The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder

  • Michael Maes
  • Andre F. Carvalho


Here, we review a novel concept namely the compensatory immune-regulatory reflex system (CIRS) as applied to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). There is evidence that a substantial subset of individuals with MDD and BD exhibit an activation of the immune-inflammatory response system (IRS), as indicated by an increased production of macrophagic M1 and T helper (Th)-1 pro-inflammatory cytokines, interleukin (IL)-6 trans-signaling, positive acute phase proteins (APPs), and complement factors. These immune aberrations appear to be evident during the course of major affective episodes of either depressive or (hypo) manic polarity. Here, we review (a) the current state of the art of CIRS functions in both mood disorders and (b) the possible role of CIRS-related biomarkers for the understanding of affective disorders within the framework of precision psychiatry that could also provide novel drug targets for both MDD and BD. CIRS-related abnormalities in mood disorders include elevated Th-2 and T regulatory (Treg) activities with increased IL-4 and IL-10 production, classical IL-6 signaling, increased levels of sIL-1R antagonist (sIL-1RA), soluble IL-2 (sIL-2R) and tumor necrosis factor–α- receptors, and positive APPs, including haptoglobin, hemopexin, α1-acid glycoprotein, α1-antitrypsin, and ceruloplasmin. It is concluded that CIRS is involved in MDD and BD by regulating the primary immune-inflammatory response, thereby contributing to spontaneous and antidepressant-promoted recovery from the acute phase of illness. Signs of activated IRS and CIRS pathways are observed in the remitted phases of both disorders indicating that there is no return to the original homeostasis after an acute episode, while later episodes of mood disorders are characterized by sensitized IRS and CIRS responses. New z-unit weighted composite biomarker scores are proposed, which reflect different aspects of IRS versus CIRS activation and may be used to estimate different IRS/CIRS activity ratios in mood and other neuroimmune disorders.


Major depression Bipolar disorder Inflammation Neuroimmune Cytokines Oxidative and nitrosative stress 


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

Authors and Affiliations

  1. 1.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  2. 2.Department of PsychiatryMedical University of PlovdivPlovdivBulgaria
  3. 3.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  4. 4.Department of Psychiatry, Faculty of MedicineUniversity of TorontoTorontoCanada
  5. 5.Centre for Addiction and Mental Health (CAMH)TorontoCanada

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