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

Cynthia H Y Fu^#^{1

2}, Mathilde Antoniades^#³, Guray Erus³, Jose A Garcia³, Yong Fan³, Danilo Arnone², Stephen R Arnott⁴, Taolin Chen^{5

6}, Ki Sueng Choi⁷, Cherise Chin Fatt⁸, Benicio N Frey^{9

10}, Vibe G Frokjaer^{11

12

13}, Melanie Ganz^{1

14}, Beata R Godlewska^{15

16}, Stefanie Hassel^{17

18}, Keith Ho¹⁹, Andrew M McIntosh²⁰, Kun Qin^{5

6

21}, Susan Rotzinger^{19

22}, Matthew D Sacchet²³, Jonathan Savitz²⁴, Haochang Shou^{3

25}, Ashish Singh³, Aleks Stolicyn²⁰, Irina Strigo²⁶, Stephen C Strother^{4

27}, Duygu Tosun²⁸, Teresa A Victor²⁴, Dongtao Wei²⁹, Toby Wise³⁰, Roland Zahn², Ian M Anderson³¹, W Edward Craighead^{32

33}, J F William Deakin³¹, Boadie W Dunlop³², Rebecca Elliott³¹, Qiyong Gong^{5

6}, Ian H Gotlib³⁴, Catherine J Harmer¹⁵, Sidney H Kennedy^{19

22}, Gitte M Knudsen^{11

12}, Helen S Mayberg⁷, Martin P Paulus²⁴, Jiang Qiu²⁹, Madhukar H Trivedi⁸, Heather C Whalley²⁰, Chao-Gan Yan³⁵, Allan H Young^{2

36}, Christos Davatzikos³

Affiliations

¹ School of Psychology, University of East London, London, UK.
² Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
³ Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.
⁴ Rotman Research Institute, Baycrest Centre, Toronto, Ontario Canada.
⁵ Huaxi MR Research Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
⁶ Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China.
⁷ Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY USA.
⁸ Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, TX USA.
⁹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario Canada.
¹⁰ Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, Ontario Canada.
¹¹ Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark.
¹² Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Psychiatry, Psychiatric Centre Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Computer Science, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁶ Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
¹⁷ Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, Alberta Canada.
¹⁸ Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada.
¹⁹ Department of Psychiatry, University Health Network, Toronto, Ontario Canada.
²⁰ Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
²¹ Department of Radiology, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
²² Centre for Depression and Suicide Studies, Unity Health Toronto, Toronto, Ontario Canada.
²³ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.
²⁴ Laureate Institute for Brain Research, Tulsa, OK USA.
²⁵ Penn Statistics in Imaging and Visualization Endeavor (PennSIVE) Center, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA USA.
²⁶ Department of Psychiatry, University of California San Francisco, San Francisco, USA.
²⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario Canada.
²⁸ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA USA.
²⁹ School of Psychology, Southwest University, Chongqing, China.
³⁰ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
³¹ Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.
³² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA USA.
³³ Department of Psychology, Emory University, Atlanta, GA USA.
³⁴ Department of Psychology, Stanford University, Stanford, CA USA.
³⁵ Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
³⁶ South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, London, UK.

^# Contributed equally.

PMID: 38948238
PMCID: PMC11211072
DOI: 10.1038/s44220-023-00187-w

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

Cynthia H Y Fu et al. Nat Ment Health. 2024.

. 2024;2(2):164-176.

doi: 10.1038/s44220-023-00187-w. Epub 2024 Jan 12.

Authors

Affiliations

¹ School of Psychology, University of East London, London, UK.
² Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
³ Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.
⁴ Rotman Research Institute, Baycrest Centre, Toronto, Ontario Canada.
⁵ Huaxi MR Research Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
⁶ Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China.
⁷ Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY USA.
⁸ Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, TX USA.
⁹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario Canada.
¹⁰ Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, Ontario Canada.
¹¹ Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark.
¹² Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Psychiatry, Psychiatric Centre Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Computer Science, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁶ Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
¹⁷ Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, Alberta Canada.
¹⁸ Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada.
¹⁹ Department of Psychiatry, University Health Network, Toronto, Ontario Canada.
²⁰ Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
²¹ Department of Radiology, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
²² Centre for Depression and Suicide Studies, Unity Health Toronto, Toronto, Ontario Canada.
²³ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.
²⁴ Laureate Institute for Brain Research, Tulsa, OK USA.
²⁵ Penn Statistics in Imaging and Visualization Endeavor (PennSIVE) Center, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA USA.
²⁶ Department of Psychiatry, University of California San Francisco, San Francisco, USA.
²⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario Canada.
²⁸ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA USA.
²⁹ School of Psychology, Southwest University, Chongqing, China.
³⁰ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
³¹ Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.
³² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA USA.
³³ Department of Psychology, Emory University, Atlanta, GA USA.
³⁴ Department of Psychology, Stanford University, Stanford, CA USA.
³⁵ Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
³⁶ South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, London, UK.

^# Contributed equally.

PMID: 38948238
PMCID: PMC11211072
DOI: 10.1038/s44220-023-00187-w

Abstract

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.

Keywords: Depression; Predictive markers.

PubMed Disclaimer

Conflict of interest statement

Competing interestsS.R.A. has consulted for Indoc Research Canada. B.W.D. has received research support from Boehringer-Ingelheim, Compass, Pathways, NIMH, Otsuka, and Uson and honoraria for consulting from Aya Biosciences, Myriad Neuroscience, Otsuka, Sophren Therapeutics, Cerebral Therapeutics, Sage. C.H.Y.F. has received grant funding from Brain and Behavior (NARSAD), Eli Lilly and Co. Milken Institute, Flow Neuroscience, MRC, NIMH, Rosetrees Trust, and Wellcome Trust and is Section Editor of Brain Research Bulletin. C.J.H. serves as a consultant for P1vital, Lundbeck, Servier, and Compass Pathways. She holds grant income from Zogenix and J&J. S.H.K. has received funding for consulting or speaking engagements from Abbvie, Boehringer-Ingelheim, Janssen, Lundbeck, Lundbeck Institute, Merck, Otsuka Pfizer, Sunovion, and Servier. He has received research support from Abbott, Brain Canada, CIHR (Canadian Institutes of Health Research), Janssen, Lundbeck, Ontario Brain Institute, Otsuka, Pfizer, and SPOR (Canada’s Strategy for Patient-Oriented Research). He has stock/stock options in Field Trip Health. G.M.K. has received honoraria as a speaker for Sage Biogen and as a consultant for Sanos. H.S.M. has received grant funding from NIH and consulting and IP licenses fees from Abbott Labs. A.M.M. has received research support from Eli Lilly, Janssen, and The Sackler Trust. A.M.M. has also received speaker fees from Illumina and Janssen. W.E.C. serves on the National Advisory Board of the George West Mental health Foundation, as a board member of Hugarheill ehf (an Icelandic company dedicated to the prevention of depression), and on the scientific advisory boards of AIM for Mental Health and the Anxiety and Depression Association of America; he is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations, and he receives book royalties from John Wiley. H.S. has received grant funding from NIH. S.C.S. received research support from Brain Canada, CIHR (Canadian Institutes of Health Research), Ontario Brain Institute, and CFI (Canadian Foundation for Innovation). S.C.S. is a founder and shareholder of ADMdx, Inc. D.T. has received grant funding from NIH. M.H.T. received research support from NIH, PCORI, and AFSP, is a consultant for Alkermes Inc., Alto Neuroscience Inc, Axsome Therapeutics, Boegringer Ingelheim, GH Research, GreenLight VitalSign6 Inc, Heading Health, Inc., Janssen Pharmaceutical, Legion Health, Merck Sharp & Dohme Corp., Mind Medicine Inc., Navitor, Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka Canada Pharmaceutical Inc, Otsuka Pharmaceutical Development & Commercialization, Inc. (MDD section adviser), SAGE Therapeutics, Signant Health, and Takeda Pharmaceuticals Inc and receives editorial compensation from Oxford University Press. A.H.Y. reports the following conflicts of interest: paid lectures and advisory boards for the following companies: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis; consultant to Johnson & Johnson and to Livanova; received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova; principal investigator in the Restore-Life VNS registry study funded by LivaNova; UK chief investigator for Novartis MDD study MIJ821A12201; principal investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression’; principal investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’; principal investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’; no shareholdings in pharmaceutical companies; deputy editor of BJPsych Open. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK); Janssen (UK). R.Z. is a private psychiatrist service provider at The London Depression Institute and co-investigator on a Livanova-funded observational study of vagus nerve stimulation for depression. R.Z. has received honoraria for talks at medical symposia sponsored by Lundbeck as well as Janssen. He has collaborated with EMIS PLC and advises Depsee Ltd. He is affiliated with the D’Or Institute of Research and Education, Rio de Janeiro, and advises the Scients Institute, USA. Authors A. Singh, A. Stolicyn, B.R.G., B.N.F., C.C.F., C.-G.Y., C.D., D.A., D.W., G.E., H.C.W., I.H.G., I.M.A., I.S., J.F.W.D., J.Q., J.S., J.A.G., K.H., K.S.C., K.Q., M.P.P., M.A., M.D.S., M.G., Q.G., R.E., S.H., S.R., T.A.V., T.C., T.W., V.G.F., and Y.F. declare that they have no competing interests.

Figures

**Fig. 1. Neuroanatomical patterns across the dimensions.**
False discovery rate- (FDR-) corrected voxel-wise comparison of gray-matter volume differences in Dimension 1 (top row) and Dimension 2 (bottom row) versus controls are presented in transverse, sagittal, and coronal sections. Color bar indicates strength of group differences (MIDAS statistic) between MDD and healthy control participants.

**Fig. 2. Depressive symptoms across the dimensions and treatment groups.**
Difference in percentage change in HAM-D scores across HYDRA dimensions (D1 (n = 164) and D2 (n = 195), n = 359) and binary treatment groups following treatment with SSRI medications (n = 250) and placebo (n = 109). Data are presented using a bar plot as mean values and 95th percentile error bars. The asterisks (*) indicate significant differences between the two subgroups using linear regression model (two-sided P < 0.05).

**Fig. 3. Depressive symptoms across the dimensions and all four treatment groups.**
Difference in percentage change in HAM-D scores across HYDRA dimensions (D1 (n = 164) and D2 (n = 195), n = 359) and four different treatment groups following treatment with SSRI sertraline (SER, n = 98), SSRI escitalopram (ESC, n = 116), SSRI citalopram (CIT, n = 36), and placebo (PLA, n = 109). Data are presented using a bar plot as mean values and 95th percentile error bars. The asterisks (*) indicate significant differences between the two subgroups using linear regression model (two-sided P < 0.05).

**Fig. 4. Relationship between dimension membership and change in depressive symptoms following treatment.**
Relationship between the support vector machine hyperplane (x axis) distance for each participant and the percentage change in HAM-D scores (y axis) following treatment with sertraline, escitalopram, citalopram, or placebo. Positive and negative values represent the distance from the hyperplane separating patients into D1 and D2. The larger the value, the more certain the classification within that dimension. Linear regression model shows a significant interaction between hyperplane distance and sertraline treatment (β = 2.73, P = 0.046 (two-sided), 95% CI (0.04 to 5.4). The shaded areas represent the 95% confidence intervals.

**Fig. 5. Neuroanatomical case-control differences.**
a,b, FDR-corrected voxel-wise comparison of gray-matter volume differences between the whole MDD participant group versus healthy controls (a) and after controlling for medication status (b). c, Gray-matter volume differences between MDD participants in a first episode of depression and healthy controls. The color bars indicate the strength of the group differences (MIDAS statistic) between MDD and healthy control participants.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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