Comparison of inflammatory cytokine levels among type I/type II and manic/hypomanic/euthymic/depressive states of bipolar disorder

J Affect Disord. 2014 Sep;166:187-92. doi: 10.1016/j.jad.2014.05.009. Epub 2014 May 21.


Objective: Inflammatory cytokines have been suggested to be the trait or state markers of bipolar disorder, but with inconsistent results. This may be related to small sample sizes and poor control of some important confounding factors.

Methods: Gender/age-matched outpatients with bipolar disorder and normal controls were enrolled. The clinical symptoms were rated using the Montgomery Åsberg Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble P-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed by enzyme-linked immunosorbent assays.

Results: In total, 130 patients with bipolar disorder and 130 normal subjects were enrolled. Among the patients with bipolar disorder, 77 (59.2%) had bipolar I disorder, 53 (40.8%) had bipolar II disorder; 75 (57.7%) were in a euthymic state, 14 (10.8%) were in a manic/hypomanic state, and 41 (31.5%) were in a depressive state. The 130 bipolar patients had significantly higher levels of all cytokines than the normal controls (all p<0.0001). Using multivariate regression analysis with controlling of age, gender, BMI, smoking, duration of illness, and medication grouping, the patients with bipolar II disorder had significantly lower levels of sTNF-R1 than the patients with bipolar I disorder (p=0.038); the patients in a depressive state had significantly lower levels of sTNF-R1 than the patients in manic/hypomanic and euthymic states (p=0.009).

Conclusion: The study supported the association of bipolar disorder with inflammatory dysregulation, and sTNF-R1 may be a potential biomarker for staging bipolar disorder.

Keywords: Bipolar disorder; Inflammatory cytokines.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / blood
  • Bipolar Disorder / blood*
  • Bipolar Disorder / psychology*
  • C-Reactive Protein / metabolism
  • Case-Control Studies
  • Cytokines / blood*
  • Female
  • Humans
  • Inflammation / blood
  • Male
  • Middle Aged
  • Outpatients
  • P-Selectin / blood
  • Receptors, Interleukin-2 / blood
  • Receptors, Interleukin-6 / blood
  • Receptors, Tumor Necrosis Factor, Type I / blood*


  • Biomarkers
  • Cytokines
  • P-Selectin
  • Receptors, Interleukin-2
  • Receptors, Interleukin-6
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • C-Reactive Protein