Doi:10.1016/j.eurpsy.2007.09.006

Available online at www.sciencedirect.com Transcranial direct stimulation and fluoxetine Keywords: Transcranial direct current stimulation; Fluoxetine; Brain stimulation; Electrical stimulation; Major depression; Treatment We compared the results of patients who received active and sham tDCS in a randomized, double-blind study as described in An increasing number of investigations on the use of inva- detail elsewhere In summary, the parameters of stimulation sive and non-invasive brain stimulation for the treatment of de- were: 2 mA of intensity for 20 min for 10 days (anodal electrode pression have been performed in the last decade on the left dorsolateral prefrontal cortex and cathode electrode We recently showed that a simple and powerful technique of on the contralateral supraorbital area). All patients were as- brain modulation e transcranial direct current stimulation sessed at baseline and after 2, 4, and 6 weeks after the onset (tDCS) e is effective to reduce depressive symptoms of treatment (tDCS or fluoxetine). Rating scales included the In tDCS, low amplitude direct currents are injected into the Beck Depression Inventory (BDI) and the 21-item Hamilton brain via scalp electrodes As shown by recent model- Depression Rating Scale (HDRS). In addition, we measured ing studies, a significant amount of electric current can reach general cognitive performance using the mini-mental state the brain using appropriately large electrodes and suitable examination (MMSE). Rating was performed by a trained and placements An important question is whether the anti- experienced psychologist (M.L.M.). We used a mixed linear depressant effects induced by tDCS are similar to those of model to analyze mood changes throughout the trial. We mod- standard medical treatment. We compared the findings of a par- eled mood change (as indexed by BDI and HDRS) using the allel-group, randomized, double-blind clinical trial investigat- covariates of time, group and interaction term between group ing the effects of active vs. sham tDCS with an open-label trial and time. Because the fluoxetine data were originated from an in which patients with similar clinical characteristics received open arm of this study, we used the BDI as the primary outcome to decrease the influence of the unblinded rater.
Forty-two patients with major depression participated in the (mean Æ SD)). Diagnosis of unipolar major depressive disor- der was confirmed by a licensed, senior clinical psychiatrist (S.P.R.) using the structured clinical interview for DSM-IV axis I disorders. Patients were required to be off medications (antidepressants) for 2 months prior to the trial. Exclusion cri- teria were neurological disorders, any comorbid axis I disor- participation. Furthermore, patients with major depression and psychotic features or axis II disorders were excluded.
Written, informed consent was obtained from all participants tDCS e transcranial direct current stimulation; DLPFC e dorsolateral prefron-tal cortex; HDRS before inclusion in the study, which was approved by the local e Hamilton Depression Rating Scale; SD e standard devi- ethics committee. The study was performed at the Psychiatric a As indexed by the number of failed antidepressants.
Institute of the University of Sao Paulo.
b p-Value e one-way ANOVA for continuous variables and Fisher’s exact 0924-9338/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.eurpsy.2007.09.006 Letter to the editor / European Psychiatry 23 (2008) 74e76 Fig. 1. Depression scores (as indexed by the Beck Depression Inventory (BDI)) change over time. BDI scores were assessed at baseline and after 2, 4 and 6 weeksof the treatment onset. Each point represents mean and error bars represent S.E.M.
Patients were moderately depressed (see characteristics in the fact that the fluoxetine trial was open strengthens the find- e there were no significant differences in demographic ings of antidepressant efficacy of active tDCS, since tDCS was and clinical characteristics among the three groups of treat- applied in a sham-controlled, double-blind fashion, and in ment). For our primary outcome (BDI), the mixed model re- a placebo-controlled trial fluoxetine might have been found (F6,117 ¼ 5.49, p ¼ 0.0001). In addition, further models com- In summary, our findings encourage further prospective paring two groups showed a significant difference between ac- studies to explore the comparison between tDCS and tive and sham tDCS groups (F3,87 ¼ 7.29, p ¼ 0.0002); but not between fluoxetine and active tDCS (F3,120 ¼ 0.72, p ¼ 0.54).
The comparison between fluoxetine and sham tDCS only reached a trend for a significant difference (F3,57 ¼ 2.21,p ¼ 0.09) (see Immediately after 2 weeks of treatment, This work was supported by a research grant from FAPESP depression was decreased by 43.1% (Æ30.9) in the active tDCS group and by 15.0% (Æ35.2) in the fluoxetine group; af- (DK071851-01) and the Harvard University David Rockefeller ter 6 weeks, however, depression reduction was similar in both groups of treatment (36.2% (Æ38.9) and 38.1% (Æ36.9), re- Jorge Paulo Lemann Fellowship. A.P.-L. is sup- ported by an NIH grant K24 RR018875. The authors are spectively). The HDRS scores revealed similar results: a signif- thankful to Barbara Bonetti for the invaluable help in the co- icant overall interaction term (F6,117 ¼ 11.05, p < 0.0001) and significant differences between active and sham tDCS groups(F3,87 ¼ 4.04, p ¼ 0.01), and sham tDCS and fluoxetine(F3,57 ¼ 16.4, p < 0.0001); but not between fluoxetine and active tDCS (F3,120 ¼ 2.01, p ¼ 0.11).
The results of this study show that the antidepressant effects [1] Boggio PS, Rigonatti S, Myczkowski M, Nitsche M, Pascual-Leone A, of non-invasive brain stimulation with tDCS are similar to Fregni F. A randomized double-blind clinical trial on the efficacy of cor- those of a 6-week course of fluoxetine at a relatively small tical DC stimulation in the treatment of major depression. Int J Neuro-psychopharmacol, in press.
dose of 20 mg/day. However, the antidepressant benefit of [2] Fregni F, Marcolin MA, Myczkowski M, Amiaz R, Hasey G, Rumi DO, tDCS appears to become significant faster than the benefit of et al. Predictors of antidepressant response in clinical trials of transcranial magnetic stimulation. Int J Neuropsychopharmacol 2006;9(6):641e54.
We acknowledge that this study has several limitations.
[3] Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual- First, the comparison was made with different groups of pa- Leone A. Treatment of major depression with transcranial direct currentstimulation. Bipolar Disord 2006;8:203 tients that therefore could have had different baseline clinical [4] Kosel M, Frick C, Lisanby SH, Fisch HU, Schlaepfer TE. Magnetic characteristics; however, these were identical across these seizure therapy improves mood in refractory major depression. Neuro- three groups regarding baseline clinical and demographic characteristics. Furthermore, these patients were recruited in [5] Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, the same service and during a similar period of time. Second, Hamani C, et al. Deep brain stimulation for treatment-resistant depres-sion. Neuron 2005 Mar 3;45(5):651 the fluoxetine trial was open-label, therefore a greater placebo [6] Miranda PC, Lomarev M, Hallett M. Modeling the current distribution response is possible. We therefore used the BDI as the main during transcranial direct current stimulation. Clin Neurophysiol outcome to reduce the bias of the unblinded rater. In addition, Letter to the editor / European Psychiatry 23 (2008) 74e76 [7] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol [8] Nitsche MA. Transcranial direct current stimulation: a new treatment for depression? Bipolar Disord 2002;4(Suppl. 1):98 [9] Pascual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcra- nial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 1996;348:233 [10] Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS) for treatment-resistant de- pression: efficacy, side effects, and predictors of outcome. Neuropsycho- [11] Wagner T, Fregni F, Fecteau S, Grodzinsky A, Zahn M, Pascual-Leone A.
Transcranial direct current stimulation: a computer-based human model study. Neuroimage 2007;35(3):1113e24.
Department of Psychiatry, University of Sao Paulo, Berenson-Allen Center for Noninvasive Brain Stimulation, Centro de Cieˆncias Biolo´gicas e da Sau´de, *Corresponding author. Tel.: þ1 617 667 5272; Department of Psychiatry, University of Sao Paulo, Sao Paulo, 1 Both authors have contributed equally to this work.

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