To facilitate the development of a personalized approach to the treatment of patients with major depression, this study is designed to elaborate the clinical and neurobiological phenotype of depressed patients with increased inflammation. Mounting data suggest that inflammation may play an important role in the development of major depression. For example, cytokines released as part of the inflammatory response have been found to interact with virtually every pathophysiologic domain relevant to depression including neuroendocrine function and neurotransmitter metabolism. Of note, depressed patients with increased inflammation may be less responsive to conventional antidepressant therapy and may be at increased risk for other medical disorders. Preliminary data from our group suggest that depending on the patient population one third or more of patients with major depression exhibit increased inflammation as reflected by a plasma c- reactive protein (CRP) concentration >3mg/L. Nevertheless, the clinical and neurobiological phenotype of depressed patients with increased inflammation has yet to be established. Data on the impact of the inflammatory cytokine, interferon (IFN)-alpha, on patients with infectious diseases and cancer may provide important clues regarding features that may be uniquely associated with increased inflammation in patients with major depression including 1) prominent neurovegetative symptoms such as psychomotor retardation and fatigue;2) flattening of the diurnal cortisol curve;and 3) increased plasma and cerebrospinal fluid (CSF) concentrations of metabolites of indoleamine 2,3 dioxygenase including kynurenine, quinolinic acid and kynurenic acid, which has been shown to reduce dopamine release in the basal ganglia. These neurobiologic changes in turn have been associated with IFN-alpha-induced increases in peripheral blood and/or CSF concentrations of tumor necrosis factor-alpha and interleukin-6 and their soluble receptors as well as chemokines such as monocyte chemoattractant protein-1. In addition, relevant cytokine signaling pathways including p38 mitogen activated protein kinase appear to be involved. To test the hypothesis that these clinical and neurobiological features associated with IFN-alpha will also be associated with increased inflammation in patients with major depression, 150 depressed patients with high (n=50), medium (n=50) and low (n=50) inflammation (as defined by a CRP >3, 1-3 and <1 mg/L, respectively) will be examined. All subjects will undergo neuropsychiatric assessments and blood and CSF sampling for the above noted variables during a 2- day inpatient stay. In addition, given the association of early life stress, increased body mass index, treatment resistance and dysregulated sleep with inflammation, these factors will also be examined. Elaboration of pathophysiologic pathways (and related endophenotypes) specific to depressed patients with increased inflammation will foster development of new therapies and biomarkers relevant to an individualized approach to diagnosis, treatment and prevention of major depression.
Recent data suggest that increased inflammation may play a role in the development of major depression in a significant percentage of depressed patients. Data also suggest that depressed patients with increased inflammation may be less responsive to conventional antidepressant treatment strategies and may be at increased risk for the development of other medical disorders including cardiovascular disease, diabetes and cancer. This project seeks to elaborate potentially unique clinical and neurobiological features of depressed patients with increased inflammation in order to reveal novel targets for the development of new therapies and biomarkers relevant to a personalized approach to diagnosis, treatment and prevention of major depression.
|Haroon, Ebrahim; Miller, Andrew H; Sanacora, Gerard (2017) Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology 42:193-215|
|Miller, Andrew H; Haroon, Ebrahim; Felger, Jennifer C (2017) Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation. Neuropsychopharmacology 42:334-359|
|Raison, Charles L; Miller, Andrew H (2017) Pathogen-Host Defense in the Evolution of Depression: Insights into Epidemiology, Genetics, Bioregional Differences and Female Preponderance. Neuropsychopharmacology 42:5-27|
|Goldsmith, David R; Haroon, Ebrahim; Woolwine, Bobbi J et al. (2016) Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun 56:281-8|
|Haroon, E; Fleischer, C C; Felger, J C et al. (2016) Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry 21:1351-7|
|Miller, Andrew H; Raison, Charles L (2016) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16:22-34|
|Felger, J C; Li, Z; Haroon, E et al. (2016) Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 21:1358-65|
|Weinberger, Jeremy F; Raison, Charles L; Rye, David B et al. (2015) Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun 47:193-200|
|Felger, Jennifer C; Haroon, Ebrahim; Miller, Andrew H (2015) Risk and Resilience: Animal Models Shed Light on the Pivotal Role of Inflammation in Individual Differences in Stress-Induced Depression. Biol Psychiatry 78:7-9|
|Miller, Andrew H; Raison, Charles L (2015) Are Anti-inflammatory Therapies Viable Treatments for Psychiatric Disorders?: Where the Rubber Meets the Road. JAMA Psychiatry 72:527-8|
Showing the most recent 10 out of 26 publications