Dr. George and Colleagues Reply

To the Editor: With the ability to noninvasively interrupt or augment cortical activity, repetitive transcranial magnetic stimulation is a powerful new tool using an innovative paradigm (altering regional brain activity or circuits); and we welcome rigorous critical discussion.

Jeffrey A. Mattes, M.D., argues that our statistical analysis was incorrect. We have analyzed these data in multiple ways for several different reviewers and have found positive effects. Obviously, a crossover design study for depression has many limitations, but this study was a step in a natural progression from open studies of transcranial magnetic stimulation in depression to this quick crossover study and now to more rigorous double-blind, parallel designs. Among the 15 ongoing double-blind transcranial magnetic stimulation studies in depression, one report has even directly compared transcranial magnetic stimulation with ECT, finding equal efficacy (1). A large U.S. multisite transcranial magnetic stimulation trial for depression in medication-free unipolar patients is now under way, and the combined results from this work will have the statistical power to completely settle the issue of transcranial magnetic stimulation’s putative antidepressant effect within the next 2 years.

Eugene A.M. Schouten, M.D., and colleagues report on an open study of seven patients in which some had modest declines in Hamilton Depression Rating Scale scores while several nonresponders were taking benzodiazapines. They question whether benzodiazapines block the putative transcranial magnetic stimulation antidepressant effect. Their comments highlight the major issue in this emerging field, which is why are there such widely different ranges in antidepressant effects (11 of 17 psychotically depressed patients had a greater than 50% drop in Hamilton rating scale scores with 1 week [2]; 21 of 50 (42%) had a greater than 50% drop in a 1-week open trial [3]). The likely reason for these varying effect sizes is that we do not yet understand transcranial magnetic stimulation’s effects on neurons nor its antidepressant actions. Numerous variables, including concomitant medication use, have varied across the studies to date (e.g., population, transcranial magnetic stimulation coil, intensity, frequency, dose). The transcranial magnetic stimulation field, now organized as the International Society of Transcranial Stimulation, is maintaining an active clinical trials database (http://www.ists.unibe.ch/ists/TMSAvery.htm). Sorting through all of these parameters in clinical trials will be slow and expensive. We place great hope in recent efforts by our group at the Medical University of South Carolina and others in combining transcranial magnetic stimulation and functional neuroimaging, particularly echoplanar blood-oxygen-level-dependent functional magnetic resonance imaging (4). By examining regional brain changes during transcranial magnetic stimulation in health and disease, carefully varying the parameters (e.g., intensity, location, frequency), and observing real-time changes in local and remote brain activity, it is hoped that one can identify combinations of parameters that are more likely to have the most potent antidepressant effects. The combination of rigorous double-blind clinical trials with neuroimaging will likely help transcranial magnetic stimulation assume its position within psychiatry, either as an interesting investigative tool (at the least) or as a powerful new form of therapy for depression and other disorders—or both.