Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo
Authors: Antoniades Mathilde , Fu Cynthia , Erus Guray , Garcia Jose , Fan Yong , Arnone Danilo , Arnott Stephen , Chen Taolin , Choi Ki Sueng , Fatt Cherise Chin , Frey Benicio , Frokjaer Vibe , Ganz Melanie , Godlewska Beata , Hassel Stefanie , Ho Keith , McIntosh Andrew , Qin Kun , Rotzinger Susan , Sacchet Matthew , Savitz Jonathan , Shou Haochang , Singh Ashish , Stolicyn Aleks , Strigo Irina , Strother Stephen , Tosun Duygu , Victor Teresa , Wei Dongtao , Wise Toby , Zahn Roland , Anderson Ian , Deakin J.F. William , Dunlop Boadie , Elliott Rebecca , Gong Qiyong , Gotlib Ian , Harmer Catherine , Kennedy Sidney , Knudsen Gitte , Mayberg Helen , Paulus Martin , Qiu Jiang , Trivedi Madhukar , Whalley Heather , Yan Chao-Gan , Young Allan , Davatzikos Christos 
Published: December 2022

Abstract
Importance: Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Identifying neuroimaging-based biomarkers might aid in defining the disease-related dimensions that characterize MDD and predict treatment response.
Objective: To investigate the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressant or placebo.
Design: Big data consortium (COORDINATE-MDD) sharing raw MRI data in first episode and recurrent MDD, deep clinical phenotyping, and state-of-the art machine learning analysis, involving harmonization of multi-center MRI data and the application of semi-supervised machine learning clustering, HYDRA, to regional brain volumes.
Setting: International, multi-center, community-based MDD and healthy controls.
Participants: International sample (N=1384), consisting of medication-free, first episode and recurrent MDD individuals (N=685) in a current depressive episode of moderate to severe intensity, that is not treatment resistant depression, and healthy controls (N=699). Prospective longitudinal treatment response data were available in a subset of MDD individuals (N=359 MDD). Treatments were SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Treatment duration was 6-8 weeks, and symptom severity was measured by clinician-rated scales.
Main outcomes: First episode and recurrent MDD is optimally characterized by two neuroanatomical dimensions, which show distinct treatment effects to placebo and SSRI antidepressant medications.
Results: Dimension 1 is characterized by preserved gray and white matter (N=290 MDD), whereas Dimension 2 is characterized by widespread subtle reductions in gray and white matter (N=395 MDD) relative to healthy controls. There are no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, but there is a significant dimension by treatment response interaction effect. Dimension 1 shows a significant decrease in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%), whereas Dimension 2 shows a comparable improvement to either SSRI (46.9%) or placebo (42.2%) (β=-18.3, 95% CI (-0.34 to -0.2), p=0.03).
Conclusions and Relevance: Neuroimaging-based markers may aid in characterizing the MDD dimensions that predict treatment response. In an iterative process, we can characterize the disease-based dimensions that comprise MDD.