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1.  Relative Hypo- and Hypercortisolism Are Both Associated with Depression and Lower Quality of Life in Bipolar Disorder: A Cross-Sectional Study 
PLoS ONE  2014;9(6):e98682.
Background
Depression in unipolar and bipolar disorders is associated with hypothalamic-pituitary-adrenal-axis (HPA-axis) hyperactivity. Also, unipolar disorder has recently been shown to exhibit HPA-axis hypoactivity. We studied for the first time how HPA-axis hypo- and hyperactivity relate to depression and disease burden in bipolar disorder. We were interested in studying hypocortisolism; characterized by increased HPA-axis negative feedback sensitivity and lower basal cortisol levels together with the opposite HPA-axis regulatory pattern of hypercortisolism.
Methods
This cross-sectional study includes 145 type 1 and 2 bipolar outpatients and 145 matched controls. A dexamethasone-suppression-test (DST) measures the negative feedback sensitivity and a weight-adjusted very-low-dose DST was employed, which is sensitive in identifying hypocortisolism and hypercortisolism. The 25th and 75th percentiles of control post-DST values were used as cut-offs identifying patients exhibiting relative hypo-, and hypercortisolism. Self-report questionnaires were employed: Beck-Depression-Inventory (BDI), Montgomery-Åsberg-Depression-Rating-Scale (MADRS-S), World-Health-Organization-Quality-of-Life-Assessment–100 and Global-Assessment-of-Functioning.
Results
Patients exhibiting relative hypocortisolism expectedly exhibited lowered basal cortisol levels (p = 0.046). Patients exhibiting relative hypercortisolism expectedly exhibited elevated basal levels (p<0.001). Patients exhibiting relative hypocortisolism showed 1.9–2.0 (BDI, p = 0.017, MADRS-S, p = 0.37) and 6.0 (p<0.001) times increased frequencies of depression and low overall life quality compared with patients exhibiting mid post-DST values (eucortisolism). Adjusted Odds Ratios (OR:s) for depression ranged from 3.8–4.1 (BDI, p = 0.006, MADRS-S, p = 0.011) and was 23.4 (p<0.001) for life quality. Patients exhibiting relative hypercortisolism showed 1.9–2.4 (BDI, p = 0.017, MADRS-S, p = 0.003) and 4.7 (p<0.001) times higher frequencies of depression and low overall life quality compared with patients exhibiting eucortisolism. Adjusted OR:s for depression ranged from 2.2–2.7 (BDI, p = 0.068, MADRS-S, p = 0.045) and was 6.3 (p = 0.008) for life quality.
Limitations
The cross-sectional design and lack of pre-established reference values of the DST employed.
Conclusions
Relative hypocortisolism and relative hypercortisolism were associated with depression and lower life quality, providing novel insights into the detrimental role of stress in bipolar disorder.
doi:10.1371/journal.pone.0098682
PMCID: PMC4059634  PMID: 24932586
2.  Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder 
Biological psychology  2013;93(1):150-158.
Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.
doi:10.1016/j.biopsycho.2013.01.018
PMCID: PMC3687535  PMID: 23410758
Stress; Depression; Diurnal cortisol slope; Cortisol awakening response; Dexamethasone suppression test; Inflammation; Health; Disease
3.  Cross-National Analysis of the Associations among Mental Disorders and Suicidal Behavior: Findings from the WHO World Mental Health Surveys 
PLoS Medicine  2009;6(8):e1000123.
Using data from over 100,000 individuals in 21 countries participating in the WHO World Mental Health Surveys, Matthew Nock and colleagues investigate which mental health disorders increase the odds of experiencing suicidal thoughts and actual suicide attempts, and how these relationships differ across developed and developing countries.
Background
Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts.
Methods and Findings
Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9–8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5–5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies.
Conclusions
This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Suicide is a leading cause of death worldwide. Every 40 seconds, someone somewhere commits suicide. Over a year, this adds up to about 1 million self-inflicted deaths. In the USA, for example, where suicide is the 11th leading cause of death, more than 30,000 people commit suicide every year. The figures for nonfatal suicidal behavior (suicidal thoughts or ideation, suicide planning, and suicide attempts) are even more shocking. Globally, suicide attempts, for example, are estimated to be 20 times as frequent as completed suicides. Risk factors for nonfatal suicidal behaviors and for suicide include depression and other mental disorders, alcohol or drug abuse, stressful life events, a family history of suicide, and having a friend or relative commit suicide. Importantly, nonfatal suicidal behaviors are powerful predictors of subsequent suicide deaths so individuals who talk about killing themselves must always be taken seriously and given as much help as possible by friends, relatives, and mental-health professionals.
Why Was This Study Done?
Experts believe that it might be possible to find ways to decrease suicide rates by answering three questions. First, which individual mental disorders are predictive of nonfatal suicidal behaviors? Although previous studies have reported that virtually all mental disorders are associated with an increased risk of suicidal behaviors, people often have two or more mental disorders (“comorbidity”), so many of these associations may reflect the effects of only a few disorders. Second, do some mental disorders predict suicidal ideation whereas others predict who will act on these thoughts? Finally, are the associations between mental disorders and suicidal behavior similar in developed countries (where most studies have been done) and in developing countries? By answering these questions, it should be possible to improve the screening, clinical risk assessment, and treatment of suicide around the world. Thus, in this study, the researchers undertake a cross-national analysis of the associations among mental disorders (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV]) and nonfatal suicidal behaviors.
What Did the Researchers Do and Find?
The researchers collected and analyzed data on the lifetime presence and age-of-onset of mental disorders and of nonfatal suicidal behaviors in structured interviews with nearly 110,000 participants from 21 countries (part of the World Health Organization's World Mental Health Survey Initiative). The lifetime presence of each of the 16 disorders considered (mood disorders such as depression; anxiety disorders such as post-traumatic stress disorder [PTSD]; impulse-control disorders such as attention deficit/hyperactivity disorder; and substance misuse) predicted first suicide attempts in both developed and developing countries. However, the increased risk of a suicide attempt associated with each disorder varied. So, for example, in developed countries, after controlling for comorbid mental disorders, major depression increased the risk of a suicide attempt 3-fold but drug abuse/dependency increased the risk only 2-fold. Similarly, although the strongest predictors of suicide attempts in developed countries were mood disorders, in developing countries the strongest predictors were impulse-control disorders, substance misuse disorders, and PTSD. Other analyses indicate that mental disorders were generally more predictive of the onset of suicidal thoughts than of suicide plans and attempts, but that anxiety and poor impulse-control disorders were the strongest predictors of suicide attempts in both developed and developing countries.
What Do These Findings Mean?
Although this study has several limitations—for example, it relies on retrospective self-reports by study participants—its findings nevertheless provide a more detailed understanding of the associations between mental disorders and subsequent suicidal behaviors than previously available. In particular, its findings reveal that a wide range of individual mental disorders increase the chances of an individual thinking about suicide in both developed and developing countries and provide new information about the mental disorders that predict which people with suicidal ideas will act on such thoughts. However, the findings also show that only half of people who have seriously considered killing themselves have a mental disorder. Thus although future suicide prevention efforts should include a focus on screening and treating mental disorders, ways must also be found to identify the many people without mental disorders who are at risk of suicidal behaviors.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000123.
The US National Institute of Mental Health provides information about suicide in the US: statistics and prevention
The UK National Health Service provides information about suicide, including statistics about suicide in the UK and links to other resources
The World Health Organization provides global statistics about suicide and information on suicide prevention
MedlinePlus provides links to further information and advice about suicide and about mental health (in English and Spanish)
Further details about the World Mental Health Survey Initiative and about DSM-IV are available
doi:10.1371/journal.pmed.1000123
PMCID: PMC2717212  PMID: 19668361
4.  The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression 
PLoS ONE  2009;4(1):e4324.
Background
In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated.
Methodology/Principal Findings
In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome.
Conclusions/Significance
Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response.
doi:10.1371/journal.pone.0004324
PMCID: PMC2629564  PMID: 19177168
5.  Cortisol and ACTH Responses to the Dex/CRH Test: Influence of Temperament 
Hormones and behavior  2008;53(4):518-525.
Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58) = 4.86, p < .05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58) = 5.28, p <.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53) = 3.37, p < .05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.
doi:10.1016/j.yhbeh.2007.12.004
PMCID: PMC2637444  PMID: 18294637
Cortisol; Dex/CRH test; HPA axis; temperament; personality; inhibition
6.  Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Depressed Children and Adolescents: A Meta-Analysis 
Psychoneuroendocrinology  2009;34(9):1272-1283.
Summary
Research findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: a) 17 published studies of HPA-axis response to the dexamethasone suppression test in depressed youth (DST; N=926) and b) 17 studies of basal HPA-axis functioning (N=1,332). We also examined descriptively studies that used corticotropin releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was .57, z = 4.18 p< .01. The global standardized mean difference effect size in basal HPA-axis functioning was .20, z = 4.53, p < .01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.
doi:10.1016/j.psyneuen.2009.03.016
PMCID: PMC2796553  PMID: 19406581
HPA-Axis; Depression; Children; Adolescents; Dexamethasone Suppression Test
7.  Familial Longevity Is Marked by Lower Diurnal Salivary Cortisol Levels: The Leiden Longevity Study 
PLoS ONE  2012;7(2):e31166.
Background
Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity.
Methods
Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors.
Results
Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28).
Conclusion
Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed.
doi:10.1371/journal.pone.0031166
PMCID: PMC3278433  PMID: 22348049
8.  Combined biological tests for suicide prediction 
Psychiatry research  2007;150(2):187-191.
Disturbances in serotonin neuroregulation and in hypothalamic-pituitary-adrenal axis activity are both likely, and possibly independent, factors in the genesis of suicidal behavior. This analysis considers whether clinically accessible measures of these two disturbances have additive value in the estimation of risk for suicide. Seventy-four inpatients with RDC major or schizoaffective depressive disorders entered a prospective follow-up study from 1978–1981, underwent a dexamethasone suppression test (DST) and had fasting serum cholesterol levels available in the medical record. As reported earlier, patients who had had an abnormal DST result were significantly more likely to commit suicide during follow-up. Serum cholesterol concentrations did not differ by DST result and low cholesterol values were associated with subsequent suicide when age and sex were included as covariates. These results indicate that, with the use of age-appropriate thresholds, serum cholesterol concentrations may be combined with DST results to provide a clinically useful estimate of suicide risk.
doi:10.1016/j.psychres.2006.01.021
PMCID: PMC1880882  PMID: 17289156
Dexamethasone suppression test; cholesterol; cortisol; depressive disorder
9.  In Search of HPA Axis Dysregulation in Child and Adolescent Depression 
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression.
doi:10.1007/s10567-011-0084-5
PMCID: PMC3095794  PMID: 21290178
Depression; Childhood and adolescence; Hypothalamic–pituitary–adrenal (HPA) axis; Developmental psychopathology
10.  Genetic load is associated with hypothalamic–pituitary–adrenal axis dysregulation in macaques 
Genes, brain, and behavior  2012;10.1111/j.1601-183X.2012.00856.x.
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from −21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 ‘high’ and 19 ‘low’ animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the ‘risk’ genotypes from these three loci was detected, with an increasing number of ‘risk’ genotypes associated with a blunted ACTH response (P =0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.
doi:10.1111/j.1601-183X.2012.00856.x
PMCID: PMC3595329  PMID: 22998353
ACTH; CRH; dexamethasone; DST; polymorphism; rhesus; serotonin
11.  Glucocorticoid receptor dysfunction: consequences for the pathophysiology and treatment of mood disorders 
Indian Journal of Psychiatry  2003;45(2):5-14.
Background:
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in mood disorders is one of the most robust findings in biological psychiatry. However, considerable debate surrounds the nature of the core abnormality, its cause, consequences and treatment implications.
Aims:
To review the evidence for the role of HPA axis dysfunction in the pathophysiology of mood disorders with particular reference to corticosteroid receptor pathology.
Methods:
A selective review of the published literature in this field, focusing on human studies.
Results:
The nature of basal HPA axis dysregulation described in both manic and depressed bipolars appears to be similar to those described in MDD. But studies using the dexamethasone/ corticotropin releasing hormone (dex/CRH) test and dexamethasone suppression test (DST) have shown that HPA axis dysfunction is more prevalent in bipolar than in unipolar disorder. There is robust evidence for corticotropin releasing hormone (CRH) hyperdrive and glucocorticoid receptor (GR) dysfunction in mood disorders, with increasing evidence for disorders within the AVP system.
Conclusion:
HPA axis dysfunction is prevalent in patients with mood disorder, particularly those with psychotic disorders and bipolar affective disorder. This may be secondary to genetic factors, early life adversities or both. Dysfunction of GR may be the underlying abnormality and preliminary findings suggest that it is a potential target for novel therapies.
Declaration of interest:
None
PMCID: PMC2952148  PMID: 21206827
Mood disorders; pathophysiology; Glncocorticoid Receptor
12.  Stress Sensitivity in Metastatic Breast Cancer: Analysis of Hypothalamic-Pituitary-Adrenal Axis Function 
Psychoneuroendocrinology  2006;31(10):1231-1244.
The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process.
We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 minutes later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1 mg of dexamethasone administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0..28 to .30 at different times of the post dexamethasone administration day, all p<.01) . Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 minutes after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=−0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5 mg of dexamethasone to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66 p<.0001, N = 74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.
doi:10.1016/j.psyneuen.2006.09.004
PMCID: PMC1790857  PMID: 17081700
Cortisol; HPA; stress; dexamethasone; CRF; metastatic breast cancer
13.  Longitudinal Changes in Cortisol Secretion and Conversion to Psychosis in At-Risk Youth 
Journal of abnormal psychology  2010;119(2):401-408.
Elevations in hypothalamic–pituitary–adrenal (HPA) axis activity have been implicated in the origins and exacerbation of mental disorders. Several lines of investigation suggest HPA activity, indexed by increased cortisol, is elevated in patients with schizophrenia and other psychotic disorders. This study examined the relation of cortisol levels and longitudinal changes with psychotic outcomes in at-risk adolescents. Participants were 56 adolescents who met risk criteria for psychosis, namely, schizotypal personality disorder (n = 5), prodromal symptom criteria based on the Structured Interview for Prodromal Symptoms (n = 17), or both (n = 34). Of these, 14 subsequently met DSM–IV criteria for an Axis I psychotic disorder (schizophrenia, schizoaffective disorder, or mood disorder with psychotic features). Participants were assessed at baseline and then followed longitudinally. Salivary cortisol was sampled multiple times at initial assessment, interim follow-up, and 1-year follow-up. Area under the curve (AUC) was computed from the repeated cortisol measures. The findings indicate that at-risk subjects who subsequently developed psychosis showed significantly higher cortisol at the first follow-up, a trend at the 1-year follow-up, and a significantly larger AUC when compared to those who did not convert. A similar pattern of group differences emerged from analyses excluding those who may have converted prior to the 1-year follow-up. These findings converge with previous reports on HPA activity in psychosis, as well as theoretical assumptions concerning the effects of cortisol elevations on brain systems involved in psychotic symptoms. Future research with larger samples is needed to confirm and extend these results.
doi:10.1037/a0018399
PMCID: PMC3052257  PMID: 20455612
risk for psychosis; cortisol; adolescents
14.  Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder 
Journal of affective disorders  2011;136(3):350-358.
Background
Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol.
Method
Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined.
Results
A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups.
Limitations
The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account.
Conclusions
Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.
doi:10.1016/j.jad.2011.11.027
PMCID: PMC3683957  PMID: 22154566
Bipolar; Suicide; Cortisol; HPA axis; Biomarker
15.  Cortisol Responses to Psychosocial Stress Predict Depression Trajectories: Social-Evaluative Threat and Prior Depressive Episodes as Moderators 
Journal of affective disorders  2012;143(1-3):223-230.
Background
Alterations of hypothalamic-pituitary-adrenal (HPA) function are well-established in adults with current depression. HPA alterations may persist into remission and confer increased risk for recurrence.
Methods
A modified version of the Trier Social Stress Test (TSST) was administered at baseline to 32 young adults with remitted major depressive disorder and 36 never-depressed controls. Participants were randomly assigned to either a ‘high–stress’ condition involving social evaluation or a ‘low-stress’ control condition. Cortisol concentrations were measured in saliva samples throughout the TSST. Participants were assessed again after 6 months for the occurrence of stressful life events and depressive symptoms/disorders during the follow-up period.
Results
Participants who exhibited enhanced cortisol reactivity in the low-stress condition showed increases in depressive symptoms over follow-up, after controlling for stressful life events during the follow-up period. Anticipatory stress cortisol and cortisol reactivity each interacted with history of depressive episodes to predict depression trajectories.
Limitations
The single TSST administration limits conclusions about whether alterations of cortisol reactivity represent trait-like vulnerability factors or consequences (“scars’) of past depression.
Conclusions
These results extend previous findings on stress sensitivity in depression and suggest that altered HPA function during remission could reflect an endophenotype for vulnerability to depression recurrence. Findings support interactive models of risk for depression recurrence implicating HPA function, depression history, and sensitivity to minor stressors. Results may have implications for interventions that match treatment approaches to profiles of HPA function.
doi:10.1016/j.jad.2012.05.059
PMCID: PMC3489962  PMID: 22858210
depression; cortisol; hypothalamic-pituitary-adrenal axis; stress; recurrence; social-evaluative threat
16.  The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression 
Psychoneuroendocrinology  2012;38(1):115-121.
Introduction
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).
Methods
Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00 h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00 h all subjects were given 0.5 mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed.
Results
There were no significant group differences for cortisol at baseline: F (2,47) = .19, p= .83. There were significant group differences for post-fludrocortisone cortisol: F (2,47) = 5.13, p = .01, which were significantly higher in PMDs compared to HCs (p = .007), but not compared to NPMDs (p = .18). There were no differences between NPMD’s and HC’s (p= .61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200 hrs than NPMDs (p =.01) or HCs (p = .009).
Conclusions
Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.
doi:10.1016/j.psyneuen.2012.05.006
PMCID: PMC3633490  PMID: 22727477
Mineralocorticoid receptor; HPA axis; Fludrocortisone; Psychotic Major Depression; Cortisol; Hippocampus
17.  Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus 
Psychoneuroendocrinology  2011;37(1):27-38.
Environmental stress has been demonstrated to increase susceptibility for mood and anxiety disorders, and hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis, the primary endocrine response to stress, is often observed in these patients. HPA axis activation is initiated by corticotropin-releasing factor (CRF) from the hypothalamus, leading to the hypothesis that hypothalamic CRF overexpression contributes to HPA axis hyperactivity in psychiatric patients. In addition, elevated CRF in cerebrospinal fluid is observed in mood and anxiety disorder patients, suggesting that CRF is also being overproduced from extrahypothalamic sources such as the central amygdala (CeA) and overactivity of the amygdala in neuroimaging studies is a consistent finding in anxiety and depression patients. Due to the importance of CRF and the amygdala in the etiology of stress-sensitive psychiatric disorders, the present study sought to further dissect the impact of CRF overexpression (OE) in the amygdala on downstream behavioral, endocrine, and gene-expression changes typically associated with chronic stress. To test the hypothesis that elevated CRF output from the amygdala would reproduce HPA axis hyperactivity and behavioral symptoms of chronic stress, we developed a lentiviral vector in which 3.0Kb of the CRF promoter drives overexpression of CRF (LVCRFp3.0CRF). In adult male rats, Experiment-1 examined behavioral consequences of chronic CRF overexpression from the amygdala; the dexamethasone (Dex) /CRF test was used to measure HPA axis reactivity. Experiment-2 focused on HPA axis disruptions; the dexamethasone-suppression and CRF-stimulation tests as well as the Dex/CRF test were used. In both experiments, expression of HPA-axis related transcripts were assessed.
doi:10.1016/j.psyneuen.2011.04.014
PMCID: PMC3164918  PMID: 21616602
Amygdala; Anxiety; Corticotropin-Releasing Factor (CRF); Depression; Hypothalamic Pituitary Adrenal (HPA) Axis; Lentivirus
18.  Neuroendocrine Predictors of Emotional and Behavioral Adjustment in Boys: Longitudinal Follow-Up of a Community Sample 
Psychoneuroendocrinology  2012;37(12):2042-2046.
Background
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in adults and children with mood and anxiety disorders and is thought to be involved in the pathogenesis of these disorders. We recently studied a diverse community sample of boys and found associations of behavioral problems, including symptoms of depression and anxiety, with basal and stress-induced cortisol concentrations. Here we examine cortisol-emotional/behavioral associations at a two-year follow-up and test whether initial cortisol is predictive of worsening of emotional/behavioral problems two years later.
Method
Seventy-eight 10–14 year-old boys and their mothers completed a battery of psychosocial assessments, provided morning and afternoon saliva samples, and participated in a home visit involving mildly stressful tasks and saliva collection for cortisol assay during a two-year follow-up assessment.
Results
Consistent with the findings from our time 1 assessment, greater declines in cortisol across the home-visit challenge task were significantly associated with internalizing and externalizing behaviors as well as attention problems and social problems at the two-year follow-up. In addition, morning and afternoon cortisol concentrations at the initial assessment were significant positive predictors of the later development of child depressive symptoms at follow-up after controlling for initial depressive symptoms.
Conclusion
These findings demonstrate that children in the community with internalizing and externalizing behavior problems have altered patterns of HPA axis stress reactivity. In addition, our prospective findings suggest that elevated cortisol concentrations may influence the later development of emotional/behavioral problems in boys.
doi:10.1016/j.psyneuen.2012.04.004
PMCID: PMC3458171  PMID: 22575356
children; adolescents; boys; depression; cortisol; anxiety; HPA axis; stress reactivity; longitudinal; prospective
19.  Modeling Cortisol Dynamics in the Neuro-endocrine Axis Distinguishes Normal, Depression, and Post-traumatic Stress Disorder (PTSD) in Humans 
PLoS Computational Biology  2012;8(2):e1002379.
Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (n = 3) in each category and created a model subject (n = 1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative feedback loop may cause hypersensitive neuro-endocrine axis that results in hypocortisolemia in PTSD.
Author Summary
PTSD is an anxiety disorder that occurs among persons exposed to a traumatic event involving life threat and injury. This is a co-morbid psychiatric disorder that occurs along with depression. Cortisol is an informative endocrine biomarker that can distinguish PTSD from other co-morbid disorders. In comparison to normal subjects, hypocortisolemia was observed during the night in PTSD, while hypercortisolemia was observed in depressed subjects. From analyzing the clinical data, Yehuda et al. hypothesized that hypocortisolemia in PTSD was due to the strong negative feedback loop operating in the neuroendocrine axis under severe stress. We complemented this hypothesis by constructing a mathematical model for cortisol dynamics in HPA axis and estimated the kinetic parameters that fitted the cortisol time series obtained from the clinical data of normal, depressed and PTSD patients. The parameters obtained from the simulated phenotypes also strongly support the hypothesis that, due to disruptive negative feedback loops, cortisol levels are different in normal, PTSD and depressed subjects during the night. Importantly, the model predicted the transitions from normal to various diseased states, and these transitions were shown to occur due to changes in the strength of the negative feedback loop and the stress intensity in the neuro-endocrine axis.
doi:10.1371/journal.pcbi.1002379
PMCID: PMC3280965  PMID: 22359492
20.  Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010 
PLoS Medicine  2013;10(11):e1001547.
In this paper, Ferrari and colleagues analyzed the burden of depressive disorders in GBD 2010 and identified depressive disorders as a leading cause of burden. The authors present severity proportions; burden by country, region, age, sex, and year; as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Please see later in the article for the Editors' Summary
Background
Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Methods and Findings
Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders.
Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and dysthymia for 1.4% (0.9%–2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and dysthymia for 0.5% (0.3%–0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs.
Conclusions
GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depressive disorders are common mental disorders that occur in people of all ages across all world regions. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—can make people feel that life is no longer worth living. People affected by depression lose interest in the activities they used to enjoy and can also be affected by physical symptoms such as disturbed sleep. Major depressive disorder (MDD, also known as clinical depression) is an episodic disorder with a chronic (long-term) outcome and increased risk of death. It involves at least one major depressive episode in which the affected individual experiences a depressed mood almost all day, every day for at least 2 weeks. Dysthymia is a milder, chronic form of depression that lasts for at least 2 years. People with dysthymia are often described as constantly unhappy. Both these subtypes of depression (and others such as that experienced in bipolar disorder) can be treated with antidepressant drugs and with talking therapies.
Why Was This Study Done?
Depressive disorders were a leading cause of disease burden in the 1990 and 2000 Global Burden of Disease (GBD) studies, collaborative scientific efforts that quantify the health loss attributable to diseases and injuries in terms of disability adjusted life years (DALYs; one DALY represents the loss of a healthy year of life). DALYs are calculated by adding together the years of life lived with a disability (YLD, a measure that includes a disability weight factor reflecting disease severity) and the years of life lost because of disorder-specific premature death. The GBD initiative aims to provide data that can be used to improve public-health policy. Thus, knowing that depressive disorders are a leading cause of disease burden worldwide has helped to prioritize depressive disorders in global public-health agendas. Here, the researchers analyze the burden of MDD and dysthymia in GBD 2010 by country, region, age, and sex, and calculate the burden of suicide and ischemic heart disease attributable to depressive disorders (depression is a risk factor for suicide and ischemic heart disease). GBD 2010 is broader in scope than previous GBD studies and quantifies the direct burden of 291 diseases and injuries and the burden attributable to 67 risk factors across 187 countries.
What Did the Researchers Do and Find?
The researchers collected data on the prevalence, incidence, remission rates, and duration of MDD and dysthymia and on the excess deaths caused by these disorders from published articles. They pooled these data using a statistical method called Bayesian meta-regression and calculated YLDs for MDD and dysthymia using disability weights collected in population surveys. MDD accounted for 8.2% of global YLDs in 2010, making it the second leading cause of YLDs. Dysthymia accounted for 1.4% of global YLDs. MDD and dysthymia were also leading causes of DALYs, accounting for 2.5% and 0.5% of global DALYs, respectively. The regional variation in the burden was greater for MDD than for dysthymia, the burden of depressive disorders was higher in women than men, the largest proportion of YLDs from depressive disorders occurred among adults of working age, and the global burden of depressive disorders increased by 37.5% between 1990 and 2010 because of population growth and ageing. Finally, MDD explained an additional 16 million DALYs and 4 million DALYs when it was considered as a risk factor for suicide and ischemic heart disease, respectively. This “attributable” burden increased the overall burden of depressive disorders to 3.8% of global DALYs.
What Do These Findings Mean?
These findings update and extend the information available from GBD 1990 and 2000 on the global burden of depressive disorders. They confirm that depressive disorders are a leading direct cause of the global disease burden and show that MDD also contributes to the burden allocated to suicide and ischemic heart disease. The estimates of the global burden of depressive disorders reported in GBD 2010 are likely to be more accurate than those in previous GBD studies but are limited by factors such as the sparseness of data on depressive disorders from developing countries and the validity of the disability weights used to calculate YLDs. Even so, these findings reinforce the importance of treating depressive disorders as a public-health priority and of implementing cost-effective interventions to reduce their ubiquitous burden.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001547.
The US National Institute of Mental Health provides information on all aspects of depression
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
MedlinePlus provides links to other resources about depression (in English and Spanish)
The World Health Organization provides information on depression and on the global burden of disease (in several languages)
Information about the Global Burden of Disease initiative is available
beyondblue provides many resources on depression
The Queensland Centre for Mental Health Research provides information on epidemiology and the global burden of disease specifically for mental disorders
doi:10.1371/journal.pmed.1001547
PMCID: PMC3818162  PMID: 24223526
21.  Enhanced Cortisol Suppression Following Dexamethasone Administration in Domestic Violence Survivors 
The American journal of psychiatry  2005;162(6):1192-1199.
Objective
The authors compared responses of female domestic violence survivors and a matched group of nontraumatized participants to a low-dose (0.5 mg) dexamethasone suppression test (DST).
Method
Seventy female domestic violence survivors and 14 nontraumatized women matched for age and race were recruited. Participants were assessed for trauma severity, severity of PTSD and depressive symptoms, and DST cortisol response. Of the domestic violence survivors who were DST-compliant, comparisons were made among those with PTSD (N=15), those with PTSD plus depression (N=27), and those with no PTSD or depression diagnosis (N=8) along with the nontraumatized comparison subjects (N=14).
Results
Domestic violence survivors with PTSD, regardless of whether or not they had comorbid depression, had significantly lower baseline cortisol levels at 9:00 a.m. than the healthy subjects and trauma survivors with no diagnosis. Survivors with a sole diagnosis of PTSD showed significantly greater cortisol suppression to dexamethasone than did healthy subjects or the group diagnosed with PTSD plus depression.
Conclusions
These findings agree with previous studies showing hypothalamicpituitary-adrenal (HPA) axis abnormalities in PTSD. The findings suggest that the chronic nature of domestic violence leads to a severe dysregulation of the HPA axis.
doi:10.1176/appi.ajp.162.6.1192
PMCID: PMC2977515  PMID: 15930069
22.  Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults 
Background
Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1β) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1β gene polymorphisms and HPA axis function assessed with the DEX/CRH test.
Methods
DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels.
Results
The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction.
Conclusions
Our results suggest that genetic variations in the IL-1β gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1β gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.
doi:10.1186/1744-9081-7-23
PMCID: PMC3141407  PMID: 21726461
23.  Hypothalamic-pituitary-adrenal axis functioning and dysfunctional attitude in depressed patients with and without childhood neglect 
BMC Psychiatry  2014;14:45.
Background
To date, the relationships between childhood neglect, hypothalamic-pituitary-adrenal (HPA) axis functioning and dysfunctional attitude in depressed patients are still obscure.
Methods
The Childhood Trauma Questionnaire (CTQ) was used to assess childhood emotional neglect and physical neglect. Twenty-eight depressed patients with childhood neglect and 30 depressed patients without childhood neglect from Guangzhou Psychiatric Hospital were compared with 29 age- and gender-matched control subjects without childhood neglect and 22 control subjects with childhood neglect. Cortisol awakening response, the difference between the cortisol concentrations at awakening and 30 minutes later, provided a measure of HPA axis functioning. The Dysfunctional Attitude Scale measured cognitive schema.
Results
HPA axis functioning was significantly increased in depressed patients with childhood neglect compared with depressed patients without childhood neglect (p < 0.001). HPA axis activity in the control group with childhood neglect was significantly higher than in the depressed group without childhood neglect (p < 0.001). Total scores of childhood neglect were positively correlated with HPA axis functioning and dysfunctional attitude scores, but not with severity of depression. We did not find correlations with HPA axis functioning and dysfunctional attitude or with the Hamilton Rating Scale for Depression scores.
Conclusions
Childhood neglect may cause hyperactivity of the HPA axis functioning and dysfunctional attitude, but does not affect depression severity.
doi:10.1186/1471-244X-14-45
PMCID: PMC3937002  PMID: 24548345
Depression; Childhood neglect; HPA axis functioning; Dysfunctional attitude scale
24.  Can Variation in Hypothalamic-Pituitary-Adrenal (HPA)-Axis Activity Explain the Relationship between Depression and Cognition in Bipolar Patients? 
PLoS ONE  2012;7(5):e37119.
Background
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning.
Methodology/Principal Findings
In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition.
Conclusions/Significance
As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.
doi:10.1371/journal.pone.0037119
PMCID: PMC3351438  PMID: 22606339
25.  Adrenocortical and Pituitary Glucocorticoid Feedback in Abstinent Alcohol-Dependent Women 
Background
The long-term ingestion of alcohol diminishes hypothalamic–pituitary–adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone.
Methods
Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 μg/kg), a synthetic ACTH (1–24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes.
Results
Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone.
Conclusion
Significant differences in pituitary–adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.
doi:10.1111/j.1530-0277.2010.01164.x
PMCID: PMC4038906  PMID: 20331575
Adrenal Cortex; Alcoholism; Cosyntropin; Dexamethasone; Pituitary-Adrenal System; Gender; Female

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