RELATE and PREDICT TRD;A pharmacological and neuroimaging study investigating neurobiological effects of Selective Serotonin Reuptake Inhibitors and Norepinephrine Reuptake inhibitors on dopaminergic reward-learning signals and prediction of clinical (non-) response in Major Depressive Disorder

Major depressive disorder (MDD) is a major burden for society. The
pathophysiology of MDD remains, however, an enigma. Usually MDD is treated with
serotonergic/noradrenergic antidepressants. Non-response (<50% improvement of
symptom-severity) occurs frequently and causes prolonged hospitalizations and
suicides. Non-response to more classes of antidepressants represents increasing
levels of treatment resistant depression (TRD). Previous research addressed
pharmacological strategies for non-response to antidepressants but could not
resolve why symptoms do not improve in ~35% of patients. It has been suggested
that in TRD non-serotonergic/non-noradrenergic subtypes of MDD are
over-represented. Recent cross-sectional studies in MDD indeed suggest
dysfunctions in dopamine and/or glutamate/GABA systems and diminished
reward/reinforcement learning. However, over-representation of
non-serotonergic/non-noradrenergic subtypes as putative mechanisms for TRD
remains to be demonstrated. Furthermore, to what extent contemporary
serotonergic/noradrenergic antidepressants already influence these putative
underlying mechanisms in humans remains unexplored.
Whether depression (MDD) patients with a high TRD-level have dysfunctional
dopamine and/or glutamate/GABA systems can be demonstrated with novel
multimodality neuroimaging techniques like functional Magnetic Resonance
Imaging (fMRI) and [11C]Raclopride Positron Emission Tomography (PET).
Besides early improvement within the first 2 weeks (>=20% decrease in HDRS),
neuropsychological tests that measure changes in facial recognition within 1
week are likely able to predict response to an antidepressant.

The proposed study aims to examine:
I. whether MDD-patients with a high TRD-level have diminished
reward/reinforcement learning, dysfunctional dopaminergic, glutamatergic and/or
GABA-ergic neurotransmission (relative to no-TRD patients/controls)
II. how treatment with the contemporary antidepressants escitalopram and
nortriptyline affect these dysfunctions in no-TRD and high-TRD patients.
III. prediction of treatment-outcomes within the first weeks of antidepressant
treatment

Randomized, double-blind, placebo-controlled study comparing escitalopram and
nortriptyline (dosed on blood-levels) versus placebo.

Subjects will be requested to participate in MRI and PET-scanning, the latter
will use a minor-moderate dose of radioactivity. There are no direct benefits
for subjects to participate. General benefit will be the better understanding
of the involvement of the dopamine system in TRD. When TRD is indeed
characterized by diminished reward/reinforcement learning, dysfunctions in
dopamine and/or glutamate/GABA systems, in the future MRI-scans and/or
[11C]Raclopride PET-scans might enable us to subtype MDD-patients and predict
treatment-outcomes, which ultimately may prevent the development of TRD.
Furthermore, developing treatment strategies targeting these dysfunctions is
desirable.