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

Major Depressive Disorder Clinical Trial

— ELECT-TDCS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01894815
• Other study ID #: ELECT-TDCS
• Secondary ID: FAPESP 2012/2091
• Status: Completed
• Phase: Phase 3
• First received: July 3, 2013
• Last updated: December 1, 2016
• Start date: October 2013
• Est. completion date: November 2016

Study information

• Verified date: December 2016
• Source: University of Sao Paulo
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 245
• Est. completion date: November 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Disease
• Major Depressive Disorder
• Major Depressive Disorder, Recurrent, Unspecified
• Major Depressive Disorder, Single Episode, Unspecified
• Recurrence

Intervention

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.

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:
• Sham tDCS + Placebo Pill
This group receives sham tDCS and placebo pill.

Locations

Country	Name	City	State
Brazil	Hospital Universitário, Universidade de São Paulo	São Paulo
Brazil	Institute of Psychiatry, HC-FMUSP	São Paulo	SP

Sponsors (3)

Lead Sponsor	Collaborator
University of Sao Paulo	Brain & Behavior Research Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Change in HDRS	Continuous measure (score changes).	Weeks 0, 3, 6, 8, 10	No
Secondary	Change in Montgomery-Asberg Depression Rating Scale (MADRS)	Continuous measure (score changes).	Weeks 0, 3, 6, 10	No
Secondary	Change in Beck Depression Inventory (BDI)		Weeks 0, 3, 6, 10	No
Secondary	Change in Positive and Negative Affect Scale (PANAS)		Weeks 0, 3, 6, 10	No
Secondary	Change in State-Trait Anxiety Inventory (STAI)		Weeks 0, 3, 6, 10	No
Secondary	Hamilton Rating Scale for Depression, 17 items (HAMD17)	Response (=50% improvement from week 0 to 10)	Week 10	No
Secondary	Hamilton Rating Scale for Depression, 17 items (HAMD17)	Remission (HAMD17 =7) at week 10.	Week 10	No
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	Young Manic Rating Scale (YMRS)	Assessment of treatment-emergent hypomania/mania, defined as YRMS>8.	Week 3 and Week 10.	Yes
Secondary	Predictor of response	Age (years)	Week 10	No
Secondary	Predictor of response	Gender	Week 10	No
Secondary	Predictor of response	Low wage (less than 5 monthly wages in Brazil)	Week 10	No
Secondary	Predictor of response	Recurrent depression	Week 10	No
Secondary	Predictor of response	Chronic depression	Week 10	No
Secondary	Predictor of response	Refractory depression	Week 10	No
Secondary	Predictor of response	Severe depression	Week 10	No
Secondary	Predictor of response	Benzodiazepine use	Week 10	No
Secondary	Predictor of response	Higher education (>15 years of schooling)	Week 10	No
Secondary	Predictor of response	Age of onset of the depressive episode (years)	Week 10	No
Secondary	Predictor of response	Any anxiety disorder	Week 10	No
Secondary	Predictor of response	Physical activity	Week 10	No
Secondary	Predictor of response	melancholic depression	Week 10	No
Secondary	Predictor of response	atypical depression	Week 10	No
Secondary	Predictor of response	smoking status	Week 10	No
Secondary	Predictor of response	hypertension	Week 10	No
Secondary	Predictor of response	diabetes mellitus	Week 10	No
Secondary	Predictor of response	ethnicity	Week 10	No
Secondary	Predictor of response	marital status	Week 10	No
Secondary	Predictor of response	employment status	Week 10	No
Secondary	Predictor of response	obesity	Week 10	No
Secondary	Predictor of response	familial psychiatry history	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Novelty seeking	Week 10	No
Secondary	Predictor of response	Any tDCS related adverse event.	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Harm avoidance	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Reward Dependence	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Persistence	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Cooperativeness	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Self-transcendence	Week 10	No
Secondary	Predictor of response	Temperament and Character Inventory - Self-directedness	Week 10	No
Secondary	Predictor of response	FAS verbal fluency test	Week 10	Yes
Secondary	Predictor of response	Digit span forward	Week 10	Yes
Secondary	Predictor of response	Digit span backward	Week 10	Yes
Secondary	Predictor of response	Trail Making Test - A	Week 10	Yes
Secondary	Predictor of response	Trail Making Test - B	Week 10	Yes
Secondary	Predictor of response	Symbol digit	Week 10	Yes
Secondary	Predictor of response	Montreal Cognitive Assessment	Week 10	Yes
Secondary	Predictor of response	Motor Cortical Excitability - Cortical silent period (left and right hemispheres)	Week 3 and 10	No
Secondary	Predictor of response	Motor Cortical Excitability - Intracortical inhibition (left and right hemispheres)	Week 3 and 10	No
Secondary	Predictor of response	Motor Cortical Excitability - Intracortical facilitation (left and right hemispheres)	Week 3 and 10	No
Secondary	Predictor of response	Heart rate variability - HF	Week 3 and 10	No
Secondary	Predictor of response	Heart rate variability - LF	Week 3 and 10	No
Secondary	Predictor of response	Heart rate variability - RMSSD	Week 3 and 10	No

External Links

•   Trial information for participants and investigators.