TMS Approaches for Major Depression: Is There a Clear Winner?

Pauline Anderson

January 16, 2017

There are few differences in clinical efficacy and tolerability with different types of repetitive transcranial magnetic stimulation (rTMS) for major depression, new research shows.

A systematic review of randomized clinical trials comparing the efficacy and tolerability of rTMS modalities showed they were largely equal but, to some extent, favored bilateral rTMS and priming low-frequency rTMS in the treatment of major depressive disorder (MDD).

"In clinical practice, physicians often choose high-frequency stimulation because there have been more studies using this approach, but we can now say that this is not necessarily the case; physicians might also use other forms of stimulation such as bilateral and low frequency," lead author, Andre R. Brunoni, MD, PhD, Institute of Psychiatry, University of Sao Paulo, Brazil, told Medscape Medical News.

The findings were published online December 28 in JAMA Psychiatry.

No Head-to-Head Trials

The authors note that although several types of rTMS have been investigated in the treatment of MDD, little is known about their comparative efficacy.

TMS induces changes in brain activity according to the applied frequency. High-frequency (HF)-rTMS (usually ≥ 10 Hz) induces an increase, whereas low-frequency (LF)-rTMS (usually ≤ 1 Hz) has the opposite effect.

It's believed that depression is caused by hypoactivity of the left and hyperactivity of the right dorsolateral prefrontal cortex (DLPFC), so to change brain activity in this area and restore normal function in patients with resistant depression, HF-rTMS is applied to the left and LF-rTMS applied to the right DLPFC. Priming TMS (pTMS) is used to "prime" the brain with HF stimulation to optimize subsequent LF stimulation.

Some of the newer rTMS interventions include accelerated, deep, and synchronized rTMS.

Other, novel forms of rTMS therapy are also emerging. For example, deep (H coil) TMS over the left DLPFC uses a different coil format to stimulate deeper cortical and subcortical structures; low-field synchronized TMS (sTMS) theoretically performs a stimulation synchronized to an individual's alpha frequency; and theta-burst stimulation (TBS) uses short sessions to inhibit the right or stimulate the left DLPFC.

TBS sessions are only about 5 minutes long compared with other strategies that last at least 30 minutes because they require relatively lengthy intervals between stimulations to reduce the risk of seizures. TBS can be given at a higher frequency for longer periods and needs shorter intervals, said Dr Brunoni.

To compare various types of TMS and their impact on MDD, the investigators carried out a systematic review as well as a network meta-analysis (NMA). Dr Brunoni, noted this was the first NMA for rTMS in depression.

In contrast to a standard pairwise meta-analysis, an NMA allows the comparison of different rTMS interventions, even if they have not been directly compared in head-to-head trials.

The investigators searched various databases for randomized clinical trials (RCTs) that enrolled patients with a primary diagnosis of an acute unipolar or bipolar depressive episode and compared at least two types of rTMS.

The analysis included 81 studies, most of which were conducted between 2000 and 2010, with information on a total of 101 comparisons between nine different rTMS groups, including sham.

Of the 4233 patients included in the 81 studies, the mean age was 46 years and 59.1% were female. Most trials recruited only patients with treatment-resistant depression (74.1%), had performed 10 to 15 rTMS sessions (69.1%), and used rTMS as add-on therapy (69.1%) — often to antidepressant medication.

There were no important differences across the comparisons with respect to patients' age, baseline severity, sex distribution, and number of sessions.

Primary outcome measures were response rates, which were defined as a 50% or greater improvement from baseline according to the study's primary depression scale and acceptability, as indicated by the dropout rate.

The secondary outcome was remission rate, defined as a score of 7 or less on the Hamilton Depression Rating Scale (HDRS])-17, 8 or less on the HDRS-21, or 10 or less on the Montgomery-Asberg Depression Rating Scale.

Clinical Guidance

Investigators found that 21.0% of the studies had an overall low bias risk, 67.9% had an unclear bias risk (mainly because of imprecisions in reporting randomization or allocation procedures and/or imperfect blinding), and 11.1% had a high bias risk.

Dr Brunoni said he doesn't believe that the relatively large amount of imperfect blinding had a major influence on the review's results.

"When we compared more recent studies, which used very good blinding methods, with older studies that had less effective blinding, the results were basically the same."

Direct evidence from the standard pairwise meta-analysis showed that bilateral, HF- and LF-rTMS, and TBS, were significantly more effective than sham with respect to response (odds ratio [OR], 3.39 [95% confidence interval [CI], 1.91 - 6.02]; OR, 3.28 [95% CI, 2.33 - 4.61]; OR, 2.48 [95% CI, 1.22 - 5.05]; OR, 2.57 [95% CI, 1.17 - 5.62], respectively).

Priming TMS (pTMS) has not been directly compared with sham in terms of response. None of the active interventions appeared to perform better when contrasted with another active comparator.

In the NMA analysis, bilateral, HF and LF, as well as pTMS, appeared to be more effective than sham. Also, bilateral rTMS was more effective than sTMS.

The authors note the estimated relative ranking of treatments implied that pTMS and bilateral rTMS perform better among all rTMS interventions in terms of efficacy.

However, they add, the findings are imprecise for most comparisons, and so no definitive evidence of superiority could be supported for any particular intervention.

Nevertheless, as "all the techniques seemed to be equally effective," this should help "guide clinical practice," in that physicians can choose HF, LF, or bilateral TMS, or TBS with some degree of confidence, said Dr Brunoni.

As for acceptability, the evidence showed that all active interventions were similar to sham, indicating that they were all well-tolerated, said Dr Brunoni. This, he said, is an important finding.

"Antidepressants are often not acceptable and patients discontinue them; this didn't happen with TMS."

Looking at remission, the authors found similar results as for response, although they were "more uncertain."

The study results suggest that both bilateral stimulation and TBS "are promising techniques" and should be further studied, said Dr Brunoni.

However, some of the newer rTMS interventions, including accelerated, deep, and synchronized rTMS, were not more effective than sham.

This, said Dr Brunoni, may inform clinical practice as it shows that these newer methods — many of which have been subject to "hype" — are not better than the more classic approaches.

However, he stressed that since the findings were imprecise for most comparisons between TMS interventions because of the insufficient number of available studies, the review could not provide definitive evidence of superiority.

No Clear Winner

Commenting on the findings for Medscape Medical News, Mark S. George, MD,distinguished professor of psychiatry, radiology, and neuroscience, and director, brain stimulation laboratory, Medical University of South Carolina, Charleston, said the review's finding that TMS is effective is not new.

"There have now been over 15 meta-analyses of TMS for the treatment of depression, and all found that it works," said Dr George, a leader in the field who was involved in the first TMS studies almost 20 years ago that led to the treatment's approval by the US Food and Drug Administration.

What this new review tried to do was see if one approach is better than another, he said.

"TMS works, but we ought to be able to make it better. The original choice of parameters — where to stimulate and what rhythms to use — were really best guesses, and it's highly likely that there are better answers out there."

Although the new analysis did suggest that some approaches are more promising than others, "there is not an absolutely new clear winner."

There have been few head-to-head trials comparing the approaches the review found promising — bilateral and pTMS — to other approaches, according to Dr George.

He also pointed out that "who you put into a trial determines the outcome" and some of the trials in the analysis may have included more or less treatment-resistant patients.

"While they tried to control for that, it's really impossible without head-to-head trials," he said. "So the results here are interesting, but have to be viewed with a grain of salt because there really are no head-to-head trials."

Formal comparisons are needed "to see if the hints from this review of the literature really do stand up in clinical trials," he added.

Dr Brunoni is supported by grants from the Brain & Behavior Research Foundation, Sao Paulo State Foundation, and National Council for Scientific and Technological Development. He is a recipient of a research fellowship award from CNPq. The Laboratory of Neuroscience receives financial support from the Associação Beneficente Alzira Denise Hertzog da Silva. Dr George has no relevant conflicts of interest.

JAMA Psychiatry. Published online December 28, 2016. Full text

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