A common symptom geometry of mood improvement under sertraline and placebo associated with distinct neural patterns.

Importance: Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments.
Objective: To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment.
Design: Double blind randomized controlled trial.
Setting: Multicenter.
Participants: Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study.
Interventions: Either 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 Measures: To 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.
Results: 192 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 Relevance: Using 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.
Competing Interests: Declarations A.A. and J.D.M. hold equity with Neumora Therapeutics (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding(N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No.16/149,903, filed on October 2, 664 2018, U.S. Application for PCT International Application No.18/054, 009 filed on October 2, 2018. J.L.J. is an employee of Manifest Technologies, has previously worked for Neumora, and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019. C.F. consults for Manifest Technologies and formerly consulted for RBNC (formerly BlackThorn Therapeutics). Z.T. has previously consulted for Neumora and consults for Manifest Technologies. G.R. holds equity and consults in Neumora and Manifest Technologies. J.D. and A.K. consult for Neurotherapeutix Medical Services. A.K. and A.M. have previously consulted for Neumora. J.H.K. holds equity in Biohaven Pharmaceuticals, Biohaven Pharmaceuticals Medical Sciences, Clearmind Medicine, EpiVario, Neumora Therapeutics, Tempero Bio, Terran Biosciences, Tetricus, and Spring Care. J.H.K. consults for AE Research Foundation, Aptinyx, Biohaven Pharmaceuticals, Biogen, Bionomics, Limited (Australia), BioXcel Therapeutics, Boehringer Ingelheim International, Cerevel Therapeutics, Clearmind Medicine, Cybin IRL, Delix Therapeutics, Eisai, Enveric Biosciences, Epiodyne, EpiVario, Evidera, Freedom Biosciences, Janssen Research & Development, Jazz Pharmaceuticals, Leal Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Perception Neuroscience, Praxis Precision Medicines, PsychoGenics, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Tempero Bio, Terran Biosciences, and Tetricus. All other co-authors declare no competing interests.