Other electromagnetic stimulation transcranial magnetic stimulation TMS

In spite of the absence of major corporate sponsors, a fair amount of therapeutic research has been conducted into the possible antidepressant effects of repetitive transcranial magnetic stimulation (rTMS). A number of good recent reviews describe the studies in detail. (Burt et al., 2002; George et al., 1999; Holtzheimer et al., 2002; Pridmore et al., 2001). However, compared with the evidence necessary for the licensing of antidepressant drugs, the number and quality of trials, as well as the number of subjects included in those trials, are limited. The stimulation parameters employed in different studies are rather diverse, suggesting the familiar 'apples and oranges' problem. For example, George et al. (1997) treated 12 outpatients in a blind, crossover study, using 20 Hz over the left dorsolateral prefrontal cortex and sham treatment. The simple rationale for this approach was that neuroimaging studies had shown reduced metabolism in this brain area, and stimulation at higher frequencies was expected to increase cortical activity under the coil.

Based on a rather similar hypothesis, Klein et al. (1999) treated 71 depressed patients with the slow stimulation frequency of 1 Hz over the right dorsolateral prefrontal cortex. Their assumption was that TMS at 1 Hz would reduce cortical activity in the right prefrontal cortex and bring the relative imbalance between left and right hemisphere deactivation back into equilibrium. It is clearly problematic to lump these two studies together to compute an average effect size, although they are based on similar theoretical premises. Spontaneous remission and placebo response rates in depressive illness vary considerably (20-60%), so

Bias Assessment Plot

Sample size 80

Risk difference

Figure 7.2 Funnel plot of effect size (risk difference, x-axis) plotted against number of patients in study (y-axis); sham-controlled trials of TMS. Kendall's test of bias on standardised effect versus variance (Begg and Mazumdar): -0.27, P = 0.22 (NS). Computation and graphics were done with StatsDirect, Version 1.9.15, May 2002

that even sizeable improvement rates in open TMS studies of depression may not indicate superiority to placebo.

A serious problem in evaluating TMS is the absence of a true placebo condition. Previous strategies include angling the stimulation coil away from the head surface. However, there is some evidence that subjects can distinguish between flat and angled coil positions by the strength of superficial nerve and muscle stimulation. Some authors have further cast doubt on the assumption that with an angled coil no activation of cortical tissue occurs, arguing that therapeutic effects may be expected from this supposed placebo treatment (George et al., 1999).

With these caveats, it is of interest to look at the effect sizes of some published studies. We recently computed the effect sizes of 11 randomised sham-controlled studies with 102 actively treated patients, using StatsDirect (Version 1.9.15; 5 May 2002; www.statsdirect.com) and a modification of the data provided by Holtzheimer (Holtzheimer et al., 2002). Studies with smaller numbers clearly show a larger variability (Figure 7.2) and Q ('non-combinability' for risk difference) is 18.3 (df = 10, P = 0.0501), just missing statistical significance. This suggests that, as predicted above, some variability exists between studies. The (random-effects) pooled risk difference is 16%, with an approximate 95% confidence interval of 7-26% (DerSimonian-Laird-x2 = 11.9, df = 1,P = 0.0006; Figure 7.3).

Pascual-Leone 1996 George 1997 Klein 1999 Loo1999 Kimbrell 1999 Padberg 1999 Berman 2000 Eschweiler 2000 George 2000 Avery2000 Garcia-Toro 2001

DL pooled risk difference = 0.164056 (95% CI = 0.070678 to 0.257433)

Figure 7.3 Meta-analysis of randomised, sham controlled trials of TMS, comparing proportion of patients improved after TMS with those improved after sham intervention (risk difference). Computation and graphics were done with StatsDirect, Version 1.9.15, May 2002

In summary, these are interesting preliminary results, suggesting that TMS may have anti-depressant effects. However, there is no convincing evidence so far that a particular stimulation mode, be it frequency or placement over the head, is superior to others. This casts doubt on any hypotheses about the action of TMS and suggests that non-specific effects may be important.

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