TEST for Major Depression

Overseen By Aidan Wade

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Mental Health (NIMH)

Disqualifiers: Pregnancy, Substance abuse, Suicidal, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

35 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: People with TRD are often helped by electroconvulsive therapy (ECT). But ECT can affect memory and thinking. Researchers want to study a treatment called TEST that uses less electricity. Objective: To study the safety and feasibility of TEST and assess its antidepressant effects. Eligibility: Adults aged 25-64 with major depression that has not been relieved by current treatments. Design: Participants will be admitted to the NIH Clinical Center for 5 18 weeks over 2 3 treatment phases. Their medications may be adjusted. Participants will be interviewed about their depression, side effects, and other treatments they are receiving. They will complete questionnaires. They will give blood and urine samples. Their brain waves and heart rhythm will be recorded. They will take tests of memory, attention, mental functioning, and thinking. Participants will have magnetic resonance imaging (MRI) scans of the head and brain. They will lie on a table that slides in and out of the scanner. Pictures of brain chemicals will also be taken. They may complete tasks during the MRI. Participants will receive TEST and/or sham treatments. They may receive optional ECT. An intravenous catheter will be placed in an arm vein to receive general anesthesia. Two electrodes will be placed on the front of their head. An electric current will be passed from the ECT machine through the electrodes. For sham treatments, they will not receive the electric current. Their breathing, heart rate, brain function, blood pressure, and body movements will be measured. Participants will have 7 follow-up visits over 6 months. Visits can be done via telehealth. Participation will last for up to 42 weeks.

Will I have to stop taking my current medications?

Participants must stay on the same daily dose of their psychiatric medications for at least 6 weeks before starting the trial and throughout the study, unless the investigator advises otherwise. If you need to reduce your medication dosage, it must be done at least 4 weeks before the trial begins.

Is transcranial electric stimulation therapy (TEST) safe for humans?

Transcranial electric stimulation, including tDCS and tACS, is generally considered safe for humans, with no serious adverse events reported in over 18,000 sessions. Mild side effects like headaches and skin sensations are possible, but serious issues are rare. ^{1 2 3 4 5}

How is Transcranial Electric Stimulation Therapy (TEST) different from other treatments for major depression?

Transcranial Electric Stimulation Therapy (TEST), also known as transcranial direct current stimulation (tDCS), is unique because it is a non-invasive brain stimulation technique that modulates brain activity using a low electrical current. Unlike traditional antidepressant medications, it does not involve drugs and can be administered at home under supervision, offering a potential alternative for those who do not respond well to medications. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment Transcranial Electric Stimulation Therapy (TEST) for major depression?

Research shows that transcranial direct current stimulation (tDCS), a part of TEST, is a promising non-drug therapy for major depression, with studies indicating it can be effective for acute episodes and potentially beneficial when combined with other treatments. ^{6 9 10 11 12}

Research Team

William T Regenold, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Adults aged 25-64 with major depression not improved by standard treatments, including medication or rTMS. They must be stable on current psychiatric medications for at least 4 weeks before and during the trial, agree to use effective contraception if applicable, and not have a history of substance abuse in the past year or certain medical conditions that could interfere with the study.

Inclusion Criteria

Willingness to provide written permission for communication between the Investigator/Research Staff and healthcare provider, and provide emergency contact information

Ability to understand and sign a written informed consent document as determined by the Investigator

For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening

Exclusion Criteria

Being an NIMH employee or an immediate family member of an NIMH employee

I do not have any health issues that would stop me from completing the study.

Expression of recent or current active suicidal ideas and an explicit plan or intent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase I

Participants receive TEST or sham treatments, with monitoring of safety and feasibility

2-3 weeks

Approximately 3 visits per week

Treatment Phase II

Continuation of TEST or sham treatments, with further monitoring and assessments

2 weeks

Approximately 3 visits per week

Treatment Phase III

Final phase of TEST or sham treatments, with comprehensive assessments

4-13 weeks

Approximately 3 visits per week

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

7 visits, can be done via telehealth

Treatment Details

Interventions

• Transcranial Electric Stimulation Therapy (TEST)

Trial Overview The TEST procedure is being studied as an alternative to ECT for treatment-resistant depression. It involves less electricity than traditional ECT and aims to reduce side effects like memory loss. Participants will undergo MRI scans, interviews, questionnaires, blood tests, and brain function assessments over several phases lasting up to 42 weeks.

Participant Groups

Group I: Transcranial Electric Stimulation Therapy (TEST) Experimental Treatment 3 Interventions

TEST involves bifrontal electrical brain stimulation at a dose below the seizure threshold, applied in the same manner as standard electroconvulsive therapy (ECT), with scalp electrodes, under anesthesia, using a standard ECT device (modified or unmodified) that can deliver a range of doses below seizure threshold.

Group II: Sham TEST Placebo Group 1 Intervention

Anesthesia alone

Transcranial Electric Stimulation Therapy (TEST) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Transcranial Direct Current Stimulation (tDCS) for:

• Major Depressive Disorder
• Chronic Pain
• Stroke Rehabilitation

Approved in European Union as Transcranial Direct Current Stimulation (tDCS) for:

• Major Depressive Disorder
• Chronic Pain
• Stroke Rehabilitation
• Schizophrenia

Approved in Canada as Transcranial Direct Current Stimulation (tDCS) for:

• Major Depressive Disorder
• Chronic Pain
• Stroke Rehabilitation

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

Transcranial direct current stimulation (tDCS) significantly improved depressive symptoms in patients who had not responded to previous pharmacological treatments, with a notable reduction in scores on the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) after just five days of treatment.

The study found that the effectiveness of tDCS was influenced by prior medication use; specifically, benzodiazepines were linked to poorer outcomes, while dual-reuptake inhibitors showed a positive interaction with tDCS effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: findings from a naturalistic study. Brunoni, AR., Ferrucci, R., Bortolomasi, M., et al.[2020]

In a case series of 16 treatment-resistant depression patients, home-administered transcranial direct current stimulation (HA-tDCS) showed clinical benefits, with 5 out of 12 patients responding within 6 weeks and 9 maintaining improvements after 12 weeks of treatment.

HA-tDCS was found to be safe and well-tolerated, with no significant cognitive impairments reported over up to 2 years of treatment, although two patients experienced mild side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Clinical Case Series of Acute and Maintenance Home Administered Transcranial Direct Current Stimulation in Treatment-Resistant Depression. Le, B., Alonzo, A., Bull, M., et al.[2023]

In the SELECT-TDCS trial, transcranial direct current stimulation (tDCS) was effective in treating major depression, with 52% of participants responding positively during the crossover phase after previously receiving sham treatment.

During the follow-up phase, the average duration of response to tDCS was 11.7 weeks, but patients with treatment-resistant depression had a significantly lower survival rate (10%) compared to non-refractory patients (77%), highlighting the need for optimized continuation protocols to prevent relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The sertraline versus electrical current therapy for treating depression clinical study (select-TDCS): results of the crossover and follow-up phases. Valiengo, L., Benseñor, IM., Goulart, AC., et al.[2014]

In a study involving 22 patients with treatment-resistant major depression, anodal transcranial direct current stimulation (tDCS) did not show a significant improvement in depression scores compared to placebo after 2 weeks of treatment.

Despite the lack of overall efficacy in reducing depression scores, tDCS was associated with increased positive emotions, suggesting potential benefits that warrant further investigation with improved protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study. Palm, U., Schiller, C., Fintescu, Z., et al.[2022]

Transcranial direct current stimulation (tDCS) significantly reduced depression scores compared to sham treatment, with the most effective results seen when tDCS was combined with medication, particularly selective serotonin re-uptake inhibitors (SSRIs).

The study included 12 randomized, sham-controlled trials with 251 participants receiving active tDCS and 204 receiving sham, showing that while tDCS alone or combined with psychotherapy did not significantly improve outcomes, the combination with medication led to a higher response rate and a greater reduction in depression scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is transcranial direct current stimulation, alone or in combination with antidepressant medications or psychotherapies, effective in treating major depressive disorder? A systematic review and meta-analysis. Wang, J., Luo, H., Schülke, R., et al.[2022]

The study evaluates the efficacy and safety of transcranial alternating current stimulation (tACS) in treating major depressive disorder (MDD) over 8 weeks, involving 92 drug-naive patients who received either active or sham stimulation.

The primary outcome is the remission rate measured by the Hamilton depression rating scale, with the study aiming to demonstrate that tACS can effectively reduce depression symptoms with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol on transcranial alternating current stimulation for the treatment of major depressive disorder: a randomized controlled trial. Wang, HX., Wang, K., Zhang, WR., et al.[2023]

Low intensity transcranial electrical stimulation (TES) is considered safe, with no serious adverse events reported in over 18,000 sessions across various populations, including healthy individuals and patients with neurological or psychiatric conditions.

While moderate adverse events like skin burns from tDCS are rare, mild adverse events such as headaches and fatigue are more common, and the safety profile is consistent across different age groups and vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Antal, A., Alekseichuk, I., Bikson, M., et al.[2023]

In a study involving 1,019 participants across 4 sites, adverse events (AEs) following multiple sessions of transcranial electrical stimulation (tES) were found to be influenced more by factors like testing site and session number rather than the stimulation itself, suggesting a good safety profile for repeated use.

The effectiveness of blinding procedures was found to be less reliable for tDCS and tACS compared to tRNS, indicating a need for improved blinding methods, especially when using higher stimulation intensities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinding efficacy and adverse events following repeated transcranial alternating current, direct current, and random noise stimulation. Sheffield, JG., Ramerpresad, S., Brem, AK., et al.[2022]

Transcranial electrical stimulation (tES), including tDCS and MHF-tPCS, was found to be well tolerated in healthy subjects over a six-week period, with common side effects being mild skin sensations like tingling and itching, which were less frequent than in the sham-tDCS group.

The MHF-tPCS group showed significantly higher compliance in completing sessions compared to the sham-tDCS group, indicating that this waveform may be more acceptable for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of Repeated Application of Transcranial Electrical Stimulation with Limited Outputs to Healthy Subjects. Paneri, B., Adair, D., Thomas, C., et al.[2018]

Cranial electrotherapy stimulation (CES) was tested as an add-on treatment for tic disorders (TD) in a study involving 62 patients aged 6-17 years, showing a reduction in tic severity after 4 weeks of treatment.

While both active CES and sham CES groups experienced improvements in tic severity, the difference was not statistically significant, suggesting that the observed benefits may be largely due to a placebo effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, randomized, sham-controlled study of cranial electrotherapy stimulation as an add-on treatment for tic disorders in children and adolescents. Wu, WJ., Wang, Y., Cai, M., et al.[2021]

Transcranial direct current stimulation (tDCS) is a promising noninvasive treatment for major depression, showing potential for significant clinical gains in recent studies, although past trials had mixed results due to varied methodologies.

Current evidence is not yet sufficient to fully endorse tDCS as a standard treatment for depression, but optimizing stimulation parameters, such as individualization and longer sessions, could enhance its effectiveness and warrant further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation as a therapeutic tool for the treatment of major depression: insights from past and recent clinical studies. Murphy, DN., Boggio, P., Fregni, F.[2009]

The ELECT-TDCS study is a Phase-III clinical trial involving 240 patients that aims to compare the efficacy of transcranial direct current stimulation (tDCS) to the antidepressant escitalopram, with the goal of demonstrating that tDCS is not inferior to escitalopram in treating major depressive disorder.

If successful, tDCS could provide a non-pharmacological treatment option for depression that is virtually free of adverse effects, making it a promising alternative for patients who struggle with traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Brunoni, AR., Sampaio-Junior, B., Moffa, AH., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: findings from a naturalistic study. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

A Clinical Case Series of Acute and Maintenance Home Administered Transcranial Direct Current Stimulation in Treatment-Resistant Depression. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

The sertraline versus electrical current therapy for treating depression clinical study (select-TDCS): results of the crossover and follow-up phases. [2014]

4. United States pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Is transcranial direct current stimulation, alone or in combination with antidepressant medications or psychotherapies, effective in treating major depressive disorder? A systematic review and meta-analysis. [2022]

6. China pubmed.ncbi.nlm.nih.gov

Protocol on transcranial alternating current stimulation for the treatment of major depressive disorder: a randomized controlled trial. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

Blinding efficacy and adverse events following repeated transcranial alternating current, direct current, and random noise stimulation. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Tolerability of Repeated Application of Transcranial Electrical Stimulation with Limited Outputs to Healthy Subjects. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A double-blind, randomized, sham-controlled study of cranial electrotherapy stimulation as an add-on treatment for tic disorders in children and adolescents. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation as a therapeutic tool for the treatment of major depression: insights from past and recent clinical studies. [2009]

12. Brazil pubmed.ncbi.nlm.nih.gov

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. [2015]