Increased global integration in the brain after psilocybin therapy for depression

Apr 12, 2022Nature medicine

Brain networks become more connected after psilocybin treatment for depression

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Abstract

The antidepressant response to psilocybin was rapid and sustained, correlated with decreases in brain network modularity.

Psilocybin therapy was assessed in two clinical trials for its effects on depression.
Both trials indicated that psilocybin could lead to significant improvements in depressive symptoms.
fMRI results showed that psilocybin treatment is associated with increased integration of brain networks.
Higher-order functional networks rich in 5-HT2A receptors exhibited greater connectivity and flexibility following psilocybin treatment.
In contrast, escitalopram treatment resulted in milder antidepressant effects without changes in brain network organization.

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Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

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Increased global integration in the brain after psilocybin therapy for depression

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