Deep Brain Stimulation in Patients With Chronic Treatment Resistant Depression (STHYM)

Major depressive disorders are real public health issues in terms of diagnosis and treatment. Some forms of depression are chronic and resistant to treatment (TRD). In these forms suicide risk is important.

Patients with TRD are potential candidates for neurosurgical interventions to treat depression. However, psychosurgery interventions based upon lesions, showed their limitations related to 1. the large variability in neurosurgical gestures, 2. their side effects, and of course 3. the irreversible damage caused by the surgery.

Thus, deep brain stimulation (DBS) could represent an opportunity for patients suffering from TRD. Our preliminary study based upon the stimulation of the accumbens nucleus showed encouraging results. The investigators have thus planned a randomized controlled trial versus sham stimulation to confirm the therapeutic value of nucleus accumbens DBS.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder; Major Depressive Disorder; Recurrent Depressive Disorder
• Intervention / Treatment: Device: DBS; Device: SHAM

Detailed Description

Because of their recurrent nature, their prevalence and their consequences, major depressive disorders are real public health issues in terms of diagnosis and treatment.

Some forms of depression are chronic and resistant to treatment (TRD), either unipolar (repeated episodes of depression) or bipolar (repeated episodes of depression and manic and/or hypomanic episodes). In these forms suicide risk is important.

Patients with TRD are potential candidates for neurosurgical interventions to treat depression. The benefit of neurosurgical procedures is expected to be important in these patients.

Psychosurgery interventions based upon lesions, however, showed their limitations related to 1/ the large variability in neurosurgical gestures, 2/ their side effects, and of course 3/ the irreversible damage caused by the surgery.

Current brain imaging data yielded fresh information about the pathophysiology of depression and suggested new therapeutic approaches in TRD.

Modulation of sub-caudate specific pathways, which are part of orbitofrontal and anterior cingulate cortico-subcortical loops should allow for a diminution of depressive symptoms.

The modulation of these specific pathways, initially targeted by classical neurosurgery, could benefit from current developments in functional neurosurgery.

Deep brain stimulation (DBS) may represent an opportunity for patients suffering from TRD. Our preliminary study based upon the stimulation of the accumbens nucleus showed encouraging results. The investigators have thus planned a randomized controlled trial versus sham stimulation to confirm the therapeutic value of nucleus accumbens DBS.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Marseille, France
    • APHM
  • Paris, France
    • APHP Pitié Salpétrière
  • Poitiers, France
    • CHS
  • Rouen, France
    • CHS
  • Toulouse, France
    • CHU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 70 years
• DSM-IV (DSM = Diagnostic and Statistical Manual) criteria for a recurrent depressive disorder or bipolar disorder
• Duration of the episode > 2 years

• Severity of the episode attested by :

  • A HDRS score > 21
  • A CGI score ≥ 4
  • A GAF < 50
• Persistence of severity criteria during the screening

• Following characteristics resistance in case of recurrent depressive disorder :

  • Stage V of the classification of Thase and Rush
  • Unsuccessful treatment by the association of two antidepressants (or intolerance/contra-indications)
  • Unsuccessful treatment by the association for at least 6 weeks of one of the following treatments : lithium , thyroid hormone , buspirone , pindolol with an antidepressant (or intolerance/contra-indications)
  • Unsuccessful treatment by the combination of a second-generation antipsychotic (olanzapine, risperidone, amisulpride, aripiprazole, clozapine and quetiapine) to an antidepressant (or intolerance/contra-indications)
  • Unsuccessful treatment by a structured psychotherapy

• Following characteristics of resistance in case of bipolar disorder:

  • Unsuccessful treatment by lithium (or intolerance/contra-indications)
  • Unsuccessful treatment by at least one mood stabilizer anticonvulsant (or intolerance/contra-indications)
  • Unsuccessful treatment by at least one second-generation antipsychotic (or intolerance/contra-indications)
  • Unsuccessful treatment by the combination of two mood stabilizers with at least an anticonvulsant (or intolerance/contra-indications)
  • Unsuccessful treatment by electro-convulsive therapy sessions (or intolerance/contra-indications)
  • Unsuccessful treatment by at least one antidepressant , mood stabilizer combination (or intolerance/contra-indications)
  • Unsuccessful treatment by a structured psychotherapy
• Understanding the conduct of the study
• Giving a written informed consent
• Benefiting from the french social insurance

Non-Inclusion Criteria:

• Comorbid axis 1 disorder (except dysthymia, generalized anxiety disorder, social phobia, panic disorder)
• Alcohol or other psychoactive substances dependence (except nicotine)
• Suicidal risk during the last month assessed by the MINI (Mini International Neuropsychiatric Interview), the DIGS (Diagnostic Interview for Genetic Studies) and the item 3 of the HDRS
• Suicide attempt in the last 6 months or two suicide attempts in the previous two years
• History of forensic act or furious mania
• Depressive episode with congruent or incongruent psychotic features or history of a depressive episode with psychotic features
• Comorbid cluster A or B personality disorders according to the DSM IV-TR evaluated using the SCID2 (Structured Clinical Interview for DSM-IV)
• Cognitive Impairment (Mattis < 130)
• MRI (Magnetic Resonance Imaging) contraindication to stimulation or contraindications for MRI
• Major somatic disease making it impossible to set up the study treatment
• Pregnant women, or nursing or childbearing potential without effective contraception
• Involuntary commitment
• Guardianship
• Participation in another study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DBS; The medical device includes: Either a pacemaker ACTIVA PC (Ref 37601) two-channel (Medtronic USA) or two pacemakers Activa SC (Ref 37603) to a channel (Medtronic USA); Two DBS electrodes with four contacts (type Medtronic DBS 3389). Patients will be operated with the usual stereotactic surgical procedure. The target is the Accumbens nucleus. The two electrodes are implanted in a single session under local anaesthesia or intermittent sedation (propofol parenteral without intubation early intervention). Day 0 is defined by the surgery. The DBS is "on" during 6 months (between Month 1 and Month 7). Stimulation will also be on after Month 7.	Device: DBS
Sham Comparator: SHAM; The medical device includes: Either a pacemaker ACTIVA PC (Ref 37601) two-channel (Medtronic USA) or two pacemakers Activa SC (Ref 37603) to a channel (Medtronic USA); Two DBS electrodes with four contacts (type Medtronic DBS 3389). Patients will be operated with the usual stereotactic surgical procedure. The target is the Accumbens nucleus. The two electrodes are implanted in a single session under local anaesthesia or intermittent sedation (propofol parenteral without intubation early intervention). Day 0 is defined by the surgery. The DBS is "off" during 6 months (between Month 1 and Month 7). Possibility to active the stimulation after Month 7.	Device: SHAM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response = 50 % decrease of the HDRS-17 (Hamilton depression rating scale, 17 items version) (yes/no)	Response is defined as a 50 % decrease of the HDRS-17 (Hamilton depression rating scale, 17 items version)	Month 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission (yes/no)	Remission is defined as an HDRS-17 score < 7	Month 7
CGI (Clinical global impressions) amelioration (yes/no)	Score of 1 or 2 (item 2 of the CGI)	Month 7
GAF (Global assessment of functioning)	Presence of a score ≥ 60	Month 7
HDRS-17 (Hamilton depression rating scale, 17 items version)	Score	Month 7
MADRS (Montgomery-Asberg Depression Rating Scale)	Score	Month 7
BDI (Beck Depression Inventory)	Score	Month 7
CGI (Clinical global impressions)	Score	Month 7
LARS (Lille Apathy Rating scale)	Score	Month 7
GAF (Global assessment of functioning)	Score	Month 7
Neuropsychological assessment		Day -7 ; Month 1; Month 7; Month 13; Month 19; Month 24
Cerebral metabolism (PET scans)		Day -7; Month 7
Adverse events	Adverse events occuring during the study.	Month 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HDRS-17 (Hamilton depression rating scale, 17 items version)	Longitudinal evolution of the score	Month -3 ; Month -1; Day -7; Day 15; Month 1; Day 45; Month 2 ; Day 75 ; Month 3; Month 4; Month 5; Month 6; Month 7; Month 8; Month 9; Month 10; Month 13; Month 16; Month 19; Month 22; Month 24
MADRS (Montgomery-Asberg Depression Rating Scale)	Longitudinal evolution of the score	Month -3 ; Month -1; Day -7; Day 15; Month 1; Day 45; Month 2 ; Day 75 ; Month 3; Month 4; Month 5; Month 6; Month 7; Month 8; Month 9; Month 10; Month 13; Month 16; Month 19; Month 22; Month 24
BDI (Beck Depression Inventory)	Longitudinal evolution of the score	Day -7; Day 15; Month 1; Day 45; Month 2 ; Day 75 ; Month 3; Month 4; Month 5; Month 6; Month 7; Month 8; Month 9; Month 10; Month 13; Month 16; Month 19; Month 22; Month 24
CGI (Clinical global impressions)	Longitudinal evolution of the score	Month -3 ; Month -1; Day-7; Day15; Month 1; Day 45; Month 2 ; Day 75 ; Month 3; Month 4; Month 5; Month 6; Month 7; Month 8; Month 9; Month 10; Month 13; Month 16; Month 19; Month 22; Month 24
LARS (Lille Apathy Rating scale)	Longitudinal evolution of the score	Day -7; Month 1; Month 7; Month 13; Month 19; Month 24
GAF (Global assessment of functioning)	Longitudinal evolution of the score	Month -3 ; Month -1; Day -7; Month 1; Month 7; Month 13; Month 19; Month 24
YMRS (Young Mania Rating Scale)	Longitudinal evolution of the score	Day -7; Month 1; Month 7; Month 13; Month 19; Month 24
MATHYS (Multidimensional Assessment of Thymic States)	Longitudinal evolution of the score	Day -7; Month 1; Month 7; Month 13; Month 19; Month 24
Response (50 % decrease of the HDRS-17)	During the whole follow up	Month 24
Remission	During the whole follow up Remission is defined as an HDRS-17 score < 7	M24

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Study Chair: Jean Michel Reymann, CIC INSERM 0203 CHU Rennes; Study Chair: Florian Naudet, CIC INSERM 0203 CHU Rennes; Principal Investigator: Bruno Millet, Groupe Hospitalier Pitie-Salpetriere

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2014
• Primary Completion (Actual): July 3, 2017
• Study Completion (Actual): November 27, 2018

Study Registration Dates

• First Submitted: October 8, 2013
• First Submitted That Met QC Criteria: October 25, 2013
• First Posted (Estimate): October 31, 2013

Study Record Updates

• Last Update Posted (Actual): December 27, 2019
• Last Update Submitted That Met QC Criteria: December 26, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Bipolar disorder; Recurrent depressive disorder; Deep brain stimulation; Major depressive disorder; Accumbens
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Disease; Bipolar Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: 35RC08_8902