Repetitive Transcranial Magnetic Stimulation as an Augmentative Strategy for Treatment-resistant Depression

A Meta-analysis of Randomized, Double-blind and Sham-Controlled Study

Bangshan Liu; Yan Zhang; Li Zhang; Lingjiang Li


BMC Psychiatry. 2014;14(342) 

In This Article


Depression is a global severe disease. In a report of world health organization (WHO),[1] MDD ranked thirdly in global disease burden in 2004 and ranked firstly in moderate and high income countries. Unfortunately, even under the guidelines of the most competent specialists, more than 30% of patients cannot achieve a clinical response to an antidepressant regimen or psychotherapy;[2] these patients, which are called treatment-resistant depression (TRD) patients, exerted extremely severe burden on themselves and their families. So the treatment of TRDs has become one of the most important and pressing problem in psychiatry. With the development of neuroscience and psychiatry, we are now able to treat some TRDs with some physical method, such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation tDCS). Among these methods, ECT is the oldest and most effective while often criticized by the adverse effects of seizure induction and cognitive side effects,[3,4] and patients who accepted ECT treatment often have to bear the stigma on this therapy.[5] the limitations of ECT has resulted great interest in the two newly non-invasive neuromodulation methods: rTMS and tDCS, which are both of relatively low adverse effects and similar magnitude of antidepressant effects compared with antidepressant drugs.[6]

rTMS utilizes an electromagnet that generates local magnetic field pulses to modulate brain functions. It is believed that rTMS modulates the activity of local neural circuits by decreasing or increasing the excitability of cortical neurons, depending on the parameters of stimulation. Usually, frequency higher than 5Hz is considered to increase cortical excitability and frequency lower than 1Hz decrease.[7,8] In view of this function, researchers have studied the efficacy of rTMS on different psychiatric disorders, such as schizophrenia and depression, based on the hypothesis of alleviating psychiatric symptoms by modulating local brain activity. In 1995 George et al.[9] firstly tried to apply rTMS in the treatment of MDD. After that, numerous literatures about the efficacy of rTMS on MDD have been published. In these studies, the parameters of rTMS were most commonly set as high frequency stimulation focused on the left dorsal lateral prefrontal cortex (LDLPFC) and low frequency on the right dorsal lateral prefrontal cortex (RDLPFC).[10]

At present, several meta-analyses[11–26] have indicated that rTMS is effective for MDD patients. But most studies had focused on both treatment-resistant and non-resistant patients and had chosen continuous data, namely, change from baseline of HAMD or MADRS scores as the primary outcome except for the study reported by Lam et al.,[19] which focused on the treatment-resistant depression patients and chose dichotomous data, such as response rates and remission rates as the primary outcomes. The former kind of data tends to reserve the information of each RCT as much as possible, while the latter is easier for doctors and patients to understand. Nevertheless, the study by Lam et al. contained unexpected high heterogeneity, and included RCTs that designed rTMS as either monotherapy or augmentation to antidepressants, which may be on suspicion of mixing studies of great heterogeneity together.

In view of the above disadvantages of the previous meta-analyses, we designed this meta-analysis focused on RCTs which studied the efficacy of rTMS used as an augmentative strategy for antidepressants in treatment-resistant depression. The term "treatment-resistant" in this study is defined as failing to respond to at least one adequate antidepressant treatment,[27] the "adequate treatment" means the medication should have been taken for at least 4 weeks and the following dose levels were considered adequate: for tricyclic antidepressants a dose equivalent to impramine 200 mg daily; for SSRIs a dose equivalent to paroxetine 40 mg daily; for venlafaxine 225 mg daily; and for mirtazapine 60 mg daily.[28,29] And "augmentative" in this study means either combination of rTMS and stable antidepressant treatment or simultaneous association of medication regimen and rTMS. Response rates and NNT were chosen as the primary outcomes. The baseline of HAMD scores, remission rates and dropout rates were selected as secondary outcomes. We synthesized the data of RCTs meeting the inclusion criteria in order to reduce the complexity and contradictions of different RCTs with relatively small samples collected from available databases and literatures. Sensitivity and subgroup analyses were conducted further to explore the source of heterogeneity and potential factors which may influence the efficacy of rTMS on TRD.