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

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.


Supplementary Method 1. Description of main datasets in this study
Full descriptions of the datasets are available in: Fu CHY, Erus G, Fan Y, Antoniades M, et al., AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder: COORDINATE-MDD consortium design and rationale.BMC Psychiatry.Jan 23 2023;23(1):59.doi:10.1186/s12888-022-04509-7.
Main datasets in this study are as follows: 1. Canadian Biomarker Integration Network in Depression (CAN-BIND) is a national depression program with recruitment from 7 centers (MacQueen et al., 2019).Treatment protocol is 8-week trial with SSRI antidepressant (escitalopram) followed by an augmentation trial if there is poor treatment response (i.e., less than 50% improvement in depressive symptoms).MRI scans have been acquired at baseline, weeks 2 and 8 in both MDD and healthy participants.
2. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is a multisite, randomized, placebo-controlled clinical trial with recruitment from 4 centers (Trivedi et al., 2016).Treatment protocol is an 8-week double-blind randomized allocation to SSRI (escitalopram) or placebo, with double-blind cross over switch to another antidepressant if there is poor treatment response.MRI scans have been acquired in MDD and healthy participants at baseline.
4. King's College London cohort consists of 4 studies (Green et al., 2012;Nouretdinov et al., 2011;Sankar et al., 2016;Wise et al., 2017Wise et al., , 2018)).MRI scans have been acquired in MDD and healthy participants, and the treatment study is an 8-week selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant (duloxetine) with MRI scans at baseline, weeks 2 and 8 in both MDD and healthy participants.
5. Laureate Institute for Brain Research (LIBR) cohort consists of MRI data in first episode and recurrent MDD and matched healthy controls from 2 studies (Ford et al., 2019;Misaki et al., 2016;Zheng et al., 2021).

Predictors of Remission in Depression to
Individual and Combined Treatments (PReDICT) study is a 12-week randomized clinical trial of treatment-naïve MDD participants with 3 treatment arms: SSRI (escitalopram), SNRI (duloxetine), or CBT, with an augmentation trial if is there no remission.MRI scans were acquired at baseline (Dunlop et al., 2012).9. Southwest University (SWU) cohort consists of a community-based recruitment which includes first episode and recurrent MDD and healthy control participant (Liu et al., 2017(Liu et al., , 2021;;Hu et al., 2021).

Supplementary Method 2. Estimation of years of education
Wherever raw text was provided, it was converted into years of education.Unless indicated we assumed that the degree was completed and allocated the maximum number of years associated with completing the degree or diploma.The calculation assumed that participants started school at the age of 5.

Supplementary Results 1. Comparison of estimated prior medication status across HYDRA dimensions
In order to compare medication exposure across HYDRA dimensions we used a Chi-squared test to determine if the dimensions differed in the number of MDD participants with first episode or recurrent depression.In Dimension 1, 201 participants had recurrent MDD and 89 participants had first episode MDD.In D2, 222 patients had recurrent MDD and 173 had first episode MDD.The Chi-squared test showed a significant difference between the dimensions (Χ 2 =11.6, p=0.0007).

Supplementary Results 2. Interaction between HYDRA dimensions and treatment outcomes whilst controlling for medication and education
The interaction between HYDRA dimension and treatment group was examined using a linear regression model with the percentage change in the clinician-rated depressive symptom scale (continuous) as the outcome variable and HYDRA dimension (categorical, 2 groups) and treatment group (categorical, 2 groups: SSRI and placebo) as the independent variables whilst controlling for age, sex, site, years of education (as a proxy for IQ) and medication status (using first-episode or recurrent MDD as a proxy measure).

Supplementary Figure 2
Additional transverse views for dimensions 1 and 2 (top and bottom rows respectively), indicating areas with significant differences from controls.Colour represents direction and strength of group differences as indicated by the colour bar.Supplementary Table 5. Results from linear model used to examine regional volumetric differences between patients with first-episode depression (n=255) and healthy controls (n=558) with age, sex and years of education as covariates.Two-sided p values are presented along with FDR-corrected p values to account for multiple comparisons.Bold lettering indicates volume differences that are significant after FDR correction.

Table 2 .
Demographic information for healthy control participants by siteAge was not part of our inclusion/exclusion criteria so it was just happenstance that the groups have different age ranges.The number of controls by age above 65 is as follows:

Table 3 .
Demographic information for MDD participants by site

Table 4 .
List of structural MUSE regions of interest used in the HYDRA model