Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review

Objectives: The therapeutic effects of transcranial magnetic stimulation
(TMS) and transcranial direct current stimulation in patients with
major depression have shown promising results; however, there is a lack
of mechanistic studies using biological markers (BMs) as an outcome.
Therefore, our aim was to review noninvasive brain stimulation trials
in depression using BMs.
Methods: The following databases were used for our systematic review:
MEDLINE, Web of Science, Cochrane, and SCIELO. We examined
articles published before November 2012 that used TMS and
transcranial direct current stimulation as an intervention for depression
and had BM as an outcome measure. The search was limited to human
studies written in English.
Results: Of 1234 potential articles, 52 articles were included. Only
studies using TMS were found. Biological markers included immune and
endocrine serum markers, neuroimaging techniques, and electrophysiological
outcomes. In 12 articles (21.4%), end point BM measurements
were not significantly associated with clinical outcomes. All studies
reached significant results in the main clinical rating scales. Biological
marker outcomes were used as predictors of response, to understand
mechanisms of TMS, and as a surrogate of safety.
Conclusions: Functional magnetic resonance imaging, single-photon
emission computed tomography, positron emission tomography, magnetic
resonance spectroscopy, cortical excitability, and brain-derived
neurotrophic factor consistently showed positive results. Brain-derived
neurotrophic factor was the best predictor of patients’ likeliness to respond.
These initial results are promising; however, all studies investigating
BMs are small, used heterogeneous samples, and did not take
into account confounders such as age, sex, or family history. Based on
our findings, we recommend further studies to validate BMs in noninvasive
brain stimulation trials in MDD.
Dr Fregni is granted by The Christopher and Dana Reeve Foundation, The Ruth Judy Goldberg Foundation, The National Institutes of Health, and by the American Heart Association.