Sertraline vs. ELectrical Current Therapy for Treating Depression Clinical Trial - SELECT TDCS: Design, rationale and objectives

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Abstract

Background

Despite significant advancements in psychopharmacology, treating major depressive disorder (MDD) is still a challenge considering the efficacy, tolerability, safety, and economical costs of most antidepressant drugs. One approach that has been increasingly investigated is modulation of cortical activity with tools of non-invasive brain stimulation — such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS). Due to its profile, tDCS seems to be a safe and affordable approach.

Methods and design

The SELECT TDCS trial aims to compare sertraline vs. tDCS in a double-blinded, randomized, factorial trial enrolling 120 participants to be allocated to four groups to receive sertraline + tDCS, sertraline, tDCS or placebo. Eligibility criteria are moderate-to-severe unipolar depression (Hamilton Depression Rating Scale > 17) not currently on sertraline treatment. Treatment will last 6 weeks and the primary outcome is depression change in the Montgomery–Asberg Depression Rating Score (MADRS). Potential biological markers that mediate response, such as BDNF serum levels, Val66Met BDNF polymorphism, and heart rate variability will also be examined. A neuropsychological battery with a focus on executive functioning will be administered.

Discussion

With this design we will be able to investigate whether tDCS is more effective than placebo in a sample of patients free of antidepressants and in addition, we will be able to secondarily compare the effect sizes of sertraline vs. tDCS and also the comparison between tDCS and combination of tDCS and sertraline.

Introduction

Major Depressive Disorder (MDD) is a psychiatric condition whose core features are depressed mood and anhedonia (lack of pleasure from activities once considered joyful). Auxiliary symptoms include: excessive guilt, sleep disturbances, low self-esteem, and weight changes. MDD is one of the main causes of disability and absenteeism worldwide and has high lifetime prevalence (up to 20%) [1], [2], being even higher in patients with concomitant somatic illness or other psychiatric conditions [3]. Also, MDD presents high rates of relapse (nearly 80%) and of treatment-resistance (nearly 33%) [4], [5].

Depression treatment is based on antidepressant drugs that also present side effects leading to drug discontinuation and treatment withdrawal such as sexual dysfunction and weight gain [6]; and they usually take more than two (usually four to eight) weeks for full efficacy [7], increasing the time span of MDD. Therefore, considering the burden, severity, and prevalence of the disease, new therapeutic regimens for MDD are needed.

Along those lines, non-invasive brain stimulation techniques are novel and promising treatments that have desirable characteristics such as lack of significant systemic effects and potential for better control of dosage. Repetitive transcranial magnetic stimulation (rTMS) has been recently approved in several countries for depression management, but it is costly and non-portable. Transcranial direct current stimulation (tDCS), on the other hand, is more economical and portable [8], being based on the application of weak direct currents via scalp electrodes in a simple and painless manner. The effects are polarity-dependent: anodal stimulation increases and cathodal stimulation decreases cortical excitability [9]. In MDD, the anode electrode is placed over the left dorsolateral prefrontal cortex area whose activity is impaired in depression [10]. In fact, although rTMS is advantageous considering the high temporal and spatial resolution, it is much more expensive and complicated to operate than tDCS, which is also portable and battery driven. In addition these two techniques have different mechanisms of action and it is still not clear which one would be more advantageous in terms of efficacy for treating MDD. Such aspects have instigated tDCS research in recent years [11].

Indeed, some pilot clinical trials suggested that tDCS has good antidepressant efficacy (Table 1): in a first sham-controlled trial, Fregni et al. [12] showed antidepressant efficacy of tDCS after 5 sessions. Later on, Boggio et al. [13] enrolled 40 patients and confirmed such positive effects in another double-blinded, sham-controlled trial; while Ferrucci et al. demonstrated depression improvement in an open-label trial with 14 patients. Also, Rigonatti et al. [14] compared a subgroup of Boggio et al. [13] against 20 patients taking fluoxetine. Both groups had similar efficacy after 6 weeks of treatment, but a fast, sustained response occurred in tDCS group at week 2. Finally, Loo et al. [15] did not show tDCS efficacy in one double-blinded, controlled study recruiting 40 patients after 5 days of stimulation; but found positive results after 10 days of stimulation.

Therefore, vital questions remain: (1) is the active tDCS antidepressant response effective when compared to sham tDCS, and if so, what is the effect size? Other secondary questions are: (2) is tDCS more effective or faster than pharmacotherapy? (3) What are the possible adverse effects of tDCS therapy? (4) What are possible predictors of tDCS response?

Aiming to answer these questions, we designed the Sertraline vs. Electrical Current Therapy for Treating Depression Clinical Study (SELECT TDCS), a phase II/III trial to address the safety and efficacy of tDCS in the treatment of MDD. In the present paper we discuss the rationale, methods, design and objectives of our ongoing trial. This paper aims to: (1) present and discuss important topics observed in a trial design combing pharmacotherapy and brain stimulation; (2) report in advance the methodology of an ongoing clinical trial using tDCS for MDD; (3) show our study protocol before trial results, thus giving additional assurance of adherence to the protocol. We believe that our manuscript can contribute to the development of the field by discussing the design and methods of a Phase II/III factorial clinical trial for tDCS.

Section snippets

Participants

We are enrolling patients aging from 18 to 65 years diagnosed with Major Depressive Disorder according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria and confirmed by the Mini-International Neuropsychiatric Interview (M.I.N.I.). Only patients with a Hamilton Depression Rating Scale (17-itens) (HDRS17) > 18 and low suicidal ideation are included. Exclusion criteria are other axis I disorders such as bipolar disorder, schizophrenia, alcohol and substance use

Discussion

The SELECT TDCS trial is the largest clinical trial to date testing the efficacy of tDCS. Considering previous rTMS studies, only two studies had higher samples than ours, of 301 and 127 patients respectively [22], [40]. Thus, the large sample size of SELECT TDCS decreases type I and type II errors and allows a study sample more heterogeneous than “proof-of-principle” trials, (i.e., with different degrees of refractoriness and comorbidity with anxiety disorders) thereby increasing external

Conclusion

SELECT TDCS is an ongoing clinical trial addressing the efficacy of transcranial direct current stimulation for patients with different degrees of treatment-resistant depression in a factorial design that uses sertraline as an add-on and comparator, thus allowing to tests different pharmacological/non-pharmacological associations. The investigation of the relationship of three biological markers with depression response will also contribute in understanding the pathophysiology of major

Acknowledgments

The authors are grateful to the following members who are being of invaluable help in executing the study: Edna Caetano dos Santos (study nurse), Fernanda Carvalho (study nurse), Cibele Soares (study nurse), Roberta Ferreira de Mello (study coordinator), Lays Cavallini (study coordinator) and Barbara Bonetti (study coordinator). The authors are also grateful to Clarissa Valim, MD, PhD who provided critical comments in the power analysis and statistical planning of our study; Decio Brunoni, MD,

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