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.