The effect of trauma-focused therapy on the altered T cell distribution in individuals with PTSD: evidence from a randomized controlled trial.

Posttraumatic stress disorder (PTSD) is associated with a reduced ratio of naïve cytotoxic T lymphocytes, an increased ratio of memory cytotoxic T lymphocytes, and a reduced proportion of FoxP3(+) regulatory T lymphocytes. This study investigated whether these immunological alterations are reversible through an evidence-based psychotherapeutic treatment. Therefore, 34 individuals with PTSD were randomly assigned to either a treatment condition of 12 sessions narrative exposure therapy (NET) or a waitlist control (WLC) group. PTSD symptoms were significantly reduced in the NET group, but not in the WLC group, four months post-therapy (effect size: Hedges' g = -1.61). One year after therapy, PTSD symptoms were improved even further in the NET group compared to baseline (Hedges' g = -1.96). This symptom improvement was mirrored in an increase in the originally reduced proportion of regulatory T cells (Tregs) in the NET group at the one-year follow-up, when comparing subgroups matched for baseline Treg numbers. However, no changes were found for the initially reduced proportion of CD45RA(+)CCR7(+) naïve T lymphocytes. In conclusion, NET was effective in reducing trauma-related PTSD symptoms and had a positive effect on the proportion of Tregs cells, thus demonstrating an effect of psychotherapy on an immunological level. Yet, the shift in the proportion of naïve and memory T lymphocytes in individuals with PTSD, discussed in the literature as a correlate of premature immunosenescence, was not reversible and thus might render these patients permanently more susceptible to infectious diseases.

Reduced peripheral expression of the glucocorticoid receptor α isoform in individuals with posttraumatic stress disorder: a cumulative effect of trauma burden.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a serious psychiatric condition that was found to be associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis and changes in glucocorticoid (GC) responsiveness. The physiological actions of GCs are primarily mediated through GC receptors (GR) of which isoforms with different biological activities exist. This study aimed to investigate whether trauma-experience and/or PTSD are associated with altered expression of GR splice variants. METHODS: GRα and GRß mRNA expression levels were determined by real-time quantitative PCR in whole blood samples of individuals with chronic and severe forms of PTSD (n = 42) as well as in ethnically matched reference subjects (non-PTSD, n = 35). RESULTS: Individuals suffering from PTSD exhibited significantly lower expression of the predominant and functionally active GRα isoform compared to non-PTSD subjects. This effect remained significant when accounting for gender, smoking, psychotropic medication or comorbid depression. Moreover, the GRα expression level was significantly negatively correlated with the number of traumatic event types experienced, both in the whole sample and within the PTSD patient group. Expression of the less abundant and non-ligand binding GRß isoform was comparable between patient and reference groups. CONCLUSIONS: Reduced expression of the functionally active GRα isoform in peripheral blood cells of individuals with PTSD seems to be a cumulative effect of trauma burden rather than a specific feature of PTSD since non-PTSD subjects with high trauma load showed an intermediate phenotype between PTSD patients and individuals with no or few traumatic experiences.

Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder.

BACKGROUND: Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. METHODS: We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. RESULTS: Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48 ± 0.11 vs. 0.36 ± 0.14 ng/ml, p = 0.01), 2-AG (8.93 ± 3.20 vs. 6.26±2.10 ng/ml, p<0.01), OEA (5.90 ± 2.10 vs. 3.88 ± 1.85 ng/ml, p<0.01), SEA (2.70 ± 3.37 vs. 0.83 ± 0.47, ng/ml, p<0.05) and significantly lower plasma levels of OLDA (0.12 ± 0.05 vs. 0.45 ± 0.59 ng/ml, p<0.05) than healthy controls. Moreover, PTSD patients had higher 2-AG plasma levels (8.93 ± 3.20 vs. 6.01 ± 1.32 ng/ml, p = 0.03) and also higher plasma concentrations of PEA (4.06 ± 1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without evidence of PTSD. CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = -0.68, p<0.01). CAPS subscores for intrusions (r = -0.65, p<0.01), avoidance (r = -0.60, p<0.01) and hyperarousal (r = -0.66, p<0.01) were all negatively related to OLDA plasma concentrations. CONCLUSIONS: PTSD appears to be associated with changes in plasma EC/NAE concentrations. This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts.

Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with an enhanced risk for cardiovascular and other inflammatory diseases. Chronic low-level inflammation has been suggested as a potential mechanism linking these conditions. METHODS: We investigated plasma cytokine levels as well as spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production by peripheral blood mononuclear cells (PBMCs) in a group of 35 severely traumatized PTSD patients compared to 25 healthy controls. RESULTS: Spontaneous production of interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α by isolated PBMCs was significantly higher in the PTSD compared to the control group and even correlated with PTSD symptom severity within the PTSD group. In contrast, circulating plasma levels of pro- and anti-inflammatory cytokines such as IL-6, IL-8, IL-10, TNF-α, or monocyte chemotactic protein (MCP)-1 were not significantly altered in PTSD patients compared to healthy controls. CONCLUSIONS: Our findings indicate that PBMCs of PTSD patients are already pre-activated in vivo, providing further evidence for low-grade inflammation in PTSD. This might possibly represent one psychobiological pathway from PTSD to poor physical health.

Victims of rape show increased cortisol responses to trauma reminders: a study in individuals with war- and torture-related PTSD.

Studies investigating cortisol responses to trauma-related stressors in patients with posttraumatic stress disorder (PTSD) have yielded inconsistent results, demonstrating that cortisol responses were enhanced or unaffected when confronted with trauma reminders. This study investigated the effect of the type of trauma experienced on both salivary and plasma cortisol responses during confrontation with trauma-related material. Participants were 30 survivors of war and torture, with and without rape among the traumatic events experienced. Participants of both groups (raped vs. non-raped) fulfilled DSM-IV criteria of PTSD. Plasma and salivary cortisol levels were measured at three time points during a standardized clinical interview: once before and twice after assessing individual traumatic experiences. Results show that groups did not differ in basal plasma and salivary cortisol levels. However, differential salivary cortisol responses were observed in PTSD patients who had been raped compared to those who had not been raped (p<.05) but had experienced an equal number of traumatic events and showed equally high PTSD symptom severity. Whereas salivary cortisol levels decreased in the course of the interview for the group with no past experience of rape (p<.05), those PTSD patients who had been raped showed a significant cortisol increase when reminded of their traumatic events (p<.001). This effect was not found in plasma cortisol. Our results indicate that the type of traumatic stress experienced contributes to cortisol responses during the confrontation with trauma-related material. We hypothesize, that the nearness of the perpetrator during the traumatic event might shape later psychophysiological responding to trauma reminders.

Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli--evidence from a randomized controlled treatment trial.

BACKGROUND: Little is known about the neurobiological foundations of psychotherapy for Posttraumatic Stress Disorder (PTSD). Prior studies have shown that PTSD is associated with altered processing of threatening and aversive stimuli. It remains unclear whether this functional abnormality can be changed by psychotherapy. This is the first randomized controlled treatment trial that examines whether narrative exposure therapy (NET) causes changes in affective stimulus processing in patients with chronic PTSD. METHODS: 34 refugees with PTSD were randomly assigned to a NET group or to a waitlist control (WLC) group. At pre-test and at four-months follow-up, the diagnostics included the assessment of clinical variables and measurements of neuromagnetic oscillatory brain activity (steady-state visual evoked fields, ssVEF) resulting from exposure to aversive pictures compared to neutral pictures. RESULTS: PTSD as well as depressive symptom severity scores declined in the NET group, whereas symptoms persisted in the WLC group. Only in the NET group, parietal and occipital activity towards threatening pictures increased significantly after therapy. CONCLUSIONS: Our results indicate that NET causes an increase of activity associated with cortical top-down regulation of attention towards aversive pictures. The increase of attention allocation to potential threat cues might allow treated patients to re-appraise the actual danger of the current situation and, thereby, reducing PTSD symptoms. REGISTRATION OF THE CLINICAL TRIAL: Number: NCT00563888Name: "Change of Neural Network Indicators Through Narrative Treatment of PTSD in Torture Victims" ULR: http://www.clinicaltrials.gov/ct2/show/NCT00563888.

Early processing of threat cues in posttraumatic stress disorder-evidence for a cortical vigilance-avoidance reaction.

BACKGROUND: The present study investigated the influence of posttraumatic stress disorder (PTSD) on early visual processing of affective stimuli in survivors of war and torture. METHODS: Trauma-exposed refugees with (n = 36) and without (n = 21) PTSD as well as unexposed control subjects (n = 16) participated in a magnetoencephalography study with pictures that varied in emotional content. RESULTS: We found evidence for a biphasic cortical response in patients with PTSD in comparison with the two control groups. In response to aversive (relative to neutral or positive) pictures, PTSD patients showed elevated cortical activity over right prefrontal areas as early as 130-160 msec after stimulus onset followed by a decrease of the affect-related response in the parieto-occipital cortex at 206-256 msec. CONCLUSIONS: The increased early activity in the right prefrontal cortex most likely represents an enhanced alarm response or the fear network toward aversive stimuli in PTSD, whereas the subsequent decreased activation in right parieto-occipital areas in response to aversive pictures seems to reflect the tendency to disengage from emotional content. This finding is consistent with the hypothesis of a vigilance-avoidance reaction pattern to threat in anxiety disorders and helps to reconcile contradicting results of over- and under-responsiveness in the sensory processing of threatening stimuli in PTSD.