High-definition Transcranial Direct Current Stimulation (HD-tDCS) in Late-life Depression (LLD)

Study Overview
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Brief Summary
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To determine the efficacy of a 2-week daily programme (10 sessions) of HD-tDCS to augment antidepressant therapy in subjects with late-life depression who had residual depressive symptoms despite adequate dosage and duration of antidepressant therapy.

Detailed Description
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Background: Hong Kong is facing a significant challenge in ageing population. A significant proportion of older adults suffered from depression. As the local population is ageing rapidly, the burden of late-life depression (LLD) will continue to increase. LLD is associated with a poorer long term prognosis, a more chronic course and a higher relapse rate comparing with adult-onset depression. Treatment response towards medication is unsatisfactory. Over 50% of patients with LLD do not achieve symptomatic remission. With the growing ageing population in Hong Kong, LLD becomes a pressing problem. The mainstream treatment of LLD is antidepressant and electroconvulsive therapy (ECT). Despite these methods being shown to be effective, there are limitations in each of these treatments. A new treatment option or augmentation therapy would be needed to improve the treatment response in LLD. Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation method. It applies a weak, direct electric current over the scalp region. It is a very safe intervention tool. It exerts the treatment effect probably through the change in the activity of neurons and modulation in synaptic release probability uptake and sensitivity. It enhances the long-term plasticity (LTP) and changes the rate of neurotransmitter release. High-definition tDCS (HD-tDCS) allows for more accuracy and focus on targeting the specific brain region. Recent evidence suggested that tDCS and serotonin enhance each other's function. Controversial outcomes were reported in previous randomised controlled trials (RCT) focusing on adult patients with depression. There is no RCT done among patients with LLD. An open-label pilot study was conducted by our team in 2018 which showed a significant improvement in depressive symptoms and mild improvement in cognitive domains after 2 weeks of HD-tDCS intervention. Objectives: This study is a double-blinded randomized sham-controlled trial to test the effectiveness of HD-tDCS as augmentation therapy for antidepressants in patients with LLD. The investigators hypothesized that active HD-tDCS is significantly more effective than sham control in reducing depressive symptoms. Design: The current study is a 2-week intervention trial of HD-tDCS with 4-week and 12-week post-intervention observation. All eligible participants must receive at least four weeks of antidepressant treatment before the tDCS intervention. Then they will be randomised to receive either active HD-tDCS (a-HD-tDCS) or sham-HD-tDCS (s-HD-tDCS) intervention for two weeks with five sessions per week. Both the participants and the investigators responsible for assessments and data analysis will be blinded to the group allocation. Total ten sessions HD-tDCS will be delivered. Each session would last for 30 minutes. After HD-tDCS intervention, participants would continue their medications for at least for 12 more weeks until all post-intervention assessments are complete. Data Analysis: Primary outcome and secondary outcomes assessment would be carried out at baseline, immediately after the intervention and follow up assessments at 4 and 12 weeks. The primary outcome will be the change of Hamilton depression rating scale (HAM-D-17). Secondary outcomes will include cognitive assessments, anxiety symptoms, daily functioning and adverse effects of the intervention. Intention-to treat analysis would be carried out. Intention-to-treat analysis would be carried out. Significance: The result of the current study would provide further data on the effectiveness of HD-tDCS as augmentative therapy with antidepressants in LLD patients.

Official Title
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High-definition Transcranial Direct Current Stimulation (HD-tDCS) as Augmentation Therapy in Late-life Depression (LLD) With Suboptimal Response to Treatment - Double-blinded Randomized Sham-controlled Trial

Conditions
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Depression in Old Age

Intervention / Treatment
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* Device: High-definition Transcranial Direct Current Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 60 years of age or above Right-handedness, as determined by the Edinburgh Handedness Inventory (to homogenise neuroanatomical targeting) Chinese ethnicity Fulfil the criteria of Major Depressive Disorder (single or recurrent episode) and in partial remission, defined by the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Presence of mild to severe level of depressive symptoms measured and defined by HAM-D-17 score ≥8 and ≤ 52[22] Suboptimal treatment response with at least one adequate antidepressant trial defined as full or best tolerated doses at least 6 weeks Stable dosage of antidepressants or other treatments for depression in recent 4 weeks Valid informed written consent Exclusion Criteria: A DSM-5 diagnosis other than Depressive Disorders (e.g., bipolar and related disorders, schizophrenia spectrum and other psychotic disorders). A Hong Kong Chinese version of the Montreal Cognitive Assessment (HK-MoCA) score below the second percentile according to the subject's age and education level (to exclude subjects with existing dementia) Alcohol or substance dependence Active suicidal ideation or a suicide attempt within the past month Concomitant unstable medical condition or major neurological conditions Significant communication impairment

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: active HD-tDCS<br>The participants will be instructed to relax during the first 5 minutes of the session while the equipment is set up. A mild stimulation (with a level of only 2 milliamps stimulation) will be delivered for 20 minutes, with the current gradually increased and decreased over 30 seconds. The patients will be instructed to relax and remain motionless during the intervention. The administrator will closely monitor the impedance throughout each session and record any side effects experienced by the participants. The participants will be allowed 5 minutes of rest after the intervention and will be actively asked about any discomfort. Each session will last around 30 minutes, with a total of 10 sessions (two consecutive weeks of treatment for 5 days per week). | Device: High-definition Transcranial Direct Current Stimulation<br>* The HD-tDCS will be administered by the program device called Starstim (Neuroelectrics). All participants will receive the treatment by using the same model of device. The HD-tDCS device can be portable and controlled wirelessly via computer software developed by the manufacturer. The montages will be a '4 × 1 ring set-up', which is the most commonly used HD-tDCS setting. The centre anode electrode is surrounded by four return cathode electrodes. The anode will be placed over the left dorsal lateral prefrontal cortex. Conductive electrode gel will be applied on the scalp at all designated electrode stimulation areas. A cap appropriate for each participants' head size will be used to ensure that the electrodes are secured in place. Impedance checks will be performed using the Starstim software before each treatment session.<br>|
| Sham Comparator: sham-HD-tDCS<br>The procedure for sham stimulation will be identical, except that the current will be gradually ramped down to zero after the first 30 s, thus giving the same initial sensation of HD-tDCS. The stimulator will be programmed to switch the current on and off, so no intervention by the operator will be required. The computer will be placed behind the subjects' heads so they cannot see the readout. | Device: High-definition Transcranial Direct Current Stimulation<br>* The HD-tDCS will be administered by the program device called Starstim (Neuroelectrics). All participants will receive the treatment by using the same model of device. The HD-tDCS device can be portable and controlled wirelessly via computer software developed by the manufacturer. The montages will be a '4 × 1 ring set-up', which is the most commonly used HD-tDCS setting. The centre anode electrode is surrounded by four return cathode electrodes. The anode will be placed over the left dorsal lateral prefrontal cortex. Conductive electrode gel will be applied on the scalp at all designated electrode stimulation areas. A cap appropriate for each participants' head size will be used to ensure that the electrodes are secured in place. Impedance checks will be performed using the Starstim software before each treatment session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Depressive symptoms | the clinical response rate and the remission rate as measured with the HAM-D-17. A clinical response will be defined as a reduction of 50% or more in the HAM-D-17 score. A HAM-D-17 score of 7 or less will be used as an indicator of remission. Scores range from 0 to 52, with higher scores indicating more severe depression. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Global Cognition | Using the Hong Kong Chinese version of the Montreal Cognitive Assessment. The total score ranges from 0-30 with higher scores indicating better cognition. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in the Working Memory | Measured by forward and backward digit span. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in the Executive Functioning | Measured by the Trail Making Test Parts A and B. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in the Verbal Fluency | Measured by category verbal fluency test. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in the Attention | Measured by the Stroop test. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in the Anxiety symptoms | Measured by the Hamilton Anxiety Rating Scale (HAMA). It is a widely used clinician-rated scale ranging from 0-56, with higher marks represent more severe in anxiety symptoms. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in Daily functioning | Instrumental activities of daily living will be assessed with the Hong Kong Chinese version of the Lawton Instrumental Activities of Daily Living Scale. The daily functioning would be assessed with a total score ranging from 0 to 27. A higher score indicates a higher functioning level. | Assessed at baseline, immediately after the intervention, and 4 and 12 weeks after the intervention. | 
| Change in Adverse effects and risk indicators | checklist of potential adverse effects associated with t-DCS administration will be generated from the available literature. Risk indicators such as suicidal risk or severe self-neglect that would necessitate immediate changes to treatment will be directly assessed according to the risk and needs. | Assessed immediately after each (in total 10) individual treatment session. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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augmentation therapy, late-life depression