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Technology Evaluation
Center (TEC)


TRANSCRANIAL MAGNETIC STIMULATION FOR DEPRESSION

EXECUTIVE SUMMARY

Background:  Depression is a serious psychiatric condition that sometimes does not respond to standard treatments such as medication and/or psychotherapy.  Transcranial magnetic stimulation (TMS) has been studied in patients with depression.  The U.S. Food and Drug Administration (FDA) granted de novo marketing clearance for a specific TMS device for patients who have not responded to one adequate trial of antidepressant medication. 

Objective:  This Assessment will review the available evidence to determine if TMS therapy is effective for the treatment of depression.

Search methods:  A search of the MEDLINE® database (via PubMed) was completed for the period up through January 2011.  The search strategy used the terms “transcranial magnetic” and “depression” as textwords or subject terms.  Articles were limited to those published in English language and enrolling human subjects.  The MEDLINE® search was supplemented by an examination of article bibliographies and relevant review articles, which were searched for citations. 

Study selection:  The search was intended to review sham-controlled studies of TMS.  To that end, meta-analyses of such trials were searched for and selected.  The 6 most recent meta-analyses were selected for presentation.  In light of FDA de novo 510(k) marketing clearance of a specific TMS device, the clinical trial of that device was selected for detailed presentation.  We also selected sham-controlled trials published subsequent to that study which have not been included in prior meta-analyses that evaluated the use of TMS in treatment-resistant patients.

Main results:  The largest and most recent meta-analysis included 30 double-blind sham-controlled trials with a total of 1,383 patients.  All the meta-analyses have some common limitations.  All of the studies assess outcomes at the time of the end of TMS treatment, which is between 1 and 4 weeks.  Only a few of the meta-analyses attempted to synthesize the relatively few studies that assessed outcome beyond the acute treatment period; but these periods tended to be short (i.e., 1 to 2 weeks post-treatment).  The studies analyzed within each meta-analysis varied with respect to the anatomic location of treatment, treatment intensity, stimulation frequency, pulses per session, and total number of sessions.

Five of the 6 meta-analyses found statistically significant depression scores between TMS and sham when analyzing the main set of studies.  The one meta-analysis that did not find a statistically significant difference had very strict selection criteria and, as a consequence, included only 6 studies with a total of 88 patients.  Three of the meta-analyses summarized the individual studies using the standardized mean difference (SMD).  The summary SMD for 2 of these meta-analyses was very similar: 0.39 and 0.35.  The SMD allows pooling together studies with different outcome assessment methods, but does not allow an easy translation to measures of clinical response and remission.  The one meta-analysis that pooled response and remission rates calculated a clinical response difference of 17% and a clinical remission difference of 14%.  However, these differences arise from relatively low response and remission rates for TMS (25% response rate, 17% remission rate).

One meta-analysis compared the effect of TMS in studies evaluating patients with treatment-resistant and nontreatment-resistant depression, and found no difference in effect.  In sum, the meta-analyses of sham-controlled studies of TMS are consistent with a short-term antidepressant effect of TMS of uncertain clinical significance.  The studies give no information regarding the durability of the effect beyond the treatment period, which was generally between 1 and 4 weeks.  The outcome measures used in the meta-analyses make it difficult to assess the clinical significance of the antidepressant effect in terms of response or remission rates.

The randomized trial reviewed in detail here is the largest sham-controlled trial of TMS with 301 evaluable subjects.  The primary outcome was evaluated at 4 weeks and showed a 2.1-point difference on the Montgomery and Asberg Depression Rating Scale (MADRS), which was not statistically significant.  Other outcomes evaluated at 4 weeks using other depression scales and a comparison of the difference in response rates showed a statistically significant difference.  Remission rates did not differ between treatment arms at 4 weeks using any of the depression scales.  At 4 weeks, patients who did not have a response to treatment could drop out of the study to enter an open-label treatment extension study.  Due to a high proportion of imputed values beyond 4 weeks, results of the study beyond 4 weeks may not be reliable.  Sensitivity analyses using imputed values rather than last-value-carried-forward values showed no difference in mean depressions scores using any of the scales at 6 weeks.

A subgroup analysis of the clinical trial showed an interaction with amount of prior treatment failure.  Treatment effects appeared to be mostly restricted to the group of patients with one prior treatment failure.  Clinical response and remission rates were not reported for this subgroup analysis, however. 

The open-label extension study treated nonresponders to the randomized trial with 6 weeks of active TMS.  Mean change from baseline was greater than the randomized clinical trial, indicating either placebo effects or bias from expectations.  Response rates ranged from 26 to 42%, and remission rates ranged from 11 to 27%, depending on original treatment assignment and depression scale.  Given the open-label design and lack of a control group for the extension study, it is difficult to make inferences of effectiveness from this study.

A long term follow-up study of this clinical trial evaluated relapse and retreatment rates for patients who achieved at least partial response to trial or open-label TMS or sham.  TMS retreatment was needed in 38/99 patients, and 10/99 patients had a relapse of depression.  It is difficult to make conclusions regarding the durability of TMS treatment in this study, as all patients had initiated antidepressants and there was no control group.

In terms of safety, the major adverse effects of TMS are headache and pain or discomfort at the site of application of the device.  The clinical trial did not appear to cause significant adverse effects that could be attributed to TMS.  Other review articles examining the safety of TMS have not raised concerns about adverse effects beyond headache and pain or discomfort.

Recent clinical trials of TMS published subsequent to the publication of the FDA pivotal trial included one trial of TMS versus antidepressant treatment, 2 trials of TMS alone versus sham, and 5 trials of TMS versus sham with concurrent antidepressant treatment for both groups.  The trial of TMS versus antidepressant treatment showed no statistically significant differences between groups, but the study had weak statistical power and tended to favor antidepressant therapy.  The studies of TMS alone versus sham showed statistically significant differences in favor of TMS, but outcomes were only assessed at the end of TMS treatment.  The studies of TMS versus sham with concurrent antidepressant treatment did not show statistically significant differences at the last follow-up assessments, which ranged from 4 to 12 weeks post treatment.

Authors’ comments and conclusions:  The meta-analyses and recent clinical trials of TMS generally show statistically significant effects on depression outcomes at the end of the TMS treatment period.  However, there is a lack of rigorous evaluation beyond the period of treatment.  Although short-term studies are consistent with changes in depression scores due to TMS, the clinical significance and durability of the effect are not well characterized.  More recent studies which have evaluated long term outcomes in randomized patients have not shown statistically significant differences at the later time points, but such studies have been relatively small and are likely statistically underpowered.  The largest randomized, clinical trial showed a greater effect in patients with only one prior treatment failure, with possibly minimal or no effect in patients with greater than one prior treatment failure.  One meta-analysis indicated no difference in effect between patients with treatment-resistant and nontreatment-resistant depression. 

The indication for which TMS received approval, one prior failure of an adequate antidepressant course, is unusual.  A change in antidepressant therapy is usually indicated at this point and has been shown to have a success rate similar to the first course.  The current body of evidence cannot determine in a rigorous way whether TMS would be as effective as a second course of antidepressant therapy.  Other important gaps in current knowledge include whether TMS is effective as an adjunctive treatment to second-line drug therapy, the durability of TMS treatment, and the effectiveness of retreatment.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether TMS for the treatment of depression meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria. 

1.         The technology must have final approval from the appropriate governmental regulatory bodies.

Devices for transcranial stimulation have received clearance by the U.S. Food and Drug Administration (FDA) for diagnostic uses. One device, NeoPulse (Neuronetics, Atlanta, GA) received approval in Canada and Israel as a therapy for depression. Although initially examined by the U.S. Food and Drug Administration (FDA) under a traditional 510(k) application, the NeoPulse, now known as NeuroStar® TMS, received 510(k) clearance for marketing as a “de novo” device (assessed as low risk, no predicate device) in 2008. NeuroStar® TMS is indicated for the treatment of patients with depression who have failed one 6-week course of antidepressant medication.

2.         The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

An important limitation of the evidence is lack of information beyond the acute period of treatment.  Most of the clinical trials evaluate the outcomes at the point of the last TMS treatment, between 1 and 4 weeks.  Very few studies evaluated patients beyond this time period.  Recent clinical trials have not shown statistically significant results at follow-up points out to 12 weeks beyond treatment.  Although meta-analyses are consistent with short-term antidepressant effects, the clinical significance of the effect is uncertain.  The large clinical trial of TMS reviewed in this assessment did not unequivocally demonstrate efficacy, as the principal endpoint was not statistically significant at 4 weeks, and some results were sensitive to the methods of analysis.  A subsequent clinical trial using the same device and similar treatment protocol showed statistical significance and the remission of depression at the end of TMS treatment.  The patients in whom TMS is indicated are usually treated with a second course of antidepressant therapy.  The clinical trial, which was sham controlled without active treatment, cannot determine whether TMS would be more or less successful than this standard treatment.

3.         The technology must improve the net health outcome; and

4.         The technology must be as beneficial as any established alternatives.

The available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives.  Comparison to alternatives using other observational studies may not be valid due to unmeasured differences in severity of depression between studies and other differences in studies.

5.         The improvement must be attainable outside the investigational settings.

It has not yet been demonstrated whether TMS improves health outcomes in the investigational setting.  Therefore, it cannot be demonstrated whether improvement is attainable outside the investigational settings.

For the above reasons, transcranial magnetic stimulation for the treatment of depression does not meet the TEC criteria.