Repetitive transcranial magnetic stimulation for the ...€¦ · 1998). For continuous data the studies included in the pooled analysis were tested for statistical homogeneity using

BackgroundBackground Repetitive transcranialRepetitive transcranial

magnetic stimulation (rTMS)maybeusefulmagnetic stimulation (rTMS)maybeuseful

in the treatmentof depressionbut resultsin the treatmentof depression but results

fromtrials have been inconclusive to date.fromtrials have been inconclusive to date.

AimsAims To assess the efficacyof rTMSinTo assess the efficacyof rTMSin

treatingdepression.treatingdepression.

MethodMethod Weconducted a systematicWe conducted a systematic

reviewofrandomisedcontrolledtrials thatreviewofrandomisedcontrolledtrials that

comparedrTMSwith shaminpatientswithcomparedrTMSwith shaminpatientswith

depression.We assessed the qualityofdepression.We assessed the qualityof

designof all studies andconducted ameta-designof all studies and conducted ameta-

analysis of data fromtrialswith similaranalysis of data fromtrialswith similar

rTMS delivery.rTMS delivery.

ResultsResults Weincluded a total of14 trials.We included a total of14 trials.

Thequalityoftheincludedstudieswaslow.The qualityoftheincluded studieswaslow.

Pooled analysis using the Hamilton RatingPooled analysis using the Hamilton Rating

Scale for Depression showed an effect inScale for Depression showed an effect in

favourof rTMS comparedwith shamafterfavourof rTMS comparedwith shamafter

2 weeks oftreatment (standardisedmean2 weeks oftreatment (standardisedmean

differencedifference¼770.35; 95% CI0.35; 95% CI770.66 to0.66 to

770.04), butthiswasnot significant atthe0.04), butthiswasnot significant atthe

2-week follow-up (standardisedmean2-week follow-up (standardisedmean

differencedifference¼770.33; 95% CI0.33; 95% CI770.84 to0.84 to

0.17).0.17).

ConclusionsConclusions Currenttrials are of lowCurrenttrials are of low

quality andprovide insufficientevidence toqualityandprovide insufficientevidence to

supportthe use of rTMSinthe treatmentsupportthe use of rTMSinthe treatment

of depression.of depression.

Declaration of interestDeclaration of interest The studyThe study

was fundedby the Ministerio de Sanidadywas fundedby the Ministerio de Sanidady

Consumo,Instituto de Salud Carlos III,Consumo,Instituto de Salud Carlos III,

Spain (grant no. 00/10099).T.E.S. isSpain (grant no. 00/10099).T.E.S. is

involved in one ofthe studies included ininvolved in one ofthe studies included in

this reviewand is also Secretary^this review and is also Secretary^

Treasurerofthe International Society forTreasurerofthe International Society for

Transcranial Stimulation.Transcranial Stimulation.

Repetitive transcranial magnetic stimula-Repetitive transcranial magnetic stimula-

tion (rTMS) is a non-invasive techniquetion (rTMS) is a non-invasive technique

used to stimulate the human brainused to stimulate the human brain in vivoin vivo

using very strong, pulsed magnetic fields.using very strong, pulsed magnetic fields.

The technique involves the delivery of aThe technique involves the delivery of a

magnetic pulse to the cortex of a subjectmagnetic pulse to the cortex of a subject

through a hand-held stimulating coil ap-through a hand-held stimulating coil ap-

plied directly to the head. The magneticplied directly to the head. The magnetic

pulses pass unimpeded through the skullpulses pass unimpeded through the skull

and induce an electrical current in the un-and induce an electrical current in the un-

derlying tissue, which in turn is able to de-derlying tissue, which in turn is able to de-

polarise neurons (Hallet, 2000). Given itspolarise neurons (Hallet, 2000). Given its

relative non-invasiveness, its potential torelative non-invasiveness, its potential to

stimulate very focused areas of the brainstimulate very focused areas of the brain

and indications that it may have therapeu-and indications that it may have therapeu-

tic effects in neuropsychiatric disorders,tic effects in neuropsychiatric disorders,

especially affective disorders (Georgeespecially affective disorders (George et alet al,,

1999), rTMS has been the focus of con-1999), rTMS has been the focus of con-

siderable research and clinical interest insiderable research and clinical interest in

recent years. Clinical interest originatesrecent years. Clinical interest originates

mainly from about 15 placebo-controlledmainly from about 15 placebo-controlled

clinical studies involving around 200 sub-clinical studies involving around 200 sub-

jects with depressive disorder or bipolarjects with depressive disorder or bipolar

disorder in the depressed phase. It has beendisorder in the depressed phase. It has been

shown that rTMS has effects on the brainshown that rTMS has effects on the brain

(Ji(Ji et alet al, 1998; Keck, 1998; Keck et alet al, 2000), but, 2000), but

whether its properties are clinically usefulwhether its properties are clinically useful

and constitute meaningful alternatives toand constitute meaningful alternatives to

currently available treatments remains tocurrently available treatments remains to

be determined. Today rTMS presents an in-be determined. Today rTMS presents an in-

teresting and potentially promising techni-teresting and potentially promising techni-

que but to our knowledge there has beenque but to our knowledge there has been

no systematic evaluation of its efficacyno systematic evaluation of its efficacy

using meta-analysis techniques. We under-using meta-analysis techniques. We under-

took a systematic review of all availabletook a systematic review of all available

randomised trials and conducted a meta-randomised trials and conducted a meta-

analysis of relevant data to assess theanalysis of relevant data to assess the

efficacy of rTMS in treating depression.efficacy of rTMS in treating depression.

METHODMETHOD

Identification of studiesIdentification of studies

We searched Medline (1966–March 2002),We searched Medline (1966–March 2002),

Embase (1974–March 2002). PsycLitEmbase (1974–March 2002). PsycLit

(1980–2001), the Register of Clinical Trials(1980–2001), the Register of Clinical Trials

of the Cochrane Collaboration Depression,of the Cochrane Collaboration Depression,

Neurosis and Anxiety Review GroupNeurosis and Anxiety Review Group

(January 2002) and the Cochrane Con-(January 2002) and the Cochrane Con-

trolled Trials Register (January 2002)trolled Trials Register (January 2002) usingusing

the search termsthe search terms MAGNETIC-STIMU-MAGNETIC-STIMU-

LATION, TMS, rTMS, DEPRESSION,LATION, TMS, rTMS, DEPRESSION,

DEPRESSIVE DISORDER and DYS-DEPRESSIVE DISORDER and DYS-

THMIC DISORDER and included papersTHMIC DISORDER and included papers

published in all languages. Where possible,published in all languages. Where possible,

we contacted authors of identified random-we contacted authors of identified random-

ised controlled trials (RCTs) for additionalised controlled trials (RCTs) for additional

information or other relevant studies.information or other relevant studies.

Inclusion criteriaInclusion criteria

Studies included were randomised trialsStudies included were randomised trials

that compared rTMS given at any fre-that compared rTMS given at any fre-

quency and at any localisation with a shamquency and at any localisation with a sham

intervention in patients of any age andintervention in patients of any age and

gender with a diagnosis of depression (de-gender with a diagnosis of depression (de-

pressive disorders or bipolar disorders inpressive disorders or bipolar disorders in

depressed phase), with or without psychoticdepressed phase), with or without psychotic

symptoms according to either DSM–IVsymptoms according to either DSM–IV

(American Psychiatric Association, 1994)(American Psychiatric Association, 1994)

or ICD–10 (World Health Organization,or ICD–10 (World Health Organization,

1993).1993).

Selection procedure, dataSelection procedure, dataextraction and quality assessmentextraction and quality assessment

Potentially relevant studies were obtained,Potentially relevant studies were obtained,

examined independently and quantitativeexamined independently and quantitative

and qualitative data were extractedand qualitative data were extracted

independently using a standard form.independently using a standard form.

Our quality assessment of the studiesOur quality assessment of the studies

addressed three main criteria: adequateaddressed three main criteria: adequate

concealment of randomisation; intention-concealment of randomisation; intention-

to-treat analysis; and blinding. To assessto-treat analysis; and blinding. To assess

the adequacy of randomisation conceal-the adequacy of randomisation conceal-

ment, we looked for evidence from thement, we looked for evidence from the

study report of robust concealment ofstudy report of robust concealment of

group allocation, such as a centralised sys-group allocation, such as a centralised sys-

tem or a process in which allocations weretem or a process in which allocations were

pre-numbered, coded and kept in lockedpre-numbered, coded and kept in locked

files or in sequentially numbered, sealed,files or in sequentially numbered, sealed,

opaque envelopes (Clarke & Oxman,opaque envelopes (Clarke & Oxman,

2001). For intention-to-treat analysis we2001). For intention-to-treat analysis we

looked for evidence that all patients initi-looked for evidence that all patients initi-

ally randomised had been included in theally randomised had been included in the

analysis, regardless of whether they hadanalysis, regardless of whether they had

completed the study or not. We also lookedcompleted the study or not. We also looked

for post-treatment follow-up. With respectfor post-treatment follow-up. With respect

to blinding, for practical reasons the profes-to blinding, for practical reasons the profes-

sional giving the rTMS intervention itselfsional giving the rTMS intervention itself

(whether active rTMS or sham), cannot be(whether active rTMS or sham), cannot be

blinded. If the patients had been blindedblinded. If the patients had been blinded

to the treatment allocation, and the out-to the treatment allocation, and the out-

comes had been assessed either by an asses-comes had been assessed either by an asses-

sor who was also blinded to the allocationsor who was also blinded to the allocation

or by the patient themselves, we classifiedor by the patient themselves, we classified

the trial as being single blind withthe trial as being single blind with

evaluation by external assessors.evaluation by external assessors.

4 8 04 8 0

BR IT I SH JOURNAL OF P SYCHIATRYBR IT I SH JOURNAL OF P SYCHIATRY ( 2 0 0 3 ) , 1 8 2 , 4 8 0 ^ 4 9 1( 2 0 0 3 ) , 1 8 2 , 4 8 0 ^ 4 9 1 R E V I E W A R T I C L ER E V I E W A R T I C L E

Repetitive transcranial magnetic stimulationRepetitive transcranial magnetic stimulation

for the treatment of depressionfor the treatment of depression

Systematic review and meta-analysisSystematic review and meta-analysis

JOSE LUIS R. MARTIN, MANUEL J. BARBANOJ, THOMAS E. SCHLAEPFER,JOSE¤ LUIS R. MARTIN, MANUEL J. BARBANOJ, THOMAS E. SCHLAEPFER,ELINOR THOMPSON, VICTOR PEREZ and JAIME KULISEVSKYELINOR THOMPSON, VI¤ CTOR PE¤ REZ and JAIME KULISEVSKY

TR ANSCRANIAL MAGNETIC ST IMULATION FOR DEPRES S IONTRANSCRANIAL MAGNETIC ST IMULATION FOR DEPRES S ION

We also looked at details of each trialWe also looked at details of each trial

design and noted whether there had beendesign and noted whether there had been

factors such as concurrent medication orfactors such as concurrent medication or

therapeutic setting that may havetherapeutic setting that may have

influenced health outcomes and conse-influenced health outcomes and conse-

quently the apparent performance of thequently the apparent performance of the

interventions.interventions.

Outcome measuresOutcome measures

The main outcome measure was remissionThe main outcome measure was remission

of symptoms, determined by any of theof symptoms, determined by any of the

following measures: time to adjunctivefollowing measures: time to adjunctive

treatment; readmission to hospital ortreatment; readmission to hospital or

hospital discharge; time off work; orhospital discharge; time off work; or

appropriate psychometric scales. Accept-appropriate psychometric scales. Accept-

ability of treatment (as measured byability of treatment (as measured by

withdrawals from trial) was considered aswithdrawals from trial) was considered as

a secondary outcome.a secondary outcome.

Data synthesisData synthesis

We undertook a methodological qualityWe undertook a methodological quality

assessment of all the included studies. Weassessment of all the included studies. We

conducted a pooled analysis of data fromconducted a pooled analysis of data from

those trials in which the intervention giventhose trials in which the intervention given

was homogeneous (same localisation, fre-was homogeneous (same localisation, fre-

quency and duration of treatment), usingquency and duration of treatment), using

scores from the Hamilton Rating Scale forscores from the Hamilton Rating Scale for

Depression (HRSD; Hamilton, 1960,Depression (HRSD; Hamilton, 1960,

1967), because this psychometric scale1967), because this psychometric scale

was the only outcome measure that waswas the only outcome measure that was

reported by all the studies. In addition wereported by all the studies. In addition we

conducted a second pooled analysis of dataconducted a second pooled analysis of data

from those studies with homogeneous inter-from those studies with homogeneous inter-

ventions that had used the Beck Depressionventions that had used the Beck Depression

Inventory (BDI; BeckInventory (BDI; Beck et alet al, 1961) as a sec-, 1961) as a sec-

ondary outcome measure. A third pooledondary outcome measure. A third pooled

analysis was conducted for treatment andanalysis was conducted for treatment and

acceptability (measured by withdrawals).acceptability (measured by withdrawals).

In the cross-over studies we excluded aIn the cross-over studies we excluded a

possible carry-over effect between the dif-possible carry-over effect between the dif-

ferent phases of the trials by using infor-ferent phases of the trials by using infor-

mation only from the first phase (Jadad,mation only from the first phase (Jadad,

1998). For continuous data the studies1998). For continuous data the studies

included in the pooled analysis were testedincluded in the pooled analysis were tested

for statistical homogeneity using afor statistical homogeneity using a ww22 testtest

and, because homogeneity was found, theand, because homogeneity was found, the

pooled standardised mean difference waspooled standardised mean difference was

calculated under a fixed-effect modelcalculated under a fixed-effect model

weighted by the inverse variance methodweighted by the inverse variance method

(Cochrane Collaboration, 2000; Sutton(Cochrane Collaboration, 2000; Sutton

et alet al, 2000). For binary outcomes the, 2000). For binary outcomes the

relative risks were calculated using arelative risks were calculated using a

Mantel–Haenszel fixed-effect model (Co-Mantel–Haenszel fixed-effect model (Co-

chrane Collaboration, 2000; Suttonchrane Collaboration, 2000; Sutton et alet al,,

2000) and 95% confidence intervals were2000) and 95% confidence intervals were

calculated. Standardised mean differencecalculated. Standardised mean difference

(Geddes(Geddes et alet al, 2002) rather than weighted, 2002) rather than weighted

mean difference was used in the pooledmean difference was used in the pooled

analysis to take account of the differentanalysis to take account of the different

versions of HRSD and BDI used in theversions of HRSD and BDI used in the

different studies.different studies.

RESULTSRESULTS

We identified 85 references, from whichWe identified 85 references, from which

we excluded 48 (see Appendix 1 andwe excluded 48 (see Appendix 1 and

Fig. 1): seventeen trials with no controlFig. 1): seventeen trials with no control

group (Hoflichgroup (Hoflich et alet al, 1993; George, 1993; George et alet al,,

1995, 1998; Geller1995, 1998; Geller et alet al, 1997; Epstein, 1997; Epstein etet

alal, 1998; Feinsod, 1998; Feinsod et alet al, 1998; Figiel, 1998; Figiel et alet al,,

1998; Garcıa1998; Garcıa et alet al, 1998; Menkes, 1998; Menkes et alet al,,

1999; Nahas1999; Nahas et alet al, 1999; Pridmore, 1999;, 1999; Pridmore, 1999;

PridmorePridmore et alet al, 1999; Reid & Pridmore,, 1999; Reid & Pridmore,

1999; Schouten1999; Schouten et alet al, 1999; Triggs, 1999; Triggs et alet al,,

1999; Conca1999; Conca et alet al, 2000; Zheng, 2000);, 2000; Zheng, 2000);

nine review articles (Markwortnine review articles (Markwort et alet al,,

1997; George1997; George et alet al, 1999, 1999aa,,bb; Pridmore &; Pridmore &

Belmaker, 1999; TormosBelmaker, 1999; Tormos et alet al, 1999;, 1999;

Hansen, 2000; KrystalHansen, 2000; Krystal et alet al, 2000; Szuba, 2000; Szuba

et alet al, 2000; Walter, 2000; Walter et alet al, 2001); seven trial, 2001); seven trial

reports whose efficacy outcomes had beenreports whose efficacy outcomes had been

published elsewhere (Koppipublished elsewhere (Koppi et alet al, 1997;, 1997;

TenebackTeneback et alet al, 1999; Kozel, 1999; Kozel et alet al, 2000;, 2000;

LittleLittle et alet al, 2000; Speer, 2000; Speer et alet al, 2000; Loo, 2000; Loo

et alet al, 2001; Moser, 2001; Moser et alet al, 2002); nine studies, 2002); nine studies

on healthy volunteers (Georgeon healthy volunteers (George et alet al, 1996;, 1996;

Pascual-LeonePascual-Leone et alet al, 1996, 1996aa; Bohning; Bohning et alet al,,

1999; Clark1999; Clark et alet al, 2000; D’Alfonso, 2000; D’Alfonso et alet al,,

2000; Mosimann, 2000; Loo2000; Mosimann, 2000; Loo et alet al, 2000;, 2000;

HabelHabel et alet al, 2001); one with no report of, 2001); one with no report of

any randomisation process (Stikhinaany randomisation process (Stikhina et alet al,,

1999); one descriptive study (Turnier-Shea1999); one descriptive study (Turnier-Shea

et alet al, 1999);, 1999); two with outcomes other thantwo with outcomes other than

depression (Grisarudepression (Grisaru et alet al, 1998; Nahas, 1998; Nahas

et alet al, 2000); and two in which rTMS was, 2000); and two in which rTMS was

given after a previous intervention of sleepgiven after a previous intervention of sleep

deprivation (Eichhammerdeprivation (Eichhammer et alet al, 2002;, 2002;

PadbergPadberg et alet al, 2002). We also excluded a, 2002). We also excluded a

further sixteen studies that were either stillfurther sixteen studies that were either still

in progress without completed quantitativein progress without completed quantitative

data available or for which we are awaitingdata available or for which we are awaiting

data (Shajahan, 2000; Woodruff, 2000;data (Shajahan, 2000; Woodruff, 2000;

the Avery–George–Hotzheimer databasethe Avery–George–Hotzheimer database

of rTMS Depression Studies, at http://of rTMS Depression Studies, at http://

www.ists.unibe.ch/ists/TMSAvery.htm).www.ists.unibe.ch/ists/TMSAvery.htm).

We excluded four RCTs and one con-We excluded four RCTs and one con-

trol clinical trial (CCT) from the identifiedtrol clinical trial (CCT) from the identified

trials because there was either no shamtrials because there was either no sham

comparison group (Concacomparison group (Conca et alet al, 1996;, 1996;

GrunhausGrunhaus et alet al, 2000; Pridmore, 2000;, 2000; Pridmore, 2000;

PridmorePridmore et alet al, 2000) or because, although, 2000) or because, although

a sham group was included alongside twoa sham group was included alongside two

randomly allocated active treatment groupsrandomly allocated active treatment groups

the sham group itself had not been gener-the sham group itself had not been gener-

ated by a randomisation process (Kolbingerated by a randomisation process (Kolbinger

et alet al, 1995). A detailed analysis of these five, 1995). A detailed analysis of these five

studies was included as part of a widerstudies was included as part of a wider

systematic review (Martinsystematic review (Martin et alet al, 2002)., 2002).

Among the remaining sixteen random-Among the remaining sixteen random-

ised controlled studies there was clinicalised controlled studies there was clinical

heterogeneity with respect to four variables:heterogeneity with respect to four variables:

localisation of rTMS application (leftlocalisation of rTMS application (left

dorsolateral prefrontal cortex, right pre-dorsolateral prefrontal cortex, right pre-

frontal cortex, vertex or multiple sites;frontal cortex, vertex or multiple sites;

frequency of rTMS (high or low); durationfrequency of rTMS (high or low); duration

of treatment – 10 consecutive workingof treatment – 10 consecutive working

days (2 weeks) or 5 consecutive workingdays (2 weeks) or 5 consecutive working

days (1 week); and number of interventionsdays (1 week); and number of interventions

a day (one or more) (see Fig. 1). Two stu-a day (one or more) (see Fig. 1). Two stu-

dies (Pascual-Leonedies (Pascual-Leone et alet al, 1996, 1996bb; Speer; Speer etet

alal, 2001) are awaiting evaluation of design, 2001) are awaiting evaluation of design

data and methodological quality to bedata and methodological quality to be

included, and additional quantitative infor-included, and additional quantitative infor-

mation is needed for these studies to bemation is needed for these studies to be

analysed.analysed.

A total of thirteen published (GeorgeA total of thirteen published (George etet

alal, 1997, 2000; Avery, 1997, 2000; Avery et alet al, 1999; Kimbrell, 1999; Kimbrell

et alet al, 1999; Klein, 1999; Klein et alet al, 1999; Loo, 1999; Loo et alet al,,

1999; Padberg1999; Padberg et alet al, 1999; Berman, 1999; Berman et alet al,,

2000; Eschweiler2000; Eschweiler et alet al, 2000; Garcıa-Toro, 2000; Garcıa-Toro

et alet al, 2001, 2001aa,,bb; Manes; Manes et alet al, 2001; Szuba, 2001; Szuba

et alet al, 2001) and one study in preparation, 2001) and one study in preparation

(further details available from the authors(further details available from the authors

upon request) met the inclusion criteria forupon request) met the inclusion criteria for

assessing the effectiveness of rTMSassessing the effectiveness of rTMS vv. a. a

sham intervention (see Appendix 2). Thesham intervention (see Appendix 2). The

majority of these studies (13/14) comparedmajority of these studies (13/14) compared

left-sided, high-frequency rTMS (left–high)left-sided, high-frequency rTMS (left–high)

with a group receiving sham, whereas onewith a group receiving sham, whereas one

study (Kleinstudy (Klein et alet al, 1999) compared right-, 1999) compared right-

sided, low-frequency rTMS for 2 weekssided, low-frequency rTMS for 2 weeks

(right–low–2). Treatment duration was for(right–low–2). Treatment duration was for

2 weeks in nine of the left–high studies2 weeks in nine of the left–high studies

(left–high–2) and for 1 week (left–high–1)(left–high–2) and for 1 week (left–high–1)

in the remaining three studies. Among thein the remaining three studies. Among the

12 left–high studies, all used the HRSD as12 left–high studies, all used the HRSD as

a primary indicator of efficacy, whereasa primary indicator of efficacy, whereas

nine (seven with available data) also usednine (seven with available data) also used

the BDI as a secondary outcome. A quanti-the BDI as a secondary outcome. A quanti-

tative analysis of pooled data from the left–tative analysis of pooled data from the left–

high–1 and left–high–2 studies on each ofhigh–1 and left–high–2 studies on each of

these outcome scales was possible. Twothese outcome scales was possible. Two

studies (Kimbrellstudies (Kimbrell et alet al, 1999; Padberg, 1999; Padberg et alet al,,

2002) included a third left-sided, low-2002) included a third left-sided, low-

frequency (left–low) comparison arm. Be-frequency (left–low) comparison arm. Be-

cause of differences in the nature of thecause of differences in the nature of the

intervention applied with respect to locali-intervention applied with respect to locali-

sation and frequency, these two compari-sation and frequency, these two compari-

sons (left–low–1 and left–low–2) were notsons (left–low–1 and left–low–2) were not

included in the quantitative analysis, butincluded in the quantitative analysis, but

were included in the qualitative reviewwere included in the qualitative review

along with the one right–low–2 study andalong with the one right–low–2 study and

with one study that compared differentwith one study that compared different

doses of rTMS per day (Szubadoses of rTMS per day (Szuba et alet al, 2000)., 2000).

Study populationsStudy populations

The mean age of study participants rangedThe mean age of study participants ranged

from 41.8 to 60.87 years and the ratio offrom 41.8 to 60.87 years and the ratio of

4 814 81

MARTIN ET ALMARTIN ET AL

4 8 24 8 2

Fig. 1Fig. 1 Process of inclusion of studies for review and analysis: rTMS, repetitive transcranialmagnetic stimulation;HRSD,HamiltonRating Scale forDepression; BDI, BeckProcess of inclusion of studies for review and analysis: rTMS, repetitive transcranialmagnetic stimulation;HRSD,Hamilton Rating Scale forDepression; BDI, Beck

Depression Inventory; ECT, electroconvulsive therapy; mt, motor threshold; *some studies of 2 weeks’durationmeasured outcomes at both1and 2 weeks.Depression Inventory; ECT, electroconvulsive therapy; mt, motor threshold; *some studies of 2 weeks’durationmeasured outcomes at both1and 2 weeks.


males to females ranged from 0.09 to 2.33males to females ranged from 0.09 to 2.33

(Table 1). Thirteen of fourteen studies in-(Table 1). Thirteen of fourteen studies in-

cluded in the qualitative review recruitedcluded in the qualitative review recruited

patients who only fulfilled the criteria forpatients who only fulfilled the criteria for

major depression or major depressive ill-major depression or major depressive ill-

ness as classified by DSM–IV criteria. Onlyness as classified by DSM–IV criteria. Only

one study recruited patients with criteriaone study recruited patients with criteria

that included minor depression (Manesthat included minor depression (Manes etet

alal, 2001). Some studies recruited only, 2001). Some studies recruited only

patients with unipolar depression whereaspatients with unipolar depression whereas

others also recruited patients with bipolarothers also recruited patients with bipolar

depression in the depressed phase. Almostdepression in the depressed phase. Almost

all studies specified that patients who wereall studies specified that patients who were

at a high risk of suicide and/or possible riskat a high risk of suicide and/or possible risk

of convulsions were excluded.of convulsions were excluded.

Quality of included studiesQuality of included studies

Most of the studies were of low method-Most of the studies were of low method-

ological quality. Apart from one study withological quality. Apart from one study with

70 patients (Klein70 patients (Klein et alet al, 1999), the rest used, 1999), the rest used

sample sizes of 6–40 patients (mediansample sizes of 6–40 patients (median¼19).19).

RandomisationRandomisation

Most studies gave only general descriptionsMost studies gave only general descriptions

of the randomisation process and noneof the randomisation process and none

described the methods of concealing allo-described the methods of concealing allo-

cation. One study (Kleincation. One study (Klein et alet al, 1999), 1999)

described only the generation of the allo-described only the generation of the allo-

cation sequence through randomised listscation sequence through randomised lists

of numbers generated by a computer pro-of numbers generated by a computer pro-

gram and another (further details availablegram and another (further details available

from the authors upon request) reported afrom the authors upon request) reported a

‘generation of randomised numbers’ with-‘generation of randomised numbers’ with-

out giving details of the allocation processout giving details of the allocation process

involved.involved.

Intention-to-treatIntention-to-treat

Although there were withdrawals from sixAlthough there were withdrawals from six

of the included thirteen studies, only twoof the included thirteen studies, only two

studies (Bermanstudies (Berman et alet al, 2000; Eschweiler, 2000; Eschweiler etet

alal, 2000) undertook an intention-to-treat, 2000) undertook an intention-to-treat

analysis by including the last observationanalysis by including the last observation

carried forward in the analysis. Threecarried forward in the analysis. Three

studies (Averystudies (Avery et alet al, 1999; Garcıa-Toro, 1999; Garcıa-Toro

et alet al, 2001, 2001aa,,bb) included a period of post-) included a period of post-

treatment follow-up of 2 weeks, onetreatment follow-up of 2 weeks, one

study included a period of post-treatmentstudy included a period of post-treatment

follow-up of 1 week (Manesfollow-up of 1 week (Manes et alet al, 2001), 2001)

and another study (Eschweilerand another study (Eschweiler et alet al,,

2000) included a period of post-treatment2000) included a period of post-treatment

follow-up of 1 week between the first andfollow-up of 1 week between the first and

second phase of the cross-over design.second phase of the cross-over design.

One study used the post-treatment follow-One study used the post-treatment follow-

up for only one patient who respondedup for only one patient who responded

totally and for three who responded par-totally and for three who responded par-

tially, but it did not report on the rest oftially, but it did not report on the rest of

the patients treated in the study (Bermanthe patients treated in the study (Berman

et alet al, 2000)., 2000).

BlindingBlinding

Although most of the studies stated thatAlthough most of the studies stated that

they were double blind or double masked,they were double blind or double masked,

they were, more accurately, single blindthey were, more accurately, single blind

with evaluation by external assessors.with evaluation by external assessors.

Nine (seven with available data) studiesNine (seven with available data) studies

also used the BDI, in which the patientsalso used the BDI, in which the patients

themselves evaluated their response tothemselves evaluated their response to

treatment.treatment.

Confounding factorsConfounding factors

Only three (BermanOnly three (Berman et alet al, 2000; Manes, 2000; Manes etet

alal, 2001; Szuba, 2001; Szuba et alet al, 2001) of the further, 2001) of the further

studies stated that the patients were all freestudies stated that the patients were all free

of psychotic medication for 1 week beforeof psychotic medication for 1 week before

the study and during the study period itself.the study and during the study period itself.

In seven of fourteen studies the patientsIn seven of fourteen studies the patients

were described as medication resistantwere described as medication resistant

(failed at least one trial of pharmacological(failed at least one trial of pharmacological

therapy during the current depressive epi-therapy during the current depressive epi-

sode) but in some cases pharmacologicalsode) but in some cases pharmacological

treatmentstreatments were continued and in somewere continued and in some

cases notcases not (Table 2).(Table 2).

Although most studies stated that theyAlthough most studies stated that they

excluded patients at a high risk of suicide,excluded patients at a high risk of suicide,

some studies recruited only out-patientssome studies recruited only out-patients

(George(George et alet al, 1997, 2000; Avery, 1997, 2000; Avery et alet al,,

1999; Manes1999; Manes et alet al, 2001; further details, 2001; further details

available from the authors upon request),available from the authors upon request),

others recruited only in-patients (Kleinothers recruited only in-patients (Klein

et alet al, 1999; Loo, 1999; Loo et alet al, 1999), some both, 1999), some both

in-patients and out-patients (Bermanin-patients and out-patients (Berman et alet al,,

2000; Garcıa-Toro2000; Garcıa-Toro et alet al, 2001, 2001bb) and others) and others

did not specify (Kimbrelldid not specify (Kimbrell et alet al, 1999; Pad-, 1999; Pad-

bergberg et alet al, 1999; Eschweiler, 1999; Eschweiler et alet al, 2000;, 2000;

Garcıa-ToroGarcıa-Toro et alet al, 2001, 2001aa; Szuba; Szuba et alet al, 2001)., 2001).

Quantitative analysesQuantitative analyses

RepetitiveTMS (left dorsolateral prefrontalRepetitiveTMS (left dorsolateral prefrontalcortex and high frequency) v. shamTMScortex and high frequency) v. shamTMS

Hamilton Rating Scale for DepressionHamilton Rating Scale for Depression. Twelve. Twelve

studies contributed to this analysis, givingstudies contributed to this analysis, giving

an overall sample of 217 patients (119an overall sample of 217 patients (119

in the treatment group and 98 in thein the treatment group and 98 in the

placebo group). A subgroup analysis wasplacebo group). A subgroup analysis was

conducted by duration of treatment (1conducted by duration of treatment (1

or 2 weeks) and for those studies that in-or 2 weeks) and for those studies that in-

cluded follow-up data (at 1 or 2 weeks).cluded follow-up data (at 1 or 2 weeks).

After 2 weeks of treatment the standard-After 2 weeks of treatment the standard-

ised mean difference (SMD) for rTMSised mean difference (SMD) for rTMS

(left dorsolateral prefrontal cortex, high(left dorsolateral prefrontal cortex, high

frequency)frequency) vv. sham TMS was. sham TMS was 770.350.35

(95% CI(95% CI 770.66 to0.66 to 770.04;0.04; PP¼0.03;0.03;

nn¼9), showing a difference in favour of9), showing a difference in favour of

rTMS. For those studies that reportedrTMS. For those studies that reported

data after 1 week of treatment or onlydata after 1 week of treatment or only

gave treatment for 1 week, the SMD forgave treatment for 1 week, the SMD for

rTMS (left dorsolateral prefrontal cortex,rTMS (left dorsolateral prefrontal cortex,

high frequency)high frequency) vv. sham rTMS was not. sham rTMS was not

significant, atsignificant, at 770.18 (95% CI0.18 (95% CI 770.64 to0.64 to

0.27;0.27; PP¼0.4;0.4; nn¼5). After 1 week of5). After 1 week of

post-treatment follow-up, the SMD waspost-treatment follow-up, the SMD was

0.08 (95% CI0.08 (95% CI 770.64 to0.64 to 770.81;0.81; PP¼0.8;0.8;

nn¼2). After 2 weeks of post-treatment fol-2). After 2 weeks of post-treatment fol-

low-up,low-up, the SMD was not statistically sig-the SMD was not statistically sig-

nificant:nificant: 770.33 (95% CI0.33 (95% CI 770.84 to 0.17;0.84 to 0.17;

PP¼0.2;0.2; nn¼3) (Fig. 2).3) (Fig. 2).

Beck Depression InventoryBeck Depression Inventory. Seven studies. Seven studies

contributed to this analysis, giving an over-contributed to this analysis, giving an over-

all sample size of 145 patients (81 in theall sample size of 145 patients (81 in the

treatment group and 64 in the placebotreatment group and 64 in the placebo

group). No difference between rTMS andgroup). No difference between rTMS and

sham TMS was shown for any of the timesham TMS was shown for any of the time

periods. After 1 week of treatment, theperiods. After 1 week of treatment, the

SMD for the rTMS over the left dorsolat-SMD for the rTMS over the left dorsolat-

eral prefrontal cortex and high-frequencyeral prefrontal cortex and high-frequency

v.v. sham TMS was 0.18 (95% CIsham TMS was 0.18 (95% CI 770.470.47

to 0.82;to 0.82; PP¼0.6;0.6; nn¼3). The SMD after 23). The SMD after 2

weeks of treatment wasweeks of treatment was 770.24 (95% CI0.24 (95% CI

770.58 to 0.11;0.58 to 0.11; PP¼0.18;0.18; nn¼6).6). The SMDThe SMD

after 2 weeks ofafter 2 weeks of post-treatment follow-post-treatment follow-

up wasup was 770.06 (95% CI0.06 (95% CI 770.56 to 0.43;0.56 to 0.43;

PP¼0.8;0.8; nn¼3) (Fig. 3).3) (Fig. 3).

The analyses were repeated using aThe analyses were repeated using a

random-effects model, but this did notrandom-effects model, but this did not

alter the results.alter the results.

Acceptability of treatmentAcceptability of treatment. Four studies. Four studies

(left–high–2) reported withdrawals of pa-(left–high–2) reported withdrawals of pa-

tients during the intervention period, withtients during the intervention period, with

a total sample size of 114 patients (63 ina total sample size of 114 patients (63 in

the treatment group and 51 in the placebothe treatment group and 51 in the placebo

group). The relative risk, using agroup). The relative risk, using a fixed-fixed-

effect model for rTMSeffect model for rTMS v.v. shamsham rTMSrTMS

for all patients was 0.88 (95% CI 0.37for all patients was 0.88 (95% CI 0.37

to 2.13;to 2.13; PP¼0.8), which is a0.8), which is a statisticallystatistically

non-significant difference.non-significant difference.

DISCUSSIONDISCUSSION

EfficacyEfficacy

We found that there is currently insufficientWe found that there is currently insufficient

evidence to suggest that rTMS is effective inevidence to suggest that rTMS is effective in

the treatment of depression and that thethe treatment of depression and that the

trials conducted to date have been of rela-trials conducted to date have been of rela-

tively low quality. These results do not,tively low quality. These results do not,

however, exclude the possibility that thehowever, exclude the possibility that the

intervention may be of benefit.intervention may be of benefit.

Although the SMD between activeAlthough the SMD between active

treatment and sham groups was significanttreatment and sham groups was significant

in favour of the active group whenin favour of the active group when

measured by the HRSD immediately aftermeasured by the HRSD immediately after

2 weeks of treatment with left-sided, high-2 weeks of treatment with left-sided, high-

frequency rTMS, this difference was notfrequency rTMS, this difference was not

corroborated by a significant difference incorroborated by a significant difference in

4 8 34 8 3


4 8 44 8 4

Table 1Table 1 Summary of transcranialmagnetic stimulation (TMS) placebo-controlled trialsSummary of transcranial magnetic stimulation (TMS) placebo-controlled trials

StudyStudy ParticipantsParticipants InterventionIntervention

AuthorAuthor DesignDesign nn (withdrawals)(withdrawals) PathologyPathology Mean ageMean age

(s.d.)(s.d.)

Male/Male/

femalefemale

TypeType11 Duration ofDuration of

treatment periodtreatment period

(weeks)(weeks)22

EschweilerEschweiler et alet al, 2000, 2000 Cross-overCross-over 12 (3)12 (3) Major depressionMajor depression

(DSMÎV)(DSMÎV)

57 (8)57 (8) 4/84/8 Left-side 10Hz, 90%Left-side 10Hz, 90%

motor threshold,motor threshold,

20 tps of 10 s20 tps of 10 s

1 (first phase)1 (first phase)

PadbergPadberg et alet al, 1999, 1999 ParallelParallel 18 (0)18 (0) Major depressionMajor depression

(DSMÎV)(DSMÎV)

51.2 (16.1)51.2 (16.1) 7/117/11 Left-side 10 or 0.3Hz,Left-side 10 or 0.3Hz,

90% motor threshold,90% motor threshold,

5 or 10 tps of 5 s5 or 10 tps of 5 s

11

GeorgeGeorge et alet al, 1997, 1997 Cross-overCross-over 12 (0)12 (0) Major depressionMajor depression

(DSMÎV)(DSMÎV)

41.8 (12.4)41.8 (12.4) 1/111/11 Left-side 20Hz, 80%Left-side 20Hz, 80%




AveryAvery et alet al, 1999, 1999 ParallelParallel 6 (0)6 (0) Major depressionMajor depression

or bipolar disorderor bipolar disorder

(depressed phase)(depressed phase)

(DSMÎV)(DSMÎV)

44.5 (8.48)44.5 (8.48) 1/51/5 Left-side 10Hz, 80%Left-side 10Hz, 80%



2 (+2 follow-up)2 (+2 follow-up)

BermanBerman et alet al, 2000, 2000 ParallelParallel 20 (3)20 (3) Major depressiveMajor depressive

episode (DSMÎV)episode (DSMÎV)

42.3 (10.1)42.3 (10.1) 14/614/6 Left-side, 20Hz, 80%Left-side, 20Hz, 80%



22

Garc|a-ToroGarc|¤ a-Toro et alet al, 2001, 2001bb ParallelParallel 28 (3 TMS, 3 sham)28 (3 TMS, 3 sham) Major depressionMajor depression

(DSMÎV)(DSMÎV)

TMS 43.2 (13.1).TMS 43.2 (13.1).

Sham 45.0 (18.3)Sham 45.0 (18.3)

10/1210/12 Left-side, 20Hz, 90%Left-side, 20Hz, 90%




Garc|a-ToroGarc|¤ a-Toro et alet al, 2001, 2001aa ParallelParallel 40 (3 TMS, 2 sham)40 (3 TMS, 2 sham) Major depressionMajor depression

(DSMÎV)(DSMÎV)

TMS 51.5 (15.9).TMS 51.5 (15.9).

Sham 50.0Sham 50.0

(11.0)(11.0)





GeorgeGeorge et alet al, 2000, 2000 ParallelParallel 32 (2)32 (2) Major depressionMajor depression

or bipolar disorderor bipolar disorder

(depressed phase)(depressed phase)

(DSMÎV)(DSMÎV)

44.5 (8.4)44.5 (8.4) 11/1911/19 Left-side, 5 or 20Hz,Left-side, 5 or 20Hz,

100% motor thresh-100% motor thresh-

old, 40 tps of 8 or 2 sold, 40 tps of 8 or 2 s

22

KimbrellKimbrell et alet al, 1999, 1999 Cross-overCross-over 8 (0)8 (0) Major depressionMajor depression

(DSMÎV)(DSMÎV)

42.46 (15)42.46 (15) 6/76/7 Left-side, 20Hz, 80%Left-side, 20Hz, 80%




LooLoo et alet al, 1999, 1999 ParallelParallel 18 (0)18 (0) Major depressiveMajor depressive

episode (DSMÎV)episode (DSMÎV)

TMS 45.7 (14.7).TMS 45.7 (14.7).

Sham 50.9Sham 50.9

(14.7)(14.7)




22

MosimannMosimann et alet al,,

in preparationin preparation33

ParallelParallel 24 (0)24 (0) Major depressionMajor depression

(DSMÎV)(DSMÎV)




22

KleinKlein et alet al, 1999, 1999 ParallelParallel 70 (3)70 (3) Major depressionMajor depression

(DSMÎV)(DSMÎV)

58.2 (17.2)58.2 (17.2) 17/5317/53 Right-side, 1Hz, 110%Right-side, 1Hz, 110%



22

ManesManes et alet al, 2001, 2001 ParallelParallel 20 (0)20 (0) Major or minorMajor or minor

depressiondepression

(DSMÎV)(DSMÎV)





SzubaSzuba et alet al, 2001, 2001 ParallelParallel 16 (2)16 (2) Major depressionMajor depression

(DSMÎV)(DSMÎV)

TMS 39.7 (12.1).TMS 39.7 (12.1).

Sham 33.4 (9.3)Sham 33.4 (9.3)




22

1. Left-side, left dorsolateral prefrontal cortex; right-side, right dorsolateral prefrontal cortex; tps, trains per session.1. Left-side, left dorsolateral prefrontal cortex; right-side, right dorsolateral prefrontal cortex; tps, trains per session.

2. Working days: 1week2. Working days: 1week¼5 days; 2 weeks5 days; 2 weeks¼10 days.10 days.

3. Further details available from the authors upon request.3. Further details available from the authors upon request.


the BDI. Furthermore, analysis of the re-the BDI. Furthermore, analysis of the re-

sults of those studies that tested patientssults of those studies that tested patients

at 2 weeks after the intervention periodat 2 weeks after the intervention period

showed that any differences between theshowed that any differences between the

two groups had disappeared. Equally,two groups had disappeared. Equally,

analysis of data from trials that providedanalysis of data from trials that provided

results after 1 week of treatment showedresults after 1 week of treatment showed

no significant effect.no significant effect.

Methodological considerationsMethodological considerations

The included studies all had serious meth-The included studies all had serious meth-

odological weaknesses. Of particular noteodological weaknesses. Of particular note

was the small sample size (medianwas the small sample size (median¼19), a19), a

factor that is known to introduce bias be-factor that is known to introduce bias be-

cause uncontrolled variables that may influ-cause uncontrolled variables that may influ-

ence outcomes may not be sufficientlyence outcomes may not be sufficiently

evenly distributed between treatment andevenly distributed between treatment and

control groups (Colton, 1974). In all exceptcontrol groups (Colton, 1974). In all except

three of the studies, all or a proportion ofthree of the studies, all or a proportion of

the patients (in both treatment and controlthe patients (in both treatment and control

groups) enrolled in the trials were ongroups) enrolled in the trials were on

some form of psychotropic medication.some form of psychotropic medication.

Although, in some cases, the authors statedAlthough, in some cases, the authors stated

that patients were ‘medication resistant’ thethat patients were ‘medication resistant’ the

definition of resistant was unclear and thedefinition of resistant was unclear and the

potential for concurrent medication topotential for concurrent medication to

interfere with the possible performanceinterfere with the possible performance

of the rTMS intervention cannot beof the rTMS intervention cannot be

discounted.discounted.

None of the included studies providedNone of the included studies provided

information in the published report on theinformation in the published report on the

method of allocation concealment used.method of allocation concealment used.

One of the major sources of selection biasOne of the major sources of selection bias

in randomised trials is failure to concealin randomised trials is failure to conceal

adequately the group to which a particularadequately the group to which a particular

patient has been assigned until after thatpatient has been assigned until after that

patient’s eligibility for the trial has beenpatient’s eligibility for the trial has been

assessed (Clarke & Oxman, 2001). Indeed,assessed (Clarke & Oxman, 2001). Indeed,

lack of allocation concealment has beenlack of allocation concealment has been

reported to cause more bias than otherreported to cause more bias than other

components of the allocation processcomponents of the allocation process

(Schulz(Schulz et alet al, 1995). For example, in cer-, 1995). For example, in cer-

tain RCTs the patients who are mosttain RCTs the patients who are most

likely to respond are included only inlikely to respond are included only in

the active treatment arm (Berger & Exner,the active treatment arm (Berger & Exner,

1999).1999).

The person who gives an interventionThe person who gives an intervention

such as rTMS obviously cannot be blindedsuch as rTMS obviously cannot be blinded

as to whether they are actually administer-as to whether they are actually administer-

ing the active treatment or a shaming the active treatment or a sham

intervention. It is therefore more accurateintervention. It is therefore more accurate

to consider the trials as having been singleto consider the trials as having been single

blind with an evaluation by externalblind with an evaluation by external

blinded assessors (Martin & Casado Colla-blinded assessors (Martin & Casado Colla-

do, 2002). Although, as Day (2000) hasdo, 2002). Although, as Day (2000) has

observed, blinding of outcome assessmentobserved, blinding of outcome assessment

may be more important than blinding ad-may be more important than blinding ad-

ministration, there is nevertheless potentialministration, there is nevertheless potential

for patients to guess their group allocationfor patients to guess their group allocation

through non-verbal (albeit unintentional)through non-verbal (albeit unintentional)

communication with the administrator ofcommunication with the administrator of

the intervention. A further threat to thethe intervention. A further threat to the

efficacy of the blind arises from the natureefficacy of the blind arises from the nature

of the sham intervention. As recent authorsof the sham intervention. As recent authors

have commented (Wassermann & Lisanby,have commented (Wassermann & Lisanby,

2001), depending on the way in which the2001), depending on the way in which the

sham is delivered, the physical sensationsham is delivered, the physical sensation

experienced can differ when receiving shamexperienced can differ when receiving sham

and active treatment, effectively unblindingand active treatment, effectively unblinding

the patient.the patient.

4 8 54 8 5

Table 2Table 2 Patients’medication regimens during the studiesPatients’medication regimens during the studies

EschweilerEschweiler et alet al, 2000, 200011 All patients received constant doses of at least one antidepressant, five patients also received neuroleptics, four receivedAll patients received constant doses of at least one antidepressant, five patients also received neuroleptics, four received

benzodiazepines and two received lithiumbenzodiazepines and two received lithium

PadbergPadberg et alet al, 1999, 1999 Three patients remained unmedicated. Last antidepressant was kept at a stable dose for 15 patientsThree patients remained unmedicated. Last antidepressant was kept at a stable dose for 15 patients

GeorgeGeorge et alet al, 1997, 199711 Antidepressant medication tapered for 9 patients. Three patients had experienced a partial response to a 10-week, stable-doseAntidepressantmedication tapered for 9 patients. Three patients had experienced a partial response to a 10-week, stable-dose

antidepressant trial; these regimens were continuedantidepressant trial; these regimens were continued

AveryAvery et alet al, 1999, 1999 Patients taking stable, ineffective doses of medication for at least 6 weeks continued on the same dose during the study. PatientsPatients taking stable, ineffective doses of medication for at least 6 weeks continued on the same dose during the study. Patients

on no medication for at least 6 weeks continued on no medication during the studyon no medication for at least 6 weeks continued on no medication during the study

BermanBerman et alet al, 2000, 2000 All patients free of antidepressants, neuroleptics and benzodiazepines for the week prior to initialising rTMS treatment, withAll patients free of antidepressants, neuroleptics and benzodiazepines for the week prior to initialising rTMS treatment, with

tapers beginning earlier as necessary.Chloral hydrate given when required for insomnia to in-patientstapers beginning earlier as necessary.Chloral hydrate given when required for insomnia to in-patients

Garc|a-ToroGarc|¤ a-Toro et alet al, 200, 20011bb11 All underwent 1week wash-out, off all medications. All patients started on sertraline (50mg for 2 weeks, later increased, ifAll underwent 1week wash-out, off all medications. All patients started on sertraline (50mg for 2 weeks, later increased, if

necessary, depending on clinical response) at same time as rTMS treatment. All except two taking benzodiazepines at study entrynecessary, depending on clinical response) at same time as rTMS treatment. All except two taking benzodiazepines at study entry

Garc|a-ToroGarc|¤ a-Toro et alet al, 200, 20011aa Patients had taken the same antidepressantmedication for 6 weeks before study and continued this throughout the studyPatients had taken the same antidepressantmedication for 6 weeks before study and continued this throughout the study

GeorgeGeorge et alet al, 2000, 200011 Patients free of antidepressantmedications for at least 2 weeks before study entry, three patients with bipolar disorder requiredPatients free of antidepressant medications for at least 2 weeks before study entry, three patients with bipolar disorder required

ongoingmood stabilisers or benzodiazepines for anxietyongoingmood stabilisers or benzodiazepines for anxiety

KimbrellKimbrell et alet al, 1999, 199911 Ninemedication-free patients with unipolar depression; one patient with bipolar II disorder, on lithium; three with bipolar INinemedication-free patients with unipolar depression; one patient with bipolar II disorder, on lithium; three with bipolar I

disorder, one on lithium and carbamazepine, one on lithium and lamotrigine and onemedication-free. Patients with bipolardisorder, one on lithium and carbamazepine, one on lithium and lamotrigine and onemedication-free. Patients with bipolar

disorder who had had previous relapse during a major depressive episode when onmood stabilisers remained on thesedisorder who had had previous relapse during a major depressive episode when onmood stabilisers remained on these

medicationsmedications

LooLoo et alet al, 1999, 1999 Five patients had antidepressants withdrawn 5 days before rTMS. Patients on steady doses of antidepressants failing to show anFive patients had antidepressants withdrawn 5 days before rTMS. Patients on steady doses of antidepressants failing to show an

effect weremaintained for 2 weeks before and throughout the study; nine patients received venlafaxine; four receivedeffect weremaintained for 2 weeks before and throughout the study; nine patients received venlafaxine; four received

nefazadonenefazadone

MosimannMosimann et alet al,,

in preparationin preparation22

Antidepressant medication not an exclusion criterion.Dose stable for at least 2 weeks and no new psychoactive drug startedAntidepressantmedication not an exclusion criterion.Dose stable for at least 2 weeks and no new psychoactive drug started

for at least 6 weeks before the first rTMSfor at least 6 weeks before the first rTMS

KleinKlein et alet al, 1999, 199911 Patients: none were treatment-resistant. Patients weremaintainedwith their previousmedication regimen throughout the coursePatients: nonewere treatment-resistant. Patients weremaintained with their previous medication regimen throughout the course

of the studyof the study

ManesManes et alet al, 2001, 2001 All patients werewithdrawn over 5 days from all antidepressantmedications. They were drug-free 4 days before treatmentAll patients were withdrawn over 5 days from all antidepressant medications. They were drug-free 4 days before treatment

SzubaSzuba et alet al, 2001, 200111 Patients were free of anypsychotropic medication for 7 days before study treatment (30 days for fluoxetine, monoamine oxidasePatients were free of anypsychotropic medication for 7 days before study treatment (30 days for fluoxetine, monoamine oxidase

inhibitor antidepressants or neuroleptics) or electroconvulsive treatment in the previous 30 daysinhibitor antidepressants or neuroleptics) or electroconvulsive treatment in the previous 30 days

rTMS, repetitive transcranialmagnetic stimulation.rTMS, repetitive transcranial magnetic stimulation.1. Studies without explicit inclusion criteria for medication-resistant patients.1. Studies without explicit inclusion criteria for medication-resistant patients.2. Further details available from the authors upon request.2. Further details available from the authors upon request.


Measurement of treatment outcomes inMeasurement of treatment outcomes in

depression is difficult and most clinicaldepression is difficult and most clinical

studies have made use of scales or inven-studies have made use of scales or inven-

tories, of which the most common is thetories, of which the most common is the

HRSD, based on a semi-structured inter-HRSD, based on a semi-structured inter-

view. Some authors (Hotopfview. Some authors (Hotopf et alet al, 1999), 1999)

have reported that rating scales based onhave reported that rating scales based on

semi-structured interviews are moresemi-structured interviews are more

susceptible to observation bias than aresusceptible to observation bias than are

self-applied questionnaires such as theself-applied questionnaires such as the

BDI. The lack of consistency in effect asBDI. The lack of consistency in effect as

determined by the two scales – a positivedetermined by the two scales – a positive

result after 2 weeks of treatment as mea-result after 2 weeks of treatment as mea-

sured by the HRSD and a negative resultsured by the HRSD and a negative result

for the BDI – makes definitive conclusionsfor the BDI – makes definitive conclusions

about the nature of the change in mood ofabout the nature of the change in mood of

the patients impossible. Because of diffi-the patients impossible. Because of diffi-

culties with interpreting results fromculties with interpreting results from

psychometric scales (Rosenberg, 2000)psychometric scales (Rosenberg, 2000)

and the subjective or unstable characterand the subjective or unstable character

of this psychopathology, the use of otherof this psychopathology, the use of other

more objective outcome measures such asmore objective outcome measures such as

readmissions to hospital, time to hospitalreadmissions to hospital, time to hospital

discharge, time to adjunctive treatmentdischarge, time to adjunctive treatment

4 8 64 8 6

7

TreatmentTreatment ControlControl SMD (95% CI)SMD (95% CI)

((nn)) ((nn))

One weekOne weekEschweilerEschweiler et alet al, 2000, 2000 55 55 0.00 (0.00 (771.24 to 1.24)1.24 to 1.24)

Garc|a-ToroGarc|¤ a-Toro et alet al, 2001, 2001bb 1111 1111 770.34 (0.34 (771.19 to 0.50)1.19 to 0.50)

GeorgeGeorge et alet al, 1997, 1997 77 55 770.42 (0.42 (771.58 to 0.75)1.58 to 0.75)

ManesManes et alet al, 2001, 2001 1010 1010 770.34 (0.34 (771.22 to 0.55)1.22 to 0.55)

PadbergPadberg et alet al, 1999, 1999 66 66 0.47 (0.47 (770.69 to 1.62)0.69 to 1.62)

TotalTotal 3939 37 overall effect37 overall effect 770.18 (0.18 (770.64 to 0.27),0.64 to 0.27), PP=0.4=0.4

HeterogeneityHeterogeneity ww22,, PP=0.79=0.79

One-week follow-upOne-week follow-up

(after 1week of treatment)(after 1week of treatment)

EschweilerEschweiler et alet al, 2000, 2000 55 55 0.55 (0.55 (770.73 to 1.82)0.73 to 1.82)

ManesManes et alet al, 2001, 2001 1010 1010 770.13 (0.13 (771.01 to 0.74)1.01 to 0.74)



TwoweeksTwoweeks

AveryAvery et alet al, 1999, 1999 44 22 771.02 (1.02 (772.99 to 0.94)2.99 to 0.94)

BermanBerman et alet al, 2000, 2000 1010 1010 771.30 (1.30 (772.29 to2.29 to770.32)0.32)


Garc|a-ToroGarc|¤ a-Toro et alet al, 2001, 2001aa 1717 1818 770.52 (0.52 (771.20 to 0.15)1.20 to 0.15)



KimbrellKimbrell et alet al, 1999, 1999 55 33 0.29 (0.29 (771.16 to 1.73)1.16 to 1.73)

LooLoo et alet al, 1999, 1999 99 99 770.57 (0.57 (771.52 to 0.38)1.52 to 0.38)

MosimannMosimann et alet al, in preparation, in preparation11 99 99 0.39 (0.39 (770.44 to 1.23)0.44 to 1.23)

TotalTotal 9898 77 overall effect77 overall effect 770.35 (0.35 (770.66 to0.66 to770.04),0.04), PP=0.03=0.03


Two-week follow-upTwo-week follow-up

(after 2 weeks of treatment)(after 2 weeks of treatment)






Fig. 2Fig. 2 Size of effect (remission of symptoms), in the fixed-effectmodel, of repetitive transcranial magnetic stimulation (rTMS, left localisation and high frequency),Size of effect (remission of symptoms), in the fixed-effectmodel, of repetitive transcranial magnetic stimulation (rTMS, left localisation and high frequency),

comparedwith sham rTMS for depression on the Hamilton Rating Scale for Depression; subgroup analyses by period of time. SMD, standardisedmean difference.comparedwith sham rTMS for depression on the Hamilton Rating Scale for Depression; subgroup analyses by period of time. SMD, standardisedmean difference.

1. Further details available from the authors upon request.1. Further details available from the authors upon request.


and time off work should be taken intoand time off work should be taken into

account in the assessment of rTMS in theaccount in the assessment of rTMS in the

treatment of depression.treatment of depression.

The complexity of the possible combi-The complexity of the possible combi-

nations for administering rTMS makes thenations for administering rTMS makes the

comparison of like with like particularlycomparison of like with like particularly

difficult. For our meta-analysis we cate-difficult. For our meta-analysis we cate-

gorised the three main variations ingorised the three main variations in

administration method: localisation ofadministration method: localisation of

the intervention on the skull; frequencythe intervention on the skull; frequency

given; and the duration of the treatmentgiven; and the duration of the treatment

period. In the majority of included stu-period. In the majority of included stu-

dies, rTMS was applied to the left dorso-dies, rTMS was applied to the left dorso-

lateral frontal cortex, but it has beenlateral frontal cortex, but it has been

pointed out recently that the method forpointed out recently that the method for

precisely targeting the stimulation in thisprecisely targeting the stimulation in this

area is inherently unreliable (Wassermannarea is inherently unreliable (Wassermann

& Lisanby, 2001). Evidence that this is& Lisanby, 2001). Evidence that this is

the optimal localisation is also lacking.the optimal localisation is also lacking.

With respect to the frequency given, weWith respect to the frequency given, we

classified into high (classified into high (441 Hz) and low1 Hz) and low

((441 Hz) frequency, according to custom-1 Hz) frequency, according to custom-

ary practice. Although localisation, fre-ary practice. Although localisation, fre-

quency and treatment duration were thequency and treatment duration were the

main variations, other potential differ-main variations, other potential differ-

ences in the administration of rTMS thatences in the administration of rTMS that

we did not categorise include shape ofwe did not categorise include shape of

the coil, number of trains per sessionthe coil, number of trains per session

and the duration of each train.and the duration of each train.

Data analysis considerationsData analysis considerations

In eight of the twelve studies included in theIn eight of the twelve studies included in the

meta-analysis for the HRSD and in six ofmeta-analysis for the HRSD and in six of

the seven included in the meta-analysis forthe seven included in the meta-analysis for

the BDI, the baseline mean values for thethe BDI, the baseline mean values for the

severity of depression were higher in theseverity of depression were higher in the

treatment group than in the placebo group.treatment group than in the placebo group.

Although these differences were not statisti-Although these differences were not statisti-

cally significant at the level of each indivi-cally significant at the level of each indivi-

dual study, they would have introduced adual study, they would have introduced a

potential bias within the meta-analysis ofpotential bias within the meta-analysis of

pooled data by accentuating the tendencypooled data by accentuating the tendency

for regression to the mean of the morefor regression to the mean of the more

extreme values (Davis, 1976). Our studyextreme values (Davis, 1976). Our study

was limited because individual patient datawas limited because individual patient data

were not available from all the studies andwere not available from all the studies and

an appropriate adjustment according toan appropriate adjustment according to

baseline severity was not possible. In orderbaseline severity was not possible. In order

to reduce, as much as possible, any poten-to reduce, as much as possible, any poten-

tial bias caused by these differences intial bias caused by these differences in

4 8 74 8 7

7

TreatmentTreatment ControlControl SMD (95% CI)SMD (95% CI)

((nn)) ((nn))

One weekOne week


EschweilerEschweiler et alet al, 2000, 2000 55 55 0.19 (0.19 (771.06 to 1.43)1.06 to 1.43)




TwoweeksTwo weeks





LooLoo et alet al, 1999, 1999 99 99 770.52 (0.52 (771.46 to 0.43)1.46 to 0.43)

MosimannMosimann et alet al, in preparation, in preparation11 1515 99 0.07 (0.07 (770.76 to 0.90)0.76 to 0.90)



Two-week follow-upTwo-week follow-up

(after 2 weeks of treatment)(after 2 weeks of treatment)






Fig. 3Fig. 3 Size of effect (remission of symptoms), in the fixed-effectmodel, of repetitive transcranialmagnetic stimulation (rTMS, left localisation and high frequency)Size of effect (remission of symptoms), in the fixed-effectmodel, of repetitive transcranial magnetic stimulation (rTMS, left localisation and high frequency)

comparedwith sham rTMS for depression on the Beck Depression Inventory; subgroup analyses by period of time. SMD, standardisedmean difference.1. Further detailscomparedwith sham rTMS for depression on the Beck Depression Inventory; subgroup analyses by period of time. SMD, standardisedmean difference.1.Further details

available from the authors upon request.available from the authors upon request.


baseline values, we compared final valuesbaseline values, we compared final values

on depression severity between active andon depression severity between active and

sham groups.sham groups.

Before our study, a meta-analysisBefore our study, a meta-analysis

(McNamara(McNamara et alet al, 2001) that included five, 2001) that included five

studies found demonstrable beneficial ef-studies found demonstrable beneficial ef-

fects of rTMS in depression. Our findingsfects of rTMS in depression. Our findings

differ from this earlier paper with respectdiffer from this earlier paper with respect

to the main unit of analysis: this earlierto the main unit of analysis: this earlier

study used the difference in an undefinedstudy used the difference in an undefined

rate of improvement between groups fromrate of improvement between groups from

psychometric scales used in the trials. Inpsychometric scales used in the trials. In

our meta-analysis we used the means andour meta-analysis we used the means and

standard deviations because we consideredstandard deviations because we considered

that, owing to probable baseline imbalancethat, owing to probable baseline imbalance

between the studies, these estimates reflectbetween the studies, these estimates reflect

a more precise effect size than aa more precise effect size than a

dichotomous measure such as the rate ofdichotomous measure such as the rate of

improvement apparently derived from theimprovement apparently derived from the

continuous data of the rating scales.continuous data of the rating scales.

Consequences of the weak findingsConsequences of the weak findingsabout rTMSabout rTMS

Repetitive TMS is a relatively affordableRepetitive TMS is a relatively affordable

method of applying magnetic fieldsmethod of applying magnetic fields non-non-

invasively to the human brain. If safetyinvasively to the human brain. If safety

precautions are followed, it also appearsprecautions are followed, it also appears

to be safe, at least when given within theto be safe, at least when given within the

parameters studied so far: between 1 andparameters studied so far: between 1 and

4 weeks of treatment. The non-invasive4 weeks of treatment. The non-invasive

nature of the intervention has been amongnature of the intervention has been among

the factors that have led to the impetus tothe factors that have led to the impetus to

research possible therapeutic effects in theresearch possible therapeutic effects in the

treatment of depression and especially intreatment of depression and especially in

refractory depression, because few otherrefractory depression, because few other

(and certainly no non-invasive) treatment(and certainly no non-invasive) treatment

options are currently available. The resultsoptions are currently available. The results

of our systematic review show that resultsof our systematic review show that results

to date are not very encouraging.to date are not very encouraging.

But this should not be a reason to aban-But this should not be a reason to aban-

don rTMS in affective disorders altogether.don rTMS in affective disorders altogether.

Many of the clinical treatments now usedMany of the clinical treatments now used

successfully in psychiatry have developedsuccessfully in psychiatry have developed

slowly, going through a process of initialslowly, going through a process of initial

enthusiastic approval followed by almostenthusiastic approval followed by almost

total demise and then back to sensible,total demise and then back to sensible,

widespread clinical use. Electroconvulsivewidespread clinical use. Electroconvulsive

therapy – another method of brain stimula-therapy – another method of brain stimula-

tion in affective disorders – underwent thistion in affective disorders – underwent this

very process. Evidence shows that rTMSvery process. Evidence shows that rTMS

has effects on the brain and it thereforehas effects on the brain and it therefore

has great potential as a research toolhas great potential as a research tool

(Hallett, 2000; Lisanby(Hallett, 2000; Lisanby et alet al, 2000). Data, 2000). Data

from animal studies demonstrate effectsfrom animal studies demonstrate effects

on expression of immediate early genes (Jion expression of immediate early genes (Ji

et alet al, 1998) and on neuroendocrinology, 1998) and on neuroendocrinology

(Keck(Keck et alet al, 2000), and rTMS either alone, 2000), and rTMS either alone

or combined with procedures such as func-or combined with procedures such as func-

tional neuroimaging (Speertional neuroimaging (Speer et alet al, 2000), 2000)

may be useful for testing functional connec-may be useful for testing functional connec-

tivity, neuroplasticity and information pro-tivity, neuroplasticity and information pro-

cessing. Repetitive TMS therefore can becessing. Repetitive TMS therefore can be

used to test either general hypotheses con-used to test either general hypotheses con-

cerning brain function at different levelscerning brain function at different levels

or hypotheses concerning the underlyingor hypotheses concerning the underlying

pathology of affective and other neuro-pathology of affective and other neuro-

psychiatric disorders. It is worthy of notepsychiatric disorders. It is worthy of note

that one of the only two studies includedthat one of the only two studies included

in the meta-analysis in which all the pa-in the meta-analysis in which all the pa-

tients were free of medication before andtients were free of medication before and

during the rTMS trial was also the only in-during the rTMS trial was also the only in-

dividual study that showed a statisticallydividual study that showed a statistically

significant positive effect on the HRSD forsignificant positive effect on the HRSD for

the intervention group.the intervention group.

Today, the total number of patientsToday, the total number of patients

included in studies of the efficacy ofincluded in studies of the efficacy of

rTMS in the treatment of depression fallsrTMS in the treatment of depression falls

far short of the numbers registered infar short of the numbers registered in

trials for new drug treatments. In addi-trials for new drug treatments. In addi-

tion, many technical details, such astion, many technical details, such as

where to stimulate, at what frequency,where to stimulate, at what frequency,

the total number of stimuli and thethe total number of stimuli and the

duration of the treatment, have yet to beduration of the treatment, have yet to be

resolved. There is an urgent need forresolved. There is an urgent need for

thorough, randomised, controlled, multi-thorough, randomised, controlled, multi-

centre studies involving large numberscentre studies involving large numbers

of patients. Another problem is the lackof patients. Another problem is the lack

of consensus about the possibleof consensus about the possible

explanatory mechanisms for any anti-explanatory mechanisms for any anti-

depressant effects of TMS, but this isdepressant effects of TMS, but this is

also the case for many other treatmentsalso the case for many other treatments

in psychiatry. Repetitive TMS researchin psychiatry. Repetitive TMS research

is basically empirical: many variablesis basically empirical: many variables

play a role and a large number of para-play a role and a large number of para-

meters has to be explored carefully tometers has to be explored carefully to

find the most efficacious treatment.find the most efficacious treatment.

Repetitive TMS clearly has effects onRepetitive TMS clearly has effects on

the brain, an observation that is remarkablethe brain, an observation that is remarkable

in itself and it may well be that it is ain itself and it may well be that it is a

treatment modality in search of a suitabletreatment modality in search of a suitable

application in psychiatry. It is of utmostapplication in psychiatry. It is of utmost

importance, therefore, that the long andimportance, therefore, that the long and

difficult path of research for potentialdifficult path of research for potential

clinical applications of rTMS in affectiveclinical applications of rTMS in affective

disorders should continue.disorders should continue.

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

The reviewers are grateful for the advice and sup-The reviewers are grateful for the advice and sup-port of: the Instituto de Salud Carlos III, Madrid,port of: the Instituto de Salud Carlos III, Madrid,Spain (grant number 00/10099); Xavier Bonfill andSpain (grant number 00/10099); Xavier Bonfill andMontse Sacristan from the Iberoamerican CochraneMontse Sacrista¤ n from the Iberoamerican CochraneCentre and the Service of Clinical EpidemiologyCentre and the Service of Clinical Epidemiologyand Public Health, Hospital de la Santa Creu i Santand Public Health, Hospital de la Santa Creu i SantPau (Barcelona, Spain); Natalie Khin and HughPau (Barcelona, Spain); Natalie Khin and HughMcGuire from the Cochrane Collaboration Depres-McGuire from the Cochrane Collaboration Depres-sion Neurosis and Anxiety Review Group; Alfonsosion Neurosis and Anxiety Review Group; AlfonsoCasado from 3D Health Research (Barcelona,Casado from 3D Health Research (Barcelona,Spain); Julio Sanchez Meca from the Universidad deSpain); Julio Sa¤ nchez Meca from the Universidad de

Murcia (Spain); and all the trialists who shared theirMurcia (Spain); and all the trialists who shared theirdata.data.

APPENDIX1APPENDIX 1

Studies included in the reviewStudies included in the review

Avery, D.H.,Claypoole, K., Robinson, L.,Avery, D.H.,Claypoole, K., Robinson, L., et alet al (1999)(1999)Repetitive transcranial magnetic stimulation in theRepetitive transcranial magnetic stimulation in thetreatment of medication-resistant depression:treatment of medication-resistant depression:preliminary data.preliminary data. Journal of Nervous and Mental DiseaseJournal of Nervous and Mental Disease,,8787, 114^117., 114^117.

Berman, R. M., Narasimhan, M., Sanacora,G.,Berman, R. M., Narasimhan, M., Sanacora,G., et alet al(2000)(2000) A randomized clinical trial of repetitiveA randomized clinical trial of repetitivetranscranial magnetic stimulation in the treatment oftranscranial magnetic stimulation in the treatment ofmajor depression.major depression. Biological PsychiatryBiological Psychiatry,, 4747, 332^337., 332^337.

Eschweiler,W. G.,Wegerer,C., Schlotter,W.,Eschweiler,W. G.,Wegerer,C., Schlotter,W., et alet al(2000)(2000) Left prefrontal activation predicts therapeuticLeft prefrontal activation predicts therapeuticeffects of repetitive transcranial magnetic stimulationeffects of repetitive transcranial magnetic stimulation(rTMS) in major depression.(rTMS) in major depression. Psychiatry Research^Psychiatry Research^NeuroimagingNeuroimaging,, 9999, 161^172., 161^172.

Garc|a-Toro,M., Mayol, A., Amillas,H.,Garc|¤ a-Toro, M., Mayol, A., Amillas,H., et alet al (2001(2001aa))Modest adjunctive benefit with transcranial magneticModest adjunctive benefit with transcranial magneticstimulation in medication-resistant depression.stimulation in medication-resistant depression. Journal ofJournal ofAffective DisordersAffective Disorders,, 6464, 271^275., 271^275.

__ , Pascual-Leone, A., Romera, M.,, Pascual-Leone, A., Romera, M., et alet al (2001(2001bb))Prefrontal repetitive transcranialmagnetic stimulation asPrefrontal repetitive transcranialmagnetic stimulation asadd on treatment in depression.add on treatment in depression. Journal of Neurology andJournal of Neurology andPsychiatryPsychiatry,, 7171, 546^548., 546^548.

George,M. S.,Wassermann, E.M., Kimbrell,T. A.,George,M. S.,Wassermann, E.M., Kimbrell,T. A., etetalal (1997)(1997) Mood improvement following daily leftMood improvement following daily leftprefrontal repetitive transcranial magnetic stimulation inprefrontal repetitive transcranial magnetic stimulation inpatients with depression: a placebo-controlledpatients with depression: a placebo-controlledcrossover trial.crossover trial. American Journal of PsychiatryAmerican Journal of Psychiatry,, 154154,,1752^1756.1752^1756.

__ ,Nahas, Z., Molloy, M.,, Nahas, Z., Molloy, M., et alet al (2000)(2000) A controlledA controlledtrial of daily left prefrontal cortexTMS for treatingtrial of daily left prefrontal cortexTMS for treatingdepression.depression. Biological PsychiatryBiological Psychiatry,, 4848, 962^970., 962^970.

Kimbrell,T. A., Little, J.T., Dunn, R.T.,Kimbrell,T. A., Little, J.T., Dunn, R.T., et alet al (1999)(1999)Frequency dependence of antidepressant response toFrequency dependence of antidepressant response toleft prefrontal repetitive transcranial magneticleft prefrontal repetitive transcranial magneticstimulation (rTMS) as a function of baseline cerebralstimulation (rTMS) as a function of baseline cerebralglucose metabolism.glucose metabolism. Biological PsychiatryBiological Psychiatry,, 4646, 1603^1613., 1603^1613.

Klein, E., Kreinin, I., Chistyakov, A.,Klein, E., Kreinin, I., Chistyakov, A., et alet al (1999)(1999)Therapeutic efficacy of right prefrontal slow repetitiveTherapeutic efficacy of right prefrontal slow repetitivetranscranial magnetic stimulation in major depression.transcranial magnetic stimulation in major depression.Archives of General PsychiatryArchives of General Psychiatry,, 5656, 315^320., 315^320.

Loo,C., Mitchell, P., Sachdev, P.,Loo,C., Mitchell, P., Sachdev, P., et alet al (1999)(1999) Double-Double-blind controlled investigation of transcranial magneticblind controlled investigation of transcranial magneticstimulation for the treatment of resistant majorstimulation for the treatment of resistant majordepression.depression. American Journal of PsychiatryAmerican Journal of Psychiatry,, 156156,,946^948.946^948.

Manes, F., Jorge, R., Morcuende, M.,Manes, F., Jorge, R., Morcuende, M., et alet al (2001)(2001) AAcontrolled study of repetitive transcranial magneticcontrolled study of repetitive transcranial magneticstimulation as a treatment of depression in the elderly.stimulation as a treatment of depression in the elderly.International PsychogeriatricsInternational Psychogeriatrics,, 1313, 225^231., 225^231.

Padberg, F., Zwanger, P.,Thomas,H.,Padberg, F., Zwanger, P.,Thomas,H., et alet al (1999)(1999)Repetitive transcranial magnetic stimulation (rTMS) inRepetitive transcranial magnetic stimulation (rTMS) inpharmacotherapy-refractory major depression:pharmacotherapy-refractory major depression:comparative study of fast, slow and sham rTMS.comparative study of fast, slow and sham rTMS.Psychiatry ResearchPsychiatry Research,, 8888, 163^171., 163^171.

Szuba, M. P.,O’Reardon, J. P., Rai, A. S.,Szuba, M. P.,O’Reardon, J. P., Rai, A. S., et alet al (2001)(2001)Acute mood and thyroid stimulating hormone effects ofAcute mood and thyroid stimulating hormone effects oftranscranial magnetic stimulation in major depression.transcranial magnetic stimulation in major depression.Biological PsychiatryBiological Psychiatry,, 5050, 22^27., 22^27.

4 8 84 8 8


APPENDIX 2APPENDIX 2

Studies excluded in the reviewStudies excluded in the reviewAvery^George^Hotzheimer Database of rTMS DepressionAvery^George^Hotzheimer Database of rTMS DepressionStudiesStudies. http://www.ists.unibe.ch/ists/TMSAvery.htm.. http://www.ists.unibe.ch/ists/TMSAvery.htm.

Bohning, D. E., Shastri, A., McConnell, K. A.,Bohning, D. E., Shastri, A., McConnell, K. A., et alet al(1999)(1999) A combined TMS/fMRI study of intensity-A combined TMS/fMRI study of intensity-dependent TMS over motor cortex.dependent TMS over motor cortex. Biological PsychiatryBiological Psychiatry,,4545, 385^394., 385^394.

Clark, L., McTavish, S. F. B., Harmer,C. J.,Clark, L., McTavish, S. F. B.,Harmer,C. J., et alet al(2000)(2000) Repetitive transcranial magnetic stimulation toRepetitive transcranial magnetic stimulation toright prefrontal cortex does not modulate theright prefrontal cortex does not modulate thepsychostimulant effects of amphetamine rTMS andpsychostimulant effects of amphetamine rTMS andamphetamine response.amphetamine response. International Journal ofInternational Journal ofNeuropsychopharmacologyNeuropsychopharmacology,, 33, 297^302., 297^302.

Conca, A., Koppi, S., Konig, P.,Conca, A., Koppi, S., Ko« nig, P., et alet al (1996)(1996)Transcranial magnetic stimulation: A novelTranscranial magnetic stimulation: A novelantidepressive strategy?antidepressive strategy? NeuropsychobiologyNeuropsychobiology,, 3434,,204^207.204^207.

__ , Swoboda, E., Konig, P.,, Swoboda, E., Ko« nig, P., et alet al (2000)(2000) ClinicalClinicalimpacts of single transcranial magnetic stimulationimpacts of single transcranial magnetic stimulation(sTMS) as an add-on therapy in severely depressed(sTMS) as an add-on therapy in severely depressedpatients under SSRI treatment.patients under SSRI treatment. HumanHumanPsychopharmacology ^ Clinical and ExperimentalPsychopharmacology ^ Clinical and Experimental,, 1515,,429^438.429^438.

D’Alfonso, A. A. L.,Van Honk, J., Hermans, E.,D’Alfonso, A. A. L.,Van Honk, J., Hermans, E., et alet al(2000)(2000) Laterality effects in selective attention to threatLaterality effects in selective attention to threatafter repetitive transcranial magnetic stimulation at theafter repetitive transcranial magnetic stimulation at theprefrontal cortex in female subjects.prefrontal cortex in female subjects. NeuroscienceNeuroscienceLettersLetters,, 280280, 195^198., 195^198.

Eichhammer, P., Kharraz, A.,Wiegand, R.,Eichhammer, P., Kharraz, A.,Wiegand, R., et alet al(2002)(2002) Sleep deprivation in depression stabilizingSleep deprivation in depression stabilizingantidepressant effects by repetitive transcranialantidepressant effects by repetitive transcranialmagnetic stimulation.magnetic stimulation. Life SciencesLife Sciences,, 7070, 1741^1749., 1741^1749.

Epstein,C. M., Figiel,G. S., Mcdonald,W. M.,Epstein,C. M., Figiel, G. S., Mcdonald,W. M., et alet al(1998)(1998) Rapid rate transcranial magnetic stimulation inRapid rate transcranial magnetic stimulation inyoung and middle-aged refractory depressed patients.young and middle-aged refractory depressed patients.Psychiatric AnnalsPsychiatric Annals,, 2828, 36^39., 36^39.

Feinsod, M., Kreinin, B., Chistyakov, A.,Feinsod, M., Kreinin, B., Chistyakov, A., et alet al (1998)(1998)Preliminary evidence for a beneficial effect of low-Preliminary evidence for a beneficial effect of low-frequency, repetitive transcranial magnetic stimulationfrequency, repetitive transcranial magnetic stimulationin patients with major depression and schizophrenia.in patients with major depression and schizophrenia.Focus on Depression and AnxietyFocus on Depression and Anxiety,, 77, 65^68., 65^68.

Figiel,G. S., Epstein,C., Mcdonald,W.M.,Figiel,G. S., Epstein,C., Mcdonald,W.M., et alet al (1998)(1998)The use of rapid-rate transcranial magnetic stimulationThe use of rapid-rate transcranial magnetic stimulation(rTMS) in refractory depressed patients.(rTMS) in refractory depressed patients. NeuroscienceNeuroscience,,1010, 20^25., 20^25.

Garc|a, M., Mico, J., Cresp|, M.,Garc|¤ a, M., Mico¤ , J., Cresp|¤ , M., et alet al (1998)(1998)Estimulacion magnetica transcraneal repetitiva: unaEstimulacio¤ n magne¤ tica transcraneal repetitiva: unanueva intervencion neurobiologica buscando un lugar ennueva intervencio¤ n neurobiolo¤ gica buscando un lugar enpsiquiatr|a. A proposito de cinco casos.psiquiatr|¤a. A propo¤ sito de cinco casos. Psqiuiatr|a.COMPsqiuiatr|¤a.COM,,http://www.psiquiatria.com/psiquiatria/vol2num2/http://www.psiquiatria.com/psiquiatria/vol2num2/art__9.htmart__9.htm

Geller,V., Grisaru,N., Abarbanel, J. M.,Geller,V., Grisaru, N., Abarbanel, J. M., et alet al (1997)(1997)Slow magnetic stimulation of prefrontal cortex inSlow magnetic stimulation of prefrontal cortex indepression and schizophrenia.depression and schizophrenia. Progress inProgress inNeuropsychopharmacology and Biological PsychiatryNeuropsychopharmacology and Biological Psychiatry,, 2121,,105^110.105^110.

George,M. S.,Wassermann, E.M.,Williams,W. A.,George, M. S.,Wassermann, E.M.,Williams,W. A., etetalal (1995)(1995) Daily repetitive transcranial magneticDaily repetitive transcranial magneticstimulation (rTMS) improves mood in depression.stimulation (rTMS) improves mood in depression.NeuroreportNeuroreport,, 66, 1853^1856., 1853^1856.

__ ,,__ ,, __ ,, et alet al (1996)(1996)ChangesinmoodandhormoneChangesinmoodandhormonelevels after rapid-rate transcranial magnetic stimulationlevels after rapid-rate transcranial magnetic stimulation(rTMS) of the prefrontal cortex.(rTMS) of the prefrontal cortex. Journal ofJournal ofNeuropsychiatry and Clinical NeurosciencesNeuropsychiatry and Clinical Neurosciences,, 88, 172^180., 172^180.

__ , Speer, A. M., Molloy, M.,, Speer, A. M., Molloy, M., et alet al (1998)(1998) LowLowfrequency daily left prefrontal rTMS improves mood infrequency daily left prefrontal rTMS improves mood inbipolar depression: a placebo-controlled case report.bipolar depression: a placebo-controlled case report.Human PsychopharmacologyHuman Psychopharmacology,, 1313, 271^275., 271^275.

__ , Lisanby, S.H. & Sackeim,H. A. (1999, Lisanby, S.H. & Sackeim,H. A. (1999aa))Transcranial magnetic stimulation: applications inTranscranial magnetic stimulation: applications inneuropsychiatry.neuropsychiatry. Archives of General PsychiatryArchives of General Psychiatry,, 5656,,300^311.300^311.

__ ,Nahas, Z., Kozel, F. A.,, Nahas, Z., Kozel, F. A., et alet al (1999(1999bb))Improvement of depression following transcranialImprovement of depression following transcranialmagnetic stimulation.magnetic stimulation. Current Psychiatry ReportsCurrent Psychiatry Reports,, 11,,114^124.114^124.

Grisaru,N.,Chudakov, B.,Yaroslavsky,Y.,Grisaru,N.,Chudakov, B.,Yaroslavsky,Y., et alet al (1998)(1998)Transcranial magnetic stimulation in mania: a controlledTranscranial magnetic stimulation in mania: a controlledstudy.study. American Journal of PsychiatryAmerican Journal of Psychiatry,, 155155, 1608^1610., 1608^1610.

Grunhaus, L., Dannom, P.N., Schreiber, S.,Grunhaus, L., Dannom, P.N., Schreiber, S., et alet al(2000)(2000) Repetitive transcranialmagnetic stimulation is anRepetitive transcranialmagnetic stimulation is aneffective electroconvulsive therapy in the treatment ofeffective electroconvulsive therapy in the treatment ofnondelusional major depressive disorder: an open study.nondelusional major depressive disorder: an open study.Biological PsychiatryBiological Psychiatry,, 4747, 314^324., 314^324.

Habel,U.,Wild, B.,Topka,H.,Habel,U.,Wild, B.,Topka,H., et alet al (2001)(2001) TranscranialTranscranialmagnetic stimulation: no effect on mood with singlemagnetic stimulation: no effect on mood with singlepulse during learned helplessness.pulse during learned helplessness. Progress inProgress inNeuropsychopharmacology and Biological PsychiatryNeuropsychopharmacology and Biological Psychiatry,, 2525,,497^506.497^506.

Hansen, P. E. B. (2000)Hansen, P. E. B. (2000) Repetitivemagnetic stimulationRepetitivemagnetic stimulationin the treatment of depression. A review [Repetitivin the treatment of depression. A review [Repetitivtranskranial magnetisk stimulation].transkranial magnetisk stimulation]. Ugeskrift for L�gerUgeskrift for L�ger,,162162, 2310^2313., 2310^2313.

Hoflich,G., Kasper, S., Hufnagel, A.,Ho« flich, G., Kasper, S., Hufnagel, A., et alet al (1993)(1993)Application of transcranial magnetic stimulation inApplication of transcranial magnetic stimulation intreatment of drug-resistant major depression ^ atreatment of drug-resistant major depression ^ areport of two cases.report of two cases. Human PsychopharmacologyHuman Psychopharmacology,, 88,,361^365.361^365.

Kolbinger,H. M.,Hoflich, G.,Hufnagel,H.,Kolbinger,H. M.,Ho« flich, G.,Hufnagel,H., et alet al(1995)(1995) Transcranial magnetic stimulation (TMS) in theTranscranial magnetic stimulation (TMS) in thetreatment of major depression ^ a pilot study.treatment of major depression ^ a pilot study. HumanHumanPsychopharmacologyPsychopharmacology,, 1010, 305^310., 305^310.

Koppi, S., Conca, A., Swoboda, E.,Koppi, S.,Conca, A., Swoboda, E., et alet al (1997)(1997)Transcranial magnetic stimulation ^ new antidepressiveTranscranial magnetic stimulation ^ new antidepressivetherapy? [Transkranielle magnetstimulation ^ einetherapy? [Transkranielle magnetstimulation ^ eineneue antidepressive therapie?].neue antidepressive therapie?]. Psychiatria DanubinaPsychiatria Danubina,, 99,,83^88.83^88.

Kozel, F. A.,Nahas, Z., deBrux,C.,Kozel, F. A.,Nahas, Z., deBrux,C., et alet al (2000)(2000) HowHowcoil^cortex distance relates to age, motor threshold,coil^cortex distance relates to age, motor threshold,and antidepressant response to repetitive transcranialand antidepressant response to repetitive transcranialmagnetic stimulation.magnetic stimulation. Journal of Neuropsychiatry andJournal of Neuropsychiatry andClinical NeurosciencesClinical Neurosciences,, 1212, 376^384., 376^384.

Krystal, A. D.,West, M., Prado, R.,Krystal, A. D.,West, M., Prado, R., et alet al (2000)(2000) EEGEEGeffects of ECT: implications for rTMS.effects of ECT: implications for rTMS. Depression andDepression andAnxietyAnxiety,, 1212, 157^165., 157^165.

Little, J.T., Kimbrell,T. A.,Wassermann, E. M.,Little, J.T., Kimbrell,T. A.,Wassermann, E. M., et alet al(2000)(2000) Cognitive effects of 1- and 20-hertz repetitiveCognitive effects of 1- and 20-hertz repetitivetranscranial magnetic stimulation in depression:transcranial magnetic stimulation in depression:preliminary report.preliminary report. Neuropsychiatry, NeuropsychologyNeuropsychiatry, Neuropsychologyand Behavioral Neurologyand Behavioral Neurology,, 1313, 119^124., 119^124.

Loo,C. K.,Taylor, J. L., Gandevia, S. C.,Loo,C. K.,Taylor, J. L., Gandevia, S. C., et alet al (2000)(2000)Transcranial magnetic stimulation (TMS) in controlledTranscranial magnetic stimulation (TMS) in controlledtreatment studies: are some‘sham’ forms active?treatment studies: are some‘sham’ forms active?Biological PsychiatryBiological Psychiatry,, 4747, 325^331., 325^331.

__ , Sachdev, P., Elsayed,H.,, Sachdev, P., Elsayed,H., et alet al (2001)(2001) Effects ofEffects of2- to 4-week course of repetitive transcranial magnetic2- to 4-week course of repetitive transcranial magneticstimulation (rTMS) on neuropsychologic functioning,stimulation (rTMS) on neuropsychologic functioning,electroencephalogram, and auditory threshold inelectroencephalogram, and auditory threshold indepressed patients.depressed patients. Biological PsychiatryBiological Psychiatry,, 4949, 615^623., 615^623.

Markwort, S.,Cordes, P. & Aldenhoff, J. (1997)Markwort, S., Cordes, P. & Aldenhoff, J. (1997)Transcranial magnetic stimulation as a therapeuticTranscranial magnetic stimulation as a therapeuticalternative to electroconvulsive therapy in therapy-alternative to electroconvulsive therapy in therapy-resistant depressions [Die transkranielle magnetresistant depressions [Die transkranielle magnetstimulation als behandlungs alternative zurstimulation als behandlungs alternative zurelektrokrampf therapie bei therapieresistentenelektrokrampf therapie bei therapieresistentendepressionen].depressionen]. Fortschritte Neurologie, Psychiatrie undFortschritte Neurologie, Psychiatrie undIhrer GrenzgebieteIhrer Grenzgebiete,, 6565, 540^549., 540^549.

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4 9 04 9 0

CLINICAL IMPLICATIONSCLINICAL IMPLICATIONS

&& The findings from this systematic review andmeta-analysis provide insufficientThe findings from this systematic review andmeta-analysis provide insufficientevidence to suggest that repetitive transcranialmagnetic stimulation (rTMS) isevidence to suggest that repetitive transcranialmagnetic stimulation (rTMS) iseffective in the treatment of depression.effective in the treatment of depression.

&& There are several confounding factors in the included studies that shouldbekept inThere are several confounding factors in the included studies that shouldbekept inmind before considering rTMS for clinical use.mind before considering rTMS for clinical use.

&& The rTMS technique needsmore high-quality trials to show its effectiveness forThe rTMS technique needsmore high-quality trials to show its effectiveness fortherapeutic use.therapeutic use.

LIMITATIONSLIMITATIONS

&& Lack of pragmatic variables in the studies, such as time to further treatment, timeLack of pragmatic variables in the studies, such as time to further treatment, timeoff work, readmission to hospital or hospital discharge.off work, readmission to hospital or hospital discharge.

&& Individual patient data from all the studies were not available and an appropriateIndividual patient data from all the studies were not available and an appropriateadjustment according to baseline severity thereforewas not possible.adjustment according to baseline severity thereforewas not possible.

&& Poor follow-up evaluation in the studies.Poor follow-up evaluation in the studies.

JOSE LUIS R.MARTIN,MPsychSc, Iberoamerican Cochrane Centre,Hospital de la Santa Crue i Sant Pau,JOSE¤ LUIS R.MARTIN,MPsychSc, Iberoamerican Cochrane Centre,Hospital de la Santa Crue i Sant Pau,Barcelona, Spain; MANUEL J.BARBANOJ,MD,Department of Pharmacology,Hospital de la Santa Creu i SantBarcelona, Spain; MANUEL J.BARBANOJ,MD,Department of Pharmacology,Hospital de la Santa Creu i SantPau,Barcelona, Spain;THOMAS E. SCHLAEPFER,MD,University Hospital Bern, Switzerland and The JohnsPau,Barcelona, Spain;THOMAS E. SCHLAEPFER,MD,University Hospital Bern, Switzerland and The JohnsHopkins University,Baltimore,Maryland,USA; ELINORTHOMPSON,MB, Iberoamerican Cochrane Centre,Hopkins University,Baltimore,Maryland,USA; ELINORTHOMPSON,MB, Iberoamerican Cochrane Centre,Hospital de la Santa Creu i Sant Pau,Barcelona, Spain;VICTOR PEREZ,MD,Department of Psychiatry,HospitalHospital de la Santa Creu i Sant Pau,Barcelona, Spain;VI¤CTOR PE¤ REZ,MD,Department of Psychiatry,Hospitalde la Santa Creu i Sant Pau,Barcelona, Spain; JAIMEKULISEVSKY,MD,Department of Neurology,Hospital de lade la Santa Creu i Sant Pau,Barcelona, Spain; JAIMEKULISEVSKY,MD,Department of Neurology,Hospital de laSanta Creu i Sant Pau,Barcelona, SpainSanta Creu i Sant Pau,Barcelona, Spain

Correspondence: Jose Luis Rodr|guez Martin,Centro Cochrane Iberoamericano, Servei d’EpidemiologiaCorrespondence: Jose¤ Luis Rodr|¤ guez Martin,Centro Cochrane Iberoamericano, Servei d’EpidemiologiaCl|nica i Salut Publica,Hospital de la Santa Creu i Sant Pau,Universidad Autonoma de Barcelona UAB,Cl|¤ nica i Salut Pu¤ blica,Hospital de la Santa Creu i Sant Pau,Universidad Auto¤ noma de Barcelona UAB,Casa de Convalescencia,C/171Sant Antoni MCasa de Convalesce' ncia,C/171Sant Antoni Maa Claret,Barcelona 08041, Spain.E-mail:Claret,Barcelona 08041, Spain.E-mail:jrodriguezmajrodriguezma@@hsp.santpau.eshsp.santpau.es

(First received 2 August 2002, final revision 11November, 2002, accepted 3 December 2002)(First received 2 August 2002, final revision 11November, 2002, accepted 3 December 2002)


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Repetitive transcranial magnetic stimulation for the ...€¦ · 1998). For continuous data the studies included in the pooled analysis were tested for statistical homogeneity using