A randomized, double-blind assessment of the effects of vortioxetine on functional connectivity in mild cognitive impairment

Vortioxetine has been reported to alleviate cognitive deficits in patients with depression, accompanied by changes in functional connectivity (FC). An open-label study suggested potential benefits of vortioxetine in patients with mild cognitive impairment (MCI), a condition also characterized by both cognitive and FC alterations. However, controlled studies are required to rule out nonspecific treatment effects and to determine whether FC changes are generalizable to this population. To address this, we collected resting-state functional magnetic resonance imaging data from 47 patients with MCI at baseline, and after four and twelve weeks of randomized, double-blind treatment with either 10 mg or 20 mg vortioxetine, or placebo. Brain-wide FC changes were assessed using network-based R-statistics, an extension of the network-based statistics approach that allows mixed-effects modeling. Analyses were conducted with two different brain atlases to evaluate agreement across parcellations. No vortioxetine-specific FC changes were observed. Instead, we identified a widespread network of predominantly reduced FC at four and twelve weeks across all groups (ps [≤] 0.012), with no additional significant changes between twelve and four weeks. Results showed high consistency across parcellations (rs [≥] 0.96). These reductions in FC may reflect a reversal of preceding hyperconnectivity, potentially linked to compensatory network remodeling in MCI, as described in prior studies. While our findings do not support vortioxetine-specific FC effects in MCI, future research including healthy controls, pre-MCI assessments, and comparison groups with MCI and depression will be important to disentangle disease-related and treatment-related FC changes.