The Effects of Accelerated Intermittent Thetaburst Stimulation Followed by a Cognitive Control Training in Treatment Resistant Unipolar Depressed Patients
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- University Ghent
- Enrollment
- 68
- Locations
- 1
- Primary Endpoint
- Changes in depression severity - clinician-rated
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Factorial
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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.
Arms & Interventions
Active aiTBS - active CCT+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)
Intervention: aiTBS (Device)
Active aiTBS - active CCT+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)
Intervention: CCT (Behavioral)
Active aiTBS - active CCT+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)
Intervention: SSRI (Drug)
Active aiTBS - sham CCT+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)
Intervention: aiTBS (Device)
Active aiTBS - sham CCT+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)
Intervention: SSRI (Drug)
Sham aiTBS - aiTBS - active CCT+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)
Intervention: aiTBS (Device)
Sham aiTBS - aiTBS - active CCT+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)
Intervention: CCT (Behavioral)
Sham aiTBS - aiTBS - active CCT+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)
Intervention: SSRI (Drug)
Sham aiTBS - aiTBS - sham CCT+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)
Intervention: aiTBS (Device)
Sham aiTBS - aiTBS - sham CCT+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)
Intervention: SSRI (Drug)
Outcomes
Primary Outcomes
Changes in depression severity - clinician-rated
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
17-item Hamilton Rating Scale for Depression (HRSD)
Secondary Outcomes
- 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)
- 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)
- Changes in temperament and character - self-report(Intake, 10 days after aiTBS or sham (+/-D14))
- Changes in regional grey matter volume using structural MRI(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(Baseline (D0), 10 days after aiTBS or sham (+/-D14))
- Changes in the regional 5-HT transporter system(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(Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group))
- 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))
- 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)
- 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)
- 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)
- 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)
- 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)
- Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS(Baseline (D0), 10 days after aiTBS or sham (+/-D14))
- 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)
- 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)
- 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)])
- Evaluation of cognitive side-effects following iTBS vs. sham using the CANTAB battery(Baseline (D0), 3 days after aiTBS or sham (+/-D7))
- 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))
- 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)
- Changes in regional white matter microstructure and structural connectivity(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(Baseline (D0), 10 days after aiTBS or sham (+/-D14))
- 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))
- 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)
- 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)
- 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))
- Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample(At baseline (D0))
- 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))
- 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))
- 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))