Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression

J Affect Disord. 2012 Feb;136(3):386-92. doi: 10.1016/j.jad.2011.11.016. Epub 2011 Dec 12.


Background: Depression is characterized by inflammation and cell-mediated immune (CMI) activation and autoimmune reactions directed against a multitude of self-epitopes. There is evidence that the inflammatory response in depression causes dysfunctions in the metabolism of 5-HT, e.g. lowering the 5-HT precursor tryptophan, and upregulating 5-HT receptor mRNA. This study has been undertaken to examine autoimmune activity directed against 5-HT in relation to CMI activation and inflammation.

Methods: 5-HT antibodies were examined in major depressed patients (n=109) versus normal controls (n=35) in relation to serum neopterin and lysozyme, and plasma pro-inflammatory cytokines (PIC), i.e. interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of fatigue and somatic symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

Results: The incidence of anti-5-HT antibody activity was significantly higher in depressed patients (54.1%), and in particular in those with melancholia (82.9%), than in controls (5.7%). Patients with positive 5-HT antibodies showed increased serum neopterin and lysozyme, and plasma TNFα and IL-1; higher scores on the HDRS and FF scales, and more somatic symptoms, including malaise and neurocognitive dysfunctions. There was a significant association between autoimmune activity to 5-HT and the number of previous depressive episodes.

Discussion: The autoimmune reactions directed against 5-HT might play a role in the pathophysiology of depression and the onset of severe depression. The strong association between autoimmune activity against 5-HT and inflammation/CMI activation is explained by multiple, reciprocal pathways between these factors. Exposure to previous depressive episodes increases the incidence of autoimmune activity directed against 5-HT, which in turn may increase the likelihood to develop new depressive episodes. These findings suggest that sensitization (kindling) and staging of depression are in part based on progressive autoimmune responses.

MeSH terms

  • Adult
  • Autoimmunity
  • Depressive Disorder / blood
  • Depressive Disorder / immunology*
  • Depressive Disorder, Major / blood
  • Depressive Disorder, Major / immunology
  • Female
  • Humans
  • Immunity, Cellular / immunology*
  • Inflammation
  • Interleukin-1 / blood
  • Male
  • Middle Aged
  • Muramidase / blood
  • Neopterin / blood
  • Serotonin / immunology*
  • Tumor Necrosis Factor-alpha / blood


  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Serotonin
  • Neopterin
  • Muramidase