Effect of psychosocial stress on FKBP5 and NR3C1 gene expression in healthy young men

Stress diseases such as affective disorders are often characterized by a disturbed regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. This dysregulation can be explained by an impaired function of the receptors involved in the HPA-axis regulation, for example, the glucocorticoid receptors (GR). The regulation process of the HPA axis and the GR function are influenced by several genes, for instance by NR3C1 coding for the GR and also by FKBP5, a co-chaperone in the GR-complex. Binder et al. showed that common polymorphisms in FKBP5 are associated with increased FKBP5 protein expression as well as correlation between cortisol levels and peripheral blood FKBP5 mRNA expression . Regarding the effects of FKPB5 genotypes on psychosocial stress reaction, Ising and colleagues tested healthy subjects with the Trier Social Stress Test, a standardized paradigm to induce psychosocial stress . Subjects homozygous for any of the FKBP5 variants showed an incomplete normalization of the stress induced cortisol secretion. Recent studies demonstrated that FKBP5 and NR3C1 are involved in the endocrine stress reaction. Therefore, we expected changes of FKBP5 and NR3C1 mRNA expression in peripheral blood after exposure to a psychosocial stress situation. To address this, we performed a pilot study where we tested six healthy young men without history of psychiatric or severe somatic disorders and applied the trier social stress test (TSST). Before and after two consecutive TSSTs, we took blood samples with a venous catheter in order to measure ACTH and cortisol in plasma and mRNA expression of the candidate genes in peripheral blood. Blood cells were stabilized using PAXgene tubes, and gene expression was processed by qPCR. Briefly after the psychosocial stress the stress hormones ACTH and cortisol increased whereas the reaction to the second TSST was lower suggesting a habituation effect. These endocrine stress responses were followed by an alteration in FKBP5 gene expression, further underlining the importance of this gene for the neuroendocrine stress reaction. NR3C1 mRNA levels did not change after the TSST. Our preliminary data indicate an effect of psychosocial stress on the FKBP5 mRNA levels. Further research with larger samples sizes is required to replicate and extend these results.

Intercorrelations between serum-, salivary-and hair-cortisol and child-reported estimates of stress in elementary school girls To evaluate the impact of stress on children's well-being, it is important to have valid and reliable stress assessment methods. Nevertheless, selection of an appropriate method for a particular research question may not be straightforward, as there is currently no consensus on a reference method to measure stress in children. This paper examined to what extent childhood stress can be estimated accurately by commonly applied stress measures.
Ingibjörg H. Jonsdottir, Kristina Glise, Gunnar Ahlborg, Anna Sjö rs. The Institute of Stress Medicine, Gothenburg, Sweden Salivary cortisol is not a valid marker of stress-related exhaustion Salivary cortisol has frequently been used as a biomarker of chronic stress. The results have differed considerably between studies, which could to some extent be explained by the various definitions of chronic stress cases, ranging from patients with a clinically diagnosed condition to working individuals scoring high on burnout questionnaires. Thus, it is not possible to generalize findings in the literature to stress-related conditions encountered in the clinic and it is difficult to apply the knowledge in diagnosis and treatment. The aim of this study was to elucidate the usefulness of basal salivary cortisol as a marker of chronic stress in a clinical population with stress-related exhaustion. We have measured salivary cortisol concentrations in two different samples of patients with a clinically diagnosed exhaustion disorder (ED). ED is defined as physical and mental exhaustion experienced for at least two weeks, caused by exposure to one or more stressors for a minimum of six months. In the first study, 162 patients (64% females) collected saliva samples at awakening and 15 minutes thereafter to assess the cortisol awakening response. This patient group was compared with 79 healthy controls (49% females). The patients repeated the saliva sampling at follow-up assessments after 3, 6, 12, and 18 months of treatment. The second study of 68 patients (79% females) included saliva samples taken at awakening, 30 minutes thereafter and at bedtime on two consecutive days to assess the diurnal profile, and follow-up assessments after 6 and 12 months. This study included 98 healthy controls (56% females). Age, sex, BMI, antidepressant use, and physical activity were considered as potential confounders. No significant differences were found between patients and controls in salivary cortisol awakening response (first study) or diurnal profiles (second study). Furthermore, follow-up measurements in patients indicated that salivary cortisol concentrations did not change significantly during treatment. Salivary cortisol levels, at least as measured in this study, apparently provide a rather poor reflection of the longterm stress exposure experienced by the patients in this study. Thus, basal salivary cortisol measurements are not recommended as a biomarker of stress-related exhaustion.
Keywords: burnout; exhaustion; HPA-axis; longitudinal; salivary cortisol Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19310 Magdalena Buckert 1 , Christiane Schwieren 2 , Brigitte M. Kudielka 3 , Christian J. Fiebach 1 . 1 Department of Psychology, Goethe University Frankfurt, Frankfurt a. M., Germany; 2 Department of Economics, University of Heidelberg, Heidelberg, Germany; 3 Department of Psychology, University of Regensburg, Regensburg, Germany Stress and the choice of competition in an economic tournament game Rationale: Recent research on stress and decision making highlights the importance of considering the reciprocal relationship of these processes. Indeed, everyday experience suggests that economic decision situations can be stressful in and by themselves, particularly if they involve psychosocially stressful elements like competition. It is, however, at present not known whether or not physiological reactions elicited by the decision situation influence the decision that is reached. According to Salvador and Costa [Salvador, A. & Costa, R. (2009). Coping with competition: Neuroendocrine responses and cognitive variables. Neurosci Biobehav Rev, 33 (2), 160Á170], effects of competition (i.e., positive vs. negative outcomes) critically depend on the nature of applied coping strategies that are in turn related to specific physiological changes. Methods: Our study examined the physiological and subjective changes induced by an established economic laboratory competition paradigm in a mixed-gender sample of 104 healthy participants. A mental arithmetic task was performed first under a piece-rate payment scheme and afterwards under a tournament (i.e., winner-takes-itall) condition (i.e., forced competition). In a third round, subjects decided how to be paid (i.e., piece rate or tournament). Results: Our results indicate that the laboratory paradigm indeed elicited physiological reactions that were related to the voluntary choice of competition. Participants that chose tournament were more likely to appraise the situation as challenging and showed higher sympathetic nervous system reactivity and higher testosterone increase during the game.
Anxiety symptom severity differentiates HPA acute stress reactivity in children Rationale/ statement of the problem: Considerable research has focused on the relationship of anxiety with alterations in the hypothalamic-pituitary-adrenal (HPA) acute stress response. Findings, however, differ among studies on adults and children, and among different types of anxiety. This study investigates the relationship of anxiety symptom severity with HPA reactivity to the cold pressor task (CPT) in preadolescent children. We hypothesize that children with increased symptoms of anxiety will have increased cortisol (HPA) reactivity to the CPT. Methods: A social-evaluative adaptation of the CPT was used to elicit HPA acute stress reactivity among 42 children (26 female, 16 male) aged 8Á12 years (mean age, 10 years) recruited from a child anxiety disorders clinic (n 020) and from the community at large (n022). Repeated saliva samples were assayed for cortisol to determine maximum task response (TR) and area under the curve with respect to the increase from baseline (AUCi). Multidimensional anxiety measures included the Screen for Anxiety and Related Disorders (SCARED: parent and child report); State Trait Anxiety Inventory-Trait (STAI-T), and Children's Anxiety Sensitivity Index (CASI). Subjects were grouped according to recruitment source and high/low symptom measures (all subjects by anxiety measure median split); groups were compared via independent samples t-tests. Results: Maximum cortisol TR and AUCi did not differ between children recruited from the anxiety disorders clinic and the community. Among all subjects, maximum TR was significantly greater for those with high anxiety symptoms on the STAI-T (p 00.006), SCARED-C (p00.012), and SCARED-P (p 00.031), and approached significance on the CASI (p 00.056), compared to those with low symptoms on these measures. AUCi was greater among those with high symptoms on the SCARED-C (p 00.01) and SCARED-P (p 00.011), but not on the STAI-T (p 00.113) or CASI (p 00.072).
The effect of Narrative Exposure Therapy on posttraumatic stress disorder: an outpatient intervention study Narrative Exposure Therapy (NET) is a treatment method defined as a standardized, short-term intervention for treating posttraumatic stress disorder (PTSD). It comprises elements from exposure therapy and testimony therapy. NET has mainly been applied on victims of organized violence and whose life conditions are threatening and unsafe such as for refugees and asylum seekers. There are no published studies of NET applied on PTSD outpatients living in Norway with different trauma histories than war-traumas. To investigate both short-and longterm effect of NET on diagnosed PTSD symptoms, general psychological status and depression symptoms in adult patients recruited from outpatient clinics. Seventeen adult outpatients (7 males, 10 females; mean age 38.5) were assessed with the Clinical Administered PTSD-scale (CAPS) which corresponds to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the Symptom Checklist-90-Revised (SCL-90-R), the Beck Depression Inventory (BDI-II), Dissociation Experiences Scale (DES), and Impact of Event Scale-Revised (IES-R) prior to, 1 month and 6 months after NET-treatment which consisted of 8 sessions a 90 min. T-tests for dependent samples showed a significant reduction on all the symptom criteria's CAPS (symptom B, C, and D both frequency and intensity) 1 month after treatment (p's B0.005Á0.05), five patients (29.5%) no longer Salivary cortisol profiles in multiple sclerosis patients with comorbid depression and posttraumatic stress disorder Objectives: Multiple sclerosis (MS) as an inflammatory demyelinating disease of the brain and the spinal cord is associated with a high prevalence rate of major depressive disorder (MDD). Psychological stress has been linked to MS pathogenesis as well as relapse risk in established disease. Moreover, MS diagnosis itself may be a potential trigger for the development of posttraumatic stress disorder (PTSD). Both MDD as well as PTSD have been linked to altered hypothalamic-pituitary-adrenal (HPA) axis regulation and consecutively to elevated or lowered cortisol secretion. This study explores associations of PTSD and MDD with HPA activity in patients with MS. Methods: In a cross-sectional sample of female MS patients, psychological comorbidities were diagnosed using the structured clinical interview (SCID). Circadian salivary cortisol profiles (AUC) and the cortisol awakening response (CAR) as markers of HPA axis activity were assessed over the course of 2 days. On the third day, low dose oral dexamethasone suppression was examined (post-Dex CAR/AUC). Results: Forty-nine patients with relapsing-remitting MS were included. Eleven patients fulfilled diagnostic criteria for current MDD. A total of 14 patients were diagnosed with PTSD, 7 of whom developed PTSD related to MS-diagnosis. Patients with PTSD were not currently depressed. Importantly, patients with comorbid psychological disorders showed significantly lower coping resources such as self-efficacy, sense of coherence, and social support. While no significant differences were found in most measures of cortisol secretion between the three groups, we observed a trend for higher CAR after dexamethasone suppression in MS patients with PTSD. Conclusion: The present study indicates a high frequency of MDD and PTSD in MS and associations to reduced salutogenetic resources. These comorbidities might be linked to different aspects of HPA axis dysregulation and could be associated to different biological pathways. Keywords: multiple sclerosis; salivary cortisol; depression; PTSD; coping resources Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19370 Jeffrey Milush 1 , Vanessa York 1 , Aric Prather 2 , Douglas Nixon 1 , Hecht Frederick 3 , Elissa S. Epel 4 . 1

Effect of chronic stress and in vivo cortisol measures on immune cell glucocorticoid receptor expression and cellular immune activation
Chronic psychological stress increases inflammation, providing a mechanism for the elevated risk of infectious, autoimmune and cardiovascular diseases in chronically stressed persons. While the HPA axis plays an important role in mediating the link between stressful events and inflammatory processes, it is becoming increasingly clear that immune cells can become resistant to cortisol, resulting in diminished regulation of inflammation. One potential mechanism of cortisol resistance results from decreased glucocorticoid receptor (GR) expression in immune cells during elevated cortisol exposure. Chronic stress results in chronic high cortisol exposure leading to decreased immune cell GR expression that in turn is associated with greater immune activation. Using flow cytometry we measured immune activation and GR expression (geometric mean fluorescence intensity [gMFI]) in 10 immune cell subsets in 25 post-menopausal females (10 caregivers [CGs] and 15 controls [CNTLs]). MannÁWhitney and Pearson correlations were employed for statistical analysis with p B0.05 considered significant. No statistically significant difference in daily cortisol exposure was observed between CGs and CNTLs; however, CGs did exhibit greater T cell immune activation (p 00.029). Contrary to our hypothesis, T cell immune activation was not associated with decreased GR expression. In fact, CGs had equal or a trend toward greater GR expression compared to CNTLs. CGs did demonstrate a statistically significant negative correlation between total daily in vivo cortisol levels and GR expression in CD4 ' and CD8 ' T cells ( (0.74 (pB0.02) and (0.81 (p B0.02), respectively). Combining groups, we observed a positive trend in GR expression and perceived stress in two monocyte subsets (CD14 br and CD14 dim CD16 ' ). A statistically significant negative correlation between GR expression in the pro-inflammatory CD14 br CD16 ' and CD14 dim CD16 ' monocyte subsets and their relative frequency was also observed ( (0.47 (p00.02) and (0.52 (p 00.01), respectively). Elevated inflammation during chronic stress may not result simply from down-regulation of GR in immune cells. Cortisol and GR expression may influence the frequencies of pro-inflammatory monocyte subsets (CD14 br CD16 ' and CD14 dim CD16 ' ) that may be important in regulating chronic inflammation.
Keywords: chronic stress; glucocorticoid receptor; inflammation; cortisol; immune activation; flow cytometry; HPA axis Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19320 Nina Alexander, Franziska Rosenlö cher, Tobias Stalder, Julia Linke, Wolfgang Distler, Joachim Morgner, Clemens Kirschbaum. Department of Biopsychology, Technische Universität Dresden, Dresden, Germany Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term born children Background: Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamusÁpituitaryÁadrenal (HPA)-axis activity producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GCs has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. Method: The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample (N 0209 children between 6 and 10 years of age), allowing to further address sex and drug specific effects. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. Results: We observed significantly increased cortisol reactivity to acute psychosocial stress in 6Á11 years old, termborn children exposed to antenatal synthetic GC treatment compared to controls (F (3.4,345.9)05.8, p B0.001). This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced in females.

Conclusions:
The present study provides first evidence for long-lasting effects of antenatal synthetic GC exposure on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been discussed as a potential causal factor. Keywords: synthetic glucocorticoids; antenatal; HPA-axis; stress reactivity; children; trier social stress test Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19321 Mary Eileen Saczawa, Julia. A. Graber, Jeanne Brooks-Gunn. University of Florida, Gainesville, FL, USA; Teacher's College at Columbia University, New York, NY, USA The relationship between social stressors and psychopathology: a short-term longitudinal study of moderating factors Rationale: Problematic peer relationships in adolescence have long been linked with various psychological disorders, but there remain questions as to why adolescents with similar social experiences may suffer no psychological effects or why some respond with depression or anxiety while others become aggressive. Parenting style and level of chaos in the home environment have also been shown to have protective or detrimental effects in conjunction with social stressors. Adolescence is typified by substantial hormonal changes and maturation of both the pubertal and the stress systems. Ian Goodyer has suggested that atypical ratios of stress and pubertal hormones may be indicative of vulnerability for psychopathology. High cortisol and low DHEAS have been linked to depression, whereas the opposite has been found in those with aggression. This study is the first to examine the cortisol/DHEAS ratio as a moderator of peer stress in the development of psychopathology in adolescents. This investigation uses a biopsychosocial model to test the moderating role of parenting style, environmental chaos, and adrenal hormone ratios on the association between social stress and aggression or depression over a 1-year period. Methods: Participants were 156 young adolescents (50% f; M age 011 years, SD 00.7), ethnically diverse, and predominantly middle to lower SES. Depressive symptoms, aggression, social stress, and environmental chaos were assessed via survey and interview reports from mothers and children. Parenting characteristics were assessed via mother survey. Saliva and urine samples were collected on multiple mornings to measure cortisol and DHEAS, respectively. Results: Cross-sectional and longitudinal analyses indicate significant main effects of parenting style, chaos, and adrenal hormone ratios in predicting depressive symptoms and aggression and significant moderating effects on the relationship between social stressors and psychopathology. High cortisol/DHEAS ratio predicted depressive symptoms and enhanced the effects of peer problems; low ratio was predictive of aggression in adolescents with high levels of peer problems. Conclusion: The results of this study shed light on factors that may better explain the varying responses adolescents have to social stressors, thereby identifying adolescents at risk for psychological problems.
Keywords: cortisol; DHEAS; ratio; family; depression; aggression; peer Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19371 Malak Abu Shakra, Jens C. Pruessner, Alain Dagher, Marco Leyton, Robert Pihl. Department of Psychology, McGill University, Montreal, QC, Canada Why gender matters: differential effects of stress and alcohol on cortisol secretion and neural stress circuitry activation among sensation seeking and anxiety-sensitive males and females Background: Alcohol Use Disorders (AUDs) are multiphasic, multifactorial, and heterogeneous disorders for which the differential risk traits have been proposed to be associated with distinct risk profiles. However, whether these profiles are distinct in terms of neuronal and hormonal mechanisms remains less understood. Behavioral evidence has demonstrated differential motivational systems mediating the response to alcohol, two of which are the psychomotor/cue for reward and the anxiety systems that are in turn exemplified by sensation seeking (SS) and anxiety sensitive (AS) individuals, respectively. Methods: Two equally divided groups of healthy social drinker AS and SS males and females (n 048; ages 18Á26) underwent a randomized double-blind placebo-controlled fMRI design. Salivary cortisol concentration was measured every 10 min during testing. Alcohol and placebo were administered based on standardized procedures, 30 min after which scanning occurred at the height of the blood alcohol curve. Two stressors differing in form and effect were used, a random presentation of standardized emotional faces, and a mental math test [The Montreal Imaging Stress Task (MIST)] performed under and accompanied by social pressure, 50Á60% uncontrollable failure rate and negative feedback. Results: Salivary cortisol secretion relative to ground (AUCg) was significantly different between groups and within subjects. Gender showed a significant main effect (F(1,39) 00.6816, p00.013), with a females showing greater cortisol response than males. Further, a significant trait-by-gender-by-condition interaction effect was observed (F(1,39) 06.414, p 00.015), where F_AS showed elevated AUCg under placebo, a response was largely blunted by alcohol. This interaction effect was also significant in terms of amygdalae and orbitofrontal cortical activation under MIST; both regions where significantly deactivated under alcohol in F_AS (parameter estimates, pB0.05 respectively: Á2.103; Á2.229). Conclusions: These findings provide evidence for the notion that distinct risk personality profiles are associated with differential vulnerability for AUDs. They further support the self-medication theory, whereby AS individuals drink to dampen stress, rendering the former a negative reinforcer targeting and inhibiting their neural and hormonal stress circuitry.

Peripheral indices of oxidative stress are correlated with hippocampal volume in major depression and in controls
Oxidative stress (an imbalance between free radicals and the ability to neutralize them with antioxidants) occurs in several mental illnesses, including major depression (MDD). A major antioxidant in humans is glutathione peroxidase, which reduces GSSH to GSH, increasing glutathione's ability to scavenge free radicals. The brain, and the hippocampus (HC) in particular, is particularly sensitive to oxidative stress, and HC oxidative stress (particularly in the CA1 and CA3 & dentate gyrus [CA3&DG] subfields) may contribute to major depression. Nineteen medication-free subjects with MDD and 19 matched controls underwent 4T MRI scanning of the HC and had fasting morning venipuncture for peripheral oxidative stress assessment. Two of the MDD subjects did not have glutathione (GSH) and/or glutathione disulfide (GSSG) data. Because of the preliminary nature of the study, no corrections for multiple comparisons were applied. Across all subjects, the antioxidant Vitamin C was directly correlated with total HC (pB0.03) and CA3&DG (pB0.04) subfield volumes. Glutathione peroxidase was directly correlated with total HC (pB0.006) and CA1 (pB0.009) and CA3&DG (pB0.002) subfield volumes. Levels of the antioxidant and GSH were directly correlated withCA2 (pB0.02) and CA3&DG (pB0.03) subfield volumes. In the controls, a similar pattern was observed at or near the significance threshold. In the MDD group alone, glutathione peroxidase activity was directly correlated with total HC volume (pB 0.05) and tended to be directly correlated with CA3&DG subfield volume (pB0.07). The antioxidant ratio of GSH/GSSG (an index of antioxidant reserves) was directly correlated with CA2 (pB0.02) and CA3&DG (pB0.03) subfield volumes. These exploratory data are consistent with the hypothesis that oxidative stress is related to diminished hippocampal volume, with the CA3&DG subfield perhaps being the most sensitive. The relationship of peripheraloxidative stress to local oxidative stress in the HC is unknown, but studies in humans have suggested some degree of direct correlation between blood and cerebrospinal fluid (CSF) oxidative markers, and peripheral oxidative stress measures are increased in several neurodegenerative diseases.

Acute stress prompts riskier decisions in young men
There is evidence that acute stress impacts decision making (DM) under risk. It has been concluded that stress prompts riskier decisions in men. However, in the DM tasks used thus far, the expected value (EV) of reward and risk of decision options are confounded and it is, therefore, unclear which component is being affected by acute stress. We developed a new DM paradigm, in which EV of reward and risk of decision options are independent and quantifiable. Subjects (5 men, age: 31.291.92 years) completed 220 trials in which they had to repeatedly choose between a safe and a risky option associated with different EV of reward and risk. Stress was induced using the Socially Evaluated Cold Pressor Test (SECPT). Each subject received the SECPT and the corresponding control condition in random order. Comparing the stress and control condition on a trial-by-trial basis, we found that, descriptively, gamble variance, a measure for the risk associated with decision options, was about 10% higher when subjects were stressed compared with when they received the control manipulation. EV of reward on which subjects gambled did not differ between stress and control manipulation. Our data provide a first hint that risk but not reward processing in healthy young men might be affected by acute stress.

Serum leptin concentrations and telomere length in MDD and in controls
Obesity and the metabolic syndrome (MetS) predispose to multiple diseases and to accelerated cell aging as indexed by accelerated shortening of telomeres in peripheral blood mononuclear cells (PBMC's). Major depressive disorder (MDD) is often associated with MetS and is also associated with increased disease risk and PBMC telomere shortening. A potential role of leptin in telomere shortening has been suggested, but prior results have been inconsistent and no study has yet assessed this relationship in MDD. The goal of this study was to assess the relationship between serum leptin concentrations and PBMC telomere length in MDD and in controls and to assess whether this relationship is mediated by body-mass index (BMI) or the homeostatic model assessment of insulin resistance (HOMA-IR), two principal components of the MetS.
Eighteen medication-free MDD subjects (11 female, 7 male, mean age 37.1'2.7 years) and 17 healthy controls (11 female, 6 male, mean age 37.8'3.0 years) had blood drawn for assay of fasting morning levels of leptin, glucose, and insulin and PBMC telomere length. The groups did not differ on BMI (24.66'3.72 vs. 24.77'4.29,respectively,n.s.). Analyses were co-varied for age and sex, with and without BMI. In the combined group, serum leptin concentrations were inversely correlated with telomere length (r 0(0.33, pB0.02), with and without co-varying for BMI. This relationship remained significant in the MDD group alone (r 0(0.54, pB0.04) but missed significance in the controls (r 0(0.23, ns). Hierarchical linear regression, entering BMI and HOMA-IR prior to leptin (with telomere length the dependent variable) showed that BMI and HOMA-IR were not significantly correlated with telomere length (t01.04, p!0.30, and t01.49, p!0.10, respectively), but leptin concentrations remained significantly correlated with telomere length (t0(2.88, p00.007). Relatively high leptin concentrations, in the presence or absence of increased BMI and insulin resistance, may be a risk factor for telomere shortening. While this was demonstrated here in individuals with MDD, a similar relationship in nondepressed individuals cannot be ruled out because of the small sample size.
Keywords: leptin; telomeres; depression; body-mass index; insulin resistance; metabolic syndrome; obesity Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19374 Post-stress rumination after initial psychosocial stress predicts cortisol responses to repeated stress exposure Background: Rumination, defined as past-centered negative thinking, has been linked to stress physiology and suggested to affect mental and physical health. Research has shown that both state and trait rumination is correlated with cortisol responses to psychosocial stress. It has not been addressed if state rumination is associated with cortisol responses to repeated stress. Methods: Nineteen participants (aged 21Á65, mean age 053.5; nine males) were exposed to the Trier Social Stress Test (TSST) twice on consecutive days. Salivary cortisol was measured 1 min before and 1, 10, 30, 60 and 120 min post-TSST on both days. Participants provided self-reports of post-stress state rumination on both days. Participants further provided information about early adversity using the Childhood Trauma Questionnaire and self-rated depression and perceived chronic stress. Results: Cortisol responses were successfully induced on both days of testing (F [1.5, 54.5] 04.4, p 0.032). State rumination scores on day 1 were significantly correlated with cortisol increases (r 0.615, p 0.005); interestingly, state rumination scores on day 1 of testing were related to cortisol increases the following day (r0.594, p 0.007). No gender differences were found in rumination on either day (all p0n.s.). Childhood trauma, although reported at a very low level, was found to be strongly related to rumination on both days (rumination day 1: r0.547, p 0.02; rumination day 2: r0.712, p 0.009). Childhood trauma was further related to cortisol responses on the first, but not second, day of testing (day 1: r0.503, p 0.047; day 2: r 0.31, p 0n.s).
Conclusions: Post-stress rumination on day 1 was correlated with hypothalamicÁpituitaryÁadrenal (HPA) axis reactivity. Day 1 post-stress rumination was correlated with day 2 responses to the same stressor, but day 2 rumination was unrelated to the stress response on that day. This suggests that rumination has prolonged effects on stress reactivity. Other variables, such as subclinical childhood trauma, were also related to state rumination and cortisol responses. These factors are potential mediators of the relationship between state rumination and HPA axis stress reactivity. Salivary cortisol and alpha-amylase during traumatic memory encoding * relationships with intrusions and pre-existing characteristics Rationale/ statement of the problem: Cortisol levels have been extensively studied in patients with posttraumatic stress disorder (PTSD), but their specific relationship to intrusive memory symptoms is unknown. Salivary alphaamylase (sAA), an index of sympathetic activation, has never been studied in the context of PTSD. This study adopted the Trauma Film Paradigm to assess how changes in cortisol and sAA levels during memory encoding are related both to subsequent intrusive memories of the film and to individuals' pre-existing characteristics. Methods: Saliva samples were collected in the afternoon (considering the circadian rhythm of cortisol and sAA) from 58 healthy adult participants at baseline, during the film, and post-film. Measurements of pre-existing PTSD symptoms, dissociation and anxiety traits as well as intrusions of the traumatic film over the week following film viewing were assessed. Results: Results showed that cortisol levels increased, whereas sAA levels decreased in response to the film. The vividness of intrusive memories was negatively correlated with cortisol levels during and after the film. Pre-existing PTSD symptom severity was negatively correlated with cortisol levels at the post-film stage and positively correlated with sAA in both during the film and post-film stages. Moreover, dissociative traits (especially dissociative amnesia) were negatively correlated with sAA levels at baseline and during the film, while anxiety traits were positively correlated with post-film sAA levels.
Conclusions: This is the first study to investigate the relationship between cortisol, sAA, intrusive trauma memories and pre-existing psychological traits. The results supported the hypothesis that insufficient cortisol release in the immediate aftermath of trauma is a risk factor for the development of intrusive symptoms. The findings also shed light on how pre-existing characteristics affect physiological reactions to traumatic stimuli. Boosting the oxytocin system in acute trauma victims at risk for PTSD: the rationale and design of a randomized controlled trial Rationale: Currently, there are no effective interventions that prevent the development of posttraumatic stress disorder (PTSD) in recently traumatized individuals. The neuropeptide oxytocin is a potent regulator of two important processes disturbed in PTSD: it regulates physiological and behavioural stress and fear responses. In addition, oxytocin administration influences socio-emotional processes. Interestingly, high levels of acute distress after trauma and a lack of social support are risk factors for developing PTSD. Therefore, oxytocin administration appears to be a promising preventive treatment for PTSD, by hypothetically ameliorating dysregulated stress and fear responses as well as facilitating adaptive social functioning.

Methods:
We have initiated a randomized controlled trial (RCT) to investigate the effectiveness of an intranasal oxytocin treatment regimen in preventing the development of PTSD in recently traumatized individuals at increased risk for PTSD. In addition, in the same population we are conducting an fMRI study, which will create deeper insights into the neural mechanisms through which oxytocin and social context may regulate fear responses to traumatic stress. Results: In this presentation, the rationale behind stimulation of the oxytocin system in recently trauma-exposed individuals at risk for PTSD will be discussed, and an outline of the RCT will be presented. In addition, preliminary pilot data of the RCT will be shown. Lower fasting plasma glucose levels in patients with stress-related exhaustion In a recent study, we unexpectedly found lower fasting plasma glucose concentrations in patients with stress-related exhaustion compared with healthy controls. To further elucidate the reliability of these findings we now investigated possible differences in glucose and glycated haemoglobin (HbA1c) levels between all patients with Exhaustion Disorder (ED) that entered the treatment program at the Institute of Stress Medicine, Gothenburg, Sweden between 2004 and 2010 and a healthy control population. We also investigated the development of plasma glucose during 18 months of multimodal treatment and related it to changes in symptoms of burnout, depression and anxiety. The study included 383 patients (71% females, age 21Á66 years) and 199 healthy controls (50% females, age 25Á54 years). All patients fulfilled the criteria for ED, which include physical and mental exhaustion experienced for at least two weeks, caused by exposure to one or more stressors for a minimum of six months. Cardinal features are markedly reduced mental energy, impaired memory and reduced capacity to meet demands. Blood samples were drawn in the morning after fasting since 22:00 the day before. Follow-up measurements were performed after 3, 6, 12, and 18 months of treatment in the patient group. Fasting plasma glucose was significantly lower in the patients (4.790.4 mmol/L) compared with healthy controls (5.090.5 mmol/L), both in women and men. HbA1c did not differ between patients and controls. These results remained after controlling for age, BMI, WHR, physical activity, and antidepressant use. In the patient group, plasma glucose levels increased significantly from inclusion to the follow-up measurements after 12 and 18 months. Changes in glucose during treatment were not related to improvement of symptoms of depression, anxiety or burnout. We confirm our previous finding that plasma glucose levels are lower in patients with stress-related exhaustion compared with healthy controls. The increase during treatment could indicate that lower level of glucose might be a consequence of long-term stress, which is normalised during treatments. Further studies are needed to confirm if this is the case and whether this relatively small difference in glucose levels is of clinical relevance. The contagion of physiological stress: causes and consequences Rationale/ statement of the problem: The contagion of psychological states such as arousal, pain, and distress has been well established and is consistent with perceptionÁaction models of empathy. However, the recent demonstration of contagious physiological stress is more confounding because cortisol responses have been historically difficult to trace to specific subjective states or overt behaviors. Thus, it is currently unclear how someone could detect another's physiological stress (i.e., cortisol and sympathetic nervous system responses) through mere observation to produce resonating levels in themselves. It is also unclear if such resonating stress has any implications for subsequent prosocial behavior, as it does for typical empathic states like shared pain or distress. Methods: In two separate studies, we assessed salivary cortisol and salivary alpha-amylase in both speakers and observers during a modified Trier Social Stress Test (TSST). In Study One, we coded a set of nonverbal behaviors from TSST speakers to determine the behavioral indices that may signal stress reactivity between individuals. In Study Two, to examine the influence of contagious stress on prosocial behavior, participants completed poststress measures of empathy and altruism. Results: In both studies, observers and speakers showed evidence of contagious physiological stress responses. In Study One, speakers who demonstrated more gaze aversions showed the greatest cortisol reactivity. In Study Two, both speakers and observers showed evidence of increased prosocial behavior after the TSST. Conclusion: These findings demonstrate that the contagion of physiological stress is a robust phenomenon, which may be mediated through the observation of behaviors like gaze aversion that indicate another's level of stress. The experience and resonance of stress also appears to have implications for prosocial behavior.

Predicting internalizing outcomes based on psychophysiological dynamics
Background: Our insight into the neurobiological dynamics underlying the processes that may over time cumulate into syndromes like burn-out and depression is rapidly developing. A recent, though important, step has been to combine the relevant parameters of multiple domains (physiological, endocrine, social/emotional) to optimize prognostic accuracy. This is of relevance as initially subtle neurobiological disturbances associated with stress may indicate the start of a negative and potentially dangerous trend, both for physical and psychological health. Methods: On the basis of the regular monitoring of key variables of allostatic processes (like heart rate variability, corticosteroid concentrations, and psychosocial status), risks scores for internalizing development can be calculated. When repeatedly collected by means of a standardized assessment protocol, it becomes possible to conduct trend analyses, which may potentially indicate development towards aversive outcomes like burn-out (in labour environments) or for example depression. Results: On the basis of available data, algorithms have been developed combining diverse allostatic key variables into multi-level prognostic models (lowÁmediumÁhigh risk for internalizing development). On the basis of these models, a standardized assessment protocol is developed using state-of-the-art information technology to make the application as consumer friendly as possible. Conclusions: Although some technical developments are necessary to optimize the potency of assessment protocols like the present one (e.g., sensor technology able to measure or estimate corticosteroid concentrations ''on the spot''), the used algorithms do not only seem to provide valid prognostic information, though essential indicators for easy to apply preventive strategies as well. These could be instrumental in averting long-term negative psychological outcomes.
Keywords: depression; burn-out; prognostic modelling; allostasis; health Tell me what you read and I will tell you if you are stressed: stress reactivity in consumers of self-help books Background: The self-help book industry is one of the most lucrative in North America generating profits of $10 billion annually. The main purpose of self-help books is to increase the sense of worth of the readers as well as to provide them with adequate coping strategies, so they can better negotiate their stress. Despite the popularity of this literature, no study has investigated whether it impacts on people's stress reactivity. Consequently, the goal of this study was to compare consumers and non-consumers of self-help books with regard to their physiological stress response. Methods: Thirty-one healthy men and women aged between 18 and 65 took part in this study. Of this group, 16 reported being consumers of self-help books, whereas the other 15 participants reported not being consumers nor attracted by these books. During their afternoon visit to the laboratory, all participants were exposed to the Trier Social Stress Test, a validated psychosocial stressor. Salivary samples were taken throughout the session in order to quantify their cortisol levels. Participants also filled out different questionnaires assessing self-esteem, depressive symptomatology and personality traits. Results: In terms of stress reactivity, the area under the curve with respect to increase was significantly higher in consumers when compared to non-consumers. The two groups did not differ from each other in terms of depressive symptomatology and self-esteem. The consumer group scored lower on the ''extraversion'' personality trait compared to the non-consumer group. Conclusions: Healthy consumers of self-help books are more stress reactive when facing a psychosocial stressor than non-consumers of self-help books. Although the current study design does not allow concluding about the efficacy of these books, the results nonetheless suggest that further investigation about the impact of this literature is necessary. Moreover, given the considerable amount of consumers of self-help books and their poor ability to cope with stress, there is clearly a need of increasing public awareness about effective coping strategies. Subjective sleep is associated with the diurnal cortisol profile in children and adolescents Rationale/ statement of the problem: In adults, there is a robust, immediate effect of sleep on the diurnal cortisol profile. Shorter sleep duration and poorer sleep quality are associated with greater awakening response, flatter diurnal slope, and higher evening cortisol levels. Because of methodological limitations, this relation is less well-established in children and adolescents. Specifically, the use of single cortisol samples and sampling at unconventional times limit the generalizability of these findings. This study examines the influence of sleep duration, sleep quality, and daytime sleepiness on the diurnal cortisol profile in children and adolescents. Methods: Children and adolescents aged 8Á18 (N 0227, M 012.61, SD02.04, 45.8% female) participated in the Healthy Heart Project at Concordia University. Children and adolescents rated their sleep quality on a 1Á10 scale (1 0poor, 10 0excellent) and completed the Pediatric Daytime Sleepiness Scale. Parents completed the Child's Sleep Habits Questionnaire and reported their children's bedtime and waketime to derive sleep duration. Six saliva samples were collected over 2 days. Single sample (bedtime, maximum) and aggregate measures (AUC AG , AUC I , AUC TG , diurnal slope) of the diurnal cortisol profile were derived. Results: After controlling for age and day of the week, higher bedtime cortisol was associated with shorter sleep duration (r 0(0.17, p 0.01), poorer sleep quality (r 0(0.19, p 001), and greater child-report daytime sleepiness (r 00.16, p0.02). Higher AUC TG was associated with poorer sleep quality (r0(0.15, p0.02); higher AUC I was related to greater child-report daytime sleepiness (r 00.14, p 0.03). Parent-report sleep problems and daytime sleepiness were not associated with any cortisol measure. Maximum sample, AUC AG , and diurnal slope were not related to any sleep measure. Conclusion: Poorer sleep quality, greater daytime sleepiness, and shorter sleep duration were related to higher bedtime cortisol. Poorer sleep quality and greater daytime sleepiness were associated with higher AUC TG and AUC I , respectively. While child-report measures of sleep were associated with cortisol, parent-report measures were not.

Sympathetic nerve activity in takotsubo cardiomyopathy
The maintenance of cardiovascular and cerebrovascular health is based on a complex relationship between the heart and the brain. While some responses to stress are vital for survival, mental stress has also been claimed to cause cardiovascular disease. The Japanese observation from the early 1990s of a reversible stress-induced cardiomyopathy, the takotsubo cardiomyopathy (TC), a peculiar type of left ventricular (LV) dysfunction triggered by an acute strong emotional or physical stressor, supports this notion. The syndrome, mostly affecting postmenopausal women, presents signs and symptoms of acute coronary syndrome without evidence of obstructive coronary artery disease. Though the definite pathophysiology of TC remains to be identified, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis and forms the basis for treatment of this medical entity. Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24Á48 hours) and 7 in the recovery phase (1Á6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA%). All patients were investigated with ongoing medication. MSNA was lower in patients with TC as compared to matched controls, but did not differ between the acute and recovery phase of TC. RMBA%, blood pressure and heart rate did not differ between the groups. MSNA is shown to be lower in patients with TC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of TC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients. Lower DHEA and DHEA-S response during acute psychosocial stress is related to higher perceived stress at work Background: Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEA-S) increase during acute psychosocial stress is suggested to have a protective role against the negative consequences of cortisol. We have previously reported that, in adults, the capacity to produce DHEA and DHEA-S during acute psychosocial stress declines with age. Changes in DHEA and DHEA-S levels with ageing depend on changes in the zona reticularis area in the adrenal cortex, which is responsible for DHEA and DHEA-S production. Prolonged psychosocial stress may be a factor that negatively affects the zona reticularis area. This study aimed to investigate whether self-reported prolonged stress affect the capacity to produce DHEA and DHEA-S during acute psychosocial stress. Methods: 20 men and 19 women (age 30Á50 years) underwent Trier Social Stress Test (TSST). Physiological measurements were performed before, directly after the stress test and after 30 min of recovery. Perceived stress at work (during the last week) was measured by the Stress-Energy (SE) questionnaire. The participants were divided into three groups based on their scores. A general linear model (multiple regression analysis) was performed, using the magnitude of stress-induced increase of DHEA and DHEA (log) as dependent variable and age and stress level group as independent variables. Results: Both the medium stress group and the high stress group had lower DHEA and DHEA-S increase during acute psychosocial stress compared to individuals reporting low stress levels at work (p00.027 and p 00.036, respectively). Conclusions: This study indicates that prolonged stress is a factor that negatively affects the zona reticularis area in the adrenal cortex and its capacity to produce DHEA and DHEA-S during acute psychosocial stress. Symptom improvement in deep brain stimulation for obsessive-compulsive disorder is related to cortisol changes Background: Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been suggested to be related to the hypothalamic-pituitary-adrenal (HPA)-axis, we set out to study whether/how DBS affects the HPA-axis in OCD patients. Methods: We studied 16 therapy-refractory OCD patients treated with DBS of the accumbal area for at least 1 year in an ''on'' and ''off'' stimulation phase, with a 1-week interval. We measured 24-h urinary excretion of cortisol, adrenalin, and noradrenalin as well as obsessive-compulsive (Y-BOCS), depressive (Ham-D), and anxiety (HAM-A) symptom scores. Results: Eight patients who completed the study were included in the final analysis. The comparison between DBS on and off phase revealed a change in Y-BOCS (39%), HAM-D (78%), and HAM-A (56%) scores. Median cortisol levels increased by 53% in the off phase, from 93 to 143 nmol/24 h, and correlated strongly with Y-BOCS and HAM-D changes. There was no significant change in urinary adrenaline or noradrenaline excretion. Conclusions: Our findings indicate that symptom improvement in DBS for OCD patients is associated with changes in cortisol levels.
Keywords: deep brain stimulation; nucleus accumbens; hypothalamic-pituitary-adrenal axis; cortisol; catecholamines; obsessive-compulsive disorder The effects of sexual orientation on stress-reactive cortisol: are sexual minority women ruminative and men resilient?
earlier studies, the current study investigated whether sexual minorities might manifest differential cortisol levels than heterosexuals (Hs) in response to social-evaluative threat. Methods: Participants included 87 healthy adults (mean age 25, 54% men) identifying as L/G/B (n 046) or as Hs (n 041). Stress was induced using the Trier Social Stress Test (TSST), and 10 salivary cortisol samples were collected throughout a 2-hour afternoon visit. Results were analyzed through ANOVA split by sex with sexual orientation as the between-subject factor and cortisol as the with-subject factor while controlling for age, selfesteem, and disclosure status. Results: Results reveal that L/B women had higher cortisol levels than Hs women 40 min after stress exposure. As a group, G/B men had significantly lower cortisol levels in contrast to Hs men. The covarying effects of age, self-esteem, and disclosure status intermittingly contributed to time and group effects for both sexes. Conclusions: Our findings demonstrate that relative to Hs controls (1) L/B women displayed higher cortisol levels late after TSST exposure, whereas (2) G/B men displayed lower overall cortisol levels throughout testing. We previously reported that G/B men in our sample manifested lower depressive symptoms and allostatic load based on 20 biomarkers compared to Hs men. It is possible that G/B men who are able to successfully overcome stigma may be resistant to chronic stress and stress reactivity. Yet, the opposite might be true for L/B women who displayed heightened distress during recovery that may indicate ruminative processes. These results suggest that it is important to include intrasex variations such as sexual orientation as well as unique developmental challenges such as disclosure processes in future psychoneuroendocrine studies.
Keywords: sexual minority stress; cortisol; Trier Social Stress Test; stress reactivity; disclosure; rumination; resiliency Low lead levels associated with blunted cortisol reactivity in a sample of elders from the general population Background: A few weeks ago and for the first time in 20 years, US health officials have lowered the threshold for lead (Pb) poisoning from 10 to 5 g/dL in blood, but only in young children. However, elders are also a high-risk population when considering adverse effects of lead exposure. The association between low-level lead exposure and cognitive variability is well documented in elderly people, e.g. in the domain of attention and memory. Toxicokinetic studies have also demonstrated that the skeleton is the site of storage for around 95% of lead in the adult human body, resulting in a release of lead in blood in elderly people with bone demineralization. One potential mechanism explaining adverse health effects of lead exposure stands in its endocrine disrupting function, and a recent study has found significant associations in children between low-lead levels and cortisol reactivity to the cold pressure task. We hypothesized that this association between lead exposure and hypothalamoÁpituitaryÁ adrenal functioning could be observed in elders from the general population. Methods: Pb levels were determined from blood samples of 78 elderly individuals (mean age 058.37, SE 04.01) without previous occupational Pb exposure. Diurnal cortisol was measured using salivary cortisol samples collected at home over two working days at awakening, 30 min after waking, 14: 00 h, 16: 00 h and before bedtime (Â10 pm) periods. Salivary cortisol reactivity was assessed in response to the Trier Social Stress Test (TSST). Results: All participants showed blood Pb levels below the threshold limit recommended by the CDC with a mean Pb of 2.6 g/dL, SE 01.4. No association was found between lead exposure and diurnal cortisol activity (n075, r0(0.02, p00.98). However, the more exposed to lead, the lower the cortisol response following TSST was found in participants (n 074, r 0(0.26, p B0.03), even when controlling for age, and levels of education (n073, b 0(0.24, p 00.05). Conclusions: Lead levels, even at a very low level of exposure, are associated with a blunted cortisol response to the TSST. These findings support the relationship between environmental contaminants and stress, and support the idea that regulation should be applied to the aging population. The next step will be to determine whether the association between lead exposure and cognitive variability could be explained by impairment of the stress system.

Evaluation of classification criteria for the detection of cortisol pulses in repeated-measures designs
Rationale: HypothalamusÁpituitaryÁadrenal (HPA) axis reactivity, which has been considered a potential endophenotype for psychiatric disorders, is commonly investigated by repeated-measures designs utilizing frequent sampling of salivary cortisol in temporal proximity to psychosocial stressors. To remove sources of cortisol variance, which are not related to HPA axis reactivity, researchers often utilize classification criteria to identify individuals who show no cortisol response (non-responders), for example, baseline-to-peak distances of 2.5 nmol/l. However, such classification criteria have not been systematically evaluated with regard to their classification performance. Methods: As a first step, we fitted an autoregressive latent trajectory model to cortisol data, which was obtained from longitudinally sampled saliva of 504 participants, of which 309 were exposed to the Trier Social Stress Test. Different sources of time-series variance were accounted for by modeling of initial cortisol levels, amplitude of the subsequently occurring secretory episodes, and continuous cortisol elimination. Assuming zero-amplitudes for individuals who show no stress response, a mixture distribution was implemented for secretory episodes, resulting in appropriate classifications of cortisol responders, or non-responders. Then, as a second step, we evaluated the classification performance of various proposed classifiers by constructing receiving operator characteristics.
Results: Results reveal (a) that covariance and mean structure of cortisol time-series can be sufficiently accounted for by the proposed model, allowing to infer on endocrine parameters that can barely be extracted by conventional analyses and (b) that the 2.5 nmol/l criterion is suboptimal in terms of simultaneously minimizing false-positive and false-negative classifications and inferior as opposed to other classifiers. Conclusion: To maintain the low number of false positives, but to increase true-positive classifications, we suggest to lower the conventional baseline-to-peak classification threshold to 1.5 nmol/l. Furthermore, classification performance can be increased by adjusting baseline-to-peak differences for initial cortisol levels. Animal model of differential susceptibility to stress in development: implications for schizophrenia Rationale/ statement of the problem: Common gene variants predisposing for altered dopamine (DA) neurotransmission are candidates for schizophrenia-susceptibility genes, although genome-wide studies so far showed a weak association of these variants with schizophrenia. It has actually become apparent that the expression of psychotic symptoms in schizophrenia is associated with the exposure of the genetically predisposed individuals to environmental risk factors during development such as early life adversity and upbringing in an unfavorable social environment. Furthermore, it has been postulated that genetic predisposition can promote not only vulnerability in response to negative environmental input, but also resilience in response to positive environmental stimulation. Methods: We decided to test this hypothesis in the apomorphine-susceptible (APO-SUS) rat line, which was selected from Wistar rats on the basis of an extremely enhanced stereotypic gnawing response to administration of the dopamine agonist, apomorphine (APO-gnawing). The parental strain was used for comparison. Adult rats exposed as pups to poor maternal care and to post-weaning social-isolation rearing were examined for pre-pulse inhibition of acoustic startle (PPI), T-maze spontaneous alternation, contextual fear-conditioning and stress hormonal responses to a conditioned emotional stressor. Results: Adult APO-SUS rats that had experienced poor maternal care as judged from low maternal licking and grooming (LG) scores showed dramatically enhanced stress-induced ACTH levels in the face of modest increases in circulating corticosterone (CORT) and prolactin levels. These low LG offspring also developed a basal PPI-deficit, reduced acoustic startle and impaired contextual fear-conditioning, but showed enhanced short-term memory. Additional isolation rearing abolished entirely basal PPI and impaired short-term memory in these individuals. High LG offspring, on the contrary, displayed enhanced PPI in both rearing conditions that was reduced only after CORT-challenge, while the low LG was resistant to CORT. Maternal LG history alone in Wistar rats had limited effects on the behaviour or stress response of offspring. When low maternal LG history was combined with postweaning social isolation, basal APO-gnawing was decreased and PPI increased. High LG offspring reared in isolation displayed, however, the highest APO-gnawing and the lowest PPI levels among rats reared in social isolation. An injection of high dose CORT in the adult low LG offspring reduced PPI, whereas the high LG group was resistant to the acute effects of CORT. Conclusion: If exposure to negative social environment accumulates, a schizophrenia-like phenotype, characterized by a severe deficit in sensorimotor gating and brain glucocorticoid-resistance, precipitates in the genetically predisposed individuals while the non-predisposed individuals are resilient. However, the same genetically predisposed individuals are sensitive to positive environment as well, where they improve their phenotype and outperform the controls, which do not change. This is the first animal model to find strong evidence for a differential susceptibility to stress in development depending on genetic predisposition.

Early life obesity, maternal depression, and telomere length in Latino children
Telomere length (TL) is an important marker of cellular aging that can be examined from birth to death and provide information about health status and disease risk. TL shortens in early childhood with the majority of the shortening occurring by age 4. TL is associated with stress and obesity in adults. It is possible that exposure to early life stressors and excess adiposity from birth and the first year of life may impact the rate of telomere shortening. Few studies have examined TL in the first years of life, and none of them have examined stress and obesity in infants. We examined TL by qPCR using genomic DNA from dried blood spots in a sample of 109 four-year-old, lowincome Latino children and their mothers. TL is expressed as T/S (the ratio of telomeric product vs. single copy gene product). This group of children and their mothers were recruited prenatally in San Francisco at which time socio-demographic and health history was assessed. In addition, child weight and length and maternal body mass index (BMI) have been assessed annually from birth with the child's weight and length measured also at birth and 6 months of age. Maternal depressive symptoms were assessed prenatally, at 4Á6 weeks postpartum and annually throughout the follow-up period. Child behavior was evaluated using the child behavior checklist (CBCL) at 3 and 4 years of age for internalizing and externalizing behaviors. Student's t-tests were performed to compare TL in relationship to different childhood exposures Á maternal depression, child overweight and obesity, and socio-demographic factors such as child sex, ethnicity, and socioeconomic status. Factors that were significant at pB0.10 were subsequently entered into a multivariate regression model to evaluate independent predictors for shortened TL. In bivariate analysis, being obese at 6 months of age (weight/length ]95th percentile) and being obese at both 6 and 12 months of age were associated with shorter TL at age 4 (1.6290.36 versus 1.8490.34, p00.02 and 1.449 0.30 versus 1.8290.34, p00.02, respectively). Exposure to maternal depressive symptoms at age 3 was also associated with shorter TL (1.6690.25 versus 1.8190.33, p 00.07). Children of Mexican descent tended to have longer telomeres than those of Central American ancestry (1.8590.31 versus 1.7390.38, p B0.07). Exposure to maternal depressive symptoms at other timepoints in early childhood and internalizing or externalizing behavior was not associated with shorter TL. In linear multiple regression analysis, female sex (Coeff00.18, 95%CI: 0.04Á 0.31) as and maternal TL (Coeff00.18, 95% CI: 0.04Á0.31) predicted longer TL, whereas being obese at 6 and 12 months (Coeff0(0.49, 95% CI: (0.79 to 0.19) predicted shorter TL.
In this population of low-income Latino children, obesity in the first year of life was associated with shorter telomere length at age 4, independent of sex mother's TL and mother's depression. Thus, obesity early in life may shape TL, whereas obesity in the toddler and preschool years may be less associated with obesity at age 4. Childhood trauma (CT) is associated with mood and anxiety disorders in adulthood, especially with posttraumatic stress disorder (PTSD). These disorders frequently co-occur, yet few PTSD comorbidity studies have focused on samples with a range of CT severity and none have included participants with adulthood-only trauma in the same study. We investigated SCID diagnoses of comorbid mood and anxiety disorders among 69 adult PTSD patients (M age 037.94, SD 011.13; 53.6% female), with CT exposures (CTQ scores) ranging from absent to extreme. The CAPS and QIDS-SR measured PTSD and depression severity, respectively. Total CT exposure correlated with having at least one comorbid anxiety disorder diagnosis (r pb 0.42, p B.001) and logistic regression indicated that CT exposure predicted comorbid anxiety disorder diagnosis after controlling for demographics, mood disorder, and PTSD severity. Significant correlations were also identified between particular CT subtypes and the presence of a comorbid anxiety disorder. Total CT exposure did not predict current or past mood disorder diagnosis or depression severity. These findings support a relationship between CT and the presence of additional anxiety disorders in adult patients with PTSD, and highlight the need for thorough diagnostic assessment and special treatment planning to address the full spectrum of psychopathology in adult PTSD patients with significant histories of CT. Systems biology of post-traumatic stress disorder: characterization of pathways and networks involved in the development of PTSD Rationale: Life-threatening experiences, including the observations of severe trauma and/or violence, coupled with feelings of extreme fear and helplessness can result in posttraumatic stress disorder (PTSD). Unpredictability, uncontrollability, and novelty are considered key factors in eliciting and influencing the intensities of the stress responses. Personal coping strategies may affect resilience and susceptibility to stressors and, in PTSD patients, may also affect responses to stressors such as cortisol secretion. Recent interest in PTSD models focuses on the drivers of susceptibility versus resilience factors and the identification of potential targets for prevention and/or treatment of PTSD. Following a traumatic event, most individuals experience at least some symptoms of PTSD. However, many trauma survivors who develop PTSD recover over the course of months. Methods: Systems and integrative biology approaches were applied to characterize the development of PTSD using an animal model of repeated social trauma/stress. Behavioral, physiological, and histopathological consequences of repeated social stress were evaluated using a modified ''6 hour box-in-box resident-intruder'' model. At the end of the stress episodes, mouse blood samples and organs were collected and brains were dissected into 17 different regions. Transciptomic, metabolomic, proteomic, and epigenomic changes were analyzed using microarrays. Results: Pan-omic analyses of this mouse model that simulate aspects of PTSD revealed that genes involved in axonal guidance signaling, apoptosis, inflammation, corticotropin releasing hormone signaling, synaptic long-term depression, dendritic branching, and cardiac hypertrophy were upregulated in stressed mice compared to the control. Suppressed transcripts were involved in synaptic long-term potentiation, lymphocyte activation, gap junction signaling, and glucocorticoid receptor pathway. Nicotine exposure results in food consumption differences between adolescent and adult female mice Background: Individuals with disordered eating have the highest mortality rate of any psychiatric disorder and females make up the majority of the eating disordered population. Tobacco smokers have lower BMIs than do their non-smoking counterparts, and adolescent and adult females report using tobacco to lose or maintain body weight. Multiple biobehavioural factors contribute to this nicotine-body weight relationship, rodent studies suggest that reduced food intake following nicotine exposure may be a primary factor.
Objective: To examine the effects of nicotine on body weight changes in response to different food types. Methods: We used an oral nicotine administration paradigm to investigate body weight changes in the presence of standard chow, high sweet and high fat foods in adolescent (N063) and adult (N060) female C57BL/6J mice. Mice were exposed to nicotine (200 mg/ml) or water along with one of three food types for 7 days. Results: Adult mice weighed more but ate less food than did adolescents (pB0.05). Mice exposed to high fat food weighed the most, but ate the least (pB0.05). While there were no main effects of nicotine on body weight in either age group, nicotine-exposed adults consumed less food than did water-exposed adults (pB0.05), this effect was not seen in adolescents. Among the nicotine-exposed mice, adolescents consumed more food than did adults (pB0.05). Conclusions: These findings suggest, in females, the appetite suppression qualities of nicotine differ based on age, with nicotine exposure actually increasing food consumption in adolescents. Nicotine's effects on food intake do not result in body weight changes in either age group. Altered glucocorticoid action in obese pregnancy is modulated by diet and is associated with gestational weight gain but has similar influences on birthweight in males and females Rationale/ statement of the problem: One in five UK women is obese at antenatal booking. Maternal obesity increases risk of offspring obesity, behavioural and metabolic disorders. Animal studies suggest male offspring are more vulnerable to these effects than females. We hypothesised that this is mediated by altered action of maternal glucocorticoids, key regulators of development and stimulators of appetite and weight gain. Methods: Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n 0156 class III obese (BMI!40 kg/m 2 ) and n087 lean (BMIB25 kg/m 2 ) pregnant women. mRNA levels of 11-beta hydroxysteroid dehydrogenase type 2 (11bHSD2), which inactivates cortisol, were measured in n036 first trimester and n061 term placental samples. Results: Cortisol levels were significantly lower throughout pregnancy in obese than lean (p B0.05) Obese reported similar appetite and total calorie intake to lean but had significantly less gestational weight gain (10.193.7 kg vs. 5.595.6 kg, p B0.01); this inversely correlated with cortisol levels (r 0(0.27, p B0.01). Cortisol levels correlated positively with reported pregnancy intake of protein, fat, saturated fatty acids and sugars in lean (all p B0.05). Placental expression of 11bHSD2 increased in association with increasing obesity in early pregnancy (r 00.21, pB0.01) and was highest in term placenta in obese women with macrosomic (!4000 g) offspring (pB0.05). There were no gender-specific effects of maternal overnutrition on birthweight, placental gene expression or maternal glucocorticoid levels. Conclusions: Lower circulating cortisol levels in obese pregnancy, together with the more effective placental barrier to maternal glucocorticoids may be a mechanism contributing to higher birthweight in offspring of obese women. In lean women, dietary composition may regulate cortisol levels during pregnancy. Sex differences in fear conditioning: a role of the forebrain mineralocorticoid receptor Rationale: A recent study showed that a mineralocorticoid receptor (MR) gene variant, MR haplotype 2, was associated with higher levels of dispositional optimism, less thoughts of hopelessness, and lower risk of depression in women but not in men. Mice lacking the MR in the forebrain, MR CaMKCre mice, were generated to further investigate behavioral sex differences with and without the MR. Here, the hypothesis that sex differences would disappear after deletion of the MR was tested. Methods: We used male (n 08Á9) and female (n 09Á14) MR CaMKCre mice and control littermates to study fear conditioning, memory performance, and extinction. The fear-conditioning paradigm assessed both context-and cue-related fear within one experimental procedure. Results: At the end of the conditioning, all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MR CaMKCre mice remembered and feared the context more than the control mice. Furthermore, female MR CaMKCre mice were not able to extinguish this memory even on the second day of memory testing. The female mutants could also not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MR CaMKCre and control mice showed extinction and were capable to discriminate, although extinction of the MR CaMKCre mice started slower. Conclusion: The loss of forebrain MR does not eliminate sex differences but rather results in large differences in emotional and cognitive behaviors between female and male mice. This finding suggests a role of this receptor in the female prevalence of stress-and anxiety-regulated disorders. Rationale/ statement of the problem: Adverse exposures that influence growth in prenatal and early postnatal periods are thought to influence vulnerability to chronic diseases via their effects on the neuroendocrine system. In humans, assessment of the underlying mechanisms has been restricted. The aim of the present study was to investigate the effects of adverse early life exposures, specifically maternal mood, on hypothalamicÁpituitaryÁ adrenal (HPA) axis, sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) responses to an acute physiological stressor. In addition, we conducted a preliminary examination into whether effects varied by time of exposure and sex. Methods: A total of 139 individuals (mean age 15.12 years) were recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants underwent the CO 2 stress test, and indices of the PNS, SNS and HPA axis were measured. Pre-existing data on mothers' demographic and psychosocial factors during pregnancy (18 and 32 weeks) and postnatally (8 weeks and 8 months) were extracted, as were participants' clinical and demographic data at birth. Results: Increases in both prenatal and postnatal anxiety and depression were associated with greater SNS reactivity to the stressor and slower recovery, as well as blunted HPA axis responses. Programming effects on the SNS appeared restricted to male offspring only. No consistent relationships were evident for any of the measures of pre-stress function. Conclusion: We have found preliminary evidence that both pre-and postnatal maternal anxiety and depression have sustained programming effects on the SNS and HPA axis. Effects on the SNS were restricted to male offspring. The lingering effect of childhood socioeconomic status: parental education predicts diurnal cortisol trajectory in adulthood Socioeconomic disadvantage during childhood has lasting effects on adult health. Children raised by less educated parents are at higher risk for later cardiovascular disease (CVD), Alzheimer's disease, and type 2 diabetes mellitus. The mechanisms through which childhood socioeconomic status (SES) affect health are unclear. Childhood SES may shape stress physiology, including neuroendocrine processes, which may negatively impact health in adulthood. Prior literature shows that less educated individuals have flatter cortisol slopes across the day compared to those higher in education. Flattened slopes have been linked to chronic stress, CVD outcomes, breast cancer mortality, and both all-cause and CVD mortality. It is unknown whether one's childhood SES, approximated by parental education level, predicts diurnal cortisol trajectories independent of one's individual education. To this end, we recruited 20 Black and 20 White women who previously participated in the National Heart, Lung, and Blood Institute (NHLBI)-supported National Growth and Health Study (NGHS) to complete a daily stress assessment, which included salivary cortisol sampling at four times per day over two consecutive days. Mixed modeling indicated that cortisol slope across the day was a function of individual education (b time)individual education 0(0.04, SE 00.02, p00.045). Simple slope analyses revealed that women with only a high school diploma had significantly flatter cortisol slopes (b 0(0.22, SE 00.06, pB0.001) than those with more than a high school diploma (b 0(0.26, SE 00.02, p B0.001). Cortisol slopes were also a function of parental education (b time*parental education 0(0.04, SE 00.02, p 00.038). Simple slopes analyses revealed that women with parents who received only high school educations had significantly flatter cortisol slopes (b0(0.20, SE 00.06, p B0.001) compared to those with parents who received more than a high school diploma (b 0(0.24, SE 00.02, p B0.001). Importantly, the effect of parental education was independent of individual education. These findings provide preliminary evidence that parental education, a marker of childhood SES, can influence neuroendocrine activity beyond childhood, having lasting effects into adulthood with important implications for health. Tricyclic antidepressants, autonomic function and mortality in patients with coronary heart disease: data from the heart and soul study Rationale/ statement of the problem: Although tricyclic antidepressants (TCAs) are not recommended as first line therapy for depression in patients with coronary heart disease (CHD), they are still occasionally prescribed. Rationales may include resistance to other classes of antidepressants, previous response to TCAs, or treatment continuation after onset of a CHD. Despite their antidepressive effectiveness, TCAs may worsen cardiovascular prognosis because of autonomic side effects. Here, we examined potential adverse effects of TCAs on autonomic function as marked by heart rate variability (HRV) and norepinephrine (NE) levels.
Methods: A total of 956 outpatients with stable CHD, 44 used TCAs. All patients were prospectively followed for 7.292.6 years. Standard deviation of all normal RR intervals (SDNN) as a measure of HRV was calculated from 24 h-electrocardiographic recordings. NE levels were measured in plasma and 24 h-urinary samples. We also calculated hazard ratios for all-cause mortality. Results: Users of TCAs had an increased risk of mortality compared to non-users (p 00.02 in an unadjusted model, p00.01 in a model adjusted for age, sex, smoking, diabetes, congestive heart failure and depressive symptoms). When additionally adjusted for HRV and plasma NE, there was no significant association of TCA use and mortality. TCA users had an increased risk of being in the lowest tertile of HRV (pB0.01) and in the highest tertile of urinary NE (pB0.01) and plasma NE (p B0.01). Adjustment for age, sex, smoking, diabetes, congestive heart failure and depressive symptoms did not significantly change the results. Conclusion: Use of TCAs was associated with increased mortality in patients with CHD. Unfavourable changes in autonomic function as marked by low HRV and high NE levels might be a potential mechanism.
Keywords: depression; coronary heart disease; tricyclic antidepressants; heart rate variability; norepinephrine Cortisol awakening response is associated with hippocampus-dependent cognitive impairment in major depression Rationale: Cognitive deficits and alterations in cortisol secretion are characteristic features of major depression disorder (MDD). The cortisol awakening response (CAR) is altered in depression and crucially depends on hippocampus function, a brain area closely related to cognitive function. Methods: We examined 21 MDD patients without medication, 20 MDD patients treated with antidepressants, and 41 healthy control subjects (HC), matched for age, gender, and years of education. We applied several neuropsychological tests. Salivary cortisol levels were measured on two consecutive days at awakening, and 30 min and 60 min after awaking. Results: Both patient groups did not differ in severity of depression (p 00.20). Analysis of variance (ANOVA) with CAR as dependant variable revealed a significant effect of group (p 00.01). Post-hoc tests confirmed that medicated patients exhibited a smaller CAR compared to unmedicated patients (p 00.04) and HC (p 00.01), whereas differences between unmedicated patients and HC were not significant. ANOVA for Auditory Verbal Learning Task total score revealed a significant effect of group (p00.03). Post hoc tests confirmed that unmedicated patients were significantly impaired in verbal memory (p00.01) whereas medicated patients were impaired on trend-level (p00.09) when compared to HC. Differences between both patients groups were not statistically significant. Repeated-measures ANOVA revealed a significant effect for group (p00.04) regarding non-verbal memory as measured with the Rey figure. Post hoc tests showed that unmedicated patients were significantly impaired compared to medicated patients (p00.02) and compared to HC (p00.06), whereas medicated patients and HC did not differ (p 00.32). In depressed patients, but not in HC, we found a negative correlation between CAR and memory function, which was driven by the unmedicated depressed patients. Conclusion: The magnitude of the CAR is strongly associated with impaired memory function in unmedicated depressed patients even though CAR was not significantly increased in these patients. In contrast, medicated patients showed a blunted CAR and unimpaired cognitive function compared to controls. These results suggest that antidepressant treatment may reduce CAR and partially restore memory function even if depressive psychopathology is still present. Cortisol is associated with longer telomeres in human lymphocytes cultured in folate-replete and deficient conditions Background: Telomeres cap and protect the ends of chromosomes from fusion. Excessively shortened telomeres are associated with telomere dysfunction and chromosomal instability (CIN), DNA damage and an increased risk of degenerative diseases of ageing. Psychological stress has been strongly associated with accelerated telomere shortening, consistent with a wealth of evidence that chronic stress impacts negatively on health, possibly contributing to initiation of cancers, cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease. Risk for these disorders is increased by deficiency in micronutrients, such as folate, an essential co-factor required for accurate replication of DNA and maintenance of methylation (epigenome) patterns, providing protection against CIN. Methods: The aim of this preliminary study was to test the hypothesis that chronic exposure to the stress hormone cortisol impacts deleteriously on telomere length (TL) and that this effect would be further aggravated by folate (Vitamin B9) deficiency. Human lymphocytes from 3 males and 3 females (aged 5393 years) were cultured in vitro for 12 days in medium containing either 25 or 120 nM folic acid (FA), together with either 0, 550, 1300 or 3500 nM cortisol. TL (by QFISH flow cytometry), cell growth and viability were measured. Results: Cells cultured in FA-replete medium and chronically exposed to 550 or 1300 nM cortisol displayed longer TL at day 12 than cortisol-free controls (p B0.03). In FA-deficient cultures TL increased with increasing cortisol, however, this effect was not significant in this sample size. TL was longer in lymphocytes cultured in low FA conditions, compared with those in FA-replete medium (p B0.0001). The strongest cell growth was recorded in FA-replete cultures, with cortisol having no effect. Cell viability (%) was higher in cells exposed to cortisol, and this effect was strongest in FA-deficient cultures, with 16% of variance being attributable to treatment (p00.0002), and 72% to time (p B0.0001). Conclusions: The results of this study do not support the hypothesis that cortisol, folate deficiency or their interaction can explain telomere shortening associated with psychological stress. Further analyses are being performed to determine if cortisol causes changes in CIN or epigenome status and the extent to which these effects correlate with TL. The effect of intranasal oxytocin on perceiving and understanding emotion on the Mayer-Salovey-Caruso Emotional Intelligence Test Background: There is increasing evidence that oxytocin promotes empathy in humans. However, research on oxytocin and emotion recognition, a fundamental component of empathy, has yielded inconsistent results. Part of the problem is that studies have focused on limited, and varying, categories of emotional stimuli. Therefore, we investigated the effect of intranasal oxytocin on the identification of seven basic emotions (happiness, sadness, fear, excitement, surprise, disgust, and anger) using social and non-social stimuli, and we explored the effect of oxytocin on conceptual understanding of emotion. Method: Eighty-two participants were administered a 24IU dose of intranasal oxytocin or placebo in a doubleblind experiment. Participants completed the perceiving (faces, designs) and understanding (blends, changes) emotion components of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) 120 minutes after drug administration. Results: Contrary to our prediction, standardized scores for accurately detecting emotions during the faces task of the MSCEIT were lower following oxytocin administration than placebo (F(1,80) 08.861, p B.01, h 2 0.10). Accuracy ratings worsened following oxytocin because participants rated all emotions with greater intensity, particularly facial expressions of surprise and disgust. Oxytocin did not influence performance on tasks related to understanding emotions or tasks using non-social stimuli.
Conclusions: Oxytocin appears to influence the recognition of facial expressions of emotion by increasing the perceived intensity of the emotion, while having no effect on more complex processing (i.e., understanding emotion). The present findings further support the view that oxytocin influences social information processing by increasing the salience of emotional stimuli, which may have positive or negative effects depending on context. Methylphenidate does not restore the reduced serum BDNF levels in ADHD children Statement of the problem: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of trophic factors, which is the most abundant neurotrophin in the brain. BDNF exerts its effects by binding to the tropomyosin-related kinase B (TrkB) receptor. It enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in mechanisms of neuronal plasticity, such as long-term potentiation and learning. We aim to quantify the basal concentration and daily fluctuation of serum BDNF, as well as its possible change in response to prolonged release methylphenidate in an open, quasiexperimental and controlled study.
Methods: A total of 148 (115 males, 33 females) patients, of 9.77 (256) years old, were subdivided in two group. (1) Control group (n 037; 27 males, 10 females); healthy siblings of the Attention deficit hyperactivity disorder (ADHD) patients. (2) ADHD group (n 0111; 88 males, 23 females), without epilepsy and with a normal value in an abbreviated intelligence test Kaufman Brief Intelligence Test (KBIT). In all subjects, after written informed consent, we performed identical clinical, psychometric and biochemical study, before and after (only ADHD group) treatment. ADHD group were diagnosed according Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and sub-classified in the primary ADHD subtypes by EDAH scale. Measurement: BDNF by ELISA (IBL International, ref. RB59041), in serum samples obtained at 09:00 and 20:00 h, before and after 4,63 (2,3) months of the daily morning ingestion of PRMPH. Statistic: factorial analyses using statistical package STATA 12.0. Funding: Grant of Spanish government, FIS-PI07-0603.

Results:
Serum BDNF (ng/ml) in ADHD children

Different basal concentration and different response of BDNF to prolonged release methylphenidate between ADHD subtypes
Statement of the problem: Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophic receptors, appears to intervene in the pathogenesis and treatment response in Attention deficit hyperactivity disorder (ADHD), hypothesis based on the conceptualization of ADHD as a neurodevelopmental disorder and the importance of the BDNF for normal neural development. In addition, in experimental models, psychostimulants and antidepressants increase the brain concentration of BDNF. Genetic polymorphisms related with the activity of the BDNF seem to correlate with the incidence, clinical manifestations, endophenotypes or the treatment response in ADHD. We aim to define if the response to prolonged release methylphenidate treatment is different in the main ADHD subtypes, in an open, quasi-experimental and controlled study. Our results show both similar morning concentrations and daily fluctuation of BDNF, between predominantly inattentive ADHD children and healthy sibling controls. The PRMPH treatment does not modify the reduced BDNF concentration (vs. controls) in hyperactive/conduct disorder children, nor the absence of daily fluctuation; but contrary to expectation reduces the concentration in the predominantly inattentive patients to values similar to that observed at night, disappearing the highly significant basal day/night fluctuation also noted in the control group. Conclusion: Besides our data in hyperactive/conduct disorder children has been reported that the major depression is also associated with a decrease in BDNF concentration. As serum BDNF seem parallel with intra-cerebral concentration, especially in messencephalic areas, this neurotrophin could be the link between ADHD and major depression, and provide a new pathway for the development of drugs for ADHD. ''Differential effects of three classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats'' Ratioanle/ statement of the problem: The second generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, there is an increasing awareness that the use of the drug is commonly associated with serious metabolic side-effects in patients, including hyperglycemia, glucose intolerance and insulin resistance, and places patients at risk for developing cardiometabolic disorders, such as Type 2 diabetes. These side effects have been accurately modelled in rodent paradigms. We and other groups have demonstrated previously that olanzapine causes significant glucose intolerance and insulin resistance in rats.
Methods: In the present study, we directly compared three distinct classes of antidiabetic drugs, which included metformin (100 and 500 mg/kg, PO), rosiglitazone (6 and 30 mg/kg, PO) and glyburide (2 and 20 mg/kg, PO), on olanzapine-induced glucose dysregulation and insulin resistance. Adult female rats (n 08Á10 per group) were acutely treated with lower (7.5 mg/kg) or higher (15.0 mg/kg) doses of olanzapine, and glucose intolerance was assessed using the glucose tolerance test, while insulin resistance was measured using the HOMA-IR equation.
Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance that were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse olanzapine-induced glucose intolerance, despite significantly increasing insulin levels.
Conclusion: These findings indicate that oral hypoglycemic drugs which influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than those affecting primarily insulin secretion, such as glyburide. The current model may also be used to better understand the biological mechanism of glucose dysregulation caused by olanzapine and how it can be reversed. Mothers were asked to complete several questionnaires and were sent a ''cortisol packet'' with instructions to obtain child saliva samples when they awoke (T1) and 45 minutes later (T2) across 2 days. ''Responders'' were identified as children whose cortisol levels increased from T1 to T2. Results: No difference in responder group by child age was found in this sample. It may suggest a step-like model, such that emergence of positive CARwould begin in infancy (38%: Saridjan, 2010) and that rates may start to increase only around age 10 (60%: Freitag, 2009) until they stabilize in adulthood (75%: Wust, 2000). In contrast to previous literature, methodological variables, such as daily routine and time between samples (Griefahn & Robens, 2011), were not significantly associated with responder status. However, results were consistent with Saridjan and colleagues (2010), demonstrating that lower family income was associated with greater likelihood of being a responder. Maternal psychopathology had no effect on child CAR status. Interestingly, for child-specific factors, internalizing and externalizing scores had the opposite effect such that, for every increase in externalizing score the risk of being in the responder group increased by 13.5%; however, for every increase in internalizing score, the risk of being a responder decreased by 10%.
Conclusions: Future research should aim to understand the effects of pure internalizing and externalizing versus comorbidity on cortisol in larger samples. The hypothalamus Á pituitary Á adrenal axis in patients with CRPS type 1: molar cortisol to DHEA ratio increases with disease duration Background: The main complaint symptom of complex regional pain syndrome type 1 (CRPS-1) is neuropathic pain. There is significant co-morbidity between neuropathic pain and neuropsychiatric disorders, including anxiety and depression. A decrease in dehydroepiandrosterone (DHEA) or increase in the molar cortisol to DHEA ratio (molar F/D ratio) is commonly found in patients with psychiatric disorders, such as major depression and posttraumatic stress disorder. However, no information about DHEA secretion is available for patients with CRPS-1. The present study determined the molar F/D ratio within the first hour after awakening in patients with CRPS-1 undergoing combined antidepressant treatment with analgesics and non-steroidal antiinflammatory drugs. Method: To do this, cortisol and DHEA concentrations were determined from saliva samples, which were collected immediately upon awakening, 30 and 60 min after awakening and at nighttime from patients with CRPS-1 (n026) and age-matched healthy subjects (n 025). The beck depression inventory (BDI) was used to quantify depression levels in the medicated patients. The net increase in cortisol levels within the first hour after awakening (CARi) and the area under the cortisol curve with respect to ground within the first hour after awakening (CARauc) were calculated and used as an index of cortisol secretion. The area under the DHEA curve with respect to ground within the first hour after awakening (DHEAauc) was used as an index of DHEA secretion.
Results: The mean BDI scores of patients were 19.099.0 (range, 5Á41). The BDI scores were not associated with any parameters for cortisol, DHEA secretion or other disease-related parameters such as disease duration, frequency of spontaneous pain, or extension of disease spread. We did not observe a difference in indices for cortisol and DHEA secretion between patients who had a value higher than the cut-off for chronic pain (BDI score 21, n 010) or patients who had lower than cut off BDI scores (n016). Among indices for cortisol and DHEA secretion, the molar CARauc to DHEAauc (molar F/D auc ) ratio was associated with disease duration. Patients who suffered from disease for relatively longer time (subgroup 4 month 5) had a higher molar F/D auc ratio than both controls and patients who suffered for a relatively shorter time (subgroup 4 month ]). There was no difference in BDI scores between subgroups. Conclusion: We used combined analgesic treatment with tricyclic antidepressants, anticonvulsants and nonsteroidal anti-inflammatory drugs to relieve pain and pain-related symptoms, such as depression, in patients with CRPS-1, but these results indicate that DHEA secretion after the awakening period decreases in the combined treatment condition. Changes in prolactin levels and sexual functioning after switching from long-acting injectable risperidone to paliperidone palmitate in young psychotic patients: a case series Statement of the problem: Long-acting injectable (LAI) antipsychotics have been developed to increase compliance in schizophrenia. Risperidone-LAI was the first LAI atypical antipsychotic, as a biweekly injection. Paliperidone Palmitate (PP) is a recently developed LAI atypical antipsychotic that is administered monthly. PP is hydrolized to paliperidone (9-hydroxyrisperidone), the primary active metabolite of risperidone. Although both risperidone and paliperidone are associated with increases in prolactin levels, there is limited information regarding whether there are differences in sexual functioning between both compounds. We aimed to study whether there are changes in prolactin levels and/or sexual function after switching from LAI-risperidone to LAI-paliperidone. Methods: We have studied 12 psychopathologically stable subjects with a psychotic disorder (n 010 schizophrenia, 1 schizoaffective, 1 psychosis N.O.S.) attending to the Early Psychosis Program from Reus (HPU Institut Pere Mata, Spain) treated with long-acting risperidone for at least 6 months. All participants were switched to LAI. Clinical assessment was conducted at baseline and 3 months after the switch with measures of psychopathological status (Positive and Negative Symptom Scale [PANSS], Calgary Depression Scale) and sexual dysfuncion (Arizona Sexual Experiences Scale [ASEX]). Two fasting blood samples (baseline and 3 months post-switch) were obtained to determine prolactin levels in plasma. SPSS version 17.0 was used to perform the statistical analyses. Wilcoxon test was used to explore changes in continuous variables (e.g. prolactin levels, ASEX scores) during the period of the study. A p-valueB0.05 was considered to be significant.
Results: There was a significant reduction in prolactin levels from baseline to the 3-month assessment. Those subjects with higher prolactin levels seemed to show a greater reduction. In relation to sexual dysfunction, although some cases improved notably in ASEX scores, the reduction was not significant in all the samples. None of the Methods: Longitudinal data from 346 youth (171 males) were used to examine these associations. MD was measured during infancy and preschool with the Center for Epidemiologic Studies Depression scale. Morning levels of cortisol, dehydroepiandrosterone (DHEA), and testosterone were assessed at age 15 years. Internalizing and externalizing at 15, 16, 17, and 18 years were assessed with multi-informant report on the MacArthur Health and Behaviors Questionnaire using variables measuring number of symptoms (severity) and preponderance of one symptom type over the other (directionality). A two-level hierarchical linear model examined how neuroendocrine measures, early MD, and sex independently and jointly influenced mental health trajectories. Results: For severity, a two-way interaction (B 0(0.095, t0(2.25, p B0.05) revealed that adolescents with high cortisol-low DHEA had more mental health symptoms and a significant three-way interaction (B 0(0.019, t0(2.05, p B0.05) revealed that adolescents exposed to early MD with high cortisol-high DHEA also displayed more symptoms. A significant three-way interaction (B 0(0.213, t0(2.01, p B0.05) revealed that girls with high cortisol-low testosterone displayed elevated mental health symptoms and a significant four-way interaction (B 0(0.080, t 0(2.60, p00.01) revealed that girls exposed to early MD with low cortisol and high testosterone also displayed increased mental health symptoms. Directionality findings revealed altered hormone patterns predicted internalizing symptoms for girls but externalizing for boys. Conclusions: Results support the benefits of examining multiple hormones in the prediction of mental health problems and suggest additional hormone risk patterns are present in individuals exposed to early life MD.

Serotonin 2c receptor gene expression in the rhesus amygdala predicts anxious temperament
Rationale/ statement of the problem: In the central nervous system, the serotonin (5HT) neurotransmitter system plays a key role in the regulation of mood and emotion. Alterations in the 5HT system are thought to contribute to psychopathologies. In addition, drugs targeting the 5HT system are effective in the treatment of depression and anxiety disorders. Children with anxious temperament (AT) are characterized by excessive shyness, worrying, and avoidant behavior. This temperament, when stable across development, increases the risk of later developing depression and anxiety disorders. Using a well-established, nonhuman primate model of AT, we tested whether variations in the 5HT system predict individual differences in AT. We focused on the central nucleus region of the amygdala (CeA) because we have established that metabolic activity in this region is predictive of AT. Methods: Using Affymetrix GeneChip † rhesus macaque genome arrays, we assessed gene expression from CeA tissue in 24 young male rhesus monkeys phenotyped for AT. Robust regression analysis was performed with correction for multiple comparisons across all annotated transcripts that are part of the neuroactive ligand pathway (KO04080) in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: As hypothesized, variation in gene expression predicted individual differences in AT. Specifically, of the thirteen 5HT receptors assessed, only the 5HT2C receptor (5HT2C; r 0(0.57, p B0.01) was identified in the microarray analysis as significantly negatively correlated with AT. Quantitative real-time polymerase chain reaction analysis using the same CeA RNA samples confirmed this association (r0(0.65, p B0.001). Underscoring the anatomical specificity of this effect, the significant relationship between 5HT2C receptor mRNA levels and AT was not observed in the motor cortex, a brain region not associated with AT (r00.10, p 00.64). Conclusions: Previous work by others has shown robust levels of 5HT2C receptor mRNA and radioligand binding in the monkey CeA. In addition, rodent models have indicated a role for the 5HT2C receptor in anxiety-like responding. Our findings suggest that higher levels of 5HT2C receptor gene expression are associated with lower levels of AT. Increased expression of the gene encoding for this receptor may facilitate 5HT signaling in the amygdala thereby promoting adaptive responses and resilience to potentially anxiety provoking situations. Rationale: Although pessimistic individuals are at increased risk for developing cardiovascular disease, the biological mechanisms underlying this effect, and the social-environmental factors that modify these effects, remain unclear. To address this issue, we examined how pessimism, defined as the generalized tendency to expect negative outcomes, interacts with life stress exposure to predict metabolic health.
Methods: Seventy-one pre-menopausal mothers (35 had a child with autism and 36 did not Á participated in the study. They ranged from 28 to 51 years-old (M 041.3, SD05.1), had body mass indices from 17.2 to 43 (M 025.58, SD05.76), and were free of major chronic illnesses, including diabetes and metabolic syndrome. Participants provided fasting blood samples, had their body measurements taken, completed the Life Orientation Test-Revised to assess their level of pessimism (M 06.37, SD 02.96) and the Stress and Adversity Inventory to assess their exposure to chronic stress over the life course (M 07.76, SD04.35). Participants' ''metabolic risk'' was indexed based on waist circumference, glucose, ratio of total cholesterol to HDL, triglyceride levels, and systolic blood pressure.
Results: As predicted, pessimism and cumulative life stress exposure were each independently associated with greater metabolic risk, independent of age, income and caregiver status (Pessimism: b 00.49, p B0.001; Stress: b 00.33, p00.003). Moreover, when adjusting for age, income and caregiver status, pessimism interacted with cumulative stress exposure to predict greater metabolic risk (F 07.29, p 00.01). Decomposing this interaction effect revealed that pessimistic individuals experiencing high levels of cumulative life stress had the poorest metabolic health.
Conclusions: These results suggest that pessimistic individuals living under high levels of stress may have the greatest risk for cardiovascular disease and highlight pessimistic beliefs as a possible treatment target for reducing stress-related disease burden. Lower heart rate variability is associated with cancer-related fatigue in breast cancer survivors Background: Fatigue is the most common and distressing symptom reported by breast cancer survivors and yet the pathophysiology of cancer-related fatigue remains largely unknown. Fatigue is associated with lower parasympathetic and higher sympathetic nervous system activity in non-cancer samples, but only one study has demonstrated this same relationship in breast cancer survivors. This study evaluates the relationship between fatigue and basal autonomic nervous system activity as measured by heart rate variability (HRV) in a sample of breast cancer survivors. Methods: Women who had been diagnosed with early stage breast cancer before the age of 50 were recruited from the UCLA tumor registry and completed psychological questionnaires, including measures of fatigue. A subset of these women (n 030) participated in a follow-up study in which they completed measures of fatigue, energy and mood four times per day for 5 days using electronic diaries, provided 3 days of saliva samples for cortisol assessment and underwent physiological assessment including electrocardiogram (ECG). HRV was assessed via ECG R-R wave spectral and time sequence analysis. Results: Questionnaire measures of fatigue were negatively associated with indices of parasympathetic nervous system activity, B 0(3.85, p 00.04 for RMSSD (root of the mean squared difference of successive normal to normal waves) and B 0(76.97, p 00.04 for LF power % (low-frequency wave power percentage). Daily fatigue was also associated with lower basal HRV, B 0(15.1, p 00.04 for RMSSD. However, fatigue indices were not associated with sympathetic nervous system activity as measured by low-to high-frequency wave ratio. Of note, fatigue was not associated with average daily cortisol output (AUC). Conclusions: Lower HRV has been associated with increased chronic inflammation, which is elevated in cancer survivors reporting persistent fatigue, thus providing insight into potential system interactions underlying the mechanisms for cancer-related fatigue. Gender-dependent effects of body esteem and appraisal on cortisol stress responses Background: The Social Self Preservation Theory posits that situations that threaten the 'social self' elicit shame which, in turn, is linked to cortisol stress response. Body esteem may be one predictor of the propensity to respond with shame to stress. Hence, the present study aimed at assessing whether body esteem is associated with cortisol stress responses, and further, whether this relationship is mediated by cognitive appraisals of challenge and threat. Methods: We exposed 44 participants (21 F, 2192 years) to the Trier Social Stress Test (TSST). Salivary cortisol was assessed at (1, '1, '10, '30, and '50 min. Body esteem (BE) as well as subscales addressing appearance, weight, and attribution of others' judgments were assessed with the Body Esteem Scale for Adolescents and Adults (BESAA). Appraisals of challenge and threat were assessed with the Primary and Secondary Appraisal Scale (PASA).
Results: While the TSST successfully elicited cortisol stress responses (F 06.85, p 00.001), hierarchical regression analysis revealed that females with low BE showed higher cortisol stress responses than females with high BE, while the opposite was true for males (b 00.44, p00.047). The same pattern was found for the two BE subscales addressing weight and overall appearance (b 00.42, p00.04; b 00.42, p 00.04), but not for the attribution subscale (p B0.24). Body esteem was also associated with challenge appraisals in a gender-dependent manner: males with high BE reported feeling less challenged, while females with high BE reported feeling more challenged (b 0(0.63, p00.005). Neither threat nor challenge scores were themselves linked to cortisol responses. Conclusions: Despite the strong social-evaluative component of our stress test, these findings suggest that how one feels about one's weight and overall physical appearance matters more than what one thinks others may think in this regard. Interestingly, those feelings and beliefs may be associated with gender differences in stress appraisal, such that for females, high BE may be stress protective, while for men, low BE may lead to disengagement from a stressful situation. Hyperprolactinemia and amenorrhea associated with risperidone normalized after switching to olanzapine: a case report Background: Hyperprolactinemia as one of the frequent adverse effects associated with the use of antipsychotics is often neglected but can interrupt the compliance of treatment (1,2). Antipsychotic-induced hyperprolactinemia in women with schizophrenia frequently results in menstrual dysfunction (3) despite its potential to block D2 receptors. However, little (or less?) is known about the effect of olanzapine on prolactin levels in women. Methods: Ms. S, military white-collar, a 35-year-old woman with psychosis, experienced amenorrhea shortly after beginning as well as during treatment with risperidone, 6 mg/day. Previously, she had been treated with haloperidol; she recalled one other occasion when her menses had ceased for 3 months. Before treatment with risperidone, however, Ms. S had been having regular monthly menstrual periods. Medical evaluation revealed an elevated serum prolactin level (100 ng/ml), a negative pregnancy test, and normal thyroid function tests. Magnetic resonance imaging showed no evidence of pituitary adenoma. Alternative treatment with olanzapine was initiated and titrated to 20 mg/day. Results: After 2 months of olanzapine treatment, Ms. S's monthly menses resumed. Serum prolactin levels, although still elevated, trended downward to 86 ng/ml and 52 ng/ml after 2 and 4 months of olanzapine treatment, respectively. Although she has olanzapine-induced weight gain, her psychiatric condition remained in remission.
Conclusions: There are clinical trials regarding improvement of hyperprolactinemia after switching to olanzapine (4). We reviewed a case in which risperidone-induced hyperprolactinemiaÁamenorrhea normalized without clinical worsening after switching to olanzapine. Amenorrhea associated with olanzapine normalized after switching to aripiprazole: a case report Background: Amenorrhea as one of frequent adverse effects associated with the use of atypical antipyschotics is often neglected but can interrupt the compliance of treatment. There are clinical trials regarding improvement of hyperprolactinemia after switching to olanzapine while some trials regarding the opposite and the improvement with aripiprazole. Aripiprazole is an antipsychotic with partial dopamine antagonism and agonism. Its advantageous side effect profile has been described earlier. We reviewed a case in which olanzapine induced amenorrhea normalized without clinical worsening after switching to aripiprazole. Methods: Ms. C, a 36-year-old woman with psychosis, developed menstrual dysfunction and galactorrhea soon after beginning a treatment of olanzapine, 20 mg/day. She reported having monthly menses before regimen. After 3 month of treatment, menses were absent and galactorrhea began. Ms. C was not pregnant. Her prolactin level was 157.20 ng/ml, and an MRI showed no sign of pituitary adenoma. Olanzapine medication was discontinued in the patients because of galactorrhea, and raised liver enzyme activities. Aripiprazole was initiated and titrated to 15 mg/day. Results: After 1 month of aripiprazole treatment, monthly menses resumed and galactorrhea resolved. The serum prolactin fell to a normal level (27.20 ng/ml). Ms. C's psychiatric condition improved and she has remission. Conclusions: Aripiprazole's reduced potential to elevate prolactin may provide a treatment advantage for women with schizophrenia. Moreover, since menstrual cycles may normalize during treatment with aripiprazole, women treated with this drug may have improved fertility when compared with women receiving typical antipsychotics and olanzapine. In this case, aripiprazole treatment resulted in reduction of serum prolactin levels and resolution of galactorrhea. Further studies will be required to assess the comparative effects of aripiprazole and other antipsychotics on prolactin levels and resolution of galactorrhea.
Keywords: aripiprazole; olanzapine; amenorrhea; treatment; psychosis Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 -http://dx.doi.org/10.3402/ejpt.v3i0.19337 Andrew Garton, Ivan Vargas, Paige Galecki, Nestor L. Lopez-Duran. University of Michigan, Ann Arbor, MI, USA Understanding the impact of sleep duration on cortisol awakening response during early adulthood Background: The impact of sleep on basal HypothalamicÁPituitaryÁAdrenal (HPA)-axis functioning has been well documented. Specifically, decreased sleep quality and quantity are associated with higher basal cortisol levels, one index of HPA-axis functioning. Few studies, however, have examined the impact of sleep quality and quantity on the cortisol awakening response (CAR), or the diurnal peak in cortisol that occurs shortly after awakening. Investigating this association is important given that a higher CAR is associated with an increased risk for mental and physical health problems. Therefore, the current study aims to further examine the relationship between sleep and CAR in order to gain a better understanding of sleep's impact on HPA-axis functioning. Methods: 58 undergraduate students (29 males; mean age018.74) were assessed over two consecutive mornings. Each morning, participants completed a daily sleep diary to assess self-reported sleep quality and total sleep time (TST) from the previous night. Saliva samples were used to obtain morning cortisol levels. Participants were asked to provide four saliva samples by spitting into salivettes. The first sample was obtained immediately after awakening. The following three samples were obtained at 30, 45, and 60 minutes after the first sample. Participants repeated this procedure on Day 2. Results: Multilevel growth curve modeling was used in order to examine the impact of sleep quality and quantity on CAR. Results from the current study demonstrate that TST, or the total minutes slept during the preceding night on each day was significantly associated with both the intercept and slope of the model. More specifically, lower TST was associated with lower cortisol levels at awakening (t05.40, p B0.0001), but a steeper post-awakening cortisol slope (t0(2.55, p 00.01). After accounting for TST, however, sleep quality did not significantly predict any parameters in the model. Conclusions: Contrary to prior research that has reported no or a small association between sleep duration and CAR, our study shows that participants with shorter sleep duration have lower cortisol levels at awakening and a faster rate of cortisol increase following awakening. Thus, these findings suggest that the amount a person sleeps may directly impact their diurnal cortisol pattern the subsequent morning.

Determination of steroid hormones in human hair as a retrospective biomarker with HPLC-MS/MS
Statement of the problem: The analysis of steroid hormones in hair is increasingly used in psychoneuroendocrinological research as a valid and easily implementable method for the retrospective assessment of cumulative longterm hormone secretion. To determine steroid hormone concentrations in hair, most laboratories have so far relied on immunochemical assays which are fast and easy to perform, but have a reduced reliability and analytical specificity due to cross-reactivity with other substances. Furthermore, immunoassay can only measure a single steroid at one time. By contrast, liquid chromatography tandem mass spectrometry (LC-MS/MS) has better specificity, sensitivity and reproducibility, and can measure a wide spectrum of steroid hormones simultaneously.
Conclusions: This LC-MS/MS method provides a highly specific analytical strategy for the detection of seven endogenous hormones in human hair and is thus likely to further enhance the accuracy of future research in this field. Distinct panicogenic activity of sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder Rationale: The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psycho vegetative symptoms pointing to different subtypes of panic disorder have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder. Methods: We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinin tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and age-and gender-matched healthy control subjects. To measure psychophysiological changes, we repeatedly administered the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal. Cardiovascular (heart rate and blood pressure) and neuroendocrine (ACTH, Cortisol and prolactin) data were recorded simultaneously.
Results: In patients with panic disorder, 18 out of 26 experienced a sodium lactate-or a CCK-4 induced panic attack. Lactate or CCK-4-induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder. (Analysis of sodium lactate-and CCK-4-induced changes of cardiovascular and neuroendocrine parameters is in progress at the moment and results will be presented).
Conclusions: The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges and may indicate differential response to specific therapeutic interventions as well. Acute psychosocial stress determines cognitive control states in dual-task performance Rationale/ statement of the problem: A major control demand in successful dual-task performance is the taskspecific separation of task-goal representations and of the related stimulus-response translation processes. Although these cognitive control processes of task shielding and the physiological effects of acute stress share substantial neural commonalities such as their relation to the prefrontal cortex (PFC), direct empirical evidence of how specific PFC-related cognitive control processes involved in dual-tasking are influenced by acute stress is still missing. Therefore, the present study investigated the impact of acute psychosocial stress on task shielding in dual-task performance. Methods: Fifty-six healthy subjects were exposed to either an acute psychosocial stressor (the Trier Social Stress Test) or a standardised control situation prior to a dual task. The individual physiological stress response was monitored by analysing salivary a-amylase (sAA) and cortisol as markers of sympathetic nervous-system and hypothalamusÁpituitaryÁadrenal (HPA-)axis activity, respectively. Task shielding was assessed by the amount of interference of Task 2 processing on prioritised Task 1 performance (between-task interference). Results: Following successful stress induction, as indicated by increases in sAA and cortisol, stressed individuals displayed increased between-task interference relative to controls. This result was further substantiated by a correlation between treatment-related increase in cortisol, but not sAA, and between-task interference. Conclusion: Acute psychosocial stress reduces task shielding, and thus allows for more between-task interference in dual-task performance. We interpret this finding as a shift in cognitive control states from a more serial resourcedemanding to a more parallel resource-efficient task-processing mode. The results further suggest a potential role of the HPA-stress response for the development of the observed control adjustment. Depressive symptoms are not associated with leukocyte telomere length: findings from the Nova Scotia Health Survey (NSHS95) population-based study Rationale/ statement of the problem: Leukocyte telomere length (LTL), a marker of cellular aging, has been proposed as a pathogenic mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies have suggested that depression and depressive symptoms are associated with shorter LTL, but these studies are limited by small sample sizes, selective enrollment of participants (e.g. psychiatric outpatients), and lack of adjustment for cardiovascular risk factors and other covariates. The present study examines the association of LTL with depression and depressive symptoms in a large, populations-based cohort.
Methods: Participants included 2225 apparently healthy individuals from the 1995 Nova Scotia Health Survey (NSHS95) population-based study. Depressive symptoms were assessed by the Center for Epidemiological Studies-Depression (CES-D) scale. LTL was assessed by a real-time polymerase chain reaction method. Linear regression analyses were used to examine the association between LTL and depressive symptoms, probable depressive disorder (CES-D ]10 or CES-D ]16), and specific depressive symptom clusters (depressed affect, somatic concerns, positive affect, and interpersonal problems). These analyses were adjusted for clinical and demographic factors thought to potentially confound the association between depression and LTL, including: age, sex, body mass index, Framingham risk score, and previous ischemic heart disease. Cortisol predicts decreased cerebral cortical volume in 592 young non-human primates Background: Cortisol is a stress-related hormone that interacts with peripheral and neural systems. Although cortisol is important for short-term stress responses, chronically high cortisol is hypothesised to underlie the longterm effects of chronic stress, including decreased dendritic arborisation in rodent prefrontal cortex (PFC). Here we examined the relationship between variation in stress-induced cortisol levels and regional brain volume in 592 young rhesus monkeys. Methods: Cortisol was quantified from blood samples taken from 592 rhesus monkeys (m-age: 1.88 years; sex: 265 F) immediately after a human intruder presented their profile to the monkey for 30 min. T1-weighted structural MRI scans, taken within 2 weeks of testing, were transformed to an atlas-based study specific template using ANTS (http://www.picsl.upenn.edu/ANTS/). For each subject, we decomposed the final standard-space transformation into affine (linear) and deformable (nonlinear) components. We then produced a 3D map of the relative volume change from the deformable transformation, which accounts for whole-brain differences. Voxelwise robust regression analyses assessed the relationship between cortisol and brain volume, as measured using the logjacobian determinant.
Results: Those subjects with higher cortisol had significant decreases in cortical volume. More specifically, there was a significant negative relationship (FDR, qB0.05, two-tailed) between the log-jacobian and cortisol in cytoarchitectonic areas 47o, 46/9, 46 and 8 within the PFC, as well as motor area 4 and parietal area PGa (MIP).

Methods:
We examined basal telomerase activity in a sample of 72 healthy premenopausal women across a range of stress levels, including 35 mothers caring for a child with autism and 37 low-stress control mothers of healthy children. Participants completed a nightly diary over the course of a week, reporting their exposure to positive and negative events. Then they rated the extent to which they employed various emotion-regulation strategies in response to these events. Within-subject weekly means for all measures were calculated. In addition, composite scores for positive affect in response to positive daily events and negative affect in response to daily stressors were calculated, and weekly means obtained. Depressive symptoms were assessed using the Inventory of Depressive Symptoms. On day 4 of the study week, a fasting blood draw was performed to measure peripheral blood mononuclear cells (PBMC) telomerase activity. Results: Higher telomerase activity was significantly associated with the use of more resilient emotion regulation strategies, including more positive emotional responses to positive daily events (r 00.27, p 00.02) and increased savoring of positive daily events (r 00.24, p 00.04). In general, negative emotional responses and rumination in response to daily stressors were not related to telomerase with two exceptions: lower telomerase was associated with greater emotional suppression (r 0(0.34, p B0.01) and higher levels of depressive symptoms (r0(0.24, p00.05). There were no overall differences in telomerase activity between caregivers versus controls. Conclusion: These are the first findings to link daily emotion-regulation processes to telomerase activity. Daily emotion regulation strategies characterized by greater engagement with the positive and lower emotional suppression are associated with increases in telomerase, which may contribute to resilient immune cell aging. Emotion regulation, particularly in relation to the use of strategies that maintains a positive outlook in the face of stressful life exposures, may protect against cell aging. Results: GRS was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that two adolescent developmental phenotypes Á early conversion to daily smoking and rapid progression to heavy smoking Á mediated associations between the GRS and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The GRS predicted smoking risk over and above family history.
Conclusions: Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers.

PBMC telomerase activity correlates with hippocampal volume in major depression
The cellular enzyme elomerase replenishes telomeric DNA, which can be lost during repeated mitoses or during exposure to inflammation and oxidation. However, telomerase may have other, non-canonical functions, including (in animal models) antidepressant and neurogenesis-enhancing effects. In this study, we determined the relationship between telomerase activity [(measured in peripheral blood mononuclear cells (PBMCs)] and hippocampal (HC) volume in depressed individuals (MDDs) and matched controls. Nineteen medication-free subjects with MDD and 17 matched healthy controls underwent 4T MRI scanning and fasting morning venipuncture for assessment of unstimulated PBMC telomerase activity. Due to the exploratory nature of the study, corrections for multiple comparisons were not applied. Hippocampal volume was smaller, but not significantly so, in the MDDs than the controls. As reported previously, MDD subjects had significantly higher PBMC telomerase activity than the controls (p 00.007). Within the MDD group (but not in the control group or in the combined sample), PBMC telomerase activity was positively correlated with HC volume (r 00.49, p B0.04).
The relationship between telomerase activity in PBMCs and telomerase activity in the HC is unknown. Nonetheless, these results are consistent with emerging preclinical data that telomerase may have neurotrophic and antidepressant effects, may facilitate the neurotrophic effects of brain derived neruotrophic factor (BDNF) and may reverse certain signs of aging, and with clinical data that telomerase may be associated with favorable antidepressant responses. Our finding of significant telomerase/HC correlations only in the MDD subjects raises the possibility that telomerase may play a compensatory or reparative role in this disease. Influence of physical activity and acute exercise on cognitive performance and saliva testosterone in preadolescent school children Background: We investigated whether the habitual physical activity (PA) level had an impact on the acute effects of a short bout of 12 minutes of intensive exercise on cognitive performance and testosterone (T) concentration in primary school children. We further looked for associations between the T concentration and cognitive performance.
Methods: 42 students of a fourth grade (9Á10 years of age) were randomly assigned to an experimental group (EG, n027) and a control group (CG, n015). The first saliva collection took place after a normal school lesson in which the students filled out a habitual physical activity questionnaire and completed the d2-test, a test of selective attention (pre-test). While the intervention (12 min) the EG performed an intensive exercise at a heart rate (HR) of 180Á190 bpm and the CG participants watched a non-arousing movie. Afterwards, saliva samples were taken and both groups again completed the d2-test (post-test). Saliva was analyzed for testosterone. The whole sample was divided in low-and high physically active subjects by a median split. A 2 )2 )2 mixed factor ANOVA design with repeated measures was used to test for differences. Analyses were controlled for sex and BMI. Results: After the intervention participants of the experimental group showed better performances in the d2-test of concentration compared to control. We further observed a significant group (EG, CG), test (pre, post), activity level (high, low) interaction indicating a different pre-to post-test development in T concentration for high-and low-active participants in the EG and CG. Post hoc pairwise comparisons revealed that after acute exercise the T concentration decreased only in habitually low-active children.

Conclusions:
The results indicate that the intensive exercise only interacted with the hypothalamic-pituatarygonadal (HPG) axis in habitually low-active preadolescents, but had a beneficial effect on cognitive performance for all participants independent of their activity level. The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis Background: Recent meta-analyses have stimulated an active debate on whether the serotonin transporter genelinked polymorphic region (5-HTTLPR) is associated with an elevated vulnerability to psychiatric diseases on exposure to environmental adversity. As a potential mechanism explaining genotype-depended differences in stress sensitivity, altered stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis has been investigated in several experimental studies, with most of the studies comprising small samples. Methods: We evaluated the association of 5-HTTLPR genotype and cortisol reactivity to acute psychosocial stress by applying a meta-analytical technique based on 11 relevant data sets (total N 01686), which were identified through a systematic literature search up to October 2011.

MicroRNA profiling of the human stress response
Rationale/ statement of the problem: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with much of the current research efforts directed at possible mechanisms. For example, psychosocial stress in humans has recently been associated with DNA damage that plays a role in the etiology of negative health outcomes, and also with changes in DNA transcription to messenger Ribonucleic Acid (mRNA).
We have become interested in one putative regulatory element in mRNA translation to proteins: microRNA (miRNA). In this study, we aimed to investigate the relationship between psychosocial stress and changes in gene expression changes on the miRNA level, and to further investigate whether stressful life events and personality traits moderate these relationships. Methods: Using a pre-post design, 36 adults were exposed to standardized psychosocial stress in the laboratory (Trier Social Stress Test [TSST]) and completed measures on perceived and chronic stress. In addition, cortisol levels were determined from saliva samples obtained prior to stressor and at eight time points during recovery. Before and after the TSST, subjects underwent a total of three blood draws from which peripheral blood mononuclear cells (PBMCs) were extracted in order to determine miRNA gene expression levels, using the Affymetrix Genechip 2.0 microRNA array. RNA was extracted from each sample and gene expression was measured by hybridization to the miRNA microarray. In an effort to identify a miRNA expression profile for the acute stress response, we compared miRNA expression changes at baseline (before onset of the stressor) with miRNA expression at the two time points following the stressor. Results: The acute psychosocial stressor produced a higher cortisol response in a subset of the study participants (high responders). We expect these individuals to exhibit significant changes in miRNA expression from baseline to post-stress. We further hypothesize that these changes will be most significant for miRNAs that regulate expression of genes associated with the cortisol stress response. Conclusion: Our study aims to identify a miRNA signature of social stress and to correlate differences in miRNA expression with psychological variables such as early life stress and resilience, which may function to mitigate the stress response. Effects of chronic social stress on maternal behavior, anhedonia, milk intake, pup growth, and gene expression Background: Exposure to chronic social stress is a strong predictor of postpartum depression and anxiety. Recent studies have described a chronic social stress (CSS) rodent model for postpartum depression where the repeated exposure of lactating dams to novel male intruders attenuates both the display of maternal care and growth during lactation and increases self-grooming, a measure of anxiety. Investigation of the adult female offspring of these affected dams reveals an attenuated nursing efficiency that is associated with decreases in central oxytocin, prolactin, and vasopressin gene expression. Methods: The current study continued the characterization of the (CSS) model by expanding the analyses to include milk intake, saccharin intake (a measure of anhedonia), and gene expression of the stressed dams. Results: CSS decreased maternal care and saccharin intake, attenuated pup milk intake by 40%, and altered gene expression in lactating dams. Conclusions: It is concluded that CSS is an ethologically and translationally relevant model for postpartum depression and anxiety, as well as associated impairments in nursing. Cortisol levels differ after the low dose dexamethasone-suppression test in outpatients and inpatients with stress related disorders as compared to healthy subjects Rationale/ statement of the problem: The low-dose dexamethasone-suppression test (DST) has originally been introduced by Yehuda et al.

Method:
We here report data on the salivary cortisol responses to awakening (CAR) to the DST in healthy subjects (N 0102), as well as in outpatients (N 092) and inpatients (N 099) with stress related disorders. Patient groups Investigating the effects of hormonal contraceptive use on mood and sexuality Rationale: Hormonal contraception has been the subject of numerous research studies. Despite the fact pharmaceutical companies advertise the physical side effects of the medication both positive (e.g. improved acne, reduced ovarian cancer risk) and negative (e.g. increased risk of stroke, weight gain), the knowledge of the potential psychological effects are often based on Internet searches or less than credible resources. The range of empirical support for the effects of the medications on mood has been beneficial including improved mood to negative such as mental health distress. Aside from psychological research, sexual side effects including reduced libido and reduced sexual responsiveness have also been reported. The majority of the research on hormonal contraceptives has been conducted in a clinical setting. It is unclear if the preceding findings would be found with females self-selecting to use the medication as opposed to paid study participants in a clinical setting.
Methods: In order to gain a greater understanding of the relationship between hormonal contraceptive usage and affect, an Internet survey with females of childbearing age (age range: 17Á48, N 0379) was conducted to examining psychological distress (stress, anxiety, depression, and negative mood), improved mood (life satisfaction, happiness, and positive mood), and sexuality (sexual frequency and sexual satisfaction).
Results: Contrary to previous findings, results from this correlational study suggest no effects of hormonal contraceptive use on psychological distress or mood. Females using hormonal contraception did, however, report higher scores for sexual satisfaction and increased sexual activity. Conclusions: While this investigation was not experimental and, therefore, causation cannot be determined, females using hormonal contraception may be relieved that this research suggests that these drugs do not lead to psychologically harmful side effects and sexuality may be improved with usage. More research is needed to confirm these findings. The comparative study of salivary alpha-amylase and salivary cortisol reaction to electric stimulation in avoidant personality disorder Background: Avoidant personality disorder (AvPD) is a personality disorder recognized in the Diagnostic and Statistical Manual of Mental Disorders handbook (DSM-IV TR) in a person characterized by a pervasive pattern of social inhibition, feelings of inadequacy, extreme sensitivity to negative evaluation, and avoidance of social interaction. To this day, the causes of AvPD are not clearly defined, and may be influenced by a combination of social, genetic, and psychological factors. The disorder may be related to temperamental factors that are inherited. Moreover, the disorder may be related to the dysfunction of stress response systems. A role for hypothalamic-pituitary-adrenal (HPA)-axis activity in mediating stress responses has been intensively investigated for decades. Cortisol is an essential hormone in the regulation of stress response in the HPA axis, and salivary cortisol (sC) has been used as a simple, noninvasive index of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has emerged as a new biomarker for responses to psychosocial stress within the sympathetic adrenomedullary (SAM) systems. To evaluate the effects of physical stress on HPA and SAM systems, we assessed the secretion of sAA and sC in AvPD patients and healthy volunteers after exposure to electric stimulation stress. Methods: Eleven AvPD patients with no psychiatric comorbidity (7 males and 4 females, aged 25.294.4) and 126 healthy volunteers with no history of psychiatric disorder (56 males and 70 females, aged 25.994.5) participated in this study. All subjects were exposed to electric stimulation stress with the stimulator coil on their wrists. Subjects were stimulated in incremental steps until they reached their threshold stimulus, defined as the greatest stimulus they could tolerate. The greatest stimulus lasted 40 seconds. To examine sAA and sC stress responses, we measured sAA and sC levels three times immediately before, immediately after, and 20 min after the intervention.
We also determined State-Trait anxiety Inventory (STAI) scores and Profile of Mood State (POMS) scores of all subjects before the intervention. This study was approved by the Ethics Committee of Oita University. Written informed consent was obtained from all participants. Results: A significant sAA response to electric stimulation was found with peak values registered immediately after interventions in AvPD patients. However, we found no significant sAA response to electric stimulation in healthy controls. Moreover, AvPD patients always showed significantly higher sAA levels than healthy controls immediately before, immediately after, 20 min after the intervention. However, there was no significant difference in sC reactions between AvPD patients and healthy controls, and we found no significant sC response to electric stimulation in each group. The age, the proportion of males to females and the mean strength of electric stimulation in each group were statistically equal. STAI-Trait and STAI-State scores of AvPD patients were both greater than those of healthy controls. And POMS scores also showed greater subscales of tension-anxiety, depression, fatigue, confusion in AvPD patients than those of healthy patients. Conclusion: These preliminary results suggest that AvPD patients may be easily suffered from stronger feelings of tension-anxiety, depression, fatigue, and confusion compared to healthy people in stressful situation. Moreover, AvPD patients may react to stressors with SAM systems predominantly. The above indicates that the excessive acceleration of sympathetic nerves system may be related to the pathology of AvPD. Salivary alpha-amylase and cortisol responsiveness following electrical physical stress in bipolar disorder patients Background: Bipolar disorder (BP) is often associated with altered functioning of the hypothalamic-pituitaryadrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary alphaamylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in BP patients. The present study measured sAA and salivary cortisol levels in patients with BP. Methods: The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 25 patients with BP and 22 healthy volunteers following the application of electrical stimulation stress. Patients with bipolar disorder scored eight points or more on the Hamilton Depression Scale (HAM-D) scores. Results: Tension-anxiety, depression-dejection, anger-hostility, fatigue, and confusion scores in patients with bipolar disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with BP were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between BP patients and healthy controls. There was no difference in the threshold of applied electrical stimulation between BP patients and healthy controls. There were significant differences in sAA levels between patients with BP and healthy controls. There were significantly higher salivary sAA levels in female patients with BP versus controls. There was a trend toward higher salivary sAA levels in male patients with BP versus controls. Finally, there were no differences in salivary cortisol levels between BP patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness to novel and uncontrollable situations in patients with BP. Conclusions: These preliminary results suggest that sAA might be a useful biological marker of BP. Discussion: Although the number of participants in the present study is yet quite small, and no posttreatment assessment after some weeks or months could be conducted, the present findings do support the hypothesis that both bio-and neurofeedback may contribute to psycho(physio)logical recuperation after (professional) challenging periods. Initial effects may be expected on self-reported psychological well-being and working memory performance.