Vortioxetine reduces BOLD signal during performance of the N-back task in subjects remitted from depression and healthy control participants

Background: Major depressive disorder (MDD) is associated with a range of cognitive difficulties, including deficits in executive function and working memory. The neural systems responsible for this deficit have previously been investigated using the N-Back task, which showed increased activity in the dorsolateral prefrontal cortex (dlPFC), hippocampus, anterior cingulate (ACC) and precuneus in both currently depressed and remitted patients, relative to controls (1-5). Vortioxetine is an antidepressant with multi-modal activity that is thought to act by inhibiting the serotonin transporter, as well as acting directly on 5-HT receptors. Previous studies have found that vortioxetine improves performance on tasks of cognitive function in depressed patients and in animal models. This randomised, placebo controlled, multisite functional magnetic resonance imaging (fMRI) study investigated the neural systems underlying vortioxetine's influence on cognitive performance using the N-Back task in subjects remitted from depression and healthy controls. The hypothesis tested was that vortioxetine would influence the blood-oxygen-level dependent (BOLD) signal within the neural structures previously identified as hyperactive in depressed patients. Method: 96 participants were recruited from 3 academic sites in the United Kingdom. These included 48 currently remitted subjects with at least 2 previous episodes of MDD, who reported subjective cognitive difficulties, and 48 healthy controls. Participants were randomly assigned to 2 weeks treatment with either vortioxetine 20 mg per day or placebo. Participants completed a letter based N-Back task while fMRI data were collected at baseline and following 2 weeks treatment. Contrast images comparing BOLD signal during the N-Back task (i.e. 1, 2 or 3-back) vs. a 0-back control condition were generated at baseline and after treatment with vortioxetine. Change in these contrast images between the two time points was then compared between treatment groups. Group level analysis controlled for study site and gender. Predefined regions of interest in the dlPFC, hippocampi, ACC and precuneus were used, with all group level image analyses corrected at the cluster level at p<0.05. fMRI data was analysed using the fMRIB software library (FSL) version 5.05. Results: In subjects remitted from depression vortioxetine significantly reduced the BOLD signal within the right dlPFC (p = 0.05) and left hippocampus (p = 0.01). Vortioxetine did not significantly alter activity within the healthy control group. When the subject groups were analysed together, vortioxetine significantly reduced activity within the right dlPFC (p = 0.03) and left hippocampus (p = 0.03). Vortioxetine did not influence activity within the right hippocampus, left dlPFC, ACC or precuneus. Using whole brain analysis, across all subjects, vortioxetine reduced activity within the right insula, temporal-occipital fusiform gyrus and bilateral lingual gyri. Conclusions: Vortioxetine reduced the BOLD signal within the right dlPFC and left hippocampus during performance of the N-Back task. Acute and remitted major depression have been previously associated with increased activity within these regions, suggesting that treatment with vortioxetine may reverse the effects of the disorder within these neurocognitive systems. This raises the possibility that the cognitive effects of vortioxetine in major depression may be mediated, at least in part, by effects on neural systems supporting working memory (executive function).