Investigating the role of rTMS in the treatment of chronic depression

Major depressive disorder (MDD) is one of the most prevalent psychiatric
disorders and is the leading cause of disability worldwide. Despite tremendous
development in the treatment of MDD, the chronic course in 1/3 of the patients
remains a fundamental clinical problem. Repetitive transcranial magnetic
stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has been
introduced for more than a decade as an antidepressive treatment option.
However, study samples are often small and inclusion varies between treatment
resistant depression on the one hand and moderate depression on the other hand.
The current US Food and Drug Administration (FDA) Approval in the United States
is for adults who have only failed a single antidepressant trial in the current
depressive episode. Results can hardly be applied to the stepped care treatment
of MDD in the Netherlands. Moreover, patients who do not respond to combination
therapies of pharmacotherapy and psychotherapy clearly lack further options but
informative studies are missing that provide information about cost
effectiveness and follow-up outcome. Yet, additional treatment options are
necessary

(1) To investigate the effect of rTMS in a treatment set-up of 4 weeks
including sham-rTMSas a control in 2 x 50 patients who have had at least two
prior antidepressant therapies and psychotherapy according to the Dutch
guideline of depression.
(2) To analyze the change in symptoms over a follow-up course of 2 months in
the rTMS treatment and control group.
(3) To investigate the neurobiological changes related to rTMS treatment using
a combined EEG/FMRI longitudinal set-up.

A 2-year longitudinal study with 100 patients, between 18-65 years old, with
chronic depression who will either receive rTMS or sham rTMS on top of their
care as usual for 4 weeks (20 sessions) and then will be clinically
investigated again 1 week after stop of treatment.

RTMS and sham treatment will be done using Magstim Rapid 2. All rTMS parameters
used in the proposed study are within the range considered safe according to
the latest published safety guidelines (Rossi et al., 2009, 2011; Obermann et
al., 2011). Firstly, the resting motor threshold (rMT) will be defined in each
subject as the minimal stimulation intensity evoking an MEP of >= 0.05 mV in 50%
of the trials in the muscle of the right thumb (M. abductor pollicis brevis).
Note that rMT will be determined before every treatment/sham session. TMS will
be conducted in the form of *conventional rTMS*, whereby 30 trains of 10 Hz
pulses with a duration of 5 seconds and an inter-train interval of 25 seconds
are applied to the left dorsolateral prefrontal cortex (50 pulses per train,
6000 pulses per session).
We aim to control for placebo effects merely evoked by the regular treatment
and therefore include a so-called sham condition using a sham-coil, which
applies a similar electrical sensation to the skull.

All psychiatric measurements are administered routinely at our out- and
inpatient depression unit. The actual rTMS treatment will take about 30 minutes
5 times a week whereby the side effects are mild. Additional EEG and MRI
measurements do not have any side effects.