An interventional study of Stimulation-ON and Stimulation-OFF in Major Depressive Disorder, sponsored by Andrew Krystal. Recruiting at 1 site in United States. Open to participants aged 22 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-08-03.
Sponsored by Andrew Krystal · Not applicable, Interventional, and Treatment
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.
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.
2,741 studies on the registry are indexed under Depressive Disorder, Major; 559 are open to participants now.
This study's planned enrollment of 12 is below the median of 80 across 2,283 interventional studies indexed under Depressive Disorder, Major.
Browse Depressive Disorder, Major studies →Andrew Krystal is the lead sponsor of 3 studies on the registry; 2 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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.
Device: Stimulation-ON
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.
Device: Stimulation-OFF
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.
Device: Stimulation-ON Active Control
Active neurostimulation from the NeuroPace RNS® System triggered by a biomarker
No neurostimulation from the NeuroPace RNS® System
Active neurostimulation from the NeuroPace RNS® System triggered by a sham biomarker
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.
Time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
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.
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
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.
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
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.
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
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.
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
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.
Time frame: administered at Weeks 30 and every 2 weeks for the last 18 weeks of Stage 3
Stimulation site identification
Over 50% of patients move from Stage 1 to Stage 2 (stimulation site that acutely improved mood identified)
Time frame: Final study visit of Stage 1 (roughly 3-6 months after initial enrollment)
Biomarker identification in Stage 1
The number of patients in whom we can identify a neural biomarker that accounts for a significant amount of variance in depression symptom severity
Time frame: Final study visit of Stage 1 (roughly 3-6 months after initial enrollment)
Number of patients who had viable biomarker(s) identified in Stage 2
The number of patients in whom we can identify a neural biomarker utilizing the RNS system that accounts for a significant amount of variance in depression symptom severity
Time frame: Final study visit of Stage 2 (up to 1 year duration)
The number of patients in whom we can identify a neural biomarker utilizing the RNS system that accounts for a significant amount of variance in depression symptom severity
The number of patients in whom we can find a personalized biomarker of depression in terms of accounting for significant variance in depression
Time frame: Assessed at the final study visit of Stage 3 (1 year duration)
The number and type of serious adverse events for patients that occur in closed-loop deep brain stimulation with the device
The number and type of serious adverse events that occur in comparison to comparable open-loop deep brain stimulation trials
Time frame: Safety will be monitored continuously throughout the ~2 years of trial enrollment
Relationship of biomarkers identified in Stage 2 and Stage 1
The number of subjects for whom the biomarker identified with Stage 1 data is able to be replicated in Stage 2 in terms of a measure obtained from the same recording site and in a comparable frequency range accounting for a significant amount of variance in depression severity.
Time frame: Assessed at the end of Stage 2 (up to 1.5 year duration)
Achievement of Long-Term Symptom Control
Number of subjects who achieve long-term symptom control with treatment in terms of being in remission at the end of the 3 months of active therapy between the two randomized trials in Stage 3.
Time frame: Assessed at end of Stage 3 (up to 1 year duration)
Non-inferiority of closed loop vs open-loop intermittent stimulation therapy and sham stimulation
Number of subjects for whom active closed-loop therapy is associated with equal or lower MADRS scores compared with: 1) active intermittent stimulation driven by a sham biomarker control and 2) sham stimulation control.
Time frame: administered at baseline and every 2 weeks for the first 18 weeks of stage 3
Plan to share: No
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