Summary: Researchers report intermittent theta burst stimulation can help to alleviate the symptoms of major depressive disorder. 49% of patients who received the treatment reported a significant decrease in symptoms, with 32% reporting remission of depression.
In the largest study of its kind, a three-minute version of a brain stimulation treatment was shown to be just as effective as the standard 37-minute version for hard-to-treat depression.
These results were published in a new Canadian study in The Lancet co-led by the Centre for Addiction and Mental Health (CAMH) and the University Health Network’s Krembil Research Institute, in collaboration with the University of British Columbia.
The treatment is called repetitive transcranial magnetic stimulation (rTMS), which is a form of treatment that uses magnetic field pulses to non-invasively stimulate a part of the brain called the dorsolateral prefrontal cortex, which is associated with mood regulation. The study compared standard rTMS treatment, which uses high frequency (10 Hz) brain stimulation for 37.5 minutes per session, with a newer form of rTMS called intermittent theta burst stimulation (iTBS), that mimics the brain’s natural rhythms and takes just over three minutes per treatment.
“The main impact of this study is that the number of people who are able to be treated using theta burst stimulation compared to the standard form of rTMS can be increased by three to four fold,” says lead author Dr. Daniel Blumberger, Co-Director of the Temerty Centre for Therapeutic Brain Intervention at CAMH.
“These findings will have a significant impact on our ability to treat patients,” says Dr. Jonathan Downar, Co-Director, University Health Network’s rTMS Clinic; Scientist, Krembil Research Institute and senior author of the study. “This will allow every device in Canada to treat several times more people per day, meaning shorter wait lists and better access to this treatment.”
The study, conducted with Dr. Fidel Vila-Rodriguez, Assistant Professor, University of British Columbia, focused on people with treatment-resistant depression, defined as a condition whereby people do not experience a sufficient improvement in their symptoms after trying antidepressant medications. Up to 40 per cent of people with depression may experience treatment resistance.
In the study, 414 participants were randomly allocated to receive either the standard form of rTMS treatment or the shorter iTBS treatment for five days a week for up to six weeks.
For 49 per cent of study participants who had the iTBS treatment, depression symptoms reduced significantly, with 32 per cent reporting a remission of depression symptoms. Those who received standard rTMS had a remission rate of 27 per cent. Those results are consistent with previous large-scale studies and meta-analyses over the past 20 years that have confirmed the efficacy and safety of the standard form of rTMS.
rTMS treatment was approved for treating depression by Health Canada in 2002 and by the U.S. Food and Drug Administration in 2008. Due to the cost of treatment (it is not covered by public health insurance outside Quebec and Saskatchewan), it has only been made available to a fraction of the estimated 600,000 Canadians living with treatment-resistant depression each year.
“rTMS has changed my life in so many ways,” says study participant Shelley Hofer, 43, who has had treatment-resistant depression for most of her life. “I really wish it had been around a long time ago because I believe it would have been my go-to treatment. In my personal opinion, I feel rTMS could improve the lives of so many people who are still struggling to find the answers to their own mental illness.”
Source: Sean O’Malley – CAMH
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Original Research: Abstract for “Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial” by Daniel M Blumberger, MD, Fidel Vila-Rodriguez, MD, Kevin E Thorpe, MMath, Kfir Feffer, MD, Yoshihiro Noda, MD, Peter Giacobbe, MD, Yuliya Knyahnytska, MD, Prof Sidney H Kennedy, MD, Prof Raymond W Lam, Prof Zafiris J Daskalakis, MD, Jonathan Downar, MD in The Lancet. Published April 28 2018.
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial
Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.
In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with , number .
Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·01, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208).
In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness.
Canadian Institutes of Health Research.