Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review

Posttraumatic stress disorder (PTSD) is typically accompanied by acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but several studies have also used a challenge model to further assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. This paper reviews common methodology and research findings on HPA function in PTSD, and discusses the pathophysiological mechanisms underlying these findings. We reviewed the literature and selected all English-language, human subject, data driven, pharmacological and non-pharmacological challenge studies pertaining to the HPA axis, and in vitro leukocyte glucocorticoid receptor studies in adult PTSD subjects. Studies using a non-pharmacological stress paradigm (cognitive stress, trauma reminders) to stimulate the HPA axis showed an exaggerated cortisol response in PTSD. The most widely used pharmacological challenge with consistent results was the low dose dexamethasone-suppression test (DST). These DST studies showed enhanced cortisol suppression in subjects with PTSD. Different hypotheses have been purported to explain the alterations in HPA axis functioning in PTSD. The results of the reviewed challenge tests, however, did not exclusively support one of the hypothesized mechanisms. Further research assessing hormones at all levels of the HPA axis at both baseline and at challenge conditions with a proper stratification of study population, will be necessary for a better understanding of stress-responsivity on the level of the HPA axis in PTSD.     

Sex differences in physiological reactivity to acute psychosocial stress in adolescence

Females begin to demonstrate greater negative affective responses to stress than males in adolescence. This may reflect the concurrent emergence of underlying differences in physiological response systems, including corticolimbic circuitries, the hypothalamic-pituitary-adrenal axis (HPAA), and the autonomic nervous system (ANS). This review examines when sex differences in physiological reactivity to acute psychosocial stress emerge and the directionality of these differences over development. Indeed, the literature indicates that sex differences emerge during adolescence and persist into adulthood for all three physiological response systems. However, the directionality of the differences varies by system. The emerging corticolimbic reactivity literature suggests greater female reactivity, particularly in limbic regions densely innervated by gonadal hormone receptors. In contrast, males generally show higher levels of HPAA and ANS reactivity. We argue that the contrasting directionality of corticolimbic and peripheral physiological responses may reflect specific effects of gonadal hormones on distinct systems and also sex differences in evolved behavioral responses that demand different levels of peripheral physiological activation. Studies that examine both subjective reports of negative affect and physiological responses indicate that beginning in adolescence, females respond to acute stressors with more intense negative affect than males despite their comparatively lower peripheral physiological responses. This dissociation is not clearly explained by sex differences in the strength of the relationship between physiological and subjective responses. We suggest that females' greater subjective responsivity may instead arise from a greater activity in brain regions that translate stress responses to subjective awareness in adolescence. Future research directions include investigations of the role of pubertal hormones in physiological reactivity across all systems, examining the relationship of corticolimbic reactivity and negative affect, and sex differences in emotion regulation processes.     

The effect of an environmental stressor on gender differences on the awakening cortisol response

OBJECTIVES: The aim of the current study was to investigate the effect of an environmental stressor, examination stress, on waking cortisol levels. METHODS: Sixty-two subjects were tested upon awakening during periods of low and high examination stress. Samples were collected on 4 sampling days total, two of these days were during a low examination period and two of these days were during a high examination period. During each day, subjects collected salivary samples at waking, 30 min after waking, and 60 min after waking. Subjects also completed three questions asking about their present mood. RESULTS: As a group, subjects had higher negative mood on the mornings during the high examination stress period than on the mornings during the low examination stress period. Furthermore, when the sex of the subject was considered, cortisol levels were found to be significantly higher in females during the high examination period, but not in males. However, the changes in waking cortisol across the two stress periods were not correlated with the changes in psychological stress across the same sessions for either sex. In conclusion, the waking cortisol was found to be sensitive to the examination stressor protocol, but only in females. CONCLUSIONS: These findings, in conjunction with others, may help to build more comprehensive models of how the two sexes differ in hormonal and psychological stress responses.     

Associations between alcohol-use and depression symptoms in adolescence: Examining gender differences and pathways over time

Several studies examining alcohol use and depression in youth have focused on documenting prevalence of overlap, or temporal ordering in longitudinal samples. Fewer studies have examined pathways connecting alcohol use and depression over time. This study examined gender differences between depression and alcohol use across adolescence while examining peer and family pathways as possible mediators of effects. Data was collected longitudinally from 593 families from three urban public middle schools in the United States. Participants were recruited in 6th grade and followed through 9th grade. We examined gender differences using a nested model comparison approach. Results indicated the association between depression and alcohol use differs by gender. For males, depression and alcohol use were independent across adolescence, and no significant indirect pathways were observed. For females, bidirectional effects were found between alcohol use and depression, as well as an indirect effect from depression to alcohol use via peer deviance.     

Significance of family life events in middle adolescence: A survey on Finnish community adolescents

Finnish middle adolescents (n=3242) were assessed for family characters, family life events, depression and frequent drunkenness. Odds ratios for maladjustment outcomes associated with each event were computed and logistic regression models were used to estimate the effect of confounders. In the presence of serious illness or injury of a family member, increasing conflicts between parents and financial difficulties in the family, the probability of depression was twice as high than without the presence of these events. Parental unemployment, parent getting involved with the law and financial difficulties in the family were associated with frequent drunkenness. The associations between life events and depression were fairly similar among boys and girls. Among girls there were several events associated with frequent drunkenness even when family structure and socio-economic status were accounted for, while among boys there were only few. The significance of associations between family life events and depression may vary between the specific events while the associations between family life events and frequent drunkenness may be better explained with cumulative stress. Both males and females react to family stress, but the symptoms presented may differ. In case of family adversities, both internalizing and externalizing outcomes must be screened for.     

A multidimensional approach to understanding the emergence of sex differences in internalizing symptoms in adolescence

Women are more vulnerable to internalizing disorders (e.g., depression and anxiety). This study took an integrative developmental approach to investigate multidimensional factors associated with the emergence of sex differences in internalizing symptoms, using data from the Adolescent Brain Cognitive Development (ABCD) study. Indices of sex hormone levels (dehydroepiandrosterone, testosterone, and estradiol), physical pubertal development, task-based functional brain activity, family conflict, and internalizing symptoms were drawn from the ABCD study’s baseline sample (9- to 10-year-old; N = 11,844). Principal component analysis served as a data-driven dimensionality reduction technique on the internalizing subscales to yield a single robust measure of internalizing symptoms. Moderated mediation analyses assessed whether associations between known risk factors and internalizing symptoms vary by sex. Results revealed direct and indirect effects of physical pubertal development on internalizing symptoms through family conflict across sexes. No effects were found of sex hormone levels or amygdala response to fearful faces on internalizing symptoms. Females did not report overall greater internalizing symptoms relative to males, suggesting that internalizing symptoms have not yet begun to increase in females at this age. Findings provide an essential baseline for future longitudinal research on the endocrine, neurocognitive, and psychosocial factors associated with sex differences in internalizing symptoms.     

Developmental trajectory of purpose identification during adolescence: Links to life satisfaction and depressive symptoms

IntroductionWhereas evidence has shown that a sense of purpose is linked to optimal adjustment, longitudinal work investigating the development of purpose identification as well as its effect on psychological functioning among non-Western samples during adolescence is needed.MethodsThree hundred and eighty-seven senior high school students (253 female, 65.37%; mean age = 15.76 years at the first investigation) from Taiwan completed surveys four times beginning in the fall of tenth grade and ending in the spring of eleventh grade with a six-month interval. Using self-ratings, purpose identification was evaluated in all four assessments and psychological functioning was examined through life satisfaction and depressive symptoms in the first and the last survey.ResultsGrowth curve analyses revealed an increased slope in purpose identification over the first two years of high school, and such a trajectory was similar across boys and girls. Additionally, increases in purpose identification predicted enhanced life satisfaction and reduced depressive symptoms among both boys and girls. There was only one gender difference: The negative association between purpose identification trajectory and depressive symptoms was stronger for girls than for boys.ConclusionsThere is an increase in the development of identified purpose during middle adolescence among high school students in Taiwan. Such change not only promotes life satisfaction in adolescents but is also preventive of adolescent depression. As such, the current findings highlight the significance for adolescents to discover and commit to a purpose.     

Perceived stress and poly-tobacco product use across adolescence: Patterns of association and gender differences

Perceived stress—an endophenotype indicative of the tendency to appraise stress as frequent, unpredictable and unmanageable—is associated with adolescent cigarette smoking. It is unclear whether this association: (1) extends to alternative tobacco products, like electronic cigarettes and hookah (tobacco water pipe), which are increasingly popular among youth, and (2) differs by gender. In this report, data were drawn from a population-based longitudinal cohort of youth in Southern California. Perceived stress was assessed at baseline (7th or 8th grade; 2010). Electronic cigarette, hookah, combustible cigarette, and cigar use were assessed at a 4-year follow-up (11th or 12th grade; 2014). After adjusting for confounders, polytomous logistic regressions showed that a standardized baseline perceived stress score (M = 0, SD = 1) predicted electronic cigarette, hookah, combustible cigarette, and cigar use and a poly-tobacco use index at the 4-year follow-up in the overall sample. Interactions between perceived stress and gender were also observed (Interaction Ps < 0.05), which demonstrated that the association of perceived stress with tobacco product use and poly-use were stronger in females (ORs for current use range: 1.47 to 1.72) than males (ORs range: 0.93 to 1.31). Adjusting for baseline perceived stress, the change in perceived stress from baseline to follow-up was also positively associated with use and poly-use of most tobacco products in females and in males to some extent. In the current era in which teen use of alternative tobacco products is increasingly common, adolescent tobacco use and poly-use research and prevention strategies should address gender-specific origins of tobacco product use risk and consider perceived stress and other emotional endophenotypes in such risk pathways.     

Effects of gender and cigarette smoking on reactivity to psychological and pharmacological stress provocation

We examined the influence of gender and smoking status on reactivity in two human laboratory stress paradigms. Participants were 46 (21 men, 25 women) healthy individuals who completed the Trier Social Stress Task (i.e., performed speech and math calculations in front of an audience) and a pharmacological stress provocation (i.e., administration of corticotrophin releasing hormone (CRH)) after an overnight hospital stay. Approximately half (53%) of the participants were smokers. Cortisol, adrenocorticotrophin hormone (ACTH), physiologic measures (heart rate, blood pressure), and subjective stress were assessed at baseline and at several time points post-task. Men demonstrated higher baseline ACTH and blood pressure as compared to women; however, ACTH and blood pressure responses were more pronounced in women. Women smokers evidenced a more blunted cortisol response as compared to non-smoking women, whereas smoking status did not affect the cortisol response in men. Finally, there was a more robust cardiovascular and subjective response to the Trier as compared to the CRH. Although preliminary, the findings suggest that women may be more sensitive than men to the impact of cigarette smoking on cortisol response. In addition, there is some evidence for a more robust neuroendocrine and physiologic response to acute laboratory stress in women as compared to men.     

Neuroimaging predictors of onset and course of depression in childhood and adolescence: A systematic review of longitudinal studies

Major depressive disorder (MDD) often emerges during adolescence with detrimental effects on development as well as lifetime consequences. Identifying neurobiological markers that are associated with the onset or course of this disorder in childhood and adolescence is important for early recognition and intervention and, potentially, for the prevention of illness onset. In this systematic review, 68 longitudinal neuroimaging studies, from 34 unique samples, that examined the association of neuroimaging markers with onset or changes in paediatric depression published up to 1 February 2019 were examined. These studies employed different imaging modalities at baseline; structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI) or electroencephalography (EEG). Most consistent evidence across studies was found for blunted reward-related (striatal) activity (fMRI and EEG) as a potential biological marker for both MDD onset and course. With regard to structural brain measures, the results were highly inconsistent, likely caused by insufficient power to detect complex mediating effects of genetic and environmental factors in small sample sizes. Overall, there were a limited number of samples, and confounding factors such as sex and pubertal development were often not considered, whereas these factors are likely to be relevant especially in this age range.     

Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder

The hypothalamic-pituitary-adrenal (HPA) axis is compromised in major depression and bipolar disorder (BD). It is not known however whether HPA abnormalities predate the onset of these disorders. Preliminary data indicated that the adolescent offspring of parents with BD (high-risk), as compared to adolescents of parents with no mental disorder (low-risk), had higher levels of daytime salivary cortisol. The present study re-examined the cortisol increase after awakening and basal cortisol levels in a larger sample, and tested the hypothesis that high-risk offspring are more reactive to psychosocial stress than low-risk offspring. Saliva samples were collected from 58 adolescents, 29 high-risk (14 male/15 female, 16.8 years) and 29 (14 male/15 female, 16.6 years) low-risk, in their natural environment during at least two days. Twenty-five high-risk (13 male/12 female) and 25 low-risk (13 male/12 female) youth completed a child adaptation (15 years) or the standard version of the “Trier Social Stress Test”. Consistent with our previous finding, high-risk offspring had higher daytime levels of cortisol in their natural environment than low-risk offspring, and the difference was unrelated to clinical symptoms or other known confounds. Irrespective of risk status, female participants had higher daytime levels of cortisol than male participants. In contrast, there were no group differences in the cortisol response to the laboratory psychosocial stressor. The offspring of parents with BD show evidence of increased daytime basal HPA functioning with normal reactivity to psychosocial stress.     

Antecedents and sex/gender differences in youth suicidal behavior

Suicide is the second leading cause of death in youth globally; however, there is uncertainty about how best to intervene. Suicide rates are typically higher in males than females, while the converse is true for suicide attempts. We review this “gender paradox” in youth, and in particular, the age-dependency of these sex/gender differences and the developmental mechanisms that may explain them. Epidemiologic, genetic, neurodevelopmental and psychopathological research have identified suicidal behaviour risks arising from genetic vulnerabilities and sex/gender differences in early adverse environments, neurodevelopment, mental disorder and their complex interconnections. Further, evolving sex-/gender-defined social expectations and norms have been thought to influence suicide risk. In particular, how youth perceive and cope with threats and losses (including conforming to others’ or one’s own expectations of sex/gender identity) and adapt to pain (through substance use and help-seeking behaviours). Taken together, considering brain plasticity over the lifespan, these proposed antecedents to youth suicide highlight the importance of interventions that alter early environment(s) (e.g., childhood maltreatment) and/or one’s ability to adapt to them. Further, such interventions may have more enduring protective effects, for the individual and for future generations, if implemented in youth.     

Sex differences and phase of light cycle modify chronic stress effects on anxiety and depressive-like behavior

The experiment examined whether sex differences and the phase of the light cycle modified how chronic restraint stress influenced anxiety and depressive-like behavior. Rats were restrained (6 h/d/21 d) and tested on the open field (OF), elevated plus maze (EPM), forced swim test (FST), and sucrose preference (SP) test. Chronic stress increased anxiety in both males and females in different tasks during the dark phase, but not in the light phase. When tested during the dark, chronic stress decreased time and grid crossings in the center arena of the OF in males, whereas chronic stress decreased open arm entries and time in the EPM in females. For OF and EPM, an anxiety index calculation confirmed that chronic stress increased anxiety measures when taking into consideration locomotion metrics. For the FST and SP, chronic stress had a tendency to alter the immobility index and sucrose preference in both sexes, but did not reach statistical significance alone. Therefore, a separate z-score was computed for each task and summed to represent a combined z-score of depressive-like behavior. In the light phase, chronic stress increased depressive-like behavior in males, but decreased depressive-like behavior in females. Chronic stress had no statistically significant effects on depressive-like behavior in the dark phase, although the pattern of chronic stress effects on depressive-like behavior in females was similar for both light cycle phases. The results indicate that chronic restraint stress effects on anxiety and depressive-like behavior depend upon the type of task, phase of the light cycle and sex of the individual.     

A two-year longitudinal study of gender differences in responses to positive affect and depressive symptoms during middle adolescence

This study aimed to analyze the prospective associations during adolescence between depressive symptoms and response styles to positive affect and to examine gender differences. A longitudinal study was conducted with three waves separated by 1 year each to assess a non-clinical sample of 622 Spanish adolescents who were 13 and 14 years old (50.2% boys, 49.8% girls). The participants completed self-report measures of depressive symptoms and responses to positive affect (emotion-focused positive rumination, self-focused positive rumination and dampening of positive emotion). The results showed that the increase in depressive symptoms was associated with an increase in dampening and decreases in emotion-focused and self-focused positive rumination. Furthermore, girls presented more depressive symptoms, as well as higher dampening and lower self-focused positive rumination, than boys. The conclusions highlight the need to consider responses to positive affect in explaining gender differences in depressive symptoms during mid-adolescence, as well as in designing prevention programs.