Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression

  • J. Tory Toole
  • Mark A. RiceJr
  • Travis J. A. Craddock
  • Barry Nierenberg
  • Nancy G. Klimas
  • Mary Ann Fletcher
  • Joel Zysman
  • Mariana Morris
  • Gordon BroderickEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1781)


We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.

Key words

Computational modeling Homeostatic regulation Depression SSRI Stress Neurotransmitters Glutamate Serotonin Network complexity Regulatory logic Multi-stability 



Funding was provided by US Department of Defense Congressionally Directed Medical Research Program (CDMRP) awards ( GW093042, GW140142 (Broderick—PI) and GW120045 (Morris—PI). This research was conducted in collaboration with the high-performance computing team at the University of Miami Center for Computational Science (CCS) (

Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • J. Tory Toole
    • 1
  • Mark A. RiceJr
    • 1
  • Travis J. A. Craddock
    • 1
    • 2
  • Barry Nierenberg
    • 1
  • Nancy G. Klimas
    • 2
    • 3
  • Mary Ann Fletcher
    • 2
    • 3
  • Joel Zysman
    • 5
  • Mariana Morris
    • 2
    • 3
  • Gordon Broderick
    • 1
    • 4
    • 6
    Email author
  1. 1.College of Psychology, Nova Southeastern UniversityFt. LauderdaleUSA
  2. 2.Institute for Neuro-Immune Medicine, Nova Southeastern UniversityFt. LauderdaleUSA
  3. 3.Miami Veterans Affairs Medical CenterMiamiUSA
  4. 4.Department of Biomedical EngineeringRochester Institute of TechnologyRochesterUSA
  5. 5.Center for Computational Science, University of MiamiMiamiUSA
  6. 6.Center for Clinical Systems Biology, Rochester General Hospital Research InstituteRochesterUSA

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