Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2018 Oct;43(11):2221-2230.
doi: 10.1038/s41386-018-0122-9. Epub 2018 Jun 19.

Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder

Elizabeth A Bartlett  1 , Christine DeLorenzo  2 , Priya Sharma  2 , Jie Yang  3 , Mengru Zhang  4 , Eva Petkova  5 , Myrna Weissman  6 , Patrick J McGrath  6 , Maurizio Fava  7 , R Todd Ogden  8 , Benji T Kurian  9 , Ashley Malchow  9 , Crystal M Cooper  9 , Joseph M Trombello  9 , Melvin McInnis  10 , Phillip Adams  6 , Maria A Oquendo  11 , Diego A Pizzagalli  12 , Madhukar Trivedi  9 , Ramin V Parsey  2
Affiliations
Randomized Controlled Trial

Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder

Elizabeth A Bartlett et al. Neuropsychopharmacology. 2018 Oct.

Abstract

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p = 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.

PubMed Disclaimer

Conflict of interest statement

Ms. Bartlett, Dr. Ogden, Ms. Malchow, and Dr. Petkova report no conflicting interests. Dr. Yang, Dr. Sharma, and Ms. Zhang report no conflicting interests relating to this paper. Dr. DeLorenzo reports no financial disclosures. Dr. Cooper and Dr. Adams report no competing interests. Dr. McInnis has no conflicts of interest with respect to this paper. Dr. Trombello owns stock in Merck and Gilead Sciences. Within the past 36 months he has also owned stock in Johnson & Johnson. Dr. Trivedi, is or has been an advisor/consultant and received fee from (lifetime disclosure): Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb Company, Cephalon, Inc., Cerecor, CME Institute of Physicians, Concert Pharmaceuticals, Inc., Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Services, LLC, Janssen Pharmaceutica Products, LP, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America, Inc., Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Inc., Pfizer Inc., PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products Ltd., Sepracor, SHIRE Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories. In addition, he has received grants/research support from: Agency for Healthcare Research and Quality (AHRQ), Cyberonics, Inc., National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health and National Institute on Drug Abuse. In the past two years, Dr. Weissman received funding from the National Institute of Mental Health (NIMH), the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Sackler Foundation, the Templeton Foundation; and receives royalties from the Oxford University Press, Perseus Press, the American Psychiatric Association Press, and MultiHealth Systems. Dr. McGrath has received funding from the National Institute of Mental Health, 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). Dr. Fava has received research support from Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Cerecor; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-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.; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; 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 (SMRI); Synthelabo; Tal Medical; 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 (P) 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; 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.; 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; 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.; 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; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories; he has equity holdings in Compellis and PsyBrain, Inc.; he has a patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven; and he receives copyright royalties for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. Dr. Kurian has received research grant support from the following organizations: Targacept, Inc., Pfizer, Inc., Johnson & Johnson, Evotec, Rexahn, Naurex, Forest Pharmaceuticals and the National Institute of Mental Health (NIMH). Mary L. Phillips has received funding from NIMH and the Emmerling-Pittsburgh Foundation. Dr. Oquendo receives royalties for use of the Columbia Suicide Severity Rating Scale. Her family owns stock in Bristol Myers Squibb. Over the past 3 years, Dr. Pizzagalli has received honoraria/consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Pfizer, and Posit Science for activities unrelated to this project. Dr. Parsey reports no relevant or material financial interests that relate to the research described in this paper.

Figures

Fig. 1
Fig. 1
Location of Freesurfer Desikan-Killiany defined rostral middle frontal (LEFT) and rostral anterior cingulate (RIGHT) found to be significant with harmonized morphology data
Fig. 2
Fig. 2
Receiver operating characteristic (ROC) curves for classifying posttreatment remission status generated from 10-repeated 5-fold cross-validation. Averaged ROC curve shown using threshold averaging based on the random forest model using the subset of the 10 most important predictors. Mean and standard deviation for the area under the curve (AUC) shown
See this image and copyright information in PMC

References

    1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40. doi: 10.1176/appi.ajp.163.1.28. - DOI - PubMed
    1. Quitkin FM, Rabkin JD, Markowitz JM, Stewart JW, McGrath PJ, Harrison W. Use of pattern analysis to identify true drug response. A replication. Arch Gen Psychiatry. 1987;44:259–64. doi: 10.1001/archpsyc.1987.01800150071009. - DOI - PubMed
    1. Kraemer HC, Wilson GT, Fairburn CG, Agras WS. Mediators and moderators of treatment effects in randomized clinical trials. Arch Gen Psychiatry. 2002;59:877–83. doi: 10.1001/archpsyc.59.10.877. - DOI - PubMed
    1. McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821–9. doi: 10.1001/jamapsychiatry.2013.143. - DOI - PMC - PubMed
    1. Colloby SJ, Firbank MJ, Vasudev A, Parry SW, Thomas AJ, O’Brien JT. Cortical thickness and VBM-DARTEL in late-life depression. J Affect Disord. 2011;133:158–64. doi: 10.1016/j.jad.2011.04.010. - DOI - PubMed

Publication types

Substances

LinkOut - more resources