Trial PaperDepressive DisordersMajor Depressive Disorder (MDD)Neuroimaging & Brain MeasuresPsilocybin

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

In an open‑label study of 24 patients with major depressive disorder, psilocybin therapy produced an enduring increase in cognitive flexibility for at least four weeks and altered anterior cingulate cortex (ACC) biochemistry (reduced glutamate and N‑acetylaspartate) alongside increased ACC–posterior cingulate cortex dynamic functional connectivity (dFC). Paradoxically, larger post‑treatment ACC–PCC dFC increases were associated with smaller cognitive gains, while greater baseline ACC dFC predicted better baseline flexibility but less subsequent improvement, suggesting a nuanced relationship between neural and cognitive flexibility in therapeutic response.

Authors

  • Roland Griffiths
  • Alan Davis
  • Frederick Barrett

Published

Translational Psychiatry
individual Study

Abstract

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

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Study Details

References (20)

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