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Are Anti-inflammatory Therapies Viable Treatments for Psychiatric Disorders?  Where the Rubber Meets the Road

Andrew H. Miller, MD1; Charles L. Raison, MD2
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
2University of Arizona College of Medicine, Tucson
JAMA Psychiatry. 2015;72(6):527-528. doi:10.1001/jamapsychiatry.2015.22.
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This Viewpoint reports on the accumulating data indicating that inflammation may play a role in a host of psychiatric illnesses.

Accumulating data indicate that inflammation may play a role in a host of psychiatric illnesses.1 These data reveal reliable associations of inflammatory markers with psychiatric disorders, the induction of psychiatric symptoms following administration of inflammatory stimuli, the association of inflammation-related genes with psychiatric disease, and the elucidation of neurobiological and immunological mechanisms by which inflammation targets neurotransmitters and neurocircuits to change behavior. Nevertheless, whether therapeutic strategies that inhibit inflammation will be effective in treating psychiatric illnesses remains unclear. This question is not trivial given the pressing need for novel therapeutics based on the high rates of treatment resistance across disorders and on our relatively limited psychopharmacologic repertoire.

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Gastrointestinal inflammation and permeability and microbiota disruption limit the benefits of anti-inflammatory treatments in psychiatric disorders
Posted on May 13, 2015
Lisa A. Brenner, Ph.D. (1, 2), Maj Andrew Hoisington, Ph.D., P.E. (3), Christopher A. Lowry, Ph.D. (4), Teodor T. Postolache, M.D. (1, 5)
Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC; 1), University of Colorado, Anschutz Medical Campus (2), Department of Civil & Environmental Engineering, US Air Force
Conflict of Interest: None Declared

In their recently published commentary, Miller and Raison highlight that individuals with different psychiatric illnesses have elevated biomarkers of inflammation, and discuss anti-inflammatory therapies for such conditions (1). With sound reasoning and recent data, they note that the observed heterogeneity in outcomes of anti-inflammatory treatments for neuropsychiatric illnesses would be reduced if such therapies were administered only in patients with evidence of inflammation. In neuroimmunology, the distinction between systemic versus central nervous system inflammation, and fluctuations in blood-brain-barrier permeability to molecular and cellular mediators of inflammation have received considerable recent attention. However, this has not been the case in regards to systemic versus gastrointestinal inflammation, and fluctuations in gut permeability. Here, we highlight a prevalent and understudied issue in anti-inflammatory treatments, unintended proinflammatory gastrointestinal effects that may limit systemic immune modulation. The gastrointestinal tract contains stratified outer mucus and inner glycocalyx layers that protect epithelial cells. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase, and even in low doses have been shown to erode the mucus layer, and as such increase gastrointestinal inflammation, and gut permeability (2). Physiologically, the glycocalyx is bacteria-free. However, NSAIDS reduce the mucus layer, and increase luminal proximity of microbes and their products to the epithelial cells; thereby increasing risk of parietal infection, barrier penetration, and systemic inflammation (2). Furthermore, adverse effects of anti-inflammatory therapies may involve complex shifts in the composition of the gut microbiota, with low-grade inflammation resulting from a breakdown of physiological immune modulation (2). Of interest to the treatment of psychiatric disorders, animal studies demonstrate bidirectional signaling between the gut microbiota and the brain (3). Studies of anti-inflammatory therapies in psychiatric disorders should include longitudinal analyses of gut microbial communities, gut permeability, and mucosal homeostasis, vascularization, and inflammation, in concert with evaluation of their direct effects on systemic inflammatory processes. In addition, increased translational and clinical efforts aimed at studying the neuropsychiatric effects of modulating inflammation through prebiotic and probiotic interventions, as well as minimizing gastrointestinal proinflammatory and permeability side effects of certain anti-inflammatory treatments are warranted. Finally, increased understanding of individual vulnerability to undesired proinflammatory gastrointestinal side effects of anti-inflammatory treatments (4) may explain in part the heterogeneity of treatment responses and lead to increased precision of anti-inflammatory interventions in psychiatry. 

Reference List

(1) Miller AH, Raison CL. Are Anti-inflammatory Therapies Viable Treatments for Psychiatric Disorders?: Where the Rubber Meets the Road. JAMA Psychiatry 2015.

(2) Habib I, Mazulis A, Roginsky G, Ehrenpreis ED. Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: pathophysiology and clinical associations. Inflamm Bowel Dis 2014;20:2493-2502.

(3) Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 2014;34:15490-15496.

(4) Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by pharmacogenetics of safety and efficacy of non-steroidal anti- inflammatory drugs: a review. Curr Drug Metab 2014;15:326-343.

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