Genetic vulnerability to stress across psychiatric diagnoses.
Schizophrenia and Major Depressive Disorder

One of the most extensively studied and replicated gene-by-environment
interactions is the interaction between life stressors and a genetic
sensitivity to stress, often used to conceptualize the pathogenesis of
affective illnesses. Recently, it was shown that the polymorphisms in the
serotonin transporter promoter region (5-HTTLPR) and COMT are related to
sensitivity to stress. The association between both 5-HTTLPR and COMT and
increased sensitivity appears related to the interaction between medial
prefrontal cortex (mPFC), amygdala and hippocampus.
Interestingly, the hippocampus, which is highly affected by prolonged increased
levels of cortisol, is found to be decreased in both schizophrenia and major
depressive disorder (MDD). Moreover, schizophrenia and MDD share abnormal
structure and function of the amygdala and mPFC, as well as clinical and
genotypic features.

In the current proposal we hypothesize that vulnerability to stress is a
non-specific risk factor for developing either schizophrenia or MDD. Increased
stress sensitivity is hypothesized to be related to reduced prefrontal
functioning, leading to diminished inhibition of the amygdala which
consequently shows increased activation. As a result of this these subjects
will also show smaller hippocampal volumes than subjects not at genetic risk.
Being exposed to stressful life events in combination with a genetic
sensitivity to stress is expected to reinforce these effects.

This study is a three-group experimental study, in which diagnosis is the
between-subjects grouping variable. Within-subject variables are stress
susceptibility (i.e., cortisol-responsiveness after a psychosocial stressor),
brain volume and density measures of mPFC, hippocampus and amygdala as measured
with sMRI, white matter integrity and connectivity as measured with MTR and
DTI, task related brain activity as measured with fMRI (expressed in
BOLD-signal changes), and the occurrence of life-events.

Two MRI scan sessions of approximately 50minutes each will be performed: MRI is
a non-invasive technique, so there is no need for special preparation for the
subject. There are no known risks associated with the MRI acquisition and the
data are solely used for research purposes. However, structural cerebral
pathology may be noticed. If medical treatment is indicated, the subject will
be notified.

From each participant a small amount (4 x 10 ml) of EDTA blood will be taken,
by means of a venapuncture. On request, the skin can be locally anesthetized
prior to the venapuncture. If the participant refuses the puncture, a cotton
swab of buccal mucosa can be taken. Since the number of blood samples is
limited and the samples are small, the burden for participating subjects is
expected to be negligible.

No immediate benefits are to be expected from participation in this study for
the subjects. In the long run, increased understanding of the etiology and
pathophysiology of psychiatric illness in general and schizophrenia and major
depression in particular, may contribute to diagnosis, early detection and/or
prediction of treatment outcome.