Data indicate that depression is the most common mental illness, often with debilitating consequences, and although current treatments—including psychotherapy and drugs—are effective for a majority of patients, many do not achieve optimal results and/or experience undesired side effects. For this patient population, alternative therapies are needed.


Analyzing the Effects

For a large network meta-analysis published in BMJ, Julian Mutz, MSc, and colleagues aimed to assess the effectiveness of non-surgical brain stimulation techniques for the acute treatment of major depressive episodes in adults. The researchers performed a systematic search of multiple electronic databases for clinical trials that examined the clinical efficacy and acceptability of 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 among randomly allocated participants. They examined data from 113 clinical trials consisting of 6,750 patients (mean age 47.9 years; 59% women). “This is the most comprehensive review of such treatments carried out to date,” notes Mutz.

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 of low (34%), unclear (50%), or high (17%) risk of bias, and the precision of summary estimates for treatment effect varied considerably.

Ten out of 18 treatment strategies were associated with higher response compared with sham therapy (Table): bitemporal ECT (summary odds ratio [OR] 8.91), high dose right unilateral ECT (OR; 7.27), priming transcranial magnetic stimulation (OR 6.02), magnetic seizure therapy (OR; 5.55), bilateral rTMS (OR; 4.92), bilateral theta burst stimulation ( OR; 4.44), low frequency right rTMS (OR; 3.65), intermittent theta burst stimulation (OR; 3.20), high frequency left rTMS (OR; 3.17), and tDCS (OR; 2.65).

“Briefly, we found that bitemporal electroconvulsive therapy (ECT), high-dose right unilateral ECT, high-frequency left repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were more effective than sham therapy across all outcome measures in the network meta-analysis,” says Mutz. He adds that the most remarkable finding was the high level of effectiveness for many of the treatments. “The clinical trials that we included in our analyses recruited patients who were severely depressed and who had not responded to multiple drugs or psychotherapy,” he says.


Response & Discontinuation Rates

Bilateral rTMS, low-frequency right rTMS, high-frequency left rTMS, and tDCS had the narrowest confidence intervals for response rates in the study. “There is less uncertainty regarding these effect size estimates,” says Mutz.

Upon examining all-cause discontinuation rates (eg, drop out of the clinical trial for any reason) as a measure of overall treatment acceptability, Mutz and colleagues did not find active treatments to be associated with higher drop-out rates than sham therapy. However, they did not examine specific undesired side effects or adverse cognitive effects in their work, noting that more systematic studies are needed. They add that it is also crucial to further investigate clinical or biological markers of treatment response to identify individuals for whom these treatments might be most beneficial.

Mutz asserts that the main take-home messages for clinicians are that non-surgical brain stimulation treatments should be considered as alternative or add-on treatments for severe depression in patients who have not responded to drug treatments. He suggests that treatment protocols with robust evidence and more precision in treatment effect estimates (eg, high-frequency left rTMS) should be prioritized over novel protocols with a more limited evidence base.

“We are not arguing that brain stimulation should replace standard treatments, but that these treatments could be considered earlier in the treatment course,” says Mutz.