Abstract
Selective serotonin reuptake inhibitors (SSRIs) modulate serotonergic neurotransmission by blocking reuptake of serotonin from the extracellular space. Up to now, it remains unclear how SSRIs achieve their antidepressant effect. However, task-based and resting state functional magnetic resonance imaging studies, have demonstrated connectivity changes between brain regions. Here, we use positron emission tomography (PET) to quantify SSRI’s main target, the serotonin transporter (SERT), and assess treatment-induced molecular changes in the interregional relation of SERT binding potential (BPND). Nineteen out-patients with major depressive disorder (MDD) and 19 healthy controls (HC) were included in this study. Patients underwent three PET measurements with the radioligand [11C]DASB: (1) at baseline, (2) after a first SSRI dose; and (3) following at least 3 weeks of daily intake. Controls were measured once with PET. Correlation analyses were restricted to brain regions repeatedly implicated in MDD pathophysiology. After 3 weeks of daily SSRI administration a significant increase in SERT BPND correlations of anterior cingulate cortex and insula with the amygdala, midbrain, hippocampus, pallidum and putamen (p < 0.05; false discovery rate, FDR corrected) was revealed. No significant differences were found when comparing MDD patients and HC at baseline. These findings are in line with the clinical observation that treatment response to SSRIs is often achieved only after a latency of several weeks. The elevated associations in interregional SERT associations may be more closely connected to clinical outcomes than regional SERT occupancy measures and could reflect a change in the regional interaction of serotonergic neurotransmission during antidepressant treatment.
Highlights
The world health organization has estimated some 350 million people of all ages to suffer from major depressive disorder (MDD), which is associated with general disability and increased mortality (World Health Organization, 2015)
An increase was present in the molecular association of the pallidum, putamen, insula, anterior cingulate cortex (ACC), midbrain, hippocampus and amygdala, without reaching significance after correcting for multiple comparison
For all of the regions of interest (ROIs) pairs associated with the ACC and insula at positron emission tomography (PET) 1 vs. PET 2, except for amygdala-pallidum, the strength of correlations further increased at PET 1 vs. PET 3, such that changes seen in this comparison were significant after correction for multiple comparisons (p < 0.05; false discovery rate (FDR) corrected)
Summary
The world health organization has estimated some 350 million people of all ages to suffer from major depressive disorder (MDD), which is associated with general disability and increased mortality (World Health Organization, 2015). Noteworthy is the impressive increase of resting-state fMRI (rs-fMRI) studies in the last decade, i.e., the evaluation of spontaneous low-frequency brain activations in absence of a specific task (Biswal et al, 1995, 2010) These approaches have already proven to be valuable contributions in the investigation of psychiatric disorders, as previous studies investigating MDD and SSRI treatment were able to show alterations in structural and functional brain networks between the pregenual anterior cingulate cortex and the amygdala, thalamus and striatum (Greicius et al, 2007; Anand et al, 2009; Lui et al, 2011; Zhu et al, 2012; Connolly et al, 2013; Wang et al, 2014, 2015)
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