Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
A systematic review of 69 neuroimaging studies (1751 participants) found no well-replicated biomarker for ketamine's antidepressant response, but identified several promising candidates. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions, increased functional connectivity within the prefrontal cortex, and increased functional activation of the striatum. The review highlights substantial methodological heterogeneity across studies and calls for further investigation of these biomarkers.