Clinical trial NCT03288675: Stepped Care AiTBS 2 Depression Study (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
Overall status: COMPLETED
Phase: NA
Conditions: Depressive Disorder, Major
Treatment Resistant Depression
Melancholia
Keywords: Major depressive disorder
Treatment resistant depression
Accelerated intermittent thetaburst stimulation
Cognitive control training
Neuroimaging
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
First posted: 2017-09-20
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Changes in depression severity - clinician-rated
timeFrame: 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 outcomes:
measure: Changes in depression severity - self-report
timeFrame: 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
measure: Changes in suicidal thoughts - clinician-rated
timeFrame: 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
measure: Changes in melancholic features - clinician-rated
timeFrame: 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
measure: Changes in hopelessness - self-report
timeFrame: 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
measure: Changes in anxiety features - self-report
timeFrame: 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
measure: Changes in remission from depression - self-report
timeFrame: 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
measure: Changes in ruminative thinking (trait) - self-report
timeFrame: 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
measure: Changes in hedonia - self-report
timeFrame: 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
measure: Changes in anhedonia - self-report
timeFrame: 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
measure: Changes in perceived stress - self-report
timeFrame: 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
measure: Changes in responses to positive affect - self-report
timeFrame: 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
measure: Changes in cognitive emotion regulation - self-report
timeFrame: 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
measure: Changes in temperament and character - self-report
timeFrame: Intake, 10 days after aiTBS or sham (+/-D14)
measure: Differences in adverse effects following aiTBS vs. sham - self-report
timeFrame: 10 days after aiTBS or sham (+/-D14), [for the sham group 10 days after active aiTBS (+/-D28)]
measure: Changes in regional grey matter volume using structural MRI
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Changes in regional white matter microstructure and structural connectivity
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Neuronal safety/ changes in neurometabolite concentrations in left-prefrontal tissues using MRS
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Changes in functional activity connectivity at rest and during tasks in which self-referential social evaluations are presented via headphones in the scanner
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Changes in state-dependent ruminative thinking due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Changes in state-dependent mood due to hearing self-referential social evaluations presented via headphones in the scanner - self-report
timeFrame: Baseline (D0), 10 days after aiTBS or sham (+/-D14)
measure: Changes in the regional 5-HT transporter system
timeFrame: Baseline (D0), 3 days after aiTBS or sham (+/-D7), 10 days after aiTBS or sham (+/-D14)
measure: Changes in reward processing as measured with EEG /ERP
timeFrame: Baseline (D0), 10 days after active aiTBS in both groups (+/-D14 for the active group, +/-D28 for the sham group)
measure: Evaluation of cognitive side-effects following iTBS vs. sham using the CANTAB battery
timeFrame: Baseline (D0), 3 days after aiTBS or sham (+/-D7)
measure: Changes in reward processing - behavioral assessment
timeFrame: 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)
measure: Changes in working memory - behavioral assessment of near transfer
timeFrame: 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)
measure: Changes in state-dependent mood - self-report following naPASAT
timeFrame: 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)
measure: Changes in spatial working memory - behavioral assessment of far transfer
timeFrame: 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)
measure: Changes in state-dependent mood during CCT vs. control training
timeFrame: 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)
measure: Predictive influence of single nucleotide polymorphisms on treatment outcome - genetics using a saliva sample
timeFrame: At baseline (D0)
measure: Predictive influence of treatment expectancy on treatment response - self-report
timeFrame: 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)
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: University Hospital Ghent
state: East-Flanders
Study officials:
affiliation: Ghent University, University Hospital Ghent
name: Chris Baeken, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Ghent
name: Ernst Koster, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Ghent
name: Rudi De Raedt, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Ghent
name: Gilles Pourtois, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ghent University, University Hospital Ghent
name: Marie-Anne Vanderhasselt, Prof.
role: PRINCIPAL_INVESTIGATOR
References: