(S)-citalopram influences amygdala modulation in healthy subjects: a randomized placebo-controlled double-blind fMRI study using dynamic causal modeling☆
Introduction
Selective serotonin reuptake inhibitors (SSRIs), such as Citalopram or Escitalopram, are well known for their therapeutic applicability, e.g., in affective and anxiety disorders. Numerous in vitro and non-human in vivo studies, in combination with observable efficacy in patients demonstrate their effects on molecular, cellular, and clinical levels (Arborelius et al., 1999, Hiemke and Härtter, 2000, Hyttel, 1978, Moltke et al., 2001, Owens et al., 2001, Sánchez et al., 2003). However, the direct characterization of neurobiological and pharmacological effects, for example of SSRIs, on human brain networks is methodologically challenging, as it typically requires invasive procedures that are not applicable in human studies. Applying dynamic causal modeling (DCM) to functional MRI allows for non-invasive characterization of neural mechanisms and their regulation. DCM has gained particular popularity in human neuroscience as it allows for the investigation of effective connectivity patterns in a given brain network (Friston et al., 2003, Kasess et al., 2010, Schuyler et al., 2010, Seghier et al., 2010, Stephan et al., 2010). Here we endeavor to study the influence of two SSRIs on the interaction between central parts of the serotonergic system during an emotional face discrimination task.
The serotonergic system is implicated in a spectrum of psychiatric diseases, most prominently anxiety disorders and depression, which exhibit lifetime prevalence rates around 29% and 17%, respectively (Kessler et al., 2005). A wealth of animal and imaging studies speaks for the essential role of dysfunctions within the serotonergic system in the pathophysiology of these disorders. For example, serotonin transporter (SERT) knockout mice display depressive behavior (Wellman et al., 2007), while mice lacking 5-HT1A receptors show increased anxiety (Parks et al., 1998, Ramboz et al., 1998). In turn, the relationship between pathologic serotonergic transmission, depression, and anxiety is solidified by research into the association between clinical symptoms and receptor and transporter changes, focusing primarily on the 5-HT1A receptor and the serotonin transporter (Drevets et al., 2007, Meyer, 2007, Shrestha et al., 2011).
However, investigation into this relationship can also be extended to a functional level. The amygdala consistently shows reactivity in response to salient stimuli, emotion processing, and anxiety-related processes (Mathew et al., 2008). Regulation of amygdala activity is in part governed by the orbitofrontal cortex (OFC), which is specifically involved in top-down regulation of emotional content (Agustin-Pavon et al., 2012, John et al., 2013). Evidence of serotonergic influence in the amygdala and OFC is emphasized by results indicating pathophysiologic changes within these regions for disorders in which a serotonergic contribution to pathogenesis is well established (Shin and Liberzon, 2010). This influence is further underscored by studies directly linking modifications within the serotonergic system to activity changes within the amygdala and OFC. For example, ablation of serotonergic transmission by tryptophan depletion results in alteration of amygdala and OFC neural response during emotion and fear processing (Fusar-Poli et al., 2007, Hindi Attar et al., 2012). On a receptor-specific, pharmacologic level, administration of a 5-HT2A antagonist has been shown to reduce OFC activity, but increase the region’s functional coupling to the amygdala during processing of fearful faces (Hornboll et al., 2013).
However, differences have been shown among SSRIs in the clinical effectiveness they achieve. Specifically, Escitalopram, which consists solely of the (S)-citalopram enantiomer, has repeatedly shown higher anti-depressant response and remission rates than its close relative Citalopram, which is comprised of both the R- and S-enantiomer (Cipriani et al., 2009, Yevtushenko et al., 2007). These clinical differences may be attributed to differences in binding kinetics between the two enantiomers, based on the proposal that the inactive (R)- citalopram blocks (S)-citalopram mediated SERT inhibition (Klein et al., 2006, Klein et al., 2007).
Not surprisingly, SSRI administration has also been shown to affect amygdala activity related to salient stimuli in healthy controls (Bigos et al., 2008) and response to SSRIs may modulate amygdala and OFC activity in anxiogenic tasks in patients with anxiety disorders (Faria et al., 2012). In patients with major depression, amygdala response to fearful facial expressions was found to be increased compared to healthy controls. This hyperactivation, however, normalized in patients after receiving seven days treatment with Escitalopram (Godlewska et al., 2012). This proposes that SSRI mediation of amygdala activity may be relevant to therapeutic results.
DCM provides a powerful analysis framework to explain in vivo neuroimaging data in terms of functional interdependencies and causal mechanisms. We apply it for the investigation of the behavior of the serotonergic system during emotion processing and under the influence of SSRIs (Friston et al., 2003, Schuyler et al., 2010, Stephan et al., 2010). First, we expect to replicate findings from a previous study, by applying a similar fMRI task and DCM model space, in which we showed a negative modulation of the amygdala by the OFC in healthy volunteers (Sladky et al., 2013). Second, we hypothesize that the administration of SSRIs changes the effective connectivity between the OFC and the amygdala, specifically, that SSRIs increase orbitofrontal down-regulation of amygdala activation. Lastly, we aimed to distinguish and characterize the individual effects of the two Citalopram enantiomers (R)- and (S)-citalopram. The application of two different SSRIs, Citalopram, containing both (R)- and (S)-citalopram, and Escitalopram, where only the latter is present, allows for an experimental model that delineates their individual effects. Using a joint (S)-citalopram contextual input for both Citalopram and Escitalopram sessions and an additional contextual input of (R)- citalopram for the Citalopram session reflects their pharmaceutical similarity and difference (Fig. 1).
Section snippets
Participants and methods
The data used in this DCM study originates from a previous dataset (Windischberger et al., 2010) and was processed and analyzed as stated bellow.
Study medication and behavioral data
The effects of the study medication and task-related behavioral data are fully described in (Windischberger et al., 2010). In short, no significant differences in (S)-citalopram plasma levels between Escitalopram and Citalopram were found after the 10-day ingestion period. Furthermore, no significant interactions between medication (placebo, Escitalopram, Citalopram), task performance (response time, accuracy), and Spielberger State-Trait Anxiety scores were found.
Statistical parametric mapping (SPM)
SPM group results for the
Discussion
This is the first randomized placebo-controlled study to investigate the influence of SSRIs on the effective connectivity between the OFC and the amygdala. Both regions are highly relevant to the processing of social signals and emotional content, affected by various psychiatric disorders and known target sites for psychotropic medication influencing the serotonergic system.
Conclusion
This study provides strong evidence for the mediating effects of (S)-citalopram and very likely other SSRIs on the effective connectivity within the prefrontal-amygdala network. Most importantly, we found that (S)-citalopram is associated with stronger inhibition of amygdala activation via the orbitofrontal cortex. Our study is in high accordance with previous human neuroimaging and non-human neurobiological research and, for the first time, provides a mechanistic model of SSRI interaction in
Acknowledgments
We thank the staff at the Department of Psychiatry and Psychotherapy for medical and administrative support.
Disclosure and conflict of interest
Data presented here was acquired within a project funded by an investigator initiated and unrestricted research grant from H. Lundbeck A/S, Denmark to S. Kasper. The sponsors and funders participated neither in the design nor in the execution of the study, of which the authors retain full academic control. This research was also supported by an FWF grant
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Project name: Escitalopram versus Citalopram Treatment effects on cortical and subcortical activity assessed by pharmacological fMRI, EudraCT: 2005-002701-23, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2005-002701-23+