Metabolomic analysis of male combat veterans with post traumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

Fig 1. An overview of the metabolic imbalances in combat veterans with PTSD.

The most significant metabolic alterations in PTSD can be organized into different biochemical pathways, including (A) glycolysis. (B) TCA cycle. (C) fatty acid oxidation, (D) branched chain amino acid pools, (E) lipid biosynthesis, (F) essential fatty acids, (G) urea cycle and (H) purine metabolisms. Metabolites that were elevated in PTSD in comparison to combat veterans who did not have PTSD are in red font, while metabolites that are reduced are in green font. Mitochondrial events are boxed in blue. Salient metabolic consequences that can potentially contribute to the manifestations of PTSD are highlighted in yellow, as discussed in the text.