Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response

Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Molecular Psychiatry (Impact Factor: 15.15). 09/2008; 13(8):800-12. DOI: 10.1038/mp.2008.59
Source: PubMed

ABSTRACT There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.

Download full-text


Available from: Chuanhui Dong, Jun 29, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammatory disturbances have been closely associated with depression and many other neuropsychiatric diseases. Although targeting neuroinflammatory mediators with centrally-acting drugs has shown certain promise, its translation is faced with several challenges especially drug delivery and safety concerns. Here, we report that neuroinflammation-induced behavioral abnormality could be effectively attenuated with immunomodulatory agents that need not to gain brain penetration. In a rat model with intracerebral lipopolysaccharide (LPS) challenge, we validated that ginsenoside Rg1 (Rg1), a well-established anti-inflammatory agent, was unable to produce a direct action in the brain. Interestingly, peripherally-restricted Rg1 could effectively attenuate the weight loss, anorexic- and depressive-like behavior as well as neurochemical disturbances associated with central LPS challenge. Biochemical assay of neuroimmune mediators in the periphery revealed that Rg1 could mitigate the deregulation of the hypothalamic-pituitary-adrenal (HPA) axis and selectively blunt the increase in circulating interleukin (IL)-6 levels. Furthermore, these peripheral regulatory effects were accompanied by dampened microglial activation, mitigated expression of pro-inflammatory mediators and neurotoxic species in the central compartment. Taken together, our work suggested that targeting the peripheral immune system may serve as a novel therapeutic approach to neuroinflammation-induced neuropsychiatric disorders. Moreover, our findings provided the rationale for employing peripherally-active agents like Rg1 to combat mental disturbances.
    Neuroscience 10/2013; 256. DOI:10.1016/j.neuroscience.2013.10.023 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The rising burden of unipolar depression along with its often related sleep disturbances, as well as increasing rates of sleep restriction in modern society, make the search for an extended understanding of the aetiology and pathophysiology of depression necessary. Accumulating evidence suggests an important role for the immune system in mediating disrupted neurobiological and chronobiological processes in depression. This review aims to provide an overview of the neuroimmunomodulatory processes involved with depression and antidepressant treatments with a special focus on chronobiology, chronotherapeutics and the emerging field of immune-circadian bi-directional crosstalk. Increasing evidence suggests that chronobiological disruption can mediate immune changes in depression, and likewise, immune processes can mediate chronobiological disruption. This may suggest a bi-directional relationship in immune-circadian crosstalk. Furthermore, given the immunomodulatory effects of antidepressants and chronotherapeutics, as well as their associated beneficial effects on circadian disturbance, we-and others-suggest that these therapeutic agents may exert their chronobiotic effects partially via the neuroimmune system. Further research is required to better elucidate the mechanisms of immune involvement in the chronobiology of depression.
    Journal of Neural Transmission 06/2012; 119(10):1147-66. DOI:10.1007/s00702-012-0819-6 · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Objectives. Previous studies have suggested that the pathogenesis of schizophrenia and major depression involves an altered peripheral immune system. It is not clear, however, whether such changes are associated with corresponding neuroinflammatory responses and disturbances of neurotransmission. Methods. This paper reviews the current state of knowledge about the involvement of immune alterations in schizophrenia and major depression and a possible link to disturbances of glutamatergic transmission. Results. Inflammatory endogenous modulators of the NMDA receptor, the kynurenine pathway metabolites, are potential candidates for such a link. Studies of the blood and cerebrospinal fluid have suggested a schizophrenia-related upregulation of the NMDA receptor antagonist kynurenic acid in astrocytes, analogous to the ketamine psychosis model. Conversely, it has been proposed that there is depression-related microglial synthesis of the NMDA receptor agonist quinolinic acid, which is consistent with the observation that ketamine has therapeutic effects in major depression. Few publications have studied NMDA receptor modulating kynurenines in the brain, however. Conclusions. Future research on the cerebral cell-type specific distribution of kynurenine metabolites and their brain-regional concentration imbalances will be required to connect peripheral immune changes, the hypotheses of blood-brain barrier dysfunction and glial pathology with concepts of altered neurotransmission in schizophrenia and major depression.
    The World Journal of Biological Psychiatry 06/2011; 13(7):482-92. DOI:10.3109/15622975.2011.583941 · 4.23 Impact Factor