Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates

Evidence supports that hyperactivity of the hypothalamic-pituitary-adrenal axis has a pivotal role in the psychobiology of severe depression. The present study aimed at assessing hypothalamic-pituitary dopaminergic, noradrenergic, and thyroid activity in unipolar depressed patients with melancholic and psychotic features and with concomitant hypercortisolemia. Hormonal responses to dexamethasone, apomorphine (a dopamine receptor agonist), clonidine (an alpha 2-adrenoreceptor agonist) and 0800 and 2300 h protirelin (TRH) were measured in 18 drug-free inpatients with a DSM-IV diagnosis of severe major depressive disorder with melancholic and psychotic features showing cortisol nonsuppression following dexamethasone and 23 matched hospitalized healthy controls. Compared with controls, patients showed (1) lower adrenocorticotropin and cortisol response to apomorphine (p<0.015 and <0.004, respectively), (2) lower growth hormone response to clonidine (p=0.001), and (3) lower responses to TRH: 2300 h maximum increment in serum thyrotropin (TSH) level (p=0.006) and the difference between 2300 and 0800 h maximum increment in serum TSH values (p=0.0001). Our findings, in a subgroup of unipolar depressed inpatients with psychotic and melancholic features, are compatible with the hypothesis that chronic elevation of cortisol may lead to dopaminergic, noradrenergic and thyroid dysfunction.     

Measurement of ACTH and prolactin in the dexamethasone suppression test

Plasma concentrations of ACTH and prolactin were measured in psychiatric inpatients at 8 a.m. and 4 p.m. before and after the standard 1 mg overnight Dexamethasone Suppression Test (DST). Plasma concentrations of cortisol were measured at 8 a.m. and 4 p.m., and 11 p.m. before and after 1 mg dexamethasone. Dexamethasone suppressed plasma concentrations of ACTH, prolactin and cortisol in the subject group as a whole. "Cut Points" obtained using Fisher's Exact Test identified plasma ACTH values at 8 a.m. baseline, 4 p.m. baseline and 8 a.m. post-dexamethasone and plasma prolactin values at all four times that significantly differentiated patients with bipolar depressive disorder and major depressive disorder from other psychiatric patients. There were no cut points found at any of the six times for plasma levels of cortisol that significantly differentiated between these two diagnostic groups. Of interest in this subject population, basal (pre-dexamethasone) plasma concentrations were of more diagnostic information than post-dexamethasone values. These pilot findings suggest that monitoring plasma prolactin and ACTH concentrations before and after dexamethasone might increase the sensitivity and specificity of this laboratory test for depression.     

Dexamethasone suppression test and familial subtypes of unipolar depression

We have studied the suppression of plasma cortisol after dexamethasone (1 mg) and the peak post-dexamethasone cortisol values in 84 hospitalized patients with a diagnosis of primary unipolar depression. The non-suppressor responses in the three familial subgroups (Winokur) were: 11/22 in familial pure depressive disorder (FPDD), 21/49 in sporadic depressive disease (SDD) and 1/13 in depression spectrum disease (DSD) (FPDD vs. SDD, p less than 0.05; SDD vs. DSD, p less than 0.05). When considering the peak post-dexamethasone cortisol value, or the 8.30-9.00-hour values, the results in the DSD group were lower than in the other two groups (p less than 0.05). These results suggest a different behaviour of DSD as compared with FPDD and SDD.     

Effect of dexamethasone on cortisol and prolactin responses to meals in bulimic and normal women

In normal individuals, serum cortisol and prolactin concentrations have been shown to rise following a mid-day meal. To determine whether abnormalities of the hypothalamo-pituitary-adrenal axis in bulimics lead to a disrupted hormonal response to eating, cortisol and prolactin responses to meals (600 kcal, 30% protein, 30% fat, 40% carbohydrate) were studied on two consecutive days in six normal weight bulimics and six normal volunteers. Dexamethasone (1 mg orally) was administered at 2330 h after baseline sampling. During baseline sampling, cortisol concentrations were significantly higher in the bulimics (18.2 +/- 0.9 micrograms/dl, mean +/- SEM) than in the normals (12.1 +/- 0.4 micrograms/dl) (p less than 0.001). Post-dexamethasone cortisol concentrations also were higher in the bulimics (5.7 +/- 0.3 micrograms/dl) than in the normals (1.2 +/- 0.2 micrograms/dl) (p less than 0.001). The three bulimics with a major depressive disorder had higher peak post-dexamethasone cortisol concentrations than the nondepressed bulimics. Dexamethasone significantly enhanced the prolactin response to meals among both bulimics (at 90 min post onset of eating) and normals (at 60, 75 and 90 min post onset of eating). This enhancement of the prolactin response to meals by dexamethasone is opposite to the inhibitory effect of dexamethasone on stress-induced prolactin release and suggesting that stress-induced and meal-induced prolactin release involve different neuroendocrine mechanisms.     

The dexamethasone suppression test in affective illnesses and schizophrenia: relationship with psychotic symptoms

The authors studied the dexamethasone suppression test (DST) on a series of 112 inpatients including 65 patients with major depressive disorder (21 bipolars: 4 with, 17 without psychotic symptoms; 44 unipolars: 13 with, 31 without psychotic symptoms), 15 patients with depressive disorder, 10 schizoaffective and 22 schizophrenic patients. Using different diagnostic criteria, they confirm the best performances of the DST in depression for the diagnosis of a major depressive disorder, primarily endogenous. They also examined the potential influence of psychotic symptoms, suicidal behavior and family history of affective illness on the DST. The only significant difference found is in the cortisol plasma level at 4 p.m. in bipolar patients with psychotic symptoms. That fact and the high rate of abnormality of the DST in schizoaffective and schizophrenic patients indicate that psychotic symptoms per se may play a role in a dysregulation of the hypothalamo-pituitary adrenal axis.     

Use of the dexamethasone suppression test in an inpatient setting: a replication and new findings

The dexamethasone suppression test (DST) was administered to 131 depressed and 109 nondepressed psychiatric inpatients. The depressed patients were categorized according to DSM-III as minor depression, major depression without melancholia, and major depression with melancholia and/or with psychotic features. The nondepressed patients were stratified over several DSM-III subcategories. DST nonsuppression was nonspecific for major depression: the mean post-dexamethasone cortisol value and the number of nonsuppressors were not significantly different between the major depressives and the nondepressed psychiatric controls. Within the depressive sample the DST was a significant (p less than 0.01) discriminator between major and minor depression. Postdexamethasone plasma greater than or equal to 3.5 micrograms/dl at 0800h was the most sensitive (39%) and specific (94%) criterion; cortisol values at 1600h and 2300h showed no significant discriminating power for major vs. minor depression. The diagnostic utility of the DST thus appears to be limited to confirming the diagnosis of major depression, once the clinical diagnosis of depression is made. There was no significant influence of age or gender on postdexamethasone cortisol values.     

Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse

OBJECTIVE: Early adverse life events may predispose individuals to the development of mood and anxiety disorders in adulthood, perhaps by inducing persistent changes in corticotropin-releasing factor (CRF) neuronal systems. The present study sought to evaluate pituitary-adrenal responses to standard hypothalamic-pituitary-adrenal axis challenge tests in adult female survivors of childhood abuse with and without major depressive disorder. METHOD: Plasma ACTH and cortisol responses to the administration of 1 microg/kg ovine CRF and plasma cortisol responses to the administration of 250 microg ACTH(1-24) were measured in healthy women without early life stress (N=20), women with childhood abuse without major depressive disorder (N=20), women with childhood abuse and major depressive disorder (N=15), and women with major depression but no early life stress (N=11). RESULTS: Abused women without major depressive disorder exhibited greater than usual ACTH responses to CRF administration, whereas abused women with major depressive disorder and depressed women without early life stress demonstrated blunted ACTH responses. In the ACTH(1-24) stimulation test, abused women without major depressive disorder exhibited lower baseline and stimulated plasma cortisol concentrations. Abused women with comorbid depression more often suffered from posttraumatic stress disorder and reported more recent life stress than abused women without major depressive disorder. CONCLUSIONS: These findings suggest sensitization of the anterior pituitary and counterregulative adaptation of the adrenal cortex in abused women without major depressive disorder. On subsequent stress exposure, women with a history of childhood abuse may hypersecrete CRF, resulting in down-regulation of adenohypophyseal CRF receptors and symptoms of depression and anxiety.     

Plasma testosterone levels in patients with combat-related posttraumatic stress disorder

BACKGROUND: An abnormal level of androgens has been reported in various psychiatric disorders and the important role of androgens in the regulation of human sexuality, aggression, cognition, emotions and personality have been described. Previous studies in the area of stress and the hypothalamic-pituitary-gonadal (HPG) system in humans indicate that circulating testosterone levels are suppressed by physical and psychological stress. However, there is also evidence that plasma levels of testosterone can increase during potentially stressful events and may be elevated in combat-related posttraumatic stress disorder (CR-PTSD) in comparison with normal subjects and major depressive disorder patients. METHODS: The aim of the present study was to examine the possible involvement of the HPG system in chronic untreated CR-PTSD. To this end, we assessed the morning plasma levels of testosterone and cortisol in never-treated chronic CR-PTSD outpatients compared with normal healthy controls. RESULTS: There were no statistically significant differences between the CR-PTSD patients and healthy control subjects in morning plasma testosterone (547.8 +/- 152.2 ng/dl vs. 565.6 +/- 122.4 ng/dl; p = 0.7) and cortisol (19.0 +/- 8.5 microg/dl vs. 15.4 +/- 5.1 microg/dl; p = 0.1) levels. However, a significant correlation between plasma testosterone level and avoidance symptom scores of the Impact of Events Scale (IES) was found in the CR-PTSD patients (r = 0.43, p < 0.05). CONCLUSIONS: The findings of plasma testosterone levels comparable with normal controls in CR-PTSD patients may indicate that the previously described reduction in testosterone levels in normal subjects under stressful conditions may reflect the acute stress response of the HPG axis, in contrast to an adaptation of the HPG axis under chronic psychological stress.     

Dexamethasone suppression test and suicide attempts in schizophrenic patients.

The suicide attempts were assessed in 32 schizophrenic patients on whom the dexamethasone suppression test (DST) was done twice in the course of illness: in the years 1985-91 and 1996-97. In the 1985-91 period, both baseline and post-dexamethasone cortisol levels were significantly higher in the patients with previous suicide attempts and baseline cortisol was higher in the patients who were to make a future attempt. In 1996-97, DST non-suppression was shown in more than half of the patients with a history of suicide attempt and in none of those without such history: all cortisol levels were significantly higher in the patients with a history of suicide attempt. Although the mean intensity of depression was higher in the patients with a history of suicide attempt, no association between the intensity of depression and present or previous DST non-suppression status was found. It is suggested that the hyperactivity of the hypothalamic-pituitary-adrenal axis may constitute an element of diathesis for suicidal behavior in schizophrenic patients.     

Evaluation of depression in a general hospital: utility and limitations of the dexamethasone suppression test

Use of the DST was studied in medically hospitalized, depressed patients. Although complicating medical factors necessarily excluded nearly 60% of referrals, post-dexamethasone plasma cortisol values were significantly higher in 14 major depressives appropriate for the DST as compared to 12 patients with milder, subsyndromal depressive conditions. Using a plasma cortisol criterion of greater than 7 micrograms/dl, the DST identified major depression with 57% sensitivity and 92% specificity in this subsample (p less than 0.005). While limited by a high exclusion rate, the DST may be useful for confirmation of major depression in carefully screened general hospital patients. Implications for research and practice are discussed.     

The dexamethasone suppression test: its relationship to diagnoses, severity of depression and response to treatment

1. The dexamethasone suppression test (DST) was applied to 40 depressed patients, 40 healthy volunteers and 40 patients with other psychiatric disorders. 2. The post-dexamethasone cortisol level, adopted as the non-suppression criterion and established locally, was 3.0 micrograms/dl. 3. The DST sensitivity in depression was 45%, with a specificity of 95% and a positive predictive value of 90%. 4. There was a significant correlation (r = 0.38, p less than 0.05) between HDRS scores of depressed patients and their post-dexamethasone cortisol levels. 5. A prospective study of the depressed group, which was assessed with three depression rating scales, showed differences between non-suppressors and suppressors regarding to the symptoms severity and response to the treatment. It suggests that an abnormal DST result could have a prognostic value to antidepressant drugs and ECT. 6. The DST specificity in depression was also calculated from its performance in the group with other psychiatric disorders, and their diagnoses as well as the abnormal DST results were critically discussed.     

Mental Disorders in Suicide and Undetermined Death in the Lundby Study. The Contribution of Severe Depression and Alcohol Dependence

To evaluate the role of severe depression, i.e., depression with melancholic and/or psychotic features and alcohol dependence in suicide and undetermined death. The Lundby Study is a prospective, longitudinal study of a population consisting of 3563 subjects. In a long-term follow up 1947–2006 there were 66 suicide cases, including 19 undetermined deaths. Depression and alcoholism were as expected the major contributors to suicide (44% and 23% respectively). Severe depression with psychotic and/or melancholic features was diagnosed in 66% of all depressions and in 29% of all suicide cases, as compared to 15% for major depression only. Alcohol dependence was related to undetermined death. Major depressive disorder with melancholic and/or psychotic features appears to be an important contributor to accomplished suicide in the depression group, and alcohol dependence appears to be related to undetermined death.     

Vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters (n=13) and nonattempters (n=15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29+/-0.13 ng/ml vs 0.36+/-0.21 ng/ml, (F=1.1, df=1, 27, p=0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape.     

Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo-pituitary-adrenal axis.

OBJECTIVE: Although depression has been associated with hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis, recent studies among depressed elderly have found decreased cortisol levels, which may be due to underlying physical frailty associated with HPA-axis hypoactivity. The authors examined the relationship between urinary cortisol level and late-life depressive symptoms. The authors also explored whether hypo- and hypercortisolemic depressive symptoms are qualitatively different. METHODS: Data are from 881 community-dwelling participants, average age 74.2 years, of the Aging in the Chianti Area Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) scale and cortisol levels were determined in 24-hour urine samples. RESULTS: Mean urinary cortisol level was 98.9 microg/24 hours (SD=47.8), and 31% of the sample had significant depressive symptoms (CES-D > or =16). There was no linear association between urinary cortisol level and depressive symptoms; however, there was a nonlinear association between urinary cortisol level and depressive symptoms. Older persons in the lowest and highest urinary cortisol deciles were 2.2 and 1.9 times more likely to have significant depressive symptoms than older persons in all other deciles. Depressed persons with low cortisol presented more physical frailty than depressed persons with high cortisol. CONCLUSION: Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the HPA axis, which suggests distinct mechanisms for these associations.     

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.     

Factors associated with repeat suicide attempts among adolescents

OBJECTIVE: To determine potential risk factors associated with repeat suicide attempts among adolescents. METHOD: Retrospective medical record review of all patients aged 13-20 years who presented to the emergency department at an inner city tertiary hospital after attempted suicide between 1994 and 1996. Subjects were identified using the International Classification of Diseases (ICD-9) codes E950.0 to E959.9 for attempted suicide. Study variables included demographic parameters, chronic medical conditions/illnesses, psychiatric and substance abuse disorders, history of sexual abuse and previous and subsequent suicide attempts. Variables univariately associated with repetition at p < 0.25 were entered into a multiple regression analysis. RESULTS: Eighty seven per cent of patients presented with a drug overdose. Seventy-six per cent of all subjects attempted suicide in the context of a dispute or relationship break-up. At least one psychiatric disorder was present in 76% of subjects at the index attempt. The most frequently diagnosed disorders were depression (45.5%) and drug (34%) and alcohol abuse (27%). Variables predicting repetition within 12 months were drug (OR = 3.891, p = 0.02) and alcohol abuse (OR = 3.56, p = 0.05), non-affective psychotic disorders (OR = 3.81, p = 0.04), and chronic medical conditions/illness (OR = 3.29, p = 0.03). A history of sexual abuse was almost significant (OR = 3.03, p = 0.06). CONCLUSIONS: Adolescents most likely to re-attempt suicide with 12 months present with either substance abuse, non-affective psychotic disorders, chronic medical conditions, or a history of sexual abuse. All adolescents with a possible suicide attempt should receive a comprehensive mental health and psychosocial assessment. Closer scrutiny of the role of chronic illnesses and sexual abuse in both future research and clinical management is urged. A broad based, multidisciplinary intervention approach is recommended.     

Age, medical illness, and the DST in depressed general hospital inpatients

A dexamethasone suppression test (DST) was administered to 89 general hospital inpatients as part of an evaluation of depressed mood. Among the 55 patients with major depressive disorder (MDD), age was positively correlated with postdexamethasone cortisol (r=.317, p=.002 at 4 p.m.). The patients without MDD did not show this effect. Postdexamethasone cortisol concentrations of 15 micrograms/dl or greater were seen in 31% of 32 patients over 60 with MDD; they did not occur in 23 patients under 60 with MDD. The results suggest a clinically relevant effect of age on the DST in patients with MDD.     

Cortisol escape from suppression by dexamethasone during depression is strongly predicted by basal cortisol hypersecretion and increasing age combined.

We determined baseline 0800h plasma cortisol concentrations, 24-hr urinary free cortisol (UFC) excretion, the post-dexamethasone cortisol values at 0800h and 1600h, and the 0800h dexamethasone concentrations in 60 depressed patients categorized according to the DSM-III. Up to 59% of the variability in the 0800h post-dexamethasone cortisol values could be explained by the multiple regression on UFC, 0800h basal plasma cortisol, age (all positively related), and dexamethasone concentrations (negatively related). The 1600h post-dexamethasone cortisol data were best explained (i.e., 55% of the variance) by the multiple regression on basal plasma cortisol, UFC (positive) and dexamethasone (negative). After controlling for UFC, baseline plasma cortisol, and age no significant effects of the depressive state (diagnostic classification or severity of illness) on the post-dexamethasone cortisol values could be detected. It can be deduced that cortisol non-suppression during depression is related strongly to baseline cortisol hypersecretion and increasing age. These factors are additive and contribute independently towards cortisol escape from suppression by dexamethasone.     

未治疗抑郁障碍患者自杀风险与认知情绪调节策略的关系

目的探讨具有自杀风险的抑郁障碍患者在认知情绪调节策略方面的特征及其影响因素,以早期识别具有自杀风险的患者,有针对性地给予干预。方法选取117例来自北京回龙观医院门诊、经简明国际神经精神访谈(MINI)5. 0中文版筛查符合抑郁障碍诊断标准的未治疗抑郁障碍患者,根据MINI 5. 0中文版自杀模块的访谈结果,将患者分为自杀风险组(n=52)和无自杀风险组(n=65)。采用认知情绪调节问卷(CERQ-C)进行认知调节策略的测评,采用汉密尔顿抑郁量表17项版(HAMD-17)评定抑郁症状的严重程度。结果抑郁障碍患者自杀风险发生率为44. 4%(52/117)。与无自杀风险组相比,自杀风险组患者更多见于女性、未婚、平均年龄更小、发病年龄更早、HAMD-17总评分更高、伴精神病性症状率较高,自杀风险组自我责难、接受、沉思、灾难化4个认知调节策略维度及消极认知情绪调节评分均高于无自杀风险组(P均<0. 05)。Logistic回归分析显示,女性(OR=3. 539,95%CI:1. 383~9. 057)、发病年龄(OR=0. 931,95%CI:0. 895~0. 968)、HAMD-17总评分(OR=1. 207,95%CI:1. 063~1. 370)和灾难化(OR=1. 143,95%CI:1. 002~1. 305)与抑郁障碍患者自杀风险相关(P均<0. 05)。结论女性、发病年龄早、抑郁症状严重和灾难化可能为未治疗抑郁障碍患者自杀风险的危险因素。     

Cortisol response to clonidine in panic disorder: comparison with depressed patients and normal controls

Abnormalities in regulation of noradrenergic function have been proposed as part of the pathology of depressive and panic anxiety disorders. However, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function have largely been limited to patients with depressive disorders. Using the cortisol response to clonidine, an alpha 2-adrenergic receptor agonist, this study examined the relationship between the noradrenergic system and the HPA axis in 10 patients with major depression (4 unipolar, 6 bipolar), 10 patients with panic disorder, and 10 normal controls. Baseline cortisol was significantly elevated in depressed as compared with panic patients, but not with controls. Depressed patients also tended to exhibit a greater absolute fall in plasma cortisol (5.2 +/- 4.0 micrograms/dl) compared with panic patients (1.7 +/- 2.4 micrograms/dl) (p less than 0.06, t-test). When expressed as a percentage of baseline, however, the cortisol response to clonidine did not differ significantly between diagnostic groups (p greater than 0.10). Basal levels of cortisol were highly correlated with the degree of decrease in cortisol induced by clonidine in the group of 30 subjects (r = -0.81, p less than 0.0001). These findings are discussed in the context of the utility of clonidine as a probe of the functional relatedness of the noradrenergic system and the HPA axis in these disorders.