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Functional connectivity of salience and affective networks among remitted depressed patients predicts episode recurrence

Neuropsychopharmacology volume 48, pages 1901–1909 (2023)Cite this article

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Abstract

Recurrent episodes in major depressive disorder (MDD) are common but the neuroimaging features predictive of recurrence are not established. Participants in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study who achieved remission after 12 weeks of treatment withcognitive behavior therapy, duloxetine, or escitalopram were prospectively monitored for up to 21 months for recurrence. Neuroimaging markers predictive of recurrence were identified from week 12 functional magnetic resonance imaging scans by analyzing whole-brain resting state functional connectivity (RSFC) using seeds for four brain networks that are altered in MDD. Neuroimaging correlates of established clinical predictors of recurrence, including the magnitude of depressive (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) symptom severity at time of remission, and a comorbid anxiety disorder were examined for their similarity to the neuroimaging predictors of recurrence. Of the 344 patients randomized in PReDICT, 61 achieved remission and had usable scans for analysis, 9 of whom experienced recurrence during follow-up. Recurrence was predicted by: 1) increased RSFC between subcallosal cingulate cortex (SCC) and right anterior insula, 2) decreased RSFC between SCC and bilateral primary visual cortex, and 3) decreased RSFC between insula and bilateral caudate. Week 12 depression and anxiety scores were negatively correlated with RSFC strength between executive control and default mode networks, but they were not correlated with the three RSFC patterns predicting recurrence. We conclude that altered RSFC in SCC and anterior insula networks are prospective risk factors associated with MDD recurrence, reflecting additional sources of risk beyond clinical measures.

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Fig. 1: Significant resting state connectivity patterns predicting recurrence and their change from baseline to week 12.
Fig. 2: Significant correlations between residual anxiety and depression severity scores and functional connectivity of the DLPFC.

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Funding

Supported by NIH grants P50 MH077083, RO1 MH080880, UL1 RR025008, M01 RR0039, K23 MH086690 and funding from the Fuqua family foundations. Forest Laboratories and Elli Lilly donated the study medications (escitalopram and duloxetine, respectively).

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Author notes

  1. These authors contributed equally W. Edward Craighead, Helen S. Mayberg.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, USA

    Boadie W. Dunlop & W. Edward Craighead

  2. Department of Neurology and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, USA

    Jungho Cha, Ki Sueng Choi & Helen S. Mayberg

  3. Department of Psychiatry and Behavioral Sciences, Institute for Early Life Adversity Research, University of Texas at Austin Dell Medical School, Austin, USA

    Charles B. Nemeroff

  4. Department of Psychology, Emory University, Atlanta, USA

    W. Edward Craighead

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  1. Boadie W. Dunlop
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Contributions

BWD drafted the manuscript. BWD, CBN, WEC, and HSM designed the study. BWD, WEC, and HSM collected the study data. JC and KC analyzed the imaging data and prepared the figures. All authors edited the manuscript and approved the final version.

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Correspondence to Boadie W. Dunlop.

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Competing interests

Dr. Dunlop has received research support from Boehringer Ingelheim, Compass Pathways, NIMH, Otsuka, Sage, Usona Institute, and Takeda and has served as a consultant for Biohaven, Cerebral Therapeutics, Greenwich Biosciences, Myriad Neuroscience, NRx Pharmaceuticals, Otsuka, Sage, and Sophren Therapeutics. Dr. Cha reports no financial relationships with commercial interests. Dr. Choi has served as a consultant for Abbott Laboratories. Dr. Nemeroff has served as a consultant for AbbVie, ANeuroTech (division of Anima BV), Signant Health, Magstim, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, Pasithea Therapeutic Corp., GoodCap Pharmaceuticals, Inc., Senseye, Clexio, Ninnion Therapeutics, EmbarkNeuro, SynapseBio, BioXcel Therapeutics, and Relmada Therapeutics; he has served on scientific advisory boards ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Heading Health, Pasithea Therapeutic Corp., and Sage; he holds stock in Seattle Genetics, Antares, Inc., Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, Naki Health, Relmada Therapeutics; he serves on the Board of Directors for Gratitude America, ADAA, and Lucy Scientific Discovery, Inc.; and he is named on U.S. patents 6,375,990B1 and 7,148,027B2. Dr. Craighead serves on the National Advisory Board for the George West Mental Health Foundation, as a board member of Hugarheill ehf (an Icelandic company dedicated to the prevention of depression), and as a scientific advisory board member for AIM for Mental Health and the Anxiety and Depression Association of America; he is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations; and he receives book royalties from John Wiley. Dr. Mayberg has received consulting and intellectual property licensing fees from Abbott Neuromodulation.

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Dunlop, B.W., Cha, J., Choi, K.S. et al. Functional connectivity of salience and affective networks among remitted depressed patients predicts episode recurrence. Neuropsychopharmacol. 48, 1901–1909 (2023). https://doi.org/10.1038/s41386-023-01653-w

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