Cerebral Blood Perfusion Predicts Response to Sertraline versus Placebo for Major Depressive Disorder in the EMBARC Trial
Year: 2019
Type: article
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).
Source: EClinicalMedicine
Authors: Crystal M. Cooper, Cherise R. Chin Fatt, Manish Jha, Gregory A. Fonzo, Bruce D. Grannemann, Thomas 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
Institutions: The University of Texas Southwestern Medical Center, VA Palo Alto Health Care System, Mental Illness Research, Education and Clinical Centers, Stanford Medicine, Stanford University, The University of Texas at Austin, Massachusetts General Hospital, New York State Psychiatric Institute, Columbia University, University of Michigan, Stony Brook University, University of Pittsburgh, Johns Hopkins University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: John Templeton Foundation, Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Bayer, GlaxoSmithKline, Novartis, Sanofi, Medtronic, Massachusetts General Hospital, Biogen, Patient-Centered Outcomes Research Institute, CeNeRx, Columbia University, International OCD Foundation, Pharmavite, Stanley Medical Research Institute, Boston University, Takeda Pharmaceuticals U.S.A., University of Texas Southwestern Medical Center, Tufts University, Sunovion, National Alliance for Research on Schizophrenia and Depression, Jazz Pharmaceuticals, Massachusetts Medical Society, Indivior, Santa Fe Institute, Hersh Foundation, Amarin Corporation, ACADIA Pharmaceuticals, Orexigen Therapeutics, Avanir Pharmaceuticals, Cerecor, American Society of Clinical Psychopharmacology, BrainCells, FORUM Pharmaceuticals, Forest Research Institute, Vistagen Therapeutics, University of Oxford, Covidien, Eisai, Shire, H. Lundbeck A/S, National Institutes of Health, Agency for Healthcare Research and Quality, Defense Advanced Research Projects Agency, Johnson and Johnson, Transportation Security Administration, Amarin Pharma, Solvay Pharmaceuticals, Minnesota Supercomputing Institute, University of Minnesota, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Alternative Medicine, Janssen Research and Development, Janssen Pharmaceuticals
OpenAlex ID: W2945509633