ASSOCIATIONS BETWEEN ESCITALOPRAM AND PSILOCYBIN THERAPY AND BRAIN RESTING-STATE FUNCTIONAL CONNECTIVITY IN MAJOR DEPRESSIVE DISORDER
Authors: Harding *Rebecca , Ertl Natalie , Zafar Rayyan 
Published: February 2025

Major Depressive Disorder (MDD) is a highly prevalent mental health condition characterized by symptoms including anhedonia, which is defined as diminished pleasure, and impulsivity, which has been linked to increased substance abuse, self-harm and suicidal tendencies. Both anhedonia and impulsivity have been contributed to alterations in reward system function, with the striatum being a central hub involved in processing and regulating reward-related information. Selective serotonin reuptake inhibitors are currently the first-line treatment for patients with MDD. In recent years, there has been growing interest in the potential therapeutic benefits of psilocybin for the treatment of depression and there is mounting evidence suggesting that psychedelics may modulate the reward system.Here, we aim to employ seed-voxel analysis on resting-state functional magnetic resonance imaging (fMRI) data to investigate the effects of escitalopram and psychedelic therapy on the reward pathways within the associative, limbic and sensorimotor striatal subdivisions as well as the amygdala and hippocampus in patients with MDD.

In this secondary analysis of a trial, 45 MDD patients were randomly assigned to either psilocybin therapy (n=24) or escitalopram (n=21) treatment groups. Participants underwent a 10 min long resting- state functional magnetic resonance imaging scan both before and after a 6-week intervention. Analyses examined the connectivity of three striatal networks and the amygdala and hippocampus using seed- based analysis methods. Changes in between-network connectivity, within-network connectivity and intra-striatal connectivity were examined. Changes in anhedonia and impulsivity from pre- to post- treatment were assessed.

Both Escitalopram and psilocybin therapy groups demonstrated reductions in impulsivity and anhedonia scores. Significant interaction effects were found with the amygdala network, where there was a significant psilocybin &gt;escitalopram change in connectivity with a region in the left anterior insula extending into the left putamen. There was a significant escitalopram &gt;psilocybin change in connectivity with a region in the right cerebellum around Crus I extending up to the occipital cortex. There was a significant psilocybin &gt;escitalopram change in connectivity in the limbic striatal network with the bilateral insula, the paracingulate and the temporoparietal junction. Post-hoc analysis revealed this interaction effect was driven by a reduction in connectivity in with the insula in the escitalopram group. A significant correlation was found between the escitalopram induced reduction in connectivity with the insula and the limbic striatum and a reduction in anhedonia.

Reduced connectivity between the limbic striatal network and insula correlated with reductions in anhedonia in the escitalopram group. The insula is an area linked to salience and attentional control, which may reveal the reduction in influence of emotional processing from the limbic regions on the bottom-up detection of salient events. In psilocybin, an increase in connectivity between the amygdala and temporoparietal regions was observed, which may indicate enhanced sensory integration and with reward processing. These results show varying treatment effects on striatal connectivity and the implicit difference in treatment effect on underlying neural circuitry.