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) |
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