Sex dependent influence of a functional polymorphism in steroid 5-α-reductase type 2 (SRD5A2) on post-traumatic stress symptoms.

A non-synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5-α-reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post-traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African-American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post-traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex-dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex-specific way, the severity of post-traumatic stress symptoms and risk for diagnosis of PTSD.

Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures.

BACKGROUND: Posttraumatic stress disorder (PTSD) patients show heightened fear responses to trauma reminders and an inability to inhibit fear in the presence of safety reminders. Brain imaging studies suggest that this is in part due to amygdala over-reactivity as well as deficient top-down cortical inhibition of the amygdala. Consistent with these findings, previous studies, using fear-potentiated startle (FPS), have shown exaggerated startle and deficits in fear inhibition in PTSD participants. However, many PTSD studies using the skin conductance response (SCR) report no group differences in fear acquisition. METHOD: The study included 41 participants with PTSD and 70 without PTSD. The fear conditioning session included a reinforced conditioned stimulus (CS+, danger cue) paired with an aversive airblast, and a nonreinforced conditioned stimulus (CS-, safety cue). Acoustic startle responses and SCR were acquired during the presentation of each CS. RESULTS: The results showed that fear conditioned responses were captured in both the FPS and SCR measures. Furthermore, PTSD participants had higher FPS to the danger cue and safety cue compared to trauma controls. However, SCR did not differ between groups. Finally, we found that FPS to the danger cue predicted re-experiencing symptoms, whereas FPS to the safety cue predicted hyper-arousal symptoms. However, SCR did not contribute to PTSD symptom variance. CONCLUSIONS: Replicating earlier studies, we showed increased FPS in PTSD participants. However, although SCR was a good measure of differential conditioning, it did not differentiate between PTSD groups. These data suggest that FPS may be a useful tool for translational research.

Risk and resilience: genetic and environmental influences on development of the stress response.

Exposure to stressful events during development has consistently been shown to produce long-lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by genexenvironment interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala-HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress-related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults.

Emotion dysregulation and negative affect: association with psychiatric symptoms.

OBJECTIVE: A growing body of research focuses on the development and correlates of emotion dysregulation, or deficits in the ability to regulate intense and shifting emotional states. Current models of psychopathology have incorporated the construct of emotion dysregulation, suggesting its unique and interactive contributions, along with childhood disruptive experiences and negative affect, in producing symptomatic distress. Some researchers have suggested that emotion dysregulation is simply a variant of high negative affect. The aim of this study was to assess the construct and incremental validity of self-reported emotion dysregulation over and above childhood trauma and negative affect in predicting a range of psychopathology. METHOD: Five hundred thirty individuals aged 18 to 77 years (62% female) were recruited from the waiting areas of the general medical and obstetric/gynecologic clinics in an urban public hospital in Atlanta, Georgia. Participants completed a battery of self-report measures obtained by interview, including the Childhood Trauma Questionnaire, the Positive and Negative Affect Schedule, and the Emotion Dysregulation Scale. Regression analyses examined the unique and incremental associations of these self-report measurements of childhood traumatic experiences, negative affect, and emotion dysregulation with concurrent structured interview-based measurements of psychiatric distress and history of self-destructive behaviors. These measures included the Clinician-Administered PTSD Scale, the Alcohol Use Disorders Identification Test, the Short Drug Abuse Screening Test, the Beck Depression Inventory, and the Global Adaptive Functioning Scale from the Longitudinal Interval Follow-Up Evaluation. The presented data were collected between 2005 and 2009. RESULTS: Regression models including age, gender, childhood trauma, negative affect, and emotion dysregulation were significantly (P ≤ .001) associated with each of the study's criterion variables, accounting for large portions of the variance in posttraumatic stress symptoms (R² = 0.21), alcohol and drug abuse (R² = 0.28 and 0.21, respectively), depression (R² = 0.55), adaptive functioning (R² = 0.14), and suicide history (omnibus χ² = 74.80, P < .001). Emotion dysregulation added statistically significant (P < .01) incremental validity to each regression model (ß = 0.25, 0.34, 0.35, 0.34, and -0.18, and Wald = 24.43, respectively). CONCLUSIONS: Results support the conceptualization of emotion dysregulation as a distinct and clinically meaningful construct associated with psychiatric distress that is not reducible to negative affect. Emotion dysregulation is a key component in a range of psychiatric symptoms and disorders and a core target for psychopharmacologic and psychosocial treatment interventions.

Cortisol suppression by dexamethasone reduces exaggerated fear responses in posttraumatic stress disorder.

PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.

Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population.

OBJECTIVE: Metabolic syndrome is associated with elevated risk for cardiovascular disease and diabetes and has increased prevalence in low-income African Americans, which constitutes a significant health disparity. The mechanisms responsible for this disparity remain unclear; the current study investigated the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome. METHOD: We assessed childhood and adult trauma history, major depressive disorder, PTSD and the components of metabolic syndrome in an urban population. We recruited 245 low-socioeconomic-status, primarily African American subjects from general medical clinics in an inner-city hospital. RESULTS: Trauma exposure was extremely prevalent, with 90.6% of subjects reporting at least one significant trauma and 18.8% of subjects meeting criteria for current PTSD. Metabolic syndrome was also prevalent in this population (33.2%), with significantly higher rates among patients with current PTSD (47.8%, P<.05). After controlling for demographics, smoking history, antipsychotic use, depression and exercise, current PTSD remained the only significant predictor of metabolic syndrome (P=.006). CONCLUSIONS: PTSD is associated with increased rates of metabolic syndrome within a traumatized, impoverished urban population. Further studies should investigate if PTSD treatment may reduce the rates of metabolic syndrome, improve overall health outcomes and decrease health care disparities in minority populations.

Pain symptomatology and pain medication use in civilian PTSD.

The comorbidity of pain syndromes and trauma-related syndromes has been shown to be high. However, there have been limited data, especially in civilian medical populations, on the role of trauma-related disorders such as posttraumatic stress disorder (PTSD) on chronic pain and pain medication use. We analyzed 647 general hospital patients in primary care and obstetrics and gynecological waiting rooms for the experience of trauma and PTSD-related stress disorders. PTSD symptoms were found to be significantly positively correlated with pain ratings (r=.282, P<0.001) and pain-related functional impairment (r=0.303, P<0.001). Those with a current PTSD diagnosis had significantly higher subjective pain and pain-related impairment ratings than those with no PTSD. Furthermore, those with a current diagnosis of PTSD were significantly more likely to have used opioid analgesics for pain control compared to those without a diagnosis of PTSD (χ(2)=8.98, P=0.011). When analyzing the separate PTSD symptom subclusters (re-experiencing, avoidance, and hyperarousal), all symptom clusters were significantly related to pain and pain-related impairment ratings, but only the avoidance cluster was significantly related to prior opioid pain medication use. We conclude that PTSD and trauma-related disorders are common in impoverished medical populations and that their presence should be examined in patients with pain syndromes. Furthermore, these data suggest that PTSD and pain may share a vulnerability pathway, including the endogenous opioid neurotransmission systems.

Personality constellations in incarcerated psychopathic men.

Advances in the operationalization of psychopathy have led to an increased understanding of the boundaries, structure, and nomological network of this construct, although significant questions remain. The empirical identification of replicable and theoretically meaningful psychopathy subtypes may help to improve the classification and diagnosis of this condition. We conducted a classification study of 91 incarcerated men who met conventional criteria for high levels of psychopathy using the Psychopathy Checklist-Revised. We expanded on the methodology of previous research on psychopathy subtypes by utilizing a comprehensive personality assessment instrument and a prototype matching approach to classification. The analyses revealed a primary (narcissistic) subtype and a secondary (hostile and dysregulated) subtype that were broadly consistent with the previous literature. External validation analyses, statistical controls, and incremental validity analyses provided substantial support for the primary and secondary subtypes.

Fear potentiation is associated with hypothalamic-pituitary-adrenal axis function in PTSD.

A central problem in posttraumatic stress disorder (PTSD) is the inability to suppress fear under safe conditions. We have previously shown that PTSD patients cannot inhibit conditioned fear. Another relevant finding in PTSD is the hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis feedback. Given their common neurobiological pathways, alterations in HPA function in PTSD may be associated with impaired fear inhibition. The present study examined the relationship between HPA axis function and fear-potentiated startle and inhibition of conditioned fear in trauma-exposed individuals. We used a conditional discrimination procedure (AX+/BX-), in which one set of shapes (AX+) was paired with aversive airblasts to the throat (danger signal), and the same X shape with a different shape (BX-) were presented without airblasts (safety signal). The paradigm also included a transfer of fear inhibition test (AB). In addition to fear-potentiated startle, blood was drawn for neuroendocrine analysis and the dexamethasone suppression test (DEX) was performed; cortisol and ACTH were assessed at baseline and post-DEX. Ninety highly traumatized individuals recruited from Grady Hospital in Atlanta, GA participated in the study. The sample was divided into those who met DSM-IV criteria for PTSD (n=29) and Non-PTSD controls (n=61) using the PTSD symptom scale (PSS). Both groups showed significant reduction in cortisol and ACTH levels after DEX. Subjects with PTSD had higher fear-potentiated startle to the safety signal, BX- (F(1,88)=4.44, p<0.05) and fear inhibition trials, AB (F(1,88)=5.20, p<0.05), both indicative of less fear inhibition in the presence of B, compared to control subjects. In addition, fear-potentiated startle to AX+, BX-, and AB was positively correlated with baseline and post-DEX ACTH in PTSD subjects. These results suggest that impaired fear inhibition and associated alterations in HPA feedback may reflect amygdala hyperactivity in subjects with PTSD.