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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
68
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.
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.
All patients will be prescribed antidepressant medication (SSRI) again when starting the CCT (vs. control training).
University Hospital Ghent
Ghent, East-Flanders, Belgium
Changes in depression severity - clinician-rated
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
Changes in depression severity - self-report
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
Changes in suicidal thoughts - clinician-rated
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
Changes in melancholic features - clinician-rated
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
Changes in hopelessness - self-report
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
Changes in anxiety features - self-report
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
Changes in remission from depression - self-report
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
Changes in ruminative thinking (trait) - self-report
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
Changes in hedonia - self-report
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
Changes in anhedonia - self-report
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
Changes in perceived stress - self-report
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
Changes in responses to positive affect - self-report
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
Changes in cognitive emotion regulation - self-report
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
Changes in temperament and character - self-report
Temperament and Character Inventory (TCI)
Time frame: Intake, 10 days after aiTBS or sham (+/-D14)
Differences in adverse effects following aiTBS vs. sham - self-report
Adverse effects questionnaire
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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).
Time frame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
Changes in the regional 5-HT transporter system
C11 DASB PET
Time frame: 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.
Time frame: 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).
Time frame: Baseline (D0), 3 days after aiTBS or sham (+/-D7)
Changes in reward processing - behavioral assessment
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)
Changes in working memory - behavioral assessment of near transfer
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)
Changes in state-dependent mood - self-report following naPASAT
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)
Changes in spatial working memory - behavioral assessment of far transfer
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)
Changes in state-dependent mood during CCT vs. control training
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)
Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample
SNP analysis
Time frame: At baseline (D0)
Predictive influence of treatment expectancy on treatment response - self-report
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)
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