title: Global arginine bioavailability, a marker of nitric oxide synthetic capacity, is decreased in PTSD and correlated with symptom severity and markers of inflammation.
abstract: BACKGROUND
  Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation.
  
  
  METHODS
  Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon [IFN]-γ and C-reactive protein [CRP]) were assessed in 56 combat-exposed males with PTSD and 65 combat-exposed males without PTSD. We assessed severity of PTSD (Clinician Administered PTSD Scale [CAPS]) and depression (Beck Depression Inventory-II [BDI-II]) as well as history of early life trauma (Early Trauma Inventory [ETI]) and affectivity (Positive and Negative Affect Schedule [PANAS]).
  
  
  RESULTS
  The GABR value was (i) significantly lower in PTSD subjects compared to controls (p=0.001), (ii) significantly inversely correlated with markers of inflammation including IL6 (p=0.04) and TNFα (p=0.02), and (iii) significantly inversely correlated with CAPS current (p=0.001) and lifetime (p<0.001) subscales, ETI (p=0.045) and PANAS negative (p=0.006). Adding antidepressant use or MDD diagnosis as covariates led to similar results. Adding age and BMI as covariates also led to similar results, with the exception of IL6 and ETI losing their significant association with GABR.
  
  
  CONCLUSIONS
  This study provides the first evidence that global arginine bioavailability, a marker of NO synthetic capacity in vivo, is lower in veterans with PTSD and is negatively associated with some markers of inflammation as well as with measures of PTSD symptom severity, negative affectivity and childhood adverse experiences. These findings add to the accumulating evidence that specific cellular dysfunction may be associated with the symptomatology of PTSD and may help to explain the higher burden of cardio-metabolic disturbances seen in this disorder.
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Bersani
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States. Electronic address: Owen.Wolkowitz@ucsf.edu.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Wolkowitz
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States; Department of Clinical Sciences, Section for Psychiatry, Lund University, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindqvist
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; James J. Peters Veterans Affairs Medical Center, New York, NY, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; James J. Peters Veterans Affairs Medical Center, New York, NY, United States.
authors.forename: Janine
authors.initials: J
authors.lastname: Flory
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; James J. Peters Veterans Affairs Medical Center, New York, NY, United States.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bierer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; James J. Peters Veterans Affairs Medical Center, New York, NY, United States.
authors.forename: Iouri
authors.initials: I
authors.lastname: Makotine
authors.affiliation: Department of Psychiatry, New York University, United States; Department of Psychiatry, Steven and Alexandra Cohen Center for Posttraumatic Stress and TBI, New York, NY, United States.
authors.forename: Duna
authors.initials: D
authors.lastname: Abu-Amara
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Coy
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States; Center for Health and Community, University of California San Francisco, San Francisco, CA, United States.
authors.forename: Elissa S
authors.initials: ES
authors.lastname: Epel
authors.affiliation: Department of Psychiatry, New York University, United States; Department of Psychiatry, Steven and Alexandra Cohen Center for Posttraumatic Stress and TBI, New York, NY, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Marmar
authors.affiliation: Department of OB/GYN and Reproductive Science, University of California San Francisco, San Francisco, CA, United States.
authors.forename: Synthia H
authors.initials: SH
authors.lastname: Mellon
mesh_terms: D000328:Adult; D001120:Arginine / Q000097:blood*; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002956:Citrulline / Q000097:blood; D003866:Depressive Disorder / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D009952:Ornithine / Q000097:blood; D011569:Psychiatric Status Rating Scales; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000378:metabolism*; D014728:Veterans / Q000523:psychology
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D002956:Citrulline; D009569:Nitric Oxide; D002097:C-Reactive Protein; D001120:Arginine; D009952:Ornithine
keywords: Global arginine bioavailability ratio; Inflammation; Nitric oxide; Posttraumatic stress disorder