Meta-Analysis of Molecular Imaging of Serotonin Transporters in Major Depression

Abstract

The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g=−0.49; 95% CI: (−0.84, −0.14)) and amygdala (Hedges' g=−0.50; 95% CI: (−0.78, −0.22)), which no individual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g=−0.24, striatum: g=−0.32, and brainstem g=−0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations (P<0.01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala (P=0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ∼10% in 5-HTT availability in MDD, which may predict altered spatial–temporal dynamics of serotonergic neurotransmission.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

“…Earlier research in this population has shown that TNF antagonism was associated with an antidepressant effect that was independent of disease improvement (Gelfand et al, 2008;Krishnan et al, 2007;Langley et al, 2010;Tyring et al, 2006). Consistent with previous studies, TNF-α explained only around 3% of and brain stem 5-HTT availability explained only around 7% variance in depression severity (Gryglewski et al, 2014;Valkanova et al, 2013).…”

A prospective, longitudinal study of platelet serotonin and plasma brain-derived neurotrophic factor concentrations in major depression: effects of vortioxetine treatment

“…Our study is the first to show in vivo effects of vortioxetine on platelet 5-HT concentrations in depressed patients, as other studies have only been conducted on healthy and younger subjects (Areberg et al 2012;Stenkrona et al 2013). A meta-analysis of molecular imaging data revealed reductions of around 10% availability in 5-HT reuptake sites in different brain regions in drug-naïve depressed patients compared to healthy subjects (Uebelhack et al 2006), which were further reduced with increased age (Gryglewski et al 2014;Rominger et al 2015). SSRIs have been found to modulate 5-HT concentration in a similar manner in platelets and neurons (Yubero-Lahoz et al 2013), and theoretically, the higher the central SERT occupancy, the lower the platelet 5-HT concentration.…”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…The SERT is responsible for 5-HT reuptake from the synaptic cleft and thus determines the magnitude and duration of the 5-HT synaptic signal. A reduction of SERT sites in the brain (particularly in midbrain and amygdala) of depressed patients has been demonstrated both by functional imaging (Gryglewski et al 2014;Yeh et al 2014) and post-mortem brain studies (Mann et al 2000). As the binding to the SERT and the 5-HT uptake capacity remain low after recovery, low SERT activity has been suggested as a trait marker for mood disorders (Lesch 2001).…”