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Lepping et al.[1] report a meta-analysis of treatment effects of rTMS on depression in which they converted improvement on the Hamilton depression rating scale (HAMD) into nominal Clinical Global Impression-Improvement (CGI-I) scores. The results showed a small difference in favor of rTMS, which the authors consider to be clinically irrelevant. They therefore conclude that rTMS cannot be recommended as a first line treatment for depression. We commend the systematic integration of published evidence as conducted by Lepping et al.[1] and applaud their efforts to investigate clinical relevance. However, their strong conclusion may be unwarranted at this point, given several critical remarks that can be made regarding their approach, and given the fact that much remains unclear when it comes to the clinical efficacy of rTMS and for that matter, of any other therapy for depression, be it antidepressant medication or psychotherapy. Indeed, before drawing strong conclusions, it would have been of interest to compare CGI-I converted scores of current treatments of depression (antidepressants and psychotherapy) to those of rTMS. Cuijpers et al.[2] recently showed that effect sizes of psychotherapy and pharmacotherapy for depression are of the same magnitude, which is between 0.3 and 0.4. For example, paroxetine increases the percentage responders from 42% to 53% and reduces the HAMD score by 3 points [3]. The findings for rTMS indeed show rather similar efficacy. Recently, Leucht et al.[4] showed that clinical efficacy of depression treatment is not inferior to that of most somatic treatments. Despite the relatively low efficacy of psychotherapy, rTMS and pharmacotherapy, these treatments are of great use for depressive patients. An explanation for this seeming contradiction is that the effect sizes retrieved in the meta-analyses result from subtracting placebo-group improvement from that in the treatment group. This is the usual scientific approach to estimate efficacy. However, in clinical practice, placebo effects are added (rather than subtracted) to the actual treatment, yielding far greater improvement rates. Especially in the field of depression, giving hope for improvement is an effective element of therapy which is present in the actual therapy but also in the placebo condition (if it is a convincing placebo, which sham rTMS apparently is; see [5]. For this reason, psychotherapy, pharmacotherapy, but also rTMS may have only modest efficacy when compared with placebo, but can nevertheless help many patients to obtain remission from depression.

Some other points of criticism are also in place.

First, Lepping et al.[1] seem to imply that indirectly computed CGI-I scores, based on HAMD ratings, are as valid as CGI-I scores made directly by an experienced clinician. We doubt this. The strength of the CGI is that it is based on a holistic assessment by an experienced clinician who has observed and interviewed the patient. The integration of all that information, in interaction with the clinician's knowledge and intuition, is reflected in the CGI score, and is not similarly present in HAMD-scores. Furthermore, the calculation from HAMD to CGI-I is described poorly and therefore difficult to reproduce. A second assumption of the authors is that the CGI is a more clinically relevant measure of the clinical state of depression than the HAMD. If that were true, and if the research community would be convinced of that, the HAMD would for long have been abandoned and have been replaced by the CGI. Notably, the results of Lepping et al. are at odds with a recent meta-analysis investigating response and remission after high frequency rTMS for depression [6]. Based on 29 RCTs, the authors found 29.3% of patients receiving rTMS were classified as responders, compared with 10.4% of those receiving sham rTMS. For remission, the rates were 18.6% and 5%, respectively. Berlim and colleagues therefore conclude that rTMS ‘seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile’.

It is unclear why Lepping et al. find a stronger improvement for sham than for rTMS for treatment-resistant depression (TRD) [1], whereas previous meta-analyses [7], with a preponderance of studies including TRD patients, reported a significantly stronger improvement for rTMS above sham.

More importantly, the authors included many studies in their analysis with suboptimal parameters. Most studies published before 2005 had small sample sizes and thus were underpowered. Indeed, more recent studies tend to show larger effect sizes [8]. It has been maintained that rTMS treatment should have a duration of at least 3 weeks of stimulation [9]; however, many studies in the analysis by Lepping et al. included shorter treatments. Moreover, in most studies, coil placement was not adequate, and may have been too posterior for targeting the DLPFC in many patients [10].

Studies showing the potential of rTMS for depression continue to be published, and can be considered as proof-of-principle. For example, a study published after the search period of Lepping et al.[1] revealed a significant difference of rTMS (at a frequency of 8–13 Hz) during 4 weeks, with a 48.5% reduction in depression severity in the rTMS group versus 19.3% in the group receiving sham [11]. Another recent study also applied an innovative approach [12]. In this randomized controlled trial, 32 patients with MD were treated for 6 weeks (thirty sessions) with either successively intermittent, activity enhancing TBS (iTBS) to the left and continuous, inhibiting TBS (cTBS) to the right dlPFC or with bilateral sham stimulation. The authors reported a larger number of responders in the cTBS (n = 9) compared to the sham stimulation (n = 4) group (odds ratio: 3.86; Wald χ2 = 3.9, P = 0.048).

To conclude, we maintain that it is far too early to discard rTMS as an effective treatment for depression. When it comes to strong conclusions, the jury is still out. However, a fair evaluation, in our opinion, would be that rTMS certainly holds promise to become a regular tool (one of many) in the psychiatrist's toolbox, as efficacy is within the same range as psychotherapy and pharmacotherapy for depression. More research is obviously needed, not only on the efficacy of different parameters, but also on the neural mechanisms involved, which may be predictive of treatment success or differentiate between responders and non-responders [13].

References

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  2. References
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    Lepping P, Schnfeldt-Lecuona C, Sambhi RS et al. A systematic review of the clinical relevance of repetitive transcranial magnetic stimulation. Acta Psychiatr Scand 2014; doi: 10.1111/acps.12276 [Epub ahead of print].
  • 2
    Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT, Reynolds CF 3rd. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry 2013;12:137148.
  • 3
    Barbui C, Furukawa TA, Cipriani A. Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials. CMAJ 2008;178:296305.
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    Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry 2012;200:97106.
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    Slotema CW, Blom JD, de Weijer AD 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;69:450456.
  • 6
    Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med 2014;44:225239.
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    Hovington CL, McGirr A, Lepage M, Berlim MT. Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses. Ann Med 2013;45:308321.
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    Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies Acta Psychiatr Scand 2007;116:165173.
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    George MS, Post RM. Daily left prefrontal repetitive transcranial magnetic stimulation for acute treatment of medication-resistant depression. Am J Psychiatry 2011;168:356364.
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    Rusjan PM, Barr MS, Farzan F et al. Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. Hum Brain Mapp 2010;31:16431652.
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    Jin Y, Phillips B. A pilot study of the use of EEG-based synchronized Transcranial Magnetic Stimulation (sTMS) for treatment of Major Depression. BMC Psychiatry 2014;14:13.
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    Plewnia C, Pasqualetti P, Große S et al. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord 2014;156:219223.
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    Downar J, Geraci J, Salomons TV et al. Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 2013; doi: 10.1016/j.biopsych.2013.10.026.