1. Modeling the acute pharmacological response to selective serotonin reuptake inhibitors in human brain using simultaneous PET/MR imaging
- Author
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Jakob Unterholzner, Wolfgang Wadsak, Marius Hienert, Markus Hartenbach, Gregor Gryglewski, Alexander Kautzky, Andreas Hahn, Rupert Lanzenberger, Thomas Vanicek, Leo Silberbauer, Paul Michenthaler, Neydher Berroterán-Infante, Theresa Balber, Lucas Rischka, Godber M Godbersen, Eva-Maria Klebermass, Murray B. Reed, Verena Pichler, Markus Mitterhauser, Siegfried Kasper, Marcus Hacker, Manfred Klöbl, G.M. James, Chrysoula Vraka, and E. Winkler-Pjrek
- Subjects
Adult ,Male ,Adolescent ,Neuroimaging ,Citalopram ,Pharmacology ,DASB ,Placebo ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,medicine ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Biological Psychiatry ,Serotonin transporter ,Serotonin Plasma Membrane Transport Proteins ,Resting state fMRI ,biology ,business.industry ,Brain ,Human brain ,Middle Aged ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Neurology ,Mechanism of action ,chemistry ,Positron-Emission Tomography ,biology.protein ,Female ,Neurology (clinical) ,Serotonin ,medicine.symptom ,business ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ± 21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.
- Published
- 2019
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