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. 2025 Aug:350:116562.
doi: 10.1016/j.psychres.2025.116562. Epub 2025 May 27.

Symptom network connectivity indices as predictors of relapse in major depressive disorder

Abraham Nunes  1 , Barbara Pavlova  2 , John-Jose Nuñez  3 , Lena C Quilty  4 , Jane A Foster  5 , Kate L Harkness  6 , Keith Ho  7 , Raymond W Lam  3 , Qingqin S Li  8 , Roumen Milev  9 , Susan Rotzinger  7 , Claudio N Soares  9 , Valerie H Taylor  10 , Gustavo Turecki  11 , Sidney H Kennedy  12 , Benicio N Frey  13 , Frank Rudzicz  14 , Rudolf Uher  15
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Free article

Symptom network connectivity indices as predictors of relapse in major depressive disorder

Abraham Nunes et al. Psychiatry Res. 2025 Aug.
Free article

Abstract

Major Depressive Disorder (MDD) demonstrates heterogeneous symptom profiles and a high relapse risk. Understanding how symptom interactions relate to relapse in MDD may enhance maintenance strategies. We thus investigated how connectivity in depressive symptom networks relates to relapse in MDD. We analyzed longitudinal data from 87 patients with remitted MDD who were followed for an average of 12 months. Patient-level symptom networks were estimated using multilevel graphical vector autoregression applied to weekly self-ratings of the Quick Inventory of Depressive Symptomatology. We calculated patient-specific network connectivity indices, including symptom network density (SND), vertex cover (VC) size, and minimal dominating set (MDS) size. Cox proportional hazards models assessed associations between these indices and time to relapse, controlling for baseline symptom severity. Higher SND and larger VC size were significantly associated with an increased relapse risk (HR for SND = 2.03, 95 % CI [1.44, 2.87], p < 0.001; HR for VC = 2.77, 95 % CI [1.79, 4.30], p < 0.001). Conversely, a larger MDS size was associated with a lower risk of relapse (HR 0.47, 95 % CI [0.31, 0.70], p < 0.001). Exploratory analyses showed that the strength centrality of sadness, difficulty concentrating, pessimism, suicidality, and low interest portend a higher relapse risk. Hyperconnectivity among depressive symptom networks may indicate vulnerability to relapse in MDD. Our results further support the potential utility of symptom network-based analyses for predicting outcomes in MDD. Future studies should evaluate whether symptom network-based analyses can provide markers for personalized treatment planning.

Keywords: Major depressive disorder; Network analysis; Relapse; Survival analysis.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AN receives funding support from Research Nova Scotia and the QEII Foundation. The Canadian Biomarker Integration Network for Depression (CAN-BIND) is supported by grants from Ontario Research Fund — Research Excellence, Ontario Brain Institute, and Janssen Pharmaceuticals R&D. RM has received consulting and speaking honoraria from AbbVie, Eisai, Janssen, Lallemand, Lundbeck, Neonmind, and Otsuka, and research grants from CAN-BIND, CIHR, Janssen, Nubiyota, OBI and OMHF. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CB Solutions, Carnot, Grand Challenges Canada, Genome BC, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Shanghai Mental Health Center,Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. CNS has received research funds from the Ontario Brain Institute (OBI), Clairvoyant Therapeutics, Eisai and ad hoc consulting honoraria from Eisi, Bayer, Idorsia, Otsuka. QSL is an employee of Janssen Research & Development, LLC and is a shareholder in Johnson & Johnson, which is the parent company of the Janssen companies. QSL declares that, except for income received from her primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. JAF has served on the Scientific Advisory Board for MRM Health NL and has received consulting/speaker fees from Klaire Labs, WebMD, Takeda Canada and Rothman, Benson, Hedges Inc. CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding is provided by the Canadian Institutes of Health Research (CIHR), Lundbeck, Servier. Funding and/or in kind support is also provided by the investigators’ universities and academic institutions. All study medications are independently purchased at wholesale market values. The Wellness Monitoring Study was partially funded by Janssen Research & Development, LLC with research funding from Janssen to University Health Network.

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