A common symptom geometry of mood improvement under sertraline and placebo associated with distinct neural patterns
Authors: Berkovitch Lucie , Lee Kangjoo , Ji Jie Lisa , Helmer Markus , Rahmati Masih , Demšar Jure , Kraljič Aleksij , Matkovič Andraž , Tamayo Zailyn , Murray John D. , Repovš Grega , Krystal John H. , Martin William J. , Fonteneau Clara , Anticevic Alan 
Published: December 2023

AbstractImportanceUnderstanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments.ObjectiveTo perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment.DesignDouble blind randomized controlled trial.SettingMulticenter.ParticipantsPatients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study.InterventionsEither sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2).Main Outcomes and MeasuresTo identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how initial clinical and neural factors predicted this measure during stage 1. To do so, we extracted resting-state global brain connectivity (GBC) at baseline at the individual level using a whole-brain functional network parcellation. In turn, we computed a linear model for each brain parcel with individual data-driven clinical improvement scores during stage 1 for each group.Results192 patients (127 women), age 37.7 years old (standard deviation: 13.5), were included. The first PC (PC1) capturing 20% of clinical variation was similar across treatment groups at stage 1 and stage 2, suggesting a reproducible pattern of symptom improvement. PC1 patients’ scores significantly differed according to treatment during stage 1, whereas no difference of response was evidenced between groups with the Clinical Global Impressions (CGI). Baseline GBC correlated to stage 1 PC1 scores in the sertraline, but not in the placebo group.Conclusions and RelevanceUsing data-driven reduction of symptoms scales, we identified a common profile of symptom improvement across placebo and sertraline. However, the neural patterns of baseline that mapped onto symptom improvement distinguished between treatment and placebo. Our results underscore that mapping from data-driven symptom improvement onto neural circuits is vital to detect treatment-responsive neural profiles that may aid in optimal patient selection for future trials.Key PointsQuestionWhat is the data-driven pattern of clinical improvement in major depressive disorder across antidepressants and placebo?FindingsClinical improvement has a shared behavioral geometry across groups but differs in terms of intensity between sertraline and placebo. Baseline resting-state global brain connectivity was correlated to improvement scores in the sertraline group only.MeaningThere is a common behavioral signature of clinical improvement that can be more robustly predicted by baseline neurobehavioral features when it is pharmacologically induced.