Patterns of response to repetitive transcranial magnetic stimulation (rTMS) in major depression: Replication study in drug-free patients

Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Journal of Affective Disorders (Impact Factor: 3.38). 06/2008; 108(1-2):59-70. DOI: 10.1016/j.jad.2007.09.007
Source: PubMed


Repetitive transcranial magnetic stimulation (rTMS) has been found to exert modest to moderate therapeutic effects in major depression, but mechanism of action and its clinical relevance have not been clarified yet. Previous trials have reported patterns of symptomatology predicting response to rTMS. As most patients also received concomitant antidepressant medication these response patterns may rather refer to combined treatment than rTMS alone. Thus, this study aims to replicate previous findings and explore patterns of response in drug-free patients.
In the Munich-Berlin Predictor Study data of 79 patients from two open clinical trials evaluating effects of high-frequency rTMS of the left dorsolateral prefrontal cortex were pooled. Previous models predicting the response to rTMS [Fregni, F., Marcolin, M.A., Myczkowski, M., Amiaz, R., Hasey, G., Rumi, D.O., Rosa, M., Rigonatti, S.P., Camprodon, J., Walpoth, M., Heaslip, J., Grunhaus, L., Hausmann, A., Pascual-Leone, A., 2006. Predictors of antidepressant response in clinical trials of transcranial magnetic stimulation. Int. J. Neuropsychopharmacol. 9, 641-654; Brakemeier, E.L., Luborzewski, A., Danker-Hopfe, H., Kathmann, N., Bajbouj, M., 2007. Positive predictors for antidepressive response to prefrontal repetitive transcranial magnetic stimulation (rTMS). J. Psychiatr. Res. 41, 395-403.] were systematically tested and new explorative regression analyses were conducted.
Of the 79 patients, 34.2% showed an antidepressant response. Previous models could not be validated. Explorative regression analysis revealed a significant model with therapy resistance, HAMD items 1 (depressed mood), and 2 (feelings of guilt) as negative and retardation as positive predictors.
No controlled study; specific statistical issues; sample size; differences concerning patient population and stimulation parameters between study sites.
In sum, this study does not confirm clinical valid and robust patterns being predictive for a response to rTMS in depression. The only exception is a high level of therapy resistance being associated with poor outcome. Future predictor studies should focus on large and homogenous samples of rTMS multicenter trials and include neurobiological variables.

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    • "Different levels of treatment refractoriness and theta-burst stimulation outcomes Although repetitive TMS is indicated for patients with major depressive disorder who have failed to receive satisfactory improvement from previous antidepressant medication, one of the factors found to confound repetitive TMS antidepressant results is treatment refractoriness (Fregni et al., 2006; Brakemeier et al., 2008). That is, a positive history of treatment refractoriness was associated with worse repetitive TMS results. "
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    ABSTRACT: Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness.
    Brain 05/2014; 137(7). DOI:10.1093/brain/awu109 · 9.20 Impact Factor
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    • "In contrast Brakemeier et al. (2007) found that patients with worse sleep disturbance were more likely to respond to rTMS. Brakemeier et al. (2008) later repeated the analyses of these two studies in 79 patients free of antidepressants but could not replicate the finding that sleep disturbance was related to outcome. However, none of these studies took into account the presence of hypersomnia or that their insomnia score was part of their outcome measure. "
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    ABSTRACT: Treatment for depression is not effective in all patients and it is therefore important to identify factors that can be used to tailor treatments. One potential factor is insomnia. Several repetitive transcranial magnetic stimulation (rTMS) studies have reported on this symptom, however, they did not take into account the presence of hypersomnia or that insomnia was related to their outcome measure. Our aim was to investigate whether baseline sleep disruption was related to rTMS treatment response. We pooled data from four clinical trials using rTMS to treat depression, including 139 subjects in data analysis. Insomnia was measured using the Hamilton Depression Rating Scale (HamD) sleep questions and hypersomnia from the Beck Depression Inventory (BDI). To reduce the possible impact of insomnia on our treatment response outcome we created an adjusted HamD score which omitted sleep items. Sleep disturbances were common in our study: 66% had insomnia and 38% hypersomnia. Using regression analysis with our adjusted HamD score we found no relation between baseline insomnia or hypersomnia and rTMS treatment response. Our data are consistent with previous studies; however, this is the first rTMS study to our knowledge that has attempted to dissociate baseline insomnia from the HamD outcome measure and to report no relationship between hypersomnia and rTMS outcome.
    05/2013; 210(1). DOI:10.1016/j.psychres.2013.04.028
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    • "Trouble du sommeil plus prononcé sur HDRS. Brakemeier et al. [4] "
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    ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a brain stimulation technique that has been investigated as a novel treatment for psychiatric disorders, notably in major depression, and has shown statistically significant effects. The authors found it necessary to propose an up-to-date review of positive predictors for antidepressive response to repetitive transcranial magnetic stimulation. Based on an exhaustive consultation of Medline data, supplemented by a manual research, only works evaluating response factors of rTMS in major depression were retained. Twenty-nine studies were retained, including meta-analyses, reviews, randomized controlled trials and open trials. The most concordant data clearly indicate that a high score of treatment resistance, a long duration of current episode, advanced age, and psychotic symptoms are negative predictors for treatment response to rTMS. In the older patients, menopausal women are especially concerned. However, some parameters should be adapted to the degree of cortical atrophy such as intensity of stimulation or total number of rTMS sessions. Previous response to rTMS therapy seems to be a good predictor contrary to non-response to electroconvulsive therapy. Adjunctive antidepressant treatment shows greater responsiveness to rTMS contrary to benzodiazepine or anticonvulsant treatment. To our knowledge, no study compares unipolar and bipolar depression, the profile of depression is not established yet. Imaging studies show that TMS antidepressant responders differed from non-responders in inferior frontal activity, at baseline, and even more so following treatment. Furthermore, reduced baseline cerebral metabolism in cerebellar, temporal, anterior cingulate and occipital regions of the brain was correlated with improvement after two weeks of fast (20Hz) left dorsolateral prefrontal cortex (DLPFC) rTMS. Additionally, a right frontal region emerges with divergent polarity in the metabolic prediction of response to low rTMS. Inhibiting right DLPFC or stimulating DLPFC shows similar results, the choice on the side of stimulation does not seem determining. Bilateral stimulation for the moment does not seem superior to unilateral stimulation. Parameters of stimulation associated with effectiveness of rTMS are an intensity of stimulation higher than 100% of the motor threshold, a number of stimulations per sessions superior to 1000, and a full number of days of treatment greater than 10. Parameters of stimulation must be adapted according to the treated patients. For example, older patients who present cortical atrophy need higher intensity of stimulation. Other criteria could influence effectiveness of rTMS in the same way. Would it be necessary, for example, to adapt the duration or the intensity of stimulation according to the severity of the depressive episode or its duration of evolution? Do antecedents of resistance to a pharmacological treatment oblige us to stimulate differently? Few studies exceed 10 days of treatment; will longer duration of treatment be more effective? Also, we did not find any data on the interest of maintenance treatment among responders. Should the characteristics of the depressive disorder or its evolution require maintenance treatment? What will be its rhythm and its duration? Should we adapt rTMS parameters to abnormalities highlighted by functional neuroimagery? The prospects for work remain numerous.
    L Encéphale 09/2012; 38(4):360-8. DOI:10.1016/j.encep.2011.08.004 · 0.70 Impact Factor
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