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Stepped Care aiTBS 2 Depression Study (Ghent) (aiTBS2-Ghent)

Primary Purpose

Depressive Disorder, Major, Treatment Resistant Depression, Melancholia

Status
Recruiting
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
aiTBS
CCT
SSRI
Sponsored by
University Ghent
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Depressive Disorder, Major focused on measuring Major depressive disorder, Treatment resistant depression, Accelerated intermittent thetaburst stimulation, Cognitive control training, Neuroimaging

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Antidepressant-free unipolar major depression with melancholic features
  • Not responding to at least two trials with an antidepressant
  • Aged between 18-65 years old

Exclusion Criteria:

  • Depression with bipolar/psychotic features
  • Dysthymia
  • Severe personality disorders
  • Active substance abuse/dependence within a year prior to inclusion
  • Pregnancy or without effective anticonception for the duration of the trial
  • ECT non-responder
  • No response to more than 9 antidepressants
  • Any neurological condition
  • Any implanted electronic device susceptible for magnetic field radiation (e.g. pacemaker)
  • Any implanted metal device in the head region
  • Current or past history of epilepsy
  • Neurosurgical interventions
  • Known allergic reaction to radiotracers or associated compounds

Healthy volunteers may be accepted as control subjects.

Sites / Locations

  • University Hospital GhentRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Experimental

Experimental

Arm Label

Active aiTBS - active CCT+SSRI

Active aiTBS - sham CCT+SSRI

Sham aiTBS - aiTBS - active CCT+SSRI

Sham aiTBS - aiTBS - sham CCT+SSRI

Arm Description

Patients receive active aiTBS treatment in the first week, and starting from week 3 receive active CCT for a period of 4 weeks in combination with an antidepressant (SSRI)

Patients receive active aiTBS treatment in the first week, and starting from week 3 receive a control training for a period of 4 weeks in combination with an antidepressant (SSRI)

Patients receive sham aiTBS treatment in the first week, real aiTBS treatment in the third week, and starting from the fifth week receive CCT for a period of 4 weeks in combination with an antidepressant (SSRI)

Patients receive sham aiTBS treatment in the first week, real aiTBS treatment in the third week, and starting from the fifth week control training for a period of 4 weeks in combination with an antidepressant (SSRI)

Outcomes

Primary Outcome Measures

Changes in depression severity - clinician-rated
17-item Hamilton Rating Scale for Depression (HRSD)

Secondary Outcome Measures

Changes in depression severity - self-report
Beck Depression Inventory (BDI-II)
Changes in suicidal thoughts - clinician-rated
Scale for suicidal ideation (SSI)
Changes in melancholic features - clinician-rated
Clinical outcomes in routine evaluation (CORE)
Changes in hopelessness - self-report
Beck hopelessness scale (BHS)
Changes in anxiety features - self-report
State/Trait Anxiety Inventory (STAI)
Changes in remission from depression - self-report
Remission from Depression Questionnaire (RDQ)
Changes in ruminative thinking (trait) - self-report
Ruminative Responses Scale (RRS)
Changes in hedonia - self-report
Temporal Experience of Pleasure Scale (TEPS)
Changes in anhedonia - self-report
Snaith-Hamilton Pleasure Scale (SHAPS)
Changes in perceived stress - self-report
Perceived Stress Scale (PSS)
Changes in responses to positive affect - self-report
Responses to Positive Affect Scale (RPA)
Changes in cognitive emotion regulation - self-report
Cognitive Emotion Regulation Questionnaire (CERQ)
Changes in temperament and character - self-report
Temperament and Character Inventory (TCI)
Differences in adverse effects following aiTBS vs. sham - self-report
Adverse effects questionnaire
Changes in regional grey matter volume using structural MRI
The analysis will be done using voxel-based morphometry
Changes in regional white matter microstructure and structural connectivity
The analysis will be done using diffusion tensor imaging (DTI)
Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS
The analysis will be evaluated using 1H MR spectroscopy
Changes in functional activity connectivity at rest and during tasks in which self-referential social evaluations are presented via headphones in the scanner
The analysis will be evaluated using resting state and task fMRI
Changes in state-dependent ruminative thinking due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
Before entering the scanner, and following each resting state fMRI (i.e. before hearing self-referential social evaluations and after hearing these evaluations), perseverative thinking will be assessed using the perseverative thinking questionnaire (PTQ).
Changes in state-dependent mood due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
Before entering the scanner, and following each resting state fMRI (i.e. before hearing self-referential social evaluations and after hearing these evaluations), mood will be assessed using visual analogue scales (VAS).
Changes in the regional 5-HT transporter system
C11 DASB PET
Changes in reward processing as measured with EEG /ERP
128 channel EEG during doors gambling task to assess effects on reward processing.
Evaluation of cognitive side-effects following iTBS vs. sham using the CANTAB battery
CANTAB battery administration (i.e. motor screening, delayed matching to sample, rapid visual information processing, one touch stockings of Cambridge, spatial working memory).
Changes in reward processing - behavioral assessment
Cambridge Gambling Task (CGT; CANTAB battery)
Changes in working memory - behavioral assessment of near transfer
Non-adaptive PASAT (naPASAT)
Changes in state-dependent mood - self-report following naPASAT
Visual analogue scales (VAS) administered following completion of the naPASAT
Changes in spatial working memory - behavioral assessment of far transfer
Spatial working memory (SWT; CANTAB battery)
Changes in state-dependent mood during CCT vs. control training
Visual analogue scales (VAS) administered following completion of the CCT (or control training)
Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample
SNP analysis
Predictive influence of treatment expectancy on treatment response - self-report
Credibility and Expectancy Questionnaire (CEQ)

Full Information

First Posted
July 14, 2017
Last Updated
December 6, 2022
Sponsor
University Ghent
Collaborators
University Hospital, Ghent
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1. Study Identification

Unique Protocol Identification Number
NCT03288675
Brief Title
Stepped Care aiTBS 2 Depression Study (Ghent)
Acronym
aiTBS2-Ghent
Official Title
The Effects of Accelerated Intermittent Thetaburst Stimulation Followed by a Cognitive Control Training in Treatment Resistant Unipolar Depressed Patients
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 5, 2017 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Ghent
Collaborators
University Hospital, Ghent

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Antidepressant-free unipolar melancholic depressed patients (at least stage 2 treatment-resistant) will be selected by a certified psychiatrist, who will administer (semi-)structured clinical interviews. Because concomitant antidepressant treatment can confound outcome results, all patients will go through a medication washout before entering the study and they will be free from any antidepressant, neuroleptic and mood stabilizer for at least two weeks before entering the treatment protocol. Only habitual benzodiazepine agents will be allowed. STEP 1: Patients will be treated with in total 20 accelerated intermittent Theta Burst Stimulation (aiTBS) sessions (3000 pulses/session) over the left dorsolateral prefrontal cortex, which will be spread over 4 days. On each stimulation day, a given patient will receive 5 sessions with a between-session delay of 15 minutes. Patients will be randomized to receive either the real aiTBS or sham treatment (first week). However, the sham group will receive real aiTBS treatment with 10 days' time interval. The investigators expect that real aiTBS treatment and not sham will result in a significant and clinical meaningful response. STEP 2: To optimize treatment and reduce relapse following the iTBS treatment, in a stepped care approach, all patients then continue with cognitive control training (CCT) ten days later. This CCT consists of 20 sessions, spread over 4 weeks. Patients will be randomized to receive either real CCT or a control training. During this follow-up treatment, all patients will be prescribed antidepressant medication (SSRI) again. As iTBS treatment effects are known to decline over time, the investigators expect that combining aiTBS with a follow-up CCT therapy will stabilize the clinical effects over time compared to receiving the iTBS treatment alone. For baseline comparisons, patients will be closely matched for gender and age with never-depressed, medication-free healthy volunteers. No volunteer will undergo treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depressive Disorder, Major, Treatment Resistant Depression, Melancholia
Keywords
Major depressive disorder, Treatment resistant depression, Accelerated intermittent thetaburst stimulation, Cognitive control training, Neuroimaging

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
68 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Active aiTBS - active CCT+SSRI
Arm Type
Active Comparator
Arm Description
Patients receive active aiTBS treatment in the first week, and starting from week 3 receive active CCT for a period of 4 weeks in combination with an antidepressant (SSRI)
Arm Title
Active aiTBS - sham CCT+SSRI
Arm Type
Experimental
Arm Description
Patients receive active aiTBS treatment in the first week, and starting from week 3 receive a control training for a period of 4 weeks in combination with an antidepressant (SSRI)
Arm Title
Sham aiTBS - aiTBS - active CCT+SSRI
Arm Type
Experimental
Arm Description
Patients receive sham aiTBS treatment in the first week, real aiTBS treatment in the third week, and starting from the fifth week receive CCT for a period of 4 weeks in combination with an antidepressant (SSRI)
Arm Title
Sham aiTBS - aiTBS - sham CCT+SSRI
Arm Type
Experimental
Arm Description
Patients receive sham aiTBS treatment in the first week, real aiTBS treatment in the third week, and starting from the fifth week control training for a period of 4 weeks in combination with an antidepressant (SSRI)
Intervention Type
Device
Intervention Name(s)
aiTBS
Other Intervention Name(s)
accelerated intermittent thetaburst stimulation
Intervention Description
In the active aiTBS arm, the patients will receive 100 cycli of thetaburst trains of 2s, separated by an inter-train-interval of 6 seconds, delivered on the left dorsolateral prefrontal cortex (DLPFC; i.e. 3000 pulses per session). On each stimulation day, a given patient will receive 5 sessions with a between-session interval of 15 minutes. The treatment protocol of in total 20 aiTBS sessions will be spread over 4 days (i.e. 60.000 pulses in total). The sham coil has been specifically developed to mimic the real one.
Intervention Type
Behavioral
Intervention Name(s)
CCT
Other Intervention Name(s)
cognitive control training
Intervention Description
By training working memory processing, the CCT aims at modulating similar prefrontal cortex regions as being stimulated previously by aiTBS, namely the DLPFC. thereby possibly stabilizing clinical effects of aiTBS over time. In total 20 sessions of CCT vs. control training (of approximately 25 minutes per session), will be spread over a period of 4 weeks.
Intervention Type
Drug
Intervention Name(s)
SSRI
Other Intervention Name(s)
selective serotonin reuptake inhibitor
Intervention Description
All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).
Primary Outcome Measure Information:
Title
Changes in depression severity - clinician-rated
Description
17-item Hamilton Rating Scale for Depression (HRSD)
Time Frame
Intake, baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Secondary Outcome Measure Information:
Title
Changes in depression severity - self-report
Description
Beck Depression Inventory (BDI-II)
Time Frame
Intake, baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in suicidal thoughts - clinician-rated
Description
Scale for suicidal ideation (SSI)
Time Frame
Intake, baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in melancholic features - clinician-rated
Description
Clinical outcomes in routine evaluation (CORE)
Time Frame
Intake, baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in hopelessness - self-report
Description
Beck hopelessness scale (BHS)
Time Frame
Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in anxiety features - self-report
Description
State/Trait Anxiety Inventory (STAI)
Time Frame
Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in remission from depression - self-report
Description
Remission from Depression Questionnaire (RDQ)
Time Frame
Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14), [for the sham group 3 days (+/-D21) and 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in ruminative thinking (trait) - self-report
Description
Ruminative Responses Scale (RRS)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in hedonia - self-report
Description
Temporal Experience of Pleasure Scale (TEPS)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in anhedonia - self-report
Description
Snaith-Hamilton Pleasure Scale (SHAPS)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in perceived stress - self-report
Description
Perceived Stress Scale (PSS)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in responses to positive affect - self-report
Description
Responses to Positive Affect Scale (RPA)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in cognitive emotion regulation - self-report
Description
Cognitive Emotion Regulation Questionnaire (CERQ)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56), 3 & 6 months follow-up
Title
Changes in temperament and character - self-report
Description
Temperament and Character Inventory (TCI)
Time Frame
Intake, 10 days after aiTBS or sham (+/-D14)
Title
Differences in adverse effects following aiTBS vs. sham - self-report
Description
Adverse effects questionnaire
Time Frame
10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)]
Title
Changes in regional grey matter volume using structural MRI
Description
The analysis will be done using voxel-based morphometry
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Changes in regional white matter microstructure and structural connectivity
Description
The analysis will be done using diffusion tensor imaging (DTI)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS
Description
The analysis will be evaluated using 1H MR spectroscopy
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Changes in functional activity connectivity at rest and during tasks in which self-referential social evaluations are presented via headphones in the scanner
Description
The analysis will be evaluated using resting state and task fMRI
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Changes in state-dependent ruminative thinking due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
Description
Before entering the scanner, and following each resting state fMRI (i.e. before hearing self-referential social evaluations and after hearing these evaluations), perseverative thinking will be assessed using the perseverative thinking questionnaire (PTQ).
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Changes in state-dependent mood due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
Description
Before entering the scanner, and following each resting state fMRI (i.e. before hearing self-referential social evaluations and after hearing these evaluations), mood will be assessed using visual analogue scales (VAS).
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Title
Changes in the regional 5-HT transporter system
Description
C11 DASB PET
Time Frame
Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14)
Title
Changes in reward processing as measured with EEG /ERP
Description
128 channel EEG during doors gambling task to assess effects on reward processing.
Time Frame
Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group)
Title
Evaluation of cognitive side-effects following iTBS vs. sham using the CANTAB battery
Description
CANTAB battery administration (i.e. motor screening, delayed matching to sample, rapid visual information processing, one touch stockings of Cambridge, spatial working memory).
Time Frame
Baseline (D0), 3 days after aiTBS or sham (+/-D7)
Title
Changes in reward processing - behavioral assessment
Description
Cambridge Gambling Task (CGT; CANTAB battery)
Time Frame
Baseline (D0), 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)], after CCT (+/-D42; for the sham group +/-D56)
Title
Changes in working memory - behavioral assessment of near transfer
Description
Non-adaptive PASAT (naPASAT)
Time Frame
Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group), after CCT (+/-D42; for the sham group +/-D56)
Title
Changes in state-dependent mood - self-report following naPASAT
Description
Visual analogue scales (VAS) administered following completion of the naPASAT
Time Frame
Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group), after CCT (+/-D42; for the sham group +/-D56)
Title
Changes in spatial working memory - behavioral assessment of far transfer
Description
Spatial working memory (SWT; CANTAB battery)
Time Frame
Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group), after CCT (+/-D42; for the sham group +/-D56)
Title
Changes in state-dependent mood during CCT vs. control training
Description
Visual analogue scales (VAS) administered following completion of the CCT (or control training)
Time Frame
Following each of the 20 CCT or control trainings (spread over +/- D15 up to D42 for the active group; spread over +/- D29 up to D56 for the sham group)
Title
Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample
Description
SNP analysis
Time Frame
At baseline (D0)
Title
Predictive influence of treatment expectancy on treatment response - self-report
Description
Credibility and Expectancy Questionnaire (CEQ)
Time Frame
After the first aiTBS or sham session (D1), after the first CCT or control session (+/- D15 for the active group, +/-D29 for the sham group)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Antidepressant-free unipolar major depression with melancholic features Not responding to at least two trials with an antidepressant Aged between 18-65 years old Exclusion Criteria: Depression with bipolar/psychotic features Dysthymia Severe personality disorders Active substance abuse/dependence within a year prior to inclusion Pregnancy or without effective anticonception for the duration of the trial ECT non-responder No response to more than 9 antidepressants Any neurological condition Any implanted electronic device susceptible for magnetic field radiation (e.g. pacemaker) Any implanted metal device in the head region Current or past history of epilepsy Neurosurgical interventions Known allergic reaction to radiotracers or associated compounds Healthy volunteers may be accepted as control subjects.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chris Baeken, Prof.
Phone
+3293325543
Email
Chris.Baeken@ugent.be
First Name & Middle Initial & Last Name or Official Title & Degree
Josefien Dedoncker, M.Sc.
Phone
+3293325894
Email
Josefien.Dedoncker@ugent.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chris Baeken, Prof.
Organizational Affiliation
Ghent University, University Hospital Ghent
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ernst Koster, Prof.
Organizational Affiliation
University Ghent
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Rudi De Raedt, Prof.
Organizational Affiliation
University Ghent
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gilles Pourtois, Prof.
Organizational Affiliation
University Ghent
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marie-Anne Vanderhasselt, Prof.
Organizational Affiliation
Ghent University, University Hospital Ghent
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Ghent
City
Ghent
State/Province
East-Flanders
ZIP/Postal Code
9000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chris Baeken, Prof.
First Name & Middle Initial & Last Name & Degree
Josefien Dedoncker, M.Sc.

12. IPD Sharing Statement

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Stepped Care aiTBS 2 Depression Study (Ghent)

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