Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children.

BACKGROUND: Animal studies suggest that prenatal stress is associated with long-term disturbance in hypothalamic-pituitary-adrenal (HPA) axis function, but evidence in humans is lacking. This study examined the long-term association between prenatal anxiety and measures of diurnal cortisol at age 10 years. METHODS: Measures of cortisol were collected at awakening, 30 min after awakening, and at 4 pm and 9 pm on 3 consecutive days in a sample of 10-year-olds (n = 74) from the Avon Longitudinal Study of Parents and Children, a prospective longitudinal cohort study of mothers and children on whom measures of anxiety and depression were collected in pregnancy and the postpartum period. Analyses examined the links between symptoms of prenatal anxiety and multiple indicators of cortisol, an index of HPA axis functioning. RESULTS: Prenatal anxiety was significantly associated with individual differences in awakening and afternoon cortisol after accounting for obstetric and sociodemographic risk (partial correlations were .32 and .25, p < .05). The effect for awakening cortisol remained significant after controlling for multiple postnatal assessments of maternal anxiety and depression. CONCLUSIONS: This study provides the first human evidence that prenatal anxiety might have lasting effects on HPA axis functioning in the child and that prenatal anxiety might constitute a mechanism for an increased vulnerability to psychopathology in children and adolescents.     

Enhanced cortisol suppression following dexamethasone administration in domestic violence survivors

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 hypothalamic-pituitary-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.     

Postdexamethasone plasma cortisol and beta-endorphin levels in depression: relationship to severity of illness

The hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in many patients with depression, probably at all levels of the axis. To determine if HPA dysregulation is associated with severity of depression, we studied a group of 66 patients with major depressive disorder. Each patient underwent a pretreatment Dexamethasone Suppression Test, with plasma postdexamethasone cortisol determination at 8:00 AM, 4:00 PM, and 11:00 PM. All three postdexamethasone cortisol levels were significantly correlated with the Hamilton Rating Scale for Depression (HRSD) scores. We also examined the "profile" measures of mean, maximum, and minimum of the three cortisol values; again, all three were significantly correlated with HRSD scores. To evaluate associations between clinical severity and HPA dysregulation at the pituitary level, we studied a second group of 44 patients with major depressive disorder. Each had postdexamethasone cortisol determinations at 4:00 PM and 11:00 PM as well as pre- and postdexamethasone beta-endorphin determinations at 4:00 PM. The cortisol data from this group followed the same pattern as in the first sample, and there was a significant relationship between HRSD score and degree of beta-endorphin nonsuppression as well. These results suggest that severity of depression is one of the determinants of dysregulation at both adrenal and pituitary levels of the HPA axis, accounting for 10%-20% of the observed variance.     

Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder

OBJECTIVE: The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). METHOD: They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects. RESULTS: Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety. CONCLUSIONS: These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.     

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.     

Peri-sleep-onset cortisol levels in children and adolescents with affective disorders.

BACKGROUND: Changes in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by patterns of cortisol secretion, have been of interest in understanding depression and anxiety disorders across the life span. Previous studies of pediatric depression have pointed to the period around sleep onset as a key time point for observing alterations in cortisol secretion associated with affective disorders. Evidence also indicates that pubertal development may influence the expression of HPA dysregulation. We hypothesized that adolescents with depression and youth with anxiety disorders exhibit elevated peri-sleep-onset cortisol. METHODS: Plasma cortisol was sampled every 20 min around sleep onset from children and adolescents with major depressive disorder (n = 116), anxiety disorders (n = 32), or no history of psychiatric disorder (control; n = 76). Sleep onset was determined by polysomnography. Classification of participants as children or adolescents was based on Tanner staging of pubertal maturation. RESULTS: Children with anxiety disorders had higher peri-sleep-onset cortisol than children with depression or control children. Adolescents with depression had marginally higher peri-sleep-onset cortisol than control adolescents and significantly higher peri-sleep-onset cortisol than children with depression. CONCLUSIONS: Depression and anxiety are associated with altered cortisol secretion around sleep onset, and these changes appear to be influenced by pubertal maturation.     

Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War veterans: relationships to posttraumatic stress disorder and health symptoms.

BACKGROUND: We aim to characterize the baseline functioning of the hypothalamic-pituitary-adrenal (HPA) axis in Gulf War veterans (GWV) and examine the extent to which posttraumatic stress disorder (PTSD) and unexplained health symptoms-which commonly co-occur-have similar or different biological correlates. METHODS: Thirty-one GWV, 20 with current PTSD and 11 without current or lifetime PTSD, and 16 healthy nondeployed subjects not exposed to the Gulf War theater underwent medical and psychiatric examination followed by blood sampling every half-hour over 24 hours for the measurement of cortisol and adrenocorticotropic hormone (ACTH). RESULTS: Gulf War veterans without PTSD or another psychiatric disorder had significantly lower 24-hour plasma ACTH levels, a significantly higher cortisol:ACTH ratio, and no difference in cortisol levels compared to nondeployed subjects and to GWV with PTSD, controlling for body mass index (BMI). Among GWV, health symptoms (mood and cognitive symptoms) were positively associated with, and hyperarousal symptoms were negatively associated with, the cortisol:ACTH ratio. Additionally, the self-reported acute effects of pesticides and of pyridostigmine bromide during deployment were associated with lower ACTH levels, controlling for BMI and PTSD. CONCLUSIONS: The data provide evidence of HPA axis dysregulation in Gulf War veterans, which may be related to Gulf War deployment exposures. Despite the overlap of chronic unexplained health symptoms and PTSD in GWV, these symptom constellations appear to be biologically distinct.     

Evidence for altered hypothalamus-pituitary-adrenal axis functioning in systemic hypertension: blunted cortisol response to awakening and lower negative feedback sensitivity

BACKGROUND: Hypothalamus-pituitary-adrenal (HPA) axis functioning in systemic hypertension is not fully understood. We explored HPA axis activity and feedback sensitivity to oral administration of dexamethasone in systemic hypertension via assessment of the cortisol awakening response (CAR) and the circadian cortisol profile. METHODS: The CAR and circadian cortisol profile were assessed in 20 unmedicated and otherwise healthy middle-aged hypertensive men and in 22 normotensive male controls. Salivary free cortisol measures for the CAR were obtained immediately after awakening and 15, 30, 45, and 60 min thereafter. Circadian cortisol secretion was sampled at 08:00, 11:00, 15:00, and 20:00 h. Assessment of the CAR was repeated on the next day after administration of 0.5mg dexamethasone at 23:00 h on the previous night. RESULTS: Hypertensives had a significantly lower CAR (p<0.02) and significantly reduced suppression of the CAR after dexamethasone administration (p<0.01) than normotensive controls. There were no significant differences in cortisol levels at awakening and in circadian cortisol profiles between hypertensives and normotensives. CONCLUSION: We found evidence for altered HPA axis activity in men with systemic hypertension evident with the CAR. Hypertensives showed relative attenuation in the CAR and in the HPA axis feedback sensitivity following dexamethasone suppression. Such alterations in HPA axis regulation might contribute to the atherosclerotic risk in hypertensive individuals.     

A combined dexamethasone/corticotropin-releasing hormone test in patients with chronic PTSD--first preliminary results

BACKGROUND: Reports about alterations of hypothalamic-pituitary-adrenocortical (HPA) function in patients with chronic posttraumatic stress disorder (PTSD) are inconsistent and controversial. More refined laboratory tests and subgrouping of PTSD patients might help to decrease variance of findings. METHODS: 14 subjects with chronic PTSD and 14 healthy controls were examined between 13:00 and 17:00 using a modified combined dexamethasone/CRH test (0.5 mg dexamethasone at 23:00, 100 microg CRH at 15:00). Plasma adenocorticotropic hormone (ACTH), cortisol and blood pressure were measured every 15 min from 14:45 until 17:00. RESULTS: No significant differences between patients and controls were found in the analyses of ACTH and cortisol levels, but a significantly elevated systolic and diastolic blood pressure in PTSD. Severity of depressive symptoms had no influence. However, explorative analyses showed that patients with a history of childhood traumatization had significantly higher post-dexamethasone-ACTH levels and a significantly lower diastolic blood pressure in comparison to patients without early trauma. CONCLUSIONS: In this first pilot study in a typical clinical sample of patients with chronic PTSD we found effects of severe adverse events in childhood on HPA axis regulation. Maybe, childhood traumatization could influence HPA axis findings in PTSD. Further research is needed, especially dose-response studies with different doses of dexamethasone in dexamethasone/CRH tests in PTSD.     

Psychobiological dysregulation in violence-exposed mothers: salivary cortisol of mothers with very young children pre- and post-separation stress

To understand the determinants of frightening/frightened and other atypical maternal behavior, the authors studied a sample of 41 inner-city mothers of very young children (ages 8-50 months), the mothers of whom had lifetime histories of interpersonal violent trauma (i.e., physical or sexual abuse, and domestic violence) and related posttraumatic stress. METHOD: The authors measured (1) maternal salivary cortisol levels before and 30 minutes after a videotaped play paradigm with their children, involving two separations and reunions; and (2) cortisol reactivity 30 minutes after separation stress. Data were analyzed using Pearson bivariate correlations, ANOVA, and multiple linear regressions. RESULTS: Salivary cortisol "baseline" values were significantly negatively correlated with childhood interpersonal violent trauma severity (i.e., trauma severity prior to age 16). However, cortisol reactivity was not significantly correlated with interpersonal violent trauma severity at this level of analysis. Although baseline salivary cortisol values were not significantly correlated with current overall psychiatric or depressive symptoms, they were negatively correlated with severity of current posttraumatic stress symptoms (PTSS) and with dissociative symptoms. Neither dimensions of negativity nor distortion of maternal attributions showed any significant association with prestress or poststress salivary cortisol levels. Salivary cortisol baseline was negatively correlated with atypical maternal behavior via measurement of the level of disrupted communication, at a trend-level of significance. CONCLUSIONS: Violent trauma-associated dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a marker for increased risk for intergenerational transmission via parenting behavior with young children. Low salivary cortisol prior to separation stress and blunted cortisol reactivity to separation may also be markers for posttraumatic stress.     

Posttraumatic stress symptoms in parentally bereaved children and adolescents

OBJECTIVE: To compare parentally bereaved children with a disaster comparison group and a nontrauma control group on measures of emotional adjustment. METHOD: Children and adolescents who had lost a parent (n = 39), had experienced a tornado disaster (n = 69), or were coping with an ongoing social or academic stressor (n = 118) completed measures of posttraumatic stress disorder (PTSD) symptoms, anxiety, and depression. Risk factors for symptoms among the bereaved children also were evaluated. RESULTS: Parentally bereaved children reported significantly more PTSD symptoms than the disaster and nontrauma control groups. Among the bereaved children, girls, younger children, and children living with a surviving parent who scored high on a measure of posttraumatic stress reported more symptoms. CONCLUSION: Children and adolescents who have lost a parent could be vulnerable to PTSD symptoms.     

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.     

Hypothalamic-pituitary-adrenal axis function in dissociative disorders, post-traumatic stress disorder, and healthy volunteers.

BACKGROUND: This study investigated basal and stress-induced hypothalamic-pituitary-adrenal (HPA)-axis alterations in dissociative disorders (DDs). METHODS: Forty-six subjects with DD without lifetime post-traumatic stress disorder (PTSD), 35 subjects with PTSD, and 58 healthy comparison (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. RESULTS: The DD group had significantly elevated urinary cortisol compared with the HC group, which was 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 with 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 stress reactivity compared with the HC group. CONCLUSIONS: The study demonstrates a distinct pattern of HPA-axis dysregulation in DDs, emphasizing the importance of further study of stress-response systems in dissociative psychopathology.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.     

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.     

Early sexual abuse and low cortisol

Post-traumatic stress disorder (PTSD) is a mental health disorder precipitated by a stressful event that produces fear or terror in the individual. Post-traumatic stress disorder studies, particularly in early sexual abuse, have been associated with neuroendocrine dysfunction, most notably the hypothalamic-pituitary-adrenal (HPA) axis. Since the literature on PTSD and neuroendocrine factors in young subjects has been sparse, the present studies were designed to look at the basal functioning of the HPA axis in response to early sexual abuse in girls aged 5 to 7 years. Morning salivary samples were collected for cortisol determination from subjects and controls who were scheduled for a physical exam by their pediatrician. The present study shows that subjects who had been abused within the last couple of months had significantly lower cortisol in comparison to control subjects (age, social economic status and race matched). The data suggest that children may have an impaired HPA axis after early trauma.     

Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder.

BACKGROUND: Preclinical studies showed that early stress results in long-term alterations in the hypothalamic-pituitary-adrenal (HPA) axis. We performed a comprehensive assessment of the HPA axis in women with and without a history of early childhood sexual abuse and posttraumatic stress disorder (PTSD). METHODS: Fifty-two women with and without a history of early childhood sexual abuse and PTSD underwent a comprehensive assessment of the HPA axis, including measurement of cortisol in plasma every 15 min over a 24-hour period and cortisol and corticotropin (ACTH) following corticotropin-releasing factor (CRF) and ACTH challenge. RESULTS: Abused women with PTSD had lower levels of cortisol during the afternoon hours (12:00-8:00 PM) of a 24-hour period compared with non-PTSD women. Their ACTH response to a CRF challenge was blunted compared with nonabused non-PTSD (but not abused non-PTSD) women. There were no differences in cortisol response to CRF and ACTH challenges between the groups. Increased PTSD symptom levels were associated with low afternoon cortisol levels. CONCLUSIONS: These findings suggest that early abuse is associated with increased CRF drive as evidenced by decreased pituitary sensitivity to CRF, whereas in abuse with PTSD there is a specific hypocortisolemia that is most pronounced in the afternoon hours.     

Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone.

BACKGROUND: Alterations of mineralocorticoid receptor (MR) mediated negative feedback inhibition of cortisol might contribute to abnormalities of hypothalamic-pituitary adrenal (HPA) activity in posttraumatic stress disorder (PTSD). METHODS: In a placebo-controlled study, we examined 11 subjects with PTSD and 11 healthy controls between 14:00 and 21:00. After pretreatment with 3 g metyrapone to inhibit basal endogenous cortisol secretion, subjects orally received in randomized order .5 mg of the MR agonist fludrocortisone or placebo. Adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were measured every 30 min until 21:00. RESULTS: Compared to placebo, fludrocortisone led to a significant decrease of ACTH and cortisol that was similar in both groups. Subjects with PTSD had higher raw cortisol and higher normed (baseline-related) ACTH and 11-deoxycortisol values after metyrapone independent of treatment with fludrocortisone or placebo. CONCLUSIONS: While HPA responses after metyrapone seem to be stronger in PTSD compared to controls, no alterations of mineralocorticoid receptor function in PTSD were found in this study.     

Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring

OBJECTIVE: The authors used a low-dose dexamethasone suppression test to examine the effect of a PTSD risk factor, parental PTSD, on cortisol negative feedback inhibition in adult offspring of Holocaust survivors with PTSD (N=13) versus without PTSD (N=12) as well as a comparison group of offspring whose parents had no Holocaust exposure (N=16). METHOD: Blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of dexamethasone at 11:00 p.m., and blood samples were obtained again at 8:00 a.m. the following day. RESULTS: Enhanced cortisol suppression in response to dexamethasone was associated primarily with parental PTSD status, with minimal contribution of subjects' own trauma-related symptoms. CONCLUSIONS: Enhanced cortisol negative feedback inhibition may be associated with PTSD because it is related to the PTSD risk factor of parental PTSD.     

The cortisol awakening response in bipolar illness: a pilot study.

OBJECTIVE: A growing body of data suggests that a significantly enhanced salivary cortisol response to waking may indicate an enduring tendency to abnormal cortisol regulation. Our objective was to apply the response test to a population already known to have long-term hypothalamo-pituitary-adrenocortical (HPA) axis dysregulation. We hypothesized that the free cortisol response to waking, believed to be genetically influenced, would be elevated in a significant percentage of cases, regardless of the afternoon Dexamethasone Suppression Test (DST) value. METHOD: Using the free cortisol response to waking and the short daytime profile, we tested 18 clinically stable, lithium-responsive subjects from our long-term naturalistic follow-up of monthly DSTs. These tests include salivary testing every 15 minutes during the first hour of waking, followed by samples taken at 3:00 PM and 8:00 PM. RESULTS: While clinically stable on lithium prophylaxis, patients with bipolar disorder (BD) showed a significantly enhanced salivary cortisol response to waking, compared with control subjects (P < 0.03). Cortisol levels 30 minutes after waking significantly exceeded those in the large normative data provided in the literature (P < 0.001). CONCLUSIONS: Our observations support the hypothesis that the free cortisol response to waking can reflect relatively enduring HPA dysregulation, even when lithium-responsive BD patients are clinically well and their DSTs are normal. Because the test is easy to administer, the free cortisol response to waking may hold promise as a marker in studies of high-risk families predisposed to, or at risk for, mood disorders.