rTMS/CBT as next step in antidepressant non-responders. A randomized comparison with current stepped care approaches to major depressive disorder

Major depressive disorder (MDD) is one of the most common psychiatric disorders
with a lifetime prevalence of 24,3% for females and 13,1% for males (De Graaf
et al, 2012). Next to the burden for patients and those who care for them, MDD
has a substantial economic impact, with estimated costs of 1.5 billion euros
per year consisting of direct costs for health care and costs due to
productivity losses. Although antidepressants and cognitive behaviour therapy
offer effective treatments for depression, 30 % of MDD patients fail to respond
and are referred to as having treatment-resistant depression (TRD). TRD
patients carry out suicide attempts more often, are more medically complex
(e.g. comorbidities) and are less productive compared to non-TRD patients.
Together with the high level of chronicity that affects almost 20 % of MDD
patients (Spijker e.a. 2004), it underlines the need for more effective
treatment strategies in TRD.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of
stimulating the brain by using magnetic fields to induce small currents in the
cerebral cortex. Since its approval by the FDA for patients with treatment
resistant depression, rTMS has been made available in specialized centers for
mood disorders around the world. In recent years a sufficient body of evidence
has been build up to establish the definite antidepressant efficacy of high
frequent rTMS over the left dorsolateral prefrontal cortex (DLPFC) (level A
evidence according to Lefaucheur e.a. 2014) and in 2017, rTMS in combination
with CBT has been approved for reimbursement for patients with TRD in the
Netherlands.

RTMS is generally investigated and found effective with respect to treatment
outcome, side-effects, application and costs in TRD-patients who failed to
respond to antidepressant therapies. Recent evidence from a large naturalistic
study (n=196) in one of the participating centres, indicates that combining
rTMS with CBT even yields additional effects, contributing to robust remission
rates of 56 % in TRD, which mostly sustained through the six-month follow-up
period (Donse e.a., 2017). This evidence warrants research to examine the
comparative efficacy of rTMS and CBT as an alternative to the most optimal
treatment steps that are currently implemented in the treatment algorithms for
treatment resistant depression. We propose to investigate rTMS+CBT in addition
to the current antidepressant treatment in the care of patients with
non-psychotic depression in comparison with the next step in treatment
algorithm prescribed by the Dutch guideline (switching / augmentation
antidepressants in combination with CBT). We aim at testing the effectiveness
in terms of clinical improvement, the need for advanced care and the prevention
of recurrence over the course of six months.

Primary Objective:
Our primary objective is to quantify whether 8 weeks of treatment with rTMS and
CBT in addition to continued pharmacotherapy will outperform the most optimal
treatment as usual step (switching or augmenting antidepressants in combination
with CBT) in terms of remission and improvement of depressive symptoms as well
as quality of life over the course of twelve months.

Secondary Objectives:
AOur second objective is to perform an economic evaluation based on the general
principles of a cost-effectiveness (utility) analysis, which will be performed
along-side the intervention. Another objective is to quantify remission
(HDRS-17 score < 7) and response (50% reduction in HDRS-17 score) after 8 weeks
of treatment, and during follow-up at 4, 6, 9 and 12 months.

90 patients (>18 yrs.) with a unipolar MDD without psychotic symptoms and
moderate treatment resistance will be recruited from 6 specialized outpatient
clinics and through the Depressie Vereniging.

The intervention consists of of max. 25 sessions of repetitive transcranial
magnetic stimulation (rTMS) over the course of 8 weeks (schema of 4, 4, 4, 3,
3, 3, 2, 2 sessions per week) and cognitive behavior therapy (CBT) on top of
continued antidepressants (AD) [rTMS + AD cont + CBT]. The control condition
consists of a switch in AD according to the Dutch stepped care guidelines and
CBT.

In this study, we will investigate whether there will be a possible benefit
resulting from the treatment for participants. Transcranial magnetic
stimulation (TMS) is a widely used non-invasive brain stimulation technique,
based on the principle of electromagnetic induction. During stimulation the
participant will likely hear the clicks of the TMS pulses and experience
stimulation of nerves and muscles of the head. The most common side effect is a
light transient headache (2-4% occurrence). A severe headache is uncommon
(0.3-0.5% occurrence). In the current study patients will be stimulated with a
protocol that falls within the safety guidelines (Rossi e.a. 2009). All
participants are screened for their relevant medical history and other TMS
safety aspects (e.g. presence of metal parts in the head). The study will give
insight whether rTMS can become an efficient add/on therapy in TRD, which is
highly relevant given the amount of patients who do not fully respond to the
current treatment options.