Deep Brain Stimulation for Depression

(PReSiDio Trial)

Overseen By Rebecca Martinez, MS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Must not be taking: Narcotics, Anticoagulants

Disqualifiers: Psychotic disorder, Substance abuse, Seizures, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

No, you don't have to stop taking your current medications. If you're on a regimen of psychotropic medication, you should not make any changes to it during the 4 weeks before entering the study and throughout its duration.

What data supports the idea that Deep Brain Stimulation for Depression is an effective treatment?

The available research shows that the NeuroPace Responsive Neurostimulation (RNS) System is primarily used for treating epilepsy, not depression. The studies focus on its effectiveness in controlling seizures for patients with epilepsy who do not respond to medication. There is no data provided here that supports its effectiveness for treating depression. ^{1 2 3 4 5}

What safety data is available for Deep Brain Stimulation using the NeuroPace RNS System?

The NeuroPace RNS System is primarily used for treating epilepsy, specifically for patients with drug-resistant partial seizures. Safety data includes potential risks such as implant site infection and bone flap osteomyelitis. The system has been approved by the U.S. FDA, indicating a level of safety validation. However, long-term risks are not fully understood, and the available studies focus on epilepsy rather than depression. ^{1 2 3 4 6}

Is the NeuroPace Responsive Neurostimulation System a promising treatment for depression?

Yes, the NeuroPace Responsive Neurostimulation System is a promising treatment for depression. It uses deep brain stimulation, which has shown to improve symptoms in people with treatment-resistant depression. Studies have reported long-term benefits, including better mood, reduced anxiety, and improved quality of life for many patients. ^{7 8 9 10 11}

What is the purpose of this trial?

Neurons are specialized types of cells that are responsible for carrying out the functions of the brain. Neurons communicate with electrical signals. In diseases such as major depression this electrical communication can go awry. One way to change brain function is using electrical stimulation to help alter the communication between groups of neurons in the brain. The purpose of this study is to test a personalized approach to brain stimulation as an intervention for depression. The study researchers will use a surgically implanted device to measure each individual's brain activity related to his/her depression. The researchers will then use small electrical impulses to alter that brain activity and measure whether these changes help reduce depression symptoms. This study is intended for patients with major depression whose symptoms have not been adequately treated with currently available therapies. The device used in this study is called the NeuroPace Responsive Neurostimulation (RNS) System. It is currently FDA approved to treat patients with epilepsy. The study will test whether personalized responsive neurostimulation can safely and effectively treat depression.

Research Team

Andrew Krystal, MD, MS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults aged 22-70 with major depression that hasn't improved after trying multiple treatments, including medication, psychotherapy, and ECT. Participants must have a consistent history of depression symptoms and not be planning any changes to their current medication regimen during the study. They should be able to attend research visits, perform at-home protocols, speak English, and provide informed consent.

Inclusion Criteria

Willing and able to attend multiple research visits and perform at-home research protocol

I am willing and able to participate in a study involving brain recording/stimulation.

Has MADRS score of > 26 at both baseline and screening visit

Exclusion Criteria

MRI (done within one year of the first visit) with significant abnormalities

Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety

Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1: Electrode Implantation and Testing

Surgical implantation of electrodes to identify personalized treatment sites and test stimulation effects on depression symptoms. Electrodes are removed at the end of this stage.

3-6 months

Stage 2: NeuroPace RNS System Implantation

Implantation of the NeuroPace RNS System and identification of personalized brain activity patterns correlated with depression symptoms over 4-12 months.

4-12 months

Stage 3: Intervention Testing

Testing the effectiveness of the intervention with ON and OFF periods over 12 months, including two 6-week periods with no stimulation.

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment. Option to continue with long-term follow-up or have the RNS System removed.

up to 1 year

Treatment Details

Interventions

• NeuroPace Responsive Neurostimulation (RNS) System

Trial Overview The trial is testing a personalized brain stimulation device called NeuroPace RNS System—approved for epilepsy—to see if it can safely treat major depression. It involves surgically implanting the device to measure brain activity related to depression and using electrical impulses to potentially alter this activity.

Participant Groups

Group I: Arm 1: Intervention (stimulation ON) Experimental Treatment 1 Intervention

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

Group II: Arm 3: Active Control (stimulation ON triggered by sham biomarker) Active Control 1 Intervention

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

Group III: Arm 2: Sham Control (stimulation OFF) Placebo Group 1 Intervention

This is a crossover trial. Each patient will receive 6 wks of stimulation ON (arm 1), stimulation OFF (arm 2), and Stimulation ON Active Control (sham biomarker) (arm 3) in random order. After 6 months of intervening therapy, this 3-period crossover study will be repeated.

NeuroPace Responsive Neurostimulation (RNS) System is already approved in United States for the following indications:

Approved in United States as NeuroPace RNS System for:

• Epilepsy

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Andrew Krystal

Lead Sponsor

Trials

2

Recruited

10+

Findings from Research

In a study involving 57 patients with medically refractory focal epilepsy, the Responsive Neurostimulation (RNS) System demonstrated a median reduction in seizure frequency of 60%, with 27% of patients achieving complete seizure freedom after a median follow-up of 23.1 months.

The surgical techniques described for implanting the RNS System were safe, with no infections or major complications reported, although some patients experienced lead fractures requiring exchanges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Operative Technique and Lessons Learned From Surgical Implantation of the NeuroPace Responsive Neurostimulation® System in 57 Consecutive Patients. Krucoff, MO., Wozny, TA., Lee, AT., et al.[2021]

The study involved 8 patients and demonstrated that using intraoperative computed tomography (iCT) during the implantation of the NeuroPace responsive neurostimulation (RNS) system allows for accurate targeting of leads, with a mean Euclidean distance error of only 2.63 mm.

Postoperative results showed a significant reduction in seizure frequency, from a median of 3.4 seizures per month preoperatively to 0.78 seizures per month, indicating the efficacy of the RNS system in managing seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implantation of Responsive Neurostimulation for Epilepsy Using Intraoperative Computed Tomography: Technical Nuances and Accuracy Assessment. Kerolus, MG., Kochanski, RB., Rossi, M., et al.[2017]

In a study involving 16 patients with medically refractory focal epilepsy, robotic-assisted implantation of the responsive neurostimulation system (RNS) led to an impressive average seizure reduction of 82% at 6 months and 90% at 1 year, demonstrating its efficacy as a treatment.

The use of the ROSA robot for targeting ictal-onset zones resulted in a highly accurate lead placement, with only a 0.165-mm discrepancy between the expected and actual lead locations, indicating a precise method for improving seizure control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Robotic-Assisted Technique to Implant the Responsive Neurostimulation System. Tran, DK., Paff, M., Mnatsakanyan, L., et al.[2021]

The NeuroPace® RNS® System is a safe and effective neuromodulation device for patients with epilepsy who do not respond to traditional antiseizure medications, providing a nondestructive alternative to surgical resection.

Clinical trials have shown that the RNS System can detect and respond to epileptiform activity by delivering targeted electrical stimulation, which may lead to improved seizure control and could be adapted for other neurological disorders using advanced machine learning techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The RNS System: brain-responsive neurostimulation for the treatment of epilepsy. Jarosiewicz, B., Morrell, M.[2021]

In patients with the RNS System for epilepsy, a significant reduction in 'long episodes' of electrographic seizures within the first week of starting new antiseizure drugs (ASDs) was highly predictive of the medication's efficacy.

In a larger multicenter study, a decrease in 'episode starts' by 50% or more within the first 1-2 weeks was 90% specific for effective medications, suggesting that early neurophysiological data can guide quicker medication adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early detection rate changes from a brain-responsive neurostimulation system predict efficacy of newly added antiseizure drugs. Quraishi, IH., Mercier, MR., Skarpaas, TL., et al.[2021]

The NeuroPace RNS System can provide symptomatic relief for patients with drug-resistant partial seizures, but it carries significant risks of implant site infection and bone flap osteomyelitis, as seen in 3 reported cases.

In this study, 10% of patients developed infections related to the RNS device, particularly after multiple battery replacements, highlighting the need for improved techniques to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implant Site Infection and Bone Flap Osteomyelitis Associated with the NeuroPace Responsive Neurostimulation System. Wei, Z., Gordon, CR., Bergey, GK., et al.[2019]

Deep brain stimulation can be effectively personalized for treating major depression by using neural biomarkers to trigger therapy when symptoms worsen, as demonstrated in a case study.

The implementation of a closed-loop therapy system led to rapid and sustained improvements in depression for the individual patient, suggesting a promising direction for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Closed-loop neuromodulation in an individual with treatment-resistant depression. Scangos, KW., Khambhati, AN., Daly, PM., et al.[2021]

Deep brain stimulation (DBS) shows promise as a treatment for patients with major depression who do not respond to conventional therapies, with about 50% of patients experiencing long-term antidepressant effects and improved social functioning.

While cognitive safety regarding attention, learning, and memory has been reported, there are potential adverse events such as wound infection and suicide, highlighting the need for larger studies to confirm safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation for major depression. Schlaepfer, TE., Bewernick, BH.[2013]

Deep brain stimulation (DBS) targeting the subcallosal cingulate cortex (SCC) shows promising efficacy for treatment-resistant depression (TRD), with response rates ranging from 23% to 92% and remission rates between 27% and 66.7% based on a review of 14 studies involving 230 patients.

The adverse effects associated with SCC DBS are generally transient and related to stimulation, indicating a favorable safety profile for this experimental treatment in TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcallosal Cingulate Cortex Deep Brain Stimulation for Treatment-Resistant Depression: A Systematic Review. Sobstyl, M., Kupryjaniuk, A., Prokopienko, M., et al.[2022]

Deep brain stimulation (DBS) targeting the nucleus accumbens showed sustained antidepressant and anxiolytic effects in 45% of the 11 patients with treatment-resistant depression over a follow-up period of up to 4 years.

All patients reported improvements in quality of life, and there were no severe adverse events related to the treatment, indicating that NAcc-DBS is a safe and potentially effective long-term intervention for TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Bewernick, BH., Kayser, S., Sturm, V., et al.[2021]

Deep brain stimulation (DBS) is a new treatment method for depressive disorders, first applied in 2005 by Helen Mayberg, targeting Brodmann area 25 to alleviate symptoms of depression.

Only 30-40 patients with treatment-resistant depression have undergone DBS, highlighting the experimental nature of this approach and the challenges associated with its application in psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Deep brain stimulation--the newest physical method of treatment of depression]. Zyss, T., Zieba, A., Hese, RT., et al.[2018]

References

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

Operative Technique and Lessons Learned From Surgical Implantation of the NeuroPace Responsive Neurostimulation® System in 57 Consecutive Patients. [2021]

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

Implantation of Responsive Neurostimulation for Epilepsy Using Intraoperative Computed Tomography: Technical Nuances and Accuracy Assessment. [2017]

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

A Novel Robotic-Assisted Technique to Implant the Responsive Neurostimulation System. [2021]

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

The RNS System: brain-responsive neurostimulation for the treatment of epilepsy. [2021]

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

Early detection rate changes from a brain-responsive neurostimulation system predict efficacy of newly added antiseizure drugs. [2021]

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

Implant Site Infection and Bone Flap Osteomyelitis Associated with the NeuroPace Responsive Neurostimulation System. [2019]

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

Closed-loop neuromodulation in an individual with treatment-resistant depression. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Deep brain stimulation for major depression. [2013]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Subcallosal Cingulate Cortex Deep Brain Stimulation for Treatment-Resistant Depression: A Systematic Review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. [2021]

11. Poland pubmed.ncbi.nlm.nih.gov

[Deep brain stimulation--the newest physical method of treatment of depression]. [2018]