroconvulsive
therapy. Depress Anxiety. 2000;12(3):118-23.
 22 patients
Randomized, single-blind, controlled study.
Two streams were conducted:
Stream 1 received non-dominant unilateral (UL) ECT only,
treatments being given 3 times per week for 2 weeks (11 patients).
Stream 2 received a combination of treatments: one UL ECT on Day
1 and rTMS on the following 4 days, all repeated once, after a 2-day
respite (11 patients).
 There was no evidence that the antidepressant effect of the ECT
only stream was superior to that of the ECT plus rTMS stream. There
was no increase in subjective side-effects in the ECT plus rTMS
stream. On the contrary, this stream was accompanied by less side
effects than the ECT only stream in this study.

rTMS versus ECT
2000
Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M
 Comparison of unlimited numbers of rapid transcranial magnetic stimulation
(rTMS) and ECT treatment sessions in major depressive episode. Int J
Neuropsychopharmacol 3:129-134.
 32 patients. Medication-resistant.
Not medication-free.
Left DLPFC
20 Hz
Intensity 100 percent motor threshold
10-16 sessions (until remission occurred or response plateaued)
Total pulses 10.000-16.000
 Gave unlimited number of rTMS sessions (mean 12.2, SD 3.4). Compared to
group of 16 patients receiving unlimited ECT treatments (mean 6.2, SD 1.6). No
significant difference between the groups in HDRS improvement. Patients receiving
ECT had significantly greater decrease in Beck Depression Inventory scores. A
significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) =
3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on
measures of depression overall, however, rTMS produced comparable results on a
number of measures. Blind raters using the 17-item Hamilton Depression Rating
Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and
the percentage improvement over the course of treatment of 55.6% (rTMS) and
66.4% (ECT), while favouring ECT, was not significantly different. Significant
differences were shown (p & 0.03) in percentage improvement on Beck Depression
Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual
Analogue ratings of mood (rTMS 42.3%; ECT, 57%).

rTMS versus ECT
2001

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Smesny S, Volz HP, Liepert J, Tauber R, Hochstetter A, Sauer H.
Repetitive transcranial magnetic stimulation (rTMS) in the acute and
long-term therapy of refractory depression--a case report].
Nervenarzt 2001 Sep;72(9):734-8
A patient with therapy-resistant major depression has been
hospitalized for 60 months during the last 7 years.
Not even five electroconvulsive therapy (ECT) series (61 single
applications) brought lasting remission of symptoms. As cognitive
deficits developed and prolonged postnarcotic recovery times were
observed, further ECT was contraindicated.
(rTMS) to the left frontal cortex
Only a few rTMS applications already caused an obvious
brightening in mood, remission of depressive delusional symptoms,
and an increase in personal interests and activities. After 4 weeks of
daily treatment, the patient was discharged from the ward. The
rTMS treatments and psychotherapeutic counseling have been
continued on an outpatient basis. Thus, pharmaco- and
psychotherapeutic interventions combined with rTMS led to
persistent symptom remission and social reintegration.
rTMS versus ECT
2001
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Dannon PN, Grunhaus L.
Effect of electroconvulsive therapy in repetitive transcranial
magnetic stimulation non-responder MDD patients: a preliminary
study. Int J Neuropsychopharmacol. 2001 Sep;4(3):265-8.
The aim was to measure the effectiveness of ECT in-patients who
had failed to respond to a course of repetitive transcranial magnetic
stimulation (rTMS) treatment.
17 patients with severe MDD who had not responded to a course of
rTMS were switched to receive ECT treatments.
7 out of 17 patients responded to ECT. (3 out of 5 non-psychotics
and 4 out of 12 psychotic patients).
ECT seems to be an effective treatment for 40% of patients who
failed to respond to rTMS treatment.
Whether this is a result of reduced responsiveness to ECT in rTMSresistant patients or a consequence of small sample size requires
further study.
rTMS versus ECT
2001
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Hasey G.
Transcranial magnetic stimulation in the treatment of mood disorder:
a review and comparison with electroconvulsive therapy. Can J
Psychiatry. 2001 Oct;46(8):720-7.
The potential for unwanted side effects is substantially reduced,
compared with ECT.
In open trials, rTMS and ECT are reported to be equally efficacious
for patients having depression without psychosis.
But the therapeutic benefits reported in double-blind sham-rTMS
controlled trials are more modest.
rTMS versus ECT
2002
Janicak PG, Dowd SM, Martis B, et al
 Repetitive transcranial magnetic stimulation versus
electroconvulsive therapy for major depression: preliminary results of a
randomized trial. Biol Psychiatry 51:659-67.
 25 patients. Medication-resistant.
Not medication-free.
Left DLPFC
10 Hz
Intensity 110 percent motor threshold
10-20 sessions
Total pulses 10.000-20.000
 Patients received either rTMS or bitemporal ECT (4-12 treatments).
There was a raw difference in mean change in HDRS between the
groups (55% with rTMS, 64% with ECT), but no statistically significant
difference. There was a 46% response rate with rTMS and a 56%
response rate with ECT (not statistically significant).

rTMS versus ECT
2002

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Dannon PN, Dolberg OT, Schreiber S, Grunhaus L.
Three and six-month outcome following courses of either ECT or
rTMS in a population of severely depressed individuals--preliminary
report. Biol Psychiatry. 2002 Apr 15;51(8):687-90.
3- and 6-month outcomes of a group of patients treated with either
ECT (n = 20) or (rTMS) (n = 21).
With or without psychotic features referred for ECT
Forty-one patients who responded to either treatment constituted the
sample.
Medications were routinely prescribed.
There were no differences in the 6-month relapse rate between the
groups.
Overall, 20% of the patients relapsed (four from the ECT group and
four from the rTMS group).
Patients reported equally low and not significantly different scores in
the HRSD (ECT group 8.4 +/- 5.6 and TMS group 7.9 +/- 7.1) at the 6month follow up.
The clinical gains obtained with rTMS last at least as long as those
obtained with ECT.
rTMS versus ECT
2003
Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN
 A randomized controlled comparison of electroconvulsive therapy
and repetitive transcranial magnetic stimulation in severe and resistant
nonpsychotic major depression. Biol Psychiatry 53:324-31.
 41 patients with nonpsychotic MDD referred for ECT
Not medication-free.
Left DLPFC
10 Hz
Intensity 90 percent motor threshold
20 sessions
Total pulses 24.000
 No significant difference in HDRS decrease between rTMS and
ECT patients. 12/20 ECT responders and 11/20 rTMS responders
(>50% decr in HDRS, final HDRS <10); no significant difference
between groups). 30% remission rate (final HAMD<9) in ECT and
rTMS groups. For ECT group, patients received unilateral ECT initially,
then bilateral ECT if no response after 6 treatments; 13 patients
received unilateral ECT, 7 received bilateral ECT -- no significant
difference in response rate between these groups.

rTMS versus ECT
2004



Conca A, Hrubos W, Di Pauli J, Konig P, Hausmann A.
ECT response after relapse during continuation repetitive
transcranial magnetic stimulation. A case report. Eur Psychiatry.
Apr;19(2):118-9.
A woman who exerted a recurrent moderate major depressive
episode, 6 months after discontinuation of maintenance ECT. She
responded to acute rTMS treatment which was followed by the rTMS
maintenance-protocol. Within 2 months of continuation rTMS she
relapsed suffering from a severe non psychotic depressive episode
and had to be switched to a successful ECT. In this patient rTMS
had a good clinical impact as an acute treatment strategy, but failed
to prevent relapse as the continuation ECT previously did in the
same patient.
rTMS versus ECT
2004
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
Kozel FA, George MS, Simpson KN.
Decision analysis of the cost-effectiveness of repetitive transcranial
magnetic stimulation versus electroconvulsive therapy for treatment of
nonpsychotic severe depression. CNS Spectr. Jun;9(6):476-82.
Compared the costs of three different treatment strategies for
nonpsychotic severe depression. 1-ECT alone
2-rTMS alone
3-rTMS followed by ECT for nonresponders (rTMS-to-ECT).
Calculated 12-month costs and quality adjusted life years (QALYs) for
the three treatment options for all nonpsychotic, severely depressed
United States patients who would have otherwise undergone ECT.
The additional cost of using ECT alone compared with rTMS alone was
460,031 US dollars per quality adjusted year of life gained. For ECT
versus rTMS-to-ECT, there was both an increased cost and a loss of
1,538 QALYs with ECT alone.
If rTMS were to be made widely available clinically in the US, it would
offer a substantial economic benefit over ECT in treating resistant
depression. Using rTMS-to-ECT offers not only an economic advantage
but also an increase in QALYs.
RECENT REVIEWS OR
META-ANALYSES
RECENT REVIEWS OR META-ANALYSES
2003
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
Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V,
Kulisevsky
Repetitive transcranial magnetic stimulation for the treatment of
depression. Systematic review and meta-analysis. JBr J Psychiatry.
2003 Jun;182:480-91.
Randomised controlled trials that compared rTMS with sham were
included.
14 studies met the criteria. The quality of the included studies was
low.
Pooled analysis using the Hamilton Rating Scale for Depression
showed an effect in favour of rTMS compared with sham after 2
weeks of treatment, but this was not significant at the 2-week followup.
RECENT REVIEWS OR META-ANALYSES
2003

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
Gershon AA, Dannon PN, Grunhaus L.
Am J Psychiatry. 2003 May;160(5):835-45.
Transcranial magnetic stimulation in the treatment of depression.
Review of English-language controlled studies of nonconvulsive TMS
therapy for depression that appeared in the MEDLINE database
through early 2002, as well as one study that was in press in 2002
and was published in 2003.
Most data support an antidepressant effect of high-frequency
repetitive TMS administered to the left prefrontal cortex.
The absence of psychosis, younger age, and certain brain physiologic
markers might predict treatment success.
Technical parameters possibly affecting treatment success include
intensity and duration of treatment, but these suggestions require
systematic testing.
TMS shows promise as a novel antidepressant treatment. Systematic
and large-scale studies are needed to identify patient populations
most likely to benefit and treatment parameters most likely to produce
success.
RECENT REVIEWS OR META-ANALYSES
2003



Padberg F, Moller HJ.
Repetitive transcranial magnetic stimulation : does it have potential in
the treatment of depression? CNS Drugs. 2003;17(6):383-403.
Though conducted with small sample sizes, the majority of the
controlled trials demonstrated significant antidepressant effects of
active rTMS compared with a sham condition. Effect sizes, however,
varied from modest to substantial, and the patient selection focused
on therapy-resistant cases. Moreover, the average treatment duration
was approximately 2 weeks, which is short compared with other
antidepressant interventions. Larger multicentre trials, which would
be mandatory to demonstrate the antidepressant effectiveness of
rTMS, have not been conducted to date. A putative future application
of rTMS may be the treatment of patients who did not tolerate or did
not respond to antidepressant pharmacotherapy before trying more
invasive strategies such as electroconvulsive therapy and vagus
nerve stimulation. Theoretically, rTMS may be also applied early in
the course of disease in order to speed up and increase the effects of
antidepressant pharmacotherapy. However, this application has not
been a focus of clinical trials to date.
RECENT REVIEWS OR META-ANALYSES
2005
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Couturier JL.
Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the
treatment of depression: a systematic review and meta-analysis. J
Psychiatry Neurosci. 2005 Mar;30(2):83-90.
1966 until July 2003.
Eighty-seven randomized controlled trials
Nineteen of these involved treatment of a major depressive episode,
and these were reviewed.
Six met more specific inclusion criteria including the use of rapid-rate
stimulation, application to the left dorsolateral prefrontal cortex,
evaluation with the 21-item Hamilton Rating Scale for Depression
(HAM-D) and use of an intent-to-treat analysis.
Two of these reported a significantly greater improvement in mood
symptoms in the treatment versus the sham group.
No different from sham treatment in major depression; however, the
power within these studies to detect a difference was generally low.
Randomized controlled trials with sufficient power to detect a clinically
meaningful difference are required.
Issues in the clinical use of rTMS:
Stimulation site
Which part of the brain?
Dorsolateral prefrontal cortex (DLPFC) was stimulated in many studies
Vertex, frontal, parietooccipital cortex and multiple studies in a few studies
Right or left
Left PLPFC was stimulated in many studies
Right side in a few studies
Intensity
80, 90, 100 or 110 percent of motor threshold
High or low frequency
High frequency (above 1 Hz) was given in many studies
Low frequency (below 1 Hz) in a few studies
Duration of treatment
Ten sessions (consecutive weekdays) in many studies
12, 14, 16, 20 sessions in a few studies
1,5, 8 sessions in a few studies
Total pulses
30, 60, 400, 500, 800, 1200, 1250, 2000, 2500, 3000, 4000, 5000, 6000, 6500, 8000, 10000,
14000, 12000, 15000, 16000, 175000, 20000, 480000 pulses were given in different studies
Which patient groups
Young or elderly?
Which type of depression?
Psychotic or non-psychotic?
Which patients with major depression benefit
from prefrontal repetitive magnetic stimulation?
Data from 10 open and 7 sham controlled studies. Comprising more than 300
patients with major depression have been published to date.
 Positive predictors for antidepressive response of prefrontal rTMS become
apparent:
1) younger age,
2) somatic signs of anxiety,
3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli,
4) cortical hypermetabolism below the 1 Hz pulsed coil.
 Negative predictors of response to prefrontal rTMS were:
1) Advanced age,
2) prefrontal atrophy,
3) cognitive impairment in neuropsychological tasks assigned to the prefrontal
cortex
4) psychotic symptoms,
5) cortical hyperactivity below 10 Hz pulsed coil
6) non-response to electroconvulsive therapy (ECT).
 Eschweiler GW, Plewnia C, Bartels M.
 Fortschr Neurol Psychiatr. 2001

In paralel studies, rTMS is only modestly
superior to sham, but nearly equally effective as
ECT. Why?




In sham studies, the coil is positioned such that less of the magnetic stimulus
penetrates the brain. The sham treatment in controls involve discharging the coil
at an angle to the head with only one edge in contact with the scalpas opposed
to holding it tangential to the scalp as in real rTMS (the coil is positioned as 90 or
45 degrees). The question of whether they are truly inactive have been debated.
Some studies may be complicated by active sham controls.
Loo CK, Taylor JL, Gandevia SC, McDarmont BN, Mitchell PB, Sachdev PS.
Transcranial magnetic stimulation (TMS) in controlled treatment studies: are
some "sham" forms active? Biol Psychiatry. 2000 Feb 15;47(4):325-31.
In nine normal subjects, single TMS pulses were administered at a range of
intensities with a "figure eight" coil held in various positions (with one edge
touching the scalpat a 45 degrees to the scalp) over the left primary motor
cortex.



Responses were measured as motor-evoked potentials in the right first dorsal
interosseus muscle.
Scalp sensation to TMS with the coil in various positions over the prefrontal area
was also assessed.
Sham variants that more closely simulated the experience of TMS also
generated more motor evoked potentials, although less than real treatment.
None of the coil positions studied met the criteria for an ideal sham.
Arrangements associated with a higher likelihood of scalp sensation were also
more likely to stimulate the cortex.
Percentage of Patients Who Responded to TMS
FIGURE Number of Petients Who Responded to Transcranial Magnetic
Stimulation (TMS) in Controlled Studies of TMS for the Treatment of
Depression, by Technical Parameters of TMS
60
50
40
30
20
10
0
10 >10
(N=70 N=69)
Duration
(days)
80-90 100-110
(N=90) (N=49)
Intensity
(percent of
motor threshold)
800- 120010001600
(N=35) (N=84)
Pulses per Day
Many studies of rTMS in
depression included both unipolar
and bipolar patients. Those with
bipolar as well as unipolar
depression usually benefited from
rTMS.
A study including both unipolar and
bipolar patients compared rTMS and
electroconvulsive therapy (ECT) and
found significant difference neither in
mania scores nor in improvement in
depression.
Janicak PG, Dowd SM, Martis B, Alam D, Beedle D,
Krasuski J, Strong MJ, Sharma R, Rosen C, Viana M:
Repetitive transcranial magnetic stimulation versus
electroconvulsive therapy for major depression:
preliminary results of a randomized trial. Biol
Psychiatry 2002 Apr 15; 51(8):659-67.
Another study conducted on 23 patients
having bipolar depression who received
either active or sham rTMS produced a
trend but not statistically significant
greater improvement in daily subjective
mood ratings post-treatment, and no one
switched to mania (15).
Nahas Z, Kozel, Li X, Anderson B, George MS: Left
prefrontal transcranial magnetic stimulation (TMS)
treatment of depression in bipolar affective disorder: a
pilot study of acute safety and efficacy. Bipolar Disord
2003 Feb; 5(1):40-7.
There are case reports showing that transcranial
magnetic stimulation has induced mania in patients
suffering from bipolar depression.

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Garcia-Toro M: Acute manic symptomatology during
repetitive transcranial magnetic stimulation in a patient with
bipolar depression. Br J Psychiatry 1999 Nov; 175:491.
Nedjat S, Folkerts HW: Induction of a reversible state of
hypomania by rapid-rate transcranial magnetic stimulation
over the left prefrontal lobe. J ECT 1999 Jun; 15(2):166-8.
Dolberg OT, Schreiber S, Grunhaus L: Transcranial
magnetic stimulation-induced switch into mania : a report of
two cases. Biol Psychiatry 2001 Mar 1; 49(5):468-70.
Ella R, Zwanzger P, Stampfer R, Preuss UW, MullerSiecheneder F, Moller HJ, Padberg F: Switch to mania after
slow rTMS of the right prefrontal cortex. J Clin Psychiatry
2002 Mar; 63(3):249.
Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C,
Masdrakis C, Politis A, Christodoulou GN: Induction of
mania by rTMS: a report of two cases. Eur Psychiatry 2003
Jun; 18(4):196-8.
rTMS in the Treatment of Mania
rTMS in the Treatment of Mania
1998
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Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH.
Transcranial magnetic stimulation in mania: a controlled
study. Am J Psychiatry. 1998 Nov;155(11):1608-10.
16 patients completed a 14-day double-blind, controlled
trial of right versus left prefrontal transcranial magnetic
stimulation at 20 Hz (2-second duration per train, 20
trains/day for 10 treatment days).
Significantly more improvement was observed in patients
treated with right than with left prefrontal transcranial
magnetic stimulation.
The therapeutic effect of transcranial magnetic stimulation
in mania may show laterality opposite to its effect in
depression.
rTMS in the Treatment of Mania
2000
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Erfurth A, Michael N, Mostert C, Arolt V.
Euphoric Mania and Rapid Transcranial Magnetic Stimulation. Am J
Psychiatry. 2000 May;157(5):835-6.
A patient with euphoric mania that was refractory to treatment with
sulthiame
Experienced marked improvement during monotherapy with right prefrontal
rapid transcranial magnetic stimulation.
Eight weeks before hospital admission she developed euphoric mania
despite lithium treatment. Lithium treatment was discontinued, and a trial
with the antiepileptic drug sulthiame was initiated—unfortunately, with no
effect after 3 weeks of treatment. Sulthiame treatment was tapered off, and
monotherapy with rapid transcranial magnetic stimulation was begun. Right
prefrontal stimulation was performed (20 trains per session, a frequency of
20 Hz for 2 seconds per train, and an intertrain interval of 1 minute).
Ms. A was given five consecutive sessions during weeks 1 and 2 and three
sessions during weeks 3 and 4. Her range of motor threshold was 66%–
76%. Her scores on the Bech-Rafaelsen Mania Scale slowly but
continuously fell (28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21,
and 8 on day 28). Her sleep disturbance and thought disorder seemed to
respond particularly well to rapid transcranial magnetic stimulation. Ms. A
was dismissed from the hospital ward. Prophylactic treatment with the thirdgeneration, putative mood-stabilizing anticonvulsant topiramate was
initiated for Ms. A for obesity.
rTMS in the Treatment of Mania
2003
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Kaptsan A, Yaroslavsky Y, Applebaum J, Belmaker RH, Grisaru N.
Right prefrontal TMS versus sham treatment of mania: a controlled
study. Bipolar Disord. 2003 Feb;5(1):36-9.
25 patients entered and 16 patients completed trial of right versus left
prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for
10 treatment days.
Right active TMS versus right sham TMS
Right TMS was no more effective than sham TMS.
It is possible that the previous results were due to an effect of left
TMS to worsen mania. Alternatively, it is noted that the present
patient group had much more psychosis than the previous study of
TMS in mania, and depression studies have reported that psychosis is
a poor prognostic sign for TMS response.
rTMS in the Treatment of Mania
2004
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Michael N, Erfurth A.
Treatment of bipolar mania with right prefrontal rapid
transcranial magnetic stimulation. J Affect Disord. 2004
Mar;78(3):253-7.
9 in-patients diagnosed with mania
Right prefrontal rapid TMS
Open and prospective study.
8 of 9 patients received TMS as add-on treatment to an
insufficient or only partially effective drug therapy.
During the 4 weeks of TMS treatment a sustained
reduction of manic symptoms in all patients.
rTMS in the Treatment of Mania
2004
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Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Lipski
H, Januel D.
Repetitive transcranial magnetic stimulation as an add-on
therapy in the treatment of mania: a case series of eight
patients. Psychiatry Res. 2004 Sep 30;128(2):199-202.
Fast rTMS (five trains of 15 s, 80% of the motor threshold, 10
Hz)
Right DLPFC
evaluated at baseline and at day 14.
Not medication-free.
Significant improvement of manic symptoms at the end of the
trial. No side effects were reported.
However, these results have to be interpreted with caution
since they derive from an open case series and all the subjects
were taking psychotropic medication during rTMS treatment.
Does rTMS Induce Mania?
Does rTMS Induce Mania?
2004
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Tan O, Tarhan N, Coban A, Baripoglu
Repetitive transcranial magnetic stimulation in medication-resistant bipolar
depression. Poster presentation in ECNS-ISNIP Joint Meeting in September
2004, California
8 patients having drug-resistant severe bipolar depression
open and uncontrolled study.
The patients also used antipsychotic and/or mood stabilizing drugs.
5 patients responded to the rTMS therapy recovering from depression. 3
patients shifted to manic episodes.
rTMS may be an effective method in the treatment of bipolar depression.
However, the fact that three patients out of eight switched to mania raises
questions about its safety even though all of these patients were also taking
antidepressant medications.
Left prefrontal cortex (Magstim, rapid, superrrapid high frequency magnetic
stimulator). Its intensity was the motor threshold that caused muscle
movement when it was applied over the motor cortex. Other values of rTMS
were 10 seconds, 25 Hz, 210 pulses and 70 trains.
The average of HDRS scores of the patients was 28.2. All responded to the
rTMS therapy, that is, showed at least 50 percent decrease in HDRS scores.
However, three patients shifted to manic episodes.
Does rTMS Induce Mania?
2004

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
Li X, Nahas Z, Anderson B, Kozel FA, George MS.
Can left prefrontal rTMS be used as a maintenance
treatment for bipolar depression? Depress Anxiety.
2004;20(2):98-100.
S7 adults with bipolar depression who responded acutely
to TMS and were then treated with TMS weekly for up to 1
year.
Left prefrontal cortex at 110% motor threshold, 5 Hz for 8
s for 40 trains.
Three subjects completed 1 full year of weekly TMS with
an average Hamilton Rating Scale for Depression of 13
(sd = 5.9) over the year.
These data suggest but do not prove that TMS might
eventually be used as an adjunctive maintenance
treatment for at least some patients with bipolar
depression.
Does rTMS Induce Mania?
2005



Hagit Cohen, Ph.D., Zeev Kaplan, M.D., Moshe
Kotler, M.D., Irena Kouperman, M.D., Regina
Moisa, B.N.S., and Nimrod Grisaru, M.D.
Repetitive Transcranial Magnetic Stimulation of
the Right Dorsolateral Prefrontal Cortex in
Posttraumatic Stress Disorder: A Double-Blind,
Placebo-Controlled Study
2 of 18 patients developed a manic episode after
the third of 10 sessions of transcranial magnetic
stimulation.
Does rTMS Induce Mania?
2005


Huang CC, Su TP, Shan IK.
A case report of repetitive transcranial
magnetic stimulation-induced mania.
Bipolar Disord. 2004 Oct;6(5):444-5.
Does rTMS Induce Mania?
2005



Sakkas P, Mihalopoulou P, Mourtzouhou P,
Psarros C, Masdrakis V, Politis A,
Christodoulou GN.
Induction of mania by rTMS: report of two
cases. Eur Psychiatry. 2003 Jun;18(4):1968.
Using an intensive methodology of rTMS in
two drug-resistant patients, we observed a
good antidepressant effect, but also,
induction of manic symptoms.
Does rTMS Induce Mania?
2001




Dolberg OT, Schreiber S, Grunhaus L.
Transcranial magnetic stimulation-induced
switch into mania: a report of two cases.
Biol Psychiatry. 2001 Mar 1;49(5):468-70.
Five times a week for 4 weeks.
A manic episode followed treatment with
transcranial magnetic stimulation in two
patients.


Garcia-Toro M.
Acute manic symptomatology during
repetitive transcranial magnetic stimulation
in a patient with bipolar depression. Br J
Psychiatry. 1999 Nov;175:491.
CONCLUSIONS
Regarding literature and the present study,
it seems that left prefrontal TMS leads to
improvement in unipolar or bipolar depression while
inducing mania;
on the other hand, right prefrontal TMS may be
useful for mania.
High and low frequency TMS
may cause opposite effects in
brain and mood (20).
Speer AM, Kimbrell TA, Wasserman EM, Repella J,
Willis MW, Herscovitch P, Post RM: Opposite effects of
high and low frequency rTMS on regional brain activity
in depressed patients. Biol Psychiatry 2000 Dec;
48(12):1133-41.
An article reviewing TMS in the treatment of
mood disorder concluded that the
antidepressant and antimanic effects of TMS
depend on clinical considerations such as
stimulus frequency, intensity, and magnetic coil
placement; in addition, biological heterogeneity
among the patients treated with TMS may also
contribute to differing efficacy accross clinical
trials (21).
Hasey G: Transcranial magnetic stimulation
in the treatment of mood disorder: a review
and comparison with electroconvulsive
therapy. Can J Psychiatry 2001 Oct;
46(8):720-7.
rTMS and OCD
rTMS and OCD
1997
Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE,
Altemus M, Wassermann EM, Post RM, Murphy DL.
 Effect of prefrontal repetitive transcranial magnetic stimulation in obsessivecompulsive disorder: a preliminary study. Am J Psychiatry. 1997
Jun;154(6):867-9.
 12 patients
 80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes
 Right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control)
site on separate days
 The patients' symptoms and mood were rated for 8 hours afterward.
 Compulsive urges decreased significantly for 8 hours after right lateral
prefrontal repetitive transcranial magnetic stimulation,
 but there were nonsignificant increases in compulsive urges after repetitive
transcranial magnetic stimulation of the midoccipital site.
 A shorter-lasting (30 minutes), modest, and nonsignificant reduction in
compulsive urges occurred after left lateral prefrontal repetitive transcranial
magnetic stimulation.
 Mood improved during and 30 minutes after right lateral prefrontal
stimulation.
 These preliminary results suggest that right prefrontal repetitive transcranial
magnetic stimulation might affect prefrontal mechanisms involved in
obsessive-compulsive disorder.

rTMS and OCD
2001
Sachdev PS, McBride R, Loo CK, Mitchell PB, Malhi GS, Croker VM.
 Right versus left prefrontal transcranial magnetic stimulation for obsessivecompulsive disorder: a preliminary investigation. J Clin Psychiatry. 2001
Dec;62(12):981-4.
 12 subjects with resistant OCD
 were allocated randomly to either right or left prefrontal rTMS
 daily for 2 weeks
 were assessed by an independent rater at 1 and 2 weeks and 1 month later.
 Subjects had an overall significant improvement in the obsessions (p < .01),
compulsions (p < .01), and total (p < .01) scores on the Yale-Brown Obsessive
Compulsive Scale (Y-BOCS) after 2 weeks and at 1-month follow-up.
 This improvement was significant for obsessions (p < .05) and tended to
significance for total Y-BOCS scores (p = .06) after correction for changes in
depression scores on the Montgomery-Asberg Depression Rating Scale.
 There was no significant difference between right- and left-sided rTMS on any
of the parameters examined.
 Two subjects (33%) in each group showed a clinically significant improvement
that persisted at I month but with relapse later in I subject.
 About one quarter of patients with resistant OCD appear to respond to rTMS
to either prefrontal lobe.

rTMS and OCD
1997
Alonso P, Pujol J, Cardoner N, Benlloch L, Deus J, Menchon JM,
Capdevila A, Vallejo J.
 Right prefrontal repetitive transcranial magnetic stimulation in
obsessive-compulsive disorder: a double-blind, placebo-controlled
study. Am J Psychiatry. 2001 Jul;158(7):1143-5.

18 sessions of real (N=10) or sham (N=8) rTMS.
 Treatments lasted 20 minutes, and the frequency was 1 Hz for both
conditions, but the intensity was 110% of motor threshold for real rTMS
and 20% for the sham condition.
 No significant changes in OCD were detected in either group after
treatment.
 Two patients who received real rTMS, with checking compulsions,
and one receiving sham treatment, with sexual/religious obsessions,
were considered responders.
rTMS and OCD
2003
Martin JL, Barbanoj MJ, Perez V, Sacristan M.
 Transcranial magnetic stimulation for the treatment of obsessivecompulsive disorder. Cochrane Database Syst Rev. 2003;(3):CD003387.
 Systematic review on the clinical efficacy and safety of transcranial
magnetic stimulation from randomised controlled trials in the treatment of
obsessive-compulsive disorder.
 An electronic search was performed including the Cochrane
Collaboration Depression, Anxiety and Neurosis Review Group trials
register (last searched June, 2002), the Cochrane Controlled Trials
Register (Issue 2, 2002), MEDLINE (1966-2002), EMBASE (1974-2002),
PsycLIT (1980-2002), and bibliographies from reviewed articles.
 3 trials were included and only 2 contained data in a suitable form for
quantitative analysis.
 It was not possible to pool any results for a meta-analysis.
 No difference was seen between rTMS and sham TMS using the
Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression
Rating Scale for all time periods analysed. There are currently insufficient
data from randomised controlled trials to draw any conclusions about the
efficacy of transcranial magnetic stimulation in the treatment of
obsessive-compulsive disorder.

rTMS and panic disorder
rTMS and panic disorder
2002
Garcia-Toro M, Salva Coll J, Crespi Font M, Andres Tauler J, Aguirre
Orue I, Bosch Calero C.
 Panic disorder and transcranial magnetic stimulation. Actas Esp
Psiquiatr. 2002 Jul-Aug;30(4):221-4.

3 patients.
 disease for at least 1 year and they had unsuccessfully followed
psychotherapy and pharmacological treatment.
 10 sessions during
 each session lasted 30 trains of 60 seconds at a frequency of 1 Hz, on
the right dorsolateral prefrontal cortex, at 110% of the motor threshold.
 All three patients experienced a modest and partial symptom
improvement that did not seemed to be clinically relevant.
 Two patients accepted to participate in a TMS second phase, where the
previous stimulation parameters were alternated with an application of 30
trains of 20 Hz during 2 seconds on the left prefrontal cortex. This alternate
application of high and low frequency TMS in each session was also well
tolerated, but failed to produce additional improvement.
rTMS and PTSD
rTMS and PTSD
1998
Grisaru N, Amir M, Cohen H, Kaplan Z.
 Effect of transcranial magnetic stimulation in posttraumatic stress
disorder: a preliminary study. Biol Psychiatry. 1998 Jul 1;44(1):52-5.
 10 PTSD patients
 One session of slow TMS with 30 pulses of 1 m/sec each, 15 to
each side of the motor cortex. Symptoms of PTSD were assessed by
using three psychological assessment scales, at four different time
points. In this first, pilot, open study, TMS was found to be effective in
lowering the core symptoms of PTSD: avoidance (as measured by the
Impact of Event Scale), anxiety, and somatization (as measured by the
Symptom Check List-90). A general clinical improvement was found (as
measured by the Clinical Global Impression scale); however, the effect
was rather short and transient.
 The present study showed TMS to be a safe and tolerable
intervention with possibly indications of therapeutic efficacy for PTSD
patients.

rTMS and PTSD
2002
Rosenberg PB, Mehndiratta RB, Mehndiratta YP, Wamer A, Rosse
RB, Balish M.
 Repetitive transcranial magnetic stimulation treatment of comorbid
posttraumatic stress disorder and major depression. J Neuropsychiatry
Clin Neurosci. 2002 Summer;14(3):270-6.
 12 patients with comorbid PTSD and major depression
 rTMS to left frontal cortex as an open-label adjunct to current
antidepressant medications. rTMS parameters were 90% of motor
threshold, 1 Hz or 5 Hz, 6.000 stimuli over 10 days. Seventy-five
percent of the patients had a clinically significant antidepressant
response after rTMS, and 50% had sustained response at 2-month
follow-up.
 Comparable improvements were seen in anxiety, hostility, and
insomnia, but only minimal improvement in PTSD symptoms.
 Left frontal cortical rTMS may have promise for treating depression
in PTSD, but there may be a dissociation between treating mood and
treating core PTSD symptoms.

rTMS and PTSD
2004
Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N.
 Repetitive transcranial magnetic stimulation of the right dorsolateral
prefrontal cortex in posttraumatic stress disorder: a double-blind,
placebo-controlled study. Am J Psychiatry. 2004 Mar;161(3):515-24.
 24 patients with PTSD were randomly assigned to receive rTMS at
low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS in a
double-blind design.
 10 daily sessions
 The 10 daily treatments of 10-Hz rTMS at 80% motor threshold over
the right dorsolateral prefrontal cortex had therapeutic effects on PTSD
patients. PTSD core symptoms (reexperiencing, avoidance) markedly
improved with this treatment. Moreover, high-frequency rTMS over the
right dorsolateral prefrontal cortex alleviated anxiety symptoms in
PTSD patients.
 In PTSD patients, 10 daily sessions of right dorsolateral prefrontal
rTMS at a frequency of 10 Hz have greater therapeutic effects than
slow-frequency or sham stimulation.

rTMS and schizophrenia
rTMS and schizophrenia
1997
Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker RH.
 Slow magnetic stimulation of prefrontal cortex in depression and
schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 1997
Jan;21(1):105-10.
 Pre-frontal cortex to study mood changes in 10 depressed patients
and 10 schizophrenic patients.
 A slow rate of stimuli was used, one per 30 seconds; maximal
intensity of about 2 Tesla was given for 30 stimuli, 15 on each side of
the brain.
 No side effects were seen and
 at least three depressed patients and two schizophrenic patients
appeared to improve, at least transiently.
 These results suggest that rapid rate TMS may not be necessary to
elicit mood effects.

rTMS and schizophrenia
1998
Feinsod M, Kreinin B, Chistyakov A, Klein E.
 Preliminary evidence for a beneficial effect of lowfrequency, repetitive transcranial magnetic stimulation in
patients with major depression and schizophrenia. Depress
Anxiety. 1998;7(2):65-8.
 10 rTMS sessions in 14 subjects with major depression
(MD) and 10 with schizophrenia.
 7 of the depressed patients reported significant
improvement in depressive symptomatology, and
 7 of the schizophrenic subjects reported amelioration of
anxiety and restlessness.

rTMS and schizophrenia
1999
Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger A,
Krystal JH, Charney DS.
 Transcranial magnetic stimulation of left temporoparietal cortex in
three patients reporting hallucinated "voices". Biol Psychiatry. 1999 Jul
1;46(1):130-2.
 1 Hz
 left temporoparietal cortex
 compared with sham
 double-blind, cross-over design.
 All three patients demonstrated greater improvement in hallucination
severity following active stimulation compared to sham stimulation.
 Two of the three patients reported near total cessation of
hallucinations for > or = 2 weeks.

rTMS and schizophrenia
1999
Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole,
Boget T, Barrantes N, Catarineu S, Font M, Lomena FJ.
 Repetitive transcranial magnetic stimulation in the treatment of
chronic negative schizophrenia: a pilot study. J Neurol Neurosurg
Psychiatry. 1999 Jul;67(1):129-30.
 6 patients (All were taking neuroleptic drugs)
 rTMS 5 days a week, during 2 weeks, over the prefrontal cortex
 20 Hz for 2 seconds, once per minute for 20 minutes at 80% motor
threshold.
 without exacerbating their psychoses. All patients tolerated the
rTMS well, with minimal side effects (mild headache and tinnitus).
 PANSS and a neuropsychological battery
 A brain SPECT study
 SPECT: The results after rTMS indicated no change in the
hypofrontality.
 Negative symptoms showed a general decrease for all patients.

rTMS and schizophrenia
1999
Klein E, Kolsky Y, Puyerovsky M, Koren D, Chistyakov
A, Feinsod M.
 Right prefrontal slow repetitive transcranial magnetic
stimulation in schizophrenia: a double-blind shamcontrolled pilot study. Biol Psychiatry. 1999 Nov
15;46(10):1451-4.
 35 inpatients
 either right prefrontal slow rTMS or sham treatment
 were rated before and after treatment for positive,
negative, and depressive symptoms.
 2-week treatment protocol.
 rTMS was not superior to sham treatment on any of the
clinical ratings.

rTMS and schizophrenia
2000
Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal
JH, Charney DS.
 Transcranial magnetic stimulation and auditory
hallucinations in schizophrenia. Lancet. 2000 Mar
25;355(9209):1073-5.
 12 patients with schizophrenia and auditory
hallucinations
 received 1 Hz
 left temporoparietial cortex.
 In a double-blind crossover trial, active stimulation
significantly reduced hallucinations relative to sham
stimulation.

rTMS and schizophrenia
2000
Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R,
Emrich HM, Schneider U.
 High frequency repetitive transcranial magnetic stimulation (rTMS)
of the dorsolateral prefrontal cortex in schizophrenic patients.
Neuroreport. 2000 Dec 18;11(18):4013-5.
 12 participants
 a double-blind crossover design,
 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at
80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2
weeks of sham stimulation.
 The Brief Psychiatric Rating Scale decreased under active rTMS (p
<0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not
change significantly.

rTMS and schizophrenia
2002
d'Alfonso AA, Aleman A, Kessels RP, Schouten
EA, Postma A, van Der Linden JA, Cahn W,
Greene Y, de Haan EH, Kahn RS.
 Transcranial magnetic stimulation of left auditory
cortex in patients with schizophrenia: effects on
hallucinations and neurocognition. J
Neuropsychiatry Clin Neurosci. 2002
Winter;14(1):77-9.
 9 medication-resistant hallucinating patients.
 A statistically significant improvement was
observed on a hallucination scale after 10 days of
TMS at the left auditory cortex.

rTMS and schizophrenia
2002
Schreiber S, Dannon PN, Goshen E, Amiaz R, Zwas TS, Grunhaus L.
 Right prefrontal rTMS treatment for refractory auditory command
hallucinations - a neuroSPECT assisted case study. Psychiatry Res. 2002 Nov
30;116(1-2):113-7.
 A schizophrenic patient with refractory command hallucinations
 treated with 10 Hz rTMS.
 over the right dorsolateral prefrontal cortex, with 1200 magnetic stimulations
administered
 daily for 20 days at 90% motor threshold.
 Regional cerebral blood flow changes were monitored with neuroSPECT.
 Clinical evaluation and scores on the Positive and Negative Symptoms
Scale and the Brief Psychiatric Rating Scale demonstrated a global
improvement in the patient's condition, with no change in the intensity and
frequency of the hallucinations.
 NeuroSPECT performed at intervals during and after treatment indicated a
general improvement in cerebral perfusion.

rTMS and schizophrenia
2003
Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F,
Carroll K, Krystal JH.
 Transcranial magnetic stimulation of left temporoparietal cortex and
medication-resistant auditory hallucinations. Arch Gen Psychiatry. 2003
Jan;60(1):49-56.
 24 patients with schizophrenia or schizoaffective disorder and
medication-resistant AHs (auditory hallucinations)
 were randomly allocated to receive rTMS or sham stimulation
 for 9 days at 90% of motor threshold.
 Patients receiving sham stimulation were subsequently offered an
open-label trial of rTMS.
 Auditory hallucinations were robustly improved with rTMS relative to
sham stimulation. Frequency and attentional salience were the 2
aspects of hallucinatory experience that showed greatest improvement.
 Duration of putative treatment effects ranged widely, with 52% of
patients maintaining improvement for at least 15 weeks.

rTMS and schizophrenia
2003
Franck N, Poulet E, Terra JL, Dalery J, d'Amato T.
 Left temporoparietal transcranial magnetic stimulation in treatmentresistant schizophrenia with verbal hallucinations. Psychiatry Res. 2003
Aug 30;120(1):107-9.
 A 21-year-old schizophrenic man, who had killed his mother in the
belief that she was a demon, failed to respond to combined treatment
with a variety of antipsychotic agents. His persistent hallucinations
consisted of two voices (God and the Devil). As an adjunct to continued
antipsychotic medication, the patient received a course of rTMS:
 10 sessions of 1-Hz stimulations near Wernicke's area.
 After rTMS, the patient's hallucinations grew less intrusive and he
no longer required isolation.
 The improvement could be a delayed effect of medication.

rTMS and schizophrenia
2003
Huber TJ, Schneider U, Rollnik J.
 Gender differences in the effect of repetitive transcranial magnetic
stimulation in schizophrenia. Psychiatry Res. 2003 Aug 30;120(1):103-5.
 12 schizophrenic patients (8 men, 4 women) were treated with highfrequency rTMS of the dominant dorsolateral prefrontal cortex.
 Their performance of the number-connection test, which assesses cognitive
processes related to the frontal lobe, was evaluated before and after rTMS.
 Women improved markedly on the test after rTMS, whereas men did not
show a significant change.
 There were no corresponding sex differences in clinical measures after
rTMS.
 The preliminary findings of sex differences in the response to rTMS, as
reflected by performance on the number-connection test, suggest the need for
investigations of a greater number of schizophrenic men and women with a
more intensive examination of the effects of rTMS on cognitive functions.

rTMS and schizophrenia
2004
Haraldsson HM, Ferrarelli F, Kalin NH, Tononi
G.
 Transcranial Magnetic Stimulation in the
investigation and treatment of schizophrenia: a
review. Schizophr Res. 2004 Nov 1;71(1):1-16.
 Reduction of auditory hallucinations after slow
TMS over auditory cortex
 Improvement of psychotic symptoms after high
frequency TMS over left prefrontal cortex.
 However, these results need to be confirmed
using better placebo conditions.

rTMS and schizophrenia
2004
Holi MM, Eronen M, Toivonen K, Toivonen P, Marttunen M, Naukkarinen H.

Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia. Schizophr Bull.
2004;30(2):429-34.

Double-blind, controlled study,

22 chronic hospitalized schizophrenia patients

10 sessions

Real or sham rTMS.

20 trains of 5-second 10-Hz stimulation at 100 percent motor threshold, 30 seconds apart.

Effects on positive and negative symptoms, self-reported symptoms, rough neuropsychological
functioning, and hormones were assessed.

Although there was a significant improvement in both groups in most of the symptom measures,
no real differences were found between the groups.

A decrease of more than 20 percent in the total PANSS score was found in 7 control subjects but
only 1 subject from the real rTMS group.

There was no change in hormone levels or neuropsychological functioning, measured by the
MMSE, in either group.

Left prefrontal rTMS (with the used parameters) seems to produce a significant nonspecific effect
of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia
patients.

rTMS and schizophrenia
2004
McIntosh AM, Semple D, Tasker K, Harrison LK, Owens DG, Johnstone
EC, Ebmeier KP.
 Transcranial magnetic stimulation for auditory hallucinations in
schizophrenia. Psychiatry Res. 2004 Jun 30;127(1-2):9-17.
 16 patients with hallucinations
 treatment-resistant for at least 2 months
 were randomised into a placebo-controlled crossover study of TMS at
 1 Hz and 80% of motor threshold
 over left temporo-parietal cortex.
 Treatment periods lasted for 4 days, with daily duration escalating from 4 to
8, 12 and 16 min on subsequent days. Each minute of stimulation was
followed by 15 s of rest to check coil position and allow the patient to move, if
necessary.
 Both patients and symptom raters were unaware of the treatment condition.
 Patients' hallucination scores improved from baseline with both real and
sham TMS,
 there was no significant difference between real and sham treatments.
 There was a trend for second treatments, whether sham or real, to be more
effective than first treatments.
 Other psychopathology scales (apart from positive symptoms) and verbal
memory were not affected by real or sham TMS.

rTMS and schizophrenia
2004
Schonfeldt-Lecuona C, Gron G, Walter H, Buchler N, Wunderlich A,
Spitzer M, Herwig U.
 Stereotaxic rTMS for the treatment of auditory hallucinations in
schizophrenia. Neuroreport. 2004 Jul 19;15(10):1669-73.
 Cross-over sham controlled study,
 Researchers guided rTMS stereotactically to inner speech-related
cortical areas in hallucinating patients.
 These areas were identified individually prior to rTMS using fMRI in
a subgroup of patients.
 Active stimulation was applied over Broca's area and over the
superior temporal gyrus as determined by fMRI, or according to
structural images in the remaining patients.
 rTMS did not lead to a significant reduction of hallucination severity.

rTMS and schizophrenia
2004
Hajak G, Marienhagen J, Langguth B, Werner S, Binder H,
Eichhammer P.
 High-frequency repetitive transcranial magnetic stimulation in
schizophrenia: a combined treatment and neuroimaging study. Psychol
Med. 2004 Oct;34(7):1157-63.
 20 patients
 Sham-controlled parallel design, with
 10 Hz rTMS over 10 days.
 Besides clinical ratings, ECD-SPECT (technetium-99 bicisate single
photon emission computed tomography) imaging was performed before
and after termination of rTMS treatment.
 Significant reduction of negative symptoms combined with a trend
for non-significant improvement of depressive symptoms in the active
stimulated group as compared with the sham stimulated group.
 Additionally, a trend for worsening of positive symptoms was
observed in the actively treated schizophrenic patients.
 In both groups no changes in regional cerebral blood flow could be
detected by ECD-SPECT.

rTMS and schizophrenia
2005
Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J,
d'Amato T, Saoud M.
 Slow transcranial magnetic stimulation can rapidly reduce resistant
auditory hallucinations in schizophrenia. Biol Psychiatry. 2005 Jan
15;57(2):188-91.
 10 right-handed schizophrenia patients
 with resistant AVH (auditory verbal hallucinations)
 received 5 days of active rTMS and 5 days of sham rTMS (2.000
stimulations per day at 90% of motor threshold)
 over the left temporoparietal cortex
 in a double-blind crossover design.
 The two weeks of stimulation were separated by a 1-week washout
period.
 AVH were robustly improved (56%) by 5 days active rTMS, whereas
no variation was observed after sham.
 Seven patients were responders to active treatment, five of whom
maintained improvement for at least 2 months.

rTMS and schizophrenia
2005
Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu
YT, Carroll K, Krystal JH.
 Temporoparietal Transcranial Magnetic Stimulation for Auditory
Hallucinations: Safety, Efficacy and Moderators in a Fifty Patient Sample. Biol
Psychiatry. 2005 Jun 2
 A preliminary report based on 24 patients with schizophrenia or
schizoaffective disorder indicated greater improvement in auditory
hallucinations following 1-hertz left temporoparietal rTMS compared to sham
stimulation.
 Data from the full 50-subject sample incorporating 26 new patients are now
presented to more comprehensively assess safety/tolerability, efficacy and
moderators of this intervention.
 Right-handed patients experiencing auditory hallucinations at least 5 times
per day were randomly allocated to receive either rTMS or sham stimulation.
 A total of 132 minutes of rTMS was administered over 9 days at 90% motor
threshold using a double-masked, sham-controlled, parallel design.
 Hallucination Change Score was more improved for rTMS relative to sham
stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004).
Hallucination frequency was significantly decreased during rTMS relative to
sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008).
There was no evidence of neurocognitive impairment associated with rTMS.

rTMS and schizophrenia
2005
Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M,
Rapisarda V, Bella R, Pennisi G.
 Repetitive transcranial magnetic stimulation in schizophrenic patients
reporting auditory hallucinations. Neurosci Lett. 2005 Jul 8;383(1-2):54-7.
Epub 2005 Apr 15.
 16 schizophrenic patients (treated with atypical antipsycothic drugs)
 Low frequency rTMS (1Hz) was performed at the 90% of resting motor
threshold (MT)
 4 sessions in four consecutive days for 15 minutes each application.
 8 patients received active stimulation, while 8 patients received sham
stimulation.
 Scale for the assessment of positive symptoms (SAPS), scale for the
assessment of negative symptoms (SANS) and a scale to asses the severity
of the auditory hallucinations (SAH) were administered at the beginning and at
regular intervals during the follow-up.
 The main finding was the long-term reduction in auditory hallucinations in
the active group, with a return to the baseline in the sham group.
 The negative symptomatology improved only in the later sessions and
lasted during the follow-up.
 The improvements in auditory hallucinations and positive symptomatology
increased and lasted during the follow-up till the end-point.

rTMS and schizophrenia
2005
Sachdev P, Loo C, Mitchell P, Malhi G.
 Transcranial magnetic stimulation for the deficit syndrome of
schizophrenia: A pilot investigation. Psychiatry Clin Neurosci. 2005
Jun;59(3):354-7.
 Open study
 4 subjects with a stable deficit syndrome of schizophrenia received
high frequency repetitive transcranial magnetic stimulation (15 Hz at
90% of motor threshold, 1800 pulses each session, daily for 20
sessions over 4 weeks) over the left dorsolateral prefrontal cortex.
 Subjects showed a significant reduction in negative symptoms and
improvement in function, with no change in positive symptoms.
 This improvement was maintained at the 1 month follow up.

rTMS and schizophrenia
2005
Saba G, Verdon CM, Kalalou K, Rocamora JF, Dumortier G,
Benadhira R, Stamatiadis L, Vicaut E, Lipski H, Januel D.
 Transcranial magnetic stimulation in the treatment of schizophrenic
symptoms: A double blind sham controlled study. J Psychiatr Res.
2005 May 7; [Epub ahead of print]
 18 schizophrenic patients
 active or sham rTMS
 10 days
 over the left temporoparietal cortex (80% of the motor threshold,
1Hz, five trains of 1min).
 Psychopathological dimensions were measured with the positive
and negative syndrome scale and clinical global impression (CGI) at
baseline and after 10 session of rTMS.
 All patients were improved at the end of the trial but no significant
group differences were found. Patients receiving sham stimulation
showed the same pattern of improvement compared to active condition
on all the subscales of the positive and negative syndrome scale and
CGI scores (p>0.05).

rTMS and schizophrenia
2005
Lee SH, Kim W, Chung YC, Jung KH, Bahk WM, Jun TY, Kim KS, George MS,
Chae JH.

A double blind study showing that two weeks of daily repetitive TMS over the left or
right temporoparietal cortex reduces symptoms in patients with schizophrenia who are
having treatment-refractory auditory hallucinations. Neurosci Lett. 2005 Mar
16;376(3):177-81

39 patients with schizophrenia with treatment-refractory AH (auditory hallucinations)

were allocated randomly to one of three groups: daily left, right, and sham rTMS
groups.

rTMS was applied to the TP3 (temporoparietal) or 4 regions with the aid of the
electroencephalography 10-20 international system

1 Hz for 20 min per day for 10 treatment days.

Symptoms were evaluated using the Auditory Hallucination Rating Scale (AHRS),
the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression--Improvement (CGI-I) scale.

For the time effect (within-subject comparison), there were significant changes in the
frequency of AHs, positive symptoms of PANSS, and CGI-I.

A between-group comparison revealed significant differences in the positive
symptoms of PANSS, and CGI-I scores.

Post hoc analysis revealed that both the right- and left-side rTMS treatment groups
exhibited better CGI-I scores compared to the sham-stimulated group.

Left sided rTMS is not superior to right or sham rTMS.

rTMS and addiction
rTMS and addiction
70-80% of regular smokers fulfill the ICD-10criteria of dependence.
 Therapeutic interventions, such as nicotine
substitution or bupropione, yield poor abstinence
rates of 30% after 12 months, at best.
 In animal experiments, repetitive transcranial
magnetic stimulation (rTMS) exhibited modulatory
effects on dopaminergic neurotransmission in
regions of the so-called reward system.

rTMS and addiction
2003
Johann M, Wiegand R, Kharraz A, Bobbe G,
Sommer G, Hajak G, Wodarz N, Eichhammer P.
 Transcranial magnetic stimulation for nicotine
dependence. Psychiatr Prax. 2003 May;30 Suppl
2:S129-31.
 11 tobacco-dependent cigarette smokers
 Active or placebo rTMS on consecutive days.
 Craving, as measured by a visual analogue
scale, is significantly decreased after active
stimulation compared to placebo-stimulation intraindividually.

rTMS and addiction
2003
Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Wodarz
N, Hajak G.
 High-frequency repetitive transcranial magnetic stimulation
decreases cigarette smoking. J Clin Psychiatry. 2003 Aug;64(8):951-3.
 14 smokers
 double-blind crossover trial
 comparing single days of active versus sham stimulation.
 Outcome measures were rTMS effects on number of cigarettes
smoked during an ad libitum smoking period and effects on craving
after a period of acute abstinence.
 20-Hz rTMS of left dorsolateral prefrontal cortex reduced cigarette
smoking significantly (p <.01) compared with sham stimulation. Levels
of craving did not change significantly.
