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Transcranial Magnetic Stimulation in Psychiatric Disorders

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Transcranial Transcranial Magnetic Magnetic Stimulation in Stimulation in Psychiatric Psychiatric Disorders Disorders Oguz Tan, Oguz Tan, Memory Center, Istanbul, Turkey Memory Center, Istanbul, Turkey
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Page 1: Transcranial  Magnetic Stimulation in Psychiatric Disorders

TranscranialTranscranial Magnetic Magnetic Stimulation in Stimulation in

Psychiatric DisordersPsychiatric DisordersOguz Tan, Oguz Tan,

Memory Center, Istanbul, TurkeyMemory Center, Istanbul, Turkey

Page 2: Transcranial  Magnetic Stimulation in Psychiatric Disorders

Transcranial Magnetic Transcranial Magnetic Stimulation in Psychiatric Stimulation in Psychiatric

DisordersDisorders Oguz Tan, Oguz Tan, Memory Center, Istanbul, TurkeyMemory Center, Istanbul, Turkey

ObjectivesObjectives: It was aimed to review the literature : It was aimed to review the literature about the clinical use of repetitive transcranial about the clinical use of repetitive transcranial magnetic stimulation (rTMS) therapy in psychiatric magnetic stimulation (rTMS) therapy in psychiatric disorders.disorders.

Methods: A medline research was done concerning Methods: A medline research was done concerning rTMS use in mood disorders, anxiety disorders, rTMS use in mood disorders, anxiety disorders, psychotic disorders, and substance use disorders.psychotic disorders, and substance use disorders.

Results: Application of rTMS in depressive patients Results: Application of rTMS in depressive patients usually lead to a significant clinical improvement. usually lead to a significant clinical improvement. Findings about the use of rTMS in manic episodes, Findings about the use of rTMS in manic episodes, anxiety disorders, psychotic disorders, and anxiety disorders, psychotic disorders, and substance use disorders are limited.substance use disorders are limited.

Coclusion: rTMS is probably a useful therapeutic tool Coclusion: rTMS is probably a useful therapeutic tool in depressive disorders. Further research is needed in depressive disorders. Further research is needed to clarify the role of rTMS in pasychiatric disorders to clarify the role of rTMS in pasychiatric disorders other than depression.other than depression.

Page 3: Transcranial  Magnetic Stimulation in Psychiatric Disorders

Repetitive transcranial magnetic stimulation in Repetitive transcranial magnetic stimulation in the treatment of depression has been intensely the treatment of depression has been intensely studied. Since 1993 until recently, approximately studied. Since 1993 until recently, approximately 70 studies evaluating clinical efficacy of rTMS in 70 studies evaluating clinical efficacy of rTMS in depression have been published. depression have been published.

Most data support an antidepressant effect of Most data support an antidepressant effect of high-frequency rTMS administered to the left high-frequency rTMS administered to the left prefrontal cortex, although most patients enrolled prefrontal cortex, although most patients enrolled in the studies had treatment-resistant and severe in the studies had treatment-resistant and severe depression.depression.

Side-effect profile of rTMS is much more favorable Side-effect profile of rTMS is much more favorable than ECT or pharmacotherapy. The only serious than ECT or pharmacotherapy. The only serious side-effect of rTMS is seizure that have occured side-effect of rTMS is seizure that have occured very rarely. very rarely.

Page 4: Transcranial  Magnetic Stimulation in Psychiatric Disorders

An important reference An important reference is:is:

www.ists.unibe.chwww.ists.unibe.chThis site contains:This site contains:

The Avery-George-Holtzheimer Database of The Avery-George-Holtzheimer Database of

rTMS Depression Studies rTMS Depression Studies UPDATED as of 11/22/2004UPDATED as of 11/22/2004

Page 5: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED SHAM-CONTROLLED STUDIESSTUDIES

33 sham-controlled studies have been conducted 33 sham-controlled studies have been conducted since 1993 until June, 2005. 19 out of these since 1993 until June, 2005. 19 out of these studies found that rTMS were superior when studies found that rTMS were superior when compared to sham stimulation. However, in compared to sham stimulation. However, in

some studies, the benefit from rTMS was modest. some studies, the benefit from rTMS was modest.

Page 6: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19961996

Pascual-Leone A, Rubio B, Pallardo F, Catala MD Pascual-Leone A, Rubio B, Pallardo F, Catala MD Rapid-rate transcranial magnetic stimulation of left Rapid-rate transcranial magnetic stimulation of left

dorsolateral prefrontal cortex in drug-resistant depression. dorsolateral prefrontal cortex in drug-resistant depression. LancetLancet 348:233-7.348:233-7.

17 patients. Medication-resistant. Cross-over study.17 patients. Medication-resistant. Cross-over study.Non medication-free.Non medication-free.Psychotic depression..Psychotic depression..Left DLPFCLeft DLPFC10 Hz10 HzIntensity 90 percent MTIntensity 90 percent MT5 sessions with active rTMS (cross-over to the other group and 5 sessions with active rTMS (cross-over to the other group and

five more sessions)five more sessions)Total pulses 10.000Total pulses 10.000Different cortical areas (vertex stimulation, right DLPFC) Different cortical areas (vertex stimulation, right DLPFC)

stimulation were stimulated.stimulation were stimulated.HAMD decreased from 25.2 to 13.8 after 5 sessions (45 HAMD decreased from 25.2 to 13.8 after 5 sessions (45

percent decrease in depression)percent decrease in depression)

Page 7: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19971997

George MS, Wassermann EM, Kimbrell TA, et al George MS, Wassermann EM, Kimbrell TA, et al Mood improvement following daily left prefrontal repetitive Mood improvement following daily left prefrontal repetitive

transcranial magnetic stimulation in patients with depression: transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. a placebo-controlled crossover trial. Am J PsychiatryAm J Psychiatry 154:1752- 154:1752-6.6.

24 patients. Not medication-resistant. Cross-over study.24 patients. Not medication-resistant. Cross-over study.Some patients are medication-free.Some patients are medication-free.Left DLPFCLeft DLPFC20 Hz20 HzIntensity 80 percent MTIntensity 80 percent MT10 sessions 10 sessions Total pulses 8.000Total pulses 8.000rTMS superior to Sham, but small decrease in depression rTMS superior to Sham, but small decrease in depression

rating.rating.

Page 8: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19991999

Avery DH, Claypoole K, Robinson L, et al Avery DH, Claypoole K, Robinson L, et al Repetitive transcranial magnetic stimulation in the Repetitive transcranial magnetic stimulation in the

treatment of medication-resistant depression: preliminary treatment of medication-resistant depression: preliminary data. data. J Nerv Ment DisJ Nerv Ment Dis 187:114-7. 187:114-7.

6 patients. Medication-resistant. 6 patients. Medication-resistant. Not medication-free.Not medication-free.Left DLPFCLeft DLPFC10 Hz10 HzIntensity 80 percent MTIntensity 80 percent MT10 sessions 10 sessions Total pulses 10.000Total pulses 10.000Slight improvement in rTMS group compared with sham. Slight improvement in rTMS group compared with sham.

No decrement in neuropsychological tests with rTMS.No decrement in neuropsychological tests with rTMS.

Page 9: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIESSHAM-CONTROLLED STUDIES19991999

Klein E, Kreinin I, Chistyakov A, et al Klein E, Kreinin I, Chistyakov A, et al Therapeutic efficacy of right prefrontal slow repetitive Therapeutic efficacy of right prefrontal slow repetitive

transcranial magnetic stimulation in major depression: a transcranial magnetic stimulation in major depression: a double-blind controlled study. double-blind controlled study. Arch Gen PsychiatryArch Gen Psychiatry 56:315-20. 56:315-20.

70 patients. Not medication-resistant.70 patients. Not medication-resistant.Not medication-free.Not medication-free.Right DLPFCRight DLPFC1 Hz1 HzIntensity 110 percent MTIntensity 110 percent MT10 sessions10 sessionsTotal pulses 1200Total pulses 1200HAM-D decreased from 25.8 to 13.7 with rTMS and 25.3 to HAM-D decreased from 25.8 to 13.7 with rTMS and 25.3 to

19.7 with sham. Three dropouts (1 rTMS, 2 sham). Of rTMS 19.7 with sham. Three dropouts (1 rTMS, 2 sham). Of rTMS patients, 49% were responders (w/ >50% decrease in HAM-D); patients, 49% were responders (w/ >50% decrease in HAM-D); of sham patients, 25% were responders.of sham patients, 25% were responders.

Page 10: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19991999

Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Gandevia S Gandevia S

Double-blind controlled investigation of transcranial Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major magnetic stimulation for the treatment of resistant major depression. depression. Am J PsychiatryAm J Psychiatry 156:946-8. 156:946-8.

18 patients. Medication-resistant.18 patients. Medication-resistant.Not-medication-free.Not-medication-free.Left DLPFCLeft DLPFC10 Hz10 HzIntensity 110 percent MTIntensity 110 percent MT10 sessions of real or sham rTMS, then permitted up to 20 10 sessions of real or sham rTMS, then permitted up to 20

sessions of real rTMSsessions of real rTMSTotal pulses 15.000Total pulses 15.000With rTMS significant decreases in HAMD after 10 With rTMS significant decreases in HAMD after 10

sessions, but not different from sham. With rTMS, 44.9% sessions, but not different from sham. With rTMS, 44.9% decrease from baseline at one month follow-up.decrease from baseline at one month follow-up.

Page 11: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19991999

Padberg F, Zwanzger P, Thoma H, et alPadberg F, Zwanzger P, Thoma H, et alRepetitive transcranial magnetic stimulation (rTMS) in Repetitive transcranial magnetic stimulation (rTMS) in

pharmacotherapy-refractory major depression: comparative pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS. study of fast, slow and sham rTMS. Psychiatry ResPsychiatry Res 88:163-71. 88:163-71.

18 patients. Medication-resistant.18 patients. Medication-resistant.Some patients are medication-free.Some patients are medication-free.Left DLPFCLeft DLPFC10 Hz or 0.3 Hz10 Hz or 0.3 HzIntensity 90 percent MTIntensity 90 percent MT5 sessions 5 sessions Total pulses 1250Total pulses 1250Not clinically meaningful antidepressant efficacy. Not clinically meaningful antidepressant efficacy.

Improvement in verbal memory scores after fast rTMS, with no Improvement in verbal memory scores after fast rTMS, with no change after slow rTMS, and a trend toward poorer scores change after slow rTMS, and a trend toward poorer scores after sham.after sham.

Page 12: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIESSHAM-CONTROLLED STUDIES19991999

Kimbrell TA, Little JT, Dunn RT, et al Kimbrell TA, Little JT, Dunn RT, et al Frequency dependence of antidepressant response to left Frequency dependence of antidepressant response to left

prefrontal repetitive transcranial magnetic stimulation (rTMS) as a prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. function of baseline cerebral glucose metabolism. Biol PsychiatryBiol Psychiatry 46:1603-13.46:1603-13.

26 patients. Medication-resistance NA. 26 patients. Medication-resistance NA. Some patients medication-free.Some patients medication-free.Left DLPFCLeft DLPFC20 Hz or 1 Hz20 Hz or 1 HzIntensity 90 percent MTIntensity 90 percent MT10 sessions 10 sessions Total pulses 8000Total pulses 80002/13 responded (greater than 50% response) There was a 2/13 responded (greater than 50% response) There was a

negative correlation between the degree of antidepressant negative correlation between the degree of antidepressant response after 1 Hz compared to 20 Hz. Better response to 20 hz response after 1 Hz compared to 20 Hz. Better response to 20 hz was associated with the degree of baseline hypometabolism was associated with the degree of baseline hypometabolism measured by PET, whereas 1 Hz rTMS tended to be associated with measured by PET, whereas 1 Hz rTMS tended to be associated with baseline hypermetabolism. 1/10 responded in 20 Hz group. 0/3 baseline hypermetabolism. 1/10 responded in 20 Hz group. 0/3 responded in sham group. Antidepressant response to rTMS might responded in sham group. Antidepressant response to rTMS might vary as as a function of stimulation frequency and may depend on vary as as a function of stimulation frequency and may depend on pretreatment cerebral metabolism.pretreatment cerebral metabolism.

Page 13: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 19991999

Stikhina N, Lyskov EB, Lomarev MP, Aleksanian ZA, Stikhina N, Lyskov EB, Lomarev MP, Aleksanian ZA, Mikhailov VO, Medvedev SVMikhailov VO, Medvedev SV

Transcranial magnetic stimulation in neurotic depression. Transcranial magnetic stimulation in neurotic depression. Zh Nevrol Psikhiatr Im S S KorsakovaZh Nevrol Psikhiatr Im S S Korsakova 99:26-9. 99:26-9.

29 patients. Medication-resistance NA. 29 patients. Medication-resistance NA. Medication-free or not NA. All patients received Medication-free or not NA. All patients received

psychotherapy.psychotherapy.Left frontalLeft frontal40 Hz 40 Hz Intensity 0.015 TeslaIntensity 0.015 Tesla10 sessions 10 sessions Total pulses 480.000Total pulses 480.000TMS significantly better than control condition.TMS significantly better than control condition.

Page 14: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20002000

Berman RM, Narasimhan M, Sanacora G, et al Berman RM, Narasimhan M, Sanacora G, et al A randomized clinical trial of repetitive transcranial A randomized clinical trial of repetitive transcranial

magnetic stimulation in the treatment of major depression. magnetic stimulation in the treatment of major depression. Biol PsychiatryBiol Psychiatry 47:332-7. 47:332-7.

20 patients. Medication-resistant.20 patients. Medication-resistant.Medication-free.Medication-free.Left DLPFCLeft DLPFC20 Hz20 HzIntensity 80 percent MTIntensity 80 percent MT10 sessions 10 sessions Total pulses 8000Total pulses 8000In rTMS group, 1/10 responded (decrease in HAM-D from In rTMS group, 1/10 responded (decrease in HAM-D from

48 to 7); in sham group 0/10 responded. Statistically 48 to 7); in sham group 0/10 responded. Statistically significant but clinically modest reductions of depressive significant but clinically modest reductions of depressive symptoms.symptoms.

Page 15: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20002000

Eschweiler GW, Wegerer C, Schlotter W, et al Eschweiler GW, Wegerer C, Schlotter W, et al Left prefrontal activation predicts therapeutic effects of Left prefrontal activation predicts therapeutic effects of

repetitive transcranial magnetic stimulation (rTMS) in major repetitive transcranial magnetic stimulation (rTMS) in major depression. depression. Psychiatry ResPsychiatry Res 99:161-72. 99:161-72.

12 patients. Not medication-resistant.12 patients. Not medication-resistant.Medication-free or not NAMedication-free or not NALeft DLPFCLeft DLPFC10 Hz10 HzIntensity 90 percent MTIntensity 90 percent MTCrossover study. 4 weeks’ duration consisting of two periods Crossover study. 4 weeks’ duration consisting of two periods

of 5 days with rTMS separated by 9 days of no stimulation of 5 days with rTMS separated by 9 days of no stimulation Total pulses 20.000Total pulses 20.000rTMS significantly better than sham, also used near rTMS significantly better than sham, also used near

infrared spectroscopy. Absence of a task-related increase of infrared spectroscopy. Absence of a task-related increase of total hemoglobin concentrations at the stimulation site, but not total hemoglobin concentrations at the stimulation site, but not at other locations, before the first active rTMS significantly at other locations, before the first active rTMS significantly predicted the clinical response to active rTMS.predicted the clinical response to active rTMS.

Page 16: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20002000

George MS, Nahas Z, Molloy M, et al George MS, Nahas Z, Molloy M, et al A controlled trial of daily left prefrontal cortex TMS for A controlled trial of daily left prefrontal cortex TMS for

treating depression. treating depression. Biol PsychiatryBiol Psychiatry 48:962-70. 48:962-70.30 patients. Medication-resistant.30 patients. Medication-resistant.Medication-freeMedication-freeLeft DLPFCLeft DLPFC5 Hz or 20 Hz or sham5 Hz or 20 Hz or shamIntensity 100 percent MTIntensity 100 percent MT10 sessions10 sessionsTotal pulses 16.000Total pulses 16.0006/10 responded (greater than 50% decrease in HAMD). 6/10 responded (greater than 50% decrease in HAMD).

3/10 responded to 20Hz. 0/10 responded to sham.3/10 responded to 20Hz. 0/10 responded to sham.

Page 17: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20012001

Garcia-Toro M, Mayol A, Arnillas H, et al Garcia-Toro M, Mayol A, Arnillas H, et al Modest adjunctive benefit with transcranial magnetic stimulation in Modest adjunctive benefit with transcranial magnetic stimulation in

medication-resistant depression. medication-resistant depression. J Affect DisordJ Affect Disord 64:271-5. 64:271-5.40 patients. Medication-resistant.40 patients. Medication-resistant.Not medication-freeNot medication-freeLeft DLPFCLeft DLPFC20 Hz20 Hz10 sessions10 sessionsIntensity 90 percent MTIntensity 90 percent MTTotal pulses 12.000Total pulses 12.000rTMS added to current antidepressant treatments. 5/17 (29%) of rTMS added to current antidepressant treatments. 5/17 (29%) of

patients initially randomized to rTMS were responders (>50% decrease in patients initially randomized to rTMS were responders (>50% decrease in HDRS). 15 sham non-responders crossed over to receive active 90% MT HDRS). 15 sham non-responders crossed over to receive active 90% MT rTMS; 4/14 (29%) patients that completed 4 weeks of treatment were rTMS; 4/14 (29%) patients that completed 4 weeks of treatment were responders. The 9 non-responders were treated with 10 additional sessions responders. The 9 non-responders were treated with 10 additional sessions of 110% MT rTMS; 3/9 (33%) were responders. Real, but not sham HF-rTMS, of 110% MT rTMS; 3/9 (33%) were responders. Real, but not sham HF-rTMS, was associated with a significant decrease in the Hamilton Depression was associated with a significant decrease in the Hamilton Depression Rating Scale, but only twelve patients decreased more than 50%Rating Scale, but only twelve patients decreased more than 50%

Page 18: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIESSHAM-CONTROLLED STUDIES20012001

Szuba MP, O'Reardon JP, Rai AS, et al Szuba MP, O'Reardon JP, Rai AS, et al Acute mood and thyroid stimulating hormone effects of Acute mood and thyroid stimulating hormone effects of

transcranial magnetic stimulation in major depression. transcranial magnetic stimulation in major depression. Biol Biol PsychiatryPsychiatry 50:22-7. 50:22-7.

14 patients. Medication-resistance NA.14 patients. Medication-resistance NA.Medication-free NAMedication-free NALeft DLPFCLeft DLPFC10 Hz10 HzNumber of sessions NANumber of sessions NAIntensity 100 percent MTIntensity 100 percent MTTotal pulses NATotal pulses NANo efficacy data presented. Patients receiving active TMS No efficacy data presented. Patients receiving active TMS

showed greater mood improvements with acute sessions of TMS showed greater mood improvements with acute sessions of TMS than patients receiving sham. Subjects are a subset of a larger than patients receiving sham. Subjects are a subset of a larger study evaluation twice daily versus once daily rTMS. The change study evaluation twice daily versus once daily rTMS. The change in TSH from pre- to post-rTMS was significantly different in TSH from pre- to post-rTMS was significantly different between active and sham sessionsbetween active and sham sessions

Page 19: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20012001

Manes F, Jorge R, Morcuende M, Yamada T, Paradiso S, Manes F, Jorge R, Morcuende M, Yamada T, Paradiso S, Robinson RG Robinson RG

A controlled study of repetitive transcranial magnetic A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. stimulation as a treatment of depression in the elderly. Int Int PsychogeriatrPsychogeriatr 13:225-31. 13:225-31.

20 patients. Medication-resistant.20 patients. Medication-resistant.Medication-free.Medication-free.Left DLPFCLeft DLPFC20 Hz20 Hz5 sessions.5 sessions.Intensity 80 percent MTIntensity 80 percent MTTotal pulses 4000Total pulses 4000Studied patients >50 years old (mean age 60.7 years, SD 9.8 Studied patients >50 years old (mean age 60.7 years, SD 9.8

years). Neuropsychological testing used MMSE (minimental state years). Neuropsychological testing used MMSE (minimental state examination); no significant difference between groups pre- or examination); no significant difference between groups pre- or post-treatment. 6 responders (3 to rTMS and 3 to sham) had post-treatment. 6 responders (3 to rTMS and 3 to sham) had significantly greater frontal lobe volume than non-responders.significantly greater frontal lobe volume than non-responders.

Page 20: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20012001

Garcia-Toro M, Pascual-Leone A, Romera M, et al Garcia-Toro M, Pascual-Leone A, Romera M, et al Prefrontal repetitive transcranial magnetic stimulation as add on Prefrontal repetitive transcranial magnetic stimulation as add on

treatment in depression. treatment in depression. J Neurol Neurosurg PsychiatryJ Neurol Neurosurg Psychiatry 71:546-8. 71:546-8.28 patients. 16 medication-resistant (a single trial of drug), 12 28 patients. 16 medication-resistant (a single trial of drug), 12

had not received medication fort he present depressive episode.had not received medication fort he present depressive episode.Patients were started on sertraline. Patients were started on sertraline. Left DLPFCLeft DLPFC20 Hz20 Hz10 sessions.10 sessions.Intensity 90 percent MTIntensity 90 percent MTTotal pulses 12.000Total pulses 12.000rTMS did not add efficacy over the use of standard antidepressant rTMS did not add efficacy over the use of standard antidepressant

medication. Studied rTMS versus sham as add-on treatment to medication. Studied rTMS versus sham as add-on treatment to sertraline for a major depressive episode. All but two patients sertraline for a major depressive episode. All but two patients received benzodiazepines. Differences in response at 2 weeks in received benzodiazepines. Differences in response at 2 weeks in HDRS and BDI, but not at 4 weeks (2 weeks after last treatment). HDRS and BDI, but not at 4 weeks (2 weeks after last treatment). Non-responders to sham were crossed over to receive 90% MT rTMS Non-responders to sham were crossed over to receive 90% MT rTMS with identical parameters. Non-responders to active 90% MT rTMS with identical parameters. Non-responders to active 90% MT rTMS crossed over to receive 110% MT rTMS.crossed over to receive 110% MT rTMS.

Page 21: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20012001

Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T, Sackeim HA Burt T, Sackeim HA

Augmentation of sertraline antidepressant treatment with Augmentation of sertraline antidepressant treatment with transcranial magnetic stimulation. transcranial magnetic stimulation. Biol PsychiatryBiol Psychiatry 49:81S. 49:81S.

36 patients. 61 percent of patients were medication-36 patients. 61 percent of patients were medication-resistant.resistant.

Not medication-free.Not medication-free.10 Hz over the left DLPFC or 1 Hz the right DLPFC or sham10 Hz over the left DLPFC or 1 Hz the right DLPFC or sham10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 16.000Total pulses 16.000Compared 10 Hz left DLPFC rTMS to 1 Hz right DLPFC rTMS Compared 10 Hz left DLPFC rTMS to 1 Hz right DLPFC rTMS

to sham rTMS, all as add-on therapy to sertraline 50 mg. to sham rTMS, all as add-on therapy to sertraline 50 mg. Remission in the active TMS group combined was 25% vs. 8% Remission in the active TMS group combined was 25% vs. 8% in the sham group (NS). Degree of medication resistance in the sham group (NS). Degree of medication resistance negatively correlated with response and remission.negatively correlated with response and remission.

Page 22: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20022002

Dolberg OT, Dannon PN, Schreiber S, Grunhaus L Dolberg OT, Dannon PN, Schreiber S, Grunhaus L Transcranial magnetic stimulation in patients with bipolar Transcranial magnetic stimulation in patients with bipolar

depression: a double blind, controlled study. depression: a double blind, controlled study. Bipolar DisordBipolar Disord 4:94-5.4:94-5.

20 patients. Medication-resistance NA.20 patients. Medication-resistance NA.Medication-free NAMedication-free NALeft DLPFCLeft DLPFCFrequency (Hz) NAFrequency (Hz) NA10 sessions10 sessionsIntensity NAIntensity NATotal pulses NATotal pulses NAPreliminary report. Response or remission rate NA. Preliminary report. Response or remission rate NA.

Depression decreased 29 percent in the active TMS group, 20 Depression decreased 29 percent in the active TMS group, 20 percent in the sham group.percent in the sham group.

Page 23: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20022002

Padberg F, Zwanzger P, Keck ME, et al Padberg F, Zwanzger P, Keck ME, et al Repetitive transcranial magnetic stimulation (rTMS) in major depression: Repetitive transcranial magnetic stimulation (rTMS) in major depression:

relation between efficacy and stimulation intensity. relation between efficacy and stimulation intensity. NeuropsychopharmacologyNeuropsychopharmacology 27:638-45.27:638-45.

31 patients. Drug-resistant.31 patients. Drug-resistant.Not medication-free.Not medication-free.Left DLPFCLeft DLPFC10 Hz10 Hz10 sessions.10 sessions.Intensity: 100 percent MT or 90 percent MT or shamIntensity: 100 percent MT or 90 percent MT or shamTotal pulses 15.000Total pulses 15.000MADRS scores: 4% decrease with sham, 15% decrease with 90% MT rTMS, MADRS scores: 4% decrease with sham, 15% decrease with 90% MT rTMS,

33% decrease with 100% rTMS. 33% decrease with 100% rTMS. 3/10 responders (>50% decr in HAMD) and 2/10 partial responders (>25% 3/10 responders (>50% decr in HAMD) and 2/10 partial responders (>25%

decr HAMD) with 100% MT rTMS, 2/10 responders and 1/10 partial responder decr HAMD) with 100% MT rTMS, 2/10 responders and 1/10 partial responder with 90% MT rTMS, 0/10 responders and 2/10 partial responders with sham with 90% MT rTMS, 0/10 responders and 2/10 partial responders with sham rTMS. rTMS.

Patients receiving rTMS had substantially fewer days in the hospital post-Patients receiving rTMS had substantially fewer days in the hospital post-treatment (43 days for 100% MT rTMS, 61 days for 90% MT rTMS, 135 days for treatment (43 days for 100% MT rTMS, 61 days for 90% MT rTMS, 135 days for sham rTMS). Improvement of depressive symptoms after rTMS significantly sham rTMS). Improvement of depressive symptoms after rTMS significantly increased with stimulation intensity across the three groups.increased with stimulation intensity across the three groups.

Page 24: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20022002

Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Feingold A, Berman RM Feingold A, Berman RM

Lack of a therapeutic effect of a 2-week sub-threshold Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-transcranial magnetic stimulation course for treatment-resistant depression. resistant depression. Psychiatry ResPsychiatry Res 113:245-54. 113:245-54.

21 patients. Medication-resistant.21 patients. Medication-resistant.Not medication-free.Not medication-free.Left DLPFCLeft DLPFC20 Hz20 Hz10 sessions.10 sessions.Intensity: 80 percent MT or shamIntensity: 80 percent MT or shamTotal pulses 8000Total pulses 8000No statistically significant difference between rTMS- and No statistically significant difference between rTMS- and

sham-treated patients. Authors suggest this may relate to sham-treated patients. Authors suggest this may relate to subthreshold rTMS intensity.subthreshold rTMS intensity.

Page 25: Transcranial  Magnetic Stimulation in Psychiatric Disorders

SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20032003

Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter J J

Antidepressant efficacy of two different rTMS procedures Antidepressant efficacy of two different rTMS procedures High frequency over left versus low frequency over right High frequency over left versus low frequency over right prefrontal cortex compared with sham stimulation. prefrontal cortex compared with sham stimulation. Eur Arch Eur Arch Psychiatry Clin NeurosciPsychiatry Clin Neurosci 253:103-9. 253:103-9.

30 patients. Medication-resistance NA30 patients. Medication-resistance NANot medication-free.Not medication-free.20 Hz over the left DLPFC (90 percent MT) or 1 Hz the right 20 Hz over the left DLPFC (90 percent MT) or 1 Hz the right

DLPFC (110 percent MT) or shamDLPFC (110 percent MT) or sham10 sessions.10 sessions.Total pulses 8000 over the left or 1200 over the rightTotal pulses 8000 over the left or 1200 over the rightPatients were started on an antidepressant medication 2 Patients were started on an antidepressant medication 2

weeks before rTMS, which was used as an add-on treatment. weeks before rTMS, which was used as an add-on treatment. Differences between the rTMS procedures regarding Differences between the rTMS procedures regarding depressive symptoms could not be found.depressive symptoms could not be found.

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SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20032003

Loo CK, Mitchell PB, Croker VM, et al Loo CK, Mitchell PB, Croker VM, et al Double-blind controlled investigation of bilateral prefrontal Double-blind controlled investigation of bilateral prefrontal

transcranial magnetic stimulation for the treatment of transcranial magnetic stimulation for the treatment of resistant major depression. resistant major depression. Psychol MedPsychol Med 33:33-40. 33:33-40.

19 patients. Drug-resistant.19 patients. Drug-resistant.Not medication-free.Not medication-free.Bilateral DLPFCBilateral DLPFC15 Hz15 Hz15 sessions.15 sessions.Intensity 90 percent MTIntensity 90 percent MTTotal pulses 27.000Total pulses 27.000No significant difference between the two groups. 2 No significant difference between the two groups. 2

responders in the rTMS groups, 1 responder in the sham responders in the rTMS groups, 1 responder in the sham group. 6 sham patients crossed over to rTMS; 1 patient in this group. 6 sham patients crossed over to rTMS; 1 patient in this group responded.group responded.

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Nahas Z, Kozel FA, Li X, Anderson B, George MS Nahas Z, Kozel FA, Li X, Anderson B, George MS Left prefrontal transcranial magnetic stimulation (TMS) Left prefrontal transcranial magnetic stimulation (TMS)

treatment of depression in bipolar affective disorder: a pilot treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. study of acute safety and efficacy. Bipolar DisordBipolar Disord 5:40-7. 5:40-7.

23 patients. Drug-resistance NA23 patients. Drug-resistance NANot medication-free.Not medication-free.Left DLPFCLeft DLPFC5 Hz5 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 16.000Total pulses 16.000No significant difference between rTMS and sham in No significant difference between rTMS and sham in

decrease in HAMD or response rate. No patients developed decrease in HAMD or response rate. No patients developed mania or hypomania during the study.mania or hypomania during the study.

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Herwig U, Lampe Y, Juengling FD, et al Herwig U, Lampe Y, Juengling FD, et al Add-on rTMS for treatment of depression: a pilot study using stereotaxic Add-on rTMS for treatment of depression: a pilot study using stereotaxic

coil-navigation according to PET data. coil-navigation according to PET data. J Psychiatr ResJ Psychiatr Res 37:267-75. 37:267-75.25 patients. Some patients are drug-resistant.25 patients. Some patients are drug-resistant.Not medication-free.Not medication-free.6 parients were given left DLPFC, 6 right, 6 sham (parietooccipital)6 parients were given left DLPFC, 6 right, 6 sham (parietooccipital)15 Hz15 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 30.000Total pulses 30.000Real stimulation improved depression moderately but significantly better Real stimulation improved depression moderately but significantly better

compared to sham. In the real condition, four out of 13 patients responded, compared to sham. In the real condition, four out of 13 patients responded, whereas none responded to sham. Left vs. right prefrontal location of whereas none responded to sham. Left vs. right prefrontal location of stimulation guided by PET-identified prefrontal hypometabolism (when stimulation guided by PET-identified prefrontal hypometabolism (when present). 11 of 25 patients had right prefrontal hypometabolism at baseline. 1 present). 11 of 25 patients had right prefrontal hypometabolism at baseline. 1 of 25 had left prefrontal hypometabolism at baseline. 13 of 25 had left=right of 25 had left prefrontal hypometabolism at baseline. 13 of 25 had left=right metabolism at baseline or no imaging data available. There was no evidence metabolism at baseline or no imaging data available. There was no evidence that using baseline prefrontal hypometabolism to guide treatment location was that using baseline prefrontal hypometabolism to guide treatment location was beneficial. Treatment groups were combined for analyses.beneficial. Treatment groups were combined for analyses.

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Nahas Z, Kozel FA, Li X, Anderson B, George MS Nahas Z, Kozel FA, Li X, Anderson B, George MS Left prefrontal transcranial magnetic stimulation (TMS) Left prefrontal transcranial magnetic stimulation (TMS)

treatment of depression in bipolar affective disorder: a pilot treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. study of acute safety and efficacy. Bipolar DisordBipolar Disord 5:40-7. 5:40-7.

23 patients. Medication-resistance NA.23 patients. Medication-resistance NA.Not medication-free.Not medication-free.Left DLPFCLeft DLPFC5 Hz5 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 16.000Total pulses 16.000No significant difference between rTMS and sham in No significant difference between rTMS and sham in

decrease in HAMD or response rate. But a trend for greater decrease in HAMD or response rate. But a trend for greater improvement in daily subjective mood ratings. No patients improvement in daily subjective mood ratings. No patients developed mania or hypomania during the study.developed mania or hypomania during the study.

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Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni JA, Kulkarni J

Transcranial magnetic stimulation in the treatment of Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. depression: a double-blind, placebo-controlled trial. Arch Gen Arch Gen PsychiatryPsychiatry 60:1002-8. 60:1002-8.

60 patients. Medication-resistance NA.60 patients. Medication-resistance NA.Not medication-free.Not medication-free.3 groups:3 groups:1-10 Hz left DLPFC1-10 Hz left DLPFC2-1 Hz right DLPFC2-1 Hz right DLPFC3-Sham3-Sham10 sessions.10 sessions.Intensity 100 percent MTIntensity 100 percent MTTotal pulses 3000 or 10.000Total pulses 3000 or 10.000Compares 10 Hz LPF stim with 1 Hz RPF stim with sham. Initial Compares 10 Hz LPF stim with 1 Hz RPF stim with sham. Initial

trial was with 10 sessions: 14-15% decr in MADRS in both rTMS trial was with 10 sessions: 14-15% decr in MADRS in both rTMS groups (1/20 patients in LPF group with >50% decr), 1% decr in groups (1/20 patients in LPF group with >50% decr), 1% decr in sham (significant difference between the treatment and sham sham (significant difference between the treatment and sham groups, but not significant difference between the treatment groups, but not significant difference between the treatment groups). 15 patients with >20% decr in MADRS by 10 sessions went groups). 15 patients with >20% decr in MADRS by 10 sessions went on to receive a total of 20 open rTMS sessions: 40% decr in MADRS on to receive a total of 20 open rTMS sessions: 40% decr in MADRS in LPF group (4/8 patients with decr >50%), 57% decr in RPF group in LPF group (4/8 patients with decr >50%), 57% decr in RPF group (4/7 patients with decr >50%). Baseline psychomotor agitation (4/7 patients with decr >50%). Baseline psychomotor agitation predicted succesful response to treatment.predicted succesful response to treatment.

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Hausmann A, Kemmler G, Walpoth M, et al Hausmann A, Kemmler G, Walpoth M, et al No benefit derived from repetitive transcranial magnetic stimulation in No benefit derived from repetitive transcranial magnetic stimulation in

depression: a prospective, single centre, randomised, double blind, sham depression: a prospective, single centre, randomised, double blind, sham controlled "add on" trial. controlled "add on" trial. J Neurol Neurosurg PsychiatryJ Neurol Neurosurg Psychiatry 75:320-2. 75:320-2.

41 patients. Medication resistance NA.41 patients. Medication resistance NA.They were medication-free, medication started at the start of rTMS.They were medication-free, medication started at the start of rTMS.Group 1: 20 Hz over the left DLPFC and subsequent sham 1 Hz over the Group 1: 20 Hz over the left DLPFC and subsequent sham 1 Hz over the

right DLPFCright DLPFCGroup 2: simulataneous bilateral active stimulation (20 Hz over the left Group 2: simulataneous bilateral active stimulation (20 Hz over the left

DLPFC, 1 Hz over the right DLPFC)DLPFC, 1 Hz over the right DLPFC)Group 3: bilateral sham stimulationGroup 3: bilateral sham stimulationIntensity 100 percent motor threshold in the 20 Hz group, 120 in the 1 Hz Intensity 100 percent motor threshold in the 20 Hz group, 120 in the 1 Hz

group group 10 sessions 10 sessions Total pulses 20.000-26.000Total pulses 20.000-26.000No significant differences between the groups. 20 Hz LPF and the No significant differences between the groups. 20 Hz LPF and the

combined 20 Hz LPF/1 Hz RPF active rTMS groups were combined for efficacy combined 20 Hz LPF/1 Hz RPF active rTMS groups were combined for efficacy analyses. Unknown if patients were treatment-resistant at baseline. The analyses. Unknown if patients were treatment-resistant at baseline. The results suggest that rTMS as an "add on" strategy, applied in a unilateral and results suggest that rTMS as an "add on" strategy, applied in a unilateral and a bilateral stimulation paradigm, does not exert an additional antidepressant a bilateral stimulation paradigm, does not exert an additional antidepressant effect.effect.

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Jorge RE, Robinson RG, Tateno A, et al Jorge RE, Robinson RG, Tateno A, et al Repetitive transcranial magnetic stimulation as treatment Repetitive transcranial magnetic stimulation as treatment

of poststroke depression: a preliminary study. of poststroke depression: a preliminary study. Biol PsychiatryBiol Psychiatry 55:398-405.55:398-405.

20 patients. Drug-resistant.20 patients. Drug-resistant.Medication-free.Medication-free.Left DLPFC Left DLPFC 10 Hz10 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 10.000Total pulses 10.0003 patients in the active rTMS group responded and one 3 patients in the active rTMS group responded and one

patient remitted, no patients in the sham group responded. 38 patient remitted, no patients in the sham group responded. 38 percent decrease in depression in the active rTMS group, 13 percent decrease in depression in the active rTMS group, 13 percent in the sham group. percent in the sham group.

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SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20042004

Holtzheimer PE, 3rd, Russo J, Claypoole KH, Roy-Byrne P, Avery DH Holtzheimer PE, 3rd, Russo J, Claypoole KH, Roy-Byrne P, Avery DH Shorter duration of depressive episode may predict response to Shorter duration of depressive episode may predict response to

repetitive transcranial magnetic stimulation. repetitive transcranial magnetic stimulation. Depress AnxietyDepress Anxiety 19:24- 19:24-30.30.

15 patients. Drug-resistant.15 patients. Drug-resistant.Medication-free.Medication-free.Left DLPFC Left DLPFC 10 Hz10 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 16.000Total pulses 16.000No significant difference between rTMS and sham; however, a No significant difference between rTMS and sham; however, a

significant negative correlation between length of current depressive significant negative correlation between length of current depressive episode and response to rTMS was found. Non-responders to sham episode and response to rTMS was found. Non-responders to sham were allowed to receive active rTMS. Patients with a current episode were allowed to receive active rTMS. Patients with a current episode shorter than 4 years showed a 52% reduction in mean HAM-D shorter than 4 years showed a 52% reduction in mean HAM-D whereas those with a current episode longer than 10 years showed whereas those with a current episode longer than 10 years showed only a 6% decrease. only a 6% decrease.

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SHAM-CONTROLLED STUDIES SHAM-CONTROLLED STUDIES 20042004

Kauffmann CD, Cheema MA, Miller BE Kauffmann CD, Cheema MA, Miller BE Slow right prefrontal transcranial magnetic stimulation as Slow right prefrontal transcranial magnetic stimulation as

a treatment for medication-resistant depression: a double-a treatment for medication-resistant depression: a double-blind, placebo-controlled study. blind, placebo-controlled study. Depress AnxietyDepress Anxiety 19:59-62. 19:59-62.

12 patients. Drug-resistant.12 patients. Drug-resistant.Not medication-free.Not medication-free.Right DLPFC Right DLPFC 10 Hz10 Hz10 sessions.10 sessions.Intensity 110 percent MTIntensity 110 percent MTTotal pulses 1200Total pulses 1200No significant difference between the groups. However, No significant difference between the groups. However,

the active TMS group showed a significant reduction in HAMD the active TMS group showed a significant reduction in HAMD over time whereas the sham group did not. Active TMS over time whereas the sham group did not. Active TMS responders relapsed in 2-3 months. Sham responders relapsed responders relapsed in 2-3 months. Sham responders relapsed in 2 weeks.in 2 weeks.

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Mosimann UP, Schmitt W, Greenberg BD, et al Mosimann UP, Schmitt W, Greenberg BD, et al Repetitive transcranial magnetic stimulation: a putative Repetitive transcranial magnetic stimulation: a putative

add-on treatment for major depression in elderly patients. add-on treatment for major depression in elderly patients. Psychiatry ResPsychiatry Res 126:123-33. 126:123-33.

24 elderly patients (mean age 62 years). Drug-resistant.24 elderly patients (mean age 62 years). Drug-resistant.Not medication-free.Not medication-free.Left DLPFC Left DLPFC 20 Hz20 Hz10 sessions.10 sessions.Intensity 100 percent MTIntensity 100 percent MTTotal pulses 16.000Total pulses 16.000No additional antidepressant effect of active rTMS.No additional antidepressant effect of active rTMS.

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SHAM-CONTROLLED STUDIESSHAM-CONTROLLED STUDIES20042004

Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA.Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA.

Repetitive transcranial magnetic stimulation is as effective as Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4.disease. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4.

42 patients. Not medication-resistant.42 patients. Not medication-resistant.Not medication-free.Not medication-free.15 Hz15 Hz10 sessions.10 sessions.Group 1: active rTMS and placebo drug treatmentGroup 1: active rTMS and placebo drug treatmentGroup 2: sham rTMS and fluoxetine 20 mg/day. Group 2: sham rTMS and fluoxetine 20 mg/day. Depression scores were improved to the same extent in both Depression scores were improved to the same extent in both

groups after two weeks of treatment (HDRS 38% for group 1, 41% for groups after two weeks of treatment (HDRS 38% for group 1, 41% for group 2). At week 8 there was a tendency for worse motor UPDRS group 2). At week 8 there was a tendency for worse motor UPDRS (Unified Parkinson’s Disease Rating Scale) scores in group 2. ADL (Unified Parkinson’s Disease Rating Scale) scores in group 2. ADL (Acitivities of Daily Living) showed improvement at week 8 only in (Acitivities of Daily Living) showed improvement at week 8 only in group 1. MMSE (Minimental State Examination) improved in both group 1. MMSE (Minimental State Examination) improved in both groups after treatment, but faster in group 1 than in group 2. There groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. rTMS has the were fewer adverse effects in group 1 than in group 2. rTMS has the same antidepressant efficacy as fluoxetine and may have the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.cognitive improvement, with fewer adverse effects.

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Koerselman F, Laman D, van Duijn H, van Duijn M, Willems Koerselman F, Laman D, van Duijn H, van Duijn M, Willems M M

A 3-month, follow-up, randomized, placebo-controlled A 3-month, follow-up, randomized, placebo-controlled study of repetitive transcranial magnetic stimulation in study of repetitive transcranial magnetic stimulation in depression. depression. J Clin Psychiatry J Clin Psychiatry 65(10):1323-1328.65(10):1323-1328.

55 patients. Drug-resistance NA.55 patients. Drug-resistance NA.Not medication-free.Not medication-free.Left DLPFC Left DLPFC 20 Hz20 Hz10 sessions.10 sessions.Intensity 80 percent MTIntensity 80 percent MTTotal pulses 8000Total pulses 8000No difference between active and 45 deg sham TMS after No difference between active and 45 deg sham TMS after

2 weeks of treatment. However, at 12 weeks, the active TMS 2 weeks of treatment. However, at 12 weeks, the active TMS group was significantly less depressed than the sham group.group was significantly less depressed than the sham group.

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SHAM-CONTROLLED STUDIESSHAM-CONTROLLED STUDIES20052005

Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski Mansur C, Myczkowski

ML, Moreno RA, Marcolin MA. Biol Psychiatry. 2005 Jan ML, Moreno RA, Marcolin MA. Biol Psychiatry. 2005 Jan 15;57(2):162-6.15;57(2):162-6.

Transcranial magnetic stimulation accelerates the Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study.double-blind placebo-controlled study.

46 patients 46 patients All patients were concomitantly taking amitriptyline (mean dose All patients were concomitantly taking amitriptyline (mean dose

110 mg/day).110 mg/day).Left DLPFCLeft DLPFC5 Hz5 Hz20 sessions20 sessionsIntensity 120 percent MTIntensity 120 percent MTTotal pulses 25.000Total pulses 25.000rTMS had a significantly faster response to amitriptyline. There rTMS had a significantly faster response to amitriptyline. There

was a significant decrease in HAM-D/17 scores, already after the was a significant decrease in HAM-D/17 scores, already after the first week of treatment compared with sham. The decrease in HAM-first week of treatment compared with sham. The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth with the sham group throughout the study (p < .001 at fourth week). week).

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rTMS versus ECTrTMS versus ECT

Since 2000 until today, 7 studies comparing Since 2000 until today, 7 studies comparing rTMS with ECT and some case reports have rTMS with ECT and some case reports have

been publishes. In non-psychotic depression, been publishes. In non-psychotic depression, it was found that the efficacy of rTMS was it was found that the efficacy of rTMS was nearly equal to that of ECT, with a much nearly equal to that of ECT, with a much

more favorable side-effect profile. more favorable side-effect profile.

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rTMS versus ECT rTMS versus ECT 20002000

Grunhaus L, Dannon PN, Schreiber S, et al Grunhaus L, Dannon PN, Schreiber S, et al Repetitive transcranial magnetic stimulation is as effective Repetitive transcranial magnetic stimulation is as effective

as electroconvulsive therapy in the treatment of nondelusional as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. major depressive disorder: an open study. Biol PsychiatryBiol Psychiatry 47:314-24.47:314-24.

40 patients referred for ECT40 patients referred for ECTrTMS group medication-free.rTMS group medication-free.Left DLPFCLeft DLPFC10 Hz 10 Hz Intensity 90 percent MTIntensity 90 percent MT20 sessions 20 sessions Total pulses 8000Total pulses 80007/16 responded to rTMS;12/18 to ECT. Among 7/16 responded to rTMS;12/18 to ECT. Among

nonpsychotic depressed 5/8 responded to rTMS; 5/10 to ECT. nonpsychotic depressed 5/8 responded to rTMS; 5/10 to ECT. Among psychotically depressed, only 2/8 responded to rTMS; Among psychotically depressed, only 2/8 responded to rTMS; 7/8 to ECT. 7/8 to ECT.

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rTMS versus ECT rTMS versus ECT 20002000

Pridmore S.Pridmore S.Substitution of rapid transcranial magnetic stimulation Substitution of rapid transcranial magnetic stimulation

treatments for electroconvulsive therapy treatments in a course of treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. electroconvulsive therapy. Depress Anxiety. Depress Anxiety. 2000;12(3):118-23.2000;12(3):118-23.

22 patients22 patientsRandomized, single-blind, controlled study. Randomized, single-blind, controlled study. Two streams were conducted: Two streams were conducted: Stream 1 received non-dominant unilateral (UL) ECT only, Stream 1 received non-dominant unilateral (UL) ECT only,

treatments being given 3 times per week for 2 weeks (11 treatments being given 3 times per week for 2 weeks (11 patients). patients).

Stream 2 received a combination of treatments: one UL ECT on Stream 2 received a combination of treatments: one UL ECT on Day 1 and rTMS on the following 4 days, all repeated once, after a Day 1 and rTMS on the following 4 days, all repeated once, after a 2-day respite (11 patients). 2-day respite (11 patients).

There was no evidence that the antidepressant effect of the There was no evidence that the antidepressant effect of the ECT only stream was superior to that of the ECT plus rTMS stream. ECT only stream was superior to that of the ECT plus rTMS stream. There was no increase in subjective side-effects in the ECT plus There was no increase in subjective side-effects in the ECT plus rTMS stream. On the contrary, this stream was accompanied by rTMS stream. On the contrary, this stream was accompanied by less side effects than the ECT only stream in this study. less side effects than the ECT only stream in this study.

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rTMS versus ECT rTMS versus ECT 20002000

Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M Comparison of unlimited numbers of rapid transcranial magnetic Comparison of unlimited numbers of rapid transcranial magnetic

stimulation (rTMS) and ECT treatment sessions in major depressive stimulation (rTMS) and ECT treatment sessions in major depressive episode. episode. Int J NeuropsychopharmacolInt J Neuropsychopharmacol 3:129-134. 3:129-134.

32 patients. Medication-resistant.32 patients. Medication-resistant.Not medication-free.Not medication-free.Left DLPFCLeft DLPFC20 Hz20 HzIntensity 100 percent motor thresholdIntensity 100 percent motor threshold10-16 sessions (until remission occurred or response plateaued)10-16 sessions (until remission occurred or response plateaued)Total pulses 10.000-16.000Total pulses 10.000-16.000Gave unlimited number of rTMS sessions (mean 12.2, SD 3.4). Gave unlimited number of rTMS sessions (mean 12.2, SD 3.4).

Compared to group of 16 patients receiving unlimited ECT treatments Compared to group of 16 patients receiving unlimited ECT treatments (mean 6.2, SD 1.6). No significant difference between the groups in HDRS (mean 6.2, SD 1.6). No significant difference between the groups in HDRS improvement. Patients receiving ECT had significantly greater decrease in improvement. Patients receiving ECT had significantly greater decrease in Beck Depression Inventory scores. A significant main effect for treatment Beck Depression Inventory scores. A significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on measures of 0.656], reflecting an advantage for ECT patients on measures of depression overall, however, rTMS produced comparable results on a depression overall, however, rTMS produced comparable results on a number of measures. Blind raters using the 17-item Hamilton Depression number of measures. Blind raters using the 17-item Hamilton Depression Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and the percentage improvement over the course of same (68.8%), and the percentage improvement over the course of treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not significantly different. Significant differences were shown (p & 0.03) in significantly different. Significant differences were shown (p & 0.03) in percentage improvement on Beck Depression Inventory ratings (rTMS, percentage improvement on Beck Depression Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings of mood (rTMS 42.3%; ECT, 57%).of mood (rTMS 42.3%; ECT, 57%).

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rTMS versus ECTrTMS versus ECT20012001

Smesny S, Volz HP, Liepert J, Tauber R, Hochstetter A, Sauer H.Smesny S, Volz HP, Liepert J, Tauber R, Hochstetter A, Sauer H. Repetitive transcranial magnetic stimulation (rTMS) in the acute Repetitive transcranial magnetic stimulation (rTMS) in the acute

and long-term therapy of refractory depression--a case report]. and long-term therapy of refractory depression--a case report]. Nervenarzt 2001 Sep;72(9):734-8Nervenarzt 2001 Sep;72(9):734-8

A patient with therapy-resistant major depression has been A patient with therapy-resistant major depression has been hospitalized for 60 months during the last 7 years. hospitalized for 60 months during the last 7 years.

Not even five electroconvulsive therapy (ECT) series (61 single Not even five electroconvulsive therapy (ECT) series (61 single applications) brought lasting remission of symptoms. As cognitive applications) brought lasting remission of symptoms. As cognitive deficits developed and prolonged postnarcotic recovery times were deficits developed and prolonged postnarcotic recovery times were observed, further ECT was contraindicated. observed, further ECT was contraindicated.

(rTMS) to the left frontal cortex (rTMS) to the left frontal cortex Only a few rTMS applications already caused an obvious Only a few rTMS applications already caused an obvious

brightening in mood, remission of depressive delusional brightening in mood, remission of depressive delusional symptoms, and an increase in personal interests and activities. symptoms, and an increase in personal interests and activities. After 4 weeks of daily treatment, the patient was discharged from After 4 weeks of daily treatment, the patient was discharged from the ward. The rTMS treatments and psychotherapeutic counseling the ward. The rTMS treatments and psychotherapeutic counseling have been continued on an outpatient basis. Thus, pharmaco- and have been continued on an outpatient basis. Thus, pharmaco- and psychotherapeutic interventions combined with rTMS led to psychotherapeutic interventions combined with rTMS led to persistent symptom remission and social reintegration.persistent symptom remission and social reintegration.

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rTMS versus ECT rTMS versus ECT 20012001

Dannon PN, Grunhaus L.Dannon PN, Grunhaus L. Effect of electroconvulsive therapy in repetitive transcranial Effect of electroconvulsive therapy in repetitive transcranial

magnetic stimulation non-responder MDD patients: a magnetic stimulation non-responder MDD patients: a preliminary study. Int J Neuropsychopharmacol. 2001 preliminary study. Int J Neuropsychopharmacol. 2001 Sep;4(3):265-8.Sep;4(3):265-8.

The aim was to measure the effectiveness of ECT in-The aim was to measure the effectiveness of ECT in-patients who had failed to respond to a course of repetitive patients who had failed to respond to a course of repetitive transcranial magnetic stimulation (rTMS) treatment. transcranial magnetic stimulation (rTMS) treatment.

17 patients with severe MDD who had not responded to a 17 patients with severe MDD who had not responded to a course of rTMS were switched to receive ECT treatments. course of rTMS were switched to receive ECT treatments.

7 out of 17 patients responded to ECT. (3 out of 5 non-7 out of 17 patients responded to ECT. (3 out of 5 non-psychotics and 4 out of 12 psychotic patients). psychotics and 4 out of 12 psychotic patients).

ECT seems to be an effective treatment for 40% of patients ECT seems to be an effective treatment for 40% of patients who failed to respond to rTMS treatment. who failed to respond to rTMS treatment.

Whether this is a result of reduced responsiveness to ECT in Whether this is a result of reduced responsiveness to ECT in rTMS-resistant patients or a consequence of small sample rTMS-resistant patients or a consequence of small sample size requires further study.size requires further study.

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rTMS versus ECTrTMS versus ECT20012001

Hasey G.Hasey G. Transcranial magnetic stimulation in the treatment of mood Transcranial magnetic stimulation in the treatment of mood

disorder: a review and comparison with electroconvulsive disorder: a review and comparison with electroconvulsive therapy. Can J Psychiatry. 2001 Oct;46(8):720-7.therapy. Can J Psychiatry. 2001 Oct;46(8):720-7.

The potential for unwanted side effects is substantially The potential for unwanted side effects is substantially reduced, compared with ECT. reduced, compared with ECT.

In open trials, rTMS and ECT are reported to be equally In open trials, rTMS and ECT are reported to be equally efficacious for patients having depression without efficacious for patients having depression without psychosis. psychosis.

But the therapeutic benefits reported in double-blind sham-But the therapeutic benefits reported in double-blind sham-rTMS controlled trials are more modest. rTMS controlled trials are more modest.

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rTMS versus ECTrTMS versus ECT20022002

Janicak PG, Dowd SM, Martis B, et al Janicak PG, Dowd SM, Martis B, et al Repetitive transcranial magnetic stimulation versus Repetitive transcranial magnetic stimulation versus

electroconvulsive therapy for major depression: preliminary electroconvulsive therapy for major depression: preliminary results of a randomized trial. results of a randomized trial. Biol PsychiatryBiol Psychiatry 51:659-67. 51:659-67.

25 patients. Medication-resistant.25 patients. Medication-resistant.Not medication-free.Not medication-free.Left DLPFCLeft DLPFC10 Hz10 HzIntensity 110 percent motor thresholdIntensity 110 percent motor threshold10-20 sessions 10-20 sessions Total pulses 10.000-20.000Total pulses 10.000-20.000Patients received either rTMS or bitemporal ECT (4-12 Patients received either rTMS or bitemporal ECT (4-12

treatments). There was a raw difference in mean change in treatments). There was a raw difference in mean change in HDRS between the groups (55% with rTMS, 64% with ECT), but HDRS between the groups (55% with rTMS, 64% with ECT), but no statistically significant difference. There was a 46% response no statistically significant difference. There was a 46% response rate with rTMS and a 56% response rate with ECT (not rate with rTMS and a 56% response rate with ECT (not statistically significant).statistically significant).

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rTMS versus ECT rTMS versus ECT 20022002

Dannon PN, Dolberg OT, Schreiber S, Grunhaus L.Dannon PN, Dolberg OT, Schreiber S, Grunhaus L. Three and six-month outcome following courses of either ECT or rTMS Three and six-month outcome following courses of either ECT or rTMS

in a population of severely depressed individuals--preliminary report. in a population of severely depressed individuals--preliminary report. Biol Psychiatry. 2002 Apr 15;51(8):687-90.Biol Psychiatry. 2002 Apr 15;51(8):687-90.

3- and 6-month outcomes of a group of patients treated with either 3- and 6-month outcomes of a group of patients treated with either ECT (n = 20) or (rTMS) (n = 21). ECT (n = 20) or (rTMS) (n = 21).

With or without psychotic features referred for ECT With or without psychotic features referred for ECT Forty-one patients who responded to either treatment constituted the Forty-one patients who responded to either treatment constituted the

sample. sample. Medications were routinely prescribed. Medications were routinely prescribed. There were no differences in the 6-month relapse rate between the There were no differences in the 6-month relapse rate between the

groups. groups. Overall, 20% of the patients relapsed (four from the ECT group and Overall, 20% of the patients relapsed (four from the ECT group and

four from the rTMS group). four from the rTMS group). Patients reported equally low and not significantly different scores in Patients reported equally low and not significantly different scores in

the HRSD (ECT group 8.4 +/- 5.6 and TMS group 7.9 +/- 7.1) at the 6-the HRSD (ECT group 8.4 +/- 5.6 and TMS group 7.9 +/- 7.1) at the 6-month follow up. month follow up.

The clinical gains obtained with rTMS last at least as long as those The clinical gains obtained with rTMS last at least as long as those obtained with ECT.obtained with ECT.

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rTMS versus ECT rTMS versus ECT 20032003

Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN A randomized controlled comparison of electroconvulsive A randomized controlled comparison of electroconvulsive

therapy and repetitive transcranial magnetic stimulation in therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. severe and resistant nonpsychotic major depression. Biol Biol PsychiatryPsychiatry 53:324-31. 53:324-31.

41 patients with nonpsychotic MDD referred for ECT 41 patients with nonpsychotic MDD referred for ECT Not medication-free.Not medication-free.Left DLPFCLeft DLPFC10 Hz10 HzIntensity 90 percent motor thresholdIntensity 90 percent motor threshold20 sessions 20 sessions Total pulses 24.000Total pulses 24.000No significant difference in HDRS decrease between rTMS and No significant difference in HDRS decrease between rTMS and

ECT patients. 12/20 ECT responders and 11/20 rTMS responders ECT patients. 12/20 ECT responders and 11/20 rTMS responders (>50% decr in HDRS, final HDRS <10); no significant difference (>50% decr in HDRS, final HDRS <10); no significant difference between groups). 30% remission rate (final HAMD<9) in ECT and between groups). 30% remission rate (final HAMD<9) in ECT and rTMS groups. For ECT group, patients received unilateral ECT rTMS groups. For ECT group, patients received unilateral ECT initially, then bilateral ECT if no response after 6 treatments; 13 initially, then bilateral ECT if no response after 6 treatments; 13 patients received unilateral ECT, 7 received bilateral ECT -- no patients received unilateral ECT, 7 received bilateral ECT -- no significant difference in response rate between these groups.significant difference in response rate between these groups.

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rTMS versus ECTrTMS versus ECT20042004

Conca A, Hrubos W, Di Pauli J, Konig P, Hausmann A.Conca A, Hrubos W, Di Pauli J, Konig P, Hausmann A. ECT response after relapse during continuation repetitive ECT response after relapse during continuation repetitive

transcranial magnetic stimulation. A case report. Eur transcranial magnetic stimulation. A case report. Eur Psychiatry. Apr;19(2):118-9.Psychiatry. Apr;19(2):118-9.

A woman who exerted a recurrent moderate major A woman who exerted a recurrent moderate major depressive episode, 6 months after discontinuation of depressive episode, 6 months after discontinuation of maintenance ECT. She responded to acute rTMS treatment maintenance ECT. She responded to acute rTMS treatment which was followed by the rTMS maintenance-protocol. which was followed by the rTMS maintenance-protocol. Within 2 months of continuation rTMS she relapsed Within 2 months of continuation rTMS she relapsed suffering from a severe non psychotic depressive episode suffering from a severe non psychotic depressive episode and had to be switched to a successful ECT. In this patient and had to be switched to a successful ECT. In this patient rTMS had a good clinical impact as an acute treatment rTMS had a good clinical impact as an acute treatment strategy, but failed to prevent relapse as the continuation strategy, but failed to prevent relapse as the continuation ECT previously did in the same patient. ECT previously did in the same patient.

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rTMS versus ECT rTMS versus ECT 20042004

Kozel FA, George MS, Simpson KN.Kozel FA, George MS, Simpson KN. Decision analysis of the cost-effectiveness of repetitive Decision analysis of the cost-effectiveness of repetitive

transcranial magnetic stimulation versus electroconvulsive transcranial magnetic stimulation versus electroconvulsive therapy for treatment of nonpsychotic severe depression. CNS therapy for treatment of nonpsychotic severe depression. CNS Spectr. Jun;9(6):476-82.Spectr. Jun;9(6):476-82.Compared the costs of three different treatment strategies for Compared the costs of three different treatment strategies for nonpsychotic severe depression. 1-ECT alonenonpsychotic severe depression. 1-ECT alone

2-rTMS alone2-rTMS alone 3-rTMS followed by ECT for nonresponders (rTMS-to-ECT). 3-rTMS followed by ECT for nonresponders (rTMS-to-ECT). Calculated 12-month costs and quality adjusted life years (QALYs) Calculated 12-month costs and quality adjusted life years (QALYs)

for the three treatment options for all nonpsychotic, severely for the three treatment options for all nonpsychotic, severely depressed United States patients who would have otherwise depressed United States patients who would have otherwise undergone ECT. undergone ECT.

The additional cost of using ECT alone compared with rTMS alone The additional cost of using ECT alone compared with rTMS alone was 460,031 US dollars per quality adjusted year of life gained. was 460,031 US dollars per quality adjusted year of life gained. For ECT versus rTMS-to-ECT, there was both an increased cost For ECT versus rTMS-to-ECT, there was both an increased cost and a loss of 1,538 QALYs with ECT alone. and a loss of 1,538 QALYs with ECT alone.

If rTMS were to be made widely available clinically in the US, it If rTMS were to be made widely available clinically in the US, it would offer a substantial economic benefit over ECT in treating would offer a substantial economic benefit over ECT in treating resistant depression. Using rTMS-to-ECT offers not only an resistant depression. Using rTMS-to-ECT offers not only an economic advantage but also an increase in QALYs. economic advantage but also an increase in QALYs.

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RECENT REVIEWS OR RECENT REVIEWS OR META-ANALYSESMETA-ANALYSES

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RECENT REVIEWS OR META-ANALYSESRECENT REVIEWS OR META-ANALYSES2003 2003

Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Kulisevsky Kulisevsky

Repetitive transcranial magnetic stimulation for the Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-treatment of depression. Systematic review and meta-analysis. JBr J Psychiatry. 2003 Jun;182:480-91.analysis. JBr J Psychiatry. 2003 Jun;182:480-91.

Randomised controlled trials that compared rTMS with Randomised controlled trials that compared rTMS with sham were included.sham were included.

14 studies met the criteria. The quality of the included 14 studies met the criteria. The quality of the included studies was low. studies was low.

Pooled analysis using the Hamilton Rating Scale for Pooled analysis using the Hamilton Rating Scale for Depression showed an effect in favour of rTMS compared Depression showed an effect in favour of rTMS compared with sham after 2 weeks of treatment, but this was not with sham after 2 weeks of treatment, but this was not significant at the 2-week follow-up.significant at the 2-week follow-up.

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RECENT REVIEWS OR META-ANALYSESRECENT REVIEWS OR META-ANALYSES20032003

Gershon AA, Dannon PN, Grunhaus L.Gershon AA, Dannon PN, Grunhaus L. Am J Psychiatry. 2003 May;160(5):835-45.Am J Psychiatry. 2003 May;160(5):835-45. Transcranial magnetic stimulation in the treatment of Transcranial magnetic stimulation in the treatment of

depression.depression. Review of English-language controlled studies of Review of English-language controlled studies of

nonconvulsive TMS therapy for depression that appeared in nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in 2003. study that was in press in 2002 and was published in 2003.

Most data support an antidepressant effect of high-frequency Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. repetitive TMS administered to the left prefrontal cortex.

The absence of psychosis, younger age, and certain brain The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. physiologic markers might predict treatment success.

Technical parameters possibly affecting treatment success Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these include intensity and duration of treatment, but these suggestions require systematic testing. suggestions require systematic testing.

TMS shows promise as a novel antidepressant treatment. TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment patient populations most likely to benefit and treatment parameters most likely to produce success. parameters most likely to produce success.

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RECENT REVIEWS OR META-ANALYSESRECENT REVIEWS OR META-ANALYSES20032003

Padberg F, Moller HJ.Padberg F, Moller HJ. Repetitive transcranial magnetic stimulation : does it have Repetitive transcranial magnetic stimulation : does it have

potential in the treatment of depression? CNS Drugs. potential in the treatment of depression? CNS Drugs. 2003;17(6):383-403.2003;17(6):383-403.

Though conducted with small sample sizes, the majority of the Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient however, varied from modest to substantial, and the patient selection focused on selection focused on therapy-resistant casestherapy-resistant cases. Moreover, the . Moreover, the average average treatment duration was approximately 2 weekstreatment duration was approximately 2 weeks, which is , which is short compared with other antidepressant interventions. Larger short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to antidepressant effectiveness of rTMS, have not been conducted to date. A putative future application of rTMS may be the treatment date. A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date. not been a focus of clinical trials to date.

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RECENT REVIEWS OR META-ANALYSESRECENT REVIEWS OR META-ANALYSES20052005

Couturier JL.Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic Efficacy of rapid-rate repetitive transcranial magnetic

stimulation in the treatment of depression: a systematic review stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. 2005 Mar;30(2):83-90.and meta-analysis. J Psychiatry Neurosci. 2005 Mar;30(2):83-90.

1966 until July 2003. 1966 until July 2003. Eighty-seven randomized controlled trials Eighty-seven randomized controlled trials Nineteen of these involved treatment of a major depressive Nineteen of these involved treatment of a major depressive

episode, and these were reviewed. episode, and these were reviewed. Six met more specific inclusion criteria including the use of Six met more specific inclusion criteria including the use of

rapid-rate stimulation, application to the left dorsolateral rapid-rate stimulation, application to the left dorsolateral prefrontal cortex, evaluation with the 21-item Hamilton Rating prefrontal cortex, evaluation with the 21-item Hamilton Rating Scale for Depression (HAM-D) and use of an intent-to-treat Scale for Depression (HAM-D) and use of an intent-to-treat analysis. analysis.

Two of these reported a significantly greater improvement in Two of these reported a significantly greater improvement in mood symptoms in the treatment versus the sham group. mood symptoms in the treatment versus the sham group.

No different from sham treatment in major depression; No different from sham treatment in major depression; however, the power within these studies to detect a difference however, the power within these studies to detect a difference was generally low. Randomized controlled trials with sufficient was generally low. Randomized controlled trials with sufficient power to detect a clinically meaningful difference are required. power to detect a clinically meaningful difference are required.

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Issues in the clinical use of Issues in the clinical use of rTMS:rTMS:Stimulation siteStimulation site

Which part of the brain?Which part of the brain? Dorsolateral prefrontal cortex (DLPFC) was stimulated in many studiesDorsolateral prefrontal cortex (DLPFC) was stimulated in many studies Vertex, frontal, parietooccipital cortex and multiple studies in a few studiesVertex, frontal, parietooccipital cortex and multiple studies in a few studies Right or leftRight or left Left PLPFC was stimulated in many studiesLeft PLPFC was stimulated in many studies Right side in a few studiesRight side in a few studiesIntensityIntensity 80, 90, 100 or 110 percent of motor threshold 80, 90, 100 or 110 percent of motor threshold High or low frequencyHigh or low frequency High frequency (above 1 Hz) was given in many studiesHigh frequency (above 1 Hz) was given in many studies Low frequency (below 1 Hz) in a few studiesLow frequency (below 1 Hz) in a few studiesDuration of treatmentDuration of treatment Ten sessions (consecutive weekdays) in many studiesTen sessions (consecutive weekdays) in many studies 12, 14, 16, 20 sessions in a few studies12, 14, 16, 20 sessions in a few studies 1,5, 8 sessions in a few studies1,5, 8 sessions in a few studiesTotal pulsesTotal pulses 30, 60, 400, 500, 800, 1200, 1250, 2000, 2500, 3000, 4000, 5000, 6000, 6500, 30, 60, 400, 500, 800, 1200, 1250, 2000, 2500, 3000, 4000, 5000, 6000, 6500,

8000, 10000, 14000, 12000, 15000, 16000, 175000, 20000, 480000 pulses were 8000, 10000, 14000, 12000, 15000, 16000, 175000, 20000, 480000 pulses were given in different studiesgiven in different studies

Which patient groupsWhich patient groups Young or elderly?Young or elderly?Which type of depression?Which type of depression? Psychotic or non-psychotic?Psychotic or non-psychotic?

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Which patients with major depression Which patients with major depression benefit from prefrontal repetitive benefit from prefrontal repetitive

magnetic stimulation?magnetic stimulation? Data from 10 open and 7 sham controlled studies. Comprising more than 300 Data from 10 open and 7 sham controlled studies. Comprising more than 300

patients with major depression have been published to date. patients with major depression have been published to date. Positive predictors for antidepressive response of prefrontal rTMS become Positive predictors for antidepressive response of prefrontal rTMS become

apparent: apparent: 1) younger age, 1) younger age, 2) somatic signs of anxiety, 2) somatic signs of anxiety, 3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli, 3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli, 4) cortical hypermetabolism below the 1 Hz pulsed coil.4) cortical hypermetabolism below the 1 Hz pulsed coil.Negative predictors of response to prefrontal rTMS were: Negative predictors of response to prefrontal rTMS were: 1) Advanced age, 1) Advanced age, 2) prefrontal atrophy, 2) prefrontal atrophy, 3) cognitive impairment in neuropsychological tasks assigned to the prefrontal 3) cognitive impairment in neuropsychological tasks assigned to the prefrontal

cortexcortex4) psychotic symptoms, 4) psychotic symptoms, 5) cortical hyperactivity below 10 Hz pulsed coil 5) cortical hyperactivity below 10 Hz pulsed coil 6) non-response to electroconvulsive therapy (ECT). 6) non-response to electroconvulsive therapy (ECT). Eschweiler GW, Plewnia C, Bartels M.Eschweiler GW, Plewnia C, Bartels M.Fortschr Neurol Psychiatr. 2001 Fortschr Neurol Psychiatr. 2001

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In paralel studies, rTMS is only In paralel studies, rTMS is only modestly superior to sham, but modestly superior to sham, but

nearly equally effective as ECT. Why? nearly equally effective as ECT. Why? In sham studies, the coil is positioned such that less of the magnetic In sham studies, the coil is positioned such that less of the magnetic

stimulus penetrates the brain. The sham treatment in controls involve stimulus penetrates the brain. The sham treatment in controls involve discharging the coil at an angle to the head with only one edge in contact discharging the coil at an angle to the head with only one edge in contact with the scalpas opposed to holding it tangential to the scalp as in real with the scalpas opposed to holding it tangential to the scalp as in real rTMS (the coil is positioned as 90 or 45 degrees). The question of whether rTMS (the coil is positioned as 90 or 45 degrees). The question of whether they are truly inactive have been debated. Some studies may be they are truly inactive have been debated. Some studies may be complicated by active sham controls.complicated by active sham controls.

Loo CK, Taylor JL, Gandevia SC, McDarmont BN, Mitchell PB, Sachdev PS.Loo CK, Taylor JL, Gandevia SC, McDarmont BN, Mitchell PB, Sachdev PS. Transcranial magnetic stimulation (TMS) in controlled treatment studies: Transcranial magnetic stimulation (TMS) in controlled treatment studies:

are some "sham" forms active? are some "sham" forms active? Biol Psychiatry. 2000 Feb 15;47(4):325-Biol Psychiatry. 2000 Feb 15;47(4):325-31.31.

In nine normal subjects, single TMS pulses were administered at a range of In nine normal subjects, single TMS pulses were administered at a range of intensities with a "figure eight" coil held in various positions (with one edge intensities with a "figure eight" coil held in various positions (with one edge touching the scalpat a 45 degrees to the scalp) touching the scalpat a 45 degrees to the scalp) over the left primary motor over the left primary motor cortex.cortex.

Responses were measured as Responses were measured as motor-evoked potentialsmotor-evoked potentials in the right in the right first first dorsal interosseus muscledorsal interosseus muscle. .

Scalp sensation to TMS with the coil in various positions over the prefrontal Scalp sensation to TMS with the coil in various positions over the prefrontal area was also assessed. area was also assessed.

Sham variants that more closely simulated the experience of TMS also Sham variants that more closely simulated the experience of TMS also generated more motor evoked potentials, although less than real generated more motor evoked potentials, although less than real treatment. None of the coil positions studied met the criteria for an ideal treatment. None of the coil positions studied met the criteria for an ideal sham. Arrangements associated with a higher likelihood of scalp sensation sham. Arrangements associated with a higher likelihood of scalp sensation were also more likely to stimulate the cortex. were also more likely to stimulate the cortex.

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FIGURE Number of Petients Who Responded to FIGURE Number of Petients Who Responded to Transcranial Magnetic Stimulation (TMS) in Controlled Transcranial Magnetic Stimulation (TMS) in Controlled Studies of TMS for the Treatment of Depression, by Studies of TMS for the Treatment of Depression, by Technical Parameters of TMSTechnical Parameters of TMS

0

10

20

30

40

50

60

Perc

en

tag

e o

f P

ati

en

ts W

ho R

esp

on

ded

to T

MS

10 >10(N=70 N=69)

Duration(days)

80-90 100-110(N=90) (N=49)

Intensity(percent of

motor threshold)

800- 1200-10001600

(N=35) (N=84)Pulses per Day

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Many studies of rTMS in Many studies of rTMS in depression included both depression included both

unipolar and bipolar unipolar and bipolar patients. Those with patients. Those with

bipolar as well as unipolar bipolar as well as unipolar depression usually depression usually

benefited from rTMS. benefited from rTMS.

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A study including both A study including both unipolar and bipolar patients unipolar and bipolar patients

compared rTMS and compared rTMS and electroconvulsive therapy electroconvulsive therapy (ECT) and found significant (ECT) and found significant difference neither in mania difference neither in mania

scores nor in improvement in scores nor in improvement in depression. depression.

Janicak PG, Dowd SM, Martis B, Alam D, Beedle Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J, Strong MJ, Sharma R, Rosen C, D, Krasuski J, Strong MJ, Sharma R, Rosen C, Viana M: Repetitive transcranial magnetic Viana M: Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for stimulation versus electroconvulsive therapy for major depression: preliminary results of a major depression: preliminary results of a randomized trial. Biol Psychiatry 2002 Apr 15; randomized trial. Biol Psychiatry 2002 Apr 15; 51(8):659-67.51(8):659-67.

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Another study conducted on 23 Another study conducted on 23 patients having bipolar patients having bipolar

depression who received either depression who received either active or sham rTMS produced a active or sham rTMS produced a

trend but not statistically trend but not statistically significant greater improvement significant greater improvement in daily subjective mood ratings in daily subjective mood ratings

post-treatment, and no one post-treatment, and no one switched to mania (15). switched to mania (15). Nahas Z, Kozel, Li X, Anderson B, George MS: Nahas Z, Kozel, Li X, Anderson B, George MS:

Left prefrontal transcranial magnetic stimulation Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar (TMS) treatment of depression in bipolar

affective disorder: a pilot study of acute safety affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003 Feb; 5(1):40-7. and efficacy. Bipolar Disord 2003 Feb; 5(1):40-7.

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There are case reports showing that There are case reports showing that transcranial magnetic stimulation has transcranial magnetic stimulation has

induced mania in patients suffering from induced mania in patients suffering from bipolar depression. bipolar depression.

Garcia-Toro M: Acute manic symptomatology during Garcia-Toro M: Acute manic symptomatology during repetitive transcranial magnetic stimulation in a patient repetitive transcranial magnetic stimulation in a patient with bipolar depression. Br J Psychiatry 1999 Nov; with bipolar depression. Br J Psychiatry 1999 Nov; 175:491.175:491.

Nedjat S, Folkerts HW: Induction of a reversible state of Nedjat S, Folkerts HW: Induction of a reversible state of hypomania by rapid-rate transcranial magnetic stimulation hypomania by rapid-rate transcranial magnetic stimulation over the left prefrontal lobe. J ECT 1999 Jun; 15(2):166-8.over the left prefrontal lobe. J ECT 1999 Jun; 15(2):166-8.

Dolberg OT, Schreiber S, Grunhaus L: Transcranial Dolberg OT, Schreiber S, Grunhaus L: Transcranial magnetic stimulation-induced switch into mania : a report magnetic stimulation-induced switch into mania : a report of two cases. Biol Psychiatry 2001 Mar 1; 49(5):468-70.of two cases. Biol Psychiatry 2001 Mar 1; 49(5):468-70.

Ella R, Zwanzger P, Stampfer R, Preuss UW, Muller-Ella R, Zwanzger P, Stampfer R, Preuss UW, Muller-Siecheneder F, Moller HJ, Padberg F: Switch to mania after Siecheneder F, Moller HJ, Padberg F: Switch to mania after slow rTMS of the right prefrontal cortex. J Clin Psychiatry slow rTMS of the right prefrontal cortex. J Clin Psychiatry 2002 Mar; 63(3):249.2002 Mar; 63(3):249.

Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis C, Politis A, Christodoulou GN: Induction of Masdrakis C, Politis A, Christodoulou GN: Induction of mania by rTMS: a report of two cases. Eur Psychiatry 2003 mania by rTMS: a report of two cases. Eur Psychiatry 2003 Jun; 18(4):196-8.Jun; 18(4):196-8.

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rTMS in the Treatment of rTMS in the Treatment of ManiaMania

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rTMS in the Treatment of ManiarTMS in the Treatment of Mania 19981998

Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. Transcranial magnetic stimulation in mania: a Transcranial magnetic stimulation in mania: a

controlled study.controlled study. Am J Psychiatry. 1998 Am J Psychiatry. 1998 Nov;155(11):1608-10.Nov;155(11):1608-10.

16 patients completed a 14-day double-blind, 16 patients completed a 14-day double-blind, controlled trial of controlled trial of right versus leftright versus left prefrontal prefrontal transcranial magnetic stimulation at 20 Hz (2-second transcranial magnetic stimulation at 20 Hz (2-second duration per train, 20 trains/day for 10 treatment duration per train, 20 trains/day for 10 treatment days). days).

Significantly more improvement was observed in Significantly more improvement was observed in patients treated with right than with left prefrontal patients treated with right than with left prefrontal transcranial magnetic stimulation. transcranial magnetic stimulation.

The therapeutic effect of transcranial magnetic The therapeutic effect of transcranial magnetic stimulation in mania may show laterality opposite to stimulation in mania may show laterality opposite to its effect in depression.its effect in depression.

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rTMS in the Treatment of ManiarTMS in the Treatment of Mania 20002000

Erfurth A, Michael N, Mostert C, Arolt V.Erfurth A, Michael N, Mostert C, Arolt V. Euphoric Mania and Rapid Transcranial Magnetic Stimulation.Euphoric Mania and Rapid Transcranial Magnetic Stimulation. Am J Am J

Psychiatry. 2000 May;157(5):835-6.Psychiatry. 2000 May;157(5):835-6. A patient with euphoric mania that was refractory to treatment with A patient with euphoric mania that was refractory to treatment with

sulthiame sulthiame Experienced marked improvement during monotherapy with Experienced marked improvement during monotherapy with right prefrontal right prefrontal

rapidrapid transcranial magnetic stimulation. transcranial magnetic stimulation. Eight weeks before hospital admission she Eight weeks before hospital admission she developed euphoric mania developed euphoric mania

despite lithiumdespite lithium treatment. Lithium treatment was discontinued, and a trial treatment. Lithium treatment was discontinued, and a trial with the antiepileptic drug with the antiepileptic drug sulthiame was initiated—unfortunately, with no sulthiame was initiated—unfortunately, with no effect after 3 weeks of treatment.effect after 3 weeks of treatment. Sulthiame treatment was tapered off, and Sulthiame treatment was tapered off, and monotherapy with rapid transcranial magnetic stimulation was begun. Right monotherapy with rapid transcranial magnetic stimulation was begun. Right prefrontal stimulation was performed (20 trains per session, a frequency of prefrontal stimulation was performed (20 trains per session, a frequency of 20 Hz for 2 seconds per train, and an intertrain interval of 1 minute). 20 Hz for 2 seconds per train, and an intertrain interval of 1 minute).

Ms. A was given five consecutive sessions during weeks 1 and 2 and three Ms. A was given five consecutive sessions during weeks 1 and 2 and three sessions during weeks 3 and 4. Her range of motor threshold was 66%–76%. sessions during weeks 3 and 4. Her range of motor threshold was 66%–76%. Her scores on the Bech-Rafaelsen Mania Scale slowly but continuously fell Her scores on the Bech-Rafaelsen Mania Scale slowly but continuously fell (28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21, and 8 on day 28). (28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21, and 8 on day 28). Her sleep disturbance and thought disorder seemed to respond particularly Her sleep disturbance and thought disorder seemed to respond particularly well to rapid transcranial magnetic stimulation. Ms. A was dismissed from well to rapid transcranial magnetic stimulation. Ms. A was dismissed from the hospital ward. Prophylactic treatment with the third-generation, the hospital ward. Prophylactic treatment with the third-generation, putative mood-stabilizing anticonvulsant topiramate was initiated for Ms. A putative mood-stabilizing anticonvulsant topiramate was initiated for Ms. A for obesity. for obesity.

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rTMS in the Treatment of ManiarTMS in the Treatment of Mania 20032003

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

Right prefrontal TMS versus sham treatment of mania: Right prefrontal TMS versus sham treatment of mania: a controlled studya controlled study. Bipolar Disord. 2003 Feb;5(1):36-9.. Bipolar Disord. 2003 Feb;5(1):36-9.

25 patients entered and 16 patients completed trial of right 25 patients entered and 16 patients completed trial of right versus left prefrontal TMS at 20 Hz, 2-sec duration per train, versus left prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for 10 treatment days. 20 trains per day for 10 treatment days.

Right active TMS versus right sham TMS Right active TMS versus right sham TMS Right TMS was no more effective than sham TMS. Right TMS was no more effective than sham TMS. It is possible that the previous results were due to an It is possible that the previous results were due to an

effect of left TMS to worsen mania. Alternatively, it is effect of left TMS to worsen mania. Alternatively, it is noted that the present patient group had much more noted that the present patient group had much more psychosis than the previous study of TMS in mania, psychosis than the previous study of TMS in mania, and depression studies have reported that psychosis and depression studies have reported that psychosis is a poor prognostic sign for TMS response.is a poor prognostic sign for TMS response.

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rTMS in the Treatment of ManiarTMS in the Treatment of Mania 20042004

Michael N, Erfurth A.Michael N, Erfurth A. Treatment of bipolar mania with right Treatment of bipolar mania with right

prefrontal rapid transcranial magnetic prefrontal rapid transcranial magnetic stimulation.stimulation. J Affect Disord. 2004 Mar;78(3):253-7. J Affect Disord. 2004 Mar;78(3):253-7.

9 in-patients diagnosed with mania 9 in-patients diagnosed with mania Right prefrontal Right prefrontal rapidrapid TMS TMS Open and prospective study. Open and prospective study. 8 of 9 patients received TMS as add-on treatment to 8 of 9 patients received TMS as add-on treatment to

an insufficient or only partially effective drug an insufficient or only partially effective drug therapy. therapy.

During the 4 weeks of TMS treatment a During the 4 weeks of TMS treatment a sustained reduction of manic symptoms in all sustained reduction of manic symptoms in all patients.patients.

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rTMS in the Treatment of ManiarTMS in the Treatment of Mania 20042004

Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Lipski H, Januel D. Lipski H, Januel D.

Repetitive transcranial magnetic stimulation as Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a an add-on therapy in the treatment of mania: a case series of eight patients. case series of eight patients. Psychiatry Res. 2004 Psychiatry Res. 2004 Sep 30;128(2):199-202. Sep 30;128(2):199-202.

Fast rTMS (five trains of 15 s, 80% of the motor Fast rTMS (five trains of 15 s, 80% of the motor threshold, 10 Hz) threshold, 10 Hz)

Right DLPFC Right DLPFC evaluated at baseline and at day 14. evaluated at baseline and at day 14. Not medication-free.Not medication-free. Significant improvement of manic symptoms at the end Significant improvement of manic symptoms at the end

of the trial. No side effects were reported. of the trial. No side effects were reported. However, these results have to be interpreted However, these results have to be interpreted

with caution since they derive from an open case with caution since they derive from an open case series and all the subjects were taking series and all the subjects were taking psychotropic medication during rTMS treatment.psychotropic medication during rTMS treatment.

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Does rTMS Induce Does rTMS Induce Mania?Mania?

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Does rTMS Induce Mania?Does rTMS Induce Mania?20042004

Tan O, Tarhan N, Coban A, Baripoglu Tan O, Tarhan N, Coban A, Baripoglu Repetitive transcranial magnetic stimulation in medication-Repetitive transcranial magnetic stimulation in medication-

resistant bipolar depression. resistant bipolar depression. Poster presentation in ECNS-ISNIP Poster presentation in ECNS-ISNIP Joint Meeting in September 2004, California Joint Meeting in September 2004, California

8 patients having drug-resistant severe bipolar depression 8 patients having drug-resistant severe bipolar depression open and uncontrolled study. open and uncontrolled study. The patients also used antipsychotic and/or mood stabilizing drugs.The patients also used antipsychotic and/or mood stabilizing drugs. 5 patients responded to the rTMS therapy recovering from 5 patients responded to the rTMS therapy recovering from

depression. 3 patients shifted to manic episodes.depression. 3 patients shifted to manic episodes. rTMS may be an effective method in the treatment of bipolar rTMS may be an effective method in the treatment of bipolar

depression. However, the fact that three patients out of eight depression. However, the fact that three patients out of eight switched to mania raises questions about its safety even though all switched to mania raises questions about its safety even though all of these patients were also taking antidepressant medications. of these patients were also taking antidepressant medications.

Left prefrontal cortex (Magstim, rapid, superrrapid high frequency Left prefrontal cortex (Magstim, rapid, superrrapid high frequency magnetic stimulator). Its intensity was the motor threshold that magnetic stimulator). Its intensity was the motor threshold that caused muscle movement when it was applied over the motor caused muscle movement when it was applied over the motor cortex. Other values of rTMS were 10 seconds, 25 Hz, 210 pulses cortex. Other values of rTMS were 10 seconds, 25 Hz, 210 pulses and 70 trains. and 70 trains.

The average of HDRS scores of the patients was 28.2. All responded The average of HDRS scores of the patients was 28.2. All responded to the rTMS therapy, that is, showed at least 50 percent decrease in to the rTMS therapy, that is, showed at least 50 percent decrease in HDRS scores. However, three patients shifted to manic episodes. HDRS scores. However, three patients shifted to manic episodes.

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Does rTMS Induce Mania?Does rTMS Induce Mania?20042004

Li X, Nahas Z, Anderson B, Kozel FA, George MS.Li X, Nahas Z, Anderson B, Kozel FA, George MS. Can left prefrontal rTMS be used as a Can left prefrontal rTMS be used as a

maintenance treatment for bipolar maintenance treatment for bipolar depression?depression? Depress Anxiety. 2004;20(2):98-100. Depress Anxiety. 2004;20(2):98-100.

S7 adults with bipolar depression who responded S7 adults with bipolar depression who responded acutely to TMS and were then treated with TMS acutely to TMS and were then treated with TMS weekly for up to 1weekly for up to 1 year. year.

Left prefrontal cortex at 110% motor threshold, 5 Left prefrontal cortex at 110% motor threshold, 5 Hz for 8 s for 40 trains. Hz for 8 s for 40 trains.

Three subjects completed 1 full year of weekly TMS Three subjects completed 1 full year of weekly TMS with an average Hamilton Rating Scale for with an average Hamilton Rating Scale for Depression of 13 (sd = 5.9) over the year. Depression of 13 (sd = 5.9) over the year.

These data suggest but do not prove that These data suggest but do not prove that TMS might eventually be used as an TMS might eventually be used as an adjunctive maintenance treatment for at adjunctive maintenance treatment for at least some patients with bipolar depression.least some patients with bipolar depression.

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Does rTMS Induce Mania?Does rTMS Induce Mania?20052005

Hagit Cohen, Ph.D., Zeev Kaplan, M.D., Moshe Hagit Cohen, Ph.D., Zeev Kaplan, M.D., Moshe Kotler, M.D., Irena Kouperman, M.D., Regina Kotler, M.D., Irena Kouperman, M.D., Regina Moisa, B.N.S., and Nimrod Grisaru, M.D.Moisa, B.N.S., and Nimrod Grisaru, M.D.

Repetitive Transcranial Magnetic Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Stimulation of the Right Dorsolateral Prefrontal Cortex in Posttraumatic Prefrontal Cortex in Posttraumatic Stress DisorderStress Disorder: A Double-Blind, Placebo-: A Double-Blind, Placebo-Controlled Study Controlled Study

2 of 18 patients developed a manic 2 of 18 patients developed a manic episode after the third of 10 sessions of episode after the third of 10 sessions of transcranial magnetic stimulation.transcranial magnetic stimulation.

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Does rTMS Induce Mania?Does rTMS Induce Mania?20052005

Huang CC, Su TP, Shan IK. Huang CC, Su TP, Shan IK. A case report of repetitive transcranial A case report of repetitive transcranial

magnetic stimulation-induced mania.magnetic stimulation-induced mania. Bipolar Disord. 2004 Oct;6(5):444-Bipolar Disord. 2004 Oct;6(5):444-5.5.

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Does rTMS Induce Mania?Does rTMS Induce Mania?20052005

Sakkas P, Mihalopoulou P, Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis Mourtzouhou P, Psarros C, Masdrakis V, Politis A, Christodoulou GN.V, Politis A, Christodoulou GN.

Induction of mania by rTMS: Induction of mania by rTMS: report of two cases.report of two cases. Eur Psychiatry. Eur Psychiatry. 2003 Jun;18(4):196-8.2003 Jun;18(4):196-8.

Using an intensive methodology of Using an intensive methodology of rTMS in two drug-resistant patients, rTMS in two drug-resistant patients, we observed a good antidepressant we observed a good antidepressant effect, but also, induction of manic effect, but also, induction of manic symptoms.symptoms.

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Does rTMS Induce Mania?Does rTMS Induce Mania?20012001

Dolberg OT, Schreiber S, Grunhaus L. Dolberg OT, Schreiber S, Grunhaus L. Transcranial magnetic stimulation-Transcranial magnetic stimulation-

induced switch into mania: a induced switch into mania: a report of two cases.report of two cases. Biol Psychiatry. Biol Psychiatry. 2001 Mar 1;49(5):468-70.2001 Mar 1;49(5):468-70.

Five times a week for 4 weeks. Five times a week for 4 weeks. A manic episode followed A manic episode followed

treatment with transcranial treatment with transcranial magnetic stimulation in two magnetic stimulation in two patients.patients.

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Garcia-Toro M.Garcia-Toro M. Acute manic symptomatology Acute manic symptomatology

during repetitive transcranial during repetitive transcranial magnetic stimulation in a patient magnetic stimulation in a patient with bipolar depression. Br J with bipolar depression. Br J Psychiatry. 1999 Nov;175:491.Psychiatry. 1999 Nov;175:491.

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CONCLUSIONSCONCLUSIONS

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Regarding literature and the present Regarding literature and the present study, study, it seems that left prefrontal TMS it seems that left prefrontal TMS leads to improvement in unipolar or leads to improvement in unipolar or bipolar depression while inducing bipolar depression while inducing mania; mania; on the other hand, right prefrontal on the other hand, right prefrontal TMS may be useful for mania. TMS may be useful for mania.

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High and low frequency High and low frequency TMS may cause opposite TMS may cause opposite effects in brain and mood effects in brain and mood

(20). (20). Speer AM, Kimbrell TA, Wasserman EM, Repella Speer AM, Kimbrell TA, Wasserman EM, Repella J, Willis MW, Herscovitch P, Post RM: Opposite J, Willis MW, Herscovitch P, Post RM: Opposite effects of high and low frequency rTMS on effects of high and low frequency rTMS on regional brain activity in depressed patients. regional brain activity in depressed patients. Biol Psychiatry 2000 Dec; 48(12):1133-41.Biol Psychiatry 2000 Dec; 48(12):1133-41.

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An article reviewing TMS in the An article reviewing TMS in the treatment of mood disorder treatment of mood disorder

concluded that the antidepressant concluded that the antidepressant and antimanic effects of TMS depend and antimanic effects of TMS depend

on clinical considerations such as on clinical considerations such as stimulus frequency, intensity, and stimulus frequency, intensity, and

magnetic coil placement; in addition, magnetic coil placement; in addition, biological heterogeneity among the biological heterogeneity among the patients treated with TMS may also patients treated with TMS may also

contribute to differing efficacy contribute to differing efficacy accross clinical trials (21). accross clinical trials (21).

Hasey G: Transcranial magnetic Hasey G: Transcranial magnetic stimulation in the treatment of mood stimulation in the treatment of mood disorder: a review and comparison with disorder: a review and comparison with electroconvulsive therapy. Can J electroconvulsive therapy. Can J Psychiatry 2001 Oct; 46(8):720-7.Psychiatry 2001 Oct; 46(8):720-7.

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rTMS and OCDrTMS and OCD

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rTMS and OCDrTMS and OCD19971997

Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, Murphy DL.M, Wassermann EM, Post RM, Murphy DL.

Effect of prefrontal repetitive transcranial magnetic stimulation Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study.in obsessive-compulsive disorder: a preliminary study. Am J Am J Psychiatry. 1997 Jun;154(6):867-9.Psychiatry. 1997 Jun;154(6):867-9.

12 patients 12 patients 80% motor threshold, 80% motor threshold, 20 Hz20 Hz/2 seconds per minute for 20 minutes /2 seconds per minute for 20 minutes Right lateral prefrontal, a left lateral prefrontal, and a midoccipital Right lateral prefrontal, a left lateral prefrontal, and a midoccipital

(control) site on separate days(control) site on separate daysThe patients' symptoms and mood were rated for 8 hours afterward. The patients' symptoms and mood were rated for 8 hours afterward. Compulsive urges decreased significantly for 8 hours after right lateral Compulsive urges decreased significantly for 8 hours after right lateral

prefrontal repetitive transcranial magnetic stimulation, prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after but there were nonsignificant increases in compulsive urges after

repetitive transcranial magnetic stimulation of the midoccipital site. repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in A shorter-lasting (30 minutes), modest, and nonsignificant reduction in

compulsive urges occurred after left lateral prefrontal repetitive transcranial compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation.magnetic stimulation.

Mood improved during and 30 minutes after right lateral prefrontal Mood improved during and 30 minutes after right lateral prefrontal stimulation.stimulation.

These preliminary results suggest that right prefrontal repetitive These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder. involved in obsessive-compulsive disorder.

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rTMS and OCDrTMS and OCD20012001

Sachdev PS, McBride R, Loo CK, Mitchell PB, Malhi GS, Croker VM.Sachdev PS, McBride R, Loo CK, Mitchell PB, Malhi GS, Croker VM.Right versus left prefrontal transcranial magnetic stimulation Right versus left prefrontal transcranial magnetic stimulation

for obsessive-compulsive disorder: a preliminary investigation.for obsessive-compulsive disorder: a preliminary investigation. J J Clin Psychiatry. 2001 Dec;62(12):981-4.Clin Psychiatry. 2001 Dec;62(12):981-4.

12 subjects with resistant OCD 12 subjects with resistant OCD were allocated randomly to either were allocated randomly to either right or leftright or left prefrontal rTMS prefrontal rTMS daily for 2 weeks daily for 2 weeks were assessed by an independent rater at 1 and 2 weeks and 1 month were assessed by an independent rater at 1 and 2 weeks and 1 month

later. later. Subjects had an overall significant improvement in the obsessions (p < Subjects had an overall significant improvement in the obsessions (p <

.01), compulsions (p < .01), and total (p < .01) scores on the Yale-Brown .01), compulsions (p < .01), and total (p < .01) scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after 2 weeks and at 1-month Obsessive Compulsive Scale (Y-BOCS) after 2 weeks and at 1-month follow-up. follow-up.

This improvement was significant for obsessions (p < .05) and tended This improvement was significant for obsessions (p < .05) and tended to significance for total Y-BOCS scores (p = .06) after correction for to significance for total Y-BOCS scores (p = .06) after correction for changes in depression scores on the Montgomery-Asberg Depression changes in depression scores on the Montgomery-Asberg Depression Rating Scale. Rating Scale.

There was no significant difference between right- and left-sided rTMS There was no significant difference between right- and left-sided rTMS on any of the parameters examined. on any of the parameters examined.

Two subjects (33%) in each group showed a clinically significant Two subjects (33%) in each group showed a clinically significant improvement that persisted at I month but with relapse later in I subject. improvement that persisted at I month but with relapse later in I subject.

About one quarter of patients with resistant OCD appear to respond to About one quarter of patients with resistant OCD appear to respond to rTMS to either prefrontal lobe. rTMS to either prefrontal lobe.

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rTMS and OCDrTMS and OCD19971997

Alonso P, Pujol J, Cardoner N, Benlloch L, Deus J, Menchon Alonso P, Pujol J, Cardoner N, Benlloch L, Deus J, Menchon JM, Capdevila A, Vallejo J.JM, Capdevila A, Vallejo J.

Right prefrontal repetitive transcranial magnetic Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a double-stimulation in obsessive-compulsive disorder: a double-blind, placebo-controlled study.blind, placebo-controlled study. Am J Psychiatry. 2001 Am J Psychiatry. 2001 Jul;158(7):1143-5.Jul;158(7):1143-5.

18 sessions of real (N=10) or sham (N=8) rTMS. 18 sessions of real (N=10) or sham (N=8) rTMS. Treatments lasted 20 minutes, and the frequency was Treatments lasted 20 minutes, and the frequency was 1 1

HzHz for both conditions, but the intensity was for both conditions, but the intensity was 110%110% of motor of motor threshold for real rTMS and 20% for the sham condition.threshold for real rTMS and 20% for the sham condition.

No significant changes in OCD were detected in either No significant changes in OCD were detected in either group after treatment. group after treatment.

Two patients who received real rTMS, with checking Two patients who received real rTMS, with checking compulsions, and one receiving sham treatment, with compulsions, and one receiving sham treatment, with sexual/religious obsessions, were considered responders. sexual/religious obsessions, were considered responders.

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rTMS and OCDrTMS and OCD20032003

Martin JL, Barbanoj MJ, Perez V, Sacristan M.Martin JL, Barbanoj MJ, Perez V, Sacristan M.Transcranial magnetic stimulation for the treatment of Transcranial magnetic stimulation for the treatment of

obsessive-compulsive disorder.obsessive-compulsive disorder. Cochrane Database Syst Rev. Cochrane Database Syst Rev. 2003;(3):CD003387.2003;(3):CD003387.

Systematic review on the clinical efficacy and safety of Systematic review on the clinical efficacy and safety of transcranial magnetic stimulation from transcranial magnetic stimulation from randomised controlled trialsrandomised controlled trials in the treatment of obsessive-compulsive disorder.in the treatment of obsessive-compulsive disorder.

An electronic search was performed including the Cochrane An electronic search was performed including the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group trials Collaboration Depression, Anxiety and Neurosis Review Group trials register (last searched June, 2002), the Cochrane Controlled Trials register (last searched June, 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE (1966-2002), EMBASE (1974-Register (Issue 2, 2002), MEDLINE (1966-2002), EMBASE (1974-2002), PsycLIT (1980-2002), and bibliographies from reviewed 2002), PsycLIT (1980-2002), and bibliographies from reviewed articles. articles.

3 trials were included and only 2 contained data in a suitable 3 trials were included and only 2 contained data in a suitable form for quantitative analysis. form for quantitative analysis.

It was not possible to pool any results for a meta-analysis. It was not possible to pool any results for a meta-analysis. No difference was seen between rTMS and sham TMS using the No difference was seen between rTMS and sham TMS using the

Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Rating Scale for all time periods analysed. There are currently Rating Scale for all time periods analysed. There are currently insufficient data from randomised controlled trials to draw any insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder. the treatment of obsessive-compulsive disorder.

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rTMS and panic disorder rTMS and panic disorder

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rTMS and panic disorderrTMS and panic disorder 20022002

Garcia-Toro M, Salva Coll J, Crespi Font M, Andres Tauler J, Garcia-Toro M, Salva Coll J, Crespi Font M, Andres Tauler J, Aguirre Orue I, Bosch Calero C.Aguirre Orue I, Bosch Calero C.

Panic disorder and transcranial magnetic stimulation. Actas Esp Panic disorder and transcranial magnetic stimulation. Actas Esp Psiquiatr. 2002 Jul-Aug;30(4):221-4.Psiquiatr. 2002 Jul-Aug;30(4):221-4.

3 patients. 3 patients. disease for at least 1 year and they had unsuccessfully followed disease for at least 1 year and they had unsuccessfully followed

psychotherapy and pharmacological treatment. psychotherapy and pharmacological treatment. 10 sessions during 10 sessions during each session lasted 30 trains of 60 seconds at a frequency of each session lasted 30 trains of 60 seconds at a frequency of 1 1

HzHz, on the , on the right right dorsolateral prefrontal cortex, at 110% of the dorsolateral prefrontal cortex, at 110% of the motor threshold. motor threshold.

All three patients experienced a modest and partial symptom All three patients experienced a modest and partial symptom improvement that did not seemed to be clinically relevant. improvement that did not seemed to be clinically relevant.

Two patients accepted to participate in a TMS second phase, Two patients accepted to participate in a TMS second phase, where the previous stimulation parameters were alternated with an where the previous stimulation parameters were alternated with an application of 30 trains of application of 30 trains of 20 Hz20 Hz during 2 seconds on the during 2 seconds on the leftleft prefrontal cortex. This alternate application of high and low prefrontal cortex. This alternate application of high and low frequency TMS in each session was also well tolerated, but failed to frequency TMS in each session was also well tolerated, but failed to produce additional improvement. produce additional improvement.

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rTMS and PTSD rTMS and PTSD

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rTMS and PTSDrTMS and PTSD 19981998

Grisaru N, Amir M, Cohen H, Kaplan Z.Grisaru N, Amir M, Cohen H, Kaplan Z.Effect of transcranial magnetic stimulation in Effect of transcranial magnetic stimulation in

posttraumatic stress disorder: a preliminary study.posttraumatic stress disorder: a preliminary study. Biol Biol Psychiatry. 1998 Jul 1;44(1):52-5.Psychiatry. 1998 Jul 1;44(1):52-5.

10 PTSD patients 10 PTSD patients One session of slow TMS with 30 pulses of 1 m/sec each, 15 One session of slow TMS with 30 pulses of 1 m/sec each, 15

to to each side of the motor cortex.each side of the motor cortex. Symptoms of PTSD were Symptoms of PTSD were assessed by using three psychological assessment scales, at assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the measured by the Clinical Global Impression scale); however, the effect was rather short and transient. effect was rather short and transient.

The present study showed TMS to be a safe and tolerable The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for intervention with possibly indications of therapeutic efficacy for PTSD patients. PTSD patients.

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rTMS and PTSDrTMS and PTSD 20022002

Rosenberg PB, Mehndiratta RB, Mehndiratta YP, Wamer A, Rosenberg PB, Mehndiratta RB, Mehndiratta YP, Wamer A, Rosse RB, Balish M.Rosse RB, Balish M.

Repetitive transcranial magnetic stimulation treatment Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major of comorbid posttraumatic stress disorder and major depression.depression. J Neuropsychiatry Clin Neurosci. 2002 J Neuropsychiatry Clin Neurosci. 2002 Summer;14(3):270-6.Summer;14(3):270-6.

12 patients with comorbid PTSD and major depression 12 patients with comorbid PTSD and major depression rTMS to left frontal cortex as an open-label adjunct to current rTMS to left frontal cortex as an open-label adjunct to current

antidepressant medications. rTMS parameters were 90% of motor antidepressant medications. rTMS parameters were 90% of motor threshold, 1 Hz or 5 Hz, 6.000 stimuli over 10 days. Seventy-five threshold, 1 Hz or 5 Hz, 6.000 stimuli over 10 days. Seventy-five percent of the patients had a clinically significant antidepressant percent of the patients had a clinically significant antidepressant response after rTMS, and 50% had sustained response at 2-month response after rTMS, and 50% had sustained response at 2-month follow-up. follow-up.

Comparable improvements were seen in anxiety, hostility, and Comparable improvements were seen in anxiety, hostility, and insomnia, but only insomnia, but only minimal improvement in PTSD minimal improvement in PTSD symptoms. symptoms.

Left frontal cortical rTMS may have promise for treating Left frontal cortical rTMS may have promise for treating depression in PTSD, but there may be a dissociation between depression in PTSD, but there may be a dissociation between treating mood and treating core PTSD symptoms. treating mood and treating core PTSD symptoms.

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rTMS and PTSDrTMS and PTSD 20042004

Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N.Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N.Repetitive transcranial magnetic stimulation of the Repetitive transcranial magnetic stimulation of the

right dorsolateral prefrontal cortex in posttraumatic stress right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study.disorder: a double-blind, placebo-controlled study. Am J Am J Psychiatry. 2004 Mar;161(3):515-24.Psychiatry. 2004 Mar;161(3):515-24.

24 patients with PTSD were randomly assigned to receive 24 patients with PTSD were randomly assigned to receive rTMS at low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS at low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS in a double-blind design. rTMS in a double-blind design.

10 daily sessions 10 daily sessions The 10 daily treatments of 10-Hz rTMS at 80% motor threshold The 10 daily treatments of 10-Hz rTMS at 80% motor threshold

over the right dorsolateral prefrontal cortex had therapeutic over the right dorsolateral prefrontal cortex had therapeutic effects on PTSD patients. PTSD core symptoms (reexperiencing, effects on PTSD patients. PTSD core symptoms (reexperiencing, avoidance) markedly improved with this treatment. Moreover, avoidance) markedly improved with this treatment. Moreover, high-frequency rTMS over the right dorsolateral prefrontal cortex high-frequency rTMS over the right dorsolateral prefrontal cortex alleviated anxiety symptoms in PTSD patients. alleviated anxiety symptoms in PTSD patients.

In PTSD patients, 10 daily sessions of right dorsolateral In PTSD patients, 10 daily sessions of right dorsolateral prefrontal rTMS at a frequency of 10 Hz have greater therapeutic prefrontal rTMS at a frequency of 10 Hz have greater therapeutic effects than slow-frequency or sham stimulation. effects than slow-frequency or sham stimulation.

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rTMS and schizophreniarTMS and schizophrenia

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rTMS and schizophreniarTMS and schizophrenia 19971997

Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker RH.RH.

Slow magnetic stimulation of prefrontal cortex in Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia. depression and schizophrenia. Prog Prog Neuropsychopharmacol Biol Psychiatry. 1997 Jan;21(1):105-Neuropsychopharmacol Biol Psychiatry. 1997 Jan;21(1):105-10.10.

Pre-frontal cortex to study mood changes in 10 depressed Pre-frontal cortex to study mood changes in 10 depressed patients and 10 schizophrenic patients. patients and 10 schizophrenic patients.

A slow rate of stimuli was used, one per 30 seconds; A slow rate of stimuli was used, one per 30 seconds; maximal intensity of about 2 Tesla was given for 30 stimuli, 15 maximal intensity of about 2 Tesla was given for 30 stimuli, 15 on each side of the brainon each side of the brain. .

No side effects were seen and No side effects were seen and at least three depressed patients and two schizophrenic at least three depressed patients and two schizophrenic

patients appeared to improve, at least transiently. patients appeared to improve, at least transiently. These results suggest that rapid rate TMS may not be These results suggest that rapid rate TMS may not be

necessary to elicit mood effects.necessary to elicit mood effects.

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rTMS and schizophreniarTMS and schizophrenia 19981998

Feinsod M, Kreinin B, Chistyakov A, Klein E.Feinsod M, Kreinin B, Chistyakov A, Klein E.Preliminary evidence for a beneficial effect Preliminary evidence for a beneficial effect

of low-frequency, repetitive transcranial of low-frequency, repetitive transcranial magnetic stimulation in patients with major magnetic stimulation in patients with major depression and schizophrenia. depression and schizophrenia. Depress Anxiety. Depress Anxiety. 1998;7(2):65-8.1998;7(2):65-8.

10 rTMS sessions in 14 subjects with major 10 rTMS sessions in 14 subjects with major depression (MD) and 10 with schizophrenia.depression (MD) and 10 with schizophrenia.

7 of the depressed patients reported significant 7 of the depressed patients reported significant improvement in depressive symptomatology, and improvement in depressive symptomatology, and

7 of the schizophrenic subjects reported 7 of the schizophrenic subjects reported amelioration of anxiety and restlessness. amelioration of anxiety and restlessness.

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rTMS and schizophreniarTMS and schizophrenia 19991999

Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger A, Krystal JH, Charney DS.A, Krystal JH, Charney DS.

Transcranial magnetic stimulation of left Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting temporoparietal cortex in three patients reporting hallucinated "voices". hallucinated "voices". Biol Psychiatry. 1999 Jul 1;46(1):130-Biol Psychiatry. 1999 Jul 1;46(1):130-2.2.

1 Hz 1 Hz left temporoparietal cortex left temporoparietal cortex compared with sham compared with sham double-blind, cross-over design. double-blind, cross-over design. All three patients demonstrated greater improvement in All three patients demonstrated greater improvement in

hallucination severity following active stimulation compared to hallucination severity following active stimulation compared to sham stimulation. sham stimulation.

Two of the three patients reported near total cessation of Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. hallucinations for > or = 2 weeks.

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rTMS and schizophreniarTMS and schizophrenia 19991999

Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole, Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole, Boget T, Barrantes N, Catarineu S, Font M, Lomena FJ. Boget T, Barrantes N, Catarineu S, Font M, Lomena FJ.

Repetitive transcranial magnetic stimulation in the Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study. treatment of chronic negative schizophrenia: a pilot study. J J Neurol Neurosurg Psychiatry. 1999 Jul;67(1):129-30.Neurol Neurosurg Psychiatry. 1999 Jul;67(1):129-30.

6 patients (All were taking neuroleptic drugs)6 patients (All were taking neuroleptic drugs)rTMS 5 days a week, during 2 weeks, over the prefrontal cortex rTMS 5 days a week, during 2 weeks, over the prefrontal cortex 20 Hz for 2 seconds, once per minute for 20 minutes at 80% 20 Hz for 2 seconds, once per minute for 20 minutes at 80%

motor threshold. motor threshold. without exacerbating their psychoses. All patients tolerated the without exacerbating their psychoses. All patients tolerated the

rTMS well, with minimal side effects (mild headache and tinnitus). rTMS well, with minimal side effects (mild headache and tinnitus). PANSS and a neuropsychological battery PANSS and a neuropsychological battery A brain SPECT study A brain SPECT study SPECT: The results after rTMS indicated no change in the SPECT: The results after rTMS indicated no change in the

hypofrontality. hypofrontality. Negative symptoms showed a general decrease for all patients. Negative symptoms showed a general decrease for all patients.

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rTMS and schizophreniarTMS and schizophrenia 19991999

Klein E, Kolsky Y, Puyerovsky M, Koren D, Klein E, Kolsky Y, Puyerovsky M, Koren D, Chistyakov A, Feinsod M.Chistyakov A, Feinsod M.

Right prefrontal slow repetitive transcranial Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study. double-blind sham-controlled pilot study. Biol Biol Psychiatry. 1999 Nov 15;46(10):1451-4.Psychiatry. 1999 Nov 15;46(10):1451-4.

35 inpatients 35 inpatients either right prefrontal slow rTMS or sham either right prefrontal slow rTMS or sham

treatment treatment were rated before and after treatment for were rated before and after treatment for

positive, negative, and depressive symptoms. positive, negative, and depressive symptoms. 2-week treatment protocol. 2-week treatment protocol. rTMS was not superior to sham treatment on any rTMS was not superior to sham treatment on any

of the clinical ratings. of the clinical ratings.

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rTMS and schizophreniarTMS and schizophrenia 20002000

Hoffman RE, Boutros NN, Hu S, Berman RM, Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS.Krystal JH, Charney DS.

Transcranial magnetic stimulation and Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. auditory hallucinations in schizophrenia. Lancet. 2000 Mar 25;355(9209):1073-5.Lancet. 2000 Mar 25;355(9209):1073-5.

12 patients with schizophrenia and auditory 12 patients with schizophrenia and auditory hallucinations hallucinations

received 1 Hz received 1 Hz left temporoparietial cortex. left temporoparietial cortex. In a double-blind crossover trial, active In a double-blind crossover trial, active

stimulation significantly reduced hallucinations stimulation significantly reduced hallucinations relative to sham stimulation. relative to sham stimulation.

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rTMS and schizophreniarTMS and schizophrenia 20002000

Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R, Emrich HM, Schneider U. Dengler R, Emrich HM, Schneider U.

High frequency repetitive transcranial magnetic High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. in schizophrenic patients. Neuroreport. 2000 Dec Neuroreport. 2000 Dec 18;11(18):4013-5.18;11(18):4013-5.

12 participants 12 participants a double-blind crossover design, a double-blind crossover design, 2 weeks of daily 2 weeks of daily left prefrontalleft prefrontal rTMS (20 2s 20 Hz rTMS (20 2s 20 Hz

stimulations at 80% motor threshold over 20 min, dorsolateral stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. preforntal cortex) and 2 weeks of sham stimulation.

The Brief Psychiatric Rating Scale decreased under active The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. anxiety (STAI) did not change significantly.

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rTMS and schizophreniarTMS and schizophrenia 20022002

d'Alfonso AA, Aleman A, Kessels RP, d'Alfonso AA, Aleman A, Kessels RP, Schouten EA, Postma A, van Der Linden JA, Schouten EA, Postma A, van Der Linden JA, Cahn W, Greene Y, de Haan EH, Kahn RS.Cahn W, Greene Y, de Haan EH, Kahn RS.

Transcranial magnetic stimulation of Transcranial magnetic stimulation of left auditory cortex in patients with left auditory cortex in patients with schizophrenia: effects on hallucinations schizophrenia: effects on hallucinations and neurocognition. and neurocognition. J Neuropsychiatry Clin J Neuropsychiatry Clin Neurosci. 2002 Winter;14(1):77-9.Neurosci. 2002 Winter;14(1):77-9.

9 medication-resistant hallucinating 9 medication-resistant hallucinating patients. patients.

A statistically significant improvement was A statistically significant improvement was observed on a hallucination scale after 10 observed on a hallucination scale after 10 days of TMS days of TMS at the left auditory cortex.at the left auditory cortex.

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rTMS and schizophreniarTMS and schizophrenia 20022002

Schreiber S, Dannon PN, Goshen E, Amiaz R, Zwas TS, Grunhaus Schreiber S, Dannon PN, Goshen E, Amiaz R, Zwas TS, Grunhaus L.L.

Right prefrontal rTMS treatment for refractory auditory Right prefrontal rTMS treatment for refractory auditory command hallucinations - a neuroSPECT assisted case study.command hallucinations - a neuroSPECT assisted case study. Psychiatry Res. 2002 Nov 30;116(1-2):113-7.Psychiatry Res. 2002 Nov 30;116(1-2):113-7.

A schizophrenic patient with refractory command hallucinations A schizophrenic patient with refractory command hallucinations treated with 10 Hz rTMS. treated with 10 Hz rTMS. over the over the rightright dorsolateral prefrontal cortexdorsolateral prefrontal cortex, with 1200 magnetic , with 1200 magnetic

stimulations administeredstimulations administereddaily for 20 days at 90% motor threshold. daily for 20 days at 90% motor threshold. Regional cerebral blood flow changes were monitored with Regional cerebral blood flow changes were monitored with

neuroSPECT. neuroSPECT. Clinical evaluation and scores on the Positive and Negative Clinical evaluation and scores on the Positive and Negative

Symptoms Scale and the Brief Psychiatric Rating Scale demonstrated Symptoms Scale and the Brief Psychiatric Rating Scale demonstrated a global improvement in the patient's condition, with no change in a global improvement in the patient's condition, with no change in the intensity and frequency of the hallucinations. the intensity and frequency of the hallucinations.

NeuroSPECT performed at intervals during and after treatment NeuroSPECT performed at intervals during and after treatment indicated a general improvement in cerebral perfusion. indicated a general improvement in cerebral perfusion.

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rTMS and schizophreniarTMS and schizophrenia 20032003

Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F, Carroll K, Krystal JH.F, Carroll K, Krystal JH.

Transcranial magnetic stimulation of left Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory temporoparietal cortex and medication-resistant auditory hallucinations.hallucinations. Arch Gen Psychiatry. 2003 Jan;60(1):49-56. Arch Gen Psychiatry. 2003 Jan;60(1):49-56.

24 patients with schizophrenia or schizoaffective disorder 24 patients with schizophrenia or schizoaffective disorder and medication-resistant AHs (auditory hallucinations) and medication-resistant AHs (auditory hallucinations)

were randomly allocated to receive rTMS or sham stimulation were randomly allocated to receive rTMS or sham stimulation for 9 days at 90% of motor threshold. for 9 days at 90% of motor threshold. Patients receiving sham stimulation were subsequently Patients receiving sham stimulation were subsequently

offered an open-label trial of rTMS.offered an open-label trial of rTMS.Auditory hallucinations were robustly improved with rTMS Auditory hallucinations were robustly improved with rTMS

relative to sham stimulation. Frequency and attentional salience relative to sham stimulation. Frequency and attentional salience were the 2 aspects of hallucinatory experience that showed were the 2 aspects of hallucinatory experience that showed greatest improvement. greatest improvement.

Duration of putative treatment effects ranged widely, with Duration of putative treatment effects ranged widely, with 52% of patients maintaining improvement for at least 15 weeks. 52% of patients maintaining improvement for at least 15 weeks.

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rTMS and schizophreniarTMS and schizophrenia 20032003

Franck N, Poulet E, Terra JL, Dalery J, d'Amato T.Franck N, Poulet E, Terra JL, Dalery J, d'Amato T.Left temporoparietal transcranial magnetic Left temporoparietal transcranial magnetic

stimulation in treatment-resistant schizophrenia with stimulation in treatment-resistant schizophrenia with verbal hallucinations.verbal hallucinations. Psychiatry Res. 2003 Aug Psychiatry Res. 2003 Aug 30;120(1):107-9.30;120(1):107-9.

A 21-year-old schizophrenic man, who had killed his A 21-year-old schizophrenic man, who had killed his mother in the belief that she was a demon, failed to respond mother in the belief that she was a demon, failed to respond to combined treatment with a variety of antipsychotic agents. to combined treatment with a variety of antipsychotic agents. His persistent hallucinations consisted of two voices (God and His persistent hallucinations consisted of two voices (God and the Devil). As an adjunct to continued antipsychotic the Devil). As an adjunct to continued antipsychotic medication, the patient received a course of rTMS: medication, the patient received a course of rTMS:

10 sessions of 10 sessions of 1-Hz1-Hz stimulations near stimulations near Wernicke's areaWernicke's area. . After rTMS, the patient's hallucinations grew less intrusive After rTMS, the patient's hallucinations grew less intrusive

and he no longer required isolation. and he no longer required isolation. The improvement could be a delayed effect of medication. The improvement could be a delayed effect of medication.

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rTMS and schizophreniarTMS and schizophrenia 20032003

Huber TJ, Schneider U, Rollnik J.Huber TJ, Schneider U, Rollnik J.Gender differences in the effect of repetitive transcranial Gender differences in the effect of repetitive transcranial

magnetic stimulation in schizophrenia.magnetic stimulation in schizophrenia. Psychiatry Res. 2003 Aug Psychiatry Res. 2003 Aug 30;120(1):103-5.30;120(1):103-5.

12 schizophrenic patients (8 men, 4 women) were treated with 12 schizophrenic patients (8 men, 4 women) were treated with high-frequency rTMS of the dominant dorsolateral prefrontal cortex. high-frequency rTMS of the dominant dorsolateral prefrontal cortex.

Their performance of the number-connection test, which Their performance of the number-connection test, which assesses cognitive processes related to the frontal lobe, was assesses cognitive processes related to the frontal lobe, was evaluated before and after rTMS. evaluated before and after rTMS.

Women improved markedly on the test after rTMSWomen improved markedly on the test after rTMS, whereas men , whereas men did not show a significant change. did not show a significant change.

There were no corresponding sex differences in clinical measures There were no corresponding sex differences in clinical measures after rTMS. after rTMS.

The preliminary findings of sex differences in the response to The preliminary findings of sex differences in the response to rTMS, as reflected by performance on the number-connection test, rTMS, as reflected by performance on the number-connection test, suggest the need for investigations of a greater number of suggest the need for investigations of a greater number of schizophrenic men and women with a more intensive examination of schizophrenic men and women with a more intensive examination of the effects of rTMS on cognitive functions.the effects of rTMS on cognitive functions.

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rTMS and schizophreniarTMS and schizophrenia 20042004

Haraldsson HM, Ferrarelli F, Kalin NH, Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G.Tononi G.

Transcranial Magnetic Stimulation in Transcranial Magnetic Stimulation in the investigation and treatment of the investigation and treatment of schizophrenia: a review.schizophrenia: a review. Schizophr Res. Schizophr Res. 2004 Nov 1;71(1):1-16.2004 Nov 1;71(1):1-16.

Reduction of auditory hallucinations after Reduction of auditory hallucinations after slow slow TMS over TMS over auditory cortexauditory cortex

Improvement of psychotic symptoms after Improvement of psychotic symptoms after high frequencyhigh frequency TMS over TMS over left prefrontalleft prefrontal cortex. cortex.

However, these results need to be However, these results need to be confirmed using better placebo conditions. confirmed using better placebo conditions.

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rTMS and schizophreniarTMS and schizophrenia 20042004

Holi MM, Eronen M, Toivonen K, Toivonen P, Marttunen M, Naukkarinen H.Holi MM, Eronen M, Toivonen K, Toivonen P, Marttunen M, Naukkarinen H.Left prefrontal repetitive transcranial magnetic stimulation in Left prefrontal repetitive transcranial magnetic stimulation in

schizophrenia.schizophrenia. Schizophr Bull. 2004;30(2):429-34. Schizophr Bull. 2004;30(2):429-34.Double-blind, controlled study, Double-blind, controlled study, 22 chronic hospitalized schizophrenia patients 22 chronic hospitalized schizophrenia patients 10 sessions10 sessionsReal or sham rTMS. Real or sham rTMS. 20 trains of 5-second 20 trains of 5-second 10-Hz10-Hz stimulation at 100 percent motor threshold, 30 seconds stimulation at 100 percent motor threshold, 30 seconds

apart.apart.Effects on positive and negative symptoms, self-reported symptoms, rough Effects on positive and negative symptoms, self-reported symptoms, rough

neuropsychological functioning, and hormones were assessed. neuropsychological functioning, and hormones were assessed. Although there was a significant improvement in both groups in most of the Although there was a significant improvement in both groups in most of the

symptom measures, no real differences were found between the groups. symptom measures, no real differences were found between the groups. A decrease of more than 20 percent in the total PANSS score was found in 7 control A decrease of more than 20 percent in the total PANSS score was found in 7 control

subjects but only 1 subject from the real rTMS group. subjects but only 1 subject from the real rTMS group. There was no change in hormone levels or neuropsychological functioning, There was no change in hormone levels or neuropsychological functioning,

measured by the MMSE, in either group. measured by the MMSE, in either group. Left prefrontal rTMS (with the used parameters) seems to produce a significant Left prefrontal rTMS (with the used parameters) seems to produce a significant

nonspecific effect of the treatment procedure but no therapeutic effect in the most nonspecific effect of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia patients. chronic and severely ill schizophrenia patients.

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rTMS and schizophreniarTMS and schizophrenia 20042004

McIntosh AM, Semple D, Tasker K, Harrison LK, Owens DG, Johnstone McIntosh AM, Semple D, Tasker K, Harrison LK, Owens DG, Johnstone EC, Ebmeier KP.EC, Ebmeier KP.

Transcranial magnetic stimulation for auditory hallucinations Transcranial magnetic stimulation for auditory hallucinations in schizophrenia.in schizophrenia. Psychiatry Res. 2004 Jun 30;127(1-2):9-17. Psychiatry Res. 2004 Jun 30;127(1-2):9-17.

16 patients with hallucinations16 patients with hallucinationstreatment-resistant for at least 2 monthstreatment-resistant for at least 2 monthswere randomised into a placebo-controlled crossover study of TMS atwere randomised into a placebo-controlled crossover study of TMS at1 Hz1 Hz and 80% of motor threshold and 80% of motor threshold over over left temporo-parietal cortex. left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating Treatment periods lasted for 4 days, with daily duration escalating

from 4 to 8, 12 and 16 min on subsequent days. Each minute of from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. the patient to move, if necessary.

Both patients and symptom raters were unaware of the treatment Both patients and symptom raters were unaware of the treatment condition. condition.

Patients' hallucination scores improved from baseline with both real Patients' hallucination scores improved from baseline with both real and sham TMS,and sham TMS,

there was no significant difference between real and sham there was no significant difference between real and sham treatments. treatments.

There was a trend for second treatments, whether sham or real, to be There was a trend for second treatments, whether sham or real, to be more effective than first treatments. more effective than first treatments.

Other psychopathology scales (apart from positive symptoms) and Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. verbal memory were not affected by real or sham TMS.

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rTMS and schizophreniarTMS and schizophrenia 20042004

Schonfeldt-Lecuona C, Gron G, Walter H, Buchler N, Schonfeldt-Lecuona C, Gron G, Walter H, Buchler N, Wunderlich A, Spitzer M, Herwig U. Wunderlich A, Spitzer M, Herwig U.

Stereotaxic rTMS for the treatment of auditory Stereotaxic rTMS for the treatment of auditory hallucinations in schizophrenia. hallucinations in schizophrenia. Neuroreport. 2004 Jul Neuroreport. 2004 Jul 19;15(10):1669-73.19;15(10):1669-73.

Cross-over sham controlled study, Cross-over sham controlled study, Researchers guided rTMS stereotactically to inner speech-Researchers guided rTMS stereotactically to inner speech-

related cortical areas in hallucinating patients. related cortical areas in hallucinating patients. These areas were identified individually prior to rTMS These areas were identified individually prior to rTMS

using fMRI in a subgroup of patients.using fMRI in a subgroup of patients.Active stimulation was applied over Broca's area and over Active stimulation was applied over Broca's area and over

the superior temporal gyrus as determined by fMRI, or the superior temporal gyrus as determined by fMRI, or according to structural images in the remaining patients. according to structural images in the remaining patients.

rTMS did not lead to a significant reduction of hallucination rTMS did not lead to a significant reduction of hallucination severity. severity.

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rTMS and schizophreniarTMS and schizophrenia 20042004

Hajak G, Marienhagen J, Langguth B, Werner S, Binder H, Hajak G, Marienhagen J, Langguth B, Werner S, Binder H, Eichhammer P.Eichhammer P.

High-frequency repetitive transcranial magnetic High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and stimulation in schizophrenia: a combined treatment and neuroimaging study.neuroimaging study. Psychol Med. 2004 Oct;34(7):1157-63. Psychol Med. 2004 Oct;34(7):1157-63.

20 patients 20 patients Sham-controlled parallel design, with Sham-controlled parallel design, with 10 Hz rTMS over 10 days. 10 Hz rTMS over 10 days. Besides clinical ratings, ECD-SPECT (technetium-99 bicisate Besides clinical ratings, ECD-SPECT (technetium-99 bicisate

single photon emission computed tomography) imaging was single photon emission computed tomography) imaging was performed before and after termination of rTMS treatment. performed before and after termination of rTMS treatment.

Significant reduction of negative symptoms combined with a Significant reduction of negative symptoms combined with a trend for non-significant improvement of depressive symptoms trend for non-significant improvement of depressive symptoms in the active stimulated group as compared with the sham in the active stimulated group as compared with the sham stimulated group. stimulated group.

Additionally, Additionally, a trend for worsening of positive symptomsa trend for worsening of positive symptoms was was observed in the actively treated schizophrenic patients. observed in the actively treated schizophrenic patients.

In both groups no changes in regional cerebral blood flow In both groups no changes in regional cerebral blood flow could be detected by ECD-SPECT.could be detected by ECD-SPECT.

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rTMS and schizophreniarTMS and schizophrenia 20052005

Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J, Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J, d'Amato T, Saoud M.d'Amato T, Saoud M.

Slow transcranial magnetic stimulation can rapidly Slow transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in schizophrenia.reduce resistant auditory hallucinations in schizophrenia. Biol Psychiatry. 2005 Jan 15;57(2):188-91.Biol Psychiatry. 2005 Jan 15;57(2):188-91.

10 right-handed schizophrenia patients 10 right-handed schizophrenia patients with resistant AVH (auditory verbal hallucinations) with resistant AVH (auditory verbal hallucinations) received 5 days of active rTMS and 5 days of sham rTMS received 5 days of active rTMS and 5 days of sham rTMS

(2.000 stimulations per day at 90% of motor threshold) (2.000 stimulations per day at 90% of motor threshold) over the over the left temporoparietal cortexleft temporoparietal cortex in a double-blind crossover design. in a double-blind crossover design. The two weeks of stimulation were separated by a 1-week The two weeks of stimulation were separated by a 1-week

washout period. washout period. AVH were robustly improved (56%) by 5 days active rTMS, AVH were robustly improved (56%) by 5 days active rTMS,

whereas no variation was observed after sham. whereas no variation was observed after sham. Seven patients were responders to active treatment, five of Seven patients were responders to active treatment, five of

whom maintained improvement for at least 2 months. whom maintained improvement for at least 2 months.

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rTMS and schizophreniarTMS and schizophrenia 20052005

Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, Carroll K, Krystal JH.YT, Carroll K, Krystal JH.

Temporoparietal Transcranial Magnetic Stimulation for Temporoparietal Transcranial Magnetic Stimulation for Auditory Hallucinations: Safety, Efficacy and Moderators in a Fifty Auditory Hallucinations: Safety, Efficacy and Moderators in a Fifty Patient Sample.Patient Sample. Biol Psychiatry. 2005 Jun 2 Biol Psychiatry. 2005 Jun 2

A preliminary report based on 24 patients with schizophrenia or A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory schizoaffective disorder indicated greater improvement in auditory hallucinations following hallucinations following 1-hertz left1-hertz left temporoparietaltemporoparietal rTMS compared to rTMS compared to sham stimulation. sham stimulation.

Data from the full 50-subject sample incorporating 26 new patients Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. efficacy and moderators of this intervention.

Right-handed patients experiencing auditory hallucinations at least 5 Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham times per day were randomly allocated to receive either rTMS or sham stimulation. stimulation.

A total of 132 minutes of rTMS was administered over 9 days at 90% A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. motor threshold using a double-masked, sham-controlled, parallel design.

Hallucination Change Score was more improved for rTMS relative to Hallucination Change Score was more improved for rTMS relative to sham stimulation (p = .008) as was the Clinical Global Impressions Scale sham stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004). Hallucination frequency was significantly decreased during (p = .0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008). There was no evidence of neurocognitive rTMS effects (p = .008). There was no evidence of neurocognitive impairment associated with rTMS. impairment associated with rTMS.

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rTMS and schizophreniarTMS and schizophrenia 20052005

Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M, Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M, Rapisarda V, Bella R, Pennisi G.Rapisarda V, Bella R, Pennisi G.

Repetitive transcranial magnetic stimulation in schizophrenic Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations.patients reporting auditory hallucinations. Neurosci Lett. 2005 Jul Neurosci Lett. 2005 Jul 8;383(1-2):54-7. Epub 2005 Apr 15.8;383(1-2):54-7. Epub 2005 Apr 15.

16 schizophrenic patients (treated with atypical antipsycothic drugs) 16 schizophrenic patients (treated with atypical antipsycothic drugs) Low frequency rTMS (1Hz) was performed at the 90% of resting motor Low frequency rTMS (1Hz) was performed at the 90% of resting motor

threshold (MT)threshold (MT)4 sessions in four consecutive days for 15 minutes each application. 4 sessions in four consecutive days for 15 minutes each application. 8 patients received active stimulation, while 8 patients received sham 8 patients received active stimulation, while 8 patients received sham

stimulation. stimulation. Scale for the assessment of positive symptoms (SAPS), scale for the Scale for the assessment of positive symptoms (SAPS), scale for the

assessment of negative symptoms (SANS) and a scale to asses the assessment of negative symptoms (SANS) and a scale to asses the severity of the auditory hallucinations (SAH) were administered at the severity of the auditory hallucinations (SAH) were administered at the beginning and at regular intervals during the follow-up. beginning and at regular intervals during the follow-up.

The main finding was the long-term reduction in auditory The main finding was the long-term reduction in auditory hallucinations in the active group, with a return to the baseline in the hallucinations in the active group, with a return to the baseline in the sham group. sham group.

The negative symptomatology improved only in the later sessions and The negative symptomatology improved only in the later sessions and lasted during the follow-up. lasted during the follow-up.

The improvements in auditory hallucinations and positive The improvements in auditory hallucinations and positive symptomatology increased and lasted during the follow-up till the end-symptomatology increased and lasted during the follow-up till the end-point. point.

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rTMS and schizophreniarTMS and schizophrenia 20052005

Sachdev P, Loo C, Mitchell P, Malhi G.Sachdev P, Loo C, Mitchell P, Malhi G.Transcranial magnetic stimulation for the deficit Transcranial magnetic stimulation for the deficit

syndrome of schizophrenia: A pilot investigation.syndrome of schizophrenia: A pilot investigation. Psychiatry Clin Neurosci. 2005 Jun;59(3):354-7.Psychiatry Clin Neurosci. 2005 Jun;59(3):354-7.

Open studyOpen study4 subjects with a stable deficit syndrome of schizophrenia 4 subjects with a stable deficit syndrome of schizophrenia

received high frequency repetitive transcranial magnetic received high frequency repetitive transcranial magnetic stimulation (stimulation (15 Hz15 Hz at 90% of motor threshold, 1800 pulses at 90% of motor threshold, 1800 pulses each session, daily for each session, daily for 20 sessions20 sessions over 4 weeks) over the over 4 weeks) over the left left dorsolateral prefrontal cortexdorsolateral prefrontal cortex. .

Subjects showed a Subjects showed a significant reduction in negative significant reduction in negative symptomssymptoms and improvement in function, with and improvement in function, with no change in no change in positive symptomspositive symptoms. .

This improvement was maintained at the 1 month follow This improvement was maintained at the 1 month follow up. up.

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rTMS and schizophreniarTMS and schizophrenia 20052005

Saba G, Verdon CM, Kalalou K, Rocamora JF, Dumortier G, Saba G, Verdon CM, Kalalou K, Rocamora JF, Dumortier G, Benadhira R, Stamatiadis L, Vicaut E, Lipski H, Januel D.Benadhira R, Stamatiadis L, Vicaut E, Lipski H, Januel D.

Transcranial magnetic stimulation in the treatment of Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: A double blind sham controlled schizophrenic symptoms: A double blind sham controlled study.study. J Psychiatr Res. 2005 May 7; [Epub ahead of print] J Psychiatr Res. 2005 May 7; [Epub ahead of print]

18 schizophrenic patients 18 schizophrenic patients active or sham rTMS active or sham rTMS 10 days 10 days over the over the left temporoparietalleft temporoparietal cortex (80% of the motor cortex (80% of the motor

threshold, threshold, 1Hz1Hz, five trains of 1min)., five trains of 1min).Psychopathological dimensions were measured with the positive Psychopathological dimensions were measured with the positive

and negative syndrome scale and clinical global impression (CGI) at and negative syndrome scale and clinical global impression (CGI) at baseline and after 10 session of rTMS. baseline and after 10 session of rTMS.

All patients were improved at the end of the trial but no All patients were improved at the end of the trial but no significant group differences were found. Patients receiving sham significant group differences were found. Patients receiving sham stimulation showed the same pattern of improvement compared to stimulation showed the same pattern of improvement compared to active condition on all the subscales of the positive and negative active condition on all the subscales of the positive and negative syndrome scale and CGI scores (p>0.05). syndrome scale and CGI scores (p>0.05).

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rTMS and schizophreniarTMS and schizophrenia 20052005

Lee SH, Kim W, Chung YC, Jung KH, Bahk WM, Jun TY, Kim KS, George MS, Chae JH.Lee SH, Kim W, Chung YC, Jung KH, Bahk WM, Jun TY, Kim KS, George MS, Chae JH.A double blind study showing that two weeks of daily repetitive TMS over A double blind study showing that two weeks of daily repetitive TMS over

the left or right temporoparietal cortex reduces symptoms in patients with the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations.schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci Lett. 2005 Mar 16;376(3):177-81Neurosci Lett. 2005 Mar 16;376(3):177-81

39 patients with schizophrenia with treatment-refractory AH (auditory 39 patients with schizophrenia with treatment-refractory AH (auditory hallucinations)hallucinations)

were allocated randomly to one of three groups: daily left, right, and sham rTMS were allocated randomly to one of three groups: daily left, right, and sham rTMS groups.groups.

rTMS was applied to the TP3 (temporoparietal) or 4 regions with the aid of the rTMS was applied to the TP3 (temporoparietal) or 4 regions with the aid of the electroencephalography 10-20 international system electroencephalography 10-20 international system

1 Hz for 20 min per day for 10 treatment days. 1 Hz for 20 min per day for 10 treatment days. Symptoms were evaluated using the Auditory Hallucination Rating Scale (AHRS), Symptoms were evaluated using the Auditory Hallucination Rating Scale (AHRS),

the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression--the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression--Severity (CGI-S), and Clinical Global Impression--Improvement (CGI-I) scale. Severity (CGI-S), and Clinical Global Impression--Improvement (CGI-I) scale.

For the time effect (within-subject comparison), there were significant changes in For the time effect (within-subject comparison), there were significant changes in the frequency of AHs, positive symptoms of PANSS, and CGI-I. the frequency of AHs, positive symptoms of PANSS, and CGI-I.

A between-group comparison revealed significant differences in the positive A between-group comparison revealed significant differences in the positive symptoms of PANSS, and CGI-I scores. symptoms of PANSS, and CGI-I scores.

Post hoc analysis revealed that both the right- and left-side rTMS treatment groups Post hoc analysis revealed that both the right- and left-side rTMS treatment groups exhibited better CGI-I scores compared to the sham-stimulated group. exhibited better CGI-I scores compared to the sham-stimulated group.

Left sided rTMS is not superior to right or sham rTMS. Left sided rTMS is not superior to right or sham rTMS.

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rTMS and addiction rTMS and addiction

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rTMS and addictionrTMS and addiction

70-80% of regular smokers fulfill the ICD-10-70-80% of regular smokers fulfill the ICD-10-criteria of dependence. criteria of dependence.

Therapeutic interventions, such as nicotine Therapeutic interventions, such as nicotine substitution or bupropione, yield poor substitution or bupropione, yield poor abstinence rates of 30% after 12 months, at abstinence rates of 30% after 12 months, at best. best.

In animal experiments, repetitive In animal experiments, repetitive transcranial magnetic stimulation (rTMS) transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called neurotransmission in regions of the so-called reward system.reward system.

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rTMS and addictionrTMS and addiction 20032003

Johann M, Wiegand R, Kharraz A, Bobbe G, Johann M, Wiegand R, Kharraz A, Bobbe G, Sommer G, Hajak G, Wodarz N, Eichhammer P.Sommer G, Hajak G, Wodarz N, Eichhammer P.

Transcranial magnetic stimulation for Transcranial magnetic stimulation for nicotine dependence. nicotine dependence. Psychiatr Prax. 2003 Psychiatr Prax. 2003 May;30 Suppl 2:S129-31.May;30 Suppl 2:S129-31.

11 tobacco-dependent cigarette smokers 11 tobacco-dependent cigarette smokers Active or placebo rTMS on consecutive Active or placebo rTMS on consecutive

days. days. Craving, as measured by a visual analogue Craving, as measured by a visual analogue

scale, is significantly decreased after active scale, is significantly decreased after active stimulation compared to placebo-stimulation stimulation compared to placebo-stimulation intra-individually. intra-individually.

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rTMS and addictionrTMS and addiction 20032003

Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Wodarz N, Hajak G.Wodarz N, Hajak G.

High-frequency repetitive transcranial magnetic High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking. stimulation decreases cigarette smoking. J Clin J Clin Psychiatry. 2003 Aug;64(8):951-3.Psychiatry. 2003 Aug;64(8):951-3.

14 smokers 14 smokers double-blind crossover trialdouble-blind crossover trialcomparing single days of active versus sham stimulation. comparing single days of active versus sham stimulation. Outcome measures were rTMS effects on number of Outcome measures were rTMS effects on number of

cigarettes smoked during an ad libitum smoking period and cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence. effects on craving after a period of acute abstinence.

20-Hz rTMS of 20-Hz rTMS of left dorsolateral prefrontal cortexleft dorsolateral prefrontal cortex reduced reduced cigarette smoking significantly (p <.01) compared with sham cigarette smoking significantly (p <.01) compared with sham stimulation. Levels of craving did not change significantly. stimulation. Levels of craving did not change significantly.


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