Abstract
Background: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. Methods: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, −1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. Results: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). Conclusions: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 20-28 |
| Number of pages | 9 |
| Journal | Biological Psychiatry: Cognitive Neuroscience and Neuroimaging |
| Volume | 6 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Keywords
- Amygdala
- Antidepressant response
- Central executive network
- Depression
- Dorsolateral prefrontal cortex
- EMBARC
- Functional connectivity
- NCT01407094
- Resting state
- Subcallosal cingulate
- Ventral striatum
- fcMRI
ASJC Scopus subject areas
- Clinical Neurology
- Biological Psychiatry
- Cognitive Neuroscience
- Radiology Nuclear Medicine and imaging
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In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Vol. 6, No. 1, 01.2021, p. 20-28.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Dorsolateral Prefrontal Cortex and Subcallosal Cingulate Connectivity Show Preferential Antidepressant Response in Major Depressive Disorder
AU - Chin Fatt, Cherise R.
AU - Cooper, Crystal
AU - Jha, Manish K.
AU - Aslan, Sina
AU - Grannemann, Bruce
AU - Kurian, Benji
AU - Greer, Tracy L.
AU - Fava, Maurizio
AU - Weissman, Myrna
AU - McGrath, Patrick J.
AU - Parsey, Ramin V.
AU - Etkin, Amit
AU - Phillips, Mary L.
AU - Trivedi, Madhukar H.
N1 - Funding Information: The EMBARC study was supported by the National Institute of Mental Health (NIMH) (Grant No. U01MH092221 [to MHT] and Grant No. U01MH092250 [to PJM, RVP, MW]) and in part by the Hersh Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Valeant Pharmaceuticals (now Bausch Health) donated Wellbutrin XL used in the study. This work was supported by the EMBARC National Coordinating Center at University of Texas Southwestern Medical Center (coordinating principal investigator MHT) and the Data Center at Columbia University and Stony Brook University. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. MHT, BK, MF, PJM, RVP, and MW were responsible for the study concept and design. MHT, CC, MKJ, BK, MF, PJM, MLP, RVP, and MW acquired the data. CRCF, CC, MKJ, SA, TLG, AE, and BG performed the data analysis and interpretation. CRCF, CC, MKJ, SA, MHT, and BG wrote the original draft of the manuscript. All authors critically revised the manuscript for important intellectual content. CRCF, SA, and BG performed the statistical analysis. MHT, PJM, EVP, and MW obtained funding. MHT supervised the study. We thank the participants, families, staff, and colleagues who made this project possible. Bruce Grannemann, M.A. died unexpectedly in the course of this project, but his efforts, energy, and dedication were invaluable for the success of this research study. MKJ has received contract research funding from Acadia Pharmaceutical and Janssen Research. BK has received grant support from Targacept Inc. Pfizer Inc. Johnson & Johnson, Evotec, Rexahn, Naurex, Forest Pharmaceuticals, and NIMH. TLG has received research funding from Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia & Depression) and contracted research support from Janssen Research & Development LLC and has received honoraria and/or consultant fees from H. Lundbeck A/S and Takeda Pharmaceuticals International Inc. MF has received research support from Abbott Laboratories, Acadia Pharmaceuticals, Alkermes Inc. American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharmaceuticals, AXSOME Therapeutics, BioResearch, BrainCells Inc. Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clintara LLC, Covance, Covidien, Eli Lilly and Company, EnVivo Pharmaceuticals Inc. Euthymics Bioscience Inc. Forest Pharmaceuticals Inc. FORUM Pharmaceuticals, Ganeden Biotech Inc. GlaxoSmithKline, Harvard Clinical Research Institute, F. Hoffmann-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen R&D LLC, Jed Foundation, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck Inc. MedAvante, Methylation Sciences Inc. Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia & Depression), National Center for Complementary and Alternative Medicine, National Coordinating Center for Integrated Medicine, National Institute of Drug Abuse, NIMH, Neuralstem Inc. NeuroRx, Novartis AG, Organon Pharmaceuticals, PamLab LLC, Pfizer Inc. Pharmacia-Upjohn, Pharmaceutical Research Associates Inc. Pharmavite LLC, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, Roche Pharmaceuticals, RCT Logic LLC (formerly Clinical Trials Solutions LLC), Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals Inc. Stanley Medical Research Institute, Synthelabo, Takeda Pharmaceuticals, Tal Medical, VistaGen Therapeutics, and Wyeth-Ayerst Laboratories; he has served as advisor or consultant to Abbott Laboratories, Acadia, Affectis Pharmaceuticals AG, Alkermes Inc. Amarin Pharma Inc. Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME Therapeutics, Bayer AG, Best Practice Project Management Inc. Biogen, BioMarin Pharmaceuticals Inc. Biovail Corporation, BrainCells Inc. Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon Inc. Cerecor, CNS Response Inc. Compellis Pharmaceuticals, Cypress Pharmaceutical Inc. DiagnoSearch Life Sciences Pvt. Ltd. Dinippon Sumitomo Pharma Co. Inc. Dov Pharmaceuticals Inc. Edgemont Pharmaceuticals Inc. Eisai Inc. Eli Lilly and Company, EnVivo Pharmaceuticals Inc. ePharmaSolutions, EPIX Pharmaceuticals Inc. Euthymics Bioscience Inc. Fabre-Kramer Pharmaceuticals Inc. Forest Pharmaceuticals Inc. Forum Pharmaceuticals, GenOmind LLC, GlaxoSmithKline, Grunenthal GmbH, Indivior, i3 Innovus/Ingenis, Intracellular, Janssen Pharmaceutica, Jazz Pharmaceuticals Inc. Johnson & Johnson Pharmaceutical Research & Development LLC, Knoll Pharmaceuticals Corp. Labopharm Inc. Lorex Pharmaceuticals, Lundbeck Inc. MedAvante Inc. Merck & Co. Inc. MSI Methylation Sciences Inc. Naurex Inc. Nestle Health Sciences, Neuralstem Inc. Neuronetics Inc. NextWave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics Inc. Organon Pharmaceuticals, Osmotica, Otsuka Pharmaceuticals, Pamlab LLC, Pfizer Inc. PharmaStar, Pharmavite LLC, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals Inc. PPD, Puretech Ventures, PsychoGenics, Psylin Neurosciences Inc. RCT Logic LLC (formerly Clinical Trials Solutions LLC), Rexahn Pharmaceuticals Inc. Ridge Diagnostics Inc. Roche, Sanofi-Aventis US LLC, Sepracor Inc. Servier Laboratories, Schering-Plough Corporation, Shenox Pharmaceuticals, Solvay Pharmaceuticals Inc. Somaxon Pharmaceuticals Inc. Somerset Pharmaceuticals Inc. Sunovion Pharmaceuticals, Supernus Pharmaceuticals Inc. Synthelabo, Taisho Pharmaceutical, Takeda Pharmaceutical Company Limited, Tal Medical Inc. Tetragenex Pharmaceuticals Inc. TransForm Pharmaceuticals Inc. Transcept Pharmaceuticals Inc. Vanda Pharmaceuticals Inc. and VistaGen; he has received speaking or publishing fees from Adamed Co. Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon Inc. CME Institute/Physicians Postgraduate Press Inc. Eli Lilly and Company, Forest Pharmaceuticals Inc. GlaxoSmithKline, Imedex LLC, Massachusetts General Hospital Psychiatry Academy/Primedia, Massachusetts General Hospital Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc. PharmaStar, United BioSource Corp. and Wyeth-Ayerst Laboratories; he has equity holdings in Compellis and PsyBrain Inc.; he has a patent for Sequential Parallel Comparison Design, which are licensed by Massachusetts General Hospital to Pharmaceutical Product Development LLC, and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by Massachusetts General Hospital to Biohaven; and he receives copyright royalties for the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, Symptoms of Depression Questionnaire, and SAFER and from Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing Co. Pte. Ltd. MHT has consulted for or served on the advisory board of AcademyHealth, Alkermes Inc. Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, ACI Clinical, Alto Neuroscience Inc. Axsome Therapeutics, American Society of Clinical Psychopharmacology (speaking fees and reimbursement), American Psychiatric Association (Deputy Editor for American Journal of Psychiatry), Avanir Pharmaceuticals, Boegringer Ingelheim, Janssen Pharmaceutical, Jazz Pharmaceutical, Johnson & Johnson Pharmaceutical Research & Development, Lundbeck Research USA, Medscape, Navitor, Otsuka America Pharmaceutical Inc. Perception Neuroscience Holdings, Pharmerit International, SAGE Therapeutics, and Takeda Global Research; he has received grants from Cancer Prevention and Research Institute of Texas, NIMH, National Institute of Drug Abuse, Johnson & Johnson, Janssen Research and Development LLC, and Patient-Centered Outcomes Research Institute; and he has received editorial compensation from Healthcare Global Village, Engage Health Media, and Oxford University Press. MW has received funding from NIMH, National Institute on Drug Abuse, Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression), Sackler Foundation, and Templeton Foundation and receives royalties from Oxford University Press, Perseus Press, American Psychiatric Association Press, and MultiHealth Systems. PJM has received funding from NIMH, New York State Department of Mental Hygiene, Research Foundation for Mental Hygiene (New York State), Forest Research Laboratories, Sunovion Pharmaceuticals, and Naurex Pharmaceuticals (now Allergan). AE has equity options in Mindstrong Health and Akili Interactive for unrelated work. MLP has received funding from NIMH. All other authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC); https://clinicaltrials.gov/ct2/show/NCT01407094; NCT01407094. Funding Information: The EMBARC study was supported by the National Institute of Mental Health (NIMH) (Grant No. U01MH092221 [to MHT] and Grant No. U01MH092250 [to PJM, RVP, MW]) and in part by the Hersh Foundation . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Valeant Pharmaceuticals (now Bausch Health) donated Wellbutrin XL used in the study. This work was supported by the EMBARC National Coordinating Center at University of Texas Southwestern Medical Center (coordinating principal investigator MHT) and the Data Center at Columbia University and Stony Brook University. Publisher Copyright: © 2020 Society of Biological Psychiatry
PY - 2021/1
Y1 - 2021/1
N2 - Background: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. Methods: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, −1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. Results: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). Conclusions: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.
AB - Background: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. Methods: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, −1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. Results: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). Conclusions: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.
KW - Amygdala
KW - Antidepressant response
KW - Central executive network
KW - Depression
KW - Dorsolateral prefrontal cortex
KW - EMBARC
KW - Functional connectivity
KW - NCT01407094
KW - Resting state
KW - Subcallosal cingulate
KW - Ventral striatum
KW - fcMRI
UR - http://www.scopus.com/inward/record.url?scp=85090571698&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090571698&partnerID=8YFLogxK
U2 - 10.1016/j.bpsc.2020.06.019
DO - 10.1016/j.bpsc.2020.06.019
M3 - Article
C2 - 32921587
AN - SCOPUS:85090571698
SN - 2451-9022
VL - 6
SP - 20
EP - 28
JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
IS - 1
ER -