Cortisol hypersecretion and cognitive impairment in depression

We attempted to investigate the relationship between hypothalamic-pituitary-adrenal axis activity and cognitive function by measuring mean urinary free cortisol (MUFC) excretion and performance on the Halstead Category Test in depressed patients and normal controls. We observed a significant relationship between category test errors and MUFC in the depressed patients, but not in the controls. While an even more robust correlation was observed between age and category test errors in the patients, it appeared that age and depression interacted to produce severe cognitive impairment. Depression-related cortisol hypersecretion or its underlying determinants may contribute to depression-related cognitive dysfunction.     

Endogenous opioid activity and beta-endorphin immunoreactivity in CSF of psychiatric patients and normal volunteers

The authors measured total opioid activity by radioreceptor assay in the CSF of 41 normal subjects and 89 unmedicated psychiatric patients, including schizophrenic, schizoaffective, depressed, and manic diagnostic groups. Schizophrenic men had significantly lower levels of opioid activity than the normal men, although these levels did not significantly differ from levels of other male patients. The authors observed higher opioid activity during mania than during depression in paired samples for 4 manic-depressive patients. beta-Endorphin immunoreactivity in a subsample of the same subjects was no different in the patient group than in the normal group, suggesting that the differences in CSF opioid activity between schizophrenic men and normal patients may be related to opioids other than beta-endorphin.     

Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia

To explore the relationship of central and peripheral adrenocorticotropic hormone (ACTH, or corticotropin) levels to hypothalamo-pituitary-adrenal axis dysfunction in patients with eating disorders, levels of cerebrospinal fluid (CSF) and plasma ACTH, cortisol, and 24-hour urinary free cortisol were measured in 16 patients with anorexia nervosa (60% +/- 1.1% of ideal body weight), 14 patients with bulimia (93.2% +/- 4.6% of ideal body weight), and 11 healthy age-matched women volunteers. The CSF, plasma, and urinary free cortisol levels were elevated in underweight anorexic patients and showed declines following weight recovery. Cortisol-binding globulin levels were similar in anorexics and controls. In contrast, underweight anorexics showed low CSF ACTH levels that returned to normal following weight recovery, and their plasma ACTH levels were normal. On hospital admission, bulimic patients demonstrated normal ACTH and cortisol levels. After their abstinence from binge-purge episodes, the CSF ACTH levels decreased significantly. Positive relationships were found among CSF, plasma, and urinary cortisol levels, and inverse relationships were seen between cortisol measures and CSF ACTH levels in patients with eating disorders. Secretion of ACTH into the CSF may respond to feedback by cortisol or, alternatively, may be suppressed by the hypersecretion of corticotropin-releasing hormone, leading to the depletion of the pro-opiomelanocortin molecule.     

Clinical studies of the endogenous opioid system

The role of the endogenous opioid system in humans was studied using three clinical research strategies. High doses of the opiate antagonist naloxone (up to 4 mg/kg) were administered to normal volunteers. Dose-dependent increases in self-ratings of tension-anxiety and anger-hostility were observed, supporting the hypothesized involvement of the endogenous opioid system in the modulation of human mood and feelings of well-being. Accompanying dose-dependent increases in systolic blood pressure and respiratory rate were found, suggesting that the lower doses of naloxone utilized in previous clinical studies were not sufficient to block the endogenous opioid system. CSF opioid activity in psychiatric patients and normals was measured using a sensitive radioreceptor assay developed by the authors. Results suggest diminished endogenous opioid system activity in some schizophrenics, and a relationship between opioid activity and state change in manic-depressive illness and anorexia nervosa. A complex but consistently observed relationship between ratings of anxiety and CSF opioid activity in normals and patients is consistent with basic science and clinical data suggesting interactions between CNS noradrenergic and opioid systems. General surgery was used as a strategy for studying the relationship of the endogenous opioid system to stress in humans; robust increases in levels of plasma beta-endorphin immunoreactivity accompanying surgical stress and an inverse relationship between patient levels of plasma beta-endorphin immunoreactivity and postoperative analgesic requirement were observed. These data support the involvement of the endogenous opioid system in the human stress response and suggest that hormonal stress response and endogenous opioid system activity may relate to human endogenous analgesic mechanisms.     

Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder

OBJECTIVE: The authors sought to carefully test, by using a technique of continuous CSF sampling, the hypothesis that basal elevations in CSF corticotropin-releasing hormone (CRH) concentrations exist in patients with posttraumatic stress disorder (PTSD). They also sought to assess the relationship among PTSD symptoms, adrenocortical activity, and CSF CRH levels. METHOD: CSF was withdrawn by means of a flexible, indwelling subarachnoid catheter over a 6-hour period, and hourly CSF concentrations of CRH were determined for 11 well-characterized combat veterans with PTSD and 12 matched normal volunteers. Twenty-four-hour urinary-free cortisol excretion was also determined. PTSD and depressive symptoms were correlated with the neuroendocrine data. RESULTS: Mean CSF CRH levels were significantly greater in PTSD patients than in normal subjects (55.2 [SD = 16.4] versus 42.3 pg/ml [SD = 15.6]). No correlation was found between CSF CRH concentrations and PTSD symptoms. While there was no significant difference between groups in 24-hour urinary-free cortisol excretion, the correlation between 24-hour urinary-free cortisol excretion and PTSD symptoms was negative and significant. CONCLUSIONS: By using a serial CSF sampling technique, the authors found high basal CSF CRH concentrations and normal 24-hour urinary-free cortisol excretion in combat veterans with PTSD, a combination that appears to be unique among psychiatric conditions studied to date.     

Cortisol in the CSF of depressed and suicidal patients

Cortisol concentrations in CSF were measured by radioimmunoassay in healthy controls, depressed patients, patients who had attempted suicide but were not depressed, and obsessive-compulsive patients. The factors that contributed most to the variance in CSF cortisol levels were a diagnosis of depression, height, and important life changes during the six months preceding the investigation. Depression was by far the most important factor. The depressed patients had significantly higher CSF cortisol levels than the controls. In obsessive-compulsive and depressed patients treated with clomipramine hydrochloride, the levels were significantly correlated with mean urinary cortisol excretion. Of the three monoamine metabolites measured, only 5-hydroxy-indoleacetic acid level was weakly correlated with CSF cortisol level. This correlation was confined to the depressed patients and could be accounted for by the common correlation with height.     

Plasma cortisol and beta-endorphin immunoreactivity in nonmajor and major depression

Plasma cortisol levels of 28 hospitalized patients meeting Research Diagnostic Criteria for major or nonmajor (minor or intermittent) depression were significantly higher than those of eight normal subjects. In contrast, plasma beta-endorphin immunoreactivity was significantly lower in patients with nonmajor depression than in those with major depression or in normal subjects. A low ratio of plasma beta-endorphin to cortisol immunoreactivity was found to characterize patients in both groups. Through the use of only this ratio, a post-hoc analysis identified 25 depressed patients and seven controls. These findings have implications for psychiatric diagnosis and the involvement of the endogenous opioid system in the pathogenesis of depression.     

Elevated CSF beta-endorphin immunoreactivity in Rett's syndrome: report of 158 cases and comparison with leukemic children.

Because some symptoms of Rett's syndrome are suggestive of excessive endogenous opioid activity, we measured the levels of beta-endorphin-like immunoreactivity in lumbar CSF from 158 affected female patients and from 13 female controls. The mean (+/- SE) control level of beta-endorphin immunoreactivity in CSF was 35.3 +/- 2.8 pg/ml (range, 23 to 48 pg/ml), whereas those with Rett's syndrome had a mean level of 95.3 +/- 3.6 pg/ml (range, 31 to 293 pg/ml). The levels of beta-endorphin immunoreactivity in initial CSF samples exceeded the control range in 90% of the patients with Rett's syndrome. The mean beta-endorphin immunoreactivity was also elevated in CSF from leukemic children (119.2 +/- 16.9 pg/ml; range, 40 to 159 pg/ml), relative to the control group. These results are consistent with the hypothesis that some symptoms of Rett's syndrome may be associated with excessive endogenous opioid levels in the CNS.     

Diurnal rhythms of plasma cortisol, beta-endorphin and prolactin, and cerebrospinal fluid amine metabolite levels before suicide. Case report

There are indications to suggest a relationship between low levels of 5-hydroxy-indoleacetic acid (5HIAA) in the cerebrospinal fluid and suicidal behavior. Many depressed patients show an elevated cortisol secretion. As beta-endorphin is derived from the same precursor as ACTH, it is expected that plasma beta-endorphin levels will also rise in depressed patients. We report here a case of severe depression with diurnal variation who showed low CSF 5HIAA prior to his suicide. In contrast, his catecholamine metabolites were 50% above the mean values of other depressed patients. Hormonal measurements, however, showed low cortisol, prolactin and beta-endorphin levels.     

Hypothalamic-pituitary-adrenocortical function in mixed and pure mania.

There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.     

CSF beta-endorphin and beta-lipotropin in Alzheimer's disease and multi-infarct dementia

We measured CSF levels of the opioid peptides beta-endorphin and beta-lipotropin in patients with Alzheimer's disease, multi-infarct dementia and controls. In both dementia groups, the mean concentration of beta-endorphin was significantly lower than in controls. The mean beta-lipotropin levels did not differ significantly in the two groups. The low CSF beta-endorphin level may relate generally to dementia.     

The dexamethasone suppression test and pituitary-adrenocortical function

The dexamethasone suppression test (DST) as now commonly carried out in psychiatric settings yields "abnormal" results in many conditions including the healthy state. To determine whether the DST accurately identifies patients with physiologically meaningful increases in pituitary-adrenocortical activity, we compared DST results to baseline urinary cortisol level. Thirty-four psychiatric inpatients underwent a 24-hour urine collection and then a DST using 1 or 2 mg of dexamethasone. With the common 1-mg DST, 24-hour urinary cortisol levels in nonsuppressors and suppressors did not differ. With the 2-mg DST, however, nonsuppressors had significantly higher urinary cortisol levels than suppressors, and all nonsuppressors had urinary cortisol levels above the normal range. Thus, the 1-mg DST may not identify the heuristically important subgroup of psychiatric patients who have a pathophysiologically meaningful alteration in pituitary-adrenal regulation.     

Cortisol secretion in endogenous depression. I. Basal plasma levels

Plasma levels of cortisol were sampled for 24 hours in 32 endogenously depressed (ED) patients and 72 normal controls who also underwent the dexamethasone suppression test. The ED patients had significantly higher mean 24-hour plasma levels of cortisol (means 24h PC). However, means 24h PC values of subjects in both groups were normally distributed, with a marked overlap between the two. Only seven ED patients had means 24h PC values higher than 2 SDs from the normal mean (greater than 10 micrograms/dL). An abnormal dexamethasone suppression test result was only partially related to basal cortisol levels. The mean plasma level of cortisol between 1 and 4 PM was found to be highly correlated with the means 24h PC value in ED patients, as has been previously reported in normal subjects and patients with various other diseases (in which it also powerfully discriminated between hypersecretors and normosecretors). This finding supports the use of mean cortisol levels between 1 and 4 PM as a reliable and convenient indication of cortisol secretion.     

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.     

CSF beta-endorphin and dynorphin in bulimia nervosa.

OBJECTIVE: Preclinical and clinical evidence suggests that central opioid dysfunction may play a role in the pathophysiology of the eating disorders. In particular, endogenous opioids are known to regulate feeding behavior, mood, perception, and neuroendocrine function, all of which are disturbed in patients with eating disorders. Although low concentrations of CSF beta-endorphin have been reported in low-weight patients with anorexia nervosa, central opioid activity in normal-weight patients with bulimia nervosa has not been reported. The authors therefore measured CSF concentrations of beta-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. METHOD: After 4 days of a low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) from 11 women with bulimia and 17 normal comparison subjects (eight women and nine men). RESULTS: The women with bulimia had significantly lower CSF concentrations of beta-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. beta-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale of the Eating Disorders Inventory. CONCLUSIONS: These data support a role for central opiates in the mediation of the pathophysiology of the signs and symptoms of bulimia nervosa, although it is impossible to rule out the effects of depression on the results.     

Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression

Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.     

Plasma measures of beta-endorphin/beta-lipotropin-like immunoreactivity in chronic pain syndrome and psychiatric subjects

This study compared basal concentrations of plasma beta-endorphin/beta-lipotropin-like immunoreactivity and dexamethasone suppression of cortisol in seven chronic pain patients, seven psychiatric disorder patients, and seven normal volunteers. Pain patients and psychiatric patients showed significantly higher basal concentrations of beta-endorphin/beta-lipotropin-like immunoreactivity compared to normal volunteers. Pain patients also had significantly higher beta-endorphin/beta-lipotropin-like immunoreactivity than psychiatric patients, even though there was no significant difference in severity of depressive symptomatology as assessed by Beck and Hamilton scores. Resistance to dexamethasone occurred in 57% of pain patients. These results may indicate that biological markers for depression occur in populations of chronic pain patients, or may reflect levels of central nervous system arousal in response to stress, pain, or nonaffective phenomena.     

Increased activity and phase delay in circadian motility rhythms in geriatric depression. Preliminary observations

Locomotor activity levels and rhythms of eight hospitalized geriatric unipolar depressed patients (DSM-III criteria) were compared with those of eight healthy elderly controls in a similar environment. Activity was measured using a wrist-worn electronic activity monitor with solid-state memory. Depressed patients had a 29% higher mean total 24-hour activity level, with no change in circadian amplitude or frequency. Daily peak activity (acrophase) averaged 2.05 hours later in depressed patients, with no overlap between the groups. The degree of phase delay correlated significantly with the 4 PM postdexamethasone serum cortisol level. These tentative findings suggest that elderly unipolar depressed patients have prominent chronobiological disturbances in the modulation of activity levels and possibly other physiological processes. These differ strikingly from reported disturbances in younger or bipolar depressed patients.     

Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test.

BACKGROUND: Plasma cortisol, beta-endorphin, corticotropin, corticotropin-releasing factor, and salivary cortisol concentrations, resting and after ingestion of 1 mg of dexamethasone, were investigated in depressed patients and controls. METHODS: Fourteen outpatients from the psychiatric department diagnosed with depressive disorder (ICD-10 Classification) participated in the study. The comparison group consisted of 12 healthy volunteers from the hospital staff. All hormones were measured using direct iodine-125 radioimmunoassay, except corticotropin-releasing factor, which included a sample preextraction and concentration step. RESULTS: The basal plasma cortisol and corticotropin-releasing factor levels in depressive disorder were significantly higher than in the healthy group. After dexamethasone administration, corticotropin-releasing factor plasma values decreased significantly in the depressed group, but showed no significant changes in the controls. In depressive disorder baseline values correlated significantly for salivary cortisol and plasma cortisol, salivary cortisol and plasma corticotropin-releasing factor and plasma corticotropin and beta-endorphin. Similar correlations were found in the healthy subjects, except for salivary cortisol and plasma corticotropin-releasing factor. CONCLUSIONS: These findings indicate that the increased corticotropin-releasing factor plasma concentrations demonstrated in depressive disorder reflect the hypothalamic corticotropin-releasing factor hypersecretion evidenced in this illness. Therefore, measurements of plasma corticotropin-releasing factor levels can be considered a reliable tool for investigating the role of this peptide in the pathophysiology of depression.     

The relationship of plasma cortisol and beta-endorphin immunoreactivity to surgical stress and postoperative analgesic requirement

It has been hypothesized that the endogenous opioid (endorphin) system is related to biologic stress responses. We have used general surgery as a naturalistic model for studying stress response in humans. Abdominal surgery, but not anesthesia induction, was associated with significant increases in plasma beta-endorphin immunoreactivity and cortisol. Both hormones decreased significantly during post-operative morphine administration. Baseline and mean surgery levels of plasma beta-endorphin immunoreactivity showed an inverse relationship with post-operative analgesic requirement. These data support involvement of the endorphin system in human stress response and in human endogenous analgesic mechanisms. Findings also support the concept that baseline or psychologically stimulated levels of arousal may also be an important determinant in the physiology of stress response and pain perception.