title: Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas.
abstract: Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding.
authors: Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
authors: Rupert
authors: R
authors: Lanzenberger
authors: Georg S
authors: GS
authors: Kranz
authors: Daniela
authors: D
authors: Haeusler
authors: Elena
authors: E
authors: Akimova
authors: Markus
authors: M
authors: Savli
authors: Andreas
authors: A
authors: Hahn
authors: Markus
authors: M
authors: Mitterhauser
authors: Christoph
authors: C
authors: Spindelegger
authors: Cecile
authors: C
authors: Philippe
authors: Martin
authors: M
authors: Fink
authors: Wolfgang
authors: W
authors: Wadsak
authors: Georgios
authors: G
authors: Karanikas
authors: Siegfried
authors: S
authors: Kasper
mesh_terms: D000328:Adult; D001596:Benzylamines; D002250:Carbon Radioisotopes; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D011903:Raphe Nuclei / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon; D055815:Young Adult
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine