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Olfactory and Brain Stimulations in Treatment-resistant Depression (COBRA)

Primary Purpose

Treatment-resistant Depression

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) combined with pleasant odors delivered during the iTBS procol.
Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) delivered alone.
Sponsored by
Hôpital le Vinatier
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Treatment-resistant Depression focused on measuring Depression, brain stimulation, anhedonia, odor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: had a primary diagnosis of single-episode or recurrent non-psychotic major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria; scored 20 or over on the MADRS (Montgomery-Åsberg Depression Rating Scale) (Montgomery and Åsberg, 1979) and scored higher than 2 on the MADRS item 8 anhedonia factor score; a stable antidepressant medication for 4 weeks prior to inclusion; be able to speak and read French; sign a consent form before intervention. Exclusion Criteria: a pre-existing condition that affects olfaction including congenital anosmia, upper respiratory tract infection, nasal and/or sinus disease, brain injury or nasal surgery; a neurological disease; other comorbid psychiatric disorders or substance abuse (except tobacco); contraindications to TMS (medical devices implanted or metallic foreign body in the head); pregnant or lactating mothers (controlled by urine pregnancy tests); measure of protection or guardianship of justice.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    iTBS active combined with an olfactory stimulation

    iTBS active alone

    Arm Description

    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) combined with pleasant odors delivered during the iTBS procol.

    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) delivered alone.

    Outcomes

    Primary Outcome Measures

    Change in MADRS score before and after intervention to characterized the number of depressed patients who reach remission criteria (MADRS ≤ 10) in each group
    MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to intervention. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. Remission is defined as a Montgomery and Asberg Depression Rating Scale (MADRS) score less than or equal to 10 at the end of 50 sessions of iTBS

    Secondary Outcome Measures

    Group differences in Montgomery-Asberg Depression Rating Scale (MADRS) score changes
    MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to intervention. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores indicating a more severe depression.
    Group differences in Beck Depressive Inventory (BDI) score changes
    BDI is a 21-item validated instrument for the self-report of depressive symptoms, with individual item scores summed to yield a total possible BDI score that ranges from 0-63. Higher scores indicating a more severe depression
    Group differences in European Test of Olfactory Capabilities (ETOC) score changes
    The ETOC is an olfactory test based on standardized odorants. It consists in the presentation of 16 odors at supraliminal concentrations. For each trial, 4 tubes are presented to the patient, but only one contains the odor. The participant has to find which one contains it. Then, the patient has to identify the odor between 4 propositions. Both tests are rated on 16. Another test will be performed to assess olfactory hedonic judgment. It consists of the presentation of 10 odors known to be pleasant. Hedonicity of each odor will be rated on an analog scale from 1 to 9 (1 for "Not at all pleasant", 5 for "Neutral" and 9 for "Extremly pleasant").
    Group differences in the Chapman Social Anhedonia Scale (SAS)
    The SAS is a 40-items 'true/false' self-report questionnaire designed to measure social anhedonia that refers to a marked preference for solitary activities. Scores can range from 0 to 40 with higher scores indicating less ability to experience pleasure from social and interpersonal experiences.
    the Chapman Physical Anhedonia Scale (PAS) score changes
    The PAS is a 61-items 'true/false' self-report questionnaire designed to measure physical anhedonia that refers to the inability to experience physical pleasures related to food, touch, smells, sex, temperature, movements, sounds and physical sensations. Scores can range from 0 to 61 with higher scores indicating less ability to experience pleasure from pleasant physical stimuli.
    Group differences in conditioned motor evoked potential (MEP) peak-to-peak amplitude changes
    Dual-site transcranial magnetic stimulation (TMS) can be used to probe effective connectivity between the left DLPFC and the left M1. Conditioned MEP amplitude evoked by dual-site TMS and measured with surface EMG is compared to MEP amplitude evoked by TMS applied over M1 alone.
    Group differences in functional connectivity changes in the targeted brain network
    Resting state functional magnetic resonance imaging (fMRI) is used to probe functional connectivity changes in the targeted brain region and related network following non-invasive brain stimulation intervention.
    Group differences in the Childhood Trauma Questionnaire (CTQ) score changes
    The CTQ is a self-administered 28-item scale to measure abuse and neglect suffered in childhood on five subscales: emotional, physical / sexual abuse, and emotional / physical neglect. Each subscale scored on a 5-point Likert scale. The score for each subscale classifies the severity of the abuse and neglect as: "none to minimal," "low to moderate," "moderate to severe" and "severe to extreme".

    Full Information

    First Posted
    November 23, 2022
    Last Updated
    December 13, 2022
    Sponsor
    Hôpital le Vinatier
    Collaborators
    Fondation de France
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05661383
    Brief Title
    Olfactory and Brain Stimulations in Treatment-resistant Depression
    Acronym
    COBRA
    Official Title
    Combining Hedonic Olfactory and BRAin Stimulations in Treatment-resistant Depression
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    January 2, 2023 (Anticipated)
    Primary Completion Date
    October 2, 2026 (Anticipated)
    Study Completion Date
    October 2, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Hôpital le Vinatier
    Collaborators
    Fondation de France

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This is a prospective, randomized, double-blind, parallel-group controlled trial. The aim of this research project is to compare the clinical benefits achieved in patients with major depressive disorder (MDD) following two types of intervention: iTBS active alone or iTBS active combined with olfactory stimulations.
    Detailed Description
    Major depressive disorder (MDD) is the most widespread psychiatric disorder, affecting 5% of adults according to the World Health Organization. Anhedonia, defined as the loss of the ability to experience pleasure, is one of the key symptoms of depression, possibly due to a dysfunction of the reward system. Intermittent theta-burst stimulation (iTBS) targeting the dorsolateral prefrontal cortex (DLPFC) has been demonstrated as an emerging treatment option for treatment-resistant depression. One explanation is that iTBS could work through modulating the reward system (increasing dopamine release). One way to improve the therapeutic benefits of non-invasive brain stimulation is to combine it with other therapeutic strategies. Interestingly, olfactory training -daily short-term exposure to pleasant odors- improves significantly depressive symptoms in MDD patients. Indeed, the olfactory system and the reward system are closely related through the olfactory tubercle, which is in the ventral striatum and directly connected to the ventral tegmental area. The general aim of this research project is to test whether a combination of iTBS targeting the left DLPFC with an olfactory training can improve treatment outcome in MDD, compared to iTBS targeting the left DLPFC alone. The investigators hypothesize that combining iTBS treatment on DLPFC with hedonic olfactory stimulation potentiates the effect of iTBS treatment administered alone on depressive symptoms, especially anhedonia (physical, social or olfactory). Moreover, the investigators also hypothesize that the superiority of the combined approach is underpinned by greater modulation of connectivity activity and strength between brain regions involved in dopaminergic transmission, compared with iTBS alone.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Treatment-resistant Depression
    Keywords
    Depression, brain stimulation, anhedonia, odor

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    This is a prospective, single-center, randomized, double-blind, parallel-group controlled trial with two arms
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Masking Description
    Patients will be block randomized (1:1) to receive either iTBS active combined with an olfactory stimulation or TBS active alone. Computer generated random numbers will be used to generate the allocation sequence. The allocation sequence will be handled by an independent person from the Administrative Department of the Hospital and will be unavailable to those who enroll and assign patients. Patients will be blind to their treatment assignment. Moreover, the medical doctors who will administer the clinical scales and the researchers that will analyze the data will be blinded to the allocation.
    Allocation
    Randomized
    Enrollment
    80 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    iTBS active combined with an olfactory stimulation
    Arm Type
    Experimental
    Arm Description
    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) combined with pleasant odors delivered during the iTBS procol.
    Arm Title
    iTBS active alone
    Arm Type
    Active Comparator
    Arm Description
    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) delivered alone.
    Intervention Type
    Device
    Intervention Name(s)
    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) combined with pleasant odors delivered during the iTBS procol.
    Intervention Description
    Device: MagPro X100 (MagVenture, Mag2Health, France) iTBS protocol targeting the left dorsolateral prefrontal cortex: 50 consecutive sessions allocated on 10 days (i.e., 5 sessions per working day, 1 hour apart, for 2 weeks). One iTBS session: burst of 3 pulses at 50 Hz repeated at 200 ms intervals for 2 s (i.e., at 5 Hz) at an intensity of 90% of rMT. A 2 s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. Pleasant odorants will be delivered using passive diffusers placed in the room dedicated to the iTBS protocol, during the all-treatment duration. During the inclusion phase, 10 odors known to be pleasant will be presented to the subject. The 3 best rated by the subject will be chosen for olfactory stimulations. During the iTBS session, a randomly selected odor from the 3 will be presented at the same time as the iTBS treatment.
    Intervention Type
    Device
    Intervention Name(s)
    Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) delivered alone.
    Intervention Description
    Device: MagPro X100 (MagVenture, Mag2Health, France) iTBS protocol targeting the left dorsolateral prefrontal cortex: 50 consecutive sessions allocated on 10 days (i.e., 5 sessions per working day, 1 hour apart, for 2 weeks). One iTBS session: burst of 3 pulses at 50 Hz repeated at 200 ms intervals for 2 s (i.e., at 5 Hz) at an intensity of 90% of rMT. A 2 s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session.
    Primary Outcome Measure Information:
    Title
    Change in MADRS score before and after intervention to characterized the number of depressed patients who reach remission criteria (MADRS ≤ 10) in each group
    Description
    MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to intervention. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. Remission is defined as a Montgomery and Asberg Depression Rating Scale (MADRS) score less than or equal to 10 at the end of 50 sessions of iTBS
    Time Frame
    4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.
    Secondary Outcome Measure Information:
    Title
    Group differences in Montgomery-Asberg Depression Rating Scale (MADRS) score changes
    Description
    MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to intervention. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores indicating a more severe depression.
    Time Frame
    4 times : Before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.
    Title
    Group differences in Beck Depressive Inventory (BDI) score changes
    Description
    BDI is a 21-item validated instrument for the self-report of depressive symptoms, with individual item scores summed to yield a total possible BDI score that ranges from 0-63. Higher scores indicating a more severe depression
    Time Frame
    4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.
    Title
    Group differences in European Test of Olfactory Capabilities (ETOC) score changes
    Description
    The ETOC is an olfactory test based on standardized odorants. It consists in the presentation of 16 odors at supraliminal concentrations. For each trial, 4 tubes are presented to the patient, but only one contains the odor. The participant has to find which one contains it. Then, the patient has to identify the odor between 4 propositions. Both tests are rated on 16. Another test will be performed to assess olfactory hedonic judgment. It consists of the presentation of 10 odors known to be pleasant. Hedonicity of each odor will be rated on an analog scale from 1 to 9 (1 for "Not at all pleasant", 5 for "Neutral" and 9 for "Extremly pleasant").
    Time Frame
    2 times : Before the Intervention (J0), immediately following the end of the Intervention (J15)
    Title
    Group differences in the Chapman Social Anhedonia Scale (SAS)
    Description
    The SAS is a 40-items 'true/false' self-report questionnaire designed to measure social anhedonia that refers to a marked preference for solitary activities. Scores can range from 0 to 40 with higher scores indicating less ability to experience pleasure from social and interpersonal experiences.
    Time Frame
    4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.
    Title
    the Chapman Physical Anhedonia Scale (PAS) score changes
    Description
    The PAS is a 61-items 'true/false' self-report questionnaire designed to measure physical anhedonia that refers to the inability to experience physical pleasures related to food, touch, smells, sex, temperature, movements, sounds and physical sensations. Scores can range from 0 to 61 with higher scores indicating less ability to experience pleasure from pleasant physical stimuli.
    Time Frame
    4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.
    Title
    Group differences in conditioned motor evoked potential (MEP) peak-to-peak amplitude changes
    Description
    Dual-site transcranial magnetic stimulation (TMS) can be used to probe effective connectivity between the left DLPFC and the left M1. Conditioned MEP amplitude evoked by dual-site TMS and measured with surface EMG is compared to MEP amplitude evoked by TMS applied over M1 alone.
    Time Frame
    2 times : before the Intervention (J0), immediately following the end of the Intervention (J15)
    Title
    Group differences in functional connectivity changes in the targeted brain network
    Description
    Resting state functional magnetic resonance imaging (fMRI) is used to probe functional connectivity changes in the targeted brain region and related network following non-invasive brain stimulation intervention.
    Time Frame
    2 times : before the Intervention (J0), immediately following the end of the Intervention (J15)
    Title
    Group differences in the Childhood Trauma Questionnaire (CTQ) score changes
    Description
    The CTQ is a self-administered 28-item scale to measure abuse and neglect suffered in childhood on five subscales: emotional, physical / sexual abuse, and emotional / physical neglect. Each subscale scored on a 5-point Likert scale. The score for each subscale classifies the severity of the abuse and neglect as: "none to minimal," "low to moderate," "moderate to severe" and "severe to extreme".
    Time Frame
    1 time : Before the Intervention (J0)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: had a primary diagnosis of single-episode or recurrent non-psychotic major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria; scored 20 or over on the MADRS (Montgomery-Åsberg Depression Rating Scale) (Montgomery and Åsberg, 1979) and scored higher than 2 on the MADRS item 8 anhedonia factor score; a stable antidepressant medication for 4 weeks prior to inclusion; be able to speak and read French; sign a consent form before intervention. Exclusion Criteria: a pre-existing condition that affects olfaction including congenital anosmia, upper respiratory tract infection, nasal and/or sinus disease, brain injury or nasal surgery; a neurological disease; other comorbid psychiatric disorders or substance abuse (except tobacco); contraindications to TMS (medical devices implanted or metallic foreign body in the head); pregnant or lactating mothers (controlled by urine pregnancy tests); measure of protection or guardianship of justice.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    SARTELET Lydie
    Phone
    0437915531
    Ext
    +33
    Email
    lydie.sartelet@ch-le-vinatier.fr
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    BRUNELIN JEROME, PhD
    Organizational Affiliation
    hospital le vinatier
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided
    IPD Sharing Plan Description
    Describe the IPD sharing plan, including what IPD are to be shared with other researchers.

    Learn more about this trial

    Olfactory and Brain Stimulations in Treatment-resistant Depression

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