Stepped Care aiTBS 2 Depression Study (Ghent)
- Conditions
- Depressive Disorder, MajorMelancholiaTreatment Resistant Depression
- Interventions
- Device: aiTBSBehavioral: CCTDrug: SSRI
- Registration Number
- NCT03288675
- Lead Sponsor
- University Ghent
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 68
- Antidepressant-free unipolar major depression with melancholic features
- Not responding to at least two trials with an antidepressant
- Aged between 18-65 years old
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Active aiTBS - active CCT+SSRI SSRI 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) Active aiTBS - sham CCT+SSRI 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) Sham aiTBS - aiTBS - active CCT+SSRI 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) Active aiTBS - active CCT+SSRI aiTBS 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) Active aiTBS - sham CCT+SSRI aiTBS 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) Sham aiTBS - aiTBS - active CCT+SSRI CCT 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) Active aiTBS - active CCT+SSRI CCT 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) Sham aiTBS - aiTBS - active CCT+SSRI aiTBS 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) Sham aiTBS - aiTBS - sham CCT+SSRI aiTBS 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) Sham aiTBS - aiTBS - sham CCT+SSRI 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)
- Primary Outcome Measures
Name Time Method Changes in depression severity - clinician-rated 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 17-item Hamilton Rating Scale for Depression (HRSD)
- Secondary Outcome Measures
Name Time Method Changes in suicidal thoughts - clinician-rated 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 Scale for suicidal ideation (SSI)
Changes in ruminative thinking (trait) - self-report 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 Ruminative Responses Scale (RRS)
Changes in temperament and character - self-report Intake, 10 days after aiTBS or sham (+/-D14) Temperament and Character Inventory (TCI)
Changes in regional grey matter volume using structural MRI Baseline (D0), 10 days after aiTBS or sham (+/-D14) The analysis will be done using voxel-based morphometry
Changes in state-dependent ruminative thinking due to hearing self-referential social evaluations presented via headphones in the scanner - self-report Baseline (D0), 10 days after aiTBS or sham (+/-D14) 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 the regional 5-HT transporter system Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14) C11 DASB PET
Changes in reward processing as measured with EEG /ERP Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group) 128 channel EEG during doors gambling task to assess effects on reward processing.
Changes in reward processing - behavioral assessment 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) Cambridge Gambling Task (CGT; CANTAB battery)
Changes in depression severity - self-report 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 Beck Depression Inventory (BDI-II)
Changes in anxiety features - self-report 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 State/Trait Anxiety Inventory (STAI)
Changes in remission from depression - self-report 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 Remission from Depression Questionnaire (RDQ)
Changes in perceived stress - self-report 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 Perceived Stress Scale (PSS)
Changes in responses to positive affect - self-report 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 Responses to Positive Affect Scale (RPA)
Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS Baseline (D0), 10 days after aiTBS or sham (+/-D14) The analysis will be evaluated using 1H MR spectroscopy
Changes in hedonia - self-report 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 Temporal Experience of Pleasure Scale (TEPS)
Changes in anhedonia - self-report 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 Snaith-Hamilton Pleasure Scale (SHAPS)
Differences in adverse effects following aiTBS vs. sham - self-report 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)] Adverse effects questionnaire
Evaluation of cognitive side-effects following iTBS vs. sham using the CANTAB battery Baseline (D0), 3 days after aiTBS or sham (+/-D7) 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 state-dependent mood - self-report following naPASAT 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) Visual analogue scales (VAS) administered following completion of the naPASAT
Changes in melancholic features - clinician-rated 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 Clinical outcomes in routine evaluation (CORE)
Changes in regional white matter microstructure and structural connectivity Baseline (D0), 10 days after aiTBS or sham (+/-D14) The analysis will be done using diffusion tensor imaging (DTI)
Changes in functional activity connectivity at rest and during tasks in which self-referential social evaluations are presented via headphones in the scanner Baseline (D0), 10 days after aiTBS or sham (+/-D14) The analysis will be evaluated using resting state and task fMRI
Changes in state-dependent mood during CCT vs. control training 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) Visual analogue scales (VAS) administered following completion of the CCT (or control training)
Changes in hopelessness - self-report 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 Beck hopelessness scale (BHS)
Changes in cognitive emotion regulation - self-report 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 Cognitive Emotion Regulation Questionnaire (CERQ)
Changes in state-dependent mood due to hearing self-referential social evaluations presented via headphones in the scanner - self-report Baseline (D0), 10 days after aiTBS or sham (+/-D14) 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).
Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample At baseline (D0) SNP analysis
Changes in working memory - behavioral assessment of near transfer 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) Non-adaptive PASAT (naPASAT)
Changes in spatial working memory - behavioral assessment of far transfer 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) Spatial working memory (SWT; CANTAB battery)
Predictive influence of treatment expectancy on treatment response - self-report 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) Credibility and Expectancy Questionnaire (CEQ)
Trial Locations
- Locations (1)
University Hospital Ghent
🇧🇪Ghent, East-Flanders, Belgium