Predicting and Understanding Neurocognitive Mechanisms of Relapse Prevention: a randomized controlled trial of preventive cognitive therapy in remitted Major Depressive Disorder using fMRI and pupillometry

Major Depressive Disorder (MDD) is the most prevalent psychiatric disorder
affecting approximately 25% of the population at least once in their lives. 40%
of patients will experience relapse into another, life-disrupting episode
within two years after recovery, which significantly contributes to the
personal and economic burden of MDD. As risk for relapse and chronic-MDD
increases dramatically with the number of previous episodes, preventing relapse
early in the disease-course is a major clinical goal. Yet, mechanisms
facilitating relapse are poorly understood, thereby hampering selection and
development of appropriate preventive treatments for individual patients.

Preventive cognitive therapy (CT) was proven effective in lowering
relapse-risk, superior to the predominantly prescribed maintenance-treatment
with antidepressant medication. Surprisingly, the working mechanisms of this
successful preventive therapy have never been studied. However, understanding
the neurocognitive mechanisms of preventive-CT in remitted-MDD will help us to
understand relapse and relapse-prevention.Unfortunately, preventive-CT is not
effective for all patients in lowering the relapse-risk and currently it is
unclear for clinicians who will benefit from preventive-CT and who will not.
Here we propose that studying the mechanisms of preventive-therapy will provide
a unique opportunity to develop markers that predict individual
preventive-treatment success.

In this study we will investigate the neurocognitive mechanisms that explain
the preventive effects of preventive cognitive therapy and we will additionally
investigate which neurocognitive measures can predict successful preventive
treatment. We hereby focus on core-abnormalities characterizing abnormal
information processing in depression: 1) abnormal attention to negative
information, leading to a selective, negative perception of the world; and 2)
inadequate regulation of mood states, reflected in an increased tendency to
engage in, and difficulty to disengage from negative mood states. Problems in
regulating attention and emotional information have been related to inadequate
top-down control exerted by the brain*s lateral- and medial-prefrontal cortex
(PFC) over limbic regions associated with primary emotion processing, such as
the amygdala, striatum, and insula. Previously we showed that functional and
structural abnormalities of the lateral- and medial-PFC, including the
pregenual-anterior-cingulate cortex (pgACC), persist in the remitted phase and
even predict an unfavourable course. Therefore these regions must be considered
critical to understand and predict relapse and preventive-treatment response
and may constitute key targets for lowering the relapse-risk. We hypothesize
that targeting the persisting frontal abnormalities is crucial and most
effective to prevent relapse and that preventive-CT is potent in doing that.

Although functional imaging may provide essential information on relapse-risk
and treatment-efficacy, it is not feasible to refer each remitted patient to
costly fMRI scanning. Therefore, we propose to translate neurocognitive
mechanisms for use in clinical practice by using the autonomic pupil dilation
response (PDR) as reflection of PFC-control over limbic areas, essential for
adequate emotion regulation. The PDR is an index of emotional arousal and
cognitive effort associated with sympathetic nervous system activity. It was
shown to predict emotion regulation success and activation of prefrontal and
limbic brain-regions associated with effortful emotion regulation in
symptomatic MDD-patients and controls . Moreover, it was shown to accurately
predict CT-response in symptomatic-MDD. Yet, its validity for predicting
regulation- and treatment-success in the remitted phase has not been
established.
We will innovatively validate the PDR as an index of brain-responsivity during
effortful emotion regulation and bias-processing in remitted-MDD before and
after preventive-CT. Translating neuroimaging research for applications in
clinical practice denotes a major step forward in preventing relapse for
individual patients.

We hypothesize that:
- remitted depressed patients will show lower prefrontal control during the
active regulation of emotional states compared to never-depressed individuals;
- preventive-CT in remitted-MDD obtains its preventive effect by boosting
control function of the lateral- and medial-PFC, thereby dampening the
activation of limbic regions for negative information. This will lower
preferential processing of negative information. At the same time, increased
PFC-control may increase preferential processing of positive information,
additionally lowering the likelihood of a prevailing negative mood.
- Furthermore, we hypothesize that pre-treatment lateral-PFC activation and
connectivity of the lateral-PFC with the medial-PFC and amygdala during
negative emotion processing predicts favourable treatment response.
- prefrontal control during emotion regulation will be reflected in pupil
dilation responsivity in remitted depressed patients and increased prefrontal
control following treatment is associated with an increase in pupil dilation
during emotion regulation.

The primary aim of this study is to understand the neurocognitive mechanisms by
which preventive cognitive therapy obtains its preventive effects in remitted
depressed patients. Using functional MRI in combination with pupillometry and
neuropsychological assessments, we will test whether preventive cognitive
therapy in remitted patients results in increased prefrontal control, and
whether this increased prefrontal control results in a decrease in attentional
biases and an increase in emotion regulation capacity.

Secondary, this study aims to:
- predict individual preventive treatment success in remitted depressed
patients based on neurocognitive measures;
- translate neurocognitive principles to clinically useful measures to predict
and monitor individual preventive cognitive therapy success.

The proposed study is a randomized controlled trial to study preventive
cognitive therapy in remitted MDD-patients. In the experimental condition,
eight sessions of preventive cognitive therapy will be prescribed and in the
control condition, no treatment is prescribed. The study is characterized by an
open design where patients and the principal investigator is informed on the
treatment condition. However, the test administrators will be blinded to the
treatment condition, in order to prevent biases in scoring the tests.

The study consists of 4 phases:
The first phase concerns the baseline measurement, including questionnaires (2
hours), neuropsychological testing (1 hour) and an functional MRI-session (1
hour). During the neuropsychological and MRI-measurement, pupil behavior will
be additionally assessed. The questionnaires and interview are administered in
order to objectify rest-abnormalities in affect, cognitions and attentional
deployment.functional MRI is administered to assess prefrontal control and
primary emotional reactivity of subcortical brain structures. At baseline a
healthy control group will be included for cross-sectional comparisons to
establish residual abnormalities in the remitted MDD group in
neuropsychological and neurophysiological measures.

In the second phase, patients will be treated with eight sessions of
protocolized preventive cognitive therapy by experienced and qualified
psychotherapists. Patients randomized to the control condition will not receive
any treatment.

The third phase concerns the follow-up measurement, in which all measurements
from the baseline measurement will be repeated. An interview to objectify
recurrence of depressive pathology according to DSM-IV criteria will also be
administered. This assessment takes place three months following the baseline
measurement.

In the fourth phase, all participants will be invited to assess the clinical
course over the past 18 months. For this purpose the SCID-I interview will be
administered in addition to a self-rated questionnaire to objectify severity of
depressive symptomatology (Inventory of Depressive Symptomatology). The purpose
of this 18-months follow-up measurement is to inventory which patients relapsed
into a new depressive episode following treatment and which patients are still
remitted. This allows us to define neurocognitive predictors of relapse and to
study how treatment-induced changes in frontal control contributed to long term
course in remitted patients. This assessments takes place 18-months after the
baseline measurement.

The experimental group will receive eight sessions of protocolized preventive
therapy, delivered in individual sessions by experienced and licensed
psychotherapists. The patients in the waiting list control group will not
receive any treatment in the interval between the baseline measurement and the
three-month follow-up measurement. Nevertheless, after the three-month
follow-up measurement, these patients will be offered preventive cognitive
therapy.

During the first and third phase (baseline and 3-month follow-up measurement,
respectively) patients and controls are requested to fill out questionnaires
about their personal situation and emotional experiences. No advantages of such
standardized inventarisation are known or to be expected. This clinical
assessment part will take about 120 minutes to complete.
Next participants will be exposed to a 3 T magnetic field for approximately 60
minutes. No side effects have been described so far. On rare occasions a
peripheral nerve (abdomen) is stimulated by the changing magnetic gradients,
this will cause an itchy feeling, but is not harmful. On the same day,
participants perform several cognitive tests, which will take up a maximum of
60 minutes. During the fMRI session and the cognitive testing, participants are
presented with pictures depicting scenes of various emotional connotation.
Pictures can be experienced as very negative and very positive. During these
sessions, we will keep track of the affective fluctuations of the participants.
Also, at the end of each measurement, an exit interview will be held in which
the purpose of the experiments is explained and in which specific attention is
paid to any possible long lasting effects of the exposure to the negative
emotional scenes.

In total, the phase 1 (baseline measurement) will take up 5 hours (including
breaks), phase 2 (treatment) approx. 6 hours, phase 3 (three-month follow-up)
5,5 hours (including breaks), and phase 4 (diagnostic interview to assess
course) will take up a maximum of one hour. In total, participation to the
study will take 19,5 hours for patients in the treatment condition, 13,5 hours
for patients in the waiting-list control condition, and 7 hours for the healthy
control participants, incl. screening (2 hrs_. The study phases are preceded by
a screening phase to determine eligibility for participating in the study. This
takes approx. 2 hours.