Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

Leor Roseman, Lysia Demetriou, Matthew B. Wall, David J. Nutt, Robin L. Carhart-Harris

Neuropharmacology, 2018, 142, 263e269.

https://doi.org/10.1016/j.neuropharm.2017.12.041

 

Abstract

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to thefirst session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.Trial registration:ISRCTN, number ISRCTN14426797.

This article is part of the Special Issue entitled “Psychedelics: New Doors, Altered Perceptions”.©2018

Keywords : Psilocybin, Psychedelics, Depression, Amygdala, fMRI, Emotional processing

 

1. Introduction

Psychedelic therapy is a re-emerging paradigm in psychiatry (dos Santos et al., 2016; Mithoefer et al., 2016). Unlike other psychopharmacological treatment models that seek to medicate patients on a chronic basis, the psychedelic model seeks to treat corepsychological issues via a small number of profound and potentially transformative psychological experiences (Pahnke et al., 1970; Watts et al., 2017). Our recent open-label study of psilocybin with psychological support for treatment-resistant depression (TRD) yielded promising results, with all patients showing some reduction in depressive symptoms at 1 week and half meeting criteria for remission at 3 weeks (Carhart-Harris et al., 2017). Furthermore, other clinical studies with psilocybin have found reductions in anxiety and depressive symptoms after psilocybin with psychological support (Griffiths et al., 2016; Ross et al., 2016). Psilocybin, a classic psychedelic and non-selective serotonin 2A receptor (5-HT2AR) agonist, was discovered and marketed in the 1950s and 60s (Hofmann et al.,1958). After much early enthusiasm about the therapeutic potential of psychedelics (Grinspoon and Bakalar, 1979; Rucker et al., 2016), a politically led about-turn in the mid-1960s and early 1970s effectively ended all research with these drugs, and it has only been in the last 10-15 years that clinical  researchers have begun to work with them again. During this renascent period, impressive results have been found for the treatment of depression (Carhart-Harris et al., 2016; Osorio et al.,2015), end of life anxiety (Gasser et al., 2014a; Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016), obsessive compulsive disorder (Moreno et al., 2006) and addiction (Bogenschutz and Johnson, 2016). The amygdala has previously been implicated in the patho-physiology of depression (Drevets et al., 1992) as well as the action of some antidepressants (Ma, 2015) and psychedelics (Kraehenmann et al., 2015; Spain et al., 2015). The amygdala is a complex subcortical structure that is sensitive to emotional stimuli (Janak and Tye, 2015; Sergerie et al., 2008). Functional MRI studies of untreated clinically depressed patients have found amygdala hyper-sensitivity to negative emotional stimuli (Drevets et al.,1992; Ma, 2015), and treatment with SSRIs has been found to attenuate this; both with chronic SSRI-use as well as early in treatment, prior to the appearance of clinical improvements (Godlewska et al., 2012). Here, we sought to explore the antidepressant action of psilocybin on amygdala responses to emotional faces using a functional magnetic resonance imaging (fMRI) paradigm that has been well-validated in the context of SSRI-based treatments for depression (Ma, 2015). Patients underwent balanced versions of an emotional faces paradigm before and one-day after treatment with psilocybin. Psilocybin has been found to be associated with improved mood in the sub-acute period days after exposure (Majic et al., 2015). Wetherefore predicted that amygdala responses to emotional faces would be altered post-treatment and that this might relate to changes in depression severity. We were particularly interested in the fearful versus neutral faces contrast, due to previous findings of reduced amygdala responses to negative emotional stimuli with SSRIs (Ma, 2015). We also predicted that the nature of the acute psychological experience under psilocybin would relate to the post-treatment changes in amygdala responses.

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