The results of this meta-analysis indicate that rapid-rate rTMS does not appear to be any more efficacious than sham therapy in treating depression. These results are in partial agreement with those of a meta-analysis by Martin et al43
who found an effect in favour of rTMS after 2 weeks of treatment (standardized mean difference = –0.35), but no significant difference at a 2-week follow-up. Martin et al43
included 14 RCTs and concluded that the trials were generally of low quality and provided insufficient evidence to support the use of rTMS in the treatment of depression. These results are in contrast with those of another meta-analysis conducted by McNamara et al.44
They found a beneficial effect of rTMS compared with placebo when 5 RCTs were included in a meta-analysis, with a difference in the rate of improvement between the treated and control group of 43% (95% CI 25%–61%). The results of a test for heterogeneity were not significant. This meta-analysis included 2 of the studies excluded from the present study. One of these involved rTMS given to the right DLPFC using a low frequency,29
and the other, a study with a multiple crossover design, included patients with psychotic features and treatment with nimodipine.36
Therefore, the present study includes more homogeneous conditions of rTMS delivery and clinical presentation of patients. In addition, the present study used data in a continuous form instead of dichotomizing the responses, thereby conserving information.45
Several new studies have been published since the meta-analysis by McNamara et al44
was conducted, and these were included in the present meta-analysis.
There are several possible explanations for the lack of benefit found for rTMS versus sham therapy in the present meta-analysis. The first, and most obvious, is that this is a valid result and rTMS is no more efficacious than placebo. A second possibility is that the most effective combination of parameters of rTMS has not been delineated. Even in the 6 studies combined in this meta-analysis, there were differences in the frequency, intensity, duration of train of pulses and days of treatment. These parameters are analogous to the dosage of a medication. If the therapeutic dosage is unknown, establishing efficacy may be difficult, if not impossible. In addition, the optimal site for the delivery of rTMS for depression has not been found. There is no evidence that the DLPFC is the best location. However, almost all of the studies encountered in this systematic review used a procedure described by Pascual-Leone et al36
in which the DLPFC is located by inducing muscle contractions in the abductor pollicis brevis and moving 5 cm anterior to this site. This method does not take into account variability in head size or shape.7
In fact, studies using post hoc localization by magnetic resonance imaging (MRI) of coil position found considerable variability in coil distance from the middle prefrontal gyrus.46,47
When the DLPFC was localized by PET before stimulation, Herwig et al38
found a moderate improvement in depressive symptoms indicating that accurate localization is important.
A further confounding variable is the sham condition. Tilting the coil off the scalp is meant to stimulate the skin to reproduce the tactile sensation of real TMS along with the acoustic effects. However, inadequate tilting may in fact stimulate the cortex, exerting possible therapeutic effects.48,49
This would reduce any possible differences in the treatment versus control groups, resulting in “negative” trials. Another difficulty arises in that the sensation of sham versus active rTMS may differ slightly, which could essentially unblind subjects in crossover trials.7
Another possible explanation for these negative findings is the low power in the 6 trials combined in the meta-analysis. For example, performing a sample size calculation based on the following assumptions, (1) a minimal clinically important decrease of 6 points on the HAM-D, (2) a standard deviation of 8 (an estimate from the 6 studies in this meta-analysis), (3) an alpha level of 0.05 and (4) power of 0.80, yields 56 subjects needed in a single trial (for formula see Friedman et al50
). This is slightly fewer than the total of 68 subjects included in the 6 trials examined in this meta-analysis, indicating that the power of each of these trials was significantly below that needed to detect a difference of this magnitude in the HAM-D. Therefore, if this difference cannot be detected because of low power, a trial may produce negative results even if there really is a difference between the treatment and control groups (type II error).
The intention of this meta-analysis was to determine the efficacy of rTMS compared with sham therapy. The comparison of rTMS with ECT has also been investigated with open51,52
protocols. Unfortunately, these studies could not be included in this meta-analysis, because the question of whether rTMS is different from ECT is a separate issue. A future review and meta-analysis may look at comparing rTMS with ECT. Although studies comparing rTMS with ECT have suggested favourable results for rTMS with no statistically significant differences between these treatments, these studies are not designed to determine equivalence. In other words, “no significant difference” does not mean these treatments are equal. Perhaps future studies with the much larger sample sizes needed to determine equivalence might be helpful in clarifying this question.
In conclusion, when rTMS was first introduced, several open trials suggested a possible antidepressant effect. The RCTs that followed provided mixed results. This meta-analysis of 6 small, but generally well-designed, studies found that rapid-rate rTMS was no more efficacious than sham therapy in treating adults with a major depressive episode. Heterogeneity in these 6 studies was not significant, indicating that combining the data was appropriate. Further RCTs with larger samples and sufficient power are needed in which the DLPFC is precisely localized and the parameters of rTMS are of sufficient intensity, frequency and duration. In addition, true sham conditions must be delineated. These steps would help answer the question of whether rTMS is efficacious in treating depression.