An estimate of placebo effect of repetitive transcranial magnetic stimulation in epilepsy

Objective: Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool in epilepsy. In recent years, several open-label trials have shown an encouraging reduction in seizure frequency in patients with epilepsy. However, the data from controlled trials are mixed with respect to antiepileptic rTMS efficacy, and the field would benefit from further carefully controlled trials. Prior to initiating new trials, it is important assess the magnitude of the placebo effect of presently used sham rTMS methods. Methods: We systematically analyzed individual subject data from three placebo-controlled trials and measured the placebo effect at follow-up intervals of 2, 4, and 8. weeks after sham rTMS treatment. Given the relatively small subgroup sample size, placebo condition data were pooled for analysis. Results: Three methods for sham rTMS were employed in the reviewed studies: (1) coil positioning orthogonal to the scalp, (2) a spring-loaded sham coil, and (3) a double active-sham coil. The placebo response overall was consistently low across follow-up intervals, both for median change in seizure frequency (Kruskal-Wallis, P> 0.4, df= 2) and for responder (defined as ≥ 50% seizure frequency reduction) rate (Fisher's exact rest, P> 0.9, df= 2). The aggregate effect of the placebo condition was a 0-2% median seizure reduction rate and a responder rate of 16-20%. Conclusion: We anticipate that these data will contribute to future power analysis as well as selection and design of sham rTMS methods for controlled rTMS trials.