From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression

N.J.C. Stapelberg, R. Pratt, D.L. Neumann, Ho Keung David Shum, S. Brandis, V. Muthukkumarasamy, B. Stantic, M. Blumenstein, J.P. Headrick

Research output: Journal article publicationReview articleAcademic researchpeer-review

20 Citations (Scopus)


Background: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs). Aims: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network. Examples of biomarkers are provided which may reflect early warning signs of impending critical transition to MDD. Results: Disruption of homeostatic feedback loops reflects the physiological transition to MDD. Putative FLTs are identified within hypothalamic-pituitary-adrenal (HPA) and sympathetic-parasympathetic axes, the kynurenine pathway, gut function and dysbiosis. Conclusions: Progression from health to disease is driven by FLTs in the PINE network, which is likely to undergo changes characteristic of system instability. Biomarkers of system instability may effectively predict the critical transition to MDD.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalNeuroscience and Biobehavioral Reviews
Publication statusPublished - 1 Jul 2018
Externally publishedYes


  • Critical transition
  • Feedback loop
  • Feedback loop transition biomarker
  • Major depressive disorder
  • Network motif
  • Psycho-immune-neuroendocrine network

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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