Presentation is loading. Please wait.

Presentation is loading. Please wait.

Transcranial Magnetic Stimulation in Psychiatric Disorders Oguz Tan, Memory Center, Istanbul, Turkey.

Similar presentations


Presentation on theme: "Transcranial Magnetic Stimulation in Psychiatric Disorders Oguz Tan, Memory Center, Istanbul, Turkey."— Presentation transcript:

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

2 Transcranial Magnetic Stimulation in Psychiatric Disorders Oguz Tan, Memory Center, Istanbul, Turkey Objectives: It was aimed to review the literature about the clinical use of repetitive transcranial magnetic stimulation (rTMS) therapy in psychiatric disorders. Methods: A medline research was done concerning rTMS use in mood disorders, anxiety disorders, psychotic disorders, and substance use disorders. Results: Application of rTMS in depressive patients usually lead to a significant clinical improvement. Findings about the use of rTMS in manic episodes, anxiety disorders, psychotic disorders, and substance use disorders are limited. Coclusion: rTMS is probably a useful therapeutic tool in depressive disorders. Further research is needed to clarify the role of rTMS in pasychiatric disorders other than depression.

3 Repetitive transcranial magnetic stimulation in the treatment of depression has been intensely studied. Since 1993 until recently, approximately 70 studies evaluating clinical efficacy of rTMS in depression have been published. Repetitive transcranial magnetic stimulation in the treatment of depression has been intensely studied. Since 1993 until recently, approximately 70 studies evaluating clinical efficacy of rTMS in depression have been published. Most data support an antidepressant effect of high- frequency rTMS administered to the left prefrontal cortex, although most patients enrolled in the studies had treatment-resistant and severe depression. Most data support an antidepressant effect of high- frequency rTMS administered to the left prefrontal cortex, although most patients enrolled in the studies had treatment-resistant and severe depression. Side-effect profile of rTMS is much more favorable than ECT or pharmacotherapy. The only serious side-effect of rTMS is seizure that have occured very rarely. Side-effect profile of rTMS is much more favorable than ECT or pharmacotherapy. The only serious side-effect of rTMS is seizure that have occured very rarely.

4 An important reference is: This site contains: The Avery-George-Holtzheimer Database of rTMS Depression Studies UPDATED as of 11/22/2004

5 SHAM-CONTROLLED STUDIES 33 sham-controlled studies have been conducted since 1993 until June, out of these studies found that rTMS were superior when compared to sham stimulation. However, in some studies, the benefit from rTMS was modest.

6 SHAM-CONTROLLED STUDIES 1996 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 dorsolateral prefrontal cortex in drug-resistant depression. Lancet 348: Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 348: patients. Medication-resistant. Cross-over study. 17 patients. Medication-resistant. Cross-over study. Non medication-free. Psychotic depression.. Left DLPFC 10 Hz Intensity 90 percent MT 5 sessions with active rTMS (cross-over to the other group and five more sessions) Total pulses Different cortical areas (vertex stimulation, right DLPFC) stimulation were stimulated. HAMD decreased from 25.2 to 13.8 after 5 sessions (45 percent decrease in depression) HAMD decreased from 25.2 to 13.8 after 5 sessions (45 percent decrease in depression)

7 SHAM-CONTROLLED STUDIES 1997 George MS, Wassermann EM, Kimbrell TA, et al George MS, Wassermann EM, Kimbrell TA, et al Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry 154: Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry 154: patients. Not medication-resistant. Cross-over study. 24 patients. Not medication-resistant. Cross-over study. Some patients are medication-free. Left DLPFC 20 Hz Intensity 80 percent MT 10 sessions Total pulses rTMS superior to Sham, but small decrease in depression rating. rTMS superior to Sham, but small decrease in depression rating.

8 SHAM-CONTROLLED STUDIES 1999 Avery DH, Claypoole K, Robinson L, et al Avery DH, Claypoole K, Robinson L, et al Repetitive transcranial magnetic stimulation in the treatment of medication-resistant depression: preliminary data. J Nerv Ment Dis 187: Repetitive transcranial magnetic stimulation in the treatment of medication-resistant depression: preliminary data. J Nerv Ment Dis 187: patients. Medication-resistant. 6 patients. Medication-resistant. Not medication-free. Left DLPFC 10 Hz Intensity 80 percent MT 10 sessions Total pulses Slight improvement in rTMS group compared with sham. No decrement in neuropsychological tests with rTMS. Slight improvement in rTMS group compared with sham. No decrement in neuropsychological tests with rTMS.

9 SHAM-CONTROLLED STUDIES 1999 Klein E, Kreinin I, Chistyakov A, et al Klein E, Kreinin I, Chistyakov A, et al Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry 56: Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry 56: patients. Not medication-resistant. Not medication-free. Right DLPFC 1 Hz Intensity 110 percent MT 10 sessions Total pulses 1200 HAM-D decreased from 25.8 to 13.7 with rTMS and 25.3 to 19.7 with sham. Three dropouts (1 rTMS, 2 sham). Of rTMS patients, 49% were responders (w/ >50% decrease in HAM-D); of sham patients, 25% were responders. HAM-D decreased from 25.8 to 13.7 with rTMS and 25.3 to 19.7 with sham. Three dropouts (1 rTMS, 2 sham). Of rTMS patients, 49% were responders (w/ >50% decrease in HAM-D); of sham patients, 25% were responders.

10 SHAM-CONTROLLED STUDIES 1999 Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Gandevia S Loo C, Mitchell P, Sachdev P, McDarmont B, Parker G, Gandevia S Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. Am J Psychiatry 156: Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. Am J Psychiatry 156: patients. Medication-resistant. 18 patients. Medication-resistant.Not-medication-free. Left DLPFC 10 Hz Intensity 110 percent MT 10 sessions of real or sham rTMS, then permitted up to 20 sessions of real rTMS Total pulses With rTMS significant decreases in HAMD after 10 sessions, but not different from sham. With rTMS, 44.9% decrease from baseline at one month follow-up. With rTMS significant decreases in HAMD after 10 sessions, but not different from sham. With rTMS, 44.9% decrease from baseline at one month follow-up.

11 SHAM-CONTROLLED STUDIES 1999 Padberg F, Zwanzger P, Thoma H, et al Padberg F, Zwanzger P, Thoma H, et al Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS. Psychiatry Res 88: Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS. Psychiatry Res 88: patients. Medication-resistant. 18 patients. Medication-resistant. Some patients are medication-free. Left DLPFC 10 Hz or 0.3 Hz Intensity 90 percent MT 5 sessions Total pulses 1250 Not clinically meaningful antidepressant efficacy. Improvement in verbal memory scores after fast rTMS, with no change after slow rTMS, and a trend toward poorer scores after sham. Not clinically meaningful antidepressant efficacy. Improvement in verbal memory scores after fast rTMS, with no change after slow rTMS, and a trend toward poorer scores after sham.

12 SHAM-CONTROLLED STUDIES 1999 Kimbrell TA, Little JT, Dunn RT, et al Kimbrell TA, Little JT, Dunn RT, et al Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. Biol Psychiatry 46: Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. Biol Psychiatry 46: patients. Medication-resistance NA. 26 patients. Medication-resistance NA. Some patients medication-free. Left DLPFC 20 Hz or 1 Hz Intensity 90 percent MT 10 sessions Total pulses /13 responded (greater than 50% response) There was a negative correlation between the degree of antidepressant response after 1 Hz compared to 20 Hz. Better response to 20 hz was associated with the degree of baseline hypometabolism measured by PET, whereas 1 Hz rTMS tended to be associated with baseline hypermetabolism. 1/10 responded in 20 Hz group. 0/3 responded in sham group. Antidepressant response to rTMS might vary as as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. 2/13 responded (greater than 50% response) There was a negative correlation between the degree of antidepressant response after 1 Hz compared to 20 Hz. Better response to 20 hz was associated with the degree of baseline hypometabolism measured by PET, whereas 1 Hz rTMS tended to be associated with baseline hypermetabolism. 1/10 responded in 20 Hz group. 0/3 responded in sham group. Antidepressant response to rTMS might vary as as a function of stimulation frequency and may depend on pretreatment cerebral metabolism.

13 SHAM-CONTROLLED STUDIES 1999 Stikhina N, Lyskov EB, Lomarev MP, Aleksanian ZA, Mikhailov VO, Medvedev SV Stikhina N, Lyskov EB, Lomarev MP, Aleksanian ZA, Mikhailov VO, Medvedev SV Transcranial magnetic stimulation in neurotic depression. Zh Nevrol Psikhiatr Im S S Korsakova 99:26-9. Transcranial magnetic stimulation in neurotic depression. Zh Nevrol Psikhiatr Im S S Korsakova 99: patients. Medication-resistance NA. 29 patients. Medication-resistance NA. Medication-free or not NA. All patients received psychotherapy. Left frontal 40 Hz Intensity Tesla 10 sessions Total pulses TMS significantly better than control condition. TMS significantly better than control condition.

14 SHAM-CONTROLLED STUDIES 2000 Berman RM, Narasimhan M, Sanacora G, et al Berman RM, Narasimhan M, Sanacora G, et al A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry 47: A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry 47: patients. Medication-resistant. 20 patients. Medication-resistant.Medication-free. Left DLPFC 20 Hz Intensity 80 percent MT 10 sessions Total pulses 8000 In rTMS group, 1/10 responded (decrease in HAM-D from 48 to 7); in sham group 0/10 responded. Statistically significant but clinically modest reductions of depressive symptoms. In rTMS group, 1/10 responded (decrease in HAM-D from 48 to 7); in sham group 0/10 responded. Statistically significant but clinically modest reductions of depressive symptoms.

15 SHAM-CONTROLLED STUDIES 2000 Eschweiler GW, Wegerer C, Schlotter W, et al Eschweiler GW, Wegerer C, Schlotter W, et al Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression. Psychiatry Res 99: Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression. Psychiatry Res 99: patients. Not medication-resistant. 12 patients. Not medication-resistant. Medication-free or not NA Left DLPFC 10 Hz Intensity 90 percent MT Crossover study. 4 weeks’ duration consisting of two periods of 5 days with rTMS separated by 9 days of no stimulation Total pulses rTMS significantly better than sham, also used near infrared spectroscopy. Absence of a task-related increase of total hemoglobin concentrations at the stimulation site, but not at other locations, before the first active rTMS significantly predicted the clinical response to active rTMS. rTMS significantly better than sham, also used near infrared spectroscopy. Absence of a task-related increase of total hemoglobin concentrations at the stimulation site, but not at other locations, before the first active rTMS significantly predicted the clinical response to active rTMS.

16 SHAM-CONTROLLED STUDIES 2000 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 treating depression. Biol Psychiatry 48: A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry 48: patients. Medication-resistant. 30 patients. Medication-resistant.Medication-free Left DLPFC 5 Hz or 20 Hz or sham Intensity 100 percent MT 10 sessions Total pulses /10 responded (greater than 50% decrease in HAMD). 3/10 responded to 20Hz. 0/10 responded to sham. 6/10 responded (greater than 50% decrease in HAMD). 3/10 responded to 20Hz. 0/10 responded to sham.

17 SHAM-CONTROLLED STUDIES 2001 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 medication-resistant depression. J Affect Disord 64: Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. J Affect Disord 64: patients. Medication-resistant. 40 patients. Medication-resistant. Not medication-free Left DLPFC 20 Hz 10 sessions Intensity 90 percent MT Total pulses rTMS added to current antidepressant treatments. 5/17 (29%) of patients initially randomized to rTMS were responders (>50% decrease in HDRS). 15 sham non-responders crossed over to receive active 90% MT rTMS; 4/14 (29%) patients that completed 4 weeks of treatment were responders. The 9 non-responders were treated with 10 additional sessions of 110% MT rTMS; 3/9 (33%) were responders. Real, but not sham HF-rTMS, was associated with a significant decrease in the Hamilton Depression Rating Scale, but only twelve patients decreased more than 50% rTMS added to current antidepressant treatments. 5/17 (29%) of patients initially randomized to rTMS were responders (>50% decrease in HDRS). 15 sham non-responders crossed over to receive active 90% MT rTMS; 4/14 (29%) patients that completed 4 weeks of treatment were responders. The 9 non-responders were treated with 10 additional sessions of 110% MT rTMS; 3/9 (33%) were responders. Real, but not sham HF-rTMS, was associated with a significant decrease in the Hamilton Depression Rating Scale, but only twelve patients decreased more than 50%

18 SHAM-CONTROLLED STUDIES 2001 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 transcranial magnetic stimulation in major depression. Biol Psychiatry 50:22-7. Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression. Biol Psychiatry 50: patients. Medication-resistance NA. 14 patients. Medication-resistance NA. Medication-free NA Left DLPFC 10 Hz Number of sessions NA Intensity 100 percent MT Total pulses NA No efficacy data presented. Patients receiving active TMS showed greater mood improvements with acute sessions of TMS than patients receiving sham. Subjects are a subset of a larger study evaluation twice daily versus once daily rTMS. The change in TSH from pre- to post-rTMS was significantly different between active and sham sessions No efficacy data presented. Patients receiving active TMS showed greater mood improvements with acute sessions of TMS than patients receiving sham. Subjects are a subset of a larger study evaluation twice daily versus once daily rTMS. The change in TSH from pre- to post-rTMS was significantly different between active and sham sessions

19 SHAM-CONTROLLED STUDIES 2001 Manes F, Jorge R, Morcuende M, Yamada T, Paradiso S, Robinson RG Manes F, Jorge R, Morcuende M, Yamada T, Paradiso S, Robinson RG A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr 13: A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr 13: patients. Medication-resistant. 20 patients. Medication-resistant.Medication-free. Left DLPFC 20 Hz 5 sessions. Intensity 80 percent MT Total pulses 4000 Studied patients >50 years old (mean age 60.7 years, SD 9.8 years). Neuropsychological testing used MMSE (minimental state examination); no significant difference between groups pre- or post- treatment. 6 responders (3 to rTMS and 3 to sham) had significantly greater frontal lobe volume than non-responders. Studied patients >50 years old (mean age 60.7 years, SD 9.8 years). Neuropsychological testing used MMSE (minimental state examination); no significant difference between groups pre- or post- treatment. 6 responders (3 to rTMS and 3 to sham) had significantly greater frontal lobe volume than non-responders.

20 SHAM-CONTROLLED STUDIES 2001 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 treatment in depression. J Neurol Neurosurg Psychiatry 71: Prefrontal repetitive transcranial magnetic stimulation as add on treatment in depression. J Neurol Neurosurg Psychiatry 71: patients. 16 medication-resistant (a single trial of drug), 12 had not received medication fort he present depressive episode. 28 patients. 16 medication-resistant (a single trial of drug), 12 had not received medication fort he present depressive episode. Patients were started on sertraline. Left DLPFC 20 Hz 10 sessions. Intensity 90 percent MT Total pulses rTMS did not add efficacy over the use of standard antidepressant medication. Studied rTMS versus sham as add-on treatment to sertraline for a major depressive episode. All but two patients received benzodiazepines. Differences in response at 2 weeks in HDRS and BDI, but not at 4 weeks (2 weeks after last treatment). Non-responders to sham were crossed over to receive 90% MT rTMS with identical parameters. Non-responders to active 90% MT rTMS crossed over to receive 110% MT rTMS. rTMS did not add efficacy over the use of standard antidepressant medication. Studied rTMS versus sham as add-on treatment to sertraline for a major depressive episode. All but two patients received benzodiazepines. Differences in response at 2 weeks in HDRS and BDI, but not at 4 weeks (2 weeks after last treatment). Non-responders to sham were crossed over to receive 90% MT rTMS with identical parameters. Non-responders to active 90% MT rTMS crossed over to receive 110% MT rTMS.

21 SHAM-CONTROLLED STUDIES 2001 Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T, Sackeim HA Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T, Sackeim HA Augmentation of sertraline antidepressant treatment with transcranial magnetic stimulation. Biol Psychiatry 49:81S. Augmentation of sertraline antidepressant treatment with transcranial magnetic stimulation. Biol Psychiatry 49:81S. 36 patients. 61 percent of patients were medication-resistant. 36 patients. 61 percent of patients were medication-resistant. Not medication-free. 10 Hz over the left DLPFC or 1 Hz the right DLPFC or sham 10 sessions. Intensity 110 percent MT Total pulses Compared 10 Hz left DLPFC rTMS to 1 Hz right DLPFC rTMS to sham rTMS, all as add-on therapy to sertraline 50 mg. Remission in the active TMS group combined was 25% vs. 8% in the sham group (NS). Degree of medication resistance negatively correlated with response and remission. Compared 10 Hz left DLPFC rTMS to 1 Hz right DLPFC rTMS to sham rTMS, all as add-on therapy to sertraline 50 mg. Remission in the active TMS group combined was 25% vs. 8% in the sham group (NS). Degree of medication resistance negatively correlated with response and remission.

22 SHAM-CONTROLLED STUDIES 2002 Dolberg OT, Dannon PN, Schreiber S, Grunhaus L Dolberg OT, Dannon PN, Schreiber S, Grunhaus L Transcranial magnetic stimulation in patients with bipolar depression: a double blind, controlled study. Bipolar Disord 4:94-5. Transcranial magnetic stimulation in patients with bipolar depression: a double blind, controlled study. Bipolar Disord 4: patients. Medication-resistance NA. 20 patients. Medication-resistance NA. Medication-free NA Left DLPFC Frequency (Hz) NA 10 sessions Intensity NA Total pulses NA Preliminary report. Response or remission rate NA. Depression decreased 29 percent in the active TMS group, 20 percent in the sham group. Preliminary report. Response or remission rate NA. Depression decreased 29 percent in the active TMS group, 20 percent in the sham group.

23 SHAM-CONTROLLED STUDIES 2002 Padberg F, Zwanzger P, Keck ME, et al Padberg F, Zwanzger P, Keck ME, et al Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 27: Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 27: patients. Drug-resistant. 31 patients. Drug-resistant. Not medication-free. Left DLPFC 10 Hz 10 sessions. Intensity: 100 percent MT or 90 percent MT or sham Total pulses MADRS scores: 4% decrease with sham, 15% decrease with 90% MT rTMS, 33% decrease with 100% rTMS. 3/10 responders (>50% decr in HAMD) and 2/10 partial responders (>25% decr HAMD) with 100% MT rTMS, 2/10 responders and 1/10 partial responder with 90% MT rTMS, 0/10 responders and 2/10 partial responders with sham rTMS. 3/10 responders (>50% decr in HAMD) and 2/10 partial responders (>25% decr HAMD) with 100% MT rTMS, 2/10 responders and 1/10 partial responder with 90% MT rTMS, 0/10 responders and 2/10 partial responders with sham rTMS. Patients receiving rTMS had substantially fewer days in the hospital post- 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 increased with stimulation intensity across the three groups. 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 sham rTMS). Improvement of depressive symptoms after rTMS significantly increased with stimulation intensity across the three groups.

24 SHAM-CONTROLLED STUDIES 2002 Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Feingold A, Berman RM Boutros NN, Gueorguieva R, Hoffman RE, Oren DA, Feingold A, Berman RM Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression. Psychiatry Res 113: Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression. Psychiatry Res 113: patients. Medication-resistant. 21 patients. Medication-resistant. Not medication-free. Left DLPFC 20 Hz 10 sessions. Intensity: 80 percent MT or sham Total pulses 8000 No statistically significant difference between rTMS- and sham- treated patients. Authors suggest this may relate to subthreshold rTMS intensity. No statistically significant difference between rTMS- and sham- treated patients. Authors suggest this may relate to subthreshold rTMS intensity.

25 SHAM-CONTROLLED STUDIES 2003 Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter J Hoppner J, Schulz M, Irmisch G, Mau R, Schlafke D, Richter J Antidepressant efficacy of two different rTMS procedures High frequency over left versus low frequency over right prefrontal cortex compared with sham stimulation. Eur Arch Psychiatry Clin Neurosci 253: Antidepressant efficacy of two different rTMS procedures High frequency over left versus low frequency over right prefrontal cortex compared with sham stimulation. Eur Arch Psychiatry Clin Neurosci 253: patients. Medication-resistance NA 30 patients. Medication-resistance NA Not medication-free. 20 Hz over the left DLPFC (90 percent MT) or 1 Hz the right DLPFC (110 percent MT) or sham 10 sessions. Total pulses 8000 over the left or 1200 over the right Patients were started on an antidepressant medication 2 weeks before rTMS, which was used as an add-on treatment. Differences between the rTMS procedures regarding depressive symptoms could not be found. Patients were started on an antidepressant medication 2 weeks before rTMS, which was used as an add-on treatment. Differences between the rTMS procedures regarding depressive symptoms could not be found.

26 SHAM-CONTROLLED STUDIES 2003 Loo CK, Mitchell PB, Croker VM, et al Loo CK, Mitchell PB, Croker VM, et al Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med 33: Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med 33: patients. Drug-resistant. 19 patients. Drug-resistant. Not medication-free. Bilateral DLPFC 15 Hz 15 sessions. Intensity 90 percent MT Total pulses No significant difference between the two groups. 2 responders in the rTMS groups, 1 responder in the sham group. 6 sham patients crossed over to rTMS; 1 patient in this group responded. No significant difference between the two groups. 2 responders in the rTMS groups, 1 responder in the sham group. 6 sham patients crossed over to rTMS; 1 patient in this group responded.

27 SHAM-CONTROLLED STUDIES 2003 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) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 5:40-7. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 5: patients. Drug-resistance NA 23 patients. Drug-resistance NA Not medication-free. Left DLPFC 5 Hz 10 sessions. Intensity 110 percent MT Total pulses No significant difference between rTMS and sham in decrease in HAMD or response rate. No patients developed mania or hypomania during the study. No significant difference between rTMS and sham in decrease in HAMD or response rate. No patients developed mania or hypomania during the study.

28 SHAM-CONTROLLED STUDIES 2003 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 coil-navigation according to PET data. J Psychiatr Res 37: Add-on rTMS for treatment of depression: a pilot study using stereotaxic coil-navigation according to PET data. J Psychiatr Res 37: patients. Some patients are drug-resistant. 25 patients. Some patients are drug-resistant. Not medication-free. 6 parients were given left DLPFC, 6 right, 6 sham (parietooccipital) 15 Hz 10 sessions. Intensity 110 percent MT Total pulses Real stimulation improved depression moderately but significantly better compared to sham. In the real condition, four out of 13 patients responded, whereas none responded to sham. Left vs. right prefrontal location of stimulation guided by PET-identified prefrontal hypometabolism (when present). 11 of 25 patients had right prefrontal hypometabolism at baseline. 1 of 25 had left prefrontal hypometabolism at baseline. 13 of 25 had left=right metabolism at baseline or no imaging data available. There was no evidence that using baseline prefrontal hypometabolism to guide treatment location was beneficial. Treatment groups were combined for analyses. Real stimulation improved depression moderately but significantly better compared to sham. In the real condition, four out of 13 patients responded, whereas none responded to sham. Left vs. right prefrontal location of stimulation guided by PET-identified prefrontal hypometabolism (when present). 11 of 25 patients had right prefrontal hypometabolism at baseline. 1 of 25 had left prefrontal hypometabolism at baseline. 13 of 25 had left=right metabolism at baseline or no imaging data available. There was no evidence that using baseline prefrontal hypometabolism to guide treatment location was beneficial. Treatment groups were combined for analyses.

29 SHAM-CONTROLLED STUDIES 2003 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) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 5:40-7. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 5: patients. Medication-resistance NA. 23 patients. Medication-resistance NA. Not medication-free. Left DLPFC 5 Hz 10 sessions. Intensity 110 percent MT Total pulses No significant difference between rTMS and sham in decrease in HAMD or response rate. But a trend for greater improvement in daily subjective mood ratings. No patients developed mania or hypomania during the study. No significant difference between rTMS and sham in decrease in HAMD or response rate. But a trend for greater improvement in daily subjective mood ratings. No patients developed mania or hypomania during the study.

30 SHAM-CONTROLLED STUDIES 2003 Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 60: Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 60: patients. Medication-resistance NA. 60 patients. Medication-resistance NA. Not medication-free. 3 groups: 1-10 Hz left DLPFC 2-1 Hz right DLPFC 3-Sham 10 sessions. Intensity 100 percent MT Total pulses 3000 or Compares 10 Hz LPF stim with 1 Hz RPF stim with sham. Initial trial was with 10 sessions: 14-15% decr in MADRS in both rTMS groups (1/20 patients in LPF group with >50% decr), 1% decr in sham (significant difference between the treatment and sham groups, but not significant difference between the treatment groups). 15 patients with >20% decr in MADRS by 10 sessions went on to receive a total of 20 open rTMS sessions: 40% decr in MADRS in LPF group (4/8 patients with decr >50%), 57% decr in RPF group (4/7 patients with decr >50%). Baseline psychomotor agitation predicted succesful response to treatment. Compares 10 Hz LPF stim with 1 Hz RPF stim with sham. Initial trial was with 10 sessions: 14-15% decr in MADRS in both rTMS groups (1/20 patients in LPF group with >50% decr), 1% decr in sham (significant difference between the treatment and sham groups, but not significant difference between the treatment groups). 15 patients with >20% decr in MADRS by 10 sessions went on to receive a total of 20 open rTMS sessions: 40% decr in MADRS in LPF group (4/8 patients with decr >50%), 57% decr in RPF group (4/7 patients with decr >50%). Baseline psychomotor agitation predicted succesful response to treatment.

31 SHAM-CONTROLLED STUDIES 2004 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 depression: a prospective, single centre, randomised, double blind, sham controlled "add on" trial. J Neurol Neurosurg Psychiatry 75: No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled "add on" trial. J Neurol Neurosurg Psychiatry 75: patients. Medication resistance NA. 41 patients. Medication resistance NA. They were medication-free, medication started at the start of rTMS. Group 1: 20 Hz over the left DLPFC and subsequent sham 1 Hz over the right DLPFC Group 2: simulataneous bilateral active stimulation (20 Hz over the left DLPFC, 1 Hz over the right DLPFC) Group 3: bilateral sham stimulation Intensity 100 percent motor threshold in the 20 Hz group, 120 in the 1 Hz group 10 sessions Total pulses No significant differences between the groups. 20 Hz LPF and the combined 20 Hz LPF/1 Hz RPF active rTMS groups were combined for efficacy analyses. Unknown if patients were treatment-resistant at baseline. The results suggest that rTMS as an "add on" strategy, applied in a unilateral and a bilateral stimulation paradigm, does not exert an additional antidepressant effect. No significant differences between the groups. 20 Hz LPF and the combined 20 Hz LPF/1 Hz RPF active rTMS groups were combined for efficacy analyses. Unknown if patients were treatment-resistant at baseline. The results suggest that rTMS as an "add on" strategy, applied in a unilateral and a bilateral stimulation paradigm, does not exert an additional antidepressant effect.

32 SHAM-CONTROLLED STUDIES 2004 Jorge RE, Robinson RG, Tateno A, et al Jorge RE, Robinson RG, Tateno A, et al Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol Psychiatry 55: Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol Psychiatry 55: patients. Drug-resistant. 20 patients. Drug-resistant.Medication-free. Left DLPFC 10 Hz 10 sessions. Intensity 110 percent MT Total pulses patients in the active rTMS group responded and one patient remitted, no patients in the sham group responded. 38 percent decrease in depression in the active rTMS group, 13 percent in the sham group. 3 patients in the active rTMS group responded and one patient remitted, no patients in the sham group responded. 38 percent decrease in depression in the active rTMS group, 13 percent in the sham group.

33 SHAM-CONTROLLED STUDIES 2004 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 repetitive transcranial magnetic stimulation. Depress Anxiety 19: Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation. Depress Anxiety 19: patients. Drug-resistant. 15 patients. Drug-resistant.Medication-free. Left DLPFC 10 Hz 10 sessions. Intensity 110 percent MT Total pulses No significant difference between rTMS and sham; however, a significant negative correlation between length of current depressive episode and response to rTMS was found. Non-responders to sham were allowed to receive active rTMS. Patients with a current episode shorter than 4 years showed a 52% reduction in mean HAM-D whereas those with a current episode longer than 10 years showed only a 6% decrease. No significant difference between rTMS and sham; however, a significant negative correlation between length of current depressive episode and response to rTMS was found. Non-responders to sham were allowed to receive active rTMS. Patients with a current episode shorter than 4 years showed a 52% reduction in mean HAM-D whereas those with a current episode longer than 10 years showed only a 6% decrease.

34 SHAM-CONTROLLED STUDIES 2004 Kauffmann CD, Cheema MA, Miller BE Kauffmann CD, Cheema MA, Miller BE Slow right prefrontal transcranial magnetic stimulation as a treatment for medication-resistant depression: a double-blind, placebo- controlled study. Depress Anxiety 19: Slow right prefrontal transcranial magnetic stimulation as a treatment for medication-resistant depression: a double-blind, placebo- controlled study. Depress Anxiety 19: patients. Drug-resistant. 12 patients. Drug-resistant. Not medication-free. Right DLPFC 10 Hz 10 sessions. Intensity 110 percent MT Total pulses 1200 No significant difference between the groups. However, the active TMS group showed a significant reduction in HAMD over time whereas the sham group did not. Active TMS responders relapsed in 2-3 months. Sham responders relapsed in 2 weeks. No significant difference between the groups. However, the active TMS group showed a significant reduction in HAMD over time whereas the sham group did not. Active TMS responders relapsed in 2-3 months. Sham responders relapsed in 2 weeks.

35 SHAM-CONTROLLED STUDIES 2004 Mosimann UP, Schmitt W, Greenberg BD, et al Mosimann UP, Schmitt W, Greenberg BD, et al Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res 126: Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res 126: elderly patients (mean age 62 years). Drug-resistant. 24 elderly patients (mean age 62 years). Drug-resistant. Not medication-free. Left DLPFC 20 Hz 10 sessions. Intensity 100 percent MT Total pulses No additional antidepressant effect of active rTMS. No additional antidepressant effect of active rTMS.

36 SHAM-CONTROLLED STUDIES 2004 Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA. Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry Aug;75(8): Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry Aug;75(8): patients. Not medication-resistant. 42 patients. Not medication-resistant. Not medication-free. 15 Hz 10 sessions. Group 1: active rTMS and placebo drug treatment Group 2: sham rTMS and fluoxetine 20 mg/day. Depression scores were improved to the same extent in both groups after two weeks of treatment (HDRS 38% for group 1, 41% for group 2). At week 8 there was a tendency for worse motor UPDRS (Unified Parkinson’s Disease Rating Scale) scores in group 2. ADL (Acitivities of Daily Living) showed improvement at week 8 only in group 1. MMSE (Minimental State Examination) improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects. Depression scores were improved to the same extent in both groups after two weeks of treatment (HDRS 38% for group 1, 41% for group 2). At week 8 there was a tendency for worse motor UPDRS (Unified Parkinson’s Disease Rating Scale) scores in group 2. ADL (Acitivities of Daily Living) showed improvement at week 8 only in group 1. MMSE (Minimental State Examination) improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.

37 SHAM-CONTROLLED STUDIES 2004 Koerselman F, Laman D, van Duijn H, van Duijn M, Willems M Koerselman F, Laman D, van Duijn H, van Duijn M, Willems M A 3-month, follow-up, randomized, placebo-controlled study of repetitive transcranial magnetic stimulation in depression. J Clin Psychiatry 65(10): A 3-month, follow-up, randomized, placebo-controlled study of repetitive transcranial magnetic stimulation in depression. J Clin Psychiatry 65(10): patients. Drug-resistance NA. 55 patients. Drug-resistance NA. Not medication-free. Left DLPFC 20 Hz 10 sessions. Intensity 80 percent MT Total pulses 8000 No difference between active and 45 deg sham TMS after 2 weeks of treatment. However, at 12 weeks, the active TMS group was significantly less depressed than the sham group. No difference between active and 45 deg sham TMS after 2 weeks of treatment. However, at 12 weeks, the active TMS group was significantly less depressed than the sham group.

38 SHAM-CONTROLLED STUDIES 2005 Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski ML, Moreno RA, Marcolin MA. Biol Psychiatry Jan 15;57(2): ML, Moreno RA, Marcolin MA. Biol Psychiatry Jan 15;57(2): Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. 46 patients 46 patients All patients were concomitantly taking amitriptyline (mean dose 110 mg/day). Left DLPFC 5 Hz 20 sessions Intensity 120 percent MT Total pulses rTMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment compared with sham. The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p <.001 at fourth week). rTMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment compared with sham. The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p <.001 at fourth week).

39 rTMS versus ECT Since 2000 until today, 7 studies comparing rTMS with ECT and some case reports have been publishes. In non-psychotic depression, it was found that the efficacy of rTMS was nearly equal to that of ECT, with a much more favorable side-effect profile.

40 rTMS versus ECT 2000 Grunhaus L, Dannon PN, Schreiber S, et al Grunhaus L, Dannon PN, Schreiber S, et al Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry 47: Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry 47: patients referred for ECT 40 patients referred for ECT rTMS group medication-free. Left DLPFC 10 Hz Intensity 90 percent MT 20 sessions Total pulses /16 responded to rTMS;12/18 to ECT. Among nonpsychotic depressed 5/8 responded to rTMS; 5/10 to ECT. Among psychotically depressed, only 2/8 responded to rTMS; 7/8 to ECT. 7/16 responded to rTMS;12/18 to ECT. Among nonpsychotic depressed 5/8 responded to rTMS; 5/10 to ECT. Among psychotically depressed, only 2/8 responded to rTMS; 7/8 to ECT.

41 rTMS versus ECT 2000 Pridmore S. Pridmore S. Substitution of rapid transcranial magnetic stimulation treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. Depress Anxiety. 2000;12(3): Substitution of rapid transcranial magnetic stimulation treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. Depress Anxiety. 2000;12(3): patients 22 patients Randomized, single-blind, controlled study. Two streams were conducted: Stream 1 received non-dominant unilateral (UL) ECT only, treatments being given 3 times per week for 2 weeks (11 patients). Stream 2 received a combination of treatments: one UL ECT on Day 1 and rTMS on the following 4 days, all repeated once, after a 2-day respite (11 patients). There was no evidence that the antidepressant effect of the ECT only stream was superior to that of the ECT plus rTMS stream. There was no increase in subjective side-effects in the ECT plus rTMS stream. On the contrary, this stream was accompanied by less side effects than the ECT only stream in this study. There was no evidence that the antidepressant effect of the ECT only stream was superior to that of the ECT plus rTMS stream. There was no increase in subjective side-effects in the ECT plus rTMS stream. On the contrary, this stream was accompanied by less side effects than the ECT only stream in this study.

42 rTMS versus ECT 2000 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 stimulation (rTMS) and ECT treatment sessions in major depressive episode. Int J Neuropsychopharmacol 3: Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode. Int J Neuropsychopharmacol 3: patients. Medication-resistant. 32 patients. Medication-resistant. Not medication-free. Left DLPFC 20 Hz Intensity 100 percent motor threshold sessions (until remission occurred or response plateaued) Total pulses Gave unlimited number of rTMS sessions (mean 12.2, SD 3.4). Compared to group of 16 patients receiving unlimited ECT treatments (mean 6.2, SD 1.6). No significant difference between the groups in HDRS improvement. Patients receiving ECT had significantly greater decrease in Beck Depression Inventory scores. A significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on measures of depression overall, however, rTMS produced comparable results on a number of measures. Blind raters using the 17-item Hamilton Depression Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and the percentage improvement over the course of treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not significantly different. Significant differences were shown (p & 0.03) in percentage improvement on Beck Depression Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings of mood (rTMS 42.3%; ECT, 57%). Gave unlimited number of rTMS sessions (mean 12.2, SD 3.4). Compared to group of 16 patients receiving unlimited ECT treatments (mean 6.2, SD 1.6). No significant difference between the groups in HDRS improvement. Patients receiving ECT had significantly greater decrease in Beck Depression Inventory scores. A significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on measures of depression overall, however, rTMS produced comparable results on a number of measures. Blind raters using the 17-item Hamilton Depression Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and the percentage improvement over the course of treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not significantly different. Significant differences were shown (p & 0.03) in percentage improvement on Beck Depression Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings of mood (rTMS 42.3%; ECT, 57%).

43 rTMS versus ECT 2001 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 and long-term therapy of refractory depression--a case report]. Nervenarzt 2001 Sep;72(9):734-8 Repetitive transcranial magnetic stimulation (rTMS) in the acute and long-term therapy of refractory depression--a case report]. Nervenarzt 2001 Sep;72(9):734-8 A patient with therapy-resistant major depression has been hospitalized for 60 months during the last 7 years. A patient with therapy-resistant major depression has been hospitalized for 60 months during the last 7 years. Not even five electroconvulsive therapy (ECT) series (61 single applications) brought lasting remission of symptoms. As cognitive deficits developed and prolonged postnarcotic recovery times were observed, further ECT was contraindicated. Not even five electroconvulsive therapy (ECT) series (61 single applications) brought lasting remission of symptoms. As cognitive deficits developed and prolonged postnarcotic recovery times were observed, further ECT was contraindicated. (rTMS) to the left frontal cortex (rTMS) to the left frontal cortex Only a few rTMS applications already caused an obvious brightening in mood, remission of depressive delusional symptoms, and an increase in personal interests and activities. After 4 weeks of daily treatment, the patient was discharged from the ward. The rTMS treatments and psychotherapeutic counseling have been continued on an outpatient basis. Thus, pharmaco- and psychotherapeutic interventions combined with rTMS led to persistent symptom remission and social reintegration. Only a few rTMS applications already caused an obvious brightening in mood, remission of depressive delusional symptoms, and an increase in personal interests and activities. After 4 weeks of daily treatment, the patient was discharged from the ward. The rTMS treatments and psychotherapeutic counseling have been continued on an outpatient basis. Thus, pharmaco- and psychotherapeutic interventions combined with rTMS led to persistent symptom remission and social reintegration.

44 rTMS versus ECT 2001 Dannon PN, Grunhaus L. Dannon PN, Grunhaus L. Effect of electroconvulsive therapy in repetitive transcranial magnetic stimulation non-responder MDD patients: a preliminary study. Int J Neuropsychopharmacol Sep;4(3): Effect of electroconvulsive therapy in repetitive transcranial magnetic stimulation non-responder MDD patients: a preliminary study. Int J Neuropsychopharmacol Sep;4(3): The aim was to measure the effectiveness of ECT in-patients who had failed to respond to a course of repetitive transcranial magnetic stimulation (rTMS) treatment. The aim was to measure the effectiveness of ECT in-patients who had failed to respond to a course of repetitive transcranial magnetic stimulation (rTMS) treatment. 17 patients with severe MDD who had not responded to a course of rTMS were switched to receive ECT treatments. 17 patients with severe MDD who had not responded to a course of rTMS were switched to receive ECT treatments. 7 out of 17 patients responded to ECT. (3 out of 5 non-psychotics and 4 out of 12 psychotic patients). 7 out of 17 patients responded to ECT. (3 out of 5 non-psychotics and 4 out of 12 psychotic patients). ECT seems to be an effective treatment for 40% of patients who failed to respond to rTMS treatment. ECT seems to be an effective treatment for 40% of patients who failed to respond to rTMS treatment. Whether this is a result of reduced responsiveness to ECT in rTMS- resistant patients or a consequence of small sample size requires further study. Whether this is a result of reduced responsiveness to ECT in rTMS- resistant patients or a consequence of small sample size requires further study.

45 rTMS versus ECT 2001 Hasey G. Hasey G. Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. Can J Psychiatry Oct;46(8): Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. Can J Psychiatry Oct;46(8): The potential for unwanted side effects is substantially reduced, compared with ECT. The potential for unwanted side effects is substantially reduced, compared with ECT. In open trials, rTMS and ECT are reported to be equally efficacious for patients having depression without psychosis. In open trials, rTMS and ECT are reported to be equally efficacious for patients having depression without psychosis. But the therapeutic benefits reported in double-blind sham-rTMS controlled trials are more modest. But the therapeutic benefits reported in double-blind sham-rTMS controlled trials are more modest.

46 rTMS versus ECT 2002 Janicak PG, Dowd SM, Martis B, et al Janicak PG, Dowd SM, Martis B, et al Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry 51: Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry 51: patients. Medication-resistant. 25 patients. Medication-resistant. Not medication-free. Left DLPFC 10 Hz Intensity 110 percent motor threshold sessions Total pulses Patients received either rTMS or bitemporal ECT (4-12 treatments). There was a raw difference in mean change in HDRS between the groups (55% with rTMS, 64% with ECT), but no statistically significant difference. There was a 46% response rate with rTMS and a 56% response rate with ECT (not statistically significant). Patients received either rTMS or bitemporal ECT (4-12 treatments). There was a raw difference in mean change in HDRS between the groups (55% with rTMS, 64% with ECT), but no statistically significant difference. There was a 46% response rate with rTMS and a 56% response rate with ECT (not statistically significant).

47 rTMS versus ECT 2002 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 in a population of severely depressed individuals--preliminary report. Biol Psychiatry Apr 15;51(8): Three and six-month outcome following courses of either ECT or rTMS in a population of severely depressed individuals--preliminary report. Biol Psychiatry Apr 15;51(8): and 6-month outcomes of a group of patients treated with either ECT (n = 20) or (rTMS) (n = 21). 3- and 6-month outcomes of a group of patients treated with either ECT (n = 20) or (rTMS) (n = 21). With or without psychotic features referred for ECT With or without psychotic features referred for ECT Forty-one patients who responded to either treatment constituted the sample. Forty-one patients who responded to either treatment constituted the sample. Medications were routinely prescribed. Medications were routinely prescribed. There were no differences in the 6-month relapse rate between the groups. There were no differences in the 6-month relapse rate between the groups. Overall, 20% of the patients relapsed (four from the ECT group and four from the rTMS group). Overall, 20% of the patients relapsed (four from the ECT group and four from the rTMS group). Patients reported equally low and not significantly different scores in the HRSD (ECT group 8.4 +/- 5.6 and TMS group 7.9 +/- 7.1) at the 6- month follow up. 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- month follow up. The clinical gains obtained with rTMS last at least as long as those obtained with ECT. The clinical gains obtained with rTMS last at least as long as those obtained with ECT.

48 rTMS versus ECT 2003 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 therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. Biol Psychiatry 53: A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. Biol Psychiatry 53: patients with nonpsychotic MDD referred for ECT 41 patients with nonpsychotic MDD referred for ECT Not medication-free. Left DLPFC 10 Hz Intensity 90 percent motor threshold 20 sessions Total pulses No significant difference in HDRS decrease between rTMS and ECT patients. 12/20 ECT responders and 11/20 rTMS responders (>50% decr in HDRS, final HDRS 50% decr in HDRS, final HDRS <10); no significant difference between groups). 30% remission rate (final HAMD<9) in ECT and rTMS groups. For ECT group, patients received unilateral ECT initially, then bilateral ECT if no response after 6 treatments; 13 patients received unilateral ECT, 7 received bilateral ECT -- no significant difference in response rate between these groups.

49 rTMS versus ECT 2004 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 transcranial magnetic stimulation. A case report. Eur Psychiatry. Apr;19(2): ECT response after relapse during continuation repetitive transcranial magnetic stimulation. A case report. Eur Psychiatry. Apr;19(2): A woman who exerted a recurrent moderate major depressive episode, 6 months after discontinuation of maintenance ECT. She responded to acute rTMS treatment which was followed by the rTMS maintenance-protocol. Within 2 months of continuation rTMS she relapsed suffering from a severe non psychotic depressive episode and had to be switched to a successful ECT. In this patient rTMS had a good clinical impact as an acute treatment strategy, but failed to prevent relapse as the continuation ECT previously did in the same patient. A woman who exerted a recurrent moderate major depressive episode, 6 months after discontinuation of maintenance ECT. She responded to acute rTMS treatment which was followed by the rTMS maintenance-protocol. Within 2 months of continuation rTMS she relapsed suffering from a severe non psychotic depressive episode and had to be switched to a successful ECT. In this patient rTMS had a good clinical impact as an acute treatment strategy, but failed to prevent relapse as the continuation ECT previously did in the same patient.

50 rTMS versus ECT 2004 Kozel FA, George MS, Simpson KN. Kozel FA, George MS, Simpson KN. Decision analysis of the cost-effectiveness of repetitive transcranial magnetic stimulation versus electroconvulsive therapy for treatment of nonpsychotic severe depression. CNS Spectr. Jun;9(6): Compared the costs of three different treatment strategies for nonpsychotic severe depression. 1-ECT alone Decision analysis of the cost-effectiveness of repetitive transcranial magnetic stimulation versus electroconvulsive therapy for treatment of nonpsychotic severe depression. CNS Spectr. Jun;9(6): Compared the costs of three different treatment strategies for nonpsychotic severe depression. 1-ECT alone 2-rTMS alone 2-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) for the three treatment options for all nonpsychotic, severely depressed United States patients who would have otherwise undergone ECT. Calculated 12-month costs and quality adjusted life years (QALYs) for the three treatment options for all nonpsychotic, severely depressed United States patients who would have otherwise undergone ECT. The additional cost of using ECT alone compared with rTMS alone was 460,031 US dollars per quality adjusted year of life gained. For ECT versus rTMS-to-ECT, there was both an increased cost and a loss of 1,538 QALYs with ECT alone. The additional cost of using ECT alone compared with rTMS alone was 460,031 US dollars per quality adjusted year of life gained. For ECT versus rTMS-to-ECT, there was both an increased cost and a loss of 1,538 QALYs with ECT alone. If rTMS were to be made widely available clinically in the US, it would offer a substantial economic benefit over ECT in treating resistant depression. Using rTMS-to-ECT offers not only an economic advantage but also an increase in QALYs. If rTMS were to be made widely available clinically in the US, it would offer a substantial economic benefit over ECT in treating resistant depression. Using rTMS-to-ECT offers not only an economic advantage but also an increase in QALYs.

51 RECENT REVIEWS OR META-ANALYSES

52 RECENT REVIEWS OR META-ANALYSES 2003 Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Kulisevsky Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Kulisevsky Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. JBr J Psychiatry Jun;182: Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. JBr J Psychiatry Jun;182: Randomised controlled trials that compared rTMS with sham were included. Randomised controlled trials that compared rTMS with sham were included. 14 studies met the criteria. The quality of the included studies was low. 14 studies met the criteria. The quality of the included studies was low. Pooled analysis using the Hamilton Rating Scale for Depression showed an effect in favour of rTMS compared with sham after 2 weeks of treatment, but this was not significant at the 2-week follow- up. Pooled analysis using the Hamilton Rating Scale for Depression showed an effect in favour of rTMS compared with sham after 2 weeks of treatment, but this was not significant at the 2-week follow- up.

53 RECENT REVIEWS OR META-ANALYSES 2003 Gershon AA, Dannon PN, Grunhaus L. Gershon AA, Dannon PN, Grunhaus L. Am J Psychiatry May;160(5): Am J Psychiatry May;160(5): Transcranial magnetic stimulation in the treatment of depression. Transcranial magnetic stimulation in the treatment of depression. Review of English-language controlled studies of nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in Review of English-language controlled studies of nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these suggestions require systematic testing. Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these suggestions require systematic testing. TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success. TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success.

54 RECENT REVIEWS OR META-ANALYSES 2003 Padberg F, Moller HJ. Padberg F, Moller HJ. Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression? CNS Drugs. 2003;17(6): Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression? CNS Drugs. 2003;17(6): Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient selection focused on therapy-resistant cases. Moreover, the average treatment duration was approximately 2 weeks, which is short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to date. A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date. Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient selection focused on therapy-resistant cases. Moreover, the average treatment duration was approximately 2 weeks, which is short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to date. A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date.

55 RECENT REVIEWS OR META-ANALYSES 2005 Couturier JL. Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci Mar;30(2): Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci Mar;30(2): until July until July Eighty-seven randomized controlled trials Eighty-seven randomized controlled trials Nineteen of these involved treatment of a major depressive episode, and these were reviewed. Nineteen of these involved treatment of a major depressive episode, and these were reviewed. Six met more specific inclusion criteria including the use of rapid-rate stimulation, application to the left dorsolateral prefrontal cortex, evaluation with the 21-item Hamilton Rating Scale for Depression (HAM-D) and use of an intent-to-treat analysis. Six met more specific inclusion criteria including the use of rapid-rate stimulation, application to the left dorsolateral prefrontal cortex, evaluation with the 21-item Hamilton Rating Scale for Depression (HAM-D) and use of an intent-to-treat analysis. Two of these reported a significantly greater improvement in mood symptoms in the treatment versus the sham group. Two of these reported a significantly greater improvement in mood symptoms in the treatment versus the sham group. No different from sham treatment in major depression; however, the power within these studies to detect a difference was generally low. Randomized controlled trials with sufficient power to detect a clinically meaningful difference are required. No different from sham treatment in major depression; however, the power within these studies to detect a difference was generally low. Randomized controlled trials with sufficient power to detect a clinically meaningful difference are required.

56 Issues in the clinical use of rTMS: Stimulation site Which part of the brain? Which part of the brain? Dorsolateral prefrontal cortex (DLPFC) was stimulated in many studies Dorsolateral prefrontal cortex (DLPFC) was stimulated in many studies Vertex, frontal, parietooccipital cortex and multiple studies in a few studies Vertex, frontal, parietooccipital cortex and multiple studies in a few studies Right or left Right or left Left PLPFC was stimulated in many studies Left PLPFC was stimulated in many studies Right side in a few studies Right side in a few studiesIntensity 80, 90, 100 or 110 percent of motor threshold 80, 90, 100 or 110 percent of motor threshold High or low frequency High frequency (above 1 Hz) was given in many studies High frequency (above 1 Hz) was given in many studies Low frequency (below 1 Hz) in a few studies Low frequency (below 1 Hz) in a few studies Duration of treatment Ten sessions (consecutive weekdays) in many studies Ten sessions (consecutive weekdays) in many studies 12, 14, 16, 20 sessions in a few studies 12, 14, 16, 20 sessions in a few studies 1,5, 8 sessions in a few studies 1,5, 8 sessions in a few studies Total pulses 30, 60, 400, 500, 800, 1200, 1250, 2000, 2500, 3000, 4000, 5000, 6000, 6500, 8000, 10000, 14000, 12000, 15000, 16000, , 20000, pulses were given in different studies 30, 60, 400, 500, 800, 1200, 1250, 2000, 2500, 3000, 4000, 5000, 6000, 6500, 8000, 10000, 14000, 12000, 15000, 16000, , 20000, pulses were given in different studies Which patient groups Young or elderly? Young or elderly? Which type of depression? Psychotic or non-psychotic? Psychotic or non-psychotic?

57 Which patients with major depression benefit from prefrontal repetitive magnetic stimulation? Data from 10 open and 7 sham controlled studies. Comprising more than 300 patients with major depression have been published to date. Data from 10 open and 7 sham controlled studies. Comprising more than 300 patients with major depression have been published to date. Positive predictors for antidepressive response of prefrontal rTMS become apparent: Positive predictors for antidepressive response of prefrontal rTMS become apparent: 1) younger age, 2) somatic signs of anxiety, 3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli, 4) cortical hypermetabolism below the 1 Hz pulsed coil. Negative predictors of response to prefrontal rTMS were: Negative predictors of response to prefrontal rTMS were: 1) Advanced age, 2) prefrontal atrophy, 3) cognitive impairment in neuropsychological tasks assigned to the prefrontal cortex 4) psychotic symptoms, 5) cortical hyperactivity below 10 Hz pulsed coil 6) non-response to electroconvulsive therapy (ECT). Eschweiler GW, Plewnia C, Bartels M. Eschweiler GW, Plewnia C, Bartels M. Fortschr Neurol Psychiatr Fortschr Neurol Psychiatr. 2001

58 In paralel studies, rTMS is only modestly superior to sham, but nearly equally effective as ECT. Why? In sham studies, the coil is positioned such that less of the magnetic stimulus penetrates the brain. The sham treatment in controls involve discharging the coil at an angle to the head with only one edge in contact with the scalpas opposed to holding it tangential to the scalp as in real rTMS (the coil is positioned as 90 or 45 degrees). The question of whether they are truly inactive have been debated. Some studies may be complicated by active sham controls. In sham studies, the coil is positioned such that less of the magnetic stimulus penetrates the brain. The sham treatment in controls involve discharging the coil at an angle to the head with only one edge in contact with the scalpas opposed to holding it tangential to the scalp as in real rTMS (the coil is positioned as 90 or 45 degrees). The question of whether they are truly inactive have been debated. Some studies may be complicated by active sham controls. Loo CK, Taylor JL, Gandevia SC, McDarmont BN, Mitchell PB, Sachdev PS. Loo CK, Taylor JL, Gandevia SC, McDarmont BN, Mitchell PB, Sachdev PS. Transcranial magnetic stimulation (TMS) in controlled treatment studies: are some "sham" forms active? Biol Psychiatry Feb 15;47(4): Transcranial magnetic stimulation (TMS) in controlled treatment studies: are some "sham" forms active? Biol Psychiatry Feb 15;47(4): In nine normal subjects, single TMS pulses were administered at a range of intensities with a "figure eight" coil held in various positions (with one edge touching the scalpat a 45 degrees to the scalp) over the left primary motor cortex. In nine normal subjects, single TMS pulses were administered at a range of intensities with a "figure eight" coil held in various positions (with one edge touching the scalpat a 45 degrees to the scalp) over the left primary motor cortex. Responses were measured as motor-evoked potentials in the right first dorsal interosseus muscle. Responses were measured as motor-evoked potentials in the right first dorsal interosseus muscle. Scalp sensation to TMS with the coil in various positions over the prefrontal area was also assessed. Scalp sensation to TMS with the coil in various positions over the prefrontal area was also assessed. Sham variants that more closely simulated the experience of TMS also generated more motor evoked potentials, although less than real treatment. None of the coil positions studied met the criteria for an ideal sham. Arrangements associated with a higher likelihood of scalp sensation were also more likely to stimulate the cortex. Sham variants that more closely simulated the experience of TMS also generated more motor evoked potentials, although less than real treatment. None of the coil positions studied met the criteria for an ideal sham. Arrangements associated with a higher likelihood of scalp sensation were also more likely to stimulate the cortex.

59 FIGURE Number of Petients Who Responded to Transcranial Magnetic Stimulation (TMS) in Controlled Studies of TMS for the Treatment of Depression, by Technical Parameters of TMS Percentage of Patients Who Responded to TMS 10 >10 (N=70 N=69) Duration (days) (N=90) (N=49) Intensity (percent of motor threshold) (N=35) (N=84) Pulses per Day

60 Many studies of rTMS in depression included both unipolar and bipolar patients. Those with bipolar as well as unipolar depression usually benefited from rTMS.

61 A study including both unipolar and bipolar patients compared rTMS and electroconvulsive therapy (ECT) and found significant difference neither in mania scores nor in improvement in depression. Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J, Strong MJ, Sharma R, Rosen C, Viana M: Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry 2002 Apr 15; 51(8):

62 Another study conducted on 23 patients having bipolar depression who received either active or sham rTMS produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment, and no one switched to mania (15). Nahas Z, Kozel, Li X, Anderson B, George MS: Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003 Feb; 5(1):40-7.

63 There are case reports showing that transcranial magnetic stimulation has induced mania in patients suffering from bipolar depression. Garcia-Toro M: Acute manic symptomatology during repetitive transcranial magnetic stimulation in a patient with bipolar depression. Br J Psychiatry 1999 Nov; 175:491. Garcia-Toro M: Acute manic symptomatology during repetitive transcranial magnetic stimulation in a patient with bipolar depression. Br J Psychiatry 1999 Nov; 175:491. Nedjat S, Folkerts HW: Induction of a reversible state of hypomania by rapid-rate transcranial magnetic stimulation over the left prefrontal lobe. J ECT 1999 Jun; 15(2): Nedjat S, Folkerts HW: Induction of a reversible state of hypomania by rapid-rate transcranial magnetic stimulation over the left prefrontal lobe. J ECT 1999 Jun; 15(2): Dolberg OT, Schreiber S, Grunhaus L: Transcranial magnetic stimulation-induced switch into mania : a report of two cases. Biol Psychiatry 2001 Mar 1; 49(5): Dolberg OT, Schreiber S, Grunhaus L: Transcranial magnetic stimulation-induced switch into mania : a report of two cases. Biol Psychiatry 2001 Mar 1; 49(5): Ella R, Zwanzger P, Stampfer R, Preuss UW, Muller- Siecheneder F, Moller HJ, Padberg F: Switch to mania after slow rTMS of the right prefrontal cortex. J Clin Psychiatry 2002 Mar; 63(3):249. Ella R, Zwanzger P, Stampfer R, Preuss UW, Muller- Siecheneder F, Moller HJ, Padberg F: Switch to mania after slow rTMS of the right prefrontal cortex. J Clin Psychiatry 2002 Mar; 63(3):249. Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis C, Politis A, Christodoulou GN: Induction of mania by rTMS: a report of two cases. Eur Psychiatry 2003 Jun; 18(4): Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis C, Politis A, Christodoulou GN: Induction of mania by rTMS: a report of two cases. Eur Psychiatry 2003 Jun; 18(4):196-8.

64 rTMS in the Treatment of Mania

65 rTMS in the Treatment of Mania 1998 Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. Transcranial magnetic stimulation in mania: a controlled study. Am J Psychiatry Nov;155(11): Transcranial magnetic stimulation in mania: a controlled study. Am J Psychiatry Nov;155(11): patients completed a 14-day double-blind, controlled trial of right versus left prefrontal transcranial magnetic stimulation at 20 Hz (2-second duration per train, 20 trains/day for 10 treatment days). 16 patients completed a 14-day double-blind, controlled trial of right versus left prefrontal transcranial magnetic stimulation at 20 Hz (2-second duration per train, 20 trains/day for 10 treatment days). Significantly more improvement was observed in patients treated with right than with left prefrontal transcranial magnetic stimulation. Significantly more improvement was observed in patients treated with right than with left prefrontal transcranial magnetic stimulation. The therapeutic effect of transcranial magnetic stimulation in mania may show laterality opposite to its effect in depression. The therapeutic effect of transcranial magnetic stimulation in mania may show laterality opposite to its effect in depression.

66 rTMS in the Treatment of Mania 2000 Erfurth A, Michael N, Mostert C, Arolt V. Erfurth A, Michael N, Mostert C, Arolt V. Euphoric Mania and Rapid Transcranial Magnetic Stimulation. Am J Psychiatry May;157(5): Euphoric Mania and Rapid Transcranial Magnetic Stimulation. Am J Psychiatry May;157(5): A patient with euphoric mania that was refractory to treatment with sulthiame A patient with euphoric mania that was refractory to treatment with sulthiame Experienced marked improvement during monotherapy with right prefrontal rapid transcranial magnetic stimulation. Experienced marked improvement during monotherapy with right prefrontal rapid transcranial magnetic stimulation. Eight weeks before hospital admission she developed euphoric mania despite lithium treatment. Lithium treatment was discontinued, and a trial with the antiepileptic drug sulthiame was initiated—unfortunately, with no effect after 3 weeks of treatment. Sulthiame treatment was tapered off, and monotherapy with rapid transcranial magnetic stimulation was begun. Right prefrontal stimulation was performed (20 trains per session, a frequency of 20 Hz for 2 seconds per train, and an intertrain interval of 1 minute). Eight weeks before hospital admission she developed euphoric mania despite lithium treatment. Lithium treatment was discontinued, and a trial with the antiepileptic drug sulthiame was initiated—unfortunately, with no effect after 3 weeks of treatment. Sulthiame treatment was tapered off, and monotherapy with rapid transcranial magnetic stimulation was begun. Right prefrontal stimulation was performed (20 trains per session, a frequency of 20 Hz for 2 seconds per train, and an intertrain interval of 1 minute). Ms. A was given five consecutive sessions during weeks 1 and 2 and three sessions during weeks 3 and 4. Her range of motor threshold was 66%– 76%. Her scores on the Bech-Rafaelsen Mania Scale slowly but continuously fell (28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21, and 8 on day 28). Her sleep disturbance and thought disorder seemed to respond particularly well to rapid transcranial magnetic stimulation. Ms. A was dismissed from the hospital ward. Prophylactic treatment with the third- generation, putative mood-stabilizing anticonvulsant topiramate was initiated for Ms. A for obesity. Ms. A was given five consecutive sessions during weeks 1 and 2 and three sessions during weeks 3 and 4. Her range of motor threshold was 66%– 76%. Her scores on the Bech-Rafaelsen Mania Scale slowly but continuously fell (28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21, and 8 on day 28). Her sleep disturbance and thought disorder seemed to respond particularly well to rapid transcranial magnetic stimulation. Ms. A was dismissed from the hospital ward. Prophylactic treatment with the third- generation, putative mood-stabilizing anticonvulsant topiramate was initiated for Ms. A for obesity.

67 rTMS in the Treatment of Mania 2003 Kaptsan A, Yaroslavsky Y, Applebaum J, Belmaker RH, Grisaru N. Kaptsan A, Yaroslavsky Y, Applebaum J, Belmaker RH, Grisaru N. Right prefrontal TMS versus sham treatment of mania: a controlled study. Bipolar Disord Feb;5(1):36-9. Right prefrontal TMS versus sham treatment of mania: a controlled study. Bipolar Disord Feb;5(1): patients entered and 16 patients completed trial of right versus left prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for 10 treatment days. 25 patients entered and 16 patients completed trial of right versus left prefrontal TMS at 20 Hz, 2-sec duration per train, 20 trains per day for 10 treatment days. Right active TMS versus right sham TMS Right 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 effect of left TMS to worsen mania. Alternatively, it is noted that the present patient group had much more psychosis than the previous study of TMS in mania, and depression studies have reported that psychosis is a poor prognostic sign for TMS response. It is possible that the previous results were due to an effect of left TMS to worsen mania. Alternatively, it is noted that the present patient group had much more psychosis than the previous study of TMS in mania, and depression studies have reported that psychosis is a poor prognostic sign for TMS response.

68 rTMS in the Treatment of Mania 2004 Michael N, Erfurth A. Michael N, Erfurth A. Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation. J Affect Disord Mar;78(3): Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation. J Affect Disord Mar;78(3): in-patients diagnosed with mania 9 in-patients diagnosed with mania Right prefrontal rapid TMS Right prefrontal rapid TMS Open and prospective study. Open and prospective study. 8 of 9 patients received TMS as add-on treatment to an insufficient or only partially effective drug therapy. 8 of 9 patients received TMS as add-on treatment to an insufficient or only partially effective drug therapy. During the 4 weeks of TMS treatment a sustained reduction of manic symptoms in all patients. During the 4 weeks of TMS treatment a sustained reduction of manic symptoms in all patients.

69 rTMS in the Treatment of Mania 2004 Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Lipski H, Januel D. Saba G, Rocamora JF, Kalalou K, Benadhira R, Plaze M, Lipski H, Januel D. Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a case series of eight patients. Psychiatry Res Sep 30;128(2): Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a case series of eight patients. Psychiatry Res Sep 30;128(2): Fast rTMS (five trains of 15 s, 80% of the motor threshold, 10 Hz) Fast rTMS (five trains of 15 s, 80% of the motor 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 of the trial. No side effects were reported. Significant improvement of manic symptoms at the end of the trial. No side effects were reported. However, these results have to be interpreted with caution since they derive from an open case series and all the subjects were taking psychotropic medication during rTMS treatment. However, these results have to be interpreted with caution since they derive from an open case series and all the subjects were taking psychotropic medication during rTMS treatment.

70 Does rTMS Induce Mania?

71 Does rTMS Induce Mania? 2004 Tan O, Tarhan N, Coban A, Baripoglu Tan O, Tarhan N, Coban A, Baripoglu Repetitive transcranial magnetic stimulation in medication-resistant bipolar depression. Poster presentation in ECNS-ISNIP Joint Meeting in September 2004, California Repetitive transcranial magnetic stimulation in medication-resistant bipolar depression. Poster presentation in ECNS-ISNIP Joint Meeting in September 2004, California 8 patients having drug-resistant severe bipolar depression 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 depression. 3 patients shifted to manic episodes. 5 patients responded to the rTMS therapy recovering from depression. 3 patients shifted to manic episodes. rTMS may be an effective method in the treatment of bipolar depression. However, the fact that three patients out of eight switched to mania raises questions about its safety even though all of these patients were also taking antidepressant medications. rTMS may be an effective method in the treatment of bipolar depression. However, the fact that three patients out of eight switched to mania raises questions about its safety even though all of these patients were also taking antidepressant medications. Left prefrontal cortex (Magstim, rapid, superrrapid high frequency magnetic stimulator). Its intensity was the motor threshold that caused muscle movement when it was applied over the motor cortex. Other values of rTMS were 10 seconds, 25 Hz, 210 pulses and 70 trains. Left prefrontal cortex (Magstim, rapid, superrrapid high frequency magnetic stimulator). Its intensity was the motor threshold that caused muscle movement when it was applied over the motor cortex. Other values of rTMS were 10 seconds, 25 Hz, 210 pulses and 70 trains. The average of HDRS scores of the patients was All responded to the rTMS therapy, that is, showed at least 50 percent decrease in HDRS scores. However, three patients shifted to manic episodes. The average of HDRS scores of the patients was All responded to the rTMS therapy, that is, showed at least 50 percent decrease in HDRS scores. However, three patients shifted to manic episodes.

72 Does rTMS Induce Mania? 2004 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 maintenance treatment for bipolar depression? Depress Anxiety. 2004;20(2): Can left prefrontal rTMS be used as a maintenance treatment for bipolar depression? Depress Anxiety. 2004;20(2): S7 adults with bipolar depression who responded acutely to TMS and were then treated with TMS weekly for up to 1 year. S7 adults with bipolar depression who responded acutely to TMS and were then treated with TMS weekly for up to 1 year. Left prefrontal cortex at 110% motor threshold, 5 Hz for 8 s for 40 trains. Left prefrontal cortex at 110% motor threshold, 5 Hz for 8 s for 40 trains. Three subjects completed 1 full year of weekly TMS with an average Hamilton Rating Scale for Depression of 13 (sd = 5.9) over the year. Three subjects completed 1 full year of weekly TMS with an average Hamilton Rating Scale for Depression of 13 (sd = 5.9) over the year. These data suggest but do not prove that TMS might eventually be used as an adjunctive maintenance treatment for at least some patients with bipolar depression. These data suggest but do not prove that TMS might eventually be used as an adjunctive maintenance treatment for at least some patients with bipolar depression.

73 Does rTMS Induce Mania? 2005 Hagit Cohen, Ph.D., Zeev Kaplan, M.D., Moshe Kotler, M.D., Irena Kouperman, M.D., Regina Moisa, B.N.S., and Nimrod Grisaru, M.D. Hagit Cohen, Ph.D., Zeev Kaplan, M.D., Moshe Kotler, M.D., Irena Kouperman, M.D., Regina Moisa, B.N.S., and Nimrod Grisaru, M.D. Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex in Posttraumatic Stress Disorder: A Double-Blind, Placebo-Controlled Study Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex in Posttraumatic Stress Disorder: A Double-Blind, Placebo-Controlled Study 2 of 18 patients developed a manic episode after the third of 10 sessions of transcranial magnetic stimulation. 2 of 18 patients developed a manic episode after the third of 10 sessions of transcranial magnetic stimulation.

74 Does rTMS Induce Mania? 2005 Huang CC, Su TP, Shan IK. Huang CC, Su TP, Shan IK. A case report of repetitive transcranial magnetic stimulation-induced mania. Bipolar Disord Oct;6(5): A case report of repetitive transcranial magnetic stimulation-induced mania. Bipolar Disord Oct;6(5):444-5.

75 Does rTMS Induce Mania? 2005 Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis V, Politis A, Christodoulou GN. Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis V, Politis A, Christodoulou GN. Induction of mania by rTMS: report of two cases. Eur Psychiatry Jun;18(4): Induction of mania by rTMS: report of two cases. Eur Psychiatry Jun;18(4): Using an intensive methodology of rTMS in two drug-resistant patients, we observed a good antidepressant effect, but also, induction of manic symptoms. Using an intensive methodology of rTMS in two drug-resistant patients, we observed a good antidepressant effect, but also, induction of manic symptoms.

76 Does rTMS Induce Mania? 2001 Dolberg OT, Schreiber S, Grunhaus L. Dolberg OT, Schreiber S, Grunhaus L. Transcranial magnetic stimulation-induced switch into mania: a report of two cases. Biol Psychiatry Mar 1;49(5): Transcranial magnetic stimulation-induced switch into mania: a report of two cases. Biol Psychiatry Mar 1;49(5): Five times a week for 4 weeks. Five times a week for 4 weeks. A manic episode followed treatment with transcranial magnetic stimulation in two patients. A manic episode followed treatment with transcranial magnetic stimulation in two patients.

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

78 CONCLUSIONS

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

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

81 An article reviewing TMS in the treatment of mood disorder concluded that the antidepressant and antimanic effects of TMS depend on clinical considerations such as stimulus frequency, intensity, and magnetic coil placement; in addition, biological heterogeneity among the patients treated with TMS may also contribute to differing efficacy accross clinical trials (21). Hasey G: Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. Can J Psychiatry 2001 Oct; 46(8):720-7.

82 rTMS and OCD

83 rTMS and OCD 1997 Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, Murphy DL. Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, Murphy DL. Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive- compulsive disorder: a preliminary study. Am J Psychiatry Jun;154(6): Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive- compulsive disorder: a preliminary study. Am J Psychiatry Jun;154(6): patients 12 patients 80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes 80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes Right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days Right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days The patients' symptoms and mood were rated for 8 hours afterward. The patients' symptoms and mood were rated for 8 hours afterward. Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder. These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.

84 rTMS and OCD 2001 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 for obsessive- compulsive disorder: a preliminary investigation. J Clin Psychiatry Dec;62(12): Right versus left prefrontal transcranial magnetic stimulation for obsessive- compulsive disorder: a preliminary investigation. J Clin Psychiatry Dec;62(12): subjects with resistant OCD 12 subjects with resistant OCD were allocated randomly to either right or left prefrontal rTMS were allocated randomly to either right or left prefrontal rTMS daily for 2 weeks daily for 2 weeks were assessed by an independent rater at 1 and 2 weeks and 1 month later. were assessed by an independent rater at 1 and 2 weeks and 1 month later. Subjects had an overall significant improvement in the obsessions (p <.01), compulsions (p <.01), and total (p <.01) scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after 2 weeks and at 1-month follow-up. Subjects had an overall significant improvement in the obsessions (p <.01), compulsions (p <.01), and total (p <.01) scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after 2 weeks and at 1-month follow-up. This improvement was significant for obsessions (p <.05) and tended to significance for total Y-BOCS scores (p =.06) after correction for changes in depression scores on the Montgomery-Asberg Depression Rating Scale. This improvement was significant for obsessions (p <.05) and tended to significance for total Y-BOCS scores (p =.06) after correction for changes in depression scores on the Montgomery-Asberg Depression Rating Scale. There was no significant difference between right- and left-sided rTMS on any of the parameters examined. There was no significant difference between right- and left-sided rTMS on any of the parameters examined. Two subjects (33%) in each group showed a clinically significant improvement that persisted at I month but with relapse later in I subject. Two subjects (33%) in each group showed a clinically significant improvement that persisted at I month but with relapse later in I subject. About one quarter of patients with resistant OCD appear to respond to rTMS to either prefrontal lobe. About one quarter of patients with resistant OCD appear to respond to rTMS to either prefrontal lobe.

85 rTMS and OCD 1997 Alonso P, Pujol J, Cardoner N, Benlloch L, Deus J, Menchon JM, Capdevila A, Vallejo J. Alonso P, Pujol J, Cardoner N, Benlloch L, Deus J, Menchon JM, Capdevila A, Vallejo J. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Am J Psychiatry Jul;158(7): sessions of real (N=10) or sham (N=8) rTMS. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Am J Psychiatry Jul;158(7): sessions of real (N=10) or sham (N=8) rTMS. Treatments lasted 20 minutes, and the frequency was 1 Hz for both conditions, but the intensity was 110% of motor threshold for real rTMS and 20% for the sham condition. Treatments lasted 20 minutes, and the frequency was 1 Hz for both conditions, but the intensity was 110% of motor threshold for real rTMS and 20% for the sham condition. No significant changes in OCD were detected in either group after treatment. No significant changes in OCD were detected in either group after treatment. Two patients who received real rTMS, with checking compulsions, and one receiving sham treatment, with sexual/religious obsessions, were considered responders. Two patients who received real rTMS, with checking compulsions, and one receiving sham treatment, with sexual/religious obsessions, were considered responders.

86 rTMS and OCD 2003 Martin JL, Barbanoj MJ, Perez V, Sacristan M. Martin JL, Barbanoj MJ, Perez V, Sacristan M. Transcranial magnetic stimulation for the treatment of obsessive- compulsive disorder. Cochrane Database Syst Rev. 2003;(3):CD Transcranial magnetic stimulation for the treatment of obsessive- compulsive disorder. Cochrane Database Syst Rev. 2003;(3):CD Systematic review on the clinical efficacy and safety of transcranial magnetic stimulation from randomised controlled trials in the treatment of obsessive-compulsive disorder. Systematic review on the clinical efficacy and safety of transcranial magnetic stimulation from randomised controlled trials in the treatment of obsessive-compulsive disorder. An electronic search was performed including the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group trials register (last searched June, 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE ( ), EMBASE ( ), PsycLIT ( ), and bibliographies from reviewed articles. An electronic search was performed including the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group trials register (last searched June, 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE ( ), EMBASE ( ), PsycLIT ( ), and bibliographies from reviewed articles. 3 trials were included and only 2 contained data in a suitable form for quantitative analysis. 3 trials were included and only 2 contained data in a suitable form for quantitative analysis. It was not possible to pool any results for a meta-analysis. It was not possible to pool any results for a meta-analysis. No difference was seen between rTMS and sham TMS using the Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Rating Scale for all time periods analysed. There are currently insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder. No difference was seen between rTMS and sham TMS using the Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Rating Scale for all time periods analysed. There are currently insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder.

87 rTMS and panic disorder

88 rTMS and panic disorder 2002 Garcia-Toro M, Salva Coll J, Crespi Font M, Andres Tauler J, Aguirre Orue I, Bosch Calero C. Garcia-Toro M, Salva Coll J, Crespi Font M, Andres Tauler J, Aguirre Orue I, Bosch Calero C. Panic disorder and transcranial magnetic stimulation. Actas Esp Psiquiatr Jul-Aug;30(4): patients. Panic disorder and transcranial magnetic stimulation. Actas Esp Psiquiatr Jul-Aug;30(4): patients. disease for at least 1 year and they had unsuccessfully followed psychotherapy and pharmacological treatment. disease for at least 1 year and they had unsuccessfully followed psychotherapy and pharmacological treatment. 10 sessions during 10 sessions during each session lasted 30 trains of 60 seconds at a frequency of 1 Hz, on the right dorsolateral prefrontal cortex, at 110% of the motor threshold. each session lasted 30 trains of 60 seconds at a frequency of 1 Hz, on the right dorsolateral prefrontal cortex, at 110% of the motor threshold. All three patients experienced a modest and partial symptom improvement that did not seemed to be clinically relevant. All three patients experienced a modest and partial symptom improvement that did not seemed to be clinically relevant. Two patients accepted to participate in a TMS second phase, where the previous stimulation parameters were alternated with an application of 30 trains of 20 Hz during 2 seconds on the left prefrontal cortex. This alternate application of high and low frequency TMS in each session was also well tolerated, but failed to produce additional improvement. Two patients accepted to participate in a TMS second phase, where the previous stimulation parameters were alternated with an application of 30 trains of 20 Hz during 2 seconds on the left prefrontal cortex. This alternate application of high and low frequency TMS in each session was also well tolerated, but failed to produce additional improvement.

89 rTMS and PTSD

90 rTMS and PTSD 1998 Grisaru N, Amir M, Cohen H, Kaplan Z. Grisaru N, Amir M, Cohen H, Kaplan Z. Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. Biol Psychiatry Jul 1;44(1):52-5. Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. Biol Psychiatry Jul 1;44(1): PTSD patients 10 PTSD patients One session of slow TMS with 30 pulses of 1 m/sec each, 15 to each side of the motor cortex. Symptoms of PTSD were assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the effect was rather short and transient. One session of slow TMS with 30 pulses of 1 m/sec each, 15 to each side of the motor cortex. Symptoms of PTSD were assessed by using three psychological assessment scales, at four different time points. In this first, pilot, open study, TMS was found to be effective in lowering the core symptoms of PTSD: avoidance (as measured by the Impact of Event Scale), anxiety, and somatization (as measured by the Symptom Check List-90). A general clinical improvement was found (as measured by the Clinical Global Impression scale); however, the effect was rather short and transient. The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for PTSD patients. The present study showed TMS to be a safe and tolerable intervention with possibly indications of therapeutic efficacy for PTSD patients.

91 rTMS and PTSD 2002 Rosenberg PB, Mehndiratta RB, Mehndiratta YP, Wamer A, Rosse RB, Balish M. Rosenberg PB, Mehndiratta RB, Mehndiratta YP, Wamer A, Rosse RB, Balish M. Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression. J Neuropsychiatry Clin Neurosci Summer;14(3): Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression. J Neuropsychiatry Clin Neurosci Summer;14(3): 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 antidepressant medications. rTMS parameters were 90% of motor threshold, 1 Hz or 5 Hz, stimuli over 10 days. Seventy-five percent of the patients had a clinically significant antidepressant response after rTMS, and 50% had sustained response at 2-month follow-up. rTMS to left frontal cortex as an open-label adjunct to current antidepressant medications. rTMS parameters were 90% of motor threshold, 1 Hz or 5 Hz, stimuli over 10 days. Seventy-five percent of the patients had a clinically significant antidepressant response after rTMS, and 50% had sustained response at 2-month follow-up. Comparable improvements were seen in anxiety, hostility, and insomnia, but only minimal improvement in PTSD symptoms. Comparable improvements were seen in anxiety, hostility, and insomnia, but only minimal improvement in PTSD symptoms. Left frontal cortical rTMS may have promise for treating depression in PTSD, but there may be a dissociation between treating mood and treating core PTSD symptoms. Left frontal cortical rTMS may have promise for treating depression in PTSD, but there may be a dissociation between treating mood and treating core PTSD symptoms.

92 rTMS and PTSD 2004 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 right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry Mar;161(3): Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry Mar;161(3): patients with PTSD were randomly assigned to receive rTMS at low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS in a double-blind design. 24 patients with PTSD were randomly assigned to receive rTMS at low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS in a double-blind design. 10 daily sessions 10 daily sessions The 10 daily treatments of 10-Hz rTMS at 80% motor threshold over the right dorsolateral prefrontal cortex had therapeutic effects on PTSD patients. PTSD core symptoms (reexperiencing, avoidance) markedly improved with this treatment. Moreover, high-frequency rTMS over the right dorsolateral prefrontal cortex alleviated anxiety symptoms in PTSD patients. The 10 daily treatments of 10-Hz rTMS at 80% motor threshold over the right dorsolateral prefrontal cortex had therapeutic effects on PTSD patients. PTSD core symptoms (reexperiencing, avoidance) markedly improved with this treatment. Moreover, high-frequency rTMS over the right dorsolateral prefrontal cortex alleviated anxiety symptoms in PTSD patients. In PTSD patients, 10 daily sessions of right dorsolateral prefrontal rTMS at a frequency of 10 Hz have greater therapeutic effects than slow-frequency or sham stimulation. In PTSD patients, 10 daily sessions of right dorsolateral prefrontal rTMS at a frequency of 10 Hz have greater therapeutic effects than slow-frequency or sham stimulation.

93 rTMS and schizophrenia

94 rTMS and schizophrenia 1997 Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker RH. Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker RH. Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry Jan;21(1): Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry Jan;21(1): Pre-frontal cortex to study mood changes in 10 depressed patients and 10 schizophrenic patients. Pre-frontal cortex to study mood changes in 10 depressed patients and 10 schizophrenic patients. A slow rate of stimuli was used, one per 30 seconds; maximal intensity of about 2 Tesla was given for 30 stimuli, 15 on each side of the brain. A slow rate of stimuli was used, one per 30 seconds; maximal intensity of about 2 Tesla was given for 30 stimuli, 15 on each side of the brain. No side effects were seen and No side effects were seen and at least three depressed patients and two schizophrenic patients appeared to improve, at least transiently. at least three depressed patients and two schizophrenic patients appeared to improve, at least transiently. These results suggest that rapid rate TMS may not be necessary to elicit mood effects. These results suggest that rapid rate TMS may not be necessary to elicit mood effects.

95 rTMS and schizophrenia 1998 Feinsod M, Kreinin B, Chistyakov A, Klein E. Feinsod M, Kreinin B, Chistyakov A, Klein E. Preliminary evidence for a beneficial effect of low- frequency, repetitive transcranial magnetic stimulation in patients with major depression and schizophrenia. Depress Anxiety. 1998;7(2):65-8. Preliminary evidence for a beneficial effect of low- frequency, repetitive transcranial magnetic stimulation in patients with major depression and schizophrenia. Depress Anxiety. 1998;7(2): rTMS sessions in 14 subjects with major depression (MD) and 10 with schizophrenia. 10 rTMS sessions in 14 subjects with major depression (MD) and 10 with schizophrenia. 7 of the depressed patients reported significant improvement in depressive symptomatology, and 7 of the depressed patients reported significant improvement in depressive symptomatology, and 7 of the schizophrenic subjects reported amelioration of anxiety and restlessness. 7 of the schizophrenic subjects reported amelioration of anxiety and restlessness.

96 rTMS and schizophrenia 1999 Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger A, Krystal JH, Charney DS. Hoffman RE, Boutros NN, Berman RM, Roessler E, Belger A, Krystal JH, Charney DS. Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices". Biol Psychiatry Jul 1;46(1): Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices". Biol Psychiatry Jul 1;46(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 hallucination severity following active stimulation compared to sham stimulation. All three patients demonstrated greater improvement in hallucination severity following active stimulation compared to sham stimulation. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks. Two of the three patients reported near total cessation of hallucinations for > or = 2 weeks.

97 rTMS and schizophrenia 1999 Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole, Boget T, Barrantes N, Catarineu S, Font M, Lomena FJ. Cohen E, Bernardo M, Masana J, Arrufat FJ, Navarro V, Valls-Sole, Boget T, Barrantes N, Catarineu S, Font M, Lomena FJ. Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study. J Neurol Neurosurg Psychiatry Jul;67(1): Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study. J Neurol Neurosurg Psychiatry Jul;67(1): 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% motor threshold. 20 Hz for 2 seconds, once per minute for 20 minutes at 80% motor threshold. without exacerbating their psychoses. All patients tolerated the rTMS well, with minimal side effects (mild headache and tinnitus). without exacerbating their psychoses. All patients tolerated the 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 hypofrontality. SPECT: The results after rTMS indicated no change in the hypofrontality. Negative symptoms showed a general decrease for all patients. Negative symptoms showed a general decrease for all patients.

98 rTMS and schizophrenia 1999 Klein E, Kolsky Y, Puyerovsky M, Koren D, Chistyakov A, Feinsod M. Klein E, Kolsky Y, Puyerovsky M, Koren D, Chistyakov A, Feinsod M. Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham- controlled pilot study. Biol Psychiatry Nov 15;46(10): Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham- controlled pilot study. Biol Psychiatry Nov 15;46(10): inpatients 35 inpatients either right prefrontal slow rTMS or sham treatment either right prefrontal slow rTMS or sham treatment were rated before and after treatment for positive, negative, and depressive symptoms. were rated before and after treatment for positive, negative, and depressive symptoms. 2-week treatment protocol. 2-week treatment protocol. rTMS was not superior to sham treatment on any of the clinical ratings. rTMS was not superior to sham treatment on any of the clinical ratings.

99 rTMS and schizophrenia 2000 Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS. Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet Mar 25;355(9209): Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet Mar 25;355(9209): patients with schizophrenia and auditory hallucinations 12 patients with schizophrenia and auditory hallucinations received 1 Hz received 1 Hz left temporoparietial cortex. left temporoparietial cortex. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation.

100 rTMS and schizophrenia 2000 Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R, Emrich HM, Schneider U. Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R, Emrich HM, Schneider U. High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. Neuroreport Dec 18;11(18): High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. Neuroreport Dec 18;11(18): participants 12 participants a double-blind crossover design, a double-blind crossover design, 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly.

101 rTMS and schizophrenia 2002 d'Alfonso AA, Aleman A, Kessels RP, Schouten EA, Postma A, van Der Linden JA, Cahn W, Greene Y, de Haan EH, Kahn RS. d'Alfonso AA, Aleman A, Kessels RP, Schouten EA, Postma A, van Der Linden JA, Cahn W, Greene Y, de Haan EH, Kahn RS. Transcranial magnetic stimulation of left auditory cortex in patients with schizophrenia: effects on hallucinations and neurocognition. J Neuropsychiatry Clin Neurosci Winter;14(1):77-9. Transcranial magnetic stimulation of left auditory cortex in patients with schizophrenia: effects on hallucinations and neurocognition. J Neuropsychiatry Clin Neurosci Winter;14(1): medication-resistant hallucinating patients. 9 medication-resistant hallucinating patients. A statistically significant improvement was observed on a hallucination scale after 10 days of TMS at the left auditory cortex. A statistically significant improvement was observed on a hallucination scale after 10 days of TMS at the left auditory cortex.

102 rTMS and schizophrenia 2002 Schreiber S, Dannon PN, Goshen E, Amiaz R, Zwas TS, Grunhaus L. Schreiber S, Dannon PN, Goshen E, Amiaz R, Zwas TS, Grunhaus L. Right prefrontal rTMS treatment for refractory auditory command hallucinations - a neuroSPECT assisted case study. Psychiatry Res Nov 30;116(1-2): Right prefrontal rTMS treatment for refractory auditory command hallucinations - a neuroSPECT assisted case study. Psychiatry Res Nov 30;116(1-2): 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 right dorsolateral prefrontal cortex, with 1200 magnetic stimulations administered over the right dorsolateral prefrontal cortex, with 1200 magnetic stimulations administered daily for 20 days at 90% motor threshold. daily for 20 days at 90% motor threshold. Regional cerebral blood flow changes were monitored with neuroSPECT. Regional cerebral blood flow changes were monitored with neuroSPECT. Clinical evaluation and scores on the Positive and Negative Symptoms Scale and the Brief Psychiatric Rating Scale demonstrated a global improvement in the patient's condition, with no change in the intensity and frequency of the hallucinations. Clinical evaluation and scores on the Positive and Negative Symptoms Scale and the Brief Psychiatric Rating Scale demonstrated a global improvement in the patient's condition, with no change in the intensity and frequency of the hallucinations. NeuroSPECT performed at intervals during and after treatment indicated a general improvement in cerebral perfusion. NeuroSPECT performed at intervals during and after treatment indicated a general improvement in cerebral perfusion.

103 rTMS and schizophrenia 2003 Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F, Carroll K, Krystal JH. Hoffman RE, Hawkins KA, Gueorguieva R, Boutros NN, Rachid F, Carroll K, Krystal JH. Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Arch Gen Psychiatry Jan;60(1): Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Arch Gen Psychiatry Jan;60(1): patients with schizophrenia or schizoaffective disorder and medication-resistant AHs (auditory hallucinations) 24 patients with schizophrenia or schizoaffective disorder 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 offered an open-label trial of rTMS. Patients receiving sham stimulation were subsequently offered an open-label trial of rTMS. Auditory hallucinations were robustly improved with rTMS relative to sham stimulation. Frequency and attentional salience were the 2 aspects of hallucinatory experience that showed greatest improvement. Auditory hallucinations were robustly improved with rTMS relative to sham stimulation. Frequency and attentional salience were the 2 aspects of hallucinatory experience that showed greatest improvement. Duration of putative treatment effects ranged widely, with 52% of patients maintaining improvement for at least 15 weeks. Duration of putative treatment effects ranged widely, with 52% of patients maintaining improvement for at least 15 weeks.

104 rTMS and schizophrenia 2003 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 stimulation in treatment- resistant schizophrenia with verbal hallucinations. Psychiatry Res Aug 30;120(1): Left temporoparietal transcranial magnetic stimulation in treatment- resistant schizophrenia with verbal hallucinations. Psychiatry Res Aug 30;120(1): A 21-year-old schizophrenic man, who had killed his mother in the belief that she was a demon, failed to respond to combined treatment with a variety of antipsychotic agents. His persistent hallucinations consisted of two voices (God and the Devil). As an adjunct to continued antipsychotic medication, the patient received a course of rTMS: A 21-year-old schizophrenic man, who had killed his mother in the belief that she was a demon, failed to respond to combined treatment with a variety of antipsychotic agents. His persistent hallucinations consisted of two voices (God and the Devil). As an adjunct to continued antipsychotic medication, the patient received a course of rTMS: 10 sessions of 1-Hz stimulations near Wernicke's area. 10 sessions of 1-Hz stimulations near Wernicke's area. After rTMS, the patient's hallucinations grew less intrusive and he no longer required isolation. After rTMS, the patient's hallucinations grew less intrusive and he no longer required isolation. The improvement could be a delayed effect of medication. The improvement could be a delayed effect of medication.

105 rTMS and schizophrenia 2003 Huber TJ, Schneider U, Rollnik J. Huber TJ, Schneider U, Rollnik J. Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiatry Res Aug 30;120(1): Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiatry Res Aug 30;120(1): schizophrenic patients (8 men, 4 women) were treated with high- frequency rTMS of the dominant dorsolateral prefrontal cortex. 12 schizophrenic patients (8 men, 4 women) were treated with high- frequency rTMS of the dominant dorsolateral prefrontal cortex. Their performance of the number-connection test, which assesses cognitive processes related to the frontal lobe, was evaluated before and after rTMS. Their performance of the number-connection test, which assesses cognitive processes related to the frontal lobe, was evaluated before and after rTMS. Women improved markedly on the test after rTMS, whereas men did not show a significant change. Women improved markedly on the test after rTMS, whereas men did not show a significant change. There were no corresponding sex differences in clinical measures after rTMS. There were no corresponding sex differences in clinical measures after rTMS. The preliminary findings of sex differences in the response to rTMS, as reflected by performance on the number-connection test, suggest the need for investigations of a greater number of schizophrenic men and women with a more intensive examination of the effects of rTMS on cognitive functions. The preliminary findings of sex differences in the response to rTMS, as reflected by performance on the number-connection test, suggest the need for investigations of a greater number of schizophrenic men and women with a more intensive examination of the effects of rTMS on cognitive functions.

106 rTMS and schizophrenia 2004 Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G. Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G. Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review. Schizophr Res Nov 1;71(1):1-16. Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review. Schizophr Res Nov 1;71(1):1-16. Reduction of auditory hallucinations after slow TMS over auditory cortex Reduction of auditory hallucinations after slow TMS over auditory cortex Improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. Improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. However, these results need to be confirmed using better placebo conditions. However, these results need to be confirmed using better placebo conditions.

107 rTMS and schizophrenia 2004 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 schizophrenia. Schizophr Bull. 2004;30(2): Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia. Schizophr Bull. 2004;30(2): Double-blind, controlled study, Double-blind, controlled study, 22 chronic hospitalized schizophrenia patients 22 chronic hospitalized schizophrenia patients 10 sessions 10 sessions Real or sham rTMS. Real or sham rTMS. 20 trains of 5-second 10-Hz stimulation at 100 percent motor threshold, 30 seconds apart. 20 trains of 5-second 10-Hz stimulation at 100 percent motor threshold, 30 seconds apart. Effects on positive and negative symptoms, self-reported symptoms, rough neuropsychological functioning, and hormones were assessed. Effects on positive and negative symptoms, self-reported symptoms, rough neuropsychological functioning, and hormones were assessed. Although there was a significant improvement in both groups in most of the symptom measures, no real differences were found between the groups. Although there was a significant improvement in both groups in most of the symptom measures, no real differences were found between the groups. A decrease of more than 20 percent in the total PANSS score was found in 7 control subjects but only 1 subject from the real rTMS group. A decrease of more than 20 percent in the total PANSS score was found in 7 control subjects but only 1 subject from the real rTMS group. There was no change in hormone levels or neuropsychological functioning, measured by the MMSE, in either group. There was no change in hormone levels or neuropsychological functioning, measured by the MMSE, in either group. Left prefrontal rTMS (with the used parameters) seems to produce a significant nonspecific effect of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia patients. Left prefrontal rTMS (with the used parameters) seems to produce a significant nonspecific effect of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia patients.

108 rTMS and schizophrenia 2004 McIntosh AM, Semple D, Tasker K, Harrison LK, Owens DG, Johnstone EC, Ebmeier KP. McIntosh AM, Semple D, Tasker K, Harrison LK, Owens DG, Johnstone EC, Ebmeier KP. Transcranial magnetic stimulation for auditory hallucinations in schizophrenia. Psychiatry Res Jun 30;127(1-2):9-17. Transcranial magnetic stimulation for auditory hallucinations in schizophrenia. Psychiatry Res Jun 30;127(1-2): patients with hallucinations 16 patients with hallucinations treatment-resistant for at least 2 months treatment-resistant for at least 2 months were randomised into a placebo-controlled crossover study of TMS at were randomised into a placebo-controlled crossover study of TMS at 1 Hz and 80% of motor threshold 1 Hz and 80% of motor threshold over left temporo-parietal cortex. over left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. Both patients and symptom raters were unaware of the treatment condition. Both patients and symptom raters were unaware of the treatment condition. Patients' hallucination scores improved from baseline with both real and sham TMS, Patients' hallucination scores improved from baseline with both real and sham TMS, there was no significant difference between real and sham treatments. there was no significant difference between real and sham treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS.

109 rTMS and schizophrenia 2004 Schonfeldt-Lecuona C, Gron G, Walter H, Buchler N, Wunderlich A, Spitzer M, Herwig U. Schonfeldt-Lecuona C, Gron G, Walter H, Buchler N, Wunderlich A, Spitzer M, Herwig U. Stereotaxic rTMS for the treatment of auditory hallucinations in schizophrenia. Neuroreport Jul 19;15(10): Stereotaxic rTMS for the treatment of auditory hallucinations in schizophrenia. Neuroreport Jul 19;15(10): Cross-over sham controlled study, Cross-over sham controlled study, Researchers guided rTMS stereotactically to inner speech-related cortical areas in hallucinating patients. Researchers guided rTMS stereotactically to inner speech-related cortical areas in hallucinating patients. These areas were identified individually prior to rTMS using fMRI in a subgroup of patients. These areas were identified individually prior to rTMS using fMRI in a subgroup of patients. Active stimulation was applied over Broca's area and over the superior temporal gyrus as determined by fMRI, or according to structural images in the remaining patients. Active stimulation was applied over Broca's area and over the superior temporal gyrus as determined by fMRI, or according to structural images in the remaining patients. rTMS did not lead to a significant reduction of hallucination severity. rTMS did not lead to a significant reduction of hallucination severity.

110 rTMS and schizophrenia 2004 Hajak G, Marienhagen J, Langguth B, Werner S, Binder H, Eichhammer P. Hajak G, Marienhagen J, Langguth B, Werner S, Binder H, Eichhammer P. High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study. Psychol Med Oct;34(7): High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study. Psychol Med Oct;34(7): 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 single photon emission computed tomography) imaging was performed before and after termination of rTMS treatment. Besides clinical ratings, ECD-SPECT (technetium-99 bicisate single photon emission computed tomography) imaging was performed before and after termination of rTMS treatment. Significant reduction of negative symptoms combined with a trend for non-significant improvement of depressive symptoms in the active stimulated group as compared with the sham stimulated group. Significant reduction of negative symptoms combined with a trend for non-significant improvement of depressive symptoms in the active stimulated group as compared with the sham stimulated group. Additionally, a trend for worsening of positive symptoms was observed in the actively treated schizophrenic patients. Additionally, a trend for worsening of positive symptoms was observed in the actively treated schizophrenic patients. In both groups no changes in regional cerebral blood flow could be detected by ECD-SPECT. In both groups no changes in regional cerebral blood flow could be detected by ECD-SPECT.

111 rTMS and schizophrenia 2005 Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J, d'Amato T, Saoud M. Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J, d'Amato T, Saoud M. Slow transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in schizophrenia. Biol Psychiatry Jan 15;57(2): Slow transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in schizophrenia. Biol Psychiatry Jan 15;57(2): 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 (2.000 stimulations per day at 90% of motor threshold) received 5 days of active rTMS and 5 days of sham rTMS (2.000 stimulations per day at 90% of motor threshold) over the left temporoparietal cortex over the left 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 washout period. The two weeks of stimulation were separated by a 1-week washout period. AVH were robustly improved (56%) by 5 days active rTMS, whereas no variation was observed after sham. AVH were robustly improved (56%) by 5 days active rTMS, whereas no variation was observed after sham. Seven patients were responders to active treatment, five of whom maintained improvement for at least 2 months. Seven patients were responders to active treatment, five of whom maintained improvement for at least 2 months.

112 rTMS and schizophrenia 2005 Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, Carroll K, Krystal JH. Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, Carroll K, Krystal JH. Temporoparietal Transcranial Magnetic Stimulation for Auditory Hallucinations: Safety, Efficacy and Moderators in a Fifty Patient Sample. Biol Psychiatry Jun 2 Temporoparietal Transcranial Magnetic Stimulation for Auditory Hallucinations: Safety, Efficacy and Moderators in a Fifty Patient Sample. Biol Psychiatry Jun 2 A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal rTMS compared to sham stimulation. A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal rTMS compared to sham stimulation. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. Hallucination Change Score was more improved for rTMS relative to sham stimulation (p =.008) as was the Clinical Global Impressions Scale (p =.0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p =.0014) and was a moderator of rTMS effects (p =.008). There was no evidence of neurocognitive impairment associated with rTMS. Hallucination Change Score was more improved for rTMS relative to sham stimulation (p =.008) as was the Clinical Global Impressions Scale (p =.0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p =.0014) and was a moderator of rTMS effects (p =.008). There was no evidence of neurocognitive impairment associated with rTMS.

113 rTMS and schizophrenia 2005 Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M, Rapisarda V, Bella R, Pennisi G. Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M, Rapisarda V, Bella R, Pennisi G. Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations. Neurosci Lett Jul 8;383(1-2):54-7. Epub 2005 Apr 15. Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations. Neurosci Lett Jul 8;383(1-2):54-7. Epub 2005 Apr 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 threshold (MT) Low frequency rTMS (1Hz) was performed at the 90% of resting motor threshold (MT) 4 sessions in four consecutive days for 15 minutes each application. 4 sessions in four consecutive days for 15 minutes each application. 8 patients received active stimulation, while 8 patients received sham stimulation. 8 patients received active stimulation, while 8 patients received sham stimulation. Scale for the assessment of positive symptoms (SAPS), scale for the assessment of negative symptoms (SANS) and a scale to asses the severity of the auditory hallucinations (SAH) were administered at the beginning and at regular intervals during the follow-up. Scale for the assessment of positive symptoms (SAPS), scale for the assessment of negative symptoms (SANS) and a scale to asses the severity of the auditory hallucinations (SAH) were administered at the beginning and at regular intervals during the follow-up. The main finding was the long-term reduction in auditory hallucinations in the active group, with a return to the baseline in the sham group. The main finding was the long-term reduction in auditory hallucinations in the active group, with a return to the baseline in the sham group. The negative symptomatology improved only in the later sessions and lasted during the follow-up. The negative symptomatology improved only in the later sessions and lasted during the follow-up. The improvements in auditory hallucinations and positive symptomatology increased and lasted during the follow-up till the end-point. The improvements in auditory hallucinations and positive symptomatology increased and lasted during the follow-up till the end-point.

114 rTMS and schizophrenia 2005 Sachdev P, Loo C, Mitchell P, Malhi G. Sachdev P, Loo C, Mitchell P, Malhi G. Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: A pilot investigation. Psychiatry Clin Neurosci Jun;59(3): Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: A pilot investigation. Psychiatry Clin Neurosci Jun;59(3): Open study Open study 4 subjects with a stable deficit syndrome of schizophrenia received high frequency repetitive transcranial magnetic stimulation (15 Hz at 90% of motor threshold, 1800 pulses each session, daily for 20 sessions over 4 weeks) over the left dorsolateral prefrontal cortex. 4 subjects with a stable deficit syndrome of schizophrenia received high frequency repetitive transcranial magnetic stimulation (15 Hz at 90% of motor threshold, 1800 pulses each session, daily for 20 sessions over 4 weeks) over the left dorsolateral prefrontal cortex. Subjects showed a significant reduction in negative symptoms and improvement in function, with no change in positive symptoms. Subjects showed a significant reduction in negative symptoms and improvement in function, with no change in positive symptoms. This improvement was maintained at the 1 month follow up. This improvement was maintained at the 1 month follow up.

115 rTMS and schizophrenia 2005 Saba G, Verdon CM, Kalalou K, Rocamora JF, Dumortier G, Benadhira R, Stamatiadis L, Vicaut E, Lipski H, Januel D. Saba G, Verdon CM, Kalalou K, Rocamora JF, Dumortier G, Benadhira R, Stamatiadis L, Vicaut E, Lipski H, Januel D. Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: A double blind sham controlled study. J Psychiatr Res May 7; [Epub ahead of print] Transcranial magnetic stimulation in the treatment of schizophrenic symptoms: A double blind sham controlled study. J Psychiatr Res 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 left temporoparietal cortex (80% of the motor threshold, 1Hz, five trains of 1min). over the left temporoparietal cortex (80% of the motor threshold, 1Hz, five trains of 1min). Psychopathological dimensions were measured with the positive and negative syndrome scale and clinical global impression (CGI) at baseline and after 10 session of rTMS. Psychopathological dimensions were measured with the positive and negative syndrome scale and clinical global impression (CGI) at baseline and after 10 session of rTMS. All patients were improved at the end of the trial but no significant group differences were found. Patients receiving sham stimulation showed the same pattern of improvement compared to active condition on all the subscales of the positive and negative syndrome scale and CGI scores (p>0.05). All patients were improved at the end of the trial but no significant group differences were found. Patients receiving sham stimulation showed the same pattern of improvement compared to active condition on all the subscales of the positive and negative syndrome scale and CGI scores (p>0.05).

116 rTMS and schizophrenia 2005 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 the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci Lett Mar 16;376(3): A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci Lett Mar 16;376(3): patients with schizophrenia with treatment-refractory AH (auditory hallucinations) 39 patients with schizophrenia with treatment-refractory AH (auditory hallucinations) were allocated randomly to one of three groups: daily left, right, and sham rTMS groups. were allocated randomly to one of three groups: daily left, right, and sham rTMS groups. rTMS was applied to the TP3 (temporoparietal) or 4 regions with the aid of the electroencephalography international system rTMS was applied to the TP3 (temporoparietal) or 4 regions with the aid of the electroencephalography 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), the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression-- Severity (CGI-S), and Clinical Global Impression--Improvement (CGI-I) scale. Symptoms were evaluated using the Auditory Hallucination Rating Scale (AHRS), the Positive and Negative Symptoms Scale (PANSS), the Clinical Global Impression-- Severity (CGI-S), and Clinical Global Impression--Improvement (CGI-I) scale. For the time effect (within-subject comparison), there were significant changes in the frequency of AHs, positive symptoms of PANSS, and CGI-I. For the time effect (within-subject comparison), there were significant changes in the frequency of AHs, positive symptoms of PANSS, and CGI-I. A between-group comparison revealed significant differences in the positive symptoms of PANSS, and CGI-I scores. A between-group comparison revealed significant differences in the positive symptoms of PANSS, and CGI-I scores. Post hoc analysis revealed that both the right- and left-side rTMS treatment groups exhibited better CGI-I scores compared to the sham-stimulated group. Post hoc analysis revealed that both the right- and left-side rTMS treatment groups exhibited better CGI-I scores compared to the sham-stimulated group. Left sided rTMS is not superior to right or sham rTMS. Left sided rTMS is not superior to right or sham rTMS.

117 rTMS and addiction

118 70-80% of regular smokers fulfill the ICD-10- criteria of dependence % of regular smokers fulfill the ICD-10- criteria of dependence. Therapeutic interventions, such as nicotine substitution or bupropione, yield poor abstinence rates of 30% after 12 months, at best. Therapeutic interventions, such as nicotine substitution or bupropione, yield poor abstinence rates of 30% after 12 months, at best. In animal experiments, repetitive transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called reward system. In animal experiments, repetitive transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called reward system.

119 rTMS and addiction 2003 Johann M, Wiegand R, Kharraz A, Bobbe G, Sommer G, Hajak G, Wodarz N, Eichhammer P. Johann M, Wiegand R, Kharraz A, Bobbe G, Sommer G, Hajak G, Wodarz N, Eichhammer P. Transcranial magnetic stimulation for nicotine dependence. Psychiatr Prax May;30 Suppl 2:S Transcranial magnetic stimulation for nicotine dependence. Psychiatr Prax May;30 Suppl 2:S tobacco-dependent cigarette smokers 11 tobacco-dependent cigarette smokers Active or placebo rTMS on consecutive days. Active or placebo rTMS on consecutive days. Craving, as measured by a visual analogue scale, is significantly decreased after active stimulation compared to placebo-stimulation intra- individually. Craving, as measured by a visual analogue scale, is significantly decreased after active stimulation compared to placebo-stimulation intra- individually.

120 rTMS and addiction 2003 Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Wodarz N, Hajak G. Eichhammer P, Johann M, Kharraz A, Binder H, Pittrow D, Wodarz N, Hajak G. High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking. J Clin Psychiatry Aug;64(8): High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking. J Clin Psychiatry Aug;64(8): smokers 14 smokers double-blind crossover trial double-blind crossover trial comparing single days of active versus sham stimulation. comparing single days of active versus sham stimulation. Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence. Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence. 20-Hz rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly (p <.01) compared with sham stimulation. Levels of craving did not change significantly. 20-Hz rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly (p <.01) compared with sham stimulation. Levels of craving did not change significantly.


Download ppt "Transcranial Magnetic Stimulation in Psychiatric Disorders Oguz Tan, Memory Center, Istanbul, Turkey."

Similar presentations


Ads by Google