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

Crystal Cooper Cortes, Cherise R. Chin Fatt, Manish K Jha, Gregory A. Fonzo, Bruce D. Grannemann, Thomas J Carmody, Aasia Ali, Sina Aslan, Jorge R.C. Almeida, Thilo Deckersbach, Maurizio Fava, Benji T. Kurian, Patrick J. McGrath, Melvin McInnis, Ramin V. Parsey, Myrna Weissman, Mary L. Phillips, Hanzhang Lu, Amit Etkin, Madhukar H Trivedi

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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: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

Original languageEnglish (US)
JournalEClinicalMedicine
DOIs
StatePublished - Jan 1 2019

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Sertraline
Major Depressive Disorder
Perfusion
Placebos
Brain
Antidepressive Agents
Therapeutics
Depression
National Institute of Mental Health (U.S.)
Parietal Lobe
Putamen
Temporal Lobe
Prefrontal Cortex
Reward
Neuroimaging
Randomized Controlled Trials
Biomarkers

ASJC Scopus subject areas

  • Medicine(all)

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Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial. / Cooper Cortes, Crystal; Chin Fatt, Cherise R.; Jha, Manish K; Fonzo, Gregory A.; Grannemann, Bruce D.; Carmody, Thomas J; Ali, Aasia; Aslan, Sina; Almeida, Jorge R.C.; Deckersbach, Thilo; Fava, Maurizio; Kurian, Benji T.; McGrath, Patrick J.; McInnis, Melvin; Parsey, Ramin V.; Weissman, Myrna; Phillips, Mary L.; Lu, Hanzhang; Etkin, Amit; Trivedi, Madhukar H.

In: EClinicalMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Cooper Cortes, C, Chin Fatt, CR, Jha, MK, Fonzo, GA, Grannemann, BD, Carmody, TJ, Ali, A, Aslan, S, Almeida, JRC, Deckersbach, T, Fava, M, Kurian, BT, McGrath, PJ, McInnis, M, Parsey, RV, Weissman, M, Phillips, ML, Lu, H, Etkin, A & Trivedi, MH 2019, 'Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial', EClinicalMedicine. https://doi.org/10.1016/j.eclinm.2019.04.007
Cooper Cortes, Crystal ; Chin Fatt, Cherise R. ; Jha, Manish K ; Fonzo, Gregory A. ; Grannemann, Bruce D. ; Carmody, Thomas J ; Ali, Aasia ; Aslan, Sina ; Almeida, Jorge R.C. ; Deckersbach, Thilo ; Fava, Maurizio ; Kurian, Benji T. ; McGrath, Patrick J. ; McInnis, Melvin ; Parsey, Ramin V. ; Weissman, Myrna ; Phillips, Mary L. ; Lu, Hanzhang ; Etkin, Amit ; Trivedi, Madhukar H. / Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial. In: EClinicalMedicine. 2019.
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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: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).",
author = "{Cooper Cortes}, Crystal and {Chin Fatt}, {Cherise R.} and Jha, {Manish K} and Fonzo, {Gregory A.} and Grannemann, {Bruce D.} and Carmody, {Thomas J} and Aasia Ali and Sina Aslan and Almeida, {Jorge R.C.} and Thilo Deckersbach and Maurizio Fava and Kurian, {Benji T.} and McGrath, {Patrick J.} and Melvin McInnis and Parsey, {Ramin V.} and Myrna Weissman and Phillips, {Mary L.} and Hanzhang Lu and Amit Etkin and Trivedi, {Madhukar H}",
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T1 - Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial

AU - Cooper Cortes, Crystal

AU - Chin Fatt, Cherise R.

AU - Jha, Manish K

AU - Fonzo, Gregory A.

AU - Grannemann, Bruce D.

AU - Carmody, Thomas J

AU - Ali, Aasia

AU - Aslan, Sina

AU - Almeida, Jorge R.C.

AU - Deckersbach, Thilo

AU - Fava, Maurizio

AU - Kurian, Benji T.

AU - McGrath, Patrick J.

AU - McInnis, Melvin

AU - Parsey, Ramin V.

AU - Weissman, Myrna

AU - Phillips, Mary L.

AU - Lu, Hanzhang

AU - Etkin, Amit

AU - Trivedi, Madhukar H

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

AB - 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: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

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