Predicting Antidepressant Treatment Response From Cortical Structure on MRI: A Mega‐Analysis From the ENIGMA‐MDD Working Group
Authors: Poirot Maarten G. , Boucherie Daphne E. , Caan Matthan W. A. , Goya‐Maldonado Roberto , Belov Vladimir , Corruble Emmanuelle , Colle Romain , Couvy‐Duchesne Baptiste , Kamishikiryo Toshiharu , Shinzato Hotaka , Ichikawa Naho , Okada Go , Okamoto Yasumasa , Harrison Ben J. , Davey Christopher G. , Jamieson Alec J. , Cullen Kathryn R. , Başgöze Zeynep , Klimes‐Dougan Bonnie , Mueller Bryon A. , Benedetti Francesco , Poletti Sara , Melloni Elisa M. T. , Ching Christopher R. K. , Zeng Ling‐Li , Radua Joaquim , Han Laura K. M. , Jahanshad Neda , Thomopoulos Sophia I. , Pozzi Elena , Veltman Dick J. , Schmaal Lianne , Thompson Paul M. , Ruhe Henricus G. , Reneman Liesbeth , Schrantee Anouk 
Published: January 2025

Accurately predicting individual antidepressant treatment response could expedite the lengthy trial‐and‐error process of finding an effective treatment for major depressive disorder (MDD). We tested and compared machine learning‐based methods that predict individual‐level pharmacotherapeutic treatment response using cortical morphometry from multisite longitudinal cohorts. We conducted an international analysis of pooled data from six sites of the ENIGMA‐MDD consortium (n = 262 MDD patients; age = 36.5 ± 15.3 years; 154 (59%) female; mean response rate = 57%). Treatment response was defined as a ≥ 50% reduction in symptom severity score after 4–12 weeks post‐initiation of antidepressant treatment. Structural MRI was acquired before, or < 14 days after, treatment initiation. The cortex was parcellated using FreeSurfer, from which cortical thickness and surface area were measured. We tested several machine learning pipeline configurations, which varied in (i) the way we presented the cortical data (i.e., average values per region of interest, as a vector containing voxel‐wise cortical thickness and surface area measures, and as cortical thickness and surface area projections), (ii) whether we included clinical data, and the (iii) machine learning model (i.e., gradient boosting, support vector machine, and neural network classifiers) and (iv) cross‐validation methods (i.e., k‐fold and leave‐one‐site‐out) we used. First, we tested if the overall predictive performance of the pipelines was better than chance, with a corrected 10‐fold cross‐validation permutation test. Second, we compared if some machine learning pipeline configurations outperformed others. In an exploratory analysis, we repeated our first analysis in three subpopulations, namely patients (i) from a single site, (ii) with comparable response rates, and (iii) showing the least (first quartile) and the most (fourth quartile) treatment response, which we call the extreme (non‐)responders subpopulation. Finally, we explored the effect of including subcortical volumetric data on model performance. Overall, performance predicting antidepressant treatment response was not significantly better than chance (balanced accuracy = 50.5%; p = 0.66) and did not vary with alternative pipeline configurations. Exploratory analyses revealed that performance across models was only significantly better than chance in the extreme (non‐)responders subpopulation (balanced accuracy = 63.9%, p = 0.001). Including subcortical data did not alter the observed model performance. Cortical structural MRI alone could not reliably predict individual pharmacotherapeutic treatment response in MDD. None of the used machine learning pipeline configurations outperformed the others. In exploratory analyses, we found that predicting response in the extreme (non‐)responders subpopulation was feasible on both cortical data alone and combined with subcortical data, which suggests that specific MDD subpopulations may exhibit response‐related patterns in structural data. Future work may use multimodal data to predict treatment response in MDD.