Major Depressive DisorderPReSiDioNCT04004169
Closed-Loop Deep Brain Stimulation for Major Depression
A study testing Stimulation-ON and Stimulation-OFF in people with Major Depressive Disorder, run by Andrew Krystal at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 22 to 70 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Stimulation-ON and Stimulation-OFF
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 18 Jul 2019to 28 Jun 2035
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 22 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 22-70
- Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID) with current episode ≥ 2 years that is treatment- resistant (4 adequate trials (including ECT), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF).
- Failed electroconvulsive therapy (ECT) due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects.
- Has MADRS score of > 26 at both baseline and screening visit
- The presence of variability on repeated administrations of MDD rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker.
- If patient is on a regimen of psychotropic medication, no changes in this regimen should be made during the 4 weeks prior to entry into and the duration of the study.
Show all 10Show fewer
- Willing and able to undergo invasive brain recording/stimulation study
- Willing and able to attend multiple research visits and perform at-home research protocol
- Willing and able to provide informed consent
- Ability to speak and read English
Who cannot join
- Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID
- Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode
- Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)
- History of suicide attempt requiring hospitalization in previous 2 years.
- Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID
- Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety
Show all 24Show fewer
- Fibromyalgia or chronic fatigue syndrome
- Current condition requiring chronic narcotic use
- History of traumatic brain injury, another neurological disorder, or developmental delay
- History of seizures
- MRI (done within one year of the first visit) with significant abnormalities
- Previous ablative intracranial surgery or previously implanted deep brain stimulation system or any previously implanted device treatment involving brain stimulation
- Implantable hardware not compatible with MRI or with the study
- Major medical co-morbidities increasing the risk of surgery including severe diabetes, major organ system failure, history of hemorrhagic stroke, need for chronic anticoagulation other than aspirin, active infection, intracranial space occupying lesion, increased intracranial pressure, cardiovascular accident within the last month, aneurysm/abnormality, retinal detachment, unstable cardiovascular disease (recent myocardial infarction, severe ischemia, severe or uncontrolled hypertension), immunocompromised state, or malignancy with < 5 years life expectancy
- Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after surgery. - Patients taking these medications will need to discuss the need/risk of continuing these medications with their physicians and the PI or study personnel may contact the treating physician(s) to discuss the risks of anticoagulation/antiaggregation therapy discontinuation
- Coagulopathy. Patients will be excluded unless assessed and cleared by hematology
- Allergies or known hypersensitivity to materials in the NeuroPace RNS® System (i.e. titanium, polyurethane, silicone, polyetherimide, stainless steel)
- Subject lives alone without possibility of caregiver support post-hospital stay
- Inability to comply with study follow-up visits
- Women who are pregnant, plan to become pregnant, or breast feeding
- Inability to speak and/or read English
- Inability to give consent
- Significant cognitive impairment or dementia (MoCA < 25)
- Likely to require ECT during the course of the study
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of California, San Francisco
San Francisco, California, 94143
Katherine Scangos, MD, PhD, 415- 476-7439, trdepression@ucsf.edu
Rebecca Martinez, MS, 415- 476-7439, rebecca.martinez@ucsf.edu
About this study
Official title: Closed-Loop Deep Brain Stimulation for Treatment-Resistant Depression
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.
Read the detailed description
This is a single-center 3-stage feasibility study of personalized closed-loop stimulation for treatment resistant Major Depressive Disorder. Depending on participant's results at each stage, he/she might not be eligible to proceed to all 3 stages.
Stage 1 of the study will involve surgically implanting small, thin electrodes in brain regions that regulate depression in order to identify personalized treatment sites. The researchers will test stimulation in the different brain regions and their effect on depression symptoms. The electrodes will be surgically removed at the end of Stage 1.
Stage 2 will involve a second brain surgery to implant the NeuroPace RNS® System. Researchers will use information from Stage 1 to decide where to implant the electrodes of the RNS System. Over the next ~4-12 months, participants will have regular study visits in the clinic where the researchers will determine a personalized brain activity pattern that correlates with depression symptoms and can be paired with stimulation to improve depression symptoms.
Stage 3 will be 12 months long and will involve turning ON and OFF the intervention to test its effectiveness. Over the course of a year, the participant will have two 6-week periods with no stimulation and will receive the intervention for the remainder of the time.
At the end of this stage the participant can choose to continue with long-term follow-up or have the RNS System surgically removed.
- Conditions
- Major Depressive Disorder
- Being tested
- Stimulation-ON, Stimulation-OFF, Stimulation-ON Active Control
- Keywords
- Major Depressive Disorder, Depression, Treatment-resistance, Deep brain stimulation, Closed-loop, Biomarker, Responsive neurostimulation, Brain surgery
- Medical subject headings
- Depressive Disorder, Major, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Stimulation-ONDevice
Active neurostimulation from the NeuroPace RNS® System triggered by a biomarker
Stimulation-OFFDevice
No neurostimulation from the NeuroPace RNS® System
Stimulation-ON Active ControlDevice
Active neurostimulation from the NeuroPace RNS® System triggered by a sham biomarker
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: Intervention (stimulation ON) | Experimental | 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. Receives: Device: Stimulation-ON |
| Arm 2: Sham Control (stimulation OFF) | Sham comparator | 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. Receives: Device: Stimulation-OFF |
| Arm 3: Active Control (stimulation ON triggered by sham biomarker) | Active comparator | 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. Receives: Device: Stimulation-ON Active Control |
What is being measured
The primary outcome is the main question the study is designed to answer.
change in MADRS score
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods). Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
Measured: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Secondary outcomes (5)
change in Montgomery Asberg Depression Rating Scale (MADRS) score after 1 year
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods at the end of Stage 3. Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
Measured: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
difference in Hamilton Depression Rating Scale (HAMD-17) score
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
Measured: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
difference in Hamilton Depression Rating Scale (HAMD-17) score after 1 year
Mean difference in Hamilton Depression Rating Scale (HAMD-17) score across the two 6-week cross-over periods at 1 year. The score for Hamilton Depression Rating Scale ranges from 0-50, with a higher score indicating more severe depression.
Measured: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
difference in the Inventory of Depressive Symptomatology Self-Report (IDS-SR) score
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.
Measured: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score after 1 year
Mean difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score across the two 6-week cross-over periods at the of Stage 3. The scores range from 0 to 27, with higher scores indicating more depressive symptoms.
Measured: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2019
- Study start18 Jul 2019
- Primary completion28 Jun 2030 (estimated)
- Study completion28 Jun 2035 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Andrew Krystal
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Andrew Krystal, University of California, San Francisco
- Investigators
- Andrew Krystal, MD, MS, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04004169
- Sponsor's protocol ID
- 17-23724
- Acronym
- PReSiDio
- Status last verified
- Jul 2026
- First submitted
- 26 Jun 2019
- Last updated
- 3 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Starkweather CK, Sugrue LP, Cajigas I, Speidel B, Krystal AD, Scangos K, Chang EF. Stereoelectroencephalography Electrode Implantation for Inpatient Workup of Treatment-Resistant Depression. Neurosurgery. 2024 Oct 1;95(4):941-948. doi: 10.1227/neu.0000000000002942. Epub 2024 Apr 19.
PubMed 39283114
Study at a glance
From the registry record, last updated by the sponsor on 3 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Closed-Loop Deep Brain Stimulation for Treatment-Resistant Depression
- ClinicalTrials.gov ID
- NCT04004169
- Acronym / sponsor ID
- PReSiDio / 17-23724
- Conditions
- Major Depressive Disorder
- Keywords
- Major Depressive Disorder, Depression, Treatment-resistance, Deep brain stimulation, Closed-loop, Biomarker, Responsive neurostimulation, Brain surgery
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Andrew KrystalUniversity, hospital or other
- Study start
- 18 Jul 2019 (actual)
- Primary completion
- 28 Jun 2030 (estimated)
- Study completion
- 28 Jun 2035 (estimated)
- First posted
- 1 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This is a single-center 3-stage feasibility study of personalized closed-loop stimulation for treatment resistant Major Depressive Disorder. Depending on participant's results at each stage, he/she might not be eligible to proceed to all 3 stages.
Stage 1 of the study will involve surgically implanting small, thin electrodes in brain regions that regulate depression in order to identify personalized treatment sites. The researchers will test stimulation in the different brain regions and their effect on depression symptoms. The electrodes will be surgically removed at the end of Stage 1.
Stage 2 will involve a second brain surgery to implant the NeuroPace RNS® System. Researchers will use information from Stage 1 to decide where to implant the electrodes of the RNS System. Over the next ~4-12 months, participants will have regular study visits in the clinic where the researchers will determine a personalized brain activity pattern that correlates with depression symptoms and can be paired with stimulation to improve depression symptoms.
Stage 3 will be 12 months long and will involve turning ON and OFF the intervention to test its effectiveness. Over the course of a year, the participant will have two 6-week periods with no stimulation and will receive the intervention for the remainder of the time.
At the end of this stage the participant can choose to continue with long-term follow-up or have the RNS System surgically removed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm 1: Intervention (stimulation ON) | Experimental | Device: Stimulation-ONThis 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. |
| Arm 2: Sham Control (stimulation OFF) | Sham comparator | Device: Stimulation-OFFThis 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. |
| Arm 3: Active Control (stimulation ON triggered by sham biomarker) | Active comparator | Device: Stimulation-ON Active ControlThis 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. |
Who may qualify
- Ages
- 22 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Age 22-70
- Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID) with current episode ≥ 2 years that is treatment- resistant (4 adequate trials (including ECT), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF).
- Failed electroconvulsive therapy (ECT) due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects.
- Has MADRS score of > 26 at both baseline and screening visit
- The presence of variability on repeated administrations of MDD rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker.
Key exclusion criteria (24 listed)
- Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID
- Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode
- Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)
- History of suicide attempt requiring hospitalization in previous 2 years.
- Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Stimulation-ONActive neurostimulation from the NeuroPace RNS® System triggered by a biomarker | Device | Arm 1: Intervention (stimulation ON) |
| Stimulation-OFFNo neurostimulation from the NeuroPace RNS® System | Device | Arm 2: Sham Control (stimulation OFF) |
| Stimulation-ON Active ControlActive neurostimulation from the NeuroPace RNS® System triggered by a sham biomarker | Device | Arm 3: Active Control (stimulation ON triggered by sham biomarker) |
Primary outcome
change in MADRS score
Time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Effect size of active compared to sham stimulation (mean difference in Montgomery Asberg Depression Rating Scale (MADRS) score before and after the sham and treatment periods). Higher MADRS score indicates more severe depression; the overall score ranges from 0 to 60.
5 secondary outcomes
change in Montgomery Asberg Depression Rating Scale (MADRS) score after 1 year
Time frame: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
difference in Hamilton Depression Rating Scale (HAMD-17) score
Time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
difference in Hamilton Depression Rating Scale (HAMD-17) score after 1 year
Time frame: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
difference in the Inventory of Depressive Symptomatology Self-Report (IDS-SR) score
Time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
difference in Inventory of Depressive Symptomatology Self-Report (IDS-SR) score after 1 year
Time frame: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2026.
- Derived from this study: PubMed 39283114Starkweather CK, Sugrue LP, Cajigas I, Speidel B, Krystal AD, Scangos K, Chang EF. Stereoelectroencephalography Electrode Implantation for Inpatient Workup of Treatment-Resistant Depression. Neurosurgery. 2024 Oct 1;95(4):941-948. doi: 10.1227/neu.0000000000002942. Epub 2024 Apr 19.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Andrew Krystal, MD, MS principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Stimulation-ON and Stimulation-OFF in people with Major Depressive Disorder, run by Andrew Krystal at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Katherine Scangos, MD, PhD (415-476-7439, trdepression@ucsf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
change in MADRS score (time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04004169, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2026.