Consider non-surgical brain stimulation for major depression — trials review

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WomanNon-surgical brain stimulation techniques, such as electro-convulsive therapy and repetitive transcranial magnetic stimulation, should be considered as alternative or add-on treatments for adults with major depressive episodes, concludes a study by  Institute of Psychiatry, Psychology & Neuroscience at Kings College London, which analysed 113 clinical trials.

The findings also suggest that more established techniques should take priority over new treatments with a more limited evidence base.

Depression is a common and debilitating illness that is usually treated with drugs and psychological therapies. But these treatments do not work for every patient and some patients experience undesired side effects.

Non-surgical brain stimulation techniques, such as electro-convulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), use electrical currents or magnetic fields to change brain activity. No-one is entirely sure how these treatments work, but for example rTMS is thought to change activity in areas of the brain that are under or overactive in depression.

Although guidelines support the use of these techniques, they tend to be used too little and too late, and previous research into their effectiveness has been limited.

A team led by Julian Mutz at the Institute of Psychiatry, Psychology & Neuroscience at Kings College London, set out to compare response (clinical efficacy) and all cause discontinuation (acceptability) of non-surgical brain stimulation for the treatment of major depressive episodes in adults.

They analysed the results of 113 clinical trials involving 6,750 patients (average age 48 years; 59% women) with major depressive disorder or bipolar depression, randomised to 18 active treatment strategies or inactive (“sham”) therapy.

Active techniques included electroconvulsive therapy (ECT), transcranial magnetic stimulation (rTMS), magnetic seizure therapy, and transcranial direct current stimulation (tDCS). Each trial was also scored as having low, high, or unclear risk of bias.

The most common treatment comparisons were high frequency left rTMS and tDCS versus sham therapy, whereas more recent treatments (such as magnetic seizure therapy and bilateral theta burst stimulation) remain understudied.

The quality of the evidence was of low (34%), unclear (50%) and high (17%) risk of bias and the precision of treatment effect estimates varied considerably, with higher levels of uncertainty for new treatments.

The researchers found that bitemporal ECT, high dose right unilateral ECT, high frequency left rTMS and tDCS, were more effective than sham therapy across all outcome measures in network meta-analysis.

For all active treatment strategies, patients were no more likely to discontinue treatment than when they received sham therapy. There were few differences in all cause discontinuation rates between active treatments.

The researchers point to some limitations. For example, a large number of studies carried an unclear risk of bias, and a focus on short term effects meant results may not apply to the long-term antidepressant effects of non-surgical brain stimulation. What’s more, the study did not examine specific undesired side effects.

However, they say their findings have implications for clinical decision making and research “in that they will inform clinicians, patients, and healthcare providers on the relative merits of multiple non-surgical brain stimulation techniques.”

The findings also highlight important research priorities in the specialty of brain stimulation, such as the need to conduct further randomised controlled trials for novel treatment protocols, they conclude.

Abstract
Objective: To estimate the comparative clinical efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults.
Design: Systematic review with pairwise and network meta-analysis.
Data sources: Electronic search of Embase, PubMed/Medline, and PsycINFO up to 8 May 2018, supplemented by manual searches of bibliographies of several reviews (published between 2009 and 2018) and included trials.
Eligibility criteria for selecting studies: Clinical trials with random allocation to electroconvulsive therapy (ECT), transcranial magnetic stimulation (repetitive (rTMS), accelerated, priming, deep, and synchronised), theta burst stimulation, magnetic seizure therapy, transcranial direct current stimulation (tDCS), or sham therapy.
Main outcome measures: Primary outcomes were response (efficacy) and all cause discontinuation (discontinuation of treatment for any reason) (acceptability), presented as odds ratios with 95% confidence intervals. Remission and continuous depression severity scores after treatment were also examined.
Results: 113 trials (262 treatment arms) that randomised 6750 patients (mean age 47.9 years; 59% women) with major depressive disorder or bipolar depression met the inclusion criteria. The most studied treatment comparisons were high frequency left rTMS and tDCS versus sham therapy, whereas recent treatments remain understudied. The quality of the evidence was typically of low or unclear risk of bias (94 out of 113 trials, 83%) and the precision of summary estimates for treatment effect varied considerably. In network meta-analysis, 10 out of 18 treatment strategies were associated with higher response compared with sham therapy: bitemporal ECT (summary odds ratio 8.91, 95% confidence interval 2.57 to 30.91), high dose right unilateral ECT (7.27, 1.90 to 27.78), priming transcranial magnetic stimulation (6.02, 2.21 to 16.38), magnetic seizure therapy (5.55, 1.06 to 28.99), bilateral rTMS (4.92, 2.93 to 8.25), bilateral theta burst stimulation (4.44, 1.47 to 13.41), low frequency right rTMS (3.65, 2.13 to 6.24), intermittent theta burst stimulation (3.20, 1.45 to 7.08), high frequency left rTMS (3.17, 2.29 to 4.37), and tDCS (2.65, 1.55 to 4.55). Network meta-analytic estimates of active interventions contrasted with another active treatment indicated that bitemporal ECT and high dose right unilateral ECT were associated with increased response. All treatment strategies were at least as acceptable as sham therapy.
Conclusions: These findings provide evidence for the consideration of non-surgical brain stimulation techniques as alternative or add-on treatments for adults with major depressive episodes. These findings also highlight important research priorities in the specialty of brain stimulation, such as the need for further well designed randomised controlled trials comparing novel treatments, and sham controlled trials investigating magnetic seizure therapy.

Authors
Julian Mutz, Vijeinika Vipulananthan, Ben Carter, René Hurlemann, Cynthia HY Fu, Allan H Young

BMJ material
BMJ abstract


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