Research paperFatty acid concentrations in patients with posttraumatic stress disorder compared to healthy controls
Introduction
The vast majority of the general adult population will experience a potentially traumatic event; about nine percent of the affected people will develop posttraumatic stress disorder (PTSD). PTSD implies great personal and societal suffering (de Vries and Olff, 2009, Kessler et al., 2003, Kessler et al., 2012), leading to an invalidating disease burden worldwide (Baxter et al., 2014, Wittchen et al., 2011). Complex biopsychosocial mechanisms determine who will develop PTSD after trauma and who is rather resilient (Christopher, 2004, Southwick et al., 2014). A better understanding of these mechanisms may help to improve preventive interventions aimed to preclude development of PTSD (Olff et al., 2013).
One important mechanism underlying PTSD-development may be fatty acid (FA)-metabolism. Long chain polyunsaturated fatty acids (LCPUFAs) are the main components of neuronal membranes, which makes them essential for normal brain functioning (Bourre, 2005). Consequently, FAs already derived much scientific attention in other major psychiatric disorders like depression and schizophrenia (Assies et al., 2010, Medema et al., 2015), providing evidence for altered FA-profiles in these disorders. However, FA-profiles may also be relevant for PTSD, because – as outlined below – FAs are found associated with other pathophysiological mechanisms in PTSD, including sympathetic activity (Matsumura et al., 2012, Pitman et al., 2012), the hypothalamic-pituitary-adrenal (HPA) axis (Mocking et al., 2013a, Mocking et al., 2015, Olff et al., 2006, Rohleder et al., 2001, Yehuda et al., 1995), endocannabinoids (Bitencourt et al., 2014, Lafourcade et al., 2011, Marsicano et al., 2002, Meijerink et al., 2013, Neumeister, 2013), neuronal survival and plasticity (Beltz et al., 2007, Calderon and Kim, 2004, Kawakita et al., 2006, McNamara, 2013, Peters et al., 2013, Pitman et al., 2012), white matter integrity (Daniels et al., 2013, Peters et al., 2013), inflammation (Assies et al., 2014, Baker et al., 2012), and oxidative stress (Michels et al., 2014, Miller and Sadeh, 2014, Ng et al., 2008, Tsaluchidu et al., 2008).
For example, omega-3 PUFAs including eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) have been found to (I) lower sympathetic activity (Delarue et al., 2003, Hamazaki et al., 2005), (II) increase brain-derived neurotrophic factor (BDNF) (Rao et al., 2007), and (III) be associated with hippocampus and amygdala gray matter volume (Conklin et al., 2007, Samieri et al., 2012), that are all implicated in PTSD-pathogenesis (Frijling et al., 2014, Frijling et al., 2015, Pitman et al., 2012). For example, promoting hippocampal neurogenesis may be of particular importance in PTSD-patients to enhance the impaired extinction learning. Moreover, EPA and arachidonic acid (AA, 20:4 n-6) are precursors for eicosanoids that regulate and stimulate inflammation, respectively (Assies et al., 2014). Of note, chronic immune activation is commonly observed in PTSD (Baker et al., 2012). Furthermore, the omega-9 monounsaturated fatty acid (MUFA) nervonic acid (NA; C24:1 n-9) may be important in myelin biosynthesis as it is found in white matter sphingolipids (Assies et al., 2010). NA decrease may therefore explain white matter reductions in PTSD. Finally, due to their double bonds, PUFAs determine neuronal membrane fluidity and peroxidizability, which are important for membrane functioning and oxidative stress susceptibility/regulation, respectively (Mocking et al., 2012). Of note, increasing evidence suggests a role for oxidative stress in PTSD-pathogenesis (Ng et al., 2008, Tsaluchidu et al., 2008), e.g. as a result of life style (including poor diet or smoking) or psychological stress (Assies et al., 2014).
In sum, literature seems to be supporting a role of FA-metabolism in PTSD. This in fact has led to randomized controlled trials supplementing omega-3 fatty acids to prevent PTSD after trauma, or examine its effects on PTSD-symptoms (Johnston, 2010, Marriott, 2013, Matsuoka et al., 2013b, Naylor and Marx, 2013). However, despite initial promising findings (Matsuoka et al., 2010, Nishi et al., 2012), effects of FA-supplementation in the context of PTSD are mostly negative. For example, importantly, a recent randomized placebo-controlled trial that tested the effects of omega-3 LCPUFA-supplementation in the prevention of PTSD showed a non-significant doubled incidence of PTSD in the intervention group compared to placebo (Matsuoka et al., 2015a). Moreover, Zeev et al. (Zeev et al., 2005) curtailed their small open-label study of omega-3 LCPUFA-supplementation in PTSD, because of possible deleterious effects as most patients showed mild to moderate tendencies towards worsening in PTSD-severity.
Given the several ongoing supplementation trials and considering the negative effects of LCPUFA-supplementation thus far (Matsuoka et al., 2015a, Zeev et al., 2005), it is noticeable that in contrast to most other psychiatric disorders little clinical research has been done into the role of FA-metabolism in PTSD-patients. Omega-3 LCPUFAs are generally supplemented with the idea to restore deficits in FA-concentrations that result because omega-3 LCPUFAs has to be obtained from diet since humans are incapable of de novo endogenous synthesis (Assies et al., 2014), and the modern Western diet is scarce in omega-3 LCPUFAs (Hallahan and Garland, 2005). However, to our knowledge, no study thus far compared FA-concentrations in PTSD-patients with controls to test whether such deficits actually exist. Some circumstantial evidence is available regarding FA-alterations in PTSD: Matsuoka et al. (2013a) found that AA and EPA levels were inversely associated with subsequent risk for developing PTSD, and Kalinic et al. (2014a) found in PTSD-patients that EPA was negatively associated with severity of PTSD-symptoms. Nevertheless, it remains to be elucidated whether PTSD-patients differ from healthy people in FA-concentrations, to see whether there actually exist FA-alterations that may need to be corrected with supplementation. If not, this may explain negative findings of FA-supplementation in PTSD thus far (Matsuoka et al., 2015a, Zeev et al., 2005), which besides being ineffective, may also lead to side effects (Assies et al., 2011, Ramsden et al., 2013).
Therefore, the aim of the present study was to investigate whether PTSD-patients differ in FA-concentrations compared to healthy controls. In a mixed-gender sample of patients with PTSD due to civilian traumatic events, we examined FA-concentrations in erythrocytes. We hypothesized that PTSD-patients would have lower concentrations of the PUFAs EPA, DHA, AA and MUFA NA compared to controls. Furthermore as measurements of overall FA-profiles, we compared patients and controls regarding FA-unsaturation, -chain length and -peroxidizability indices. Finally, we exploratively compared concentrations of other FAs of all FA-subclasses (e.g. omega-3, omega-9) between patients and controls.
Section snippets
Participants
We included 49 outpatients with PTSD due to a civilian trauma (e.g. accident, loss of loved one, sexual violence) recruited from our outpatient department and through newspaper advertisements, and 46 healthy controls recruited from newspaper advertisements and from personnel of the Academic Medical Center. Any current or lifetime mental disorder formed the exclusion criterion for controls. We excluded patients with past or present psychotic disorders, depressive disorders with psychotic
Demographic data
Table 1 shows that for the characteristics tested, PTSD-patients and healthy controls did not differ, except for higher education (p =0.041) of the controls. Demographic and dietary factors were controlled for in the analyses using propensity scores. Of the patients, 29% also fulfilled criteria for current MDD, and 41% used psychotropic medication (SSRI: n=14; SSR with benzodiazepines: n=6). Depressed PTSD-patients were more often on medication than non-depressed patients (64% vs. 31%, χ(1)2
Discussion
The present study investigated differences in FA-profiles between PTSD-patients and controls. Results show that our main outcome measure, the a priori selected primary omega-3 FA DHA, was significantly lower in PTSD-patients compared to controls after correction for diet. Moreover, outcomes of the exploratory analyses indicated additional alterations in MUFA-concentrations.
The lower DHA in the PTSD-patients compared to healthy controls was according to our hypotheses, but this effect became
Contributors
All authors have materially participated in the research and/or article preparation and have approved the final article.
Role of the funding source
The Academic Medical Center of the University of Amsterdam provided financial support (Psychotrauma research fund), but had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Acknowledgments
The authors thank the patients who gave their consent to participate in this study.
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