The use of TMS in depression resistant to other treatments is supported by inconsistent efficacy results and its assumed equivalence to another therapy, ECT, which itself is supported by inconsistent research results and has many unresolved clinical questions. Reviews agree on the inconclusive findings of available TMS research and the corresponding inability to draw firm efficacy or cost-effectiveness conclusions, while other writers characterize TMS for depression as “established” (Edelmuth, 2010). This range of interpretation confirms the uncertainty surrounding TMS.
The presence of randomized controlled trials and systematic review titles in this body of literature misleads the casual reader; the former often use problematic cross-over designs (Lathyris ,2007; Curtin, 2002), have inconsistent restrictions for concurrent antidepressant use, rely on small samples with limited follow-up, and lack other attributes of high quality research, such as reporting of randomization methods and blinding. Reviews can only be as definitive as primary studies allow.
The list of ongoing trials (Table 2) indicates overriding concerns for the research agenda implicit in the list of ongoing trials below, which are the need for more rigorous research, better reporting, and more careful editing by journals. The range of issues for in-progress research suggests that Martin’s 2003 characterization of TMS, as a technology in search of clinical application, remains valid, while even technical refinement for depression remains incomplete.
To borrow from two recent reviews (both detailed in Appendix Table 3) and for which conclusions have not been changed by more recently published research:
…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...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.‖ (Couturier, 2005).
Today, the total number of patients included in studies of the efficacy of rTMS falls far short of the numbers registered in trials for new drug treatments. In addition, many details, such as where to stimulate, at what frequency, the total number of stimuli and the duration of treatment, have yet to be resolved. There is an urgent need for thorough, randomized, controlled, multicenter studies involving large numbers of patients. Another problem is the lack of consensus about possible explanatory mechanisms for any anti-depressant effects of TMS, but this is also the case for many other treatments in psychiatry. Repetitive TMS research is largely empirical: many variables play a role and a large number of parameters have to be explored carefully to find the most efficacious treatment.
Repetitive TMS clearly has effects on the brain, an observation that is remarkable in itself and it may well be that it is a treatment modality in search of a suitable application in psychiatry. It is of utmost importance, therefore, that the long and difficult path of research for potential clinical applications of rTMS in affective disorders should continue.‖ (Martin, 2003).
FDA clearance of one TMS device for marketing (October, 2008) catalyzed the request for this review. Documents accessible at www.fda.gov are not organized for explicit alignment between research findings and FDA decisions, although substantial equivalence to “predicate device” ECT is clearly noted, as are trials with positive results.
Finally, Nelson (2009; Appendix Table 3) identifies TMS as a “decrementally cost-effective” innovation versus ECT, i.e., one adopted as cost saving but without clearly improved outcomes. TMS investigators note the attraction of its less medieval aura compared to ECT, but unresolved issues continue to parallel those noted by Greenhalgh (2005; Appendix Table 3) in a research agenda for ECT. Clearly, better treatments for depression are needed, as is research on patient preferences and acceptability of TMS versus alternatives. While studies purporting to model cost-effectiveness of TMS have been published (Kozel, 2004), the inconsistent effectiveness information and uncertainty regarding optimal technical parameters make such analyses premature.
