- Email: [email protected]
Transcranial magnetic stimulation
Physical treatment
Transcranial magnetic stimulation
be administered without anaesthesia and is non-invasive in nature, which may be among the primary reasons for the recent drive to investigate its therapeutic efficacy in the treatment of depression.5
Lucie L Herrmann
Principles and mechanisms
Klaus P Ebmeier
During TMS an electrical current is passed through an insulated wire coil placed over the patient’s scalp. The electrical current generates a magnetic field, which in turn induces a current in conducting structures such as axons, which can depolarize nerve cells directly or indirectly involved.6 Depending on stimulation intensity, duration and frequency, this may result in the temporary disruption or stimulation of brain activity. Of the brain areas targeted in the treatment of depression, the dorsolateral prefrontal cortex (DLPFC) has received most attention.7 The DLPFC is part of a network that has been implicated in the regulation of mood.8,9 It has been suggested that the left hemisphere is involved in the generation and modulation of positive affect, and the right hemisphere of negative affect.10 Since low-frequency rTMS (≤ 1Hz) results in the inhibition and high frequency (≥ 5Hz) in the activation of stimulated brain regions, rTMS may be applied to selectively ‘normalize’ abnormal activity in the prefrontal cortex (PFC).11 Several studies of rTMS in depressed patients have demonstrated improvement of depressive symptoms after both high-frequency rTMS to the left PFC and low-frequency rTMS to the right PFC.12,13
Abstract Depression has an annual prevalence of 1–6% in the community; 50–60% of depressed individuals might not respond to conventional pharmacotherapy. Transcranial magnetic stimulation (TMS) non-invasively stimulates superficial cortex in patients, for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1–20 Hz at motor threshold intensity. We present a meta-analysis of 24 studies evaluating the antidepressant effect of TMS for major depressive or bipolar disorder in treatment groups ≥10 patients. Out of 617 patients receiving active rTMS, 218 (35.3%) were classified as ‘responders’, whereas only 71 (13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. The Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI: 2.94–5.13). Heterogeneity between studies did not exceed that expected by chance and there was no significant publication bias. Based on these data, five patients (95% CI = 4–6) need to be treated in order to obtain a clinical response attributable to rTMS, a respectable effect size among psychiatric (add-on) treatments. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature indicates that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Also, more knowledge is needed regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects.
Risks and safety If appropriate guidelines are observed, rTMS conveys a very small risk of seizure induction.14 It does not cause any identifiable neuropathological lesions.15 RTMS treatment is not associated with any transient negative cognitive effects16–18 and may in fact have slight beneficial effects in some areas of cognition, such as verbal memory, psychomotor speed and concentration.19
Keywords antidepressants; controlled trials; depression; mood disorders;
Placebo effect and blinding
transcranial magnetic stimulation
Depressed individuals are susceptible to placebo effects.20 RTMS as a technologically sophisticated device-based treatment may be associated with even greater placebo response.21 Patients receiving real or sham rTMS should have identical expectations,22 but for rTMS trials no satisfactory placebo condition has been established. Placebo rTMS should result in scalp and noise sensation identical to active rTMS, without any actual cortical stimulation. Yet, generating a degree of scalp sensation typically results in PFC stimulation.23,24 If the coil is angled away at 45°, it may not be entirely inactive17,25 and corresponds to an ‘attenuated real’ condition.24 Similarly, if the coil is angled away at 90°, the placebo condition appears to be less painful than the real rTMS. A novel form of sham rTMS involves placing a sheet of metal between the coil and the patient’s head, so that the magnetic field is blocked, while noise sensation remains very similar to that of real rTMS.26 In principle, it may be possible to generate the surface stimulation electrically, but published data are missing. In an rTMS procedure it is of course also difficult to blind the operator.5
Depression is common, with an annual prevalence from 1–6% in the community.1 It is associated with a high rate of recurrence2; up to 50–60% of depressed individuals may not respond to conventional pharmacotherapy.3 This reinforces the need to find alternative treatments.4 Repetitive transcranial magnetic stimulation (rTMS) holds considerable promise. It can
Lucie L Herrmann MA is a Trainee in Clinical Psychology at the Institute of Psychiatry, King’s College, London, UK. She trained in Marburg, Aberdeen, Edinburgh and Oxford, UK. Conflicts of interest: none declared. Klaus P Ebmeier MD is Professor of Old Age Psychiatry at the University of Oxford, UK. He trained in Bonn and Aberdeen. His main research interests are the causes and treatment of depression and dementia. Conflict of interests: Recipient of travel expenses Magstim Co.
PSYCHIATRY 8:4
130
© 2009 Elsevier Ltd. All rights reserved.
Physical treatment
We used a chi-square analysis (random effects, Peto odds ratio) for numbers of responders in each group (as defined by a 50% reduction in depression severity scores). This non-parametric test has the advantage of being robust and less affected by the presence of outliers. We decided to use the Peto rather than the DerSimonian-Laird approach, as this is better suited to trials where both treatment arms are relatively equal in size and where an event (i.e. treatment response) is relatively rare in at least one treatment arm. Cochran Q was computed to test for noncombinability of data and bias was assessed. In order to define the treatment-specific effect of rTMS and to generate clinically meaningful data that can aid the interpretation of results, we also determined the ‘number of patients needed to treat’ (NNT = 1/Absolute Risk Reduction).
Patients may be generally aware of their study condition, particularly in studies with crossover design. This could explain the poor efficacy of rTMS reported in several studies.23 An entirely inactive sham condition that nevertheless mimics the real rTMS in terms of scalp, noise and pain sensation is therefore urgently required. In an effort to design alternative sham approaches, Rossi and colleagues recently developed a possibly more appropriate sham stimulation, a wooden tool that optically looks like a conventional figure-of-eight coil and mirrors the scalp sensation induced by real rTMS whilst leaving both the visual impact and acoustic sensation of real rTMS unaltered.27 Future research is needed to explore the efficacy of rTMS in comparison to sham treatment using such specially adapted sham coils.
Efficacy
Results Data relating to treatment response, were available from 24 studies (leading to an overall sample size of 1160 participants).12,18,22,30– 50 Out of 617 patients receiving active rTMS, 218 (= 35.3%) were classified as ‘responders’, while only 71 (= 13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. A Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI = 2.94 to 5.13) (Figure 1). Heterogeneity between studies did not exceed that expected by chance (Cochran’s Q = 23.6; p >0.05). There was no significant publication bias. Kendall’s τb was -0.04 (p >0.05), while the intercept in the regression of normalized odds ratios on precision was 0.98 (Egger bias; 95% CI = −0.06 to 2.01). Based on these data, a total of 4.49, conventionally rounded up to five, patients (95% CI = 3.71 to 5.72) need to be treated in order to obtain a clinical response attributable to rTMS.
During the last decade there has been an increase in randomized controlled studies examining the therapeutic efficacy of rTMS in the treatment of depression.5 The first published studies of focal stimulation of the PFC were of cross-over design. These studies found decreases in scores on the Hamilton Depression Rating Scale that were statistically, as well as clinically significant.28,29 Many of the subsequent placebo-controlled studies reported similar findings. However, the differences between real and sham groups were often of only marginal clinical significance. Some studies failed to demonstrate an advantage of rTMS over sham rTMS altogether. As treatment efficacy of rTMS in depression has been highly variable with often underpowered designs, the aim of this contribution is to update and review the existing literature on randomized placebocontrolled rTMS trials of the treatment of depression. Methods Randomized controlled publications investigating the efficacy of rTMS in the treatment of depression were identified by using Embase and Medline searches with the term (“depression” OR ‘depressed’) AND (‘transcranial’ OR ‘TMS’) including the years 1996 to 2007. Additional studies were identified from previous meta-analyses and by manual cross-referencing. Unpublished studies were not included, as TMS research is primarily academic, i.e. there is a motivation to publish good quality, even negative, research, and registration in the relevant trial databases is neither obligatory nor commonly implemented. A total of 1312 studies were identified with the above search term. Studies were included if: • they were of randomized parallel or cross-over design with sham control, • with both patients and investigators (i.e. baseline and outcome assessors, as opposed to the treatment team) unaware of the treatment conditions, • they consisted of at least 10 patients with a diagnosis of major depressive or bipolar disorder in each treatment group, • they employed a version of the Hamilton Depression Rating Scale (HDRS) or Montgomery-Åsberg Depression Rating Scale (MADRS) in order to measure outcome, • Baseline and follow-up scores were available or could be derived. Altogether, 1288 publications did not satisfy the above inclusion criteria. Of these, 17 studies were excluded because there were fewer than 10 patients in each group.
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Discussion Patients treated with rTMS are 3.88 times more likely to show a clinical response than patients receiving sham treatment. For clinicians it is of importance to be able to estimate the amount of benefit of an intervention in relation to other approved interventions for the same outcome measure. Based on the data included in this study, 4 to 6 patients need to be treated in order to achieve a clinical response that is due to active rTMS. As such, the clinical efficacy of rTMS certainly falls within the range of NNTs generally accepted for psychiatric (add-on) treatments and is similar to other anti-depressant treatments. It has been estimated that most psychiatric treatments have NNTs in the range of 3 to 6.51 In particular, the NNT for Lithium, a common add-on treatment for treatment-resistant depression, is 4,52 whereas the NNT for add-on cognitive-behavioural therapy, a treatment that is equally difficult to conceal from the patient, is 5.51 A recent review that systematically investigated this issue in elderly patients with depression reported that NNTs varied from 4 to 8 for tricyclic antidepressants and selective serotonin reuptake inhibitors, respectively.53 A further argument to offer rTMS as an option is that the NNT approach is only one avenue of clinical decisionmaking and needs to be integrated with patient and care-giver preferences as well as local context and constraints.54 Length of remission after rTMS treatment Only one previous meta-analysis (based on 3 individual RCTs) investigated whether the beneficial effects of rTMS are sustained 131
© 2009 Elsevier Ltd. All rights reserved.
Physical treatment
Figure 1
at 2 weeks after completion of rTMS.55 This review indicated that, at follow-up, any differences between the two treatment groups disappear. The authors did not take into account illness severity scores at the end of treatment, but only compared scores at follow-up. We were able to replicate the results of this report, including a total of 10 studies together with a more sensitive meta-analytic procedure that took into account variability in symptom severity scores at completion of the treatment. Our results suggest that although both rTMS and sham groups tend to improve during the follow-up period, real rTMS does not convey any advantage over sham rTMS. This result is also somewhat reassuring as it indicates that rTMS does not convey any adverse
PSYCHIATRY 8:4
rebound effects, i.e. participants do not get worse following completion of rTMS.
Conclusion Our review shows that rTMS results in significantly greater response rates and decreases in depressive symptoms than sham rTMS. Not only is the overall effect size large, but it also appears that the clinical efficacy of rTMS, as demonstrated by numbers needed to treat, falls within the range generally accepted for psychiatric (add-on) treatments and is similar to other psychiatric treatments. Moreover, rTMS does not seem to be associated 132
© 2009 Elsevier Ltd. All rights reserved.
Physical treatment
with any negative post-treatment effects. On the downside, any beneficial rTMS treatment effects may be relatively short-lived, possibly rendering this treatment less cost-effective. Finally, we failed to uncover any significant predictors of treatment efficacy, with the exception of stimulation intensity over 80% of motor threshold. Future research strategies may involve finding more effective treatment parameters by experimentation, and very large treatment studies comparable to the recent commercial trial reported by O’Reardon and colleagues.47 Such large studies may facilitate the isolation of systematic variables affecting rTMS efficacy. To date, the most appropriate role for rTMS as a treatment in depression is yet to be determined, whether it be as a standalone treatment or add-on to other treatments.56 ◆
stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol 1998; 108: 1–16. 15 Dwork AJ, Arango V, Underwood M, et al. Absence of histological lesions in primate models of ECT and magnetic seizure therapy. Am J Psychiatry 2004; 161: 576–78. 16 Holtzheimer Iii PE, Russo J, Claypoole K, et al. Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation. Depress Anxiety 2004; 19: 24–30. 17 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 2004; 126: 123–33. 18 Avery DH, Holtzheimer Iii PE, Fawaz W, et al. A controlled study of repetitive transcranial magnetic stimulation in medication-resistant major depression. Biol Psychiatry 2006; 59: 187–94. 19 Hausmann A, Pascual-Leone A, Kemmler G, et al. No deterioration of cognitive performance in an aggressive unilateral and bilateral antidepressant rTMS add-on trial. J Clin Psychiatry 2004; 65: 772–82. 20 Schatzberg AF, Kraemer HC. Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biol Psychiatry 2000; 47: 736–44. 21 Kaptchuk TJ, Goldman P, Stone DA, et al. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000; 53: 786–92. 22 Jorge RE, Robinson RG, Tateno A, et al. Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol Psychiatry 2004; 55: 398–405. 23 Fitzgerald PB, Brown TL, Daskalakis ZJ. The application of transcranial magnetic stimulation in psychiatry and neurosciences research. Acta Psychiatr Scand 2002; 105: 324–40. 24 Loo CK, Taylor JL, Gandevia SC, et al. Transcranial magnetic stimulation (TMS) in controlled treatment studies: are some “sham” forms active? Biol Psychiatry 2000; 47: 325–31. 25 Boutros NN, Gueorguieva R, Hoffman RE, et al. Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression. Psychiatry Res 2002; 113: 245–54. 26 Miniussi C, Bonato C, Bignotti S, et al. Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression? Clin Neurophysiol 2005; 116: 1062–71. 27 Rossi S, Ferro M, Cincotta M, et al. A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS). Clin Neurophysiol 2007; 118: 709–16. 28 Pascual-Leone A, Rubio B, Pallardo F, et al. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drugresistant depression. Lancet 1996; 348: 233–37. 29 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 1997; 154: 1752–56. 30 Klein E, Kolsky Y, Puyerovsky M, et al. Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham- controlled pilot study. Biol Psychiatry 1999; 46: 1451–54. 31 Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry 2000; 47: 332–37. 32 George MS, Nahas Z, Molloy M, et al. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry 2000; 48: 962–70.
References 1 Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996; 276: 293–99. 2 Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during 15 years of observational followup. Am J Psychiatry 1999; 156: 1000–06. 3 Kupfer DJ, Charney DS. “Difficult-to-treat depression”. Biol Psychiatry 2003; 53: 633–34. 4 Daskalakis ZJ. Repetitive transcranial magnetic stimulation for the treatment of depression: to stimulate or not to stimulate? J Psychiatry Neurosci 2005; 30: 81–82. 5 Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Repetitive transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev 2002; CD003493. 6 Post A, Keck ME. Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? J Psychiatr Res 2001; 35: 193–215. 7 Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci 2005; 30: 83–90. 8 Ochsner KN, Ray RD, Cooper JC, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 2004; 23: 483–99. 9 Phan KL, Wager T, Taylor SF, et al. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002; 16: 331–48. 10 Davidson RJ. Well-being and affective style: neural substrates and biobehavioural correlates. Philos Trans R Soc Lond B Biol Sci 2004; 359: 1395–411. 11 Schutter DJ, van Honk J. A framework for targeting alternative brain regions with repetitive transcranial magnetic stimulation in the treatment of depression. J Psychiatry Neurosci 2005; 30: 91–97. 12 Fitzgerald PB, Brown TL, Marston NAU, et al. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebocontrolled trial. Arch Gen Psychiatry 2003; 60: 1002–08. 13 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 1999; 56: 315–20. 14 Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the safety of repetitive transcranial magnetic
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44 Su TP, Huang CC, Wei IH. Add-on rTMS for medication-resistant depression: a randomized, double-blind, sham-controlled trial in Chinese patients. J Clin Psychiatry 2005; 66: 930–37. 45 McDonald WM, Easley K, Byrd EH, et al. Combination rapid transcranial magnetic stimulation in treatment refractory depression. Neuropsychiatr Dis Treat 2006; 2: 85–94. 46 Anderson IM, Delvai NA, Ashim B, et al. Adjunctive fast repetitive transcranial magnetic stimulation in depression. Br J Psychiatry 2007; 190: 451–52. 47 O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry 2007; 62: 1208–16. 48 Stern WM, Tormos JM, Press DZ, et al. Antidepressant effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebocontrolled trial. J Neuropsychiatry Clin Neurosci 2007; 19: 179–86. 49 Loo CK, Mitchell PB, McFarquhar TF, et al. A sham-controlled trial of the efficacy and safety of twice-daily rTMS in major depression. Psychol Med 2007; 37: 341–49. 50 Mogg A, Pluck G, Eranti SV, et al. A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression. Psychol Med 2007: 1–11. 51 Pinson L, Gray GE. Psychopharmacology: number needed to treat: an underused measure of treatment effect. Psychiatr Serv (Washington, D.C.) 2003; 54: 145–54. 52 Bauer M, Forsthoff A, Baethge C, et al. Lithium augmentation therapy in refractory depression-update 2002. Eur Arch Psychiatry Clin Neurosci 2003; 253: 132–39. 53 Katona C, Livingston G. How well do antidepressants work in older people? A systematic review of number needed to treat. J Affect Disord 2002; 69: 47–52. 54 McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice. Ann Intern Med 1997; 126: 712–20. 55 Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. Br J Psychiatry 2003; 182: 480–91. 56 Mitchell PB, Loo CK. Transcranial magnetic stimulation for depression. Aust N Z J Psychiatry 2006; 40: 406–13.
33 Garcia-Toro M, Mayol A, Arnillas H, et al. Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. J Affect Disord 2001; 64: 271–75. 34 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 2001; 71: 546–48. 35 Manes F, Jorge R, Morcuende M, et al. A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr 2001; 13: 225–31. 36 Padberg F, Zwanzger P, Keck ME, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 2002; 27: 638–45. 37 Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003; 5: 40–47. 38 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 2003; 37: 267–75. 39 Rumi DO, Gattaz WF, Rigonatti SP, et al. Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. Biol Psychiatry 2005; 57: 162–66. 40 Rossini D, Lucca A, Zanardi R, et al. Transcranial magnetic stimulation in treatment-resistant depressed patients: a doubleblind, placebo-controlled trial. Psychiatry Res 2005; 137: 1–10. 41 Januel D, Dumortier G, Verdon CM, et al. A double-blind sham controlled study of right prefrontal repetitive transcranial magnetic stimulation (rTMS): therapeutic and cognitive effect in medication free unipolar depression during 4 weeks. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 126–30. 42 Fitzgerald PB, Benitez J, de Castella A, et al. A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am J Psychiatry 2006; 163: 88–94. 43 Garcia-Toro M, Salva J, Daumal J, et al. High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression. Psychiatry Res: Neuroimaging 2006; 146: 53–57.
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Transcranial magnetic stimulation
be administered without anaesthesia and is non-invasive in nature, which may be among the primary reasons for the recent drive to investigate its therapeutic efficacy in the treatment of depression.5
Lucie L Herrmann
Principles and mechanisms
Klaus P Ebmeier
During TMS an electrical current is passed through an insulated wire coil placed over the patient’s scalp. The electrical current generates a magnetic field, which in turn induces a current in conducting structures such as axons, which can depolarize nerve cells directly or indirectly involved.6 Depending on stimulation intensity, duration and frequency, this may result in the temporary disruption or stimulation of brain activity. Of the brain areas targeted in the treatment of depression, the dorsolateral prefrontal cortex (DLPFC) has received most attention.7 The DLPFC is part of a network that has been implicated in the regulation of mood.8,9 It has been suggested that the left hemisphere is involved in the generation and modulation of positive affect, and the right hemisphere of negative affect.10 Since low-frequency rTMS (≤ 1Hz) results in the inhibition and high frequency (≥ 5Hz) in the activation of stimulated brain regions, rTMS may be applied to selectively ‘normalize’ abnormal activity in the prefrontal cortex (PFC).11 Several studies of rTMS in depressed patients have demonstrated improvement of depressive symptoms after both high-frequency rTMS to the left PFC and low-frequency rTMS to the right PFC.12,13
Abstract Depression has an annual prevalence of 1–6% in the community; 50–60% of depressed individuals might not respond to conventional pharmacotherapy. Transcranial magnetic stimulation (TMS) non-invasively stimulates superficial cortex in patients, for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1–20 Hz at motor threshold intensity. We present a meta-analysis of 24 studies evaluating the antidepressant effect of TMS for major depressive or bipolar disorder in treatment groups ≥10 patients. Out of 617 patients receiving active rTMS, 218 (35.3%) were classified as ‘responders’, whereas only 71 (13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. The Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI: 2.94–5.13). Heterogeneity between studies did not exceed that expected by chance and there was no significant publication bias. Based on these data, five patients (95% CI = 4–6) need to be treated in order to obtain a clinical response attributable to rTMS, a respectable effect size among psychiatric (add-on) treatments. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature indicates that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Also, more knowledge is needed regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects.
Risks and safety If appropriate guidelines are observed, rTMS conveys a very small risk of seizure induction.14 It does not cause any identifiable neuropathological lesions.15 RTMS treatment is not associated with any transient negative cognitive effects16–18 and may in fact have slight beneficial effects in some areas of cognition, such as verbal memory, psychomotor speed and concentration.19
Keywords antidepressants; controlled trials; depression; mood disorders;
Placebo effect and blinding
transcranial magnetic stimulation
Depressed individuals are susceptible to placebo effects.20 RTMS as a technologically sophisticated device-based treatment may be associated with even greater placebo response.21 Patients receiving real or sham rTMS should have identical expectations,22 but for rTMS trials no satisfactory placebo condition has been established. Placebo rTMS should result in scalp and noise sensation identical to active rTMS, without any actual cortical stimulation. Yet, generating a degree of scalp sensation typically results in PFC stimulation.23,24 If the coil is angled away at 45°, it may not be entirely inactive17,25 and corresponds to an ‘attenuated real’ condition.24 Similarly, if the coil is angled away at 90°, the placebo condition appears to be less painful than the real rTMS. A novel form of sham rTMS involves placing a sheet of metal between the coil and the patient’s head, so that the magnetic field is blocked, while noise sensation remains very similar to that of real rTMS.26 In principle, it may be possible to generate the surface stimulation electrically, but published data are missing. In an rTMS procedure it is of course also difficult to blind the operator.5
Depression is common, with an annual prevalence from 1–6% in the community.1 It is associated with a high rate of recurrence2; up to 50–60% of depressed individuals may not respond to conventional pharmacotherapy.3 This reinforces the need to find alternative treatments.4 Repetitive transcranial magnetic stimulation (rTMS) holds considerable promise. It can
Lucie L Herrmann MA is a Trainee in Clinical Psychology at the Institute of Psychiatry, King’s College, London, UK. She trained in Marburg, Aberdeen, Edinburgh and Oxford, UK. Conflicts of interest: none declared. Klaus P Ebmeier MD is Professor of Old Age Psychiatry at the University of Oxford, UK. He trained in Bonn and Aberdeen. His main research interests are the causes and treatment of depression and dementia. Conflict of interests: Recipient of travel expenses Magstim Co.
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Physical treatment
We used a chi-square analysis (random effects, Peto odds ratio) for numbers of responders in each group (as defined by a 50% reduction in depression severity scores). This non-parametric test has the advantage of being robust and less affected by the presence of outliers. We decided to use the Peto rather than the DerSimonian-Laird approach, as this is better suited to trials where both treatment arms are relatively equal in size and where an event (i.e. treatment response) is relatively rare in at least one treatment arm. Cochran Q was computed to test for noncombinability of data and bias was assessed. In order to define the treatment-specific effect of rTMS and to generate clinically meaningful data that can aid the interpretation of results, we also determined the ‘number of patients needed to treat’ (NNT = 1/Absolute Risk Reduction).
Patients may be generally aware of their study condition, particularly in studies with crossover design. This could explain the poor efficacy of rTMS reported in several studies.23 An entirely inactive sham condition that nevertheless mimics the real rTMS in terms of scalp, noise and pain sensation is therefore urgently required. In an effort to design alternative sham approaches, Rossi and colleagues recently developed a possibly more appropriate sham stimulation, a wooden tool that optically looks like a conventional figure-of-eight coil and mirrors the scalp sensation induced by real rTMS whilst leaving both the visual impact and acoustic sensation of real rTMS unaltered.27 Future research is needed to explore the efficacy of rTMS in comparison to sham treatment using such specially adapted sham coils.
Efficacy
Results Data relating to treatment response, were available from 24 studies (leading to an overall sample size of 1160 participants).12,18,22,30– 50 Out of 617 patients receiving active rTMS, 218 (= 35.3%) were classified as ‘responders’, while only 71 (= 13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. A Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI = 2.94 to 5.13) (Figure 1). Heterogeneity between studies did not exceed that expected by chance (Cochran’s Q = 23.6; p >0.05). There was no significant publication bias. Kendall’s τb was -0.04 (p >0.05), while the intercept in the regression of normalized odds ratios on precision was 0.98 (Egger bias; 95% CI = −0.06 to 2.01). Based on these data, a total of 4.49, conventionally rounded up to five, patients (95% CI = 3.71 to 5.72) need to be treated in order to obtain a clinical response attributable to rTMS.
During the last decade there has been an increase in randomized controlled studies examining the therapeutic efficacy of rTMS in the treatment of depression.5 The first published studies of focal stimulation of the PFC were of cross-over design. These studies found decreases in scores on the Hamilton Depression Rating Scale that were statistically, as well as clinically significant.28,29 Many of the subsequent placebo-controlled studies reported similar findings. However, the differences between real and sham groups were often of only marginal clinical significance. Some studies failed to demonstrate an advantage of rTMS over sham rTMS altogether. As treatment efficacy of rTMS in depression has been highly variable with often underpowered designs, the aim of this contribution is to update and review the existing literature on randomized placebocontrolled rTMS trials of the treatment of depression. Methods Randomized controlled publications investigating the efficacy of rTMS in the treatment of depression were identified by using Embase and Medline searches with the term (“depression” OR ‘depressed’) AND (‘transcranial’ OR ‘TMS’) including the years 1996 to 2007. Additional studies were identified from previous meta-analyses and by manual cross-referencing. Unpublished studies were not included, as TMS research is primarily academic, i.e. there is a motivation to publish good quality, even negative, research, and registration in the relevant trial databases is neither obligatory nor commonly implemented. A total of 1312 studies were identified with the above search term. Studies were included if: • they were of randomized parallel or cross-over design with sham control, • with both patients and investigators (i.e. baseline and outcome assessors, as opposed to the treatment team) unaware of the treatment conditions, • they consisted of at least 10 patients with a diagnosis of major depressive or bipolar disorder in each treatment group, • they employed a version of the Hamilton Depression Rating Scale (HDRS) or Montgomery-Åsberg Depression Rating Scale (MADRS) in order to measure outcome, • Baseline and follow-up scores were available or could be derived. Altogether, 1288 publications did not satisfy the above inclusion criteria. Of these, 17 studies were excluded because there were fewer than 10 patients in each group.
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Discussion Patients treated with rTMS are 3.88 times more likely to show a clinical response than patients receiving sham treatment. For clinicians it is of importance to be able to estimate the amount of benefit of an intervention in relation to other approved interventions for the same outcome measure. Based on the data included in this study, 4 to 6 patients need to be treated in order to achieve a clinical response that is due to active rTMS. As such, the clinical efficacy of rTMS certainly falls within the range of NNTs generally accepted for psychiatric (add-on) treatments and is similar to other anti-depressant treatments. It has been estimated that most psychiatric treatments have NNTs in the range of 3 to 6.51 In particular, the NNT for Lithium, a common add-on treatment for treatment-resistant depression, is 4,52 whereas the NNT for add-on cognitive-behavioural therapy, a treatment that is equally difficult to conceal from the patient, is 5.51 A recent review that systematically investigated this issue in elderly patients with depression reported that NNTs varied from 4 to 8 for tricyclic antidepressants and selective serotonin reuptake inhibitors, respectively.53 A further argument to offer rTMS as an option is that the NNT approach is only one avenue of clinical decisionmaking and needs to be integrated with patient and care-giver preferences as well as local context and constraints.54 Length of remission after rTMS treatment Only one previous meta-analysis (based on 3 individual RCTs) investigated whether the beneficial effects of rTMS are sustained 131
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Figure 1
at 2 weeks after completion of rTMS.55 This review indicated that, at follow-up, any differences between the two treatment groups disappear. The authors did not take into account illness severity scores at the end of treatment, but only compared scores at follow-up. We were able to replicate the results of this report, including a total of 10 studies together with a more sensitive meta-analytic procedure that took into account variability in symptom severity scores at completion of the treatment. Our results suggest that although both rTMS and sham groups tend to improve during the follow-up period, real rTMS does not convey any advantage over sham rTMS. This result is also somewhat reassuring as it indicates that rTMS does not convey any adverse
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rebound effects, i.e. participants do not get worse following completion of rTMS.
Conclusion Our review shows that rTMS results in significantly greater response rates and decreases in depressive symptoms than sham rTMS. Not only is the overall effect size large, but it also appears that the clinical efficacy of rTMS, as demonstrated by numbers needed to treat, falls within the range generally accepted for psychiatric (add-on) treatments and is similar to other psychiatric treatments. Moreover, rTMS does not seem to be associated 132
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with any negative post-treatment effects. On the downside, any beneficial rTMS treatment effects may be relatively short-lived, possibly rendering this treatment less cost-effective. Finally, we failed to uncover any significant predictors of treatment efficacy, with the exception of stimulation intensity over 80% of motor threshold. Future research strategies may involve finding more effective treatment parameters by experimentation, and very large treatment studies comparable to the recent commercial trial reported by O’Reardon and colleagues.47 Such large studies may facilitate the isolation of systematic variables affecting rTMS efficacy. To date, the most appropriate role for rTMS as a treatment in depression is yet to be determined, whether it be as a standalone treatment or add-on to other treatments.56 ◆
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