rTMS + Cognitive Therapy for Depression

Overseen By Carlos A Zarate, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Mental Health (NIMH)

Must be taking: Antidepressants

Must not be taking: Seizure threshold-lowering drugs

Disqualifiers: Substance abuse, Tinnitus, Seizure history, others

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

Compensation: Varies

Number of Visits: 34

Duration: 6-7 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Repetitive transcranial magnetic stimulation (rTMS) is a treatment for depression. It stimulates the brain. Researchers want to see if using magnetic resonance imaging (MRI) scans helps locate the best area for rTMS in each person. They also want to find other ways to make it more effective. Objective: To study the effects of combining MRI- guided transcranial magnetic stimulation (TMS) and talk therapy on the brain in people with depression. Eligibility: Adults ages 18-75 with a major depressive disorder and current depression. If taking an antidepressant, should have been doing so for at least 4 weeks. Design: Participants will be screened with medical and psychiatric history, psychiatric evaluation, physical exam, and blood and urine tests. Phase 1 is 1-4 visits in 1 week. Participants will have: * Brain MRI. Participants will lie on a table in a scanner. * Questions about their medical history and psychology symptoms * Tests of mood and thinking * Tests of brain activity. Participants may do tasks during these tests: * A cone with magnetic detectors is put on the head. * A cap with electrodes is put on the scalp. * TMS. A brief electrical current passes through a wire coil on the scalp. * A metal disk will be placed on the arm. A nerve will be stimulated with a small electrical shock. Phase 2 is about 6 to 7 weeks. * There will be 30 daily sessions of combined therapy and repetitive TMS (rTMS) for 6 weeks. * Participants will receive rTMS and another therapy by computer. * For rTMS, repeated pulses will pass through the coil. * This is followed by up to 3 additional visits, when: * Participants will repeat Phase 1 tests * Participants will rate their depression symptoms. Phase 3 is 3 visits over 3 months. Participants will rate their depression symptoms and repeat some of the previous questionnaires and tests of mood and thinking.

Do I need to stop my current medications to join the trial?

If you are currently taking an antidepressant, you must have been on a stable dose for at least four weeks before joining the study and continue at the same dosage throughout the trial.

What data supports the effectiveness of the treatment rTMS + Cognitive Therapy for Depression?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can improve symptoms in people with major depressive disorder (MDD), and it has been found to enhance cognitive flexibility in patients with depression. This suggests that rTMS, when combined with cognitive therapy, may be effective in treating depression. ^{1 2 3 4 5}

Is rTMS generally safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for humans, with safety guidelines established and updated over the years. While there have been some adverse events like seizures, these are rare, and safety protocols are in place to minimize risks. ^{6 7 8 9 10}

How is the rTMS + Cognitive Therapy treatment for depression different from other treatments?

The rTMS + Cognitive Therapy treatment is unique because it combines repetitive transcranial magnetic stimulation (rTMS), which uses magnetic fields to stimulate nerve cells in the brain, with cognitive therapy, a type of talk therapy. This combination aims to improve both mood and cognitive flexibility, offering a novel approach compared to traditional treatments like medication or electroconvulsive therapy. ^{1 2 3 5 11}

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Adults aged 18-75 with major depressive disorder, who have not responded to at least one antidepressant or ECT (unless within the last year), and are on a stable medication dose for four weeks. Participants must understand the study, consent to it, commit to an intensive treatment schedule, use birth control if applicable, and have a depression severity score above set thresholds.

Inclusion Criteria

Native English language speaker

All subjects must have undergone a screening assessment under protocol 01-M-0254, The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers

I have depression that didn't improve after trying at least one antidepressant or ECT, except if ECT was in the last year.

Exclusion Criteria

Subjects meeting criteria for Axis II cluster A or B diagnosis based upon DSM-IV TR criteria, which in the judgment of the Investigator may hinder the subjects in completing the procedures required by the study protocol

I have anxiety or PTSD, but my main issue is depression.

You have a higher chance of having seizures due to certain medical conditions or medications that make it more likely.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1-4 visits (in-person)

Treatment

Participants receive 30 daily sessions of combined therapy and repetitive TMS (rTMS) for 6 weeks, with additional visits for repeat tests and symptom rating

6-7 weeks

30 visits (in-person) for treatment, up to 3 additional visits for testing

Follow-up

Participants are monitored for safety and effectiveness after treatment, with standard care for depression and relapse prevention strategy

3 months

3 visits (in-person)

Treatment Details

Interventions

• Active TMS + Cognitive therapy
• Sham TMS + Cognitive therapy
• Sham TMS + mindfulness exercises
• TMS
• TMS+SST

Trial Overview The trial is testing whether combining MRI-guided transcranial magnetic stimulation (TMS) with cognitive therapy improves depression symptoms more effectively than sham TMS plus cognitive therapy. It includes initial evaluations followed by six weeks of daily sessions and subsequent follow-ups over three months.

Participant Groups

Group I: Active TMS+ Cognitive Therapy Experimental Treatment 1 Intervention

active

Group II: Sham TMS + Cognitive Therapy Placebo Group 1 Intervention

inactive

Active TMS + Cognitive therapy is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder (MDD)
• Treatment-resistant depression
• Obsessive-compulsive disorder (OCD)
• Posttraumatic stress disorder (PTSD)

Approved in European Union as rTMS for:

• Major Depressive Disorder (MDD)
• Treatment-resistant depression

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a study involving 19 middle-aged and elderly patients with refractory depression, those receiving active repetitive transcranial magnetic stimulation (rTMS) showed significant improvements in cognitive flexibility compared to those receiving sham treatment.

The active rTMS was specifically targeted at the anterior portion of the left middle frontal gyrus, suggesting a potential mechanism for enhancing cognitive function in patients with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved executive functioning following repetitive transcranial magnetic stimulation. Moser, DJ., Jorge, RE., Manes, F., et al.[2019]

Repetitive transcranial magnetic stimulation (rTMS) has been shown to be a safe and effective treatment for major depressive disorder (MDD), supported by multiple randomized controlled trials and extensive literature review.

The consensus recommendations from a group of 17 expert clinicians and researchers provide detailed guidance on the clinical application of rTMS, ensuring its safe and effective use in treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. McClintock, SM., Reti, IM., Carpenter, LL., et al.[2022]

In a study involving 10 adults with major depressive disorder, long-term maintenance therapy using repetitive transcranial magnetic stimulation (rTMS) showed that 7 participants experienced significant benefits, with some maintaining improvement without additional antidepressant medications.

The treatment was found to be safe, with no serious adverse events reported and a zero seizure rate across 1831 rTMS sessions, suggesting that rTMS could be a viable long-term option for managing depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term maintenance therapy for major depressive disorder with rTMS. O'Reardon, JP., Blumner, KH., Peshek, AD., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has been shown to have a clear clinical effect in treating major depressive disorder, particularly with left high-frequency rTMS, based on a review of 24 meta-analyses.

The study suggests that rTMS is a justified treatment option for some patients with depression, while also highlighting the need for further research on its efficacy in different stimulation methods and in patients who have not previously received medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A happiness magnet? Reviewing the evidence for repetitive transcranial magnetic stimulation in major depressive disorder. Pridmore, W., Pridmore, S.[2021]

In a study of 93 patients with major depressive disorder, augmentative rTMS treatment led to a significantly greater reduction in depression (48% decrease) and anxiety symptoms (53% decrease) compared to standard therapy alone (24% and 30% decrease, respectively).

The study found that rTMS treatment resulted in a 33% higher rate of remission compared to standard therapy, with a number needed to treat (NNT) of 3, indicating that rTMS is an effective and safe option for enhancing treatment outcomes in MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety and Tolerability of Augmentative rTMS in Treatment of Major Depressive Disorder (MDD): A Prospective Cohort Study in Croatia. Filipcic, I., Milovac, Z., Sucic, S., et al.[2019]

In a study involving 18 subjects with major depression, repetitive transcranial magnetic stimulation (rTMS) for up to 4 weeks was found to be generally safe, with no significant mean deficits in neuropsychologic function or auditory thresholds.

However, two patients experienced mild high-frequency hearing loss, indicating that while rTMS is safe for most, individual responses may vary and warrant further investigation into long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. Loo, C., Sachdev, P., Elsayed, H., et al.[2019]

Repetitive transcranial magnetic stimulation (rTMS) is generally safe for older adults with late-life depression, with only 12.4% reporting any adverse events and serious adverse events occurring in just 1.5% of cases, based on a review of 11 studies involving 353 patients.

The most common adverse events were mild, such as headaches (6.9%) and discomfort at the stimulation site (2.7%), although some serious adverse events, including psychiatric hospitalization and increased suicidal ideation, were noted in case reports, highlighting the need for further research to ensure safety in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. Overvliet, GM., Jansen, RAC., van Balkom, AJLM., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is generally a well-tolerated treatment for depression, with mild side effects like headaches being the most common, while severe adverse effects are rare.

Special precautions are necessary for certain groups, such as adolescents, pregnant women, and individuals with metal implants, but with proper assessment and monitoring, rTMS can be safely administered to many patients with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. Taylor, R., Galvez, V., Loo, C.[2019]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

Repetitive transcranial magnetic stimulation (rTMS) is a promising therapy for depression that may selectively modulate neuronal activity with fewer side effects compared to electroconvulsive therapy (ECT).

While rTMS shows potential efficacy similar to ECT in open trials for non-psychotic depression, its benefits in double-blind studies are more modest, indicating that further optimization and research are needed to fully realize its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. Hasey, G.[2017]

References

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

Improved executive functioning following repetitive transcranial magnetic stimulation. [2019]

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

Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. [2022]

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

Long-term maintenance therapy for major depressive disorder with rTMS. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A happiness magnet? Reviewing the evidence for repetitive transcranial magnetic stimulation in major depressive disorder. [2021]

5. Croatia pubmed.ncbi.nlm.nih.gov

Efficacy, Safety and Tolerability of Augmentative rTMS in Treatment of Major Depressive Disorder (MDD): A Prospective Cohort Study in Croatia. [2019]

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

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. [2019]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

10. Ireland pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. [2022]

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

Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. [2017]