Influence of stress vulnerability on type and course of bipolar disorder

Stress causes a spectrum of autonomic, endocrine and behavioural responses.
There is ample evidence that bipolar disorder is associated with a chronic
dysregulation of the Hypothalamic- Pituitary- Adrenal axis. Cortisol is the
central hormone in the stress-response and has its effect through the
Mineralocorticoid Receptor (MR) and the Glucocorticoid Receptor (GR). Recently,
several polymorphisms of both the MR and GR have been found to be associated
with dysregulation of the HPA-axis and with mood disorders. Results of an
earlier study performed by us confirmed the impact of the ER22/23EK
polymorphism and the 9beta polymorphism on course and symptoms( Spijker et al
2007)

1. Define risk profiles based on retrospective data in a cohort of bipolar
patients. These profiles will be based on the effects of various combinations
of MR and GR genotypes involved in stress regulation on symptoms, course of the
illness and neurocognitive functioning.

2. A prospective study involving the above mentioned cohort and a cohort of
recently diagnosed patients. We will investigate whether the GR and MR
polymorphisms are able to predict the course of the disease in this cohort and
in a second cohort of newly diagnosed patients prospectively. The influence of
life events and social support in relation to genotype and symptoms and course
of the disorder will be measured.

The influence of GR and MR on neurocognitive functioning will be tested also.
This part of the study will be described in a future addendum.

The results of this research will be highly relevant in understanding the
relation between stress and psychopathology, and give impetus to new forms of
therapy. It will enable clinicians to early identify patients with a high risk
on a bad prognosis of the illness and thereby possibilities for early
prevention.

This study consists of both a cross-sectional and prospective approach
including 400 patients with bipolar disorder. In the cross-sectional approach,
all patients will be interviewed and neurocognitively tested to define
phenotype and endophenotype; a blood sample will be taken to analyse genotypes
of cortisol receptors.
In the prospective approach two cohorts of patients will be followed for three
years to monitor course of the illness through the Life Chart Method, the
Social Support List and Serious Life Event Scale. Cohort A exists of all
patients included in the cross-sectional part of the study, we expect to
include around 200 for the prospective part of the study. Cohort B exists of
patients with recently diagnosed bipolar disorder, we expect to include around
200 patients for the prospective part of the study.
Neurocognitive testing of all patients will be described in a future addendum.
From a subgroup of patients, first degree family members will be asked to
participate in the study. This part of the study will also be described in
detail in a future addendum

Of all patients one blood sample is needed. This is in the patients group
almost completed, as we studied the relation between genotypes and phenotype of
bipolar disorder last year . In the cross-sectional approach (phase 1) all
patients need to come for an interview for about an hour to complete
questionnaires and a short neurocognitive attention test. In the subgroup of
patients and their first degree relatives phenotype will be defined by the
Symptom Checklist and the MINI. Genotyping of GR and MR will be performed in
patients and their first degree relatives.