Neural Correlates of SSRI Drug Response: Impact of Stress System Genes

This pharmaco MRI (phMRI) study seeks to expand knowledge on the impact of stress system genes (NR3C1 and FKPB5) on brain functionality and development in Major Depressive Disorder (MDD), specifically on neural correlates of successful antidepressant drug response. Thirty acutely depressed patients will undergo three magnetic resonance imaging (MRI) scanning sessions at baseline, four hours and eight weeks after escitalopram treatment initiation. Structural MRI as well as three functional MRI (fMRI) scans will be performed to assess the neural effects of antidepressant drug action. Moreover genotyping and expression patterns for NR3C1 and FKPB5 as well as basal cortisol levels will be assessed, as these measures are increasingly regarded as highly promising peripheral biomarkers for the prediction of antidepressant drug response. Based on prior evidence suggesting that the effects of antidepressants and risk genes of depression converge on identical brain regions and systems, we combine two outstanding neuroimaging approaches, Imaging Genetics and phMRI, with the goal to gain pivotal insights in genetic influences on the response to selective serotonin re-uptake inhibitors (SSRI). As similar regions are also affected by prolonged stress exposure, we hypothesize stress systems genes to bias the neural response to SSRIs in particular in brain regions such as the amygdala and hippocampus. Furthermore, we assume peripheral stress system measures to correlate with neural response patterns to SSRIs in these regions.

Major depressive disorder (MDD) is a heritable and stress-related illness that constitutes the second leading cause of disability worldwide. Unfortunately, available treatments are frequently failing short on curing all symptoms of MDD. Such moderate efficacy of todays treatments is likely based on the lacking understanding of brain mechanisms related to symptom alleviation in MDD. Hence, we initiated a brain imaging study with the goal to decrypt neural mechanisms related to symptom change during antidepressive treatment of MDD patients. Twenty-seven patients suffering from a concurrent major depressive episode were invited to participate in this study. All participants have been treated with Escitalopram, the most frequently prescribed antidepressant. During this eight weeks lasting clinical trial patients have been scanned four-times with Magnetic Resonance Imaging (MRI). Additionally, stress hormones and genetic information have been assessed. This study revealed that a very stress-sensitive brain organ, the hippocampus, shows anatomical signs of recovery at initial phases of treatment and even before patients reported symptom alleviation. This finding was paralleled by changes of stress hormones. Notably, recovery of the hippocampus promoted a higher connectivity with a brain system that has been related to rumination (default mode network, DMN), which is a key symptom of depression. Interestingly, our studies additionally suggest that successful treatment comes with a reduced activation in the DMN, even though some hyperactivity persisted even after remission, which indicate a further need for prophylactic treatment after psychological recovery. Summarizing this study was able to identify important stress-related brain mechanisms mediating depression recovery. Future studies will demonstrate if this mechanism is suitable to study new antidepressive treatments or to predict treatment success of a specific antidepressant medication.