William Osler wisely admonished clinicians to use new treatments “while they still work and while they are still safe.” Medicine in general, and psychiatry specifically, have seen numerous promising therapies eventually fail. This reality is made more poignant given that serious disorders such as depression often are resistant to existing treatments.
While the recent addition of several antidepressants has reduced many of the safety and tolerability concerns associated with the older-generation agents, the effect on efficacy is less impressive. Thus, a substantial proportion of depressed patients do not achieve satisfactory response, at times still experience significant tolerability problems (eg, sexual dysfunction, weight gain), and continue to need more effective options. One strategy to circumvent this situation involves combination approaches with additional antidepressants, mood stabilizers, or second-generation antipsychotics. While such regimens often are beneficial, they can present their own problems, such as an increase in cost, adverse effects, clinically relevant drug–drug interactions, and noncompliance.
Nonpharmacologic, biological therapies have helped to overcome some of these obstacles. Electroconvulsive therapy (ECT) is the most established and time-tested example. While often effective for more severely ill patients, ECT also is compromised by numerous drawbacks. These include the associated stigma; adverse cognitive effects; reluctance on the part of many clinicians to prescribe the treatment; patients' unwillingness to accept the treatment; the lack of availability to many; and substantial cost.
All of these factors demand the development of innovative strategies. Enter transcranial magnetic stimulation (TMS) as a potential alternative therapy. This approach uses a device that can produce a localized magnetic pulse that induces neuronal depolarization. When delivered as multiple stimulations in a rapid fashion over a brief timeframe, it is referred to as repetitive TMS (rTMS).
While rTMS initially was employed by Barker et al.1 as a neuro-physiological probe, subsequent application for therapeutic purposes has led to a series of preliminary reports of efficacy. Perhaps as important is an excellent safety and tolerability profile. The application of rTMS has been primarily, but not exclusively, for the treatment of depression. Several reviews and meta-analyses have concluded that rTMS may have clinically relevant antidepressant effects, but a definitive conclusion awaits appropriate large, well-controlled trials.2,3
In this context, one such multi-center trial is now under way in the United States, and another multicenter trial funded by the National Institute of Mental Health is about to begin. The results of these two carefully designed and executed studies should resolve the remaining questions surrounding the potential value of rTMS for refractory depression. The goal of this issue is to highlight important aspects of the body of work that has brought the clinical application of rTMS to this point.
In This Issue
Heeding Osler's comment, well-conceived and executed studies are the first mandatory step to determine the lasting value of an experimental treatment. In this context, the assessment of novel devices versus new drugs to treat various psychiatric disorders poses an interesting set of design-related challenges. Adequacy of a placebo or sham procedure, duration of treatment and dosing strategy are just three examples. With the arrival of several recent potential alternatives to medication or ECT, there is also a need to develop guidelines as to their position along a continuum of treatment options for more severe or refractory depression. Thus, the risk-benefit ratio must be applied to such varied procedures as bright light therapy, rTMS, vagal nerve stimulation, and deep brain stimulation. Further, there is the question of whether they may best serve as stand-alone or augmentation therapies. This is the topic of Dr. Demitrack's thoughtful and articulate discussion, “Examining the Safety and Effectiveness of Transcranial Magnetic Stimulation for Depression.”
Our group4 has reported on the possible efficacy of rTMS in depressed patients who would be referred for ECT due to severity of symptoms or insufficient benefit from medication trials. Our pilot study failed to find a difference in efficacy between rTMS and ECT. Further, these results were similar to those reported by investigators in Israel, Australia, and Great Britain. This data, combined with positive results in less severe, treatment-refractory depression, builds a case for rTMS as a possible alternative to or an intermediate step between medication and ECT. We review these issues in “The Potential Role of Repetitive Transcranial Magnetic Stimulation in Treating Severe Depression.”
In their article “Functional Magnetic Resonance Imaging and Transcranial Magnetic Stimulation for Major Depression,” Dr. Kozel and colleagues discuss the complementary roles that techniques such as blood oxygen level dependent functional magnetic resonance imaging, diffusion tensor imaging, and rTMS can play. They posit the intriguing argument that interleaving of these techniques can provide a powerful tool to study relevant neurocircuitry and ultimately unlock the neuropathology underlying depression, and perhaps other disorders such as schizophrenia.5 From a clinical perspective, these novel approaches may provide more refined targeting of rTMS to treat these conditions.
Finally, in “Using rTMS to Treat Neuropsychiatric Disorders Other than Depression,” Dr. Khurshid and I have produced a summary of the potential clinical utility of rTMS for other disorders. As when ECT was first introduced, rTMS is being considered for a variety of neuropsychiatric conditions. Early reports indicate a possible role for rTMS in areas including pain management, schizophrenia, mania, and obsessive-compulsive disorder. In this context, however, there are numerous problems to resolve. For example, while much information has been gained in the application of rTMS for treatment of depression, comparatively little data is available to indicate what the optimal treatment parameters should be for these other disorders.
rTMS appears to be a valuable and powerful tool to probe the central nervous system, especially when combined with neuroimaging techniques. In this context, rTMS may help to elucidate the neuropathology of depression and other neuropsychiatric disorders.
Well-conceived trials accounting for the unique issues raised by experimental, device-based therapeutics are unde rway. When concluded, they should provide definitive answers regarding the therapeutic promise of rTMS for depression, and in the future perhaps for other disorders as well. Combine this with its consistent excellent safety and tolerability record and it appears that this technique is poised to “pass or fail” Osler's sage admonition regarding new treatments.
- Barker AT, Freeston IL, Jalinous R, Jarratt JA. Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery. 1987;20(1):100–109. doi:10.1097/00006123-198701000-00024 [CrossRef]3808249
- Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry. 2003;160(5):835–845. doi:10.1176/appi.ajp.160.5.835 [CrossRef]12727683
- Schlaepfer TE, Kosel M, Nemeroff CB. Efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of affective disorders. Neuropsychopharmacology. 2003;28(2):201–205. doi:10.1038/sj.npp.1300038 [CrossRef]12589372
- Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry. 2002;51(8):659–667. doi:10.1016/S0006-3223(01)01354-3 [CrossRef]11955466
- Haraldsson HM, Ferrarelli F, Kalin NH, Tononi G. Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review. Schizophr Res. 2004;71(1):1–16. doi:10.1016/j.schres.2003.10.006 [CrossRef]15374567