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1.  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.
PMCID: PMC3052257  PMID: 20455612
risk for psychosis; cortisol; adolescents
2.  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.
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.
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.
PMCID: PMC3351438  PMID: 22606339
3.  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.
PMCID: PMC2637444  PMID: 18294637
Cortisol; Dex/CRH test; HPA axis; temperament; personality; inhibition
4.  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.
PMCID: PMC1880882  PMID: 17289156
Dexamethasone suppression test; cholesterol; cortisol; depressive disorder
5.  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.
PMCID: PMC3595329  PMID: 22998353
ACTH; CRH; dexamethasone; DST; polymorphism; rhesus; serotonin
6.  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.
PMCID: PMC3095794  PMID: 21290178
Depression; Childhood and adolescence; Hypothalamic–pituitary–adrenal (HPA) axis; Developmental psychopathology
7.  Low-dose dexamethasone challenge in women with atypical major depression: pilot study 
To examine if atypical depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis.
Eight women with atypical major depression and 11 controls with no history of psychiatric illness, matched on age and body mass index, were challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and 1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol samples were drawn at 8 am and 3 pm on the following day.
After the 0.50-mg dexamethasone challenge, mean suppression of morning cortisol was significantly greater in patients with atypical depression (91.9;, standard deviation [SD] 6.8%) than in the controls (78.3%, SD 10.7%; p < 0.01).
These preliminary data add to the growing body of literature that suggests atypical depression, in contrast to classic melancholia, may be associated with exaggerated negative feedback regulation of the HPA axis.
PMCID: PMC149795  PMID: 11836976
corticotropin-releasing hormone; depression, atypical, dexamethasone; hormones; hydrocortisone; mood disorders; stress
8.  Dex/CRH test cortisol response in outpatients with major depression and matched healthy controls 
Psychoneuroendocrinology  2009;34(8):1208-1213.
The dexamethasone/corticotropin releasing hormone (Dex/CRH) test has been proposed as a potential tool for identifying endophenotypes relevant to mood disorders. An exaggerated cortisol response to the test during major depressive episodes has been demonstrated for inpatients with melancholic or psychotic features. A diminished hormone response has been observed in chronically depressed outpatients.
Following a battery of self-report and interview assessments, 68 adults completed the Dex/CRH test. Thirty-four met structured interview criteria for current major depressive disorder and 34 age- and sex-matched control subjects had no current or lifetime DSM-IV depressive disorder. Effect of diagnosis on cortisol response to the Dex/CRH test was examined in a repeated measures general linear model.
The matched groups were equivalent with regard to childhood adversity. Cortisol response to the Dex/CRH test among subjects with current MDD was not significantly different from that seen in matched healthy controls. Independent of diagnosis, an exploratory analysis showed a trend-level association between maltreatment history and diminished cortisol response; no interactive effects with depression diagnosis were detected.
The results do not support the hypothesis that elevated cortisol response to the Dex/CRH test represents a marker for major depressive episodes.
PMCID: PMC3580166  PMID: 19375869
Childhood abuse; Mood disorders; Depression; Cortisol; HPA axis; Early life stress
9.  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.
PMCID: PMC3687535  PMID: 23410758
Stress; Depression; Diurnal cortisol slope; Cortisol awakening response; Dexamethasone suppression test; Inflammation; Health; Disease
10.  The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models 
Translational Psychiatry  2012;2(3):e92-.
A compelling association has been observed between cardiovascular disease (CVD) and depression, suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality. Systemic immune activation, hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship. Although a differential epidemiological association between CVD and depression subtypes is evident, it has not been determined if this indicates subtype specific biological mechanisms. A comprehensive systematic literature search was conducted using PubMed and PsycINFO databases yielding 147 articles for this review. A complex pattern of systemic immune activation, endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes. The findings of this review suggest that diagnostic subtypes rather than a unifying model of depression should be considered when investigating the bidirectional biological relationship between CVD and depression. The suggested model of a subtype-specific biological relationship between depression and CVDs has implications for future research and possibly for diagnostic and therapeutic processes.
PMCID: PMC3309537  PMID: 22832857
biological mechanisms; cardiovascular disease; endothelial dysfunction; inflammation; subtypes of depression
11.  HPA axis function and symptoms in adolescents at clinical high risk for schizophrenia 
Schizophrenia research  2012;135(0):170-174.
Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance.
Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms.
Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated.
Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.
PMCID: PMC3716011  PMID: 22226904
Cortisol; Psychosis; Schizophrenia; Risk; Prodrome; Prodromal
12.  Glucocorticoid receptor dysfunction: consequences for the pathophysiology and treatment of mood disorders 
Indian Journal of Psychiatry  2003;45(2):5-14.
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.
To review the evidence for the role of HPA axis dysfunction in the pathophysiology of mood disorders with particular reference to corticosteroid receptor pathology.
A selective review of the published literature in this field, focusing on human studies.
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.
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:
PMCID: PMC2952148  PMID: 21206827
Mood disorders; pathophysiology; Glncocorticoid Receptor
Depression and anxiety  2011;28(5):383-392.
The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.
In two test sessions, subjects received 1 μg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges.
The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST.
CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders.
PMCID: PMC3243643  PMID: 21328636
trauma; gender; HPA axis; hypothalamic–pituitary–adrenal axis; cortisol; corticotropin
14.  The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression 
Psychoneuroendocrinology  2012;38(1):115-121.
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).
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.
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).
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.
PMCID: PMC3633490  PMID: 22727477
Mineralocorticoid receptor; HPA axis; Fludrocortisone; Psychotic Major Depression; Cortisol; Hippocampus
15.  Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy 
Neurobiology of disease  2009;34(3):457-461.
Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo-pituitary-adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positive combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression.
PMCID: PMC2683188  PMID: 19285131
Epilepsy; depression; co-morbidity; hypothalamo-pituitary-adrenocortical axis; chronic stress
16.  Hypothalamic-Pituitary-Adrenal Axis Function in Dissociative Disorders, PTSD, and Healthy Volunteers 
Biological psychiatry  2006;61(8):966-973.
This study investigated basal and stress-induced HPA axis alterations in dissociative disorders (DD).
Forty-six subjects with DD without lifetime PTSD, 35 subjects with PTSD, and 58 HC subjects, free of current major depression, were studied as inpatients. After a 24-hour urine collection and hourly blood sampling for ambient cortisol determination, a low-dose dexamethasone suppression test was administered, followed by the Trier Social Stress Test.
The DD group had significantly elevated urinary cortisol compared to the HC group, more pronounced in the absence of lifetime major depression, whereas the PTSD and HC groups did not differ. The DD group demonstrated significantly greater resistance to, and faster escape from, dexamethasone suppression compared to the HC group, whereas the PTSD and HC groups did not differ. The three groups did not differ in cortisol stress reactivity, but both psychiatric groups demonstrated a significant inverse correlation between dissociation severity and cortisol reactivity, after controlling for all other symptomatology. The PTSD subgroup with comorbid DD tended to have blunted reactivity compared to the HC group.
The study demonstrates a distinct pattern of HPA axis dysregulation in DD, emphasizing the importance of further study of stress response systems in dissociative psychopathology.
PMCID: PMC2567868  PMID: 17137559
cortisol; HPA axis; neuroendocrinology; dissociative disorders; PTSD; stress
17.  Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile 
BMC Medicine  2013;11:129.
Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline.
PMCID: PMC3661358  PMID: 23672628
Depression; Metabolic syndrome; Inflammation; Cortisol; Autonomic Tone; Cardiovascular; Obesity; Symptom profile; Treatment
18.  Management of Medication-Related Cardiometabolic Risk in Patients with Severe Mental Illness 
Severe psychotic disorders, which on their own may be a risk factor for metabolic disorder and cardiovascular illness, are clinically compounded by the significant adverse side effects of antipsychotic medications. The majority of patients with severe psychotic disorders (i.e., schizophrenia, bipolar disorder, mania, and depression) must take antipsychotic medications to treat their psychoses and, subsequently, will require efficacious interventions to manage the metabolic consequences of pharmacologic treatment to mitigate excessive mortality associated with cardiovascular illness. We have reviewed the metabolic consequences of antipsychotic treatment and discussed pilot findings from a new nonpharmacologic intervention study looking at the clinical benefits of regular exercise as a management tool for the cardiometabolic risk factors in a cohort with severe mental illness.
PMCID: PMC3702958  PMID: 23864926
Mental illness; Cardiometabolic disorder; Antipsychotics; Exercise
19.  Decreased ACTH and Cortisol Responses to Stress in Healthy Adults Reporting Significant Childhood Maltreatment 
Biological psychiatry  2007;62(10):1080-1087.
Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with Major Depressive Disorder and Post-Traumatic Stress Disorder.
Plasma adrenocorticotropin (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (N=50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL; n=23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL; n=27).
Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group × time effect characterized the relatively blunted ACTH response of the MAL group. Emotional Neglect (=−.34, p=.02) and Sexual Abuse (=+.31, p=.03) strongly predicted maximal cortisol release.
In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.
PMCID: PMC2094109  PMID: 17662255
Trier Social Stress Test; HPA Axis; Childhood; Abuse; Cortisol; ACTH; Reactivity; Endophenotype
20.  Childhood Parental Loss and Adult Hypothalamic-Pituitary-Adrenal Function 
Biological psychiatry  2008;63(12):1147-1154.
Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders.
Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test.
Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss.
These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.
PMCID: PMC2650434  PMID: 18339361
childhood parental loss; parental death; depression; cortisol; HPA axis
21.  Mechanisms Underlying the Comorbidity Between Depressive and Addictive Disorders in Adolescents: Interactions Between Stress and HPA Activity 
The American journal of psychiatry  2009;166(3):361-369.
Depression may be a precursor to substance use disorder in some youngsters, and substance abuse might complicate the subsequent course of depression. This study examined whether hypothalamic-pituitary-adrenal (HPA) activity and stressful life experiences are related to the development of substance use disorder in depressed and nondepressed adolescents, and whether substance use disorder predicts a worsening course of depression.
Urinary-free cortisol was measured for 3 nights in 151 adolescents with no prior history of substance use disorder (55 depressed, 48 at high risk for depression, and 48 normal subjects). Information was obtained on recent stressful life experiences. The participants were followed for up to 5 years to assess the onset of substance use disorder, course of depression, and stressful experiences. The relationships among depression, cortisol as a measure of HPA activity, stressful experiences, and substance use disorder were examined.
Elevated cortisol was associated with onset of substance use disorder. Stressful life experiences moderated this relationship. Cortisol and stress accounted for the effects of a history or risk of depression on the development of substance use disorder. Substance use disorder was associated with higher frequency of subsequent depressive episodes.
Higher cortisol prior to the onset of substance use disorder may indicate vulnerability to substance use disorder. Stressful experiences increase the risk for substance use disorder in such vulnerable youth. The high prevalence of substance use disorders in depressed individuals may be explained, in part, by high levels of stress and increased HPA activity.
PMCID: PMC2770585  PMID: 19223436
22.  Depressive Symptom Profiles and Severity Patterns in Outpatients with Psychotic versus Nonpsychotic Major Depression 
Comprehensive psychiatry  2008;49(5):421-429.
Previous research suggests that patients with psychotic major depression (PMD) may differ from those with nonpsychotic major depression (NMD) not only in terms psychotic features, but also in their depressive symptom presentation. The present study contrasted the rates and severity of depressive symptoms in outpatients diagnosed with PMD versus NMD.
The sample consisted of 1,112 patients diagnosed with major depression, of which 60 (5.3%) exhibited psychotic features. Depressive symptoms were assessed by trained diagnosticians at intake using the Structured Clinical Interview for DSM-IV and supplemented by severity items from the Schedule for Affective Disorders and Schizophrenia.
PMD patients were more likely to endorse the presence of weight loss, insomnia, psychomotor agitation, indecisiveness, and suicidality compared to NMD patients. Furthermore, PMD patient showed higher levels of severity on several depressive symptoms, including depressed mood, appetite loss, insomnia, psychomotor disturbances (agitation and retardation), fatigue, worthlessness, guilt, cognitive disturbances (concentration and indecisiveness), hopelessness, and suicidal ideation. The presence of psychomotor disturbance, insomnia, indecisiveness, and suicidal ideation were predictive of diagnostic status even after controlling for the effects of demographic characteristics and other symptoms.
These findings are consistent with past research suggesting that PMD is characterized by a unique depressive symptom profile in addition to psychotic features and higher levels of overall depression severity. The identification of specific depressive symptoms in addition to delusions/hallucinations that can differentiate PMD versus NMD patients can aid in the early detection of the disorder. These investigations also provide insights into potential treatment targets for this high-risk population.
PMCID: PMC2601715  PMID: 18702928
23.  Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression 
Translational Psychiatry  2013;3(11):e322-.
Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic–pituitary–adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of ⩾16 on the Centre for Epidemiology Studies-Depression scale or a diagnosis of current major depression based on the Mini International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) in the ACE gene were genotyped and diurnal cortisol secretion, as an index of HPA axis activity, was measured. Multivariable analyses were adjusted for socio-demographic and vascular factors, cognitive impairment, and apolipoprotein E. Strong significant associations were found between all seven SNPs and DEP and, in particular, first-onset DEP in persons without a past history of depression (P-values ranging from 0.005 to 0.0004). These associations remained significant after correction for multiple testing. The genotypes that were associated with an increased risk of DEP were also significantly associated with an increase in cortisol secretion under stress conditions. Variants of the ACE gene influence cortisol secretion and appear as susceptibility factors for late-life depression in the elderly population. Whether this could represent a common pathophysiological mechanism linking HPA axis and late-life depression remains to be explored.
PMCID: PMC3849962  PMID: 24193727
Angiotensin-converting enzyme; cortisol; elderly; HPA axis; late-life depression; prospective study
24.  Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Depressed Children and Adolescents: A Meta-Analysis 
Psychoneuroendocrinology  2009;34(9):1272-1283.
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.
PMCID: PMC2796553  PMID: 19406581
HPA-Axis; Depression; Children; Adolescents; Dexamethasone Suppression Test
25.  Mind and body: how the health of the body impacts on neuropsychiatry 
It has long been established in traditional forms of medicine and in anecdotal knowledge that the health of the body and the mind are inextricably linked. Strong and continually developing evidence now suggests a link between disorders which involve Hypothalamic-Pituitary-Adrenal axis (HPA) dysregulation and the risk of developing psychiatric disease. For instance, adverse or excessive responses to stressful experiences are built into the diagnostic criteria for several psychiatric disorders, including depression and anxiety disorders. Interestingly, peripheral disorders such as metabolic disorders and cardiovascular diseases are also associated with HPA changes. Furthermore, many other systemic disorders associated with a higher incidence of psychiatric disease involve a significant inflammatory component. In fact, inflammatory and endocrine pathways seem to interact in both the periphery and the central nervous system (CNS) to potentiate states of psychiatric dysfunction. This review synthesizes clinical and animal data looking at interactions between peripheral and central factors, developing an understanding at the molecular and cellular level of how processes in the entire body can impact on mental state and psychiatric health.
PMCID: PMC3866391  PMID: 24385966
mind-body interactions; psychiatric diseases; stress response; HPA axis; mood disorders; peripheral disorders; inflammatory processes

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