Effect of Citalopram on Emotion Processing in Humans: A Combined 5-HT1A [11C]CUMI-101 PET and Functional MRI Study

Abstract

A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to play a critical role in affect processing. Thus we investigated the effect of acute citalopram on emotional processing and the relationship between DRN 5-HT1A receptor availability and amygdala reactivity. Thirteen (mean age 48±9 years) healthy male subjects received either a saline or citalopram infusion intravenously (10 mg over 30 minutes) on separate occasions in a single-blind, random order, cross-over design. On each occasion, participants underwent a block design face-emotion processing task during fMRI known to activate the amygdala. Ten subjects also completed a positron emission tomography (PET) scan to quantify DRN 5-HT1A availability using [11C]CUMI-101.Citalopram infusion when compared to saline resulted in a significantly increased bilateral amygdala responses to fearful vs. neutral faces (Left p=0.025; Right p=0.038 FWE-corrected). DRN [11C]CUMI-101availability significantly positively correlated with the effect of citalopram on the left amygdala response to fearful faces (Z=2.51, p=0.027) and right amygdala response to happy faces (Z=2.33, p=0.032). Our findings indicate that the initial effect of SSRI treatment is to alter processing of aversive stimuli, and that this is linked to DRN 5-HT1A receptors in line with evidence that 5-HT1A receptors have a role in mediating emotional processing.

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder

“…Finally, neuropsychological testing, fMRI and PET were typically collected on separate days and locations. The anatomical cross-localization could be off in such instances, and the measurements could be weakened by day-session specific parameters (Selvaraj et al, 2017; Hamilton et al, 2018). As the relationships were quite robust, there may have been additional links that were missed.…”

“…Evidence of abnormal 5-HT (5-hydroxytyptamine refers to G protein coupled receptors and ligand-gated ion channels, also known as serotonin receptors) function in MDD is building, including for 5-HT 1A specifically ( 1A is a subtype of 5-HT receptor which is the most widespread 5-HT receptor, including within cortex and medial temporal structures). Past human imaging studies of 5-HT 1A binding potential (BP) have focused on areas of binding where serotonin receptors are more densely populated, including the raphe, as well as frontal, cingulate and medial temporal cortices (Marazziti et al, 1994; Oquendo et al, 2003; Parsey et al, 2006, 2010; Drevets et al, 2007; Selvaraj et al, 2017; Kranz et al, 2018). 5-HT 1A receptors regulate the firing of 5-HT neurons presynaptically in the raphe nuclei and are expressed postsynaptically in many different cortical and subcortical brain regions (Schlumpf et al, 1987; Kaufman et al, 2015; Zanderigo et al, 2018).…”

“…We further investigated relationships of fMRI BOLD responses during a Cognitive Control task based upon 5-HT 1A BP in the MDD sample, including fMRI BOLD responses based upon degree of 5-HT 1A BP ND in the MDD sample [Hyp 4 of lowered 5-HT 1A BP ND correlated with lowered activation in Cognitive Control region(s)]. Cross-modality comparisons are relatively rare in MDD (multimodal imaging can be simultaneous or on separate days), but they illustrate the value in integrating localization, function, and neurotransmitter density (Kalin et al, 2008; Selvaraj et al, 2017; Hamilton et al, 2018; Kranz et al, 2018; Piel et al, 2018). Analyses were also conducted with the HC group to verify the general or MDD specific nature of these relationships (Hyp 5).…”

Cognitive neuropsychological theory: Reconciliation of psychological and biological approaches for depression

“…This effect of citalopram was explored in a recent PET study (Selvaraj et al 2018). In healthy individuals who received citalopram infusion as compared to saline there was an enhanced amygdala response to fearful vs neutral facial expressions.…”

Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

“…[ 11 C](+)PHNO, for example, is frequently selected as a tracer because it binds preferentially (though not selectively) to dopamine D 3 receptors, and its preference for this subtype is higher than that of dopamine D 2/3 antagonist ligands like [ 11 C]raclopride . [ 11 C]CUMI‐101 is used in clinical studies, not because of its ability to image the high‐affinity state of serotonin 5‐HT 1A receptors (which is actually under doubt—see below) but because of its high subtype‐selectivity and imaging contrast. [ 11 C]carfentanil and [ 18 F]TZTP are the only tracers available for µ‐opioid and muscarinic M 1 receptors, so in their case, there are no antagonist tracers with which they could be compared head‐to‐head.…”