Escitalopram, Placebo and tDCS in Depression: a Non-inferiority Trial

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Escitalopram and Transcranial Direct Current Stimulation in Major Depressive Disorder: a Double-blind, Placebo-controlled, Randomized, Non-inferiority Trial

Conditions
-----------------
Major Depressive Disorder, Major Depressive Disorder, Recurrent, Unspecified, Major Depressive Disorder, Single Episode, Unspecified

Intervention / Treatment
-----------------
* Drug: Escitalopram oxalate
* Device: transcranial direct current stimulation
* Other: Sham tDCS + Placebo Pill


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HAMD17>=17 more than 8 years of schooling OR able to read, speak and understand the Portuguese language. Low suicide risk. Exclusion Criteria: Bipolar disorders. Schizophrenia and other psychotic disorders. Anxiety disorders, if it is the primary diagnosis (comorbidity with depression is not an exclusion disorder) Substance abuse or dependence. Depression symptoms better explained by medical conditions. Neurologic conditions (e.g., stroke, multiple sclerosis, brain tumor). Severe medical conditions. Pregnancy/breast-feeding. Severe suicidal ideation, suicidal planning or recent (<4 weeks) suicide attempt. Contra-indications to escitalopram. Current use of escitalopram in the current depressive episode. Use of escitalopram in a prior depressive episode that was not effective. Contra-indications to tDCS. Previous use of tDCS (current or previous depressive episode).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active tDCS / placebo pill<br>transcranial direct current stimulation, using the parameters specified in Interventions. | Device: transcranial direct current stimulation<br>* 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.<br>* Other names: tDCS - Soterix Medical Device for Clinical Trials;|
| Active Comparator: Sham tDCS / escitalopram<br>Escitalopram oxalate (Reconter), 10mg/day (first 3 weeks) and 20mg/day (week 3 to week 10). | Drug: Escitalopram oxalate<br>* 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.<br>* Other names: Reconter;|
| Placebo Comparator: Sham tDCS / placebo pill<br>For sham tDCS, the device is automatically turned off after 30 second of stimulation and remains turned off during the 30-min session. For placebo pill, the pill has the same size, taste and color than escitalopram, and placebo and escitalopram will be provided in identical bottles, differing only according to a random-generated number placed in the label. | Other: Sham tDCS + Placebo Pill<br>* This group receives sham tDCS and placebo pill.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Weeks 0 and 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HDRS | Continuous measure (score changes). | Weeks 0, 3, 6, 8, 10 | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | Continuous measure (score changes). | Weeks 0, 3, 6, 10 | 
| Change in Beck Depression Inventory (BDI) |  | Weeks 0, 3, 6, 10 | 
| Change in Positive and Negative Affect Scale (PANAS) |  | Weeks 0, 3, 6, 10 | 
| Change in State-Trait Anxiety Inventory (STAI) |  | Weeks 0, 3, 6, 10 | 
| Hamilton Rating Scale for Depression, 17 items (HAMD17) | Response (≥50% improvement from week 0 to 10) | Week 10 | 
| Hamilton Rating Scale for Depression, 17 items (HAMD17) | Remission (HAMD17 ≤7) at week 10. | 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. | 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. | Up to Week 10. | 
| Young Manic Rating Scale (YMRS) | Assessment of treatment-emergent hypomania/mania, defined as YRMS>8. | Week 3 and Week 10. | 
| Predictor of response | Age (years) | Week 10 | 
| Predictor of response | Gender | Week 10 | 
| Predictor of response | Low wage (less than 5 monthly wages in Brazil) | Week 10 | 
| Predictor of response | Recurrent depression | Week 10 | 
| Predictor of response | Chronic depression | Week 10 | 
| Predictor of response | Refractory depression | Week 10 | 
| Predictor of response | Severe depression | Week 10 | 
| Predictor of response | Benzodiazepine use | Week 10 | 
| Predictor of response | Higher education (>15 years of schooling) | Week 10 | 
| Predictor of response | Age of onset of the depressive episode (years) | Week 10 | 
| Predictor of response | Any anxiety disorder | Week 10 | 
| Predictor of response | Physical activity | Week 10 | 
| Predictor of response | melancholic depression | Week 10 | 
| Predictor of response | atypical depression | Week 10 | 
| Predictor of response | smoking status | Week 10 | 
| Predictor of response | hypertension | Week 10 | 
| Predictor of response | diabetes mellitus | Week 10 | 
| Predictor of response | ethnicity | Week 10 | 
| Predictor of response | marital status | Week 10 | 
| Predictor of response | employment status | Week 10 | 
| Predictor of response | obesity | Week 10 | 
| Predictor of response | familial psychiatry history | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Novelty seeking | Week 10 | 
| Predictor of response | Any tDCS related adverse event. | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Harm avoidance | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Reward Dependence | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Persistence | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Cooperativeness | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Self-transcendence | Week 10 | 
| Predictor of response | Temperament and Character Inventory - Self-directedness | Week 10 | 
| Predictor of response | FAS verbal fluency test | Week 10 | 
| Predictor of response | Digit span forward | Week 10 | 
| Predictor of response | Digit span backward | Week 10 | 
| Predictor of response | Trail Making Test - A | Week 10 | 
| Predictor of response | Trail Making Test - B | Week 10 | 
| Predictor of response | Symbol digit | Week 10 | 
| Predictor of response | Montreal Cognitive Assessment | Week 10 | 
| Predictor of response | Motor Cortical Excitability - Cortical silent period (left and right hemispheres) | Week 3 and 10 | 
| Predictor of response | Motor Cortical Excitability - Intracortical inhibition (left and right hemispheres) | Week 3 and 10 | 
| Predictor of response | Motor Cortical Excitability - Intracortical facilitation (left and right hemispheres) | Week 3 and 10 | 
| Predictor of response | Heart rate variability - HF | Week 3 and 10 | 
| Predictor of response | Heart rate variability - LF | Week 3 and 10 | 
| Predictor of response | Heart rate variability - RMSSD | Week 3 and 10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
major depressive disorder, major depression, depressive disorder, major depressive episode