Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls

Abstract

Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.

Figure 1

Effect of vortioxetine on the Trail Making Test (TMT)-A test. The more negative the number, the greater the improvement across treatment. *P<0.05 for when the subject groups were analysed separately. Error bars represent s.e.m.

Figure 2

Vortioxetine reduced blood-oxygen-level-dependent (BOLD) signal within (a) the right dorsolateral prefrontal cortex (dlPFC) and (b) left hippocampus across all participants. Red voxels show significant difference (cluster corrected P<0.05) between treatment groups in the change of N-back–0-back contrast across treatment within the prespecified anatomical masks across all subjects. Bar charts illustrate the mean (±s.e.m.) of the extracted signal change separated by treatment and subject group.