First Author (Year) |
Study Title |
Country, Funder(s) |
Intervention Tested |
Study Size |
Inclusion Criteria, Patient Demographics |
Trial Type |
Findings |
Investigational Brain Stimulation Target: Subcallosal Cingulate Gyrus (SCG)
|
Ramasubbu (2020) |
Long versus short pulse width subcallosal cingulate stimulation for treatment-resistant depression: a randomised, double-blind, crossover trial |
Canada --- • Alberta Innovates Health Solutions |
Condition after Short-Pulse-Width Bilateral SCG vs Condition after Long-Pulse-Width Bilateral SCG |
22 |
• Adults (ages 20 - 70) • Disabling Major Depressive Disorder and Bipolar Disorder not responding to treatment for more than 1 year • No psychosis • No obsessive compulsive disorder • No unstable, severe medical, or neurological disorders
Length: 12 months |
Randomized, Double-Blind, Crossover Trial
Approved by the Conjoint Health Research Ethics board at the University of Calgary |
• 45% responded or remitted at 6 mos. (10/22) • 50% responded or remitted at 12 mos. 11/22) • 27% in remission at 12 mos.(6/22) • 27% partially responded at 12 mos. (6/22) • Compared with short pulse width, the long pulse width group had higher remission rates, lower absolute non-response rates, and lower relapse rates • One-third of non-responders who were crossed over became responders after 6 mos.
Major Adverse Events: • Perioperative seizure (3/22) • Anxiety (7/22) • Worsening depression (5/22) • Head pain (5/22) • Infection (1/22) • Suicidality (4/22) • Suicide (1/22) |
Eitan (2017) |
One Year Double Blind Study of High vs Low Frequency Subcallosal Cingulate Stimulation for Depression |
Israel, France, United Kingdom --- • St. Jude Medical |
Condition after High (130 Hz) Frequency Bilateral SCG vs Condition after Low (20 Hz) Frequency Bilateral SCG |
9 |
• Adults (ages 21 - 70) • Single or Recurrent Treatment-Resistant Major Depressive Disorder, diagnosed before age 45 • Current depressive episode lasting at least 1 year • No psychosis, personality disorder, or medical co-morbidity • Not bipolar • At least 6 mos. remission from any co-morbid obsessive compulsive disorder, post-traumatic stress disorder, panic disorder, bulimia or anorexia nervosa • No response to at least 4 antidepressant regimens • No response to electroconvulsive therapy or vagus nerve stimulation within 1 mo. of study, no requirement to receive such therapy during the study • No substance dependence within the previous 12 mos. • No substantial suicide risk or more than 3 attempts in the last 12 mos. • No changes in antidepressant medications at least 4 weeks prior to the study • No neurologic disorder • No cardiac pacemaker • Not pregnant
Length: 13 months |
Randomized, Double-Blind, Crossover Study
Ethics Committee Approvals |
• 1 responder at 6 mos. • High frequency stimulation yielded better results than low frequency after 6 mos. • Effect 6 mos. after crossover higher than the 6 mos. before • Recruitment stopped with 9 patients at 3 centers (original design was for 60 patients at eight centers over 2 years)
Major Adverse Events: • Post-surgical headache (1/9) |
Holtzheimer (2017) |
Subcallosal cingulate deep brain stimulation for treatment- resistant depression: a multi-site, randomized, sham-controlled trial
|
United States --- • Abbott (previously St. Jude Medical) |
Condition after 6 Mos. Bilateral SCG vs Condition after 6 Mos. Sham
|
90 |
• Adults (ages 21 - 70) • Medication-resistant, unipolar, Major Depressive Disorder diagnosed before 45 years of age • Current depressive episode lasting at least 1 year (average: about 12 years) • No response to at least 4 anti-depressive drug regimens • Failure of or inability to receive electroconvulsive therapy • Failure of psychotherapy • No substantial risk of suicide • No psychotic, personality, or substance-use disorder • No neurologic disorder
Length: 12 months, plus open-label followup |
Double Blinded Crossover Study followed by an Open-Label Study
Performed with FDA Investigational Device Exemption Approvals and Approved by the Institutional Review Board |
• 20% Active stimulation responders at 6 mos. (12/60) • 5% Active stimulation remitters at 6 mos. (3/60) • Sham group showed no significant improvement in scores after 6 mos. of active stimulation (30) • Sponsor ended enrollment after futility analysis showed 17% chance of success • During open-label followup, response was achieved in 26 (29%) patients at 12 months, 41 (53%) at 18 months, and 38 (49%) at 24 months; remission in 13 (14%) patients at 12 months, 14 (18%) at 18 months, and 20 (26%) at 24 months
• In participants with up to 2 years of open-label active stimulation, 48% achieved an antidepressant response and 25% achieved remission
Major Adverse Events: • Infection (6/90) • Anxiety (4/90) • Worsening depression (1/90) • Head pain (1/90) • Skin erosion (1/90) • Suicidality (5/90) • Suicide (2/90) • Perioperative seizure (1/90) |
Puigdemont (2015)
|
A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression
|
Spain --- • Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain • Fondo de Investigacion Sanitaria, Spain |
In Previously Implanted Patients in Remission: Condition after 3 Mos. SCG vs Condition after 3 Mos. Sham |
5 |
• Adults (ages 18 - 70) • Medication Resistant Major Depressive Disorder, in stable remission from chronic SCG DBS • Prior to initial implantation: score of 4 in the Thase-Rush index & Hamilton Depression Rating Scale score of 18 or more • Failure of or inability to receive electroconvulsive therapy • No change in antidepressant medication in the preceding month • No acute, serious, or unstable illness, substance abuse, concomitant metal illness, or personality disorder • Not pregnant
Length: 6 months
|
Double-Blind, Randomized, Sham-Controlled Crossover Pilot Study |
• Depression remitted at end of active stimulation (4/5) • Progressive worsening or depression recurrence with discontinuation of stimulation (3/2) • Patients with higher depression scores during sham stimulation showed a significant treatment effect (χ(2)1 = 5.0, p = 0.025)
Major Adverse Events: None |
Holtzheimer (2012) |
Subcallosal cingulate deep brain stimulation for treatment- resistant unipolar and bipolar depression |
United States --- • National Institutes of Health • Dana Foundation • Emory Healthcare • Stanley Medical Research Institute • Woodruff Foundation • St. Jude Medical |
Condition after Bilateral SCG vs Condition before Implantation |
17 |
• Adults (ages 18 - 70) • Disabling Major Depressive Disorder (10/17) • Bipolar Disorder (7/17) • Current depressive episode lasting at least 12 months • No response to at least 4 anti-depressive drug regimens • Failure of or inability to receive electroconvulsive therapy • No recent suicidal ideation, substance abuse, or personality disorder
Length: 24 months
|
Prospective Cohort Study Performed with FDA Investigational Device Exemption Approvals and Approved by the Institutional Review Board |
• Significant improvement seen at 24 months (average of 72.4% improvement) • Discontinuation of stimulation resulted in recurrence of depression • 92% of patients had at least a 50% improvement in their depression score • 58% of patients achieved remission • Improvement in overall daily function (average of 132.2% improvement) Major Adverse Events: • Suicidality (3/17) • Worsening depression (2/17) • Anxiety (5/17) • Infection (5/17) • System malfunction (3/17) |
Lozano (2012) |
A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment- resistant depression |
United States Canada --- • St. Jude Medical |
Condition after Bilateral SCG vs Condition before Implantation |
21 |
• Adults (ages 30 - 60) • Disabling Major Depressive Disorder diagnosed before 35 years of age • No Bipolar Disorder • Current depressive episode lasting at least 24 months • No response to at least 4 anti-depressive drug regimens • Failure of or inability to receive electroconvulsive therapy • No recent suicidal ideation, substance abuse, or personality disorder • No neurologic disorder • No cardiac pacemaker • Not pregnant
Length: 12 months
|
Prospective Cohort Study Approved by each Institutional Review Board |
• Significant improvement seen at 12 months (average of 41.4% improvement) • 29% of patients had at least a 50% improvement in their depression score • 62% of patients had at least a 40% improvement in their depression score Major Adverse Events: • Suicidality (2/21) • Infection (1/21) • System malfunction (1/21) • Nausea/Vomiting (7/21) |
Kennedy (2011) |
Deep brain stimulation for treatment- resistant depression: follow-up after 3 to 6 years |
United States Canada --- • University Health Network, Toronto |
Condition after Bilateral SCG vs Condition before Implantation |
20 |
• Adults (ages 30 - 60) • Disabling Major Depressive Disorder diagnosed before 35 years of age • No Bipolar Disorder • Current depressive episode lasting at least 1 year • No response to at least 4 anti-depressive drug regimens • Failure of or inability to receive electroconvulsive therapy • No recent suicidal ideation, substance abuse, or personality disorder • No neurologic disorder • No cardiac pacemaker • Not pregnant
Length: 3-6 years (average 42 months)
|
Prospective Cohort Study Approved by Institutional Research Ethics Board |
• At 3 years, 75% of patients had at least a 50% improvement in their depression score • 42.9% of patients achieved remission • At last follow-up, 64.3% of patients had at least a 50% improvement in their depression score • Significant improvement in overall daily function seen over time Major Adverse Events: • Suicidality (3/20) • Worsening depression (3/20) • Perioperative seizure (1/20) • Infection (3/20) |
McNeely (2008) |
Neuro- psychological impact of Cg25 deep brain stimulation for treatment- resistant depression: preliminary results over 12 months |
Canada --- • Brain & Behavior Research Foundation |
Condition after Bilateral SCG vs Condition before Implantation |
6 |
• Adults (ages 37 - 59) • Severe Major Depressive Disorder • Current depressive episode lasting at least 1 year • No response to at least 4 anti-depressive drug regimens • Failure of electroconvulsive therapy (5/6)
Length: 12 months
|
Prospective Cohort Study Approved by each Institutional Ethical Review Committee |
• Significant improvement seen at 12 months (average of 60% improvement) • No negative effects on cognition with chronic stimulation Major Adverse Events: None |
Investigational Brain Stimulation Target: Supero-Lateral Branch of the Medial Forebrain Bundle (slMFB) |
Coenen (2019) |
Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial |
Germany --- • Medtronic |
Condition with Bilateral slMFB Stimulation vs Condition before Implantation |
16 |
• Adults (ages 20 - 75) • Severe treatment-resistant depression (1 bipolar patient) • At least 4 episodes of depression or chronic episode > 2 years • No response to at least 3 antidepressant drug regimens • Failure of electroconvulsive therapy • Failure of psychotherapy • Stable medication for at least 6 weeks before study entry • No comorbid psychiatric disorders (e.g., substance dependency, schizoaffective disorder, posttraumatic stress disorder, severe personality disorder) or surgical contraindication • No pregnancy
Length: 14 months |
Phase I clinical single-center trial with sham-controlled, staggered onset design
Approved by the Institutional Review Board |
• A strong acute antidepressant response in most stimulated patients within 1 week • 100% responders for at least 1 mo. (16/16) • On average, patients reached response during 60.4% of months they participated • Mean time to response: 1 week in most (10) patients; 2 weeks in 2 patients, 3 weeks in 1 patient, 10 weeks in 1 patient, and 28 weeks in 1 patient • 50% remitters at 12 mos. (8/16) • Stimulus interruption (e.g. battery depletion) led to worsening symptoms and 1 relapse
Major Adverse Events: • Infections at site of implanted pulse generator (2/16) • Hyperkinesia (1/16) • Wound healing/ skin erosion (1/16) • Suicide attempt |
Fenoy (2018) |
A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression |
United States --- • Medtronic |
Condition after Bilateral slMFB vs Condition before Implantation |
5 |
• Adults (ages 22 - 65) • Single or Recurrent Treatment-Resistant Major Depressive Disorder, diagnosed before age 45 • At least 5 years since 1st depressive episode • No bipolar disorder, non-affective psychotic disorder, schizophrenia, or schizoaffective disorder, severe personality disorder, significant neurological disorder • No changes in antidepressant medications at least 4 weeks prior to the study • No previous surgery to destroy the target region of the brain, or surgical contraindications to DBS
Length: 12 months |
Prospective Cohort Study
Performed with FDA Investigational Device Exemption Approvals and Approved by the Institutional Review Board |
• Rapid antidepressant effects; insertional effect of 28% mean score reduction during 4-week sham phase, then >50% reduction in 3/6 patients 1 week after stimulation started (1 patient responder dropped out after 2 weeks to move for family reasons) • 80% response rate at 12 weeks (4/5) • Fluctuating response over time in two patients due to family stressors (2/5) • 80% remitters at 12 mos. (4/5)
Major Adverse Events: None |
Bewernick (2017) |
Deep brain stimulation to the medial forebrain bundle for depression - long-term outcomes and a novel data analysis strategyGermany --- • Medtronic |
Germany --- • Medtronic |
Condition with Bilateral slMFB Stimulation vs Condition before Implantation |
8 |
• Adults (ages 20 - 70) • Severe treatment-resistant depression • No response to at least 3 antidepressant drug regimens • Failure of electroconvulsive therapy • Failure of psychotherapy • Stable medication for 6 weeks before and after surgery • No medical co-morbidity • No psychotic or personality disorder, or neurological disorder other than other than motor tics or Tourette syndrome • No pregnancy
Length: 4 years |
Prospective Cohort Study
Approved by the Institutional Review Board |
• 85% response rate at 3 mos. • 75% responded at 12 mos. (6/8). • 50% remitters (4/8)
Major Adverse Event: • Intracranial bleeding during surgery (1/8) |
Investigational Brain Stimulation Target: Nucleus Accumbens (NAcc)
|
Bewernick (2012) |
Long-term effects of nucleus accumbens deep brain stimulation in treatment- resistant depression: evidence for sustained efficacy |
United States Germany --- • Medtronic Inc. • Volkswagen Foundation |
Condition after Bilateral N Ac vs Condition before Implantation |
11 |
• Adults (ages 32 - 65) • Disabling Major Depressive Disorder diagnosed at least 5 years ago • Current depressive episode lasting at least 2 years • No response to at least 4 anti-depressive drug regimens • Failure of electroconvulsive therapy • Failure of psychotherapy • No psychotic or personality disorder • No neurologic disorder
Length: 24 months
|
Prospective Cohort Study Approved by each Institutional Review Board |
• Significant improvement seen at 12 months (average of 37.3% improvement) • Significant improvement seen at 24 months (average of 39.4% improvement) • 45.5% of patients had at least a 50% improvement in their depression score • Improvement in concurrent anxiety (average of 37% improvement) • No negative effects on cognition with chronic stimulation Major Adverse Events: • Suicidality (1/11) • Seizure (2/11) • Trouble with swallowing (3/11) |
Schlaepfer (2008) |
Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression |
Germany --- • Medtronic Inc. |
Condition with Bilateral N Ac Stimulation vs Condition without Stimulation vs Condition before Implantation |
3 |
• Adults (ages 37 - 66) • Severe Major Depressive Disorder • No response to anti-depressive drugs • Failure of electroconvulsive therapy • Failure of psychotherapy
Length: 12.3 ± 9.3 months (4 week crossover)
|
Double Blinded Crossover Study followed by a Prospective Cohort Study Approved by the Institutional Review Board |
• Improvement seen after one week of stimulation (average of 27.2% improvement) • Effect was significantly diminished when stimulation was turned off for one week (average of only 6.7% improvement from baseline) • Significant improvement seen at last follow-up (average of 80% improvement) Major Adverse Events: None |
Investigational Brain Stimulation Target: Ventral Anterior Limb of the Internal Capsule (vALIC)
|
van der Wal (2020) |
Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression |
The Netherlands --- • Academic Medical Center, Amsterdam, the Netherlands |
Condition During 1-Year Maintenance with Bilateral vALIC Stimulation vs Condition after Optimization vs Condition before Implantation |
18 |
• Adults (ages 18 - 65) • Major Depressive Disorder > 2 years • No response to at least 2 antidepressant drug regimens • Inadequate response or reliance on electroconvulsive therapy • No unstable physical condition or surgical contraindication • No neurologic disorder • No psychosis, antisocial personality disorder, or bipolar disorder • No alcohol or substance abuse in the last 6 mos. • No participation in a SPECT study in the year prior to the study • No pregnancy
Length (maintenance): 12 months |
Maintenance Phase after Randomized Crossover Active-Sham Phase subsequent to an initial Optimization Phase
Approved by the Hospital Medical Ethics Boards |
• 44.4% responders at 12 mos. (8/18) • 27.8% remitters at 12 mos. (5/18) • Treatment deemed effective in 32% of patients on an intention-to-treat basis after 2 years follow-up, compared to 40% after optimization • All patients who did not, or only minimally, improve in the first year did not improve in the second • Symptoms remained stable after optimization as rated by clinicians; patients' subjective ratings improved
Major Adverse Events: • Increased depressive thoughts (1) • Autointoxication (1) • Suicide attempt (1) |
Bergfeld (2016) |
Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression A Randomized Clinical Trial |
The Netherlands --- • Academic Medical Center, Amsterdam, the Netherlands |
Condition after Bilateral vALIC Stimulation vs Condition before Implantation |
25 |
• Adults (ages 18 - 65) • Major Depressive Disorder > 2 years • No response to at least 2 antidepressant drug regimens • Inadequate response or reliance on electroconvulsive therapy • No unstable physical condition or surgical contraindication • No neurologic disorder • No psychosis, antisocial personality disorder, or bipolar disorder • No alcohol or substance abuse in the last 6 mos. • No participation in a SPECT study in the year prior to the study • No pregnancy
Length: 15 months |
Open-Label Optimization (12 mos.) followed by a Randomized Crossover Active-Sham Phase (12 weeks)
Approved by the Hospital Medical Ethics Boards |
• 40% responders after optimization (10/25) • 24% partially responded (6/25) • 20% remitters following optimization phase (5/25) • Patients experienced significantly more depressive symptoms during sham compared to active stimulation
Major Adverse Events: • Severe nausea during surgery (1/25) • Suicidal ideation (2/25) • Suicide attempt (4/25) |
Investigational Brain Stimulation Target: Ventral Capsule/Ventral Striatum
|
Dougherty (2015) |
A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression |
United States --- • Medtronic Inc. |
Condition after Bilateral VC/VS Stimulation vs Condition without Stimulation vs Condition before Implantation |
30 |
• Adults (ages ≥18) • Major Depressive Disorder ≥ 2 years • No response to at least 4 trials of antidepressant therapies (1 which may have been a complete course of electroconvulsive therapy), including 3 trials during the current episode • Inadequate response to ≥ 6 weeks of psychotherapy • Psychiatric treatment regimen unchanged ≥ 30 days prior to screening • No bipolar disorder, psychotic disorder or symptoms, obsessive compulsive disorder, or primary Axis 1 disorder • No surgical contraindications • No substance dependence in the last 12 mos. • No imminent suicide risk
Length: 24 - 45 months |
Randomized Sham-Controlled Trial: blinded treatment (16 weeks) followed by open-label phase
Approved by the Institutional Review Boards |
• 20% responders to active stimulation during 16-week sham-control phase (3/15) vs. 14.3% responders to sham (2/14) • 13% remitters at 12 mos. (4/30) • 20%, 26.7%, and 23.3% responded at 12, 18, and 24 mos. during the open-label continuation phase • During long-term follow-up NO responders stayed continuously in that status; 5 held responder levels for at least 6 mos. • During the blinded phase, only individuals in the active-stimulation group experienced irritability, suicidal ideation, hypomania, disinhibition, and/or mania • Most subjects elected to continue stimulation after 24 mos. (26/30)
Major Adverse Events: • Worsening depression (8/30) • Implant site infection (5/30) • Lead revision (3/30) • Suicide attempt (4/30) • Suicide (1/30) |
Malone (2009) |
Deep brain stimulation of the ventral capsule /ventral striatum for treatment- resistant depression |
United States --- • Medtronic Inc. |
Condition after Bilateral VC/VS Stimulation vs Condition before Implantation |
15 |
• Adults (ages 18 - 55) • Severe Major Depressive Disorder (14/15) diagnosed at least 5 years ago • Current depressive episode lasting at least 2 years • Severe Bipolar Disorder (1/15) • No response to at least 5 anti-depressive drug regimens after at least 4 weeks • Failure of electroconvulsive therapy • Failure of psychotherapy • No psychotic or neurologic disorder • No recent suicidal ideation, substance abuse, or personality disorder • Not pregnant
Length: 23.5 ± 14.9 months
|
Prospective Cohort Study Performed with FDA Investigational Device Exemption Approvals and Approved by the Institutional Review Board |
• Significant improvement seen at 12 months (average of 45.5% improvement) • Significant improvement seen at last follow-up (average of 55.8% improvement) • At last follow-up, 53.3% of patients had at least a 50% improvement in their depression score and 40% of patients were considered to be in remission • Improvement in overall daily function (average of 61.8% improvement) Major Adverse Events: • Suicidality (2/15) • Worsening depression (1/15) • Lead Fracture (1/15) |