open access publication

Article, 2024

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo

Nature Mental Health, ISSN 2731-6076, Volume 2, 2, Pages 164-176, 10.1038/s44220-023-00187-w


Fu, Cynthia H Y 0000-0003-4313-3500 (Corresponding author) [1] [2] Antoniades, Mathilde [3] [4] Erus, Guray 0000-0001-6633-4861 [3] [4] Garcia, Jose A 0009-0000-2703-0777 [3] [4] Fan, Yong 0000-0001-9869-4685 [3] [4] Arnone, Danilo 0000-0003-3831-2301 [2] Arnott, Stephen R. [5] Chen, Taolin [6] [7] [8] Choi, Ki Sueng [9] Fatt, Cherise Chin [10] Frey, Benicio Noronha 0000-0001-8267-943X [11] [12] Frokjaer, Vibe Gedsø [13] [14] [15] Ganz, Melanie [1] [14] Godlewska, Beata Renata 0000-0002-5973-3765 [16] [17] Hassel, Stefanie [18] Ho, Keith [19] Mcintosh, Andrew Mark 0000-0002-0198-4588 [20] Qin, Kun 0000-0003-1254-6388 [6] [7] [8] [21] [22] Rotzinger, Susan Elizabeth [19] [23] Sacchet, Matthew D [24] [25] Savitz, Jonathan B 0000-0001-8143-182X [26] Shou, Haochang [3] [4] Singh, Ashish 0000-0003-4486-3636 [3] [4] Stolicyn, Aleks 0000-0002-1147-7539 [20] Strigo, Irina A 0000-0002-8799-716X [27] Strother, Stephen C. [5] Tosun, Duygu 0000-0001-8644-7724 [27] Victor, Teresa A 0000-0002-0112-2902 [26] Wei, Dong-Tao 0000-0003-2544-8015 [28] Wise, Toby 0000-0002-9021-3282 [2] Zahn, Roland 0000-0002-8447-1453 [2] Anderson, Ian Muir 0000-0003-2205-9209 [29] Craighead, Wade Edward 0000-0001-9957-0027 [30] Deakin, John Francis William 0000-0002-2750-962X [29] Dunlop, Boadie Waid 0000-0002-4653-0483 [30] Elliott, Rebecca M 0000-0002-7602-010X [29] Gong, Qi-Yong 0000-0002-5912-4871 [6] [7] [8] Gotlib, Ian Henry 0000-0002-3622-3199 [31] Harmer, Catherine J 0000-0002-1609-8335 [17] Kennedy, Sidney H 0000-0001-5339-7185 [19] [23] Knudsen, Gitte Moos 0000-0003-1508-6866 [14] [15] Mayberg, Helen Susan 0000-0002-1672-2716 [9] Paulus, Martin P 0000-0002-0825-3606 [26] Qiu, Jiang [28] Trivedi, Madhukar H 0000-0002-2983-1110 [10] Whalley, Heather Clare 0000-0002-4505-8869 [20] Yan, Chao-Gan 0000-0003-3413-5977 [32] Young, Allan Hunter 0000-0003-2291-6952 [2] [33] Davatzikos, Christos A 0000-0002-1025-8561 (Corresponding author) [3] [4]


  1. [1] University of East London
  2. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  3. [2] King's College London
  4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  5. [3] University of Pennsylvania
  6. [NORA names: United States; America, North; OECD];
  7. [4] University of Pennsylvania Health System
  8. [NORA names: United States; America, North; OECD];
  9. [5] University of Toronto
  10. [NORA names: Canada; America, North; OECD];


Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (β = –18.3, 95% CI (–34.3 to –2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.


Hydra, MDD individuals, MRI data, SSRI antidepressant medications, age, antidepressant medication, antidepressants, associated with disease, brain volume, case-control study, changes, clinical syndrome, consortium, control, correlation, data, depression, depressive disorder, depressive episode, depressive symptoms, dimension 1, dimension 2, dimensions, disease, disorders, duration, effect, episodes, findings, first-episode, healthy controls, heterogeneous clinical syndrome, illness, improvement, individuals, inhibitors, interaction, interaction effects, international sample, longitudinal data, major depressive disorder, markers, matter, medication, medication-free individuals, moderate severity, neuroanatomical correlates, neuroimaging-based markers, objective, patterns, placebo, predicting treatment response, prospective longitudinal data, raw MRI data, reduction, regional brain volumes, response, response to placebo, response to selective serotonin reuptake inhibitors, reuptake inhibitors, samples, selective serotonin reuptake inhibitor medications, selective serotonin reuptake inhibitors, serotonin reuptake inhibitors, severity, study, symptoms, syndrome, treatment, treatment response, treatment response to selective serotonin reuptake inhibitors, treatment-resistant depression, volume, white matter, years, years of illness


  • Ontario Brain Institute
  • National Institute of Mental Health
  • Medical Research Council
  • Canadian Institute for Advanced Research
  • Brain & Behavior Research Foundation
  • National Institute on Aging
  • Rosetrees Trust
  • National Natural Science Foundation of China
  • Lister Institute of Preventive Medicine
  • Lundbeck Foundation
  • National Institute of Biomedical Imaging and Bioengineering
  • National Institute for Health and Care Research
  • National Institute on Drug Abuse
  • Ministry of Education of the People's Republic of China
  • South London and Maudsley NHS Foundation Trust
  • National Institute of General Medical Sciences
  • Wellcome Trust
  • Canadian Institutes of Health Research

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