Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial

Abstract

Background Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could “accurately” identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. Methods For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the “preferred” treatment. Remission rates were calculated for participants “accurately” treated based on the composite moderator ( lucky ) versus “inaccurately” treated ( unlucky ). Findings Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. Interpretation This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. Funding National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center. Trial Registration. Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: ...

Functional Neuroimaging in Psychiatry—Aiding in Diagnosis and Guiding Treatment. What the American Psychiatric Association Does Not Know

“…Cerebral perfusion can also be measured using arterial spin labeling in an MRI and was recently shown to predict SSRI response (131). In a sample of 231 patients with Major Depressive Disorder, increased perfusion in the putamen, anterior insula, inferior temporal gyrus, parahippocampal gyrus, inferior parietal lobule, and the orbitofrontal cortex predicted a positive response to the SSRI antidepressant sertraline (131). Further studies of the value of cerebral perfusion neuroimaging, using SPECT and arterial spin labeling in guiding effective treatment are ongoing.…”

Neuroimaging as a Tool for Individualized Treatment Choice in Depression: the Past, the Present and the Future

“…Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC), another large multisite trial [33], provided interesting observations on sertraline and placebo response over 8 weeks of treatment, with about 300 neuroimaging datasets available for analysis. Responders to sertraline, as compared to placebo, were characterized by higher baseline connectivity within the default mode network (DMN), greater betweennetwork connectivity of the DMN and executive control networks [34], an abnormal pattern of baseline pretreatment ventro-striatal response to reward expectancy and prediction error [35], and abnormal perfusion across a number of structures [36]. Intriguingly, some brain patterns seemed to favour placebo over sertraline.…”

Cerebral perfusion in depression: Relationship to sex, dehydroepiandrosterone sulfate and depression severity

“…Previous studies revealed a link between perfusion and depression, reporting both increases and decreases in perfusion in frontal, striatal, and limbic regions in the context of MDD ( Duhameau et al, 2010 , Li et al, 2018 , Lui et al, 2009 , Orosz et al, 2012 , Vasic et al, 2015 ). Another recent study found reduced cerebral blood flow (CBF) in the right parahippocampal gyrus, the thalamus, and fusiform and middle temporal gyri as well as the bilateral insula, and increased CBF in the bilateral inferior parietal lobules in depressed adults ( Cooper et al, 2019a ).…”