Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited for issues such as refractoriness and adverse effects. In this context, the investigators investigate a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). To prove that tDCS is similarly effective than antidepressants would have a tremendous impact in clinical psychiatry, since tDCS is virtually absent of adverse effects. Its ease of use, portability and low price are also interesting characteristics for using in primary and secondary health care. Thus, our aim is to compare tDCS against a fully dosed, effective antidepressant. The study will be a non-inferiority, randomized, double-blinded, placebo-controlled, three-arm trial comparing active tDCS/placebo pill, sham tDCS/escitalopram 20mg/day and sham tDCS/placebo pill. Our primary aim is to show that tDCS is not inferior to escitalopram 20mg/day with a noninferiority margin of at least 50% of the escitalopram-placebo effect.
Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited for issues such as refractoriness and adverse effects. In this context, the researchers investigate a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). In a prior clinical trial with 120 patients with MDD, the investigators demonstrated that the combination of tDCS with sertraline 50mg/day had increased, faster effects on depressive symptoms (Brunoni et al., JAMA Psychiatry, 2013). However, although the investigators suggested that tDCS vs. sertraline had similar efficacy, such comparison was compromised due to the low sertraline dose and also because the comparison of sertraline vs. placebo was not significant. To prove that tDCS is similarly effective than antidepressants would have a tremendous impact in clinical psychiatry, since tDCS is virtually absent of adverse effects. Its ease of use, portability and low price are also interesting characteristics for using in primary and secondary health care. Thus, our aim is to compare tDCS against a fully dosed, effective antidepressant. The study will be a non-inferiority, randomized, double-blinded, placebo-controlled, three-arm trial comparing active tDCS/placebo pill, sham tDCS/escitalopram 20mg/day and sham tDCS/placebo pill for ten weeks, randomizing 240 patients with MDD in a 3:3:2 ratio (less to placebo). Our primary aim is to show that tDCS is not inferior to escitalopram 20mg/day with a noninferiority margin of at least 50% of the escitalopram-placebo effect. As secondary aims, the researchers will investigate putative biomarkers for tDCS response. This is important considering the large sample size of this study and also the paucity of tDCS studies - therefore, the identification of such biomarkers could generate new hypothesis for future studies and for tDCS' mechanisms of action. The biomarkers will be: genetic polymorphisms (BDNF, SLC6A4, THP1, 5HT2A); serum markers (BDNF); motor cortical excitability (cortical silent period, intracortical inhibition, intracortical facilitation); heart rate variability; and neuroimaging (structural volume of the dorsolateral prefrontal and anterior cingulate cortex, white matter tracts of the prefrontal cortex and posterior cingulate cortex connectivity). This project represents a novel research line in our Institution, and the investigators thereby propose the onset of a new center denominated C.I.N.A. (Interdisciplinary Center for Applied Neuromodulation) that will foment the use and development of projects using neuromodulation techniques. This new center will also interact with other centers on the fields of clinical research, neurosciences and neuropsychiatry.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
245
The investigators will use 10mg and 20mg pills. The investigators will up-titrate escitalopram from 10 to 20mg/day according to the patient tolerability. The maximum dose (20mg/day) is sought to be achieved at week 3.
The anode will be applied over the F3 area and the cathode over the F4 area. The current dose is 2mA, current density is 0.8 A/m2. Electrodes will be 5x5cm in size. The investigators will apply 15 daily, consecutive tDCS sessions (excluding weekends) and after that one session per week until the primary endpoint.
This group receives sham tDCS and placebo pill.
Hospital Universitário, Universidade de São Paulo
São Paulo, São Paulo, Brazil
Institute of Psychiatry, HC-FMUSP
São Paulo, São Paulo, Brazil
Changes in Hamilton Rating Scale for Depression, 17 items (HAMD17)
Continuous measure (score changes). Non-inferiority assessment: the difference between tDCS to escitalopram should be \>50% of escitalopram to placebo efficacy.
Time frame: Weeks 0 and 10
Change in HDRS
Continuous measure (score changes).
Time frame: Weeks 0, 3, 6, 8, 10
Change in Montgomery-Asberg Depression Rating Scale (MADRS)
Continuous measure (score changes).
Time frame: Weeks 0, 3, 6, 10
Change in Beck Depression Inventory (BDI)
Time frame: Weeks 0, 3, 6, 10
Change in Positive and Negative Affect Scale (PANAS)
Time frame: Weeks 0, 3, 6, 10
Change in State-Trait Anxiety Inventory (STAI)
Time frame: Weeks 0, 3, 6, 10
Hamilton Rating Scale for Depression, 17 items (HAMD17)
Response (≥50% improvement from week 0 to 10)
Time frame: Week 10
Hamilton Rating Scale for Depression, 17 items (HAMD17)
Remission (HAMD17 ≤7) at week 10.
Time frame: Week 10
Adverse events
Assessment and comparisons of tDCS and drug adverse events. We used a tDCS adverse events questionnaire (Brunoni et al., 2011) and the SAFTEE.
Time frame: Week 3 and Week 10.
Serious adverse events
Serious adverse events include treatment-emergent hypomania/mania (YMRS\>8), suicide, psychiatric hospitalization and others life-threatening or incapacitant events.
Time frame: Up to Week 10.
Young Manic Rating Scale (YMRS)
Assessment of treatment-emergent hypomania/mania, defined as YRMS\>8.
Time frame: Week 3 and Week 10.
Predictor of response
Age (years)
Time frame: Week 10
Predictor of response
Gender
Time frame: Week 10
Predictor of response
Low wage (less than 5 monthly wages in Brazil)
Time frame: Week 10
Predictor of response
Recurrent depression
Time frame: Week 10
Predictor of response
Chronic depression
Time frame: Week 10
Predictor of response
Refractory depression
Time frame: Week 10
Predictor of response
Severe depression
Time frame: Week 10
Predictor of response
Benzodiazepine use
Time frame: Week 10
Predictor of response
Higher education (\>15 years of schooling)
Time frame: Week 10
Predictor of response
Age of onset of the depressive episode (years)
Time frame: Week 10
Predictor of response
Any anxiety disorder
Time frame: Week 10
Predictor of response
Physical activity
Time frame: Week 10
Predictor of response
melancholic depression
Time frame: Week 10
Predictor of response
atypical depression
Time frame: Week 10
Predictor of response
smoking status
Time frame: Week 10
Predictor of response
hypertension
Time frame: Week 10
Predictor of response
diabetes mellitus
Time frame: Week 10
Predictor of response
ethnicity
Time frame: Week 10
Predictor of response
marital status
Time frame: Week 10
Predictor of response
employment status
Time frame: Week 10
Predictor of response
obesity
Time frame: Week 10
Predictor of response
familial psychiatry history
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Novelty seeking
Time frame: Week 10
Predictor of response
Any tDCS related adverse event.
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Harm avoidance
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Reward Dependence
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Persistence
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Cooperativeness
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Self-transcendence
Time frame: Week 10
Predictor of response
Temperament and Character Inventory - Self-directedness
Time frame: Week 10
Predictor of response
FAS verbal fluency test
Time frame: Week 10
Predictor of response
Digit span forward
Time frame: Week 10
Predictor of response
Digit span backward
Time frame: Week 10
Predictor of response
Trail Making Test - A
Time frame: Week 10
Predictor of response
Trail Making Test - B
Time frame: Week 10
Predictor of response
Symbol digit
Time frame: Week 10
Predictor of response
Montreal Cognitive Assessment
Time frame: Week 10
Predictor of response
Motor Cortical Excitability - Cortical silent period (left and right hemispheres)
Time frame: Week 3 and 10
Predictor of response
Motor Cortical Excitability - Intracortical inhibition (left and right hemispheres)
Time frame: Week 3 and 10
Predictor of response
Motor Cortical Excitability - Intracortical facilitation (left and right hemispheres)
Time frame: Week 3 and 10
Predictor of response
Heart rate variability - HF
Time frame: Week 3 and 10
Predictor of response
Heart rate variability - LF
Time frame: Week 3 and 10
Predictor of response
Heart rate variability - RMSSD
Time frame: Week 3 and 10
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