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.     

Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents.

BACKGROUND: We have previously reported higher and more variable salivary morning cortisol in 13-year-old adolescents whose mothers were depressed in the postnatal period, compared with control group adolescents whose mothers did not develop postnatal depression (PND). This observation suggested a biological mechanism by which intrafamilial risk for depressive disorder may be transmitted. In the current article, we examined whether the cortisol disturbances observed at 13 years could predict depressive symptomatology in adolescents at 16 years of age. METHODS: We measured self-reported depressive symptoms in 16-year-old adolescents who had (n = 48) or had not (n = 39) been exposed to postnatal maternal depression and examined their prediction by morning and evening cortisol indices obtained via 10 days of salivary collections at 13 years. RESULTS: Elevated morning cortisol secretion at 13 years, and particularly the maximum level recorded over 10 days of collection, predicted elevated depressive symptoms at 16 years over and above 13-year depressive symptom levels and other possible confounding factors. Morning cortisol secretion mediated an association between maternal PND and symptomatology in 16-year-old offspring. CONCLUSIONS: Alterations in steroid secretion observed in association with maternal PND may provide a mechanism by which risk for depression is transmitted from mother to offspring.     

Factors associated with the development of substance use disorder in depressed adolescents.

OBJECTIVE: To document rates of substance use disorders (SUD) in adolescents with unipolar major depressive disorder and to examine demographic, clinical, and biological factors associated with the development of SUD. METHOD: Twenty-eight adolescents with unipolar major depression and no SUD history and 35 group-matched normal controls who participated in a cross-sectional sleep polysomnography and neuroendocrine study were reassessed clinically 7 years later. RESULTS: The risk for SUD was high in both groups (34.6% in the depressed group and 24.2% in the controls). Depressed adolescents had earlier onset of SUD than controls. Depressed adolescents who developed SUD had more significant psychosocial impairment than depressed adolescents who did not develop SUD. More anxiety traits and elevated cortisol secretion near sleep onset were associated with SUD in depressed teenagers, whereas less emotional responsiveness to exciting stimuli and higher density of eye movements during REM sleep were related to depression without SUD. CONCLUSIONS: Depressed adolescents who have anxiety traits and whose hypothalamic-pituitary-adrenal axis is active when the system is normally quiescent may be at risk for developing SUD. Co-occurrence of depression and SUD is associated with serious psychosocial morbidity. Identification of risk factors for SUD in depressed teenagers may be helpful in developing more effective treatment and prevention programs.     

Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.     

Prenatal maternal biochemistry predicts neonatal biochemistry

Depressed (n = 45) and nondepressed (n = 47) mothers were recruited prenatally at an ultrasound clinic. Their urine samples were assayed for cortisol, catecholamines (norepinephrine, epinephrine, dopamine) and serotonin. Their urines were assayed again at the neonatal period, and their newborns' urines were also assayed at that time. The depressed versus the nondepressed mothers showed significantly higher cortisol and norepinephrine and significantly lower dopamine levels across the pre- and postnatal assessments. At the postnatal assessment all levels had decreased except the serotonin levels for both groups. Regression analyses on the mother's postnatal biochemistry with the prenatal biochemistry entered as predictor variables showed highly significant, specific relationships between each of the catecholamines, cortisol, and serotonin. The newborn's biochemistry (except for epinephrine) was higher than the maternal biochemistry. Regression analyses on the neonatal biochemistry with the mother's prenatal biochemistry entered as predictor variables also suggested highly significant, specific relationships. The continuity between the mother's and the newborn's neurotransmitter/ neurohormone profiles and data showing that elevated norepinephrine and cortisol predict to low birthweight and prematurity, respectively, highlight the importance of assessing these levels during pregnancy.     

PRENATAL MATERNAL BIOCHEMISTRY PREDICTS NEONATAL BIOCHEMISTRY

Depressed (n = 45) and nondepressed (n = 47) mothers were recruited prenatally at an ultrasound clinic. Their urine samples were assayed for cortisol, catecholamines (norepinephrine, epinephrine, dopamine) and serotonin. Their urines were assayed again at the neonatal period, and their newborns' urines were also assayed at that time. The depressed versus the nondepressed mothers showed significantly higher cortisol and norepinephrine and significantly lower dopamine levels across the pre- and postnatal assessments. At the postnatal assessment all levels had decreased except the serotonin levels for both groups. Regression analyses on the mother's postnatal biochemistry with the prenatal biochemistry entered as predictor variables showed highly significant, specific relationships between each of the catecholamines, cortisol, and serotonin. The newborn's biochemistry (except for epinephrine) was higher than the maternal biochemistry. Regression analyses on the neonatal biochemistry with the mother's prenatal biochemistry entered as predictor- variables also suggested highly significant, specific relationships. The continuity between the mother's and the newborn's neurotransmitter/-neurohormone profiles and data showing that elevated norepinephrine and cortisol predict to low birthweight and prematurity, respectively, highlight the importance of assessing these levels during pregnancy.     

Regulation of sleep and growth hormone in adolescent depression.

This article reviews findings of sleep, growth hormone (GH), and cortisol measures from a number of separate controlled studies of prepubertal and adolescent depression carried out by Puig-Antich and colleagues since 1978. New data are presented comparing 24-hour GH measures in adolescents with major depressive disorder (MDD) (N = 44; mean age = 14.8 +/- 2.0) to normal control adolescents (N = 37; mean age = 15.3 +/- 1.5). There were no significant overall group differences in summary GH measures between MDD and normal controls. Splitting the MDD group on the basis of suicidality (definite plan or attempt) (N = 20), revealed a significant blunting of sleep GH compared to the nonsuicidal group (N = 24). These results are discussed in the context of the other sleep and neuroendocrine findings in this population, with evidence for dysregulation around sleep onset. The influences of development on sleep and GH regulation are also considered.     

Stressful life events in anxious and depressed children

OBJECTIVE: The aim of this study was to examine the occurrence of stressful life events in anxious and depressed children. METHOD: Children (6-12 years of age) with an anxiety disorder (n = 20), depression (n = 45), and normal controls (n = 11) were assessed using the Life Events Record. Cortisol was assessed from plasma samples collected every 20 minutes from an indwelling catheter in the one and two hour window around sleep onset. RESULTS: Depressed children had significantly more events and events that were most likely independent of the child's behavior, compared to both the anxious and normal control children. Independent loss events were significantly more prevalent among the depressed children in the preceding year, compared to anxious children, with a trend toward more loss events compared to the normal controls. For both overall events and independent events, depressed females were significantly more likely to be exposed to stressful environments compared to anxious and normal control females. There were no effects of stress on cortisol secretion around sleep onset. CONCLUSIONS: The results of this study suggest that stressful life events are significantly more likely to occur in depressed children, particularly females, compared to anxious children, and that these events are predominantly characterized by independent events outside of the child's control. The results also suggest that loss events may be specific for depression in children. Interestingly, stress does not appear to impact the HPA axis in children, which is true for anxious, depressed, and normal control children. The temporal occurrence and severity, as well as the type of stressful life events as they relate to the onset and maintenance of anxiety and depression in children, need to be more fully explored.     

Minute-by-minute analysis of REM sleep timing in major depression

Sleep changes described in depressed patients may represent alterations in the timing of rapid-eye-movement (REM) sleep or sleep onset. We examined these variables in groups of healthy control subjects (n = 47), depressed outpatients (n = 98), and depressed inpatients (n = 41). Outpatient depressives had greater severity of clinical symptoms than inpatients using the Hamilton Rating Scale for Depression. The depressed inpatient group had a later mean sleep onset time than the other groups, and the depressed outpatient group had a wider range of good night times than control subjects. REM timing in each group was examined as a relative frequency distribution of REM sleep (FDRS) for each minute across the night. The FDRSs for the three groups were statistically compared using the parameters from a two-component model, which includes a deterministic sinusoidal function and a time series process for errors. The slope of the linear trend in the FDRS rhythm was smaller (less positive) for both depressed groups than for controls. The ultradian FDRS rhythm occurred at an earlier phase, relative to sleep onset, in the inpatient depressed group compared to the control group. The ultradian FDRS rhythm had a longer period in the outpatient group compared to the control and inpatient groups. When referenced to 24-hr clock time in an exploratory analysis, the depressed groups appeared to have less robust FDRS ultradian rhythms than controls, but they did not appear to have a systematic phase alteration compared to controls. Abnormalities of REM sleep timing in groups of depressed patients may reflect a disturbance of sleep initiation and generation, or difficulty in entrainment of REM, rather than a systematic phase alteration in REM sleep propensity.     

Electroencephalographic sleep profiles and hypothalamic-pituitary-adrenocortical (HPA)-activity in kindergarten children: early indication of poor sleep quality associated with increased cortisol secretion

OBJECTIVES: In children, objective data carried out from sleep EEG monitoring are scarce. Furthermore, results associating the hypothalamic-pituitary-adrenocortical (HPA)-activity with sleep EEG measurements in children are missing. Therefore, our study aimed to investigate in preschool-children the association between sleep patterns and endocrine activity. Furthermore, children's behavioral/emotional difficulties and competences were assessed in order to correlate psychological strain with sleep measures. PARTICIPANTS AND METHODS: Sixty-seven kindergarten children (35 boys and 32 girls) aged 5.34 underwent EEG-monitoring for one night. For baseline HPA-activity assessment, saliva samples were collected immediately after awakening, whereas saliva samples before, while and after a psychological challenge were used to assess the HPA-activity under stress conditions. RESULTS: Compared to girls, boys showed significantly more REM sleep time. After cluster analysis, children labeled as 'poor' sleepers (n=27; 40,30%) showed significantly increased morning cortisol values, as compared to 'good' sleepers (n=22; 32,83%). Furthermore, increased cortisol AUC values under stress conditions were significantly associated with an elevated number of awakenings after sleep onset, and more sleep time in stages 1 and 2. In addition, an increased sleep efficiency was significantly correlated with self-reported emotional/behavioral difficulties, i.e. with low degrees of impulsivity (r=-.31; p<.05) and lower degrees of social inhibition and peer victimiziation (r=-.26, p<.05). CONCLUSIONS: Our results underlined that already in preschool years, associations between objectively examined unfavorable sleep patterns, increased HPA-system activity and more difficult behavioral and psychosocial dimensions may be observed.     

Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Relationship to plasma cortisol levels before and after dexamethasone administration

We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (beta max) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the beta max values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between beta max and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n = 14) and at 11 PM after dexamethasone administration (n = 15). These data suggest that the reported decrease in beta max found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.     

Circadian secretion of cortisol in bipolar disorder

OBJECTIVE: To compare the 24-h cortisol secretion profiles of normal control subjects and patients with bipolar disorder who were in the depressive, manic and euthymic phases of the disorder. PARTICIPANTS: Eighteen patients, 25-62 years of age, in depressed (n = 5), manic (n = 5) or euthymic (n = 8) phase of bipolar disorder recruited through a psychiatric outpatient clinic, and 5 control subjects, 24-41 years of age, recruited through advertisement or word of mouth. OUTCOME MEASURES: Subjects were interviewed and symptom ratings were obtained using the Hamilton Depression Rating Scale, Beck Depression Inventory and Young Mania Scale. Blood collection began at 0800 and continued at hourly intervals for 24 h. Serum cortisol levels were assayed using a validated commercial radioimmunoassay kit. RESULTS: An analysis of variance of the area under the cortisol 24-h time-concentration curve (AUC) revealed a significant difference between the control group and patient groups (F = 3.69, p = 0.03). the mean AUCs of the patients in the depressed (263.4 micrograms/dL) and hypomanic (262.2 micrograms/dL) phases were beyond the 95% confidence interval for the controls (120.9-253.3 micrograms/dL). There were no significant group differences in cosinor acrophase and no significant effects of sex, education, age of illness onset, duration of illness or duration of mood state at time of testing on the cortisol measures. Pearson correlations between symptom rating scores and cortisol secretion variables were not significant. CONCLUSION: The increases in cortisol secretion in patients in both the depressed and manic phases of bipolar disorder suggest that cortisol level is probably not a state marker in bipolar disorder.     

The corticotropin-releasing hormone stimulation test in chronic schizophrenia

During a drug-free period a group of schizophrenic subjects (N = 9) showed normal mean basal plasma ACTH and cortisol levels in association with normal plasma ACTH and cortisol responses to an infusion of corticotropin-releasing hormone (CRH). Administration of fluphenazine had no effect on basal ACTH and cortisol levels or their responses to CRH (N = 8). These data differ from those previously reported in depressed patients, who showed elevated basal cortisol values in association with a blunted ACTH response to CRH, and add to a growing body of literature which suggests that hypothalamic-pituitary-adrenal regulation is less disturbed in schizophrenia than in depression.     

Abnormal nocturnal melatonin secretion and disordered sleep in abstinent alcoholics.

BACKGROUND: Alcoholic patients show prominent disturbance of sleep as measured by electroencephalogram, with difficulties in the onset and maintenance of sleep. Given the role of melatonin in the regulation of the sleep-wake cycle, this study examined the relationship between nocturnal expression of melatonin and sleep in alcoholics as compared with control subjects. METHODS: Alcoholic patients (n = 11) and comparison control subjects (n = 10) underwent all-night polysomnography and serial blood sampling every 30 min from 10:00 PM to 6:30 AM for measurement of circulating levels of melatonin and cortisol. RESULTS: Coupled with prolonged sleep latency, alcoholics showed lower levels of melatonin during the early part of the night and a delay in the onset of the nocturnal plateau or peak value of melatonin as compared with control subjects. The nocturnal delay of melatonin correlated with prolonged sleep latency. Circulating levels of cortisol were lower during the early part of the night and higher in the late part of night in the alcoholics as compared with the control subjects. CONCLUSIONS: A delay in the nocturnal rise of melatonin may contribute to disordered sleep in chronic alcoholics, with implications for the use of melatonin in the treatment of insomnia in recovering alcoholics.     

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.     

Serotonin dysregulation in adolescents with major depression: hormone response to meta-chlorophenylpiperazine (mCPP) infusion

This study examined central serotonin disturbance, as reflected by neuroendocrine hormones, among adolescents with major depression. Prolactin, cortisol, and growth hormone were measured following the infusion of a serotonin agonist, meta-chlorophenylpiperazine (mCPP). Twelve (M=6, F=6) medication-free adolescents with major depression (MDD) were compared with 12 (M=6, F=6) matched normal control subjects, ranging in age from 13 to 17 years. Baseline evaluations and a battery of laboratory tests were completed. mCPP, 0.1 mg/kg i. v., was administered in a placebo-controlled design. Analyses of the neuroendocrine hormones revealed that the depressed group had a higher baseline prolactin level and an augmented prolactin response to mCPP challenge than did the control group. The depressed group experienced a sharper baseline-cortisol decline between 08.00 and 11.00 h, and compared to control subjects they displayed an augmented response to the challenge. The depressed group reported more side effects than the control group during saline infusion, but not during mCPP infusion. Findings suggest that depressed adolescents have an elevated baseline prolactin level, and also experience enhanced prolactin and cortisol responses to the serotonergic challenge. These preliminary findings will be confirmed during our ongoing study.     

Effects of subchronic paroxetine administration on night-time endocrinological profiles in healthy male volunteers

To evaluate the subchronic effects of paroxetine, a selective serotonin reuptake inhibitor, on nocturnal endocrinological profiles, eight healthy male volunteers with no personal or family history of a psychiatric or neurological disease were administered paroxetine (30 mg/day) or placebo in a double-blind cross-over design. Drugs were given as a single dose at 10:00 h for a period of 4 weeks each. Between days 21 and 28 of each treatment period, sleep EEG was registered for four consecutive nights from 23:00 to 07:00 h. During the last night, hormonal profiles for prolactin, growth hormone (GH), cortisol, corticotropin (ACTH), luteinizing hormone (LH), testosterone and melatonin were determined, and area-under-the-curve values were calculated. None of the endocrinological parameters revealed any statistically significant changes. A trend could be found for an increased cortisol production under paroxetine (P = 0.069). ACTH, LH, and melatonin showed slight and non-significant decreases. Prolactin release was only marginally elevated (+7%). The mean sleep onset GH release (as measured for a time period of 180 min after sleep onset) was decreased by about 30% under paroxetine. However, statistical significance could not be reached. For hGH, there was a delayed mean GH-peak under paroxetine. Nocturnal testosterone secretion remained almost unaltered. The lack of significant endocrinological alterations might be partially explained by both adaptational phenomena under subchronic treatment conditions and the extended time span between the single morning dose and the registration period, respectively.     

Increased Cortisol Levels in Aging and Alzheimer's Disease in Postmortem Cerebrospinal Fluid

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis. On the other hand, it should be noted that postmortem ventricular CSF cortisol levels were found to be 13–16 times higher than lumbar puncture CSF cortisol levels of ambulatory patients. This means that the ventricular CSF levels probably reflect the reaction of the HPA-axis to the process of dying rather than the basal levels of this system. The exact consequences of elevated HPA-axis activity for the human brain should be studied in more detail.     

ACTH, cortisol and growth hormone 24-hour profiles in major depressive illness

Circadian rhythms of ACTH, cortisol and growth hormone have been studied in eighteen major depressives (eight unipolar and ten bipolar) as well as in eight normal controls. Both unipolar and bipolar depressed patients secreted more growth hormone than normal men. This hypersecretion occurred during waking hours rather than during sleep. An early sleep GH increase was found in all but one of the normal men, but was absent in seven of the eight unipolar depressed patients, who had instead a presleep increase. No consistent disturbance of the temporal association between sleep onset and GH secretion was found in bipolar depressed patients. Both unipolar and bipolar depressed patients had higher 24 h mean cortisol levels than normal men, but no significant difference was found for 24 h ACTH levels. An early timing of the nadir of ACTH-cortisol secretion which was observed in our depressed patients also suggest that disorders of circadian time keeping may characterize major endogenous depression.     

Depression and cortisol responses to psychological stress: a meta-analysis

The purpose of this meta-analysis is to examine the association between depression and cortisol responses to psychological stressors. A total of seven studies comparing plasma or cortisol responses to psychological stressors in clinically depressed (MDD) and non-depressed (ND) individuals (N = 196: 98 MDD, 98 ND; 83 men, 113 women; mean age = 40 years) were included. Sample size-adjusted effect sizes (Cohen's d statistic) were calculated and averaged across baseline (before stressor onset), stress (stressor onset up to 25 min after stressor offset), and recovery (more than 25 min after stressor offset) periods. Overall, MDD and ND individuals exhibited similar baseline and stress cortisol levels, but MDD patients had much higher cortisol levels during the recovery period than their ND counterparts. There was also a significant time of day effect in which afternoon studies were more likely to reveal higher baseline cortisol levels, blunted stress reactivity, and impaired recovery in MDD patients. This blunted reactivity-impaired recovery pattern observed among the afternoon studies was most pronounced in studies with older and more severely depressed patients.