rTMS for TBI-related Depression

(ADEPT Trial)

Recruiting at 4 trial locations

Overseen By Maheen M Adamson, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine

Must be taking: Psychotropic medications

Must not be taking: Tricyclics, Neuroleptics

Disqualifiers: Seizure history, Bipolar, Schizophrenia, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: Approximately 4 weeks

198 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a brain stimulation technique called repetitive transcranial magnetic stimulation (rTMS) in easing depression linked to concussions or mild traumatic brain injuries (TBI) in U.S. military members and veterans. The researchers will compare two active rTMS methods to a sham version to determine which is most effective and safe. It suits current or former military personnel who experienced a concussion over six months ago and are dealing with ongoing depression. As an unphased trial, this study allows participants to contribute to groundbreaking research that could enhance mental health treatments for military personnel.

Will I have to stop taking my current medications?

The trial requires participants to have been on a steady psychotropic medication regimen for six weeks before joining, so you may need to continue your current medications. The protocol does not specify if you must stop other medications, but you should discuss this with the study team.

What prior data suggests that rTMS is safe for treating TBI-related depression?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) is generally safe and well-tolerated. One study used rTMS on patients with depression after a traumatic brain injury (TBI), and they handled it well, with no serious side effects reported. Another study found that most people did not experience significant negative effects from rTMS. Some might have mild headaches or discomfort at the treatment site, but these usually resolve on their own.

In summary, rTMS appears to be a safe option for treating depression, even for those with a history of TBI. However, it is important to consult a healthcare provider about any concerns before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for TBI-related depression typically involve medications and psychotherapy, which can take weeks to show effectiveness. Researchers are excited about rTMS (repetitive Transcranial Magnetic Stimulation) because it offers a non-invasive, faster-acting alternative by using magnetic fields to stimulate specific areas of the brain. This trial explores two innovative approaches: one using resting state functional MRI (rsfMRI) to precisely target areas of the brain, and another using Individualized Connectome Targeting (ICT) for a more personalized treatment. These methods have the potential to enhance the precision and effectiveness of rTMS, offering hope for quicker and more targeted relief from depression symptoms.

What evidence suggests that rTMS is effective for TBI-related depression?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) can greatly reduce depression symptoms in people who have had a traumatic brain injury (TBI). In this trial, participants will be assigned to different arms to receive either active rTMS or sham rTMS. One study found that patients with TBI experienced a noticeable short-term improvement in their depression after receiving rTMS treatment aimed at the left side of the front part of the brain, which helps control mood. Stimulating this area with rTMS seems to help ease depression symptoms. Another study found that rTMS may also help with depression after a concussion. These findings suggest that rTMS is a promising option for treating depression related to TBI. ^{3 6 7 8 9}

Who Is on the Research Team?

David L Brody, MD, PhD

Principal Investigator

Uniformed Services University of the Health Sciences

Are You a Good Fit for This Trial?

This trial is for U.S. military service members or veterans aged 18-50 with a history of concussion/mild TBI and depression. They must have stable medication and therapy regimens, be able to consent in English, and have experienced specific short-term memory or consciousness changes due to TBI.

Inclusion Criteria

Baseline MADRS >13 at the time of screening indicating at least mild-moderate depressive symptoms

Under the care of a primary care and/or behavioral health provider

Current or former US military service member eligible for care at a MTF or VAMC

Exclusion Criteria

Intracranial lesion compromising the integrity of rsfMRI data

Unable to complete timeline of study

I have a fast-progressing illness like advanced cancer or major organ failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rTMS treatment targeting the dorsolateral prefrontal cortex to alleviate depressive symptoms

Approximately 4 weeks

16 sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• rTMS
• Sham rTMS

Trial Overview The study tests the effectiveness of two types of rTMS treatments on alleviating depression symptoms in individuals with a history of mild TBI. Participants will receive either actual rTMS or sham (placebo) treatment targeting the DLPFC area of the brain.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 1 Intervention

Active rTMS/resting state functional MRI (rsfMRI)-based targeting

Group II: Arm 1 Experimental Treatment 1 Intervention

Active rTMS/Individualized Connectome Targeting (ICT)

Group III: Arm 3 Placebo Group 2 Interventions

Sham rTMS

rTMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder
• Migraines
• Smoking cessation

Approved in European Union as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder

Who Is Running the Clinical Trial?

Henry M. Jackson Foundation for the Advancement of Military Medicine

Lead Sponsor

Trials

103

Recruited

94,300+

Congressionally Directed Medical Research Programs

Collaborator

Trials

59

Recruited

10,600+

Uniformed Services University of the Health Sciences

Collaborator

Trials

130

Recruited

91,100+

Published Research Related to This Trial

Repetitive transcranial magnetic stimulation (rTMS) can be safely administered to individuals with traumatic brain injury (TBI) when following specific guidelines, minimizing risks such as seizures.

In a case study of a 48-year-old man with severe TBI, rTMS treatment for post-TBI depression over 6 weeks led to a 49% reduction in depression symptoms, demonstrating its potential efficacy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury. Nielson, DM., McKnight, CA., Patel, RN., et al.[2022]

This study presents a novel case of using transcranial magnetic stimulation (TMS) to treat depression in a patient who experienced a traumatic brain injury (TBI), addressing a significant gap in treatment options for this population.

Traditionally, TBI has been seen as a risk factor for complications in TMS treatment, but this case suggests that TMS may be a safe and effective intervention for managing depression following TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for depression after a traumatic brain injury: a case study. Fitzgerald, PB., Hoy, KE., Maller, JJ., et al.[2022]

In a safety and efficacy study involving a 26-year-old man with severe traumatic brain injury (TBI), a 6-week rTMS protocol showed no adverse events, indicating it is a safe treatment option for individuals in a minimally conscious state.

The rTMS treatment was associated with a trend toward significant neurobehavioral improvements and enhanced neural conduction, suggesting its potential to facilitate recovery in patients with severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation-associated neurobehavioral gains during coma recovery. Louise-Bender Pape, T., Rosenow, J., Lewis, G., et al.[2016]

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]

Transcranial magnetic stimulation (TMS) was found to be safe and well tolerated in a study of 21 patients with depression following traumatic brain injury (TBI), with no adverse effects reported during the treatment.

While TMS did not significantly reduce depressive symptoms in these patients, it did lead to notable improvements in cognitive functions such as working memory and executive function, suggesting potential benefits for cognitive rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Investigation of Repetitive Transcranial Magnetic Stimulation for Post-Traumatic Brain Injury Depression: Safety, Tolerability, and Efficacy. Hoy, KE., McQueen, S., Elliot, D., et al.[2020]

A patient with treatment-resistant depression (TRD) showed unexpected improvement after experiencing a seizure during repetitive transcranial magnetic stimulation (rTMS), suggesting a potential link between seizure activity and therapeutic effects in TRD.

While rTMS is generally safe, known adverse events include headaches and seizures; this case highlights an unusual outcome where a seizure may have contributed to the patient's improvement, warranting further investigation into the mechanisms of rTMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. Kim, JW., Bae, KY., Kim, SW., et al.[2020]

Repetitive Transcranial Magnetic Stimulation (rTMS) has a good overall safety profile for treating depression, with common side effects like headaches being minor and manageable.

While there is a low incidence of serious side effects such as seizures and hypomania, these are linked to specific risk factors, suggesting that proper screening can enhance patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Loo, CK., McFarquhar, TF., Mitchell, PB.[2021]

In a pilot study involving 15 participants with treatment-resistant depression following traumatic brain injury, individualized rTMS targeting specific brain networks showed a significant improvement in depression symptoms, with a 56% improvement on the MADRS scale compared to 27% in the sham group.

The study found no significant adverse events, indicating that rTMS is a safe intervention for this population, and suggests that further research with larger sample sizes is needed to confirm these promising results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study. Siddiqi, SH., Trapp, NT., Hacker, CD., et al.[2020]

Repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) showed a significant short-term antidepressant effect in patients with depression following traumatic brain injury (TBI), with a standardized mean difference (SMD) of 1.03 based on seven randomized controlled trials.

While rTMS improved visuospatial memory in post-TBI patients, its effects on cognitive functions like processing speed and selective attention were not significant, and it did not show superiority over sham treatment for postconcussion syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of repetitive transcranial magnetic stimulation on depression and cognition in individuals with traumatic brain injury: a systematic review and meta-analysis. Tsai, PY., Chen, YC., Wang, JY., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) may offer a targeted treatment for depression following traumatic brain injury (TBI) with potentially fewer side effects compared to standard medications, but safety concerns regarding seizure risk must be addressed.

The review suggests that low frequency rTMS could be a safer option for TBI patients, as it is less likely to induce seizures compared to high frequency rTMS, highlighting the need for pilot safety studies before larger trials can be conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation: A potential new treatment for depression associated with traumatic brain injury. Reti, IM., Schwarz, N., Bower, A., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) shows promise as an effective treatment for various symptoms following traumatic brain injury (TBI), such as depression and dizziness, based on a review of 30 studies.

While rTMS is generally well-tolerated, there have been reports of side effects and seizures, highlighting the need for careful monitoring and standardized treatment protocols in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of repetitive transcranial magnetic stimulation (rTMS) following traumatic brain injury (TBI): A scoping review. Pink, AE., Williams, C., Alderman, N., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36737300/

Repetitive Transcranial Magnetic Stimulation for Depression ... Of these, 665 (86.4%) had data on TBI and lifetime number of head injuries while 658 had complete data related to depression outcomes.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0278584623001495

Effectiveness of rTMS and tDCS treatment for chronic TBI ... This study aims at providing a systematic review and meta-analysis on the effectiveness of repetitive transcranial magnetic stimulation (TMS) and transcranial ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34417481/

Effect of repetitive transcranial magnetic stimulation on ... In conclusion, the short-term antidepressant effect of left DLPFC rTMS in patients with TBI was significant. However, the effectiveness of rTMS ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05426967

NCT05426967 | rTMS for Military TBI-related Depression rTMS may hold a therapeutic potential for alleviating symptoms of depression after concussion. This study is a randomized, double-blind, Bayesian adaptive trial ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S109471592201399X

Repetitive Transcranial Magnetic Stimulation for ... Of these, 665 (86.4%) had data on TBI and lifetime number of head injuries while 658 had complete data related to depression outcomes. Depression symptoms ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30712461/

A Pilot Investigation of Repetitive Transcranial Magnetic ... The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02367521

Repetitive Transcranial Magnetic Stimulation (rTMS) for the ... The overarching goal of this small study is to determine the effectiveness of low frequency right (LFR) rTMS for the treatment of post-TBI depression and co- ...

8. nature.com nature.com/articles/s41598-021-95838-2

Effect of repetitive transcranial magnetic stimulation on ... We conducted a meta-analysis to assess the effectiveness of executing rTMS over dorsolateral prefrontal cortex (DLPFC) on depression, cognitive impairment and ...

9. surgicalneurologyint.com surgicalneurologyint.com/surgicalint-articles/use-of-repetitive-transcranial-magnetic-stimulation-in-traumatic-brain-injury-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials/

Use of repetitive transcranial magnetic stimulation in ... No effect was observed regarding depression but future studies are still warranted in this important clinical field. Keywords: Cognition, ...