'Deep' TMS Beats Standard TMS, Meds for Severe Depression

Batya Swift Yasgur, MA, LSW

July 31, 2019

"Deep" repetitive transcranial magnetic stimulation (rTMS) plus standard antidepressant medication is significantly more effective at reducing depression levels in patients with major depressive disorder (MDD) than standard rTMS or stand-alone pharmacotherapy, new research suggests.

In a randomized study, almost 230 participants with treatment-resistant depression (TRD) received either rTMS using an H1-coil (deep rTMS) plus pharmacotherapy, rTMS using a figure-8-coil (standard rTMS) plus pharmacotherapy, or self-standing pharmacotherapy.

Both rTMS protocols, in conjunction with pharmacotherapy, were superior to treatment with pharmacotherapy alone. In addition, secondary analysis showed significantly greater efficacy of rTMS delivered with the H1-coil vs the figure-8-coil.

Both rTMS modalities were comparably safe. No patients dropped out of the study because of adverse events.

"Although the standard H1-coil protocol uses a smaller number of pulses and has a shorter duration of session, it seems to induce a clinical effect that is at least of the same magnitude, and is in fact likely to be greater" than the figure-8-coil, lead author Igor Filipčić, MD, PhD, Psychiatric Hospital "Sveti Ivan" and the School of Medicine, University of Zagreb, Croatia, told Medscape Medical News.

"Our findings suggest an additive and clinically meaningful effect of concurrent rTMS and pharmacotherapy, greater than either treatment alone," added Filipčić, who is also on the Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Croatia.

The findings were published in the July issue of the Journal of Psychiatric Research.

Treatment Resistance

"It has been estimated that 20%–40% of patients with MDD do not benefit adequately from available interventions, including pharmacotherapy and psychotherapy," the authors write. rTMS "is a non-invasive treatment method that modulates brain electrical activity by electromagnetic induction. High-frequency rTMS (HF-rTMS) [is] applied at 10–20 Hz to the left dorsolateral prefrontal cortex."

In previous studies, figure-8-coil HF-rTMS showed efficacy vs sham treatment in improving symptoms of depression in patients with TRD.

A novel form of "deep TMS" (dTMS) using an H1-coil protocol has been approved by the US Food and Drug Administration (FDA) for treating MDD in adults whose condition does not respond to antidepressant medications in the current episode.

The H1-coil methodology delivers dTMS that targets the PFC bilaterally with preference for the left hemisphere, "where at any depth the model field is higher in the left relative to the right hemisphere," the investigators write.

"rTMS delivered with the H1-coil...allows noninvasive stimulation of brain regions to a depth that has been estimated to reach approximately 4 cm," Filipčić said.

There are few data on the safety and efficacy of dTMS. One large randomized trial has been conducted in medication-free adults. No head-to-head trial has compared the two different modalities.

To address this "knowledge gap," the researchers evaluated and compared the efficacy and safety of the two protocols. They compared both interventions as augmentive in the acute treatment of MDD, and they compared both to self-standing pharmacotherapy.

The previous trial was industry sponsored, Filipčić pointed out.

"It is worth noting that the [current] study is manufacturer independent and free of any commercial incentives to investigators of patients," he said.

Discontinuation, Remission Rates

Patients with MDD (n = 228) were randomly assigned in a 1:1:1 ratio to a 4-week treatment regimen with either H1-coil or figure-8-coil, along with standard pharmacotherapy.

Baseline demographic and clinical characteristics were comparable between the groups:

  • H1-coil (n = 72): 56.9% women; median age, 50 years; median duration of MDD, 10 years;

  • 8-coil (n = 75): 45.3% women; median age, 51 years; median duration of MDD, 7 years;

  • Control group (n = 81): 55.6% women; median age, 53 years; median duration of MDD, 9 years.

At baseline, the medications most frequently used were selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, followed by other antidepressants and antipsychotics. The percentages at which these medications were used was comparable for all three groups.

Roughly 40% in each group were also taking a benzodiazepine.

Both rTMS protocols were administered 5 days per week for 4 weeks (20 sessions total).

All-cause discontinuation rates were lowest in the 8-coil group (4%), compared to the H1-coil and the control group (9.7% and 11%, respectively).

The Hamilton Depression Rating Scale (HAM-D17) mean score was 17 in the H1-coil and 8-coil groups and 19 in the control group.

The primary outcome was the proportion of patients who achieved remission, which was defined as having a HAM-D17 score of 7 or less.

Favorable Results

The number of patients who achieved remission was higher in the dTMS/H1-coil group (60%; 95% confidence interval [CI], 48% – 71%) and the rTMS/8-coil group (43%; 95% CI, 31% – 55%) than in the control group (11%; 95% CI, 5% – 20%).

However, after adjusting for all preplanned confounders, the remission rate (HAM-D17 of ≤7) was not significantly different between the two rTMS modalities, either in the intent-to-treat (ITT) or the per-protocol (PP) populations.

The odds ratio (OR) for remission in ITT analysis of the H1-coil group vs the 8-coil group was 1.74 (95% CI, 0.79 – 3.83; P = .17).

On the other hand, in the ITT population, patients with baseline moderate/severe depression (HAM-D17 ≥17) in the H1-coil group had significantly higher odds for remission compared with patients in the figure-8-coil group (OR, 4.59; 95% CI, 1.69 – 12.48; P = .003).

No significant differences were observed in ORs for remission between patients with mild depression (HAM-D17 <7) or other sociodemographic and clinical characteristics.

The response rate, defined as a decrease in HAM-D17 score of ≥50%, was significantly better in both active treatment groups than in the control group.

It was also significantly better in the H1-coil group than in the 8-coil group (67% vs 44%, respectively) after adjustment for all preplanned confounders.

Both HFrTMS modalities were generally well tolerated. No serious adverse events were reported; the most commonly reported adverse event in both rTMS groups was headache.

The authors note that treatment parameters of rTMS modalities, such as pulse frequency, number of pulses per session, and train duration, were not matched because the study was "pragmatic, with an intent to assess the effectiveness of commonly used FDA-approved protocols in clinical practice."

However, the results were "favorable, compared to short-term efficacy of other treatment approaches, especially considering the high level of treatment resistance of this population," they write.

Moreover, the treatment delivered by the H1 coil "may be more effective for treatment of MDD severity," they note.

Clear Clinical Implications

Commenting on the study for Medscape Medical News, Chris Baeken, MD, PhD, associate professor of psychiatry, Ghent University and the Free University, Brussels, Belgium, said the findings have a clear message for clinicians.

"If depressed patients do not or partially respond to the classic antidepressant medication, add-on or better augmentation with these neurostimulation [modalities] may be beneficial to a large group of them with a slightly better outcome for the H-1 dTMS coils compared to the more commonly used figure-8 coil," said Baeken, who was not involved with the research.

Filipčić agreed.

"While some questions remain for future studies, clear clinical implications can already be derived from these findings," he said.

"Firstly, both modalities of rTMS can safely be combined with pharmacotherapy to achieve a higher likelihood of remission; and secondly, both modalities are equally safe and tolerable," he added.

The study was funded by the Psychiatric Hospital "Sveti Ivan." The study authors and Baeken have disclosed no relevant financial relationships.

J Psychiatr Res. 2019;114:113-119. Abstract

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