Pharmaco-fMRI Challenges before and after short-term Treatment of Major Depression with Escitalopram, Mirtazapine, Agomelatine or Placebo and the Relation to the Hypothalamus-Pituitary-Adrenal-Axis Activity

Background: Major Depressive Disorder (MDD) is a chronic stress related disorder characterized by depressed mood, by vegetative and cognitive symptoms. Imaging biomarkers may help to predict the impaired processing and regulation of emotions related to MDD and to antidepressant treatment response. Pharmaco neuroimaging and behavioral studies have shown that antidepressants can affect emotional processing very early after starting the treatment and independently from changes in subjective mood. Moreover, normalization of hypothalamus-pituitary-adrenal (HPA) axis regulation, which is usually disturbed in MDD, is often associated with successful recovery from depression. Therefore, we investigated the relationship between neural activation before and after short term treatment with antidepressants and HPA axis activity in relation to clinical outcome in MDD patients. Methods: We investigated 33 in-patients admitted to the Department of Psychiatry and Psychotherapy, University of Regensburg, for the treatment of MDD. Firstly, we considered the evidence for a cognitive neuropsychological model of antidepressant drug action by employing pharmaco-fMRI (3T) in a double-blind randomized placebo-controlled design to investigate the effect of short-term treatment with escitalopram, mirtazapine, agomelatine or placebo on the BOLD signal change in predefined brain regions associated with a visual facial emotional and neutral stimulation task. Additionally, all patients received the same amount of psychotherapeutic support. Results: After one week of short-term treatment we detected a statistically significant reduction in the BOLD % signal change in the bilateral amygdala, right dorsolateral prefrontal cortex and the right fusiform gyrus during the presentation of facial emotional and neutral expressions. In a second evaluation, we compared medicated patients with unmedicated (placebo treated) patients. Here we could see significant effects in the described regions but could not detect significant differences between verum and placebo groups. After that, each treatment group was investigated separately and compared together. The results showed again statistically significant effects in the above described regions, but no significant differences between the treatment groups. The clinical outcome after one week of treatment showed a partial recovery of the patients with reduced scores in the Hamilton rating scale for depression together with and correlated with BOLD % signal change in some specific regions. Moreover, the activity of the HPA axis was reduced slightly. In addition, this reduction showed significant correlations with the BOLD % signal change in some of the regions of interest. Discussion: The purpose of this study was to provide a better understanding of the interface between neural systems during antidepressant treatment, the short term effects of antidepressants on emotional processing, to bridge the gap between defined brain regions (amygdala, DLPFC, fusiform gyrus, hippocampus and insula) the fMRI BOLD signal, HPA axis hyperactivity, and the clinical status of major depressed patients. We could show that bilateral amygdala hyperactivities in depressed patients were reduced even after short term treatment. A trend to reduce and normalize also the activity in the right dorsolateral prefrontal cortex and in the right fusiform gyrus was consistent also with other fMRI studies. In addition, we could demonstrate a probable association between the HPA axis regulation and the activity in the brain regions of interest investigated in our study. We could demonstrate the onset of a normalization of the HPA axis activity, as well as the onset of clinical improvement after one week of treatment, but our study lacked statistic power to differentiate between our four treatment groups. In addition, it is possible that unspecific effects of counseling and the in-patient treatment regimen outweigh any specific pharmacological treatment effects after only one week of antidepressant treatment.