Nested positive feedback loops in the maintenance of major depression: An integration and extension of previous models

Ryan Smith, Anna Alkozei, William D.S. Killgore, Richard D. Lane

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations


Several theories of Major Depressive Disorder (MDD) have previously been proposed, focusing largely on either a psychological (i.e., cognitive/affective), biological, or neural/computational level of description. These theories appeal to somewhat distinct bodies of work that have each highlighted separate factors as being of considerable potential importance to the maintenance of MDD. Such factors include a range of cognitive/attentional information-processing biases, a range of structural and functional brain abnormalities, and also dysregulation within the autonomic, endocrine, and immune systems. However, to date there have been limited efforts to integrate these complimentary perspectives into a single multi-level framework. Here we review previous work in each of these MDD research domains and illustrate how they can be synthesized into a more comprehensive model of how a depressive episode is maintained. In particular, we emphasize how plausible (but insufficiently studied) interactions between the various MDD-related factors listed above can lead to a series of nested positive feedback loops, which are each capable of maintaining an individual in a depressive episode. We also describe how these different feedback loops could be active to different degrees in different individual cases, potentially accounting for heterogeneity in both depressive symptoms and treatment response. We conclude by discussing how this integrative model might extend understanding of current treatment mechanisms, and also potentially guide the search for markers to inform treatment selection in individual cases.

Original languageEnglish (US)
Pages (from-to)374-397
Number of pages24
JournalBrain, Behavior, and Immunity
StatePublished - Jan 2018


  • Autonomic dysregulation
  • Bayesian brain
  • Cognitive biases
  • Depression
  • Inflammation

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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