Noninvasive Brain Stimulation Effective in Resistant Depression

Batya Swift Yasgur, MA, LSW

April 01, 2019

Nonsurgical brain stimulation is a viable alternative or add-on treatment for major depressive disorder (MDD) in adults, new research suggests.

Investigators reviewed 113 clinical trials that randomized over 6700 patients (average age 48 years, approximately half women) with MDD or bipolar depression to an array of nonsurgical stimulations or sham therapy, focusing on response (efficacy) and all-cause discontinuation (acceptability).

Stimulations included electroconvulsive therapy (ECT), several types of transcranial magnetic stimulation (TMS), theta burst stimulation, magnetic seizure therapy, and transcranial direct current stimulation (tDCS).

Although the quality of some of the evidence was low and the precision of treatment effect estimates varied considerably, the researchers nevertheless found that several types of ECT as well as high-frequency left repetitive TMS (rTMS) and tDCS were more effective than sham therapy in improving depressive symptoms.

Patients were no more likely to discontinue treatment when receiving active therapy than those receiving sham therapy.

"The main take-home messages are that nonsurgical brain stimulation treatments should be considered as alternative or add-on for severe depression in patients who have not responded to drug treatments," lead author Julian Mutz, doctoral researcher, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK, told Medscape Medical News.

"Treatment protocols with robust evidence and more precision in treatment effect estimates should be prioritized over novel protocols with a more limited evidence base," he said.

The study was published online March 27 in BMJ.

Ongoing Uncertainty

"Depression is a common and debilitating illness and current treatments, including psychotherapy and drugs, are effective but do not work for every patient — and some patients experience undesired side effects," said Mutz.

"Nonsurgical brain stimulation techniques have been applied as tertiary treatments for major depressive episodes and over the past decade, novel modifications of standard rTMS have been developed to optimize treatment," the authors state.

These include deep, priming, accelerated, or synchronized TMS and theta burst stimulation.

Clinical trials have also examined the efficacy of tDCS and magnetic seizure therapy.

Previous meta-analyses examining the clinical efficacy of brain stimulation versus sham therapy provide limited insights.

Additionally, lack of head-to-head clinical trials creates uncertainty for decision makers.

For this reason, the researchers used a network meta-analysis that included both direct and indirect treatment comparisons.

"There is an ongoing need to further develop new treatments, and the main objective was to estimate the clinical efficacy and acceptability of nonsurgical brain stimulation for the acute treatment of major depressive episodes in adults," Mutz explained.

Researchers examined randomized controlled trials with a parallel-group or crossover design that compared two or more of the following: tDCS, theta burst stimulation, TMS (repetitive, accelerated, priming, deep, or synchronized), ECT, magnetic seizure therapy, or sham therapy.

Participants were adults 18 years and older and all studies had to include a clinician-administered depression rating scale.

Studies examining vagus nerve stimulation or in which drug or psychological treatments were co-initiated together with brain stimulation were excluded.

Multiple Stimulation Types

The 113 randomized controlled trials (262 treatment arms) included in the analysis consisted of a total of 6750 participants (mean age, 47.9 years; 59% female) who were randomized to treatment.

Only a small number of trials looked at recent treatment modalities, including accelerated TMS, priming TMS, bilateral theta burst stimulation, and continuous theta burst stimulation, as well as sham controlled ECT, reflecting novelty and the ethical challenges of administering sham ECT, the authors note.

Of the included studies, 34% were considered at low risk for bias, 50% at unclear risk, and 17% at high risk.

Most trials (81%) recruited only patients with treatment-resistant depression (TRD), typically defined as a minimum of two failed drug treatments. However, 13% recruited patients with both TRD and non-TRD, and the remaining 6% recruited patients with non-TRD.

Over half (59%) of the studies excluded patients with psychotic features, and 49% recruited patients with MDD only. For the trials that recruited patients with both MDD and bipolar depression (46%), most had a diagnosis of MDD. Baseline depression severity, gender, and age were similar across most treatment comparisons.

Changes in continuous depression severity score of the various sham interventions pre–post treatment were medium to large, with no evidence for subgroup differences between sham groups.

In the pairwise analysis, bitemporal ECT, high-frequency left rTMS, low-frequency right rTMS, tDCS, and deep transcranial magnetic stimulation were found to be more efficacious than sham therapy across all outcomes (response: summary odds ratio, 1.69 [minimum] to 5.50 [maximum]; remission: 2.24 to 5.54; continuous post-treatment depression severity: standardized mean difference, −0.29 to −0.77).

Bilateral rTMS was more efficacious than sham therapy for response and remission, while intermittent theta burst stimulation was more efficacious than sham therapy in terms of response.

Few Differences

On the whole, the researchers found few differences between active treatments. However, bitemporal ECT was more efficacious than low-to-moderate dose right unilateral ECT across all outcomes.

No differences were found between active treatments and sham therapy for all-cause discontinuation.

The network meta-analysis found most treatments (bitemporal ECT, high-dose right unilateral ECT, priming TMS, magnetic seizure therapy, bilateral rTMS, bilateral theta burst stimulation, low-frequency right rTMS, intermittent theta burst stimulation, high-frequency left rTMS, and tDCS) to be more efficacious than sham therapy.

All treatments were at least as acceptable as sham therapy, as shown by similar dropout rates.

Treatments with the highest probabilities of being the most efficacious in terms of response were bitemporal ECT (37%) and priming TMS (19%). Low-frequency left rTMS and continuous theta burst stimulation were least efficacious (30% each).

Bitemporal ECT and high-dose right unilateral ECT had the highest mean ranks (2.6 and 4.0, respectively) compared with sham and continuous theta burst stimulation, which had the lowest mean ranks (17.4 and 16.5, respectively).

For all-cause discontinuation, priming TMS (42%) and bilateral theta burst stimulation (23%) had the highest probabilities of being the most accepted, compared with low-frequency left rTMS (28%) and high-frequency right rTMS (24%), which had similar probabilities of being least accepted.

"Our work provides a comprehensive and up to date overview of the available evidence from randomized clinical trials and informs clinicians on the relative merits of these treatments for adult patients with major depressive episodes," Mutz said.

One Size Doesn't Fit All

Commenting on the study for Medscape Medical News, Donald Malone, Jr, MD, professor and chair, Department of Psychiatry and Psychology, and president, Lutheran Hospital, Cleveland Clinic, Ohio, who was not involved with the study, said that, "unfortunately, it [is] not a huge contribution [because] it basically assembles all of the known studies, which is a large task."

The problem, he noted, is that each subject population is unique and not easily compared.

"Moreover, these large meta-analyses are only worth the quality of the studies they assemble, [and] as noted by the authors, many of the studies aren't all that rigorous," said Malone, who is also the past president of the International Society of ECT and Neurostimulation.

"Although the conclusions regarding ECT and TMS seem to be reasonable, there is certainly nothing new," he concluded.

Also commenting on the study for Medscape Medical News, Helen Mayberg, MD, director, Center for Advanced Circuit Therapeutics and professor of neurology, neurosurgery, psychiatry, and neuroscience, and Mount Sinai professor of neurotherapeutics, Icahn School of Medicine, New York City, who was not involved with the study, said that "it is good to see the efficacy of these treatments summarized, and clearly they are effective in patients who are resistant to standard pharmacotherapy and psychotherapy."

She noted that the analysis did not evaluate durability of the sustained treatment response/remission, which was acknowledged by the authors, and that "getting people out of [a depressive] episode is a first step, but keeping them well is the long-term goal.

"This is especially important since, with increasing treatment resistance, relapse is the rule, not the exception.

"What is needed are biomarkers to guide treatment selection in TRD patients, sustainability of response once achieved by treatment type, and likelihood of recapturing response/remission after relapse," she said.

"We can't assume that one size fits all," she noted.

The authors said that their findings also highlight important research priorities in the specialty of brain stimulation, such as the need to conduct further randomized controlled trials for novel treatment protocols.

Mutz has reported receiving funding for this study from the German National Academic Foundation, the International Master in Affective Neuroscience program of Maastricht University, and the University of Florence, and for other work from the Biotechnology and Biological Sciences Research Council and Eli Lilly. Disclosures for the other authors are listed in the article. Mayberg has reported licensing the intellectual property of her group's research on deep brain stimulation to Abbott Labs and receiving support to study deep brain mechanisms with next-generation devices from the National Institutes of Health. Malone has reported no relevant financial relationships.

BMJ. Published online March 27, 2019. Full text

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