Stepped Care aiTBS 2 Depression Study (Ghent)

Study Overview
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Brief Summary
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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.

Official Title
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The Effects of Accelerated Intermittent Thetaburst Stimulation Followed by a Cognitive Control Training in Treatment Resistant Unipolar Depressed Patients

Conditions
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Depressive Disorder, Major, Treatment Resistant Depression, Melancholia

Intervention / Treatment
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* Device: aiTBS
* Behavioral: CCT
* Drug: SSRI


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active aiTBS - active CCT+SSRI<br>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) | Device: aiTBS<br>* 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.<br>* Other names: accelerated intermittent thetaburst stimulation;Behavioral: CCT<br>* 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.<br>* Other names: cognitive control training;Drug: SSRI<br>* All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).<br>* Other names: selective serotonin reuptake inhibitor;|
| Experimental: Active aiTBS - sham CCT+SSRI<br>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) | Device: aiTBS<br>* 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.<br>* Other names: accelerated intermittent thetaburst stimulation;Drug: SSRI<br>* All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).<br>* Other names: selective serotonin reuptake inhibitor;|
| Experimental: Sham aiTBS - aiTBS - active CCT+SSRI<br>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) | Device: aiTBS<br>* 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.<br>* Other names: accelerated intermittent thetaburst stimulation;Behavioral: CCT<br>* 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.<br>* Other names: cognitive control training;Drug: SSRI<br>* All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).<br>* Other names: selective serotonin reuptake inhibitor;|
| Experimental: Sham aiTBS - aiTBS - sham CCT+SSRI<br>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) | Device: aiTBS<br>* 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.<br>* Other names: accelerated intermittent thetaburst stimulation;Drug: SSRI<br>* All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).<br>* Other names: selective serotonin reuptake inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in depression severity - clinician-rated | 17-item Hamilton Rating Scale for Depression (HRSD) | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in depression severity - self-report | Beck Depression Inventory (BDI-II) | 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 | 
| Changes in suicidal thoughts - clinician-rated | Scale for suicidal ideation (SSI) | 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 | 
| Changes in melancholic features - clinician-rated | Clinical outcomes in routine evaluation (CORE) | 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 | 
| Changes in hopelessness - self-report | Beck hopelessness scale (BHS) | 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 | 
| Changes in anxiety features - self-report | State/Trait Anxiety Inventory (STAI) | 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 | 
| Changes in remission from depression - self-report | Remission from Depression Questionnaire (RDQ) | 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 | 
| Changes in ruminative thinking (trait) - self-report | Ruminative Responses Scale (RRS) | 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 | 
| Changes in hedonia - self-report | Temporal Experience of Pleasure Scale (TEPS) | 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 | 
| Changes in anhedonia - self-report | Snaith-Hamilton Pleasure Scale (SHAPS) | 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 | 
| Changes in perceived stress - self-report | Perceived Stress Scale (PSS) | 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 | 
| Changes in responses to positive affect - self-report | Responses to Positive Affect Scale (RPA) | 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 | 
| Changes in cognitive emotion regulation - self-report | Cognitive Emotion Regulation Questionnaire (CERQ) | 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 | 
| Changes in temperament and character - self-report | Temperament and Character Inventory (TCI) | Intake, 10 days after aiTBS or sham (+/-D14) | 
| Differences in adverse effects following aiTBS vs. sham - self-report | Adverse effects questionnaire | 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)] | 
| Changes in regional grey matter volume using structural MRI | The analysis will be done using voxel-based morphometry | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| Changes in regional white matter microstructure and structural connectivity | The analysis will be done using diffusion tensor imaging (DTI) | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS | The analysis will be evaluated using 1H MR spectroscopy | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| 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 | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| 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). | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| 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). | Baseline (D0), 10 days after aiTBS or sham (+/-D14) | 
| Changes in the regional 5-HT transporter system | C11 DASB PET | Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14) | 
| Changes in reward processing as measured with EEG /ERP | 128 channel EEG during doors gambling task to assess effects on reward processing. | Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group) | 
| 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). | Baseline (D0), 3 days after aiTBS or sham (+/-D7) | 
| Changes in reward processing - behavioral assessment | Cambridge Gambling Task (CGT; CANTAB battery) | 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) | 
| Changes in working memory - behavioral assessment of near transfer | Non-adaptive PASAT (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) | 
| Changes in state-dependent mood - self-report following naPASAT | Visual analogue scales (VAS) administered following completion of the 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) | 
| Changes in spatial working memory - behavioral assessment of far transfer | Spatial working memory (SWT; CANTAB battery) | 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) | 
| Changes in state-dependent mood during CCT vs. control training | Visual analogue scales (VAS) administered following completion of the CCT (or 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) | 
| Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample | SNP analysis | At baseline (D0) | 
| Predictive influence of treatment expectancy on treatment response - self-report | Credibility and Expectancy Questionnaire (CEQ) | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Major depressive disorder, Treatment resistant depression, Accelerated intermittent thetaburst stimulation, Cognitive control training, Neuroimaging