Nina Alexander

Gene-environment interactions predict cortisol responses after acute stress: implications for the etiology of depression.

BACKGROUND Growing evidence suggests that the serotonin transporter polymorphism (5-HTTLPR) interacts with adverse environmental influences to produce an increased risk for the development of depression while the underlying mechanisms of this association remain largely unexplored. As one potential intermediate phenotype, we investigated alterations of hypothalamic-pituitary-adrenal (HPA) axis responses to stress in individuals with no history of psychopathology depending on both 5-HTTLPR and stressful life events. METHODS Healthy male adults (N=100) were genotyped and completed a questionnaire on severe stressful life events (Life Events Checklist). To test for gene-by-environment interactions on endocrine stress reactivity, subjects were exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol levels were obtained at 6 time points prior to the stressor and during an extended recovery period. RESULTS Subjects homozygous for the s-allele with a significant history of stressful life events exhibited markedly elevated cortisol secretions in response to the stressor compared to all other groups, indicating a significant gene-by-environment interaction on endocrine stress reactivity. No main effect of either 5-HTTLPR (biallelic and triallelic) or stressful life events on cortisol secretion patterns appeared. CONCLUSION This is the first study reporting that 5-HTTLPR and stressful life events interact to predict endocrine stress reactivity in a non-clinical sample. Our results underpin the potential moderating role of HPA-axis hyper-reactivity as a premorbid risk factor to increase the vulnerability for depression in subjects with low serotonin transporter efficiency and a history of severe life events.

Hair Cortisol as a Biomarker of Traumatization in Healthy Individuals and Posttraumatic Stress Disorder Patients

BACKGROUND Previous evidence on endocrine correlates of posttraumatic stress disorder (PTSD) has been rather inconsistent. The analysis of cortisol in hair is a recent methodological development that may increase the quality of long-term cortisol assessments in such research. Here, we use this method to closely assess hair cortisol relationships with trauma-related characteristics and PTSD symptom patterns. METHODS Hair cortisol concentrations (HCC), diurnal salivary cortisol, and relevant psychometric data were assessed in matched groups of 28 PTSD patients and 27 traumatized and 32 nontraumatized healthy control subjects. Cortisol levels were quantified by liquid chromatography tandem mass spectrometry. RESULTS Posttraumatic stress disorder patients and traumatized control subjects exhibited 59% and 51% lower HCC than nontraumatized control subjects, respectively. Hair cortisol concentrations were found to be negatively related to the severity of intrusion symptoms, the number of different lifetime traumatic events, the frequency of traumatization, and the time interval since traumatization. The overall pattern of HCC associations was not reflected in short-term salivary cortisol findings. CONCLUSIONS Our results indicate that trauma exposure per se, either in the absence or presence of PTSD, is a crucial correlate of long-term basal cortisol levels. Particularly, the experience of multiple events with a longer time since traumatization and an increased severity of intrusion symptoms may be related to hypocortisolism. The fact that HCC findings were not consistently seen in salivary cortisol data underscores the importance of the method of cortisol assessment and highlights the utility of hair cortisol analyses for future biological psychiatry research.

Cortisol in hair and the metabolic syndrome

CONTEXT Although exposure to supraphysiological levels of glucocorticoids is known to contribute to the development of the metabolic syndrome (MetS), the importance of physiological variation in basal cortisol secretion is less clear. This issue can be addressed by using hair cortisol analysis, which for the first time allows the assessment of long-term integrated hormone levels. OBJECTIVE AND DESIGN We used the analysis of cortisol in hair (hairF) to examine associations of long-term cortisol levels with prevalence of MetS and individual cardiometabolic parameters in a large occupational cohort. In additional exploratory analyses, we also studied cardiometabolic associations with hair cortisone levels. PARTICIPANTS Participants included 1258 employees of a large aerospace company (aged 16-64 years; 84.8% males) who partook in a voluntary health assessment. MAIN OUTCOME MEASURES The first 3 cm of scalp-near hair were analyzed for glucocorticoid concentrations using liquid chromatography tandem mass spectrometry. Relevant cardiometabolic risk factors were assessed and MetS was diagnosed (according to 2009 international task force criteria). RESULTS A higher prevalence of MetS was seen in individuals falling into the third (odds ratio 1.71, 95% confidence interval 1.08-2.69) or fourth hairF quartile (odds ratio 2.42, 95% confidence interval 1.55-3.75) compared with the first quartile, in fully adjusted analyses. HairF also showed positive associations with weight-related anthropometric measures (body mass index, waist to hip ratio, waist circumference) and glycated hemoglobin. The exploratory analysis of hair cortisone also indicated relevant associations with cardiometabolic parameters. CONCLUSION Normal physiological differences in long-term cortisol secretion, as assessed in hair, show relevant relationships with MetS and individual cardiometabolic parameters.

Cortisol in hair, body mass index and stress-related measures

Hair cortisol concentrations (HCC) are assumed to reflect integrated cortisol secretion over extended periods of time and may provide a sensitive marker for stress-associated endocrine changes. Here, we report data from two independent studies of 155 (study I) and 58 participants (study II) in which HCC associations with different stress-related measures and body mass index (BMI) were investigated. Consistent evidence for positive associations between HCC and BMI was seen across both studies (study I: r=.33, p<.001; study II: r=.42, p=.001). On the other hand, findings failed to reveal reliable HCC associations with psychosocial variables, showing only a positive relationship with self-reported social overload in study II (r=.29, p=.03) but not with other stress-related measures.

Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term-born children.

CONTEXT Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus-pituitary-adrenal (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 GC has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. OBJECTIVE The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample, allowing us to further address sex- and drug-specific effects. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study comprised of 209 term-born children between 6 and 11 yr of age. 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 6- to 11-yr-old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9)=5.8; P<0.001). 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 the 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.

Variation in the serotonin transporter gene modulates selective attention to threat.

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect.

The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

BACKGROUND Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. METHODS Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. RESULTS We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. CONCLUSION Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity.

Stress-related and basic determinants of hair cortisol in humans: A meta-analysis

The analysis of hair cortisol concentrations (HCC) is a relatively new strategy to measure long-term cumulative cortisol levels, which is increasingly used in psychoneuroendocrinological research. Here, we conduct a first comprehensive meta-analysis of HCC research based on aggregated data from a total of 124 (sub)samples (66 independent studies; total N=10,289). We seek to answer two central questions: (i) Which covariates and basic features of HCC need to be considered in future research? (ii) What are the main determinants of HCC in terms of chronic stress exposure and mental health? Concerning basic characteristics, our findings identify several covariates to be considered (age, sex, hair washing frequency, hair treatment, oral contraceptive use), confirm a decline of HCC from the first to the second proximal 3cm hair segment, and show positive associations between HCC and short-term salivary cortisol measures. Regarding chronic stress, we show that stress-exposed groups on a whole exhibit 22% increased HCC. This long-term cortisol hypersecretion emerges particularly when stress is still ongoing at the time of study (+43% HCC) but is not present in conditions of past/absent stress (-9% HCC, n.s.). We also report evidence for 17%-reduced HCC in anxiety disorders, such as PTSD. Interestingly, no consistent associations with mood disorders and self-reports of perceived stress, depressiveness or social support are found. However, our findings reveal positive associations of HCC with stress-related anthropometric (body mass index, waist-to-hip ratio) and hemodynamic measures (systolic blood pressure). These meta-analytic results are discussed in the light of their practical implications and important areas for future inquiry are outlined.

Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles

The serotonin transporter (SERT) gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating the link between life stress and depression. However, respective molecular pathways of gene–environment (GxE) interaction are largely unknown. Sustained alterations in SERT gene expression profiles, possibly mediated by epigenetic modifications, are a frequent correlate of depression and may thus constitute a putative mediator of GxE interaction. Here, we aimed to investigate joint effects of 5-HTTLPR and self-reported environmental adversity throughout the lifespan (prenatal, early and recent stress/trauma) on in vivo SERT mRNA expression in peripheral blood cells. To further evaluate whether environmentally induced changes in SERT expression are mediated by epigenetic modifications, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of the SERT gene using the highly sensitive method of bisulfite pyrosequencing. Participants were 133 healthy young adults. Our findings show that both the 5-HTTLPR S allele and maternal prenatal stress/child maltreatment are associated with reduced in vivo SERT mRNA expression in an additive manner. Remarkably, individuals carrying both the genetic and the environmental risk factors exhibited 32.8% (prenatal stress) and 56.3% (child maltreatment) lower SERT mRNA levels compared with those without any risk factor. Our data further indicated that changes in SERT mRNA levels were unlikely to be mediated by DNA methylation profiles within the SERT CpG island. It is thus conceivable that the persistent changes in SERT expression may in turn relate to altered serotonergic functioning and possibly convey differential disease vulnerability associated with 5-HTTLPR and early adversity.

Elevated hair cortisol levels in chronically stressed dementia caregivers

Hair cortisol concentrations (HCC) are assumed to reflect integrated long-term cortisol levels and have been proposed as a promising endocrine marker of chronic psychological stress. The current study examined HCC in relation to caregiving burden, a well-established naturalistic model of chronic stress in humans. HCC and relevant psychosocial data were examined in 20 caregivers of relatives with dementia and 20 non-caregiver controls matched for age and sex. Results revealed elevated HCC in dementia caregivers compared to non-caregiver controls (F(1,38)=4.4, p=.04, ηp2=.10). Further, within caregivers, a trend for a positive association of HCC with self-reported caregiving burden (r=.43, p=.058) and a positive association with depressiveness (r=.48, p=.045) were observed. No other associations between HCC and subjective measures were seen. These findings concur with the notion that HCC sensitively capture endocrine aberrations in stress-exposed groups.