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TITLE: Repetitive Transcranial Magnetic Stimulation for Specific Patient Populations: Clinical and Cost-Effectiveness and Safety

DATE: 15 January 2013 CONTEXT AND POLICY ISSUES Transcranial magnetic stimulation (TMS) is a non-invasive technique for brain stimulation.1 A small coil is placed over the scalp. A strong electric current is passed through the coil wire and this produces a magnetic field that passes through the scalp and bone resulting in electrical stimulation of the cortex.2-4 The effect of the magnetic stimulation is dependent on location, intensity and frequency of the magnetic pulses.1 TMS was initially used to investigate nerve conduction.2 It can be used as a tool for brain mapping, as a probe for neuronal networks and as a modulator of brain function.5 It has been found that stimulation of the nerve cells in the brain can produce improvements in symptoms of depression.2 Its repetitive form is referred to as repetitive TMS (rTMS), and has been used for diagnostic and therapeutic purposes in a variety of neuropsychiatric disorders.1,6 The purpose of this report is to provide evidence on (i) the clinical benefits and harms of rTMS for maintenance therapy for patients with depression, auditory hallucinations, anxiety disorders, or substance use disorders, (ii) tolerability of this procedure and (iii) the cost-effectiveness of rTMS for treatment of patients with depression RESEARCH QUESTIONS 1. What is the clinical effectiveness of repetitive transcranial magnetic stimulation as

maintenance therapy for patients with depression, auditory hallucinations, anxiety disorders, or substance use disorders?

2. What is the evidence for the clinical tolerance of repetitive transcranial magnetic stimulation as maintenance therapy in all patients?

3. What is the cost-effectiveness of repetitive transcranial magnetic stimulation as maintenance therapy in patients with depression?

Repetitive Transcranial Magnetic Stimulation for Specific Patient Population 2

KEY FINDINGS Overall, for patients with depression, there appears to be a significant improvement with rTMS treatment of duration >2 weeks or >10 sessions when compared to sham. For patients with auditory hallucination or obsessive compulsive disorder there appears to be no significant improvement with rTMS treatment of duration >2 weeks or >10 sessions when compared to sham. No relevant evidence was identified for rTMS treatment for substance use disorders. Generally, the side-effects with rTMS were mild, and there appears to be no issues with respect to tolerance of the procedure. No robust evidence was identified on the cost effectiveness of rTMS compared with sham or pharmacotherapy. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 11), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, economic studies (all indications) and randomized controlled trials and non-randomized studies were searched for all indications with the exception of depression. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2007 and December 10, 2012. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for final selection, according to the criteria listed in Table 1. Table 1: Selection Criteria

Population

For clinical effectiveness, limit to the following populations:

depression;

auditory hallucinations (includes schizophrenia);

anxiety disorders (limit to OCD – obsessive compulsive disorder);

substance use disorders (limit to alcohol and illicit drugs)

Intervention

Repetitive transcranial magnetic stimulation (rTMS) used as maintenance (i.e., beyond a few weeks; not as an acute, time-limited intervention)

Comparator

Medication or no active treatment (i.e. sham)

Outcomes

Effectiveness of symptom remission

Tolerance; side effects resulting in discontinuation of treatment

Cost-effectiveness of rTMS for treatment only in patients with depression

Study Designs

Health technology assessments, systematic reviews and meta-analyses, randomized controlled trials (RCT), non-randomized studies and economic studies (cost-effectiveness studies)


Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria in Table 1, if they were published prior to 2007, or duplicate publications of the same study and did not provide additional relevant information. Studies were excluded if rTMS was given for two weeks or fewer, or 10 sessions or fewer (as generally 10 sessions were given over two weeks). Systematic reviews which included studies with a wide variety of session numbers or variable duration for rTMS and did not report data separately for the treatment duration relevant for this report were excluded. Systematic reviews which presented pooled results and had ≤50% of studies of rTMS duration less than two weeks or fewer than 10 sessions were excluded. Systematic reviews in which all included studies were reported in other systematic reviews were excluded. Non-randomized studies were excluded if higher quality studies, such as RCTs or systematic reviews were available. To address the question on tolerance, abstracts were selected for full text review, irrespective of disease conditions mentioned above as long as tolerance or drop-outs was mentioned in the abstract. Critical Appraisal of Individual Studies Critical appraisal of a study was conducted based on an assessment tool appropriate for the particular study design. The AMSTAR checklist7 was used for systematic reviews; the Downs and Black checklist8 for RCTs and non-randomized studies; and the checklist of Drummond et al.9 for economic studies. For the critical appraisal, a numeric score was not calculated. Instead, the strength and limitations of the study were described. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 270 citations. Upon screening titles and abstracts, 218 articles were excluded and 52 potentially relevant articles were selected for full-text review. No potentially relevant article was identified from the grey literature. Of these 52 articles, 41 did not satisfy the inclusion criteria and were excluded. Four systematic reviews4,5,10,11 and seven RCTs12-18 were relevant and selected for inclusion. No relevant health technology assessment was identified. One potentially relevant economic study19 was identified but was excluded because there appeared to be some discrepancies in the data reported, and correct values were unclear. Details of the study selection process are outlined in Appendix 1. Summary of Study Characteristics Characteristics of the included systematic reviews and RCTs are summarized below and details are provided in Appendix 2. In the systematic reviews, pooled estimates were calculated for all the included studies irrespective of the variability in the number of treatment sessions. However, in most instances, the estimates for each individual study with more than 10 treatment sessions were also provided.


Clinical Studies Auditory Hallucination (AH) For auditory hallucinations one systematic review10 and three RCTs12-14 were relevant for this report. The systematic review10 was published in 2012 from the Netherlands. It included 17 RCTs which compared rTMS with sham and included 337 patients. Age range of patients was not mentioned. Participants received between four to 20 sessions and results of studies with treatments >10 sessions were reported separately. Response and side-effects were reported. Of the three RCTs one was published in 2012 from Canada12 and two were published in 2011, one each from Canada13 and Netherlands.14 All three RCTs were sham controlled double blind studies, with patient numbers ranging between 17 and 62, mean patient ages between 36 and 46 years and treatment durations between 3 and 4 weeks. All three RCTs reported on response and on side-effects. Depression For depression two systematic reviews4,11 and one RCT15 were relevant for this report. Of the two systematic reviews one4 was published in 2012 from Canada and one11 from the United States of America (USA) in 2007. Both include sham controlled RCTs with patient numbers ranging between 274 and 279, and mean patient ages between 38 to 58 years. One systematic review4 included studies with participants receiving between 10 to 15 treatment sessions and in majority of these studies participants received greater than 10 sessions. One systematic review11 included studies with participants receiving between 10 to 16 treatment sessions and results of each of the studies with more than 10 treatment sessions were reported separately. One systematic4 reported on response and remission rates and drop-outs and one11 reported on change in mood scores. One RCT15 was published in 2008 from Denmark. It was single-blinded and compared rTMS to sham with the number of treatment sessions being 15. It included 49 patients and the mean age of patients in the treatment and sham groups were 53 and 58 years, respectively. Response and side-effects were reported. Obsessive compulsive disorder (OCD) For OCD, three RCTs16-18 were relevant for this report. Of the three RCTs, one16 was published in 2011 from Brazil, one17 in 2010 from USA and one18 in 2009 from Italy. All three RCTs compared rTMS with sham. Two16,17 were double-blind and one18 was single-blind. Treatment durations were between three and six weeks and patient numbers ranged between 21 and 30. In two RCTs16,17 mean ages of patients were between 39 and 40. One RCT did not report age of included patients but the inclusion criteria was 18 to 75 years. All three RCTs reported on response and two16,17 also reported on side-effects.


Substance use disorder No studies on rTMS for substance use disorders which were relevant for this report were identified. Various conditions One systematic review5 on various conditions was relevant for this report. This systematic review was published in 2010 from Netherlands. It included 51 RCTs which compared rTMS with sham. Of these 51 RCTs, 34 were on depression, seven on auditory hallucination, seven on negative symptoms in schizophrenia and three on OCD. Number of treatment sessions ranged between four and 25. Age and number of patients were not reported. Response and side effects were reported separately for each of the disease conditions. Responses were reported separately for each of the studies with more than 10 treatment sessions but not reported separately for side-effects and drop-outs. Economic study No robust evidence was identified on the cost effectiveness of rTMS compared with sham or pharmacotherapy. Summary of Critical Appraisal Critical appraisal of the included systematic reviews and RCTs are summarized below and details are provided in Appendix 3. Clinical Studies Auditory Hallucination (AH) The systematic review10 included a comprehensive literature search and described the inclusion criteria and study selection process. Details of rTMS were included but few details on patient characteristics were provided. Publication bias was explored and risk of publication bias appeared to be low. A list of excluded studies was not provided. It was not mentioned if article selection or data extraction were done in duplicate, or if quality assessment of the studies was conducted. All three RCTs12-14 were double blinded. Inclusion and exclusion criteria, patient characteristics, interventions and outcomes were described in all three. All three RCTs were for patients with medication resistant auditory hallucinations. Number of drop-outs were reported in two12,14 and not in one.13 In one RCT12 the drop-out rate was similar in the rTMS and sham groups and in one RCT14 the drop-out rate in the sham group was higher compared to the rTMS group. Sample size calculations were described in one14 and not in the other two12,13. Depression Of the two systematic reviews4,11, one4 included a comprehensive literature search and one11 included a literature search but did not specify the databases searched. Both systematic reviews stated the inclusion criteria, provided study characteristics, described the study selection and explored publication bias and found low risk of publication bias. One systematic


review4 did not mention if article selection and data extraction were done in duplicate or if quality assessment of the studies was conducted. In one systematic review,11 data extraction was done by one and checked by another and quality assessment of studies was conducted but it was not mentioned if article selection was done in duplicate. The included RCT15 was single blinded (patients blinded). Inclusion and exclusion criteria, patient characteristics, interventions, outcomes and drop-outs were described. The RCT was on patients with medication resistant major depression. The drop-outs were similar in the two groups. Sample size calculation was not described. Obsessive compulsive disorder (OCD) Of the three RCTs,16-18 two16,17 were double blind and one18 was single blind. Inclusion and exclusion criteria, patient characteristics, interventions, outcomes and drop-outs were described in all three. All three RCTs were on patients with medication resistant OCD. In two RCTs16,17 drop outs were not reported separately for the rTMS and sham groups and the total drop out was less than 15%. In one RCT18 there were no drop outs. Sample size calculation was described in one16 and not in the other two.17,18 Various conditions The systematic review5 included a comprehensive literature search, described the inclusion criteria and study selection. Details of rTMS were included but few details on patient characteristics were provided. Publication bias was explored and risk of publication bias appeared to be low. A list of excluded studies was not provided. It was not mentioned if article selection or data extraction were done in duplicate or if quality assessment of the studies was conducted. Summary of Findings The overall findings are summarized below and findings from the individual systematic reviews and RCTs are provided in Appendix 4. What is the clinical effectiveness of repetitive transcranial magnetic stimulation as maintenance therapy for patients with depression, auditory hallucinations, anxiety disorders, or substance use disorders? Auditory Hallucination (AH) The systematic review10 on patients with AH showed an effect size (standardized mean difference) of 0.40 for rTMS compared with sham for the long term studies (i.e. follow up of one month post treatment) but it was not significant (95% confidence interval [CI] -0.23 to 1.02). The effect size was 0.44 when both short and long term studies were considered and the effect was statistically significant. The authors mention that more research is needed to optimize parameters and evaluate the clinical benefit of rTMS. The side effects were not reported separately for long term studies and the side-effects reported for both rTMS and sham included headache, facial twitching, and dizziness. Number of side effects experienced was higher in the rTMS group compared to the sham group. However, the side effects were mild and the proportion of drop-outs was not higher in the rTMS group compared to the sham group.


One RCT12 showed that there was no significant difference between the rTMS, rTMS with priming and sham groups with respect to improving refractory AH in schizophrenia. Priming refers to high frequency followed by low frequency rTMS. One RCT14 showed that here was no significant difference between the rTMS, functional magnetic resonance imaging (fMRI)- guided rTMS and sham groups with respect to improving medication resistant auditory verbal hallucinations. One RCT13 showed that in clozapine-treated patients there was no significant difference between rTMS and sham groups with respect to improving refractory AH. With rTMS, there was a positive effect on general psychopathology. In one RCT,12 six patients (3 in rTMS, 1 in rTMS with priming, and 2 in sham) reported recurrent headaches and four patients (2 in rTMS and 2 in rTMS with priming) reported jaw and facial discomfort. In one RCT,14 eight patients had muscle twitching (7 in fMRI-rTMS, and 1 in sham), 8 had headaches (3 in fMRI-rTMS and 5 in rTMS) and two had dizziness (1 in rTMS and 1 in sham). In one RCT,13 two patients in the rTMS group experienced light headaches which were transient and responded to acetaminophen. There were no seizures. Overall, there appears to be no significant difference in response between rTMS and sham for auditory hallucinations. Depression Two systematic reviews4,11 on patients with depression included studies of various treatment durations. Of the two systematic reviews,4,11 one4 had more than 50% of the included studies with >10 sessions of rTMS and one11 reported results of studies with >10 sessions of rTMS separately. In one systematic,4 the response rate and remission rates were significantly higher with rTMS compared with sham. One systematic review,11 showed there was a significant improvement in mood scores with rTMS compared to sham. In one systematic review4 there was no significant difference in drop-out rates between the rTMS and sham groups. Neither of the two systematic reviews provided data on side-effects. One RCT15 showed that there was greater response (measured using various scales) with rTMS compared with sham; the difference was significant with three of the four measures used. Side effects were assessed using the Udvalg for Kliniske Undersogelser (UKU) side effects scale and 13 items were assessed. There was a significant difference for two items and for both items, the sham group scored higher. At the end of the treatment period (3 weeks) the sham group had reduced sleep compare with the rTMS group. At the end of the post treatment period (12 weeks) the sham group had greater concentration difficulties compared with the rTMS group. Overall, there appears to be a significant improvement with rTMS treatment compared to sham in patients with depression Obsessive Compulsive Disorder (OCD) For most response measures, the three RCTs16-18 on patients with OCD showed no significant difference in response between rTMS and sham. One RCT16 showed no significant difference in response with five different measurement scales. One RCT17 used eight measurement scales and showed no significant difference in response with six measurement scales and significant improvement with rTMS with two measurement scales One RCT18 used three measurement scales and showed no significant difference in response with two measurement scales and a time dependent significant improvement with rTMS with one measurement scale.


One RCT16 reported side-effects which included scalp discomfort, mild headache, cervical pain, mood swings and other less common effects and these did not have any major consequences. Scalp discomfort was more frequent in the rTMS group. There was no significant difference in the total number of events in the rTMS and sham groups. One RCT reported that there was no significant difference in common side-effects between the rTMS group and the sham group. There were no seizures or neurological complications. One RCT18 did not report on side-effects. However, all patients completed this study. Overall, there appears to be there appears to be no significant difference in response between rTMS and sham for auditory hallucinations. Substance Abuse Disorder No studies on rTMS for substance use disorders which were relevant for this report were identified. Various conditions One systematic review5 on various conditions included studies on patients with depression, OCD and other conditions. This systematic review included studies of various treatment durations. The four studies on patients with depression showed greater response with rTMS but the difference was not significant in three studies and significant in one study. The one study on patients with OCD and treatment session >10 sessions showed no significant difference between rTMS and sham groups. None of the studies on auditory hallucination had more than 10 treatment sessions and hence these results are not included. Side effects and drop-outs were not reported separately for studies with >10 treatment sessions but were summarized for all studies. Side-effects were transient and mild. What is the evidence for the clinical tolerance of repetitive transcranial magnetic stimulation as maintenance therapy in all patients? Auditory Hallucination For patients with auditory hallucinations, one systematic review10 showed that there was no significant difference between the number of drop-outs in the rTMS and sham groups (P = 0.11). It also mentioned that the side effects were mild. In one RCT,12 six patients (3 in rTMS, 1 in rTMS with priming, and 2 in sham) reported recurrent headaches. However, they did not withdraw from the study. No patients withdrew secondary to adverse effects. Authors of one RCT13 mentioned that rTMS was well tolerated; however, specific details were not provided. One RCT14 showed there was a trend towards significantly higher number of drop-outs in the sham group (P = 0.43) The evidence suggests that for patients with AH treated with rTMS there appears to be no issue with respect to tolerance.


Depression In one systematic review4 on patients with depression, there was no significant difference in drop-out rates between treatments with rTMS and sham. Drop-out rates were not mentioned in the other systematic review11 or in the RCT15 Obsessive Compulsive Disorder (OCD) Of the three RCTs16-18 on patients with OCD, in two RCTs dropouts were described but the number of drop-outs in the rTMS and sham group were not specified and in one RCT there were no drop-outs. In one RCT16 three patients (2 in rTMS group and 1 in sham group) dropped out as they were unable to attend the treatment sessions due to severity of OCD and the remaining 27 completed the study. In one RCT,17 three patients dropped out before receiving rTMS (2 for worsening depression and 1 fainted during motor threshold determination). In one RCT,18 all patients completed the study and it was mentioned that the procedure was well tolerated. Various conditions One systematic review5 on various conditions and with different durations of treatment mentioned that side-effects were transient and mild. The proportion of drop-outs was similar in the rTMS and sham groups. The drop-outs were lower for auditory verbal hallucination and OCD patients than for patients with depression and negative symptoms. Drop-out rates for treatment duration >10 sessions were not given separately. What is the cost-effectiveness of repetitive transcranial magnetic stimulation as maintenance therapy in patients with depression? No robust evidence was identified on the cost effectiveness of rTMS compared with sham or pharmacotherapy. Limitations Many of the studies were small (<30 patients) and may be underpowered. Power calculations were often not described in the study reports. There was considerable variability between the studies. They differed with respect to site of stimulation, intensity, stimulation frequency, pulses per session, and total number of sessions. With the variability in the treatment parameters and the small sample sizes, definitive conclusions regarding optimal treatment strategies are difficult. There were different rating scales used in the studies and hence comparisons were difficult. However standardized mean differences were presented. Co-morbidities and medications used by the patients varied and may impact outcomes with rTMS. Generalizability of the findings is limited as the RCTs had stringent inclusion criteria. Patients were excluded due to co-morbid conditions, or if they were on non-allowed medication. Sometimes eligible patients declined participation in the trial.


Long term follow up is lacking. Hence it is unclear if the beneficial effects will be maintained over time. Many of the study authors mentioned that further research is needed to better assess the effects of treatment with rTMS. Though there were several systematic reviews on rTMS, many could not be included as they included studies with duration of treatment that was not relevant for this report. One relevant economic study19 comparing rTMS with sham and also with pharmacotherapy was identified. However, there appeared to be discrepancies in the values presented in the article so the study could not be included, as the correct results were unclear. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Overall, for patients with depression, there appears to be a significant improvement with rTMS treatment of duration >2 weeks or >10 sessions when compared to sham. For patients with auditory hallucination or obsessive compulsive disorder there appears to be no significant improvement with rTMS treatment of duration >2 weeks or >10 sessions when compared to sham. No relevant evidence was identified for substance use disorders. Generally, the side-effects with rTMS were mild and there appear to be no issues with respect to tolerance of the procedure. No robust evidence was identified on the cost effectiveness of rTMS compared with sham or pharmacotherapy. Several factors such as comorbidities, concomitant medication, refractoriness to pharmacotherapy, disease condition and individual patient characteristics may impact outcomes with rTMS and may be worth considering when deciding on an optimal treatment strategy. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


REFERENCES

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3. Dell'osso B, Camuri G, Castellano F, Vecchi V, Benedetti M, Bortolussi S, et al. Meta-review of metanalytic studies with repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression. Clin Pract Epidemiol Ment Health [Internet]. 2011 [cited 2013 Jan 11];7:167-77. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227860/pdf/CPEMH-7-167.pdf

4. Berlim MT, Van den EF, Daskalakis ZJ. A systematic review and meta-analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression. Psychol Med. 2012 Dec 3;1-10.

5. Slotema CW, Blom JD, Hoek HW, Sommer IE. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010 Jul;71(7):873-84.

6. Hoppner J, Broese T, Wendler L, Berger C, Thome J. Repetitive transcranial magnetic stimulation (rTMS) for treatment of alcohol dependence. World J Biol Psychiatry. 2011 Sep;12 Suppl 1:57-62.

7. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 Feb 15 [cited 2013 Jan 11];7:10. Available from: http://www.biomedcentral.com/1471-2288/7/10

8. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet]. 1998 Jun [cited 2013 Jan 11];52(6):377-84. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf

9. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ [Internet]. 1996 Aug 3 [cited 2013 Jan 11];313(7052):275-83. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2351717/pdf/bmj00553-0039.pdf

10. Slotema CW, Aleman A, Daskalakis ZJ, Sommer IE. Meta-analysis of repetitive transcranial magnetic stimulation in the treatment of auditory verbal hallucinations: Update and effects after one month. Schizophr Res. 2012 Dec;142(1-3):40-5.

11. Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2351717/pdf/bmj00553-0039.pdf


analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand. 2007 Sep;116(3):165-73.

12. Blumberger DM, Christensen BK, Zipursky RB, Moller B, Chen R, Fitzgerald PB, et al. MRI-targeted repetitive transcranial magnetic stimulation of Heschl's gyrus for refractory auditory hallucinations. Brain Stimul. 2012 Oct;5(4):577-85.

13. de Jesus DR, Gil A, Barbosa L, Lobato MI, Magalhaes PV, Favalli GP, et al. A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine. Psychiatry Res. 2011 Jul 30;188(2):203-7.

14. Slotema CW, Blom JD, de Weijer AD, Diederen KM, Goekoop R, Looijestijn J, et al. Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial. Biol Psychiatry. 2011 Mar 1;69(5):450-6.

15. Bretlau LG, Lunde M, Lindberg L, Unden M, Dissing S, Bech P. Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial. Pharmacopsychiatry. 2008 Mar;41(2):41-7.

16. Mansur CG, Myczkowki ML, de Barros CS, Sartorelli MC, Bellini BB, Dias AM, et al. Placebo effect after prefrontal magnetic stimulation in the treatment of resistant obsessive-compulsive disorder: a randomized controlled trial. Int J Neuropsychopharmacol. 2011 Nov;14(10):1389-97.

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18. Ruffini C, Locatelli M, Lucca A, Benedetti F, Insacco C, Smeraldi E. Augmentation effect of repetitive transcranial magnetic stimulation over the orbitofrontal cortex in drug-resistant obsessive-compulsive disorder patients: a controlled investigation. Prim Care Companion J Clin Psychiatry [Internet]. 2009 [cited 2013 Jan 4];11(5):226-30. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781034/pdf/pcc11226.pdf

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781034/pdf/pcc11226.pdf


ABBREVIATIONS AH Auditory Hallucination

AHRS Auditory Hallucination Rating Scale

AVH Auditory Verbal Hallucination

BDI-II Beck Depression Inventory- II

BPRS Brief Psychiatric Rating Scale

CGI Clinical Global Impression scale

CGI-S Clinical Global Impression – Severity

CI confidence interval

DB double blind

FAST functional assessment staging

DLPFC dorsolateral prefrontal cortex

fMRI functional magnetic resonance imaging

HAMA-14 14-item Hamilton Anxiety Rating scale

HAMD-6 6-item Hamilton Depression Rating Scale

HAMD-17 17-item Hamilton Depression Rating Scale

HAMD-24 Hamilton Depression Rating Scale – 24 item

HARS Hamilton Anxiety Rating Scale

HCS Hallucination Change Scale

HDRS Hamilton Depression Rating Scale

Hz Hertz,

LFL low frequency left sided stimulation

MA metaanalysis,

MDI Major depression Inventory

MES Bech-Rafaelsen Melancholia scale

N number of patients

NA not applicable

NR not reported

NS not significant

OCD obsessive compulsive disorder

OCF orbitofrontal cortex

OR odds ratio

PANSS Positive and Negative symptom scale

PGI Patient Global Impression

PSYRATS Psychotic Symptoms Rating Scale

QLS Quality of Life Scale


rTMS repetitive transcranial magnetic stimulation

RCT randomized controlled trial

SF-36 [1-RP] 36-item quality of life health survey, role physical score

SMA supplementary motor area

SR-MA systematic review-metaanalysis

TMS transcranial magnetic stimulation

UKU Udvalg for Kliniske Undersogelser

USA United States of America

YBOCS Yale-Brown Obsessive Compulsive Scale

YBOCS-SR YBOCS-Self-rating

Zung-SAS Zung Self Administered Scale


APPENDIX 1: Selection of Included Studies

218 citations excluded

52 potentially relevant articles retrieved for scrutiny (full text, if

available)

No potentially relevant reports retrieved from other sources (grey

literature, hand search)

52 potentially relevant reports

41 reports excluded: -irrelevant population (5) -irrelevant intervention (17) -irrelevant comparator (2) -irrelevant outcomes (3) -already included in at least one of the selected systematic reviews or results for relevant subgroup not reported separately (6) -other (review articles, editorials)(7) -discrepancies in values reported (1)

11 reports included in review

270 citations identified from electronic literature search and

screened


APPENDIX 2: Characteristics of Included Studies

First Author, Publication Year, Country

Study Design, Duration

Patient Characteristics, Sample Size (n)

Intervention Comparators

Outcomes Measured

Auditory Hallucination – SR/MA

Slotema,10

2012, Netherlands

SR-MA (17 RCTs), Duration: 4 to 20 sessions

Patients with auditory hallucination, Age: NR, N= 337

rTMS (1Hz) Sham Response (using various scales); side-effects

Auditory Hallucination - RCT

Blumberger,12

2012, Canada

RCT (DB); 20 sessions (5 days/week for 4 weeks)

Patients with medication resistant AH; Mean age for the 3 groups: 37 to 44 years; N= 51

rTMS (LFL: 1 Hz, priming: 6+1 Hz)

Sham Response (PANSS, PSYRATS, HCS, AHRS); side effects

De Jesus,13

2011, Canada

RCT (DB); 20 sessions (5 sessions/week for 4 weeks), follow-up 8 weeks

Patients with refractory schizophrenia (AH); Mean age for the two groups= 37, 46 years; N= 17

rTMS (1 Hz) Sham Response (BPRS, QLS, CGI, AHRS, FAST); side-effects

Slotema,14

2011, Netherlands

RCT (DB); 15 sessions (over 3 weeks), follow-up 3 months

Patients with medication resistant AVH; Mean age for the three groups= 36, 38, 41; N=62

fMRI guided rTMS or rTMS (1 Hz)

Sham Response (AHRS, PANSS, PSYRATS); side-effects

Depression – SR/MA

Berlim, 4 2012,

Canada SR-MA (7 RCTs); Duration: 10 to15 sessions (>10 sessions in 4 of 7 studies)

Patients with treatment resistant major depression (MD); For all 7 studies: Age= 40 to 58 years; N= 279, For 4 studies (>10 sessions): Age= 40 to 58 years; N= 147

rTMS (1 Hz to 20 Hz), bilateral; to dorsolateral prefrontal cortex (DLPFC)

Sham Response rate, remission rate, drop-out rate

Gross,11

2007, USA

SR-MA (5 RCTs); Duration : 10 to 16 sessions (>10 sessions in 2 of 5

Patients with major depression; For all 5 RCTs: Mean age: 38 to 49 N= 274 For the 2 RCTs (> 10 sessions)::

rTMS (1 Hz to 20 Hz), In the two studies(>10 sessions): 1 Hz to right DLPFC in one and 10 Hz to

Sham Change in mood scores






Outcomes Measured

studies and results reported separately for the 2studies)

Mean age: 38 to 44 N= 95

left DLPFC in the other study

Depression - RCT

Bretlau,15

2008, Denmark

RCT (patients blinded); 15 sessions (over 3 weeks), follow-up 12 weeks

Patients with treatment resistant major depression; Mean age in the two groups: 53, 58 years; N= 49

rTMS (8 Hz), to left DLPFC (+ escitalopram)

Sham (+ escitalopram)

Response (HAMD-6, HAMD-17, MES, MDI); side-effects

Obsessive compulsive disorder (OCD) – RCT

Mansur,16

2011, Brazil

RCT (DB); 30 session over 6 weeks, follow-up 6 weeks

Patients with treatment resistant OCD; Mean age for the two groups= 42, 39 years; N= 30

rTMS (high frequency)

Sham Response (YBOCS, CGI-S, HAMA-14, HAMD-17, SF-36 [1-RP]); side-effects

Mantovani, 17

2010, USA

RCT (DB); 5 sessions/ week for 4 weeks for DB period. Sham patients and responders to rTMS had the option of receiving rTMS for an additional 4 weeks. Also, 3 months after the last rTMS responders were invited for assessing persistence of benefit

Patients with treatment resistant OCD; Mean age for the two groups= 40, 40 years; N= 21

rTMS (1 Hz); to supplementary motor area (SMA), bilaterally

Sham Response (YBOCS, YBOCS-SR, CGI-S, HAMA-14, HAMD-24, BDI-II, Zung-SAS, PGI); side-effects






Outcomes Measured

Ruffini,18

2009, Italy

RCT(single blind); 5 sessions/ week for 3 weeks; After treatment additional follow up 3 months

Patients with drug resistant OCD; age range: 18- 75 years (inclusion criteria); N= 23

rTMS (1 Hz), to left orbitofrontal cortex (OFC)

Sham Response (YBOCS, HDRS, HARS)

Various conditions – SR/MA

Slotema,5 2010,

Netherlands SR/MA [51 RCTs - sham controlled: depression (34), AVH (7), negative symptoms in schizophrenia (7), and OCD (3)]; Duration: 4 to 25 sessions (5 of 51 RCTs had > 10 sessions and results were reported separately.

Patients with various conditions; Age: NR N= NR

rTMS (low frequency, high frequency); to DLPFC (majority) and temporoparietal

Sham Response; Side-effects

AH= Auditory Hallucination, AHRS= Auditory Hallucination Rating Scale, AVH= Auditory Verbal Hallucination, BDI-II= Beck Depression Inventory- II, BPRS= Brief Psychiatric Rating Scale, CGI= Clinical Global Impression scale, CGI-S= Clinical Global Impression – Severity, DB= double blind, FAST= functional assessment staging, DLPFC= dorsolateral prefrontal cortex , fMRI= functional magnetic resonance imaging, HAMA-14= 14-item Hamilton Anxiety Rating scale, HAMD-6= 6-item Hamilton Depression Rating Scale, HAMD-24= Hamilton Depression Rating Scale – 24 item, HARS= Hamilton Anxiety Rating Scale HAMD-17= 17-item Hamilton Depression Rating Scale, HAMD-24= Hamilton Depression Rating Scale – 24 item, HARS= Hamilton Anxiety Rating Scale, HCS= Hallucination Change Scale, HDRS= Hamilton Depression Rating Scale, Hz= Hertz, LFL= low frequency left sided stimulation, MA= metaanalysis, MDI= Major depression Inventory, MES= Bech-Rafaelsen Melancholia scale, N= number of patients, NR= not reported, OCD= obsessive compulsive disorder, OCF= orbitofrontal cortex, PANSS= Positive and Negative symptom scale, PGI= Patient Global Impression, PSYRATS= Psychotic Symptoms Rating Scale, QLS= Quality of Life Scale, rTMS= repetitive transcranial magnetic stimulation, RCT= randomized controlled trial, SF-36 [1-RP]= 36-item quality of life health survey, role physical score, SMA= supplementary motor area, SR-MA= systematic review-metaanalysis, TMS= transcranial magnetic stimulation, USA= United States of America, YBOCS= Yale-Brown Obsessive Compulsive Scale, YBOCS-SR= YBOCS-Self-rating, Zung-SAS= Zung Self Administered Scale


APPENDIX 3: Summary of Study Strengths and Limitations


Strengths Limitations

Auditory Hallucination – SR/MA Slotema,

10 2012,

Netherlands The objective was stated.

The inclusion criteria were stated. Exclusion criteria implied.

Comprehensive literature search (multiple databases, cross references of articles, authors contacted if needed)

Study selection described but flow chart not presented

List of included studies provided

Characteristics of the individual studies were provided (details of rTMS but few details of patients)

Methods used to combine the findings of studies were appropriate

Publication bias was explored (fail- safe number computed; low risk of publication bias)

Conflict of interest was stated

List of excluded studies not provided but number of studies excluded and reasons for exclusion were provided

Not mentioned if article selection and data extraction were done in duplicate

Not mentioned if quality assessments of studies were conducted

Auditory Hallucination - RCT Blumberger,

12 2012,

Canada Objectives were stated.

Inclusion/ exclusion criteria were stated.

Patient characteristics, interventions, and outcomes were described.

Randomized; patients and clinical raters were blinded, operators were not blinded but were not involved in any other aspects of the study

Number discontinued or lost to follow up were reported (≤ 24%)

Intent-to-treat analysis

P-values provided

Sample size calculations not described

Of the three groups (LFL, priming, sham), patients in the LFL group had significantly shorter duration of illness compared to the other two.

Generalizability limited; uncertain as to whether study patients were representative of all patients.

De Jesus,13

2011, Canada

Objectives were stated.


Patient characteristics, interventions, and outcomes were described.

Randomized; patients and clinical raters were blinded, personal responsible for clinical care were


Sample size relatively small (N= 17)

Mean age significantly higher in the rTMS group compared to sham group

Number discontinued or lost to follow up were not reported




also blinded

Not mentioned if intent-to-treat

analysis

P-values not always provided


Slotema,

14 2011,

Netherlands Objectives were stated.


Patient characteristics, interventions, and outcomes were described

Randomized, double-blind

Sample size calculations described

Drop-outs assessed

Performed analysis also with last observation carried forward

P-values provided


Depression – SR/MA Berlim,

4 2012, Canada The objective was stated.

The inclusion and exclusion criteria were stated.

Comprehensive literature search (multiple databases, bibliographies of published meta-analyses)

Study selection described

List of included and excluded studies provided

Characteristics of the individual studies were provided


Publication bias was explored ( there was low risk of publication bias)


Not mentioned if article selection and data extraction were done in duplicate


Gross,11

2007, USA The objective was stated.


Literature search conducted but databases not specified

Flow chart of study selection presented


List of excluded studies not provided

Not mentioned if article selection was done in duplicate

Conflict of interest was not stated




Characteristics of the individual studies were provided

Data extraction was done by one and checked by another

Quality assessments of studies were conducted


Publication bias was explored ( there was low risk of publication bias)

Depression - RCT

Bretlau,15

2008, Denmark

Objectives were stated.



Randomized, patient blinded

Drop-outs described

Performed analysis with last observation carried forward

P-values provided



Obsessive compulsive disorder (OCD) - RCT

Mansur,16

2011, Brazil Objectives were stated.




Sample size determination described

Drop-outs with reasons mentioned

P-values provided

The two groups were well matched except for age of onset (p= 0.035) and duration of illness (p= 0.037)

Not intent-to-treat analysis. A “completer” analysis was performed and is probably not an issues as drop-outs were minimal and not due to side-effects of treatment


Mantovani,

17 2010,

USA Objectives were stated.




Drop-outs with reasons mentioned

P-values provided in many






instances

Ruffini,

18 2009, Italy Objectives were stated.


Interventions, and outcomes were described.

For patient characteristics data were not provided but the authors stated that there were no differences in clinical and demographic characteristics

Randomized (single blind)

No drop-outs

P-values provided


Not double blinded study


Various conditions – SR/MA

Slotema,5 2010,

Netherlands The objective was stated.


Comprehensive literature search (multiple databases, bibliographies of published meta-analyses, authors contacted if needed)

Study selection described


Characteristics of the individual studies were provided; details of the intervention were provided but details of patient characteristics were lacking


Publication bias was explored (fail safe method; low risk of publication bias)


List of excluded studies not provided

Details of patient characteristics were lacking

Not mentioned if article selection or data extraction were done in duplicate



APPENDIX 4: Main Study Findings and Authors’ Conclusions


Main Findings and Authors’ Conclusion

Auditory Hallucination – SR/MA Slotema,

10 2012,

Netherlands Main Findings: Effect size

Focus No. of studies

Weighted mean effect size

Hedges’ g 95% CI Heterogeneity (I

2)

All foci 17 0.33 0.17, 0.50 12.9%

T3P3 15 0.44 0.19, 0.68 35.7%

T3P3 5 (long term) 0.40 -0.23, 1.02 63.6%

Side effects and number of dropouts

Category rTMS (N=219) Sham (N=145)

Side effects

Headache 28 5

Twitching facial musculature 18 1

Dizziness 4 2

Other 8 2

All side effects 58 10

Number of dropouts and associated reasons

Worsening psychotic symptoms 2 4

Deterioration of mental state 0 2

Side effects 4 2

Lack of effect and inability to attend appointments

2 2

Other 2 1

Unknown 0 2

Total number (%) of dropouts 10 (4.6%) 13 (9.1%)

Authors’ Conclusion: “With the inclusion of studies with larger patient samples, the mean weighted effect size of rTMS directed at the left temporoparietal area for AVH has decreased, although the effect is still significant. The duration of the effect of rTMS may be less than one month. More research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention.” p. 40 (AVH= auditory verbal hallucination, rTMS= repetitive transcranial magnetic stimulation)

Auditory Hallucination - RCT Blumberger,

12

2012, Canada Main Findings: Response rate

Measure LFL (N= 17) Priming (N= 17)

Sham (N= 17)

p- value

PSYRATS 2 (11.8%) 1 (5.9%) 0 0.35

PANSS 1 (5.9%) 1 (5.9%) 1 (5.9%) 1




global

PANSS positive

1 (5.9%) 1 (5.9%) 1 (5.9%) 1

AHRS 1 (5.9%) 1 (5.9%) 1 (5.9%) 1 HCS 1 (5.9%) 2 (11.8%) 1 (5.9%) 1

Adverse effects and drop-outs

Category LFL Priming Sham

Adverse effects*

Jaw and facial contraction discomfort 2 2 0

Recurrent headache 3 1 2

Drop-outs*

Did not complete 4 weeks of treatment 1 2 2

*No patients withdrew secondary to adverse effects

Authors’ Conclusion: “These findings suggest that neither priming nor LFL rTMS of Heschl’s are effective at ameliorating refractory AH in schizophrenia.” p. 577 (AH= Auditory Hallucination, LFL= low frequency left sided stimulation, rTMS= repetitive transcranial magnetic stimulation)

De Jesus,13

2011, Canada

Main Findings: Response

Measure Time point Effect (mean± SD) Comment

rTMS Sham

BPRS Baseline 36.25± 8.27 33.11± 7.55

Week 4 25.13± 8.18 28± 7.34 Significant reduction w.r.t baseline for rTMS (p= 0.012) but not for sham (p=0.67)

Week 8 23.88± 7.99 29.56± 7.29 No significant improvement from 4 to 8 weeks for rTMS (p=0.68) and significant worsening for sham (p=0.042)

CGI Baseline 5.5± 1.19 5.1± 1.05 No significant differences

Week 4 5.13± 1.12 5.11± 1.05

Week 8 5± 1.06 5.11± 1.05

AHRS Baseline 31± 3.62 28.78± 7.15

Week 4 25.88± 4.99 25.22± 8.81




Week 8 27.13± 3.35 25.44± 8.61 between rTMS and sham (p> 0.05)

QLS Baseline 51.38± 20 44.56± 20.23

Week 4 NR NR

Week 8 NR NR

FAST Baseline 49± 10.32 49.44± 13.15

Week 4 NR NR

Week 8 NR NR

Adverse effects/tolerability

The authors mentioned that the procedure was well tolerated. Two patients in the rTMS group mentioned light headache after the first three sessions. However, these were transient and responded to acetaminophen. There were no seizures.

Authors’ Conclusion: “Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory hallucinations. Further studies with large sample sizes are needed to confirm these findings.” p. 203 (rTMS= repetitive transcranial magnetic stimulation)

Slotema,14

2011, Netherlands

Main Findings: Response (effect size with treatment end compared to baseline)

Measure Effect (standardized mean difference, p-value)

fMRI-rTMS rTMS Sham

AHRS 0.524, 0.10 0.508, 0.10 0.439, 0.17

PANSS (positive items)

0.310, 0.33 0.222, 0.46 0.676, 0.04

PSYRATS (AVH related items)

0.583, 0.07 0.263, 0.39 0.325, 0.31

Adverse effects/tolerability

Treatment Side effects

fMRI-rTMS Facial muscle twitching (7), headache (3), cervical pain (1), nausea (1), scalp discomfort (1)

rTMS Headache (5), dizziness (1), abdominal pain (1), fatigue (1)

Sham Facial muscle twitching (1), dizziness (1)

Number in brackets indicate number of patients

Drop-outs

There was a trend towards significantly higher number of drop-outs in the sham group (p-value = 0.43)

Authors’ Conclusion: “Low-frequency rTMS administered to the left TP or to the site of maximal hallucinatory




activation is not more effective for medication-resistant AVH than sham treatment.” p. 450 (AVH= Auditory Verbal Hallucination, rTMS= repetitive transcranial magnetic stimulation, TP= temporoparietal area)

Depression –SR/MA Berlim,

4 2012,

Canada Main Findings: Bilateral rTMS compared with sham

Outcomes Number of RCTs

OR (95% CI) Heterogeneity (I

2)

Number needed to treat (95% CI)

Response rate 7 (of which 4 had < 10 sessions)

4.3 (1.95, 9.52)

0 6 (3.9, 10.2)

Remission rate 4 (of which 2 had < 10 sessions)

6 (1.65, 21.76) 0 7 (4.1, 11.7)

Drop-out rate 6 (of which 4 had < 10 sessions)

0.53 (0.21, 1.36)

NR NR

Authors’ Conclusion: “Bilateral rTMS is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with these of standard antidepressants and unilateral rTMS. Furthermore, bilateral rTMS appears to be an acceptable treatment for depressed subjects.” p. 1 (MD= major depression, rTMS= repetitive transcranial magnetic stimulation)

Gross,11

2007, USA Main Findings:

Outcomes Number of RCTs

Standardized mean difference (95% CI)

Heterogeneity

Mood score 5 (10 to 16 sessions)

-0.76 (-1.01, -0.51) NS (p= 0.45)

1 (15 sessions) -0.82 (-1.31, -0.32) NA

1 (16 sessions) -1.49 (-2.36, -0.62) NA

Authors’ Conclusion: “Our findings suggest that recent rTMS clinical trials have shown larger antidepressant effects when compared with earlier studies” p. 165 (rTMS= repetitive transcranial magnetic stimulation)

Depression - RCT

Bretlau,15

2008, Denmark

Main Findings: Response

Measure Time (weeks) Effect size† (95% CI)

HAMD-17 3* 0.78 (0.18, 1.39)




5 0.48 (-0.12, 1.07)

8 0.64 (0.04, 1.24)

12 0.47 (-0.11, 1.07)

HAMD-6 3* 0.80 (0.20, 1.42)

5 0.65 (0.09, 1.29)

8 0.50 (-0.10, 1.09)

12 0.50 ((-0.10, 1.09)

MES 3* 0.84 (0.24, 1.46)

5 0.64 (0.02, 1.22)

8 0.65 90.04, 1.24)

12 0.46 (-0.12, 1.06)

MDI 3* 0.43 (-0.16, 1.03)

5 0.29 (-0.29, 0.88)

8 0.22 (-0.36, 0.81)

12 0.23 (-0.36, 0.81) *End of rTMS or sham treatment †Effect size is defined as the mean change in rating scale scores (baseline scores – end-point score) for patients receiving rTMS minus change scores (baseline scores – end-point score) for patients receiving sham, divided by the pooled standard deviation of the two groups

Adverse effects/ drop outs

Side effects: Side effects were assessed using the UKU side effect scale. At the end of the 3 week treatment period the sham group had reduced sleep length and at the end of post-treatment (at 12 week) the sham group had greater concentration difficulties. Of the 49 patients randomized, 3 did not receive treatment (1 in sham group and 2 in rTMS group) due to protocol violation.

Authors’ Conclusion: “High-frequency rTMS over the left cortex is an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants.” p. 41 (rTMS= repetitive transcranial magnetic stimulation)

Obsessive compulsive disorder (OCD) - RCT Mansur,

16 2011,

Brazil Main Findings: Response

Measure Time (week)

Effect (mean± standard deviation) *Between-group p-value

rTMS (N= 13) Sham (N= 14)

YBOCS 0 30.00± 3.84 29.53± 5.05 0.710

6 26.75± 6.28 27.33± 7.29 12 25.00± 8.39 26.60± 7.51

CGI-S 0 5.83± 0.58 5.67± 0.72 0.867

6 5.25± 0.96 5.27± 1.16 12 5.00± 1.41 5.00± 1.20

HAMA-14 0 25.75± 9.45 24.53± 7.15 0.637




6 18.33± 9.39 19.67± 9.26 12 18.00± 9.69 20.93± 10.47

HAMD-17 0 22.41± 7.91 21.27± 6.63 0.539

6 16.58± 7.01 17.73± 6.89 12 16.75± 7.69 20.20± 10.11

SF-36 [1-RP]

0 57.50± 16.98 47.85± 19.78 0.705

6 50.75± 17.69 54.64± 19.85 12 54.58± 20.72 53.21± 19.47

*Analysis performed with repeated-measures ANOVA

Adverse effects/ drop-outs

Side effects: Side effects included scalp discomfort, mild headache, cervical pain, mood swings, and other less common events and these had no major implications. There was no significant difference in the total number of events, between the rTMS and sham groups (p= 0.667). However, in the rTMS group, scalp discomfort was more common (number of events= 12). Drop-outs: Of the 30 patients randomized, three dropped out because of severe obsessive compulsive symptoms that prevented them from attending some or all of the treatment sessions and follow up interviews. The remaining 27 patients completed the study and were included in the analysis

Authors’ Conclusion: “In treatment-resistant OCD, active rTMS over the rDLPFC does not appear to be superior to sham rTMS in relieving obsessive-compulsive symptoms, reducing clinical severity, or improving treatment response, although there is evidence of a placebo effect.” P. 1389 (OCD= obsessive compulsive disorder, rDLPFC= right dorsolateral prefontal cortex, rTMS= repetitive transcranial magnetic stimulation)

Mantovani,

17 2010,

USA Main Findings: Response up to 4 weeks of treatment

Measure Time (week)

Effect (mean± standard deviation) *Between-group p-value

rTMS (N= 9) Sham (N= 9)

YBOCS 0 26± 5.4 26.7± 5.5 NS

4 19.4± 5.6 23.5± 9 YBOCS-SR 0 26.1± 5.7 27.3± 6.9 0.031

4 18.4± 8 25.1± 8.9 HAMD-24 0 15.3± 10.6 14.8± 7.7 NS

4 12.1± 11.4 14.1± 8.8 BDI-II 0 21.2± 15.4 15.4± 10.2 NS

4 14.5± 16.6 11.1± 10.3 HAMA-14 0 17.4± 10 14.2± 7.1 NS




4 12.2± 11.8 11.3± 6.4 Zung-SAS 0 39.3± 10 35.6± 8.3 NS

4 32.4± 6.5 32.1± 6.4 CGI-S 0 5± 0.7 5.2± 0.9 0.044

4 4.1± 0.9 5± 1.3 PGI 0 4.2± 0.9 5.2± 0.8 NS

4 3.5± 1.1 4.7± 1.3 *Repeated measures ANOVA, time x group (rTMS vs sham) interaction

Response up to 8 weeks of treatment in 12 patients completing the open-label phase

Measure Time (week)

Effect (mean± standard deviation)

rTMS(4weeks)+rTMS(4weeks) (N= 4)

Sham(4weeks)+rTMS(4weeks) (N= 8)

YBOCS 0 28.2± 5.8 27.6± 5.2 4 17.7± 2.6 25.6± 7 8 14.5± 3.6 26.3± 8.5

YBOCS-SR

0 26.5± 6 28.1± 6.9 4 17.2± 2.2 27± 7.3 8 14.7± 2.9 25.3± 8.2

Adverse effects/dropouts

Side-effects: One patient fainted during motor threshold determination; none of the others reported significant side-effects. There were no seizures or neurological complications. Ratings of common side-effects did not differ between the rTMS and sham groups. Authors mentioned that TMS sessions were well tolerated. Drop-outs: Of the 21 patients randomized 3 dropped out (2 due to worsening depression and 1 due to fainting during motor threshold determination)

Authors’ Conclusion: “The results of the first randomized sham-controlled trial of SMA stimulation in the treatment of resistant OCD support further investigation into the potential therapeutic applications of rTMS in this disabling condition.” P. 217 (OCD= obsessive compulsive disorder, rTMS= repetitive transcranial magnetic stimulation, SMA= supplementary motor area)

Ruffini,

18 2009, Italy Main Findings:

Response

Measure Result

YBOCS Significant difference between rTMS and sham until week 10 after end of rTMS (p< 0.02). After this time, the significance was lost (p<0.06)




HDRS No significant decrease after rTMS (after rTMS, p< 0.14 and after 12 weeks follow up p<0.71)

HARS No significant decrease with rTMS compared to sham (after rTMS, p<0.79 and after 12 weeks follow up, p<0.82)

Adverse effects/drop-outs

The authors mentioned that all patients completed the study and that the procedure was well tolerated

Authors’ Conclusion: “Low-frequency rTMS of the left OFC produced significant but time-limited improvement in OCD patients compared to sham treatment.” p. 226 (OCD= obsessive compulsive disorder, OFC= orbitofrontal cortex, rTMS= repetitive transcranial magnetic stimulation)

Various conditions – SR/MA Slotema,

5 2010,

Netherlands Main Findings: Response

Condition No. of studies Effect size

Hedge’s g p-value

Depression 1 (25 sessions) 0.176 0.126

1 (16 sessions) 1.118 0.006

1 (15 sessions) 0.265 0.135

1 (15 sessions) 0.791 0.120

34 (5 to 25 sessions); 43 comparisons as some studies had more than 2 groups

0.545 0.000

OCD 1 (18 sessions) 0.337 0.459

4 (10 to 18 sessions)

0.155 0.520

Adverse events/ drop-outs

Side effects and drop-outs were not reported separately for studies with > 10 sessions but for were summarized for all studies. “Side effects reported for different indications were headache, scalp discomfort, drowsiness, facial muscle twitching, tearfulness, dizziness, and nausea. All of these side effects were transient and mild and occurred more often with high-frequency than with low-frequency rTMS, and more often in rTMS directed to the DLPF than in rTMS to the temporoparietal areas. The percentage of dropouts was equal for rTMS and sham treatment, and lower for AVH and OCD than for depression and negative symptoms.” p. 882

Authors’ Conclusion: “It is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms. We do not recommend rTMS for the treatment of OCD.” p. 873




(OCD= obsessive compulsive disorder, rTMS= repetitive transcranial magnetic stimulation)

AH= Auditory Hallucination, AHRS= Auditory Hallucination Rating Scale, AVH= Auditory Verbal Hallucination, BDI-II= Beck Depression Inventory- II, BPRS= Brief Psychiatric Rating Scale, CGI= Clinical Global Impression scale, CGI-S= Clinical Global Impression – Severity, CI= confidence interval, FAST= Functional assessment staging, fMRI= functional magnetic resonance imaging, HAMD-6= 6-item Hamilton Depression Rating Scale, HAMA-14= 14-item Hamilton Anxiety Rating scale, HAMD-17= 17-item Hamilton Depression Rating Scale, HAMD-24= Hamilton Depression Rating Scale – 24 item, HARS= Hamilton Anxiety Rating Scale, HCS= Hallucination Change Scale, HDRS= Hamilton Depression Rating Scale, LFL= low frequency left sided stimulation, MA= metaanalysis, MDI= Major depression Inventory, MES= Bech-Rafaelsen Melancholia scale, N= number of patients, NA= not applicable, NR= not reported, NS= not significant, OCD= obsessive compulsive disorder, OCF= orbitofrontal cortex, OR= odds ratio, PANSS= Positive and Negative symptom scale, PGI= Patient Global Impression, PSYRATS= Psychotic Symptoms Rating Scale, QLS= Quality of Life Scale, RCT= randomized controlled trial, rDLPFC= right dorsolateral prefontal cortex , rTMS= repetitive transcranial magnetic stimulation, SD= standard deviation, SF-36 [1-RP]= 36-item quality of life health survey, role physical score, SMA= supplementary motor area, SR-MA= systematic review-metaanalysis, TMS= transcranial magnetic stimulation,T3P3= left temporoparietal area, TP= temporoparietal area , UKU= Udvalg for Kliniske Undersogelser, US=

United States, USA= United States of America, YBOCS= Yale-Brown Obsessive Compulsive Scale, YBOCS-SR= YBOCS-Self-rating, Zung-SAS= Zung Self Administered Scale

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