Corresponde

N, IOP, 67 Presi

E-mail addre

Submitted Ju

1935-861X/09/$

doi:10.1016/j.br

Brain Stimulation (2009) 2, 14–21

Controversy: Repetitive transcranial magnetic stimulationor transcranial direct current stimulation shows efficacyin treating psychiatric diseases (depression, mania,schizophrenia, obsessive-complusive disorder, panic,posttraumatic stress disorder)

Mark S. George, MDa, Frank Padberg, MDb, Thomas E. Schlaepfer, MDc,d,John P. O’Reardon, MDe, Paul B. Fitzgerald, MBBS, MPM, PhD, FRANZCPf,Ziad H. Nahas, MDa, Marco A. Marcolin, MDg

aBrain Stimulation Laboratory, Psychiatry Department, Medical University of South Carolina, Charleston, South CarolinabDepartment of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich, Munich, GermanycDepartment of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, GermanydDepartments of Psychiatry and Mental Health, The Johns Hopkins University, Baltimore, MarylandeNeuromodulation Treatment & Research Program, Department of Psychiatry, University of Pennsylvania, Philadelphia,PennsylvaniafAlfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology, Psychiatry andPsychological Medicine, Victoria, AustraliagNeuromodulation Research Lab, Psychiatry Department, University of Sao Paulo, SP, Brazil

Brain imaging studies performed over the past 20 years have generated new knowledge about thespecific brain regions involved in the brain diseases that have been classically labeled as psychiatric.These include the mood and anxiety disorders, and the schizophrenias. As a natural next step, clinicalresearchers have investigated whether the minimally invasive brain stimulation technologies (trans-cranial magnetic stimulation [TMS] or transcranial direct current stimulation [tDCS]) might potentiallytreat these disorders. In this review, we critically review the research studies that have examined TMSor tDCS as putative treatments for depression, mania, obsessive-complusive disorder, posttraumaticstress disorder, panic disorder, or schizophrenia. (Separate controversy articles deal with using TMS ortDCS to treat pain or tinnitus. We will not review here the large number of studies using TMS or tDCSas research probes to understand disease mechanisms of psychiatric disorders.) Although there is anextensive body of randomized controlled trials showing antidepressant effects of daily prefrontal

nce and reprint requests: Dr. Mark George, Brain Stimulation Laboratory, Department of Psychiatry,

dent St, Charleston, SC 29425.

ss: georgem@musc.edu

ne 6, 2008. Accepted for publication June 6, 2008.

-see front matter � 2009 Elsevier Inc. All rights reserved.

s.2008.06.001

www.brainstimjrnl.com

Medical University of South Carolina, 502

rTMS or tDCS in treatment of psychiatric diseases 15

repetitive TMS, the magnitude or durability of this effect remains controversial. US Food and DrugAdministration approval of TMS for depression was recently granted. There is much less data in allother diseases, and therapeutic effects in other psychiatric conditions, if any, are still controversial.Several issues and problems extend across all psychiatric TMS studies, including the optimal methodfor a sham control, appropriate coil location, best device parameters (intensity, frequency, dosage, anddosing schedule) and refining what subjects should be doing during treatment (activating pathologiccircuits or not). In general, TMS or tDCS as a treatment for most psychiatric disorders remains excitingbut controversial, other than prefrontal TMS for depression.� 2009 Elsevier Inc. All rights reserved.

Keywords TMS; tDCS; depression; schizophrenia; clinical trials

Both transcranial magnetic stimulation (TMS)1 andtranscranial direct current stimulation (tDCS) are remark-able new tools for investigating brain function.2 Each tech-nique can be safely applied in awake alert adults, and bothtechniques have been shown to quickly alter neuronal func-tion both directly underneath the coil and in connectedbrain regions.1,3-7 However, both interventions also clearlydiffer regarding their mode of action. Although both in-volve focal electromagnetic fields, TMS leads to depolari-zation of neurons at least when applied near or abovemotor threshold intensities, whereas tDCS is thought tomildly shift membrane potentials toward hyperpolarizationor depolarization.

Researchers have enthusiastically adopted TMS andtDCS as research tools, using these techniques safely toexcite or inhibit a brain region both in healthy volunteersand patients, and then examine the effects of focal brainstimulation on a behavior or symptom. Thus, TMS andtDCS are powerful new research tools in psychiatry,complementing and building on brain imaging studies.8 Areview of research studies in psychiatry using TMS ortDCS as probes is beyond the scope of this review.1 Rather,this review focuses on treatment trials in psychiatry usingeither TMS or tDCS. Diseases such as tinnitus, stroke,epilepsy, and dementia in which these techniques are beingresearched are excluded from this review either becausethese diseases are not classically considered ‘‘psychiatric,’’or consensus or controversy papers regarding several ofthese conditions are discussed in separate reviews. In thisarticle, we examine the controversy of whether these twobrain stimulation technologies (TMS or tDCS) are effica-cious for treating depression, mania, the anxiety disorders(obsessive-complusive disorder [OCD], panic, posttrau-matic stress disorder [PTSD]), or the schizophrenias.

Depression

TMS

Far and away the most research with TMS as a potentialtreatment has been its use as an acute treatment fordepression. It is interesting to speculate why there has

been so much work in depression, as there are clearly otherdiseases with better defined neuroanatomy and pathophys-iology. Some have argued that TMS therapeutics shouldhave been tested first in these other diseases and then laterexpanded to depression.9 One factor that contributes to theenthusiasm for using TMS in depression is the example ofelectroconvulsive therapy (ECT), where intermittent focalstimulation is the most effective treatment available.10-13

The initial work studying TMS in depression14-17 followedon the heels of the precedent of ECT as an effective brainstimulation technique for treating acute depression. EarlyTMS depression researchers questioned whether a seizureinduced by ECT was necessary, per se, for a brain stimula-tion technique to treat depression.18 This followed the pio-neering ECT studies in the early 1990s showing thatalthough a seizure was necessary for ECT to work, it alonewas not sufficient. For example, seizures induced withparietal cortex stimulation had no therapeutic effect.19 Al-though a seizure, in the right location, was critical forECT to treat depression, early researchers argued that per-haps one could focally stimulate important mood regulatingbrain regions with TMS without inducing a seizure and stillproduce an antidepressant effect.18,20 There was alsoemerging brain imaging evidence that the prefrontal cortexis dysregulated in depressed patients,21-25 and that theprefrontal cortex is shut off after ECT.2,26-28 These ECTfindings contributed to the theory that corticosubcorticalregulatory networks might be dysfunctional in depres-sion.29 Thus, early TMS depression studies were launchedattempting to reset corticolimbic governance.20,30-33 Manyof these initial studies, especially those in treatment-resis-tant patients in controlled settings, found a small but statis-tically significant antidepressant effect.34-37 Initial studieswere limited in both dosage and length of treatment, butmore recent studies have begun using TMS in a mannersuch as medications or ECT, that is, given almost dailyover 4-6 weeks. After initial enthusiasm, many small sam-ple studies were launched around the world that weredesigned modeling a study that has not replicated.38 Pre-frontal repetitive TMS (rTMS) as an antidepressant requiresat least several weeks for clinical effects to appear, and maynot work very well in psychotic depression. These small,

16 M.S. George et al

investigator-initiated trials attempting to replicate thatstudy were largely negative and the initial enthusiasm forTMS as an antidepressant quickly dissolved and was re-placed with skepticism.

However, many groups did find small effect sizes andthe research with TMS as a potential antidepressant con-tinued. To date, more than 35 individual randomized,placebo-controlled clinical trials, including more than1200 patients who had major depressive episodes havebeen conducted investigating the safety and efficacy ofrTMS as an antidepressant. Most of these studies used TMSin patients who were not taking medications. In themajority of these trials, especially those with reasonablesample sizes (.40) and in which treatment was given for atleast two weeks, investigators found significant differencesbetween active TMS and sham, with antidepressant effectsranging from modest to substantial. Many of the initialtrials had rather small sample sizes, incomplete shamdevices and short observation periods (2 weeks or less).Effect sizes seen in these earlier studies are smaller than inmore recent trials with larger samples, which used bettersham conditions, and used a longer duration of treatment.39

Numerous meta-analyses of these studies have been con-ducted.40-44 Most of these meta-analyses support the anti-depressant efficacy of rTMS, but the clinical effect sizesare modest and the ultimate clinical significance remainsunclear and is still controversial. Herrmann and Ebmeier’srecent analysis44 included 33 individual trials with 877 pa-tients and found rTMS to be more effective than shamrTMS, with a large effect size of 0.71. The average reduc-tion of depression scores after active rTMS was 33.6%compared with 17.4% after sham rTMS. The best predic-tion of a clinical response was achieved with stimulation in-tensities R90% of the resting motor threshold. Despite thepositive outcome of this meta-analysis, the authors arguethat their difficulty in identifying optimal treatment proto-cols points to a potentially nonspecific action of rTMS. In-deed, there is only preliminary data on dose/parameterresponse relations, namely, some evidence that a higher in-tensity or longer duration may lead to improved therapeuticeffects.37,45,46 Even more limited is the knowledge aboutoptimal frequency parameters and whether this should beindividualized or follow specific schedules of stimulation.

Despite the gradually accumulating body of evidenceemerging from many small investigator-initiated studiesfrom around the world, many skeptics argued that there wasno large multisite trial of TMS as an antidepressant similarto those used in the pharmaceutical world to assess theefficacy of antidepressant medications. Recently one TMSequipment manufacturer, Neuronetics, organized and con-ducted such a double-blind, multisite study, including 301medication-free patients with major depression who hadnot benefited from prior treatment and who were thenrandomly assigned to either active (n 5 155) or sham TMS(n 5 146) conditions.47 TMS sessions were conducted fivetimes per week at 10 pulses per second, 120% of motor

threshold, 3000 pulses per session, for 4-6 weeks. ActiveTMS was significantly superior to sham TMS at weeks 4and 6. Response rates were significantly higher with activeTMS on all three scales at weeks 4 and 6 (around 25% byweek 6). Remission rates were approximately twofoldhigher at week 6, with active TMS showing 16% remissionvs 9% with sham treatment. Active TMS was well toleratedwith a low dropout rate for adverse events (4.5%) that weregenerally mild and limited to transient scalp discomfort orpain. This trial was the basis of a Food and Drug Adminis-tration (FDA) approval and found an effect size for TMS(0.55 on the 17-item Hamilton Depression Rating Scale)that is similar to FDA-approved antidepressant medicationsbut lower than that observed with ECT, in which responserates range from 60-90%. An open-label extension of thistrial found a 46% response rate, which varied as a functionof the level of treatment resistance, with more treatmentresistant patients having poorer response.48

More recent studies have focused on examining thebest prefrontal location for stimulating (Fitzgerald, writtenpersonal communication, May 2008), experimenting withincreasing the dose or priming the TMS effects,45,49,50 orstimulating both left and right hemispheres.45,51

Controversy

As presented thus far, TMS as a treatment for depressionseems noncontroversial and rather straightforward. How-ever, substantial skepticism persists. For example, the UKNational Institute for Health and Clinical Excellence(NICE) report recently (November 2007) concluded thatTMS has not been shown to be effective for treatingdepression. They wrote, ‘‘There is uncertainty about theprocedure’s clinical efficacy, . TMS should therefore beperformed only in research studies.’’. Other skepticsargue that the large industry sponsored trial might havebias, and that it was not statistically significant without apost hoc correction. A particularly troubling criticism of thefield is that all TMS studies to date have required a trainedTMS operator to stand beside the patient during the 30- to50-minute treatment session every day. This operatorknows whether the patient is receiving active or shamtreatment and is thus in a position to potentially influencethe outcome, even unconsciously. In addition, the shamcoils used in many studies were either inadequate52 or po-tentially active,53 and investigators have not routinely re-ported the success or failure of their attempt to blindsubjects and their raters. So, using a very strict definition,some would argue that there still has never been a true mul-tisite randomized adequately sham-controlled trial of TMSin depression. One such trial is now underway, funded bythe National Institute of Mental Health (NIMH), with re-sults expected to be available in 2009. This trial, termedthe Optimization of TMS for the Treatment of Depression(OPT-TMS) trial, uses a ‘‘new active sham’’ techniqueand a true double-masked method in which no one who

rTMS or tDCS in treatment of psychiatric diseases 17

knows the status of the patient ever encounters the patientor their data.54,55

Other areas of controversy include the lack of definitiveinformation about how long the antidepressant effects ofTMS last after the acute episode, whether TMS can be usedin a maintenance fashion to prevent depression relapses,56-59

and whether TMS can be used in conjunction with medica-tions as an adjunctive treatment. In general, it takes largersample sizes to show an adjunctive effect of a treatment.The studies have been mixed, which examined TMS addedto patients who are still on medications, or where TMS isstarted simultaneous with new medications.60

Studies investigating prefrontal TMS for bipolar depres-sion are similarly mixed, with only a few positive studies61

and several negative trials.62 Because the baseline moodchanges more quickly as patients cycle into and out of adepression naturally, in general, it takes larger samples toshow effects in bipolar patients.

Another area of controversy involves the issue whetherTMS works as an antidepressant in elderly patients. Anearly trial failed to find antidepressant responses in patientsolder than age 60.63 This was particularly disappointing asECT works very well in elderly depressed patients who aresensitive to medication side effects. Researchers wonderedwhether the lack of TMS effect might be caused by in-creased prefrontal atrophy, with older subjects needinghigher intensities of stimulation to overcome the greaterdistance.64-67 More recent studies in which this distancehas been adjusted for in determining the TMS dose havefound clinically significant effects.68 In fact, a most recenttrial in elderly patients with vascular depression foundrobust clinically significant effects over sham.69

One final area of controversy revolves around how theTMS coil has been positioned to theoretically stimulate theprefrontal cortex. An early algorithm called the ‘‘5-cm rule’’has been used in almost all studies to date. Researchers havefound, however, that this algorithm positions the coil overpremotor and not prefrontal cortex in almost one-third ofsubjects, depending on their motor cortex location and skullsize.70 More recent studies are adopting placement algo-rithms that will hopefully overcome this limitation.71

tDCS

There have only been two small single-site trials of tDCS indepression.72,73 These are promising but in no way defini-tive. More information may emerge at the October 2008Gottingen meeting.

Mania

Several sessions of ECT are often effective at rapidlyreducing the symptoms of mania.74-77 Thus, it was hopedthat TMS might also prove useful in treating mania.78-80 Inaddition, there are some reports in which prefrontal TMS

was being used as an antidepressant when it actually trig-gered mania, especially in bipolar depressed patients.81

Thus, if ECT can treat both depression and mania, and TMScan treat depression and induce hypomania, could TMS, prop-erly applied, also treat mania? An early study was promising.Researchers applied daily TMS for 10 days to either the rightor the left prefrontal cortex in hospitalized manic patientswho were also treated with the usual standard of care.82

The patients with right-sided treatment responded more rap-idly than did those treated on the left side, although therewere group differences at baseline that might have explainedor contributed to the difference. Unfortunately, a follow-upstudy by this group failed to replicate this finding.83

There are no reports to date of using tDCS to treatmania.

OCD

OCD has a fairly well-established functional neuroanatomyinvolving the basal ganglia and orbitofrontal cortex. Thisknown anatomy has been confirmed and refined by modernneuroimaging,84-86 but for many decades this circuitryserved as the basis of ablative brain surgery for the disorder.With a known pathologic circuit involving cortical regionsthat are dysfunctional, and a history of ablative surgery asan effective treatment, early researchers hoped that focalprefrontal TMS might help with OCD symptoms. The firstTMS study was less of a treatment study than a challengestudy in which OCD patients received only 1 day of rightprefrontal TMS or sham, and then rated their symptoms.87

Twelve OCD patients were given TMS (80% motor thresh-old, 20 Hz/2 seconds per minute for 20 minutes) to a rightlateral prefrontal, a left lateral prefrontal, and a midoccipi-tal (control) site on separate days, randomly. The patients’symptoms and mood were rated for 8 hours afterward.There was a significant reduction in compulsive urges afterthe right prefrontal stimulation. A double-blind treatmentstudy in 18 OCD patients found a mathematical differencein symptoms in favor of active treatment.8 There were tworesponders in the active group and none in the sham group.There has also been a positive study of TMS over the sup-plemental motor area in patients with OCD and Tourette’ssyndrome.89 Although these studies are promising, theirsmall sample sizes and single site status leave this area sub-ject to controversy.

PTSD

There has been intense interest regarding whether TMSmight help with PTSD symptoms. As in other psychiatricdisorders, initial case series90,91 and then small studiesshowed promise, but there have been negative publishedand unpublished data as well.92 This area remains quitecontroversial.

18 M.S. George et al

Panic disorder

Despite a positive case report and open pilot trial,93,94 a re-cent small placebo-controlled trial showed no significantaction of 1 Hz rTMS compared wth sham treatment.95

Schizophrenia

Many clinicians and researchers are now referring to thedisease ‘‘schizophrenia’’ as the group of diseases called‘‘the schizophrenias.’’8 This naming convention parallelsthe method of referring to ‘‘the epilepsies,’’ in whichmany different pathophysiologies are present, all of whichresult in a seizure. In the schizophrenias, there is wide var-iation in symptoms, with different patients having more orless blunting and social isolation (so-called negative symp-toms), or auditory hallucinations and thoughts of paranoia,or problems with attention and concentration. Most re-searchers who have used TMS as a potential treatmentfor ‘‘the schizophrenias’’ have chosen to focus on a specificsubset, and then apply TMS in a targeted way that matchesthe disease, and report outcome with respect to the specificbehavior. Thus, rather than saying ‘‘TMS works for schizo-phrenia,’’ it is more appropriate to say, ‘‘TMS has beenshown to reduce XX symptoms in patients with schizophre-nia who exhibit these symptoms.’’8

Hallucinations

Auditory hallucinations are part of the positive symptoms ofschizophrenia. These types of hallucinations are believed toresult from aberrant activation of the language perceptionarea at the junction of the left temporal and parietal cortices.8

Researchers hypothesized that low-frequency TMS couldpotentially inhibit this area in patients with schizophreniaand provide relief from auditory hallucinations.96-100

A recent meta-analysis looked at the efficacy oflow-frequency TMS as a treatment of resistant auditoryhallucinations in schizophrenia.101 The authors found 10sham-controlled studies incorporating 212 patients. Theirreview concluded that slow-frequency TMS over the tem-poroparietal junction was effective in reducing auditoryhallucinations. Unfortunately, TMS had no effect on otherpositive symptoms or the cognitive deficits of schizophre-nia. Larger studies are needed to definitely establish theefficacy, tolerability, and use of TMS for schizophrenia hal-lucinations.102 This area is controversial, but there is grow-ing evidence that TMS may be at least temporarily effectivein reducing auditory hallucinations in patients withschizophrenia.

Negative symptoms

There have been six randomized controlled trials (RCTs)using intermittent daily prefrontal TMS to treat negative

symptoms in patients with schizophrenia.14,103-107 Three ofthese studies were positive. The jury is still out in this regard.

Summary and Conclusions

The use of TMS as a therapy for most psychiatric disordersis still controversial, as there are insufficient studies yet tofirmly know whether the treatment might work. A notableexception is using daily prefrontal rTMS to treat depres-sion, in which there is a consensus that there are antide-pressant effects greater than placebo. Even with TMS as anantidepressant, there is still controversy as to the size ofthese effects, whether they will have clinical use in real-world settings, and what scalp locations and treatmentparameters are optimal.

References

1. George MS, Belmaker RH. TMS in clinical psychiatry. Washington,

DC: American Psychiatric Press; 2006.

2. George MS, Nahas Z, Borckardt JJ, et al. Brain stimulation for the

treatment of psychiatric disorders. Curr Opin Psychiatry 2007;

20(3):250-254. discussion 247–249.

3. George MS, Bohning DE, Li X, et al. Neuroimaging of rTMS effects

on the brain. In: Marcolin M, Padberg F, editors. Transcranial brain

stimulation in mental disorders. Berlin: Karger; 2007.

4. George MS, Nahas Z, Kozel FA, et al. Mechanisms and state of

the art of transcranial magnetic stimulation. J ECT 2002;18(4):

170-181.

5. Li X, Nahas Z, Kozel FA, et al. Acute left prefrontal transcranial

magnetic stimulation in depressed patients is associated with imme-

diately increased activity in prefrontal cortical as well as subcortical

regions. Biol Psychiatry 2004;55(9):882-890.

6. Li X, Teneback CC, Nahas Z, et al. Interleaved transcranial magnetic

stimulation/functional MRI confirms that lamotrigine inhibits corti-

cal excitability in healthy young men. Neuropsychopharmacology

2004;29(7):1395-1407.

7. Antal A, Nitsche MA, Paulus W. Transcranial direct current stimula-

tion and the visual cortex. Brain Res Bull 2006;68(6):459-463.

8. Higgins ES, George MS. The neuroscience of clinical psychiatry: the

pathophysiology of behavior and mental illness. Baltimore: Lippin-

cott, Williams & Wilkins; 2007.

9. Ridding MC, Rothwell JC. Is there a future for therapeutic use of

transcranial magnetic stimulation? Nat Rev Neurosci 2007;8(7):

559-567.

10. Sackeim HA, Prudic J, Nobler MS, et al. Effects of pulse width and

electrode placement on the efficacy and cognitive effects of electro-

convulsive therapy. Brain Stimulation 2008;1(2):71-83.

11. Prudic J, Olfson M, Marcus SC, Fuller RB, Sackeim HA. Effective-

ness of electroconvulsive therapy in community settings [comment].

Biol Psychiatry 2004;55(3):301-312.

12. Sackeim HA, Prudic J, Devanand DP, et al. A prospective, random-

ized, double-blind comparison of bilateral and right unilateral elec-

troconvulsive therapy at different stimulus intensities. Arch Gen

Psychiatry 2000;57(5):425-434.

13. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharma-

cotherapy in the prevention of relapse following electroconvulsive

therapy: a randomized controlled trial. JAMA 2001;285(10):

1299-1307.

14. Grisaru N, Yarovslavsky U, Abarbanel J, Lamberg T, Belmaker RH.

Transcranial magnetic stimulation in depression and schizophrenia.

Eur Neuropsychopharmacology 1994;4:287-288.

rTMS or tDCS in treatment of psychiatric diseases 19

15. Hoflich G, Kasper S, Hufnagel A, Ruhmann S, Moller HJ. Applica-

tion of transcranial magnetic stimulation in treatment of drug-resist-

ant major depressionda report of two cases. Hum Psychopharmacol

1993;8:361-365.

16. Kolbinger HM, Hoflich G, Hufnagel A, Moller HJ, Kasper S. Trans-

cranial magnetic stimulation (TMS) in the treatment of major depres-

sionda pilot study. Hum Psychopharmacol 1995;10:305-310.

17. George MS, Wassermann EM, Williams WA, et al. Daily repetitive

transcranial magnetic stimulation (rTMS) improves mood in depres-

sion. Neuroreport 1995;6(14):1853-1856.

18. George MS, Wassermann EM. Rapid-rate transcranial magnetic stim-

ulation and ECT. Convuls Ther 1994;10(4):251-254. discussion

255–258.

19. Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus inten-

sity and electrode placement on the efficacy and cognitive effects of

electroconvulsive therapy. N Engl J Med 1993;328:839-846.

20. George MS. Why would you ever want to? Toward understanding the

antidepressant effect of prefrontal rTMS. Hum Psychopharmacol

1998;15(5):307-313.

21. Nobler MS, Sackeim HA, Prohovnik I, et al. Regional cerebral blood

flow in mood disorders, III: treatment and clinical response. Arch

Gen Psychiatry 1994;51:884-897.

22. Nobler MS, Oquendo MA, Kegeles LS, et al. Decreased regional

brain metabolism after ECT. Am J Psychiatry 2001;158:305-308.

23. Bench CJ, Friston KJ, Brown RG, Frackowiak RSJ, Dolan RJ.

Regional cerebral blood flow in depression measured by positron

emission tomography: the relationship with clinical dimensions.

Psychol Med 1993;23:579-590.

24. Dolan RJ, Bench CJ, Brown RG, et al. Regional cerebral blood flow

abnormalities in depressed patients with cognitive impairment.

J Neurol Neurosurg Psych 1992;55:768-773.

25. Bench CJ, Friston KJ, Brown RG, et al. The anatomy of melancho-

liadfocal abnormalities of cerebral blood flow in major depression.

Psychol Med 1992;22:607-615.

26. Sackeim HA, Long J, Luber B, et al. Physical properties and quanti-

fication of the ECT stimulus: I, basic principles. Convuls Ther 1994;

10(2):93-123.

27. Nobler MS, Sackeim H. Mechanisms of action of electroconvulsive

therapy. Psychiatric Ann 1998;28:23-29.

28. Rubin E, Sackeim H, Nobler MS, Moeller JR. Brain imaging studies

of antidepressant treatments. Psychiatric Ann 1998;24:653-658.

29. Alexander GE, DeLong MR, Strick PL. Parallel organization of func-

tionally segregated circuits linking basal ganglia and cortex. Annu

Rev Neurosci 1986;9:357-381.

30. George MS, Wassermann EM, Post RM. Transcranial magnetic stim-

ulation: a neuropsychiatric tool for the 21st century. J Neuropsychi-

atry Clin Neurosci 1996;8(4):373-382.

31. George MS, Avery D, Nahas Z, et al. rTMS studies of mood and

emotion. Electroencephalogr Clin Neurophysiol Suppl 1999;51:

304-314.

32. George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stim-

ulation: applications in neuropsychiatry. Arch Gen Psychiatry 1999;

56(4):300-311.

33. Padberg F, Zwanzger P, Thoma H, et al. Repetitive transcranial mag-

netic stimulation (rTMS) in pharmacotherapy-refractory major depres-

sion: comparative study of fast, slow and sham rTMS. Psychiatry Res

1999;88:163-171.

34. George MS, Wassermann EM, Kimbrell TA, et al. Mood improve-

ment following daily left prefrontal repetitive transcranial magnetic

stimulation in patients with depression: a placebo-controlled cross-

over trial. Am J Psychiatry 1997;154(12):1752-1756.

35. George MS, Nahas Z, Molloy M, et al. A controlled trial of daily left

prefrontal cortex TMS for treating depression. Biol Psychiatry 2000;

48(10):962-970.

36. Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical

trial of repetitive transcranial magnetic stimulation in the treatment of

major depression. Biol Psychiatry 2000;47:332-337.

37. Padberg F, Zwanzger P, Keck ME, et al. Repetitive transcranial mag-

netic stimulation (rTMS) in major depression: relation between effi-

cacy and stimulation intensity. Neuropsychopharmacology 2002;27:

638-645.

38. Pascual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate trans-

cranial magnetic stimulation of left dorsolateral prefrontal cortex in

drug-resistant depression [comments]. Lancet 1996;348(9022):

233-237.

39. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stim-

ulation in the treatment of depression. Am J Psychiatry 2003;160:

835-845.

40. Kozel FA, George MS. Meta-analysis of left prefrontal repetitive

transcranial magnetic stimulation (rTMS) to treat depression. J Psy-

chiatric Pract 2002;8:270-275.

41. Holtzheimer PE, Russo J, Avery D. A meta-analysis of repetitive

transcranial magnetic stimulation in the treatment of depression.

Psychopharmacol Bull 2001;35:149-169.

42. Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of

transcranial magnetic stimulation. Int J Neuropsychopharmacol 2002;

5(1):73-103.

43. Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Transcranial magnetic

stimulation for treating depression. Cochrane Database Syst Rev

2002;(2):CD003493.

44. Herrmann LL, Ebmeier KP. Factors modifying the efficacy of trans-

cranial magnetic stimulation in the treatment of depression: a review.

J Clin Psychiatry 2006;67(12):1870-1876.

45. Fitzgerald PB, Brown TL, Marston NAU, et al. Transcranial mag-

netic stimulation in the treatment of depression: a double-blind

placebo controlled trial. Arch Gen Psychiatry 2003;60:1002-1008.

46. Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E. Transcranial

magnetic stimulation in treatment-resistant patients: a double-blind,

placebo-controlled trial. Psychiatry Res 2005;137:1-10.

47. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of

transcranial magnetic stimulation in the acute treatment of major de-

pression: a multisite randomized controlled trial. Biol Psychiatry

2007;62(11):1208-1216.

48. Avery DH, Isenberg KE, Sampson SM, et al. Transcranial magnetic

stimulation in the acute treatment of major depressive disorder: clin-

ical response in an open-label extension trial. J Clin Psychiatry 2008;

69(3):441-451.

49. Fitzgerald PB, Benitez J, de Castella A, et al. A randomized, con-

trolled trial of sequential bilateral repetitive transcranial magnetic

stimulation for treatment-resistant depression. Am J Psychiatry

2006;163(1):88-94.

50. Fitzgerald PB, Hoy K, McQueen S, et al. Priming stimulation en-

hances the effectiveness of low-frequency right prefrontal cortex

transcranial magnetic stimulation in major depression. J Clin Psycho-

pharmacol 2008;28(1):52-58.

51. Fitzgerald PB, Huntsman S, Gunewardene R, Kulkarni J,

Daskalakis ZJ. A randomized trial of low frequency right prefrontal

cortex transcranial magnetic stimulation as augmentation in treat-

ment resistant major depression. Int J Neuropharmacol 2006;9:

655-666.

52. Lisanby SH, Gutman D, Luber B, Schroeder C, Sackeim HA,

Sham TMS. intracerebral measurement of the induced electrical field

and the induction of motor-evoked potentials. Biol Psychiatry 2001;

49(5):460-463.

53. Loo CK, Taylor JL, Gandevia SC, et al. Transcranial magnetic stim-

ulation (TMS) in controlled treatment studies: are some ‘‘sham’’

forms active? Biol Psychiatry 2000;47:325-331.

54. Borckardt J, Walker J, Branham RK, et al. Development and evalu-

ation of a portable sham tms system. Brain Stimulation 2008;1(1):

52-59.

55. Arana AB, Borckardt JJ, Ricci R, et al. Electrical Stimulation as a

sham control for rTMS: does it truly mimic the cutaneous sensation

and pain of active prefrontal rTMS? Brain Stimulation 2008;1(1):

4-51.

20 M.S. George et al

56. Li X, Nahas Z, Anderson B, Kozel FA, George MS. Can left prefron-

tal rTMS be used as a maintenance treatment for bipolar depression?

Depress Anxiety 2004;20(2):98-100.

57. Fitzgerald PB, Benitez J, de Castella AR, et al. Naturalistic study of

the use of transcranial magnetic stimulation in the treatment of de-

pressive relapse. Austr N Z J Psychiatry 2006;40(9):764-768.

58. O’Reardon JP, Blumner KH, Peshek AD, Pradilla RR, Pimiento PC.

Long-term maintenance therapy for major depressive disorder with

rTMS. J Clin Psychiatry 2005;66(12):1524-1528.

59. Schule C, Zwanzger P, Baghai T, et al. Effects of antidepressant phar-

macotherapy after repetitive transcranial magnetic stimulation in ma-

jor depression: an open followup study. J Psychiatr Res 2003;37:

145-153.

60. Herwig U, Fallgatter AJ, Hoppner J, et al. Antidepressant effects of

augmentative transcranial magnetic stimulation: randomised multi-

centre trial. Br J Psychiatry 2007;191:441-448.

61. George MS, Speer AM, Molloy M, et al. Low frequency daily left

prefrontal rTMS improves mood in bipolar depressionda place-

bo-controlled case report. Hum Psychopharmacol 1998;13(4):

271-275.

62. Nahas Z, Kozel FA, Li X, Anderson B, George MS. Left prefrontal

transcranial magnetic stimulation (TMS) treatment of depression in

bipolar affective disorder: a pilot study of acute safety and efficacy.

Bipolar Disord 2003;5(1):40-47.

63. Figiel GS, Epstein C, McDonald WM, et al. The use of rapid rate

transcranial magnetic stimulation (rTMS) in refractory depressed

patients. J Neuropsychiatry Clin Neuro 1998;10:20-25.

64. Kozel FA, Nahas Z, deBrux C, et al. How coil-cortex distance relates

to age, motor threshold, and antidepressant response to repetitive

transcranial magnetic stimulation. J Neuropsychiatry Clin Neurosci

2000;12(3):376-384.

65. McConnell KA, Nahas Z, Shastri A, et al. The transcranial magnetic

stimulation motor threshold depends on the distance from coil to un-

derlying cortex: a replication in healthy adults comparing two

methods of assessing the distance to cortex. Biol Psychiatry 2001;

49(5):454-459.

66. Nahas Z, Teneback CC, Kozel A, et al. Brain effects of TMS deliv-

ered over prefrontal cortex in depressed adults: role of stimulation

frequency and coil-cortex distance. J Neuropsychiatry Clin Neurosci

2001;13(4):459-470.

67. Mosimann UP, Marre SC, Werlen S, et al. Antidepressant effects of

repetitive transcranial magnetic stimulation in the elderly: correlation

between effect size and coil-cortex distance. Arch Gen Psychiatry

2002;59:560-561.

68. Nahas Z, Li X, Kozel FA, et al. Safety and benefits of

distance-adjusted prefrontal transcranial magnetic stimulation in de-

pressed patients 55-75 years of age: a pilot study. Depress Anxiety

2004;19(4):249-256.

69. Jorge RE, Moser DJ, Action L, Robinson RG. Treatment of vascular

depression using repetitive transcranial magnetic stimulation. Arch

Gen Psychiatry 2008;65(3):268-276.

70. Herwig U, Padberg F, Unger J, et al. Transcranial magnetic stimula-

tion in therapy studies: examination of the reliability of ‘‘standard’’

coil positioning by neuronavigation. Biol Psychiatry 2001;50(1):

58-61.

71. Herwig U, Satrapi P, Schonfeldt-Lecuona C. Using the international

10-20 EEG system for positioning of transcranial magnetic stimula-

tion. Brain Topogr 2003;16(2):95-99.

72. Fregni F, Boggio PS, Nitsche MA, et al. Treatment of major depres-

sion with transcranial direct current stimulation. Bipolar Disord

2006;8(2):203-204.

73. Boggio PS, Rigonatti SP, Ribeiro RB, et al. A randomized, double-

blind clinical trial on the efficacy of cortical direct current stimulation

for the treatment of major depression. Int J Neuropsychopharmacol

2008;11(2):249-254.

74. Gruber NP, Dilsaver SC, Shoaib AM, Swann AC. ECT in mixed

affective states: a case series. J ECT 2000;16(2):183-188.

75. Devanand DP, Polanco P, Cruz R, et al. The efficacy of ECT in mixed

affective states. J ECT 2000;16(1):32-37.

76. Hill MA, Courvoisie H, Dawkins K, Nofal P, Thomas B. ECT for the

treatment of intractable mania in two prepubertal male children. Con-

vuls Ther 1997;13(2):74-82.

77. Miller MC. ECT and mania [letter; comment]. Am J Psychiatry 1995;

152(4):654.

78. Shaldivin A, Kaptsan A, Belmaker RH, Einat H, Grisaru N. Transcra-

nial magnetic stimulation in an amphetamine hyperactivity model of

mania. Bipolar Disord 2001;3(1):30-34.

79. Belmaker RH, Grisaru N. Does TMS have bipolar efficacy in both

depression and mania? Biol Psychiatry 1998;43:755.

80. Belmaker RH, Einat H, Levkovitz Y, Segal M, Grisaru N. TMS

effects in animal models of depression and mania. In: George MS,

Belmaker RH, editors. Transcranial magnetic stimulation in neuro-

psychiatry. Washington, DC: American Psychiatric Press; 2000.

p. 99-114.

81. Nedjat S, Folkerts HW. Induction of a reversible state of hypomania

by rapid-rate transcranial magnetic stimulation over the left prefron-

tal lobe. J ECT 1999;15:166-168.

82. Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. TMS in mnia:

a controlled study. Am J Psych 1998;155(11):1608-1610.

83. Kaptsan A, Yaroslavsky Y, Applebaum J, Belmaker RH, Grisaru N.

Right prefrontal TMS versus sham treatment of mania: a controlled

study. Bipolar Disord 2003;5(1):36-39.

84. Baxter LR. Brain imaging as a tool in establishing a theory of brain

pathology in obsessive compulsive disorder. J Clin Psychiatry 1990;

51(s):22-25.

85. Baxter LR, Schwartz JM, Guze BH, Bergman K, Szuba MP. PET

imaging in obsessive compulsive disorder with and without depres-

sion. J Clin Psychiatry 1990;51:61-69.

86. Rauch SL, Jenike MA, Alpert N, et al. PET study of OCD during

symptom provocation. APA New Res Abstracts 1993;133:NR293.

87. Greenberg BD, George MS, Martin JD, et al. Effect of prefrontal re-

petitive transcranial magnetic stimulation in obsessive-compulsive

disorder: a preliminary study. Am J Psychiatry 1997;154(6):867-869.

88. Alonso P, Pujol J, Cardoner N, et al. Right prefrontal repetitive trans-

cranial magnetic stimulation in obsessive-compulsive disorder: a

double-blind, placebo-controlled study. Am J Psychiatry 2001;

158(7):1143-1145.

89. Mantovani A, Lisanby SH, Pieraccini F, et al. Repetitive transcranial

magnetic stimulation (rTMS) in the treatment of obsessive-compulsive

disorder (OCD) and Tourette’s syndrome (TS). Int J Neuropsychophar-

macol 2006;9(1):95-100.

90. McCann UD, Kimbrell TA, Morgan CM, et al. Repetitive transcranial

magnetic stimulation for posttraumatic stress disorder [letter]. Arch

Gen Psychiatry 1998;55:276-279.

91. Grisaru N, Amir M, Cohen H, Kaplan Z. Effect of transcranial mag-

netic stimulation in posttraumatic stress disorder: a preliminary

study. Biol Psychiatry 1998;44:52-55.

92. Zhang W, Davidson JR. Post-traumatic stress disorder: an evaluation

of existing pharmacotherapies and new strategies. Expert Opin Phar-

macother 2007;8(12):1861-1870.

93. Zwanzger P, Minov C, Ella R, et al. Transcranial magnetic stimula-

tion for panic. Am J Psych 2002;159:315-316.

94. Mantovani A, Lisanby SH, Pieraccini F, et al. Repetitive transcranial

magnetic stimulation (rTMS) in the treatment of panic disorder (PD)

with comorbid major depression. J Affect Disord 2007;102(1-3):

277-280.

95. Prasko J, Zalesky R, Bares M, et al. The effect of repetitive transcra-

nial magnetic stimulation (rTMS) added on to serotonin reuptake in-

hibitors in patients with panic disorder: a randomized, double blind

sham controlled study. Neuro Endocrinol Lett 2007;1:33-38.

96. Hoffman RE, Gueorguieva R, Hawkins KA, et al. Temporoparietal

transcranial magnetic stimulation for auditory hallucinations: safety,

efficacy and moderators in a fifty patient sample. Biol Psychiatry

2005;58(2):97-104.

rTMS or tDCS in treatment of psychiatric diseases 21

97. Hoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-

term depotentiation, and brain hyperexcitability disorders review.

Am J Psychiatry 2002;159(7):1093-1102.

98. Hoffman RE, Boutros NN, Hu S, et al. Transcranial magnetic stim-

ulation and auditory hallucinations in schizophrenia. Lancet 2000;

355(9209):1073-1075.

99. Hoffman RE, Boutros NN, Berman RM, et al. Transcranial magnetic

stimulation of left temporoparietal cortex in three patients reporting

hallucinated ‘‘voices’’. Biol Psychiatry 1999;46:130-132.

100. Hoffman R, Boutros N, Berman R, Krystal J, Charney D. Transcra-

nial magnetic stimulation and hallucinated ’voices’. Biol Psychiatry

1998;43:93s-310.

101. Aleman A, Sommer IE, Kahn RS. Efficacy of slow repetitive trans-

cranial magnetic stimulation in the treatment of resistant auditory

hallucinations in schizophrenia: a meta-analysis. J Clin Psychiatry

2007;68(3):416-421.

102. Fitzgerald PB, Benitez J, Daskalakis JZ, De Castella A, Kulkarni J.

The treatment of recurring auditory hallucinations in schizophrenia

with rTMS. World J Biol Psychiatry 2006;7(2):119-122.

103. Jin Y, Potkin SG, Kemp AS, et al. Therapeutic effects of individual-

ized alpha frequency transcranial magnetic stimulation (alphaTMS)

on the negative symptoms of schizophrenia. Schizophr Bull 2006;

32(3):556-561.

104. Rollnik JD, Huber TJ, Mogk H, et al. High frequency repetitive trans-

cranial magnetic stimulation (rTMS) of the dorsolateral prefrontal

cortex in schizophrenic patients. NeuroReport 2000;11(18):

4013-4015.

105. Nahas Z, McConnell K, Collins S, et al. Could left prefrontal rTMS

modify negative symptoms and attention in schizophrenia? Biol Psy-

chiatry 1999;45:37S-120.

106. Geller SG, Grisaru N, Abarnabel JM, Lemberg T, Belmaker RH.

Slow magnetic stimulation of prefrontal cortex in depression and

schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 1997;

21:105-110.

107. Schneider AL, Schneider TL, Stark H. Repetitive transcranial mag-

netic stimulation (rTMS) as an augmentation treatment for the negative

symptoms of schizophrenia: a 4-week randomized placebo controlled

study. Brain Stimulation 2008;1(2):106-111.