Salivary cortisol and posttraumatic stress disorder in a low-income community sample of women.

BACKGROUND: Studies of male combat veterans with posttraumatic stress disorder have demonstrated a profile of low cortisol. Studies with women with posttraumatic stress disorder (PTSD) have focused on childhood sexual abuse and holocaust survivors, both of whom experienced trauma during development, which could be different than adult trauma exposure. METHODS: Using an epidemiologic sample of low-income women from an urban area in Michigan, we conducted structured psychiatric interviews and saliva cortisol collection on a subsample of women with exposure to trauma but never PTSD (n = 72), recent PTSD (n = 29), and past PTSD (n = 70). Saliva cortisol was collected at awakening, 30 minutes later, at bedtime, and during a clinic visit. RESULTS: Recent trauma exposure but not past trauma exposure led to an increase in saliva cortisol. Neither recent PTSD nor past PTSD resulted in any saliva cortisol changes compared with the trauma exposed, never PTSD group. Recent major depression (past 12 months) demonstrated a weak effect (p =.08) on bedtime saliva cortisol. CONCLUSIONS: While recent trauma exposure can increase saliva cortisol, neither recent nor past PTSD affected saliva cortisol in our community sample of women. Our data do not support saliva cortisol changes associated with PTSD.     

Influence of age on the cortisol response to dexamethasone

Controversy exists regarding the association of age with postdexamethasone serum cortisol levels. We evaluated this relationship in 95 patients with major depressive disorder and 49 healthy controls. Age and 8 a.m. postdexamethasone cortisol levels were not correlated among the healthy controls, but were positively associated among the depressives. There was also a trend for age and 4 p.m. postdexamethasone cortisol levels to be positively associated in depressives. Multiple linear regression analyses revealed that these associations could not be explained by other variables such as sex, psychotic features, or familial subtype of depression. Several hypotheses that might account for these associations are examined.     

The influence of childhood abuse on cortisol levels and the cortisol awakening response in depressed and nondepressed older adults

Objectives: Childhood abuse has been associated with depression in later life. This may be related to hypothalamic-pituitary-adrenal (HPA) axis functioning. Therefore we aimed to examine the impact of childhood abuse and its interaction with depression on cortisol levels in older adults.

Methods: Data from 418 participants (mean age 70.8 years) in the Netherlands Study of Depression in Older Persons (NESDO) were used; 187 participants experienced childhood abuse; 309 participants had a diagnosis of depression. Diurnal cortisol levels were determined using six saliva samples from every participant. Multiple regression analyses were performed.

Results: Significant negative associations between childhood abuse and morning cortisol levels were found. In nondepressed persons, both psychological and sexual abuse were associated with greater dynamics of the HPA axis in response to awakening.

Conclusions: Childhood abuse is associated with lower basal cortisol levels at awakening irrespective of major depressive disorder (MDD). Higher reactivity of the HPA axis during the hour after awakening was found in nondepressed participants only, which might suggest that late-life depression modifies the effect of childhood abuse on the HPA axis. Older adults with a history of childhood abuse may be more negatively affected by stress or stressful events and this is reflected in dysregulation of the HPA axis.     

Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study.

BACKGROUND: Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, so it was expected that posttraumatic stress disorder (PTSD) would be associated with activation of this axis; however, studies have found both increased and decreased cortisol in PTSD. To address this question, we collected saliva cortisol at home in a subsample of a longitudinal epidemiologic sample. METHODS: Six hundred eighty-four persons randomly selected from the total sample of 913 were requested to collect saliva samples upon awakening and in the early evening. Of these, 538 responded with samples, 516 of whom met inclusion criteria. These were 68 exposed to trauma with lifetime PTSD, 265 exposed to trauma with no PTSD, and 183 never exposed to trauma. RESULTS: In a comparison of these three groups, lifetime PTSD revealed elevated evening saliva cortisol compared with exposed/no PTSD. When lifetime comorbidity with major depressive disorder (MDD) was included in the analysis, only persons with comorbid PTSD and MDD showed this evening elevation in cortisol. Persons with PTSD alone (never MDD) showed normal saliva cortisol levels, as did subjects with lifetime MDD alone. CONCLUSIONS: Neither exposure to trauma nor PTSD alone is associated with alterations in saliva cortisol; however, elevated cortisol is found in PTSD comorbid with lifetime MDD.     

Blunted stress cortisol reactivity and failure to acclimate to familiar stress in depressed and sub-syndromal children

Depressed adults have shown blunted or elevated cortisol reactivity in response to various forms of psychosocial stress. However, there have been few studies of cortisol reactivity in children who had early onset depression or a history of depression during the preschool–school period. The present study utilized a laboratory stress paradigm and collected salivary cortisol from preschoolers at baseline (ages 3–5 years) and 24-month follow-up (ages 5–7 years). Repeated-measures multivariate analyses of variance (MANOVAs) were used to compare cortisol reactivity to mild stress between children with Major Depressive Disorder (MDD), elevated symptoms of depression (sub-syndromal MDD), and healthy controls. For healthy children, a quadratic cortisol reactivity curve was found at baseline (n=73), which appeared flatter under similar stressful situations at follow-up (n=14), which may reflect acclimation to the paradigm. In contrast, children with MDD (n=46) and sub-syndromal MDD (n=76) showed a peak cortisol response to the novelty of lab arrival and then reduced and blunted responses to stressors at baseline. These cortisol responses persisted at follow-up in children with a history of MDD (n=41) or sub-syndromal MDD (n=73). These results suggest that the hypothalamic–pituitary–adrenal (HPA) axis shows a blunted response to stress and failed to acclimate to familiar stressful situations in depressed and sub-syndromal depressed children.     

The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder.

BACKGROUND: Because alterations in cortisol negative feedback inhibition associated with aging are generally opposite of those observed in posttraumatic stress disorder (PTSD), we examined the cortisol and glucocorticoid receptor (GR) response to dexamethasone (DEX) in older trauma survivors.METHODS: Twenty-three Holocaust survivors (9 men, 14 women), 27 combat veterans (all male), and 10 comparison subjects (7 men, 3 women) provided samples for plasma or salivary cortisol and glucocorticoid receptor determination in mononuclear leukocytes at 8:00 AM on the day of, and following, 0.5 mg of DEX at 11:00 PM.RESULTS: Greater percent suppression of cortisol and lymphocyte GR was observed in older trauma survivors with PTSD compared to survivors without PTSD and comparison subjects. There was a significant main effect of depression in the direction of reduced suppression following DEX, consistent with the effects of DEX in major depressive disorder patients. Responses to DEX were uncorrelated with PTSD symptom severity, but cortisol suppression was associated with years elapsed since the most recent, but not focal, traumatic event.CONCLUSIONS: The response to DEX is generally similar in older and younger trauma survivors, but the findings suggest that age, symptom severity, and lifetime trauma exposure characteristics may influence this response.     

Noradrenergic function and the cortisol response to dexamethasone in depression

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and the noradrenergic system have been reported in depression. To study possible interrelations between these two systems, plasma free 3-methoxy-4-hydroxyphenylglycol (MPHG) was compared with the cortisol response to dexamethasone in 64 depressed patients. Postdexamethasone cortisol nonsuppressors had higher baseline plasma free MHPG values than did cortisol suppressors. Increased severity of some depressive symptoms was associated with increased postdexamethasone cortisol levels. These results indicate that depressed patients with dexamethasone nonsuppression have increased noradrenergic turnover.     

Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone

The assessment of lysozyme activity in mononuclear leukocytes (MNLs) following the in vitro administration of dexamethasone (DEX) provides a measure of peripheral glucocorticoid sensitivity. The goal of the present study was to determine the relationship between the IC₅₀ of lysozyme activity following such challenge, and the cortisol response to oral administration of 0.50 mg DEX in 18 healthy subjects. The results demonstrated a robust association between the IC₅₀ and both cortisol decline and percent suppression of cortisol in response to low-dose DEX. However, this measure was uncorrelated with pre or post DEX cortisol levels or GR number. The high correlation between the inhibitory effect of DEX on lysozyme synthesis and two measures reflecting cortisol suppression in response to oral DEX reflects the similarities of GC responsiveness in both in vivo and in vitro models, and suggests that the in vitro assessment of lysozyme activity in MNLs may be useful in the study of neuropsychiatric or other clinical disorder.     

Use of saliva cortisol in the dexamethasone suppression test

In a sample of 26 inpatients (15 primary endogenous depressives and a heterogeneous comparison group of 11 psychiatric patients), results of the dexamethasone suppression test (DST) for endogenous depression were compared when cortisol was measured in plasma (total and free) and in saliva. Results showed a close linear relationship among plasma total and free cortisol, plasma total cortisol, and saliva cortisol, and between free plasma and saliva cortisol. A saliva cortisol cutoff point of 70 ng/dl achieved the same sensitivity (67%), specificity (91%), and diagnostic confidence (91%) as the best cutoff scores of plasma total cortisol (5 μ/dl) and plasma free cortisol (0.15 μ/dl). These results suggest that saliva cortisol, which directly reflects the biologically active fraction of cortisol, can be used as a reliable and more practical index in the DST, especially in outpatients.     

Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder.

BACKGROUND: To explore relations between neuroimmune and neuroendocrine systems relative to posttraumatic stress disorder (PTSD) treatment, cortisol and cytokine changes in response to selective serotonin reuptake inhibitor (SSRI) and placebo treatment of chronic PTSD were assessed prospectively. METHODS: Baseline measures of PTSD, depression, salivary 8 am and 4 pm cortisol, and serum interleukin-1beta (IL-1beta; pro-inflammatory) and soluble interleukin-2 receptors (IL-2R; cell-mediated immunity) were obtained for 58 PTSD and 21 control subjects. The PTSD subjects participated in a 10-week, double-blind treatment with citalopram (n = 19), sertraline (n = 18), or placebo (n = 7). RESULTS: At baseline, PTSD subjects had significantly greater PTSD, depression, and IL-1beta and lower IL-2R levels than control subjects, with no group differences found for am or pm cortisol levels. Both SSRI groups' IL-1beta correlated negatively with IL-2R; neither cytokine correlated with cortisol levels. Treatment significantly lowered PTSD, depression, and IL-1beta levels and increased IL-2R for all groups to control subject levels. After treatment, both SSRI groups' IL-1beta correlated with an end cortisol measure (one negatively, one positively). CONCLUSIONS: Our results support a complex relationship between neuroimmune and neuroendocrine systems with PTSD treatment. Implications of normalization of cytokine levels with effective SSRI treatment and placebo are discussed.     

Weight loss, cortisol levels, and dexamethasone suppression in major depressive disorder

Appetite and/or weight loss are integral, albeit not necessary, symptoms of depression. We explored the contribution of diminished appetite and/or weight loss ascertained by history to the hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation in 120 patients with primary major depressive disorder. Significant positive relationship for both appetite and weight loss with cortisol levels in plasma and cerebrospinal fluid (CSF) were observed. Plasma cortisol levels were consistently higher in patients who noted both appetite and weight loss as opposed to patients without appetite or weight loss. Depressed patients with weight loss showed higher rates of dexamethasone-nonsuppression. Age and severity of depression influenced but did not eliminate the significance of the findings, suggesting that weight loss accounts in part for the HPA-axis function changes observed in depression.     

Adrenocorticotropin and cortisol response to lysine vasopressin in relation to the outcome of the dexamethasone suppression test in major depressive disorder

The pathophysiology behind the abnormalities of the hypothalamic pituitary adrenal cortex axis found in patients with major depressive disorder was studied by the use of the vasopressin test. The response of plasma adrenocorticotropin (ACTH) and cortisol to the injection of 10 IU lysine-vasopressin (LVP) was investigated in 18 patients meeting the DSM-III criteria for major depressive episode. The response was correlated to the outcome of the dexamethasone suppression test (DST) with the use of two different cut-off points, 139 nmol/l and 200 nmol/l respectively. The results show that no significant difference was found in ACTH or cortisol response between patients having a normal or abnormal DST. The results do not seem to support the hypothesis that the abnormalities of the hypothalamic pituitary adrenal cortex axis involve a hypersecretion of corticotropin-releasing factor (CRF) and a subsequent desensitization of the corticotrophs to CRF-stimulated ACTH release.     

The neuropsychological profile of psychotic major depression and its relation to cortisol.

BACKGROUND: Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits. METHODS: Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained. RESULTS: PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory. CONCLUSIONS: While PMDs' ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory.     

The association of major depression, conduct disorder, and maternal overcontrol with a failure to show a cortisol buffered response in 4-month-old infants of teenage mothers.

BACKGROUND: Adolescent pregnancy can be associated with major depression (MD) and conduct disorder (CD). Some infants of adolescent mothers are prenatally exposed to these factors, which may result in heightened risk for perturbations of their stress systems. Between 2 and 4 months, a normal shift occurs in the adrenocortical system in which we observe a marked decrease in infant cortisol response when facing mild stressors. This study aimed to explore whether MD (lifetime, during pregnancy, postpartum), CD, and maternal overcontrol are associated with increased cortisol reactivity in 4-month-old infants of teenage mothers. METHODS: Using arm restraint as a stressor, morning salivary cortisol was taken prestressor and poststressor in 212 infants during a laboratory visit. Major depression and CD were measured with the computerized National Institute of Mental Health Diagnostic Interview Schedule (NIMH-DIS), postpartum depressive mood was measured with the Edinburgh Postnatal Depression Scale, and overcontrol was observed with the CARE-Index. RESULTS: Independent of the predictors, there was a dampened cortisol response. Infants of mothers with lifetime MD and of average to highly overcontrolling mothers showed increased cortisol reactivity. Conduct disorder and cortisol levels were not associated. CONCLUSIONS: Future studies should detect whether the absence of a dampened cortisol response in infants whose mothers have lifetime MD or display overcontrolling parenting is stable over time.     

Influence of mirtazapine on urinary free cortisol excretion in depressed patients

Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response.     

High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling

Ellenbogen MA, Santo JB, Linnen A‐M, Walker C‐D, Hodgins S. High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling.
Bipolar Disord 2010: 12: 77–86. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: The hypothalamic‐pituitary‐adrenal (HPA) axis is compromised in major depression, bipolar disorder (BD), and in the offspring of parents with major depression. Less is known about the offspring of parents with BD (FH+). The present project provides follow‐up to a previous study showing that the adolescent (mean age 16.7 years) FH+ offspring had higher salivary cortisol levels than the offspring of parents with no mental disorder (FH?) throughout the day in their natural environment, and that girls had higher cortisol levels than boys (Ellenbogen MA, Hodgins S, Walker C‐D, Adam S, Couture S. Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder. Psychoneuroendocrinology 2006; 31: 1164–1180). The goal of the present study was to determine whether FH+ offspring, approximately two years later, continued to exhibit elevated cortisol levels relative to FH? offspring during two weeks of daily sampling. Methods: The present study examined salivary cortisol levels in 24 (18.3 ± 2.6 years) FH+ and 22 (18.0 ± 2.3 years) FH? offspring who are part of the same longitudinal cohort as the previous study. Saliva was collected at 1300h and 1500h in the natural environment of the offspring during 14 consecutive days. Results: Multilevel modelling analyses indicated that FH+ offspring had higher afternoon levels of cortisol in their natural environment than FH? offspring, but group differences in slope and gender differences were not found. Conclusions: The FH+ offspring exhibited increased daytime secretion of cortisol that, at the level of the group, persisted into late adolescence and young adulthood. Perhaps this change in HPA functioning is associated with an increased vulnerability for the development of an affective disorder.     

Twenty-four-hour cortisol secretion patterns in prepubertal children with anxiety or depressive disorders.

BACKGROUND: Previous studies found few abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function in prepubertal children with anxiety or depressive disorders. In this study, we combined data from two independent, consecutive studies to achieve a larger sample size. Our goal was to identify potential alterations in the circadian pattern of cortisol secretion in anxious or depressed children. METHODS: A total of 124 prepubertal subjects from two independent samples (76 with major depressive disorder, 31 with anxiety disorders, and 17 healthy control subjects) were studied. Blood samples collected for cortisol at hourly intervals over a 24-hour period were examined. Analyses were performed aligning cortisol samples by clock-time. Additional analyses aligning samples by sleep-onset time were performed with a subsample of subjects. RESULTS: In the combined sample, significant findings emerged that were previously undetected. Anxious children exhibited significantly lower nighttime cortisol levels and an initially sluggish rise in cortisol during the nighttime when compared with depressed and healthy control children. In contrast, depressed children did not show a clear-cut pattern of differences compared with healthy control children. CONCLUSIONS: Anxious children seem to exhibit an altered pattern of nighttime cortisol secretion, with an initially sluggish or delayed nocturnal rise before reaching similar peak levels of cortisol near the time of awakening. These findings suggest subtle alterations in HPA axis function in prepubertal children with anxiety disorders.     

Lithium augmentation increases post-dexamethasone cortisol in the dexamethasone suppression test in unipolar major depression

Although considerable evidence exists on the efficacy of lithium as an augmenting agent in refractory depression, the underlying neurobiology of this phenomenon is unknown. In patients with major depression, changes of the hypothalamic-pituitary-adrenocortical (HPA) system have been detected by means of the dexamethasone suppression test (DST), when administered during treatment with tricyclic antidepressants. We investigated whether the DST also reveals alterations of the HPA system during lithium augmentation. We also sought to identify whether response to lithium augmentation can be predicted with the DST. Twenty-five patients with unipolar major depression, who did not respond to an adequate antidepressant monotherapy of at least 4 weeks, were measured for basal (pre-dexamethasone, 0800h) cortisol and ACTH levels and were administered the DST the day before initiation of lithium augmentation treatment. The same neuroendocrine procedures were repeated after 3 to 4 weeks. Criteria of response to lithium augmentation, defined as a reduction of the Hamilton Depression Rating Scale (HDRS17) score by > or =50% and an end point score of 9 or less, were determined by weekly HDRS ratings. The DST revealed a statistically significant increase of the post-dexamethasone cortisol values (P = 0.021) and an increase in the post-dexamethasone ACTH values (P = 0.051) during lithium augmentation as compared to pre-treatment baseline evaluations. The pre-dexamethasone hormone values were unchanged. The number of non-suppressors at baseline was one and increased to three at follow-up. Results of DST did not predict response to lithium augmentation, which occurred in 40% of subjects. Results suggest that lithium augmentation increases HPA system activity, as indicated by the increase of post-dexamethasone cortisol and ACTH levels measured by the DST. This is in contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants.