Escitalopram, Placebo and tDCS in Depression: a Non-inferiority Trial (ELECT-TDCS)

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

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder; Major Depressive Disorder, Recurrent, Unspecified; Major Depressive Disorder, Single Episode, Unspecified
• Intervention / Treatment: Device: transcranial direct current stimulation; Drug: Escitalopram oxalate; Other: Sham tDCS + Placebo Pill

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.

• Study Type: Interventional
• Enrollment (Actual): 245
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 05508-000
    • Hospital Universitário, Universidade de São Paulo
  • SP
    • São Paulo, SP, Brazil
      • Institute of Psychiatry, HC-FMUSP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active tDCS / placebo pill; transcranial direct current stimulation, using the parameters specified in Interventions.	Device: transcranial direct current stimulation; 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.; Other Names: tDCS - Soterix Medical Device for Clinical Trials
Active Comparator: Sham tDCS / escitalopram; Escitalopram oxalate (Reconter), 10mg/day (first 3 weeks) and 20mg/day (week 3 to week 10).	Drug: Escitalopram oxalate; 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.; Other Names: Reconter
Placebo Comparator: Sham tDCS / placebo pill; 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; This group receives sham tDCS and placebo pill.

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

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo; Brain & Behavior Research Foundation

Publications and helpful links

General Publications

• Goerigk SA, Padberg F, Chekroud A, Kambeitz J, Buhner M, Brunoni AR. Parsing the antidepressant effects of non-invasive brain stimulation and pharmacotherapy: A symptom clustering approach on ELECT-TDCS. Brain Stimul. 2021 Jul-Aug;14(4):906-912. doi: 10.1016/j.brs.2021.05.008. Epub 2021 May 26.
• Bulubas L, Padberg F, Bueno PV, Duran F, Busatto G, Amaro E Jr, Bensenor IM, Lotufo PA, Goerigk S, Gattaz W, Keeser D, Brunoni AR. Antidepressant effects of tDCS are associated with prefrontal gray matter volumes at baseline: Evidence from the ELECT-TDCS trial. Brain Stimul. 2019 Sep-Oct;12(5):1197-1204. doi: 10.1016/j.brs.2019.05.006. Epub 2019 May 8.
• Brunoni AR, Moffa AH, Sampaio-Junior B, Borrione L, Moreno ML, Fernandes RA, Veronezi BP, Nogueira BS, Aparicio LVM, Razza LB, Chamorro R, Tort LC, Fraguas R, Lotufo PA, Gattaz WF, Fregni F, Bensenor IM; ELECT-TDCS Investigators. Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression. N Engl J Med. 2017 Jun 29;376(26):2523-2533. doi: 10.1056/NEJMoa1612999.
• Brunoni AR, Sampaio-Junior B, Moffa AH, Borrione L, Nogueira BS, Aparicio LV, Veronezi B, Moreno M, Fernandes RA, Tavares D, Bueno PV, Seibt O, Bikson M, Fraguas R, Bensenor IM. The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial. Sao Paulo Med J. 2015 May-Jun;133(3):252-63. doi: 10.1590/1516-3180.2014.00351712. Epub 2015 Jun 1.

Helpful Links

• Trial information for participants and investigators.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: July 3, 2013
• First Submitted That Met QC Criteria: July 9, 2013
• First Posted (Estimate): July 10, 2013

Study Record Updates

• Last Update Posted (Estimate): December 5, 2016
• Last Update Submitted That Met QC Criteria: December 1, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: major depressive disorder; depressive disorder; major depression; major depressive episode
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Depression; Depressive Disorder; Disease; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antiparkinson Agents; Anti-Dyskinesia Agents; Citalopram; Dexetimide
• Other Study ID Numbers: ELECT-TDCS; FAPESP 2012/20911-5 (Other Grant/Funding Number: FAPESP 2012/20911-5)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No