Cytokine polymorphisms in the pathophysiology of mood disorders.
CNS Spectr. 2009 Aug;14(8):419-25
Authors: Clerici M, Arosio B, Mundo E, Cattaneo E, Pozzoli S, Dell’osso B, Vergani C, Trabattoni D, Altamura AC
INTRODUCTION: An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder.
METHODS: Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique.
RESULTS: We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed.
In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001);
bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001).
Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048).
CONCLUSION: These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.
———–
Quote from article:
Patients with MDD who do not suffer from a medical condition have been shown to have increased pro-inflammatory cytokine levels, increased acute phase proteins, and an increased expression of chemokines and adhesion molecules in the plasma or serum.
Of the pro- inflammatory cytokines that are raised, IL-6, C-reactive protein, and to a lesser extent IL-1 and TNF-α have been shown to be increased in both the blood and in CSF.
Studies in the murine model have shown the importance of the pro- inflammatory cytokines IL-6, TNF-α, and IL-1β in the inter talk between peripheral immune activation and the brain.
In addition to the changes in the pro-inflammatory cytokines, the anti-inflammatory cytokines, such as IL-10, decreased in the plasma of depressed patients.
Recent studies have also shown that some depressed patients have abnormal allelic variants of the genes for IL-1β and TNF-α. These abnormal variants are associated with an increased risk of depression and a reduced “responsiveness” to antidepressant treatments.
Systemic, low-grade inflammation, characterized by high levels of inflammatory cytokines, may play a role in the pathophysiology of depressive disorders.
In an experimental study of healthy young men, immune activation by administration of endotoxin resulted in an increase of reported depressive symptoms.
A positive correlation was observed between cytokine levels (IL-6, TNF-α, IL-1 receptor antagonist) and depressive symptoms.
Observational studies in clinically depressed patients showed increased levels of inflammatory markers among psychiatric patients with MDD.
Genes encoding cytokines are highly polymorphic and SNPs associated with increased or reduced cytokine production have been described in the promoter regions of most of such cytokines. Previous studies considered each cytokine independently as gene polymorphisms and/or production, but never investigated pro- and anti-inflammatory cytokines within mood disorders.
———-
Although genetic polymorphisms are an interesting way to study the pathophysiology of mood disorder – particularly in identifying the type of illness present (e.g. bipolar I vs. bipolar II disorder), it doesn’t address treatment and doesn’t help the individual patient.
Preferably, for clinical utility, studies should focus on measurements of cytokines in mood disorder and changes that occur with various treatments. This would help identify treatments that are effective at the intercellular signaling system level of pathology. This would also help support a multi-modal/multi-systemic pathophysiology for mental illness rather than the over-simplistic neurotransmitter models that we have today.