Serum contents of the free forms of alpha(1)-microglobulin and ulinastatin: relation to diseased states in patients with mood disorders

We have found previously that the relationship between the urinary contents of alpha(1)-microglobulin (alpha(1)M) and ulinastatin (UT) in patients with mood disorder differs from that of age-matched healthy subjects. However, it has yet to be determined whether or not the difference in the relation correlates with the contents of the free forms of alpha(1)M and UT in serum and whether changes in the existing forms of alpha(1)M and UT in serum reflect the actual disease states. The relation between serum contents of the free forms of alpha(1)M and UT in 10 patients with mood disorders was different from that of 17 age-matched healthy subjects. The regression plot between scores of the Hamilton Rating Scale for Depression and ratios of the free form content to total content (F/T ratio) of UT was more informative on the depressive state than that of alpha(1)M. The F/T ratios of UT may afford a useful objective index in monitoring the diseased state of a patient with mood disorder.     

Impairment of the correlation between urinary contents of alpha-1-microglobulin and ulinastatin is induced by intracerebroventricularly administered interleukin-6 in mice.

We have found previously that the correlation between urinary contents of alpha-1-microglobulin (alpha1M) and ulinastatin (UT) depends on the type of neuropsychiatric disease. Since interleukin (IL)-1beta and IL-6 are closely involved in pathophysiological aspects of various neuropsychiatric diseases, effects of intracerebroventricularly (i.c.v.) administered IL-1beta and IL-6 on the correlation between urinary contents of these two glycoproteins were examined in mice, a species in which alpha1M and UT and also the correlation between the urinary contents thereof are expressed similarly to humans. Indices (volume, contents of creatinine, alpha1M and UT, and alpha1M/UT ratio) in urine collected after i.c.v. administrations of 2 and 20 ng of either IL-1beta or IL-6 were not statistically different from those of the vehicle-treated (control) groups. Neither IL-1beta (2 and 20 ng) nor the lower dose of IL-6 (2 ng) affected the positive correlation between urinary contents of alpha1M and UT. However, a higher dose of IL-6 (20 ng) nullified the positive correlation for 2 days after administration. Recovery to a positive correlation was thereafter displayed. These findings suggest that central IL-6 plays an important role in correlating urinary contents of alpha1M and UT without affecting the renal functions.     

Platelet functions, alpha 2-adrenergic receptors and cytoplasmic free calcium are normal in the myotonic dystrophy of Steinert

Platelet function tests were performed on 11 patients with myotonic dystrophy of Steinert (MD) and on 21 healthy control subjects. Using citrated platelet-rich plasma or washed platelets, MD patients had normal aggregation and secretion responses after stimulation with adrenaline, ADP, collagen, PAF, arachidonic acid and thrombin. Using intact and functional washed platelets, MD patients responded normally to adrenaline and had a similar affinity and number of alpha 2-adrenergic receptors as control patients as measured by [3H]dihydroergocryptine and [3H]yohimbine binding. In addition platelets from MD patients had normal basal and stimulated levels of cytoplasmic free Ca2+ as measured with the fluorescent Ca2+ probe quin2. Thus platelet functions, alpha 2-adrenergic receptors and cytoplasmic free Ca2+ are normal in MD.     

Blunted ACTH response to hypoglycemic stress in depressed patients but not in patients with schizophrenia.

In this study, 7 hospitalized patients with major depression (MD), 5 hospitalized patients with schizophrenia (S), and 13 control subjects (C) were administered 0.15 units/kg of regular insulin at 1600 h by intravenous bolus infusion. ACTH, cortisol, and glucose levels were measured intermittently for 2h following infusion. Baseline ACTH, cortisol and glucose levels were similar in Cs, MDs, and Ss. The mean glucose nadir was equivalent for Cs, patients with MD, and patients with S. Patients with MD had a blunted ACTH response (F = 3.28; df = 12,126; p = .0004) and cortisol response (F = 4.20; df = 12,132; p = .0001) to hypoglycemia when compared to Cs and patients with S. Carroll Depression Rating Scale scores in patients with S (23 +/- 10) were similar to patients with MD (30 +/- 8) and significantly higher than in controls (1 +/- 2) (F = 55.2; df = 2.22; p = .0001). These findings suggest that patients with MD show different ACTH and cortisol responses to hypoglycemic stress which are not explained by negative feedback of baseline ACTH or cortisol, glucose nadir, or the number of depressive symptoms per se.     

Changes in the ratio of urinary α1-microglobulin to ulinastatin levels in patients with Alzheimer-type dementia and vascular dementia

Abstract Relationships between urinary levels of α1-microglobulin (α1M) and ulinastatin (UT) in patients with dementia were investigated. There were no significant differences in α1M and UT levels and α1M: UT ratios among three groups: age-matched control subjects, patients with either Alzheimer-type senile dementia (ATD) or vascular dementia (VD). Although a positive correlation was established between α1M and UT levels in these groups, the regression of the demented patients differed significantly from that of controls ( P <0.05). A tendency towards a negative correlation between α1M: UT ratios and the levels of severity or duration of the disease was displayed in the ATD group, whereas a tendency toward a positive correlation between α1M: UT ratios and the levels of severity was observed in the VD group. These results suggest that changes in the relationships between urinary levels of α1M and UT may provide a useful biochemical index for diagnoses of ATD and VD.     

Lower degree of esterification of serum cholesterol in depression: relevance for depression and suicide research

Previous studies have suggested that depression and suicide are related to alterations in total cholesterol serum concentrations, and that an altered distribution of haptoglobin (Hp) phenotypes in major depression indicates that variation on chromosome 16 may be associated with that illness. Lecithin:cholesterol acyl transferase (LCAT, EC 2.3.1.43), the enzyme that catalyzes the esterifying reaction of cholesterol in serum, is located close to the Hp gene. This study examined the serum concentrations of total and free cholesterol and the esterified cholesterol ratio in 26 healthy controls, 47 unipolar depressed subjects (16 minor, 14 simple major and 17 melancholic depressed subjects) and 12 relatives of melancholic subjects. Depressed subjects (regardless of subtype) and relatives of depressed subjects had a significantly lower esterified cholesterol ratio than normal controls. No significant differences in total or free cholesterol concentrations were found between the above study groups. In depressed subjects, there were no significant relationships between the esterified cholesterol ratio, total or free cholesterol and postdexamethasone adrenocorticotropic or cortisol values, Hp phenotypes, severity of illness or suicidal symptoms. It is hypothesized that lower esterification in serum cholesterol may constitute a vulnerability factor for depression through alterations in cell membrane microviscosity.     

Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging

The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.     

Glucocorticoid receptors, fibromyalgia and low back pain

Recently, fibromyaglia (FMS) was shown to be a disorder associated with an altered functioning of the stress response system. FMS patients display a hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin-induced hypoglycemia. We suggested that negative feedback of cortisol could be deranged. Therefore we investigated the properties and function of the glucocorticoid receptors (GR) in FMS patients and compared the results with those of healthy persons and patients with chronic low back pain (LBP a localized pain condition). Forty primary FMS patients (F:M = 36:4), 28 LBP patients (25:3) and 14 (12:2) healthy, sedentary control persons were recruited for the study.

Urinary free cortisol excretion in FMS and LBP patients was lower compared to controls. Only FMS patients displayed lower CBG and basal serum cortisol concentrations when compared to controls. However, plasma free cortisol concentrations were similar in the three groups.

There was no difference in the number of GR per cell among the three groups (FMS: 6498 ± 252, LBP: 6625 ± 284, controls: 6576 ± 304), but the dissociationh constant (K_d) of the FMS (14.5 ± 0.9 nmol/l) and LBP (14.7 ± 13 nmol/l) subjects was significantly higher than that of the controls (10.9 ± 0.8 nmol/l) (p < .05).

The maximal stimulation of the lymphocytes, as measured by the maximal thymidine incorporation (in the absence of cortisol) in the FMS group was approximately 1.5 times higher (p < .05) than in the control or LBP group. The ED₅₀ (the cortisol concentration giving 50% inhibition of the thymidine incorporation), however, was identical in all three groups.

We conclude that FMS patients have a mild hypocortisolemia, increased cortisol feedback resistance in combination probably with a reduced CRH synthesis or release in the hypothalamus. The role of the GR and mineralocorticoid receptor (MR) in the CRH regulation in the FMS patients remains to be solved.     

Prolactin levels in drug-naïve patients with schizophrenia and other psychotic disorders

Objective: Hyperprolactinaemia as a side effect of dopamine receptor blockers is common in patients with schizophrenia and other psychotic disorders and may lead to amenorrhoea, galactorrhoea, hypogonadism, subfertility and osteoporosis. The aim of our study was to determine whether hyperprolactinaemia occurs also in patients with schizophrenia and other psychotic disorders prior to any antipsychotic treatment.

Methods: Serum prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), free tetraiodothyronine (FT4) and cortisol levels were measured in 40 newly diagnosed, drug naïve, patients with schizophrenia and other psychotic disorders and in 40 age and gender matched healthy subjects.

Results: The median prolactin value was 12.5?ng/ml (range: 2–38?ng/ml) for patients and 8.6?ng/ml (range: 4–17.6?ng/ml) for healthy subjects (p?=?0.011). Patients had lower levels of T3 compared to healthy controls (mean: 1.08?ng/ml, SD: 0.16 vs. 1.18?ng/ml, 0.18, respectively; p?=?0.008). Serum TSH, FT4 and cortisol levels were similar between the two groups. Multiple regression analysis revealed that the difference in serum prolactin values was independent of thyroid function (TSH, FT4, T3) and serum cortisol levels.

Conclusions: A higher serum prolactin level was found in drug naïve, newly diagnosed patients with schizophrenia and other psychotic disorders compared to healthy controls, prior to starting any antipsychotic treatment.     

The effect of sodium valproate on serum cortisol levels in healthy subjects and depressed patients

In nine healthy subjects the i.v. injection of 800 mg of the GABA-transaminase inhibitor sodium valproate (SV) was able to suppress serum cortisol significantly when compared to saline. Three and a half hours after the administration of SV, serum cortisol was reduced to less than 50% of the basal value in each of the subjects. Among 17 depressed patients serum cortisol was reduced to less than 50% of basal value 3 1/2 h after SV in only two patients. No difference was found between nine patients with endogenous depression and eight with non-endogenous depression. The dexamethasone suppression test was abnormal in four out of 17 patients. These four patients had endogenous depression, and also an abnormal response to SV. A positive correlation was found between the effect of SV on serum cortisol, and age (r = 0.55), but not between the percentual decrease of serum cortisol and the severity of depression. The effect of SV on serum cortisol was significantly less pronounced in depressed patients than in controls but no difference was found between patients with endogenous and non-endogenous depression.     

Hair cortisol concentrations and cortisol stress reactivity in generalized anxiety disorder,major depression and their comorbidity

Studies investigating cortisol secretion in patients with generalized anxiety disorder (GAD) have reported heterogeneous findings. Further, current knowledge on the specificity of endocrine changes for GAD and/or comorbid major depression (MD) is limited. Hence, the current study investigated long-term integrated cortisol secretion, as indexed by hair cortisol concentrations (HCC), and experimentally-induced cortisol stress reactivity in relation to GAD, MD and their comorbidity. Carefully characterized groups of 17 GAD patients including 8 with comorbid MD (GAD-MD), 12 MD patients and 21 healthy controls were recruited. Alongside psychometric data, HCC (N = 43) and salivary cortisol stress reactivity in response to the Trier Social Stress Test (N = 45) were determined. Findings revealed that MD patients exhibited lower HCC compared to controls and GAD patients, with no differences between the latter two groups. Interestingly, when the GAD group was separated into two groups based on MD comorbidity, lower HCC in MD patients were found compared to controls and GAD-noMD patients, but did not show differences when compared to GAD-MD patients. No HCC differences were seen between GAD-MD or GAD-noMD patients and healthy controls. No TSST group differences emerged. Our findings suggest MD to be related to long-term attenuation in cortisol secretion. While no group differences emerged between patients with GAD, neither with nor without MD, and controls, the current results provide tentative evidence that MD determines long-term endocrine changes, with pure GAD showing a distinct pattern. Future studies are needed to confirm our findings in larger samples of pure and comorbid groups.     

Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics.

The 24-h profiles of plasma melatonin and cortisol were evaluated in 7 drug-free male paranoid schizophrenics and in 7 healthy subjects matched to the patients for age, sex, body weight, height and season of testing. Blood samples were obtained at 20.00, 22.00, 24.00, 01.00, 02.00, 06.00, 08.00 and 12.00 h. Light was turned off from 21.00 to 07.00 h. Compared with that of the normal controls, the circadian rhythm of plasma melatonin was absent in paranoid schizophrenics (F7.84 = 7.30, p less than 0.0001; two-way ANOVA with repeated measures) whereas the 24-h profile of plasma cortisol was preserved, although at a slightly higher level (F1.12 = 26.810, p less than 0.0002). The melatonin/cortisol ratio was significantly higher in healthy subjects than in the schizophrenic patients. A functional relationship between disturbances in the melatonin rhythm especially and schizophrenia may be proposed, although the significance of this relationship remains to be elucidated.     

Elevation of the cortisol-dehydroepiandrosterone ratio in drug-free depressed patients

OBJECTIVE: Elevated basal cortisol levels are a feature of depressive illness and cause deficits in learning and memory. The adrenal steroid dehydroepiandrosterone (DHEA) has antiglucocorticoid properties that may offer protection against the deleterious effects of cortisol. The authors examined the ratio of cortisol to DHEA in drug-free depressed patients and a matched comparison group. METHOD: Cortisol and DHEA were measured in saliva samples from 39 patients with unipolar depression who had been medication free for at least 6 weeks and 41 healthy comparison subjects. RESULTS: The molar cortisol-DHEA ratio was significantly higher in the depressed patients than in the healthy comparison subjects. Cortisol-DHEA ratios from saliva samples taken at 8:00 p.m. correlated positively with length of current depressive episode. CONCLUSIONS: Elevated cortisol-DHEA ratios may be a state marker of depressive illness and may contribute to the associated deficits in learning and memory. Administration of DHEA or other antiglucocorticoid treatments may reduce neurocognitive deficits in major depression.     

Cortisol, the cortisol-dehydroepiandrosterone ratio, and pro-inflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder.

BACKGROUND: Major depression in young women is often comorbid with borderline personality disorder (BPD); however, adrenal steroids and pro-inflammatory cytokines in patients with comorbid current major depressive disorder and BPD (MDD/BPD) have not been systematically examined. Therefore, our study aimed at examining serum profiles of cortisol, cytokines, and the cortisol/dehydroepiandrosterone (cortisol/DHEA) ratio in MDD/BPD patients and a healthy comparison group. METHODS: Twelve medication-free female patients with MDD/BPD and 12 healthy women were included. Serum profiles of cortisol, DHEA, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta were sampled, and the molar cortisol/DHEA ratio was determined. RESULTS: Concentrations of serum cortisol, TNF-alpha, and IL-6, as well as the cortisol/DHEA ratios were significantly increased in MDD/BPD patients as compared with the healthy comparison group. CONCLUSIONS: Depressed patients with comorbid BPD display endocrine and immune alterations similar to those observed in cases of melancholic MDD without BPD. Elevated concentrations of serum cortisol, cortisol/DHEA ratios, and pro-inflammatory cytokines might indicate a state marker in these patients and might contribute to long-term metabolic alterations that have also been associated with MDD.     

The HPA axis response to insulin hypoglycemia in depression

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, demonstrated by failure to suppress cortisol secretion after dexamethasone, is found in approximately 50% of patients with major depression (MD). In this study, we examined the response of adrenocorticotrophic hormone (ACTH) and cortisol to insulin-induced hypoglycemia in 20 healthy controls and 18 inpatients with MD [12 dexamethasone suppressors (S) and 5 dexamethasone nonsuppressors (NS)]. After the administration of 0.15 U/kg of regular insulin, both controls and patients with MD showed an increase in plasma ACTH and cortisol levels. Controls had a significantly higher ACTH peak (p less than 0.01) and ACTH increment (p less than 0.01) than MD patients. There were no statistically significant differences between patients who were S and NS. Although baseline plasma cortisol levels were significantly higher in MD patients, there were no significant differences in the peak cortisol or increment in plasma cortisol after hypoglycemia between patients with MD and controls or between patients who were S and those who were NS. These findings suggest that a defect exists in the regulation of the HPA axis at the pituitary level in MD and that this defect is not necessarily reflected in the dexamethasone suppression status of the patient.     

Sex differences in proinflammatory cytokine profiles of progressive patients in multiple sclerosis

The objective of this article is to evaluate the presence of sex differences in expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients. The predominance of females in MS and other autoimmune diseases may be related to their differential responses in many immunological settings. Recent data show beneficial effect of sex hormones on proinflammatory cytokine levels and on magnetic resonance imaging in MS. Better understanding of gender differences is warranted. In this study 124 MS subjects (M:F; 56:68) and 34 healthy controls (M:F; 12:22) were included. Stimulated peripheral blood-derived CD4+ and CD8+ T cells were analysed for interferon-gamma, interleukin (IL)-2, tumour necrosis factor alpha, IL-4, IL- 10 and IL- 13 production. There were no significant differences for these cytokines between male and female MS subjects in the whole group. Compared to males, female patients had higher proinflammatory cytokine levels in the progressive phase of the disease. In conclusion, the data presented indicate that cytokine production and sex differences in cytokine production might differ between disease phases, probably related to underlying disease mechanisms.     

Cortisol levels in relation to hippocampal sub-regions in subjects with first episode schizophrenia

The etiology of hippocampal volumetric reductions in schizophrenia is largely unknown. In addition to genetic factors, environmental factors might also play a role. High levels of glucocorticoids are known to affect hippocampal volume in disorders such as Cushing's syndrome, but the relationship between cortisol and hippocampal volumes has not been studied in schizophrenia. We obtained diurnal salivary cortisol levels and MRI images to explore the link between cortisol levels and regional hippocampal volumes in healthy controls (N=29) and subjects with first episode schizophrenia (N=16) at the time of first admission. T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Using ANOVA, cumulative daily cortisol exposure calculated as area under the curve for each subject revealed significantly higher cortisol levels in the patient group [F(1,43)=4.4 p=0.04]. However, there were no statistically significant associations between the cortisol measures and regional hippocampal volumes in the subjects, except a trend level link between anterior hippocampal volume and cortisol in the positive direction, in parallel to previous findings in healthy adolescents. Our findings do not suggest a robust association between cortisol levels and hippocampal volumes in a first episode schizophrenia sample. Larger scale studies are needed to conclude a link between the two measures, yet it is possible that the negative association that was previously shown in other disorders may not apply to schizophrenia.     

Neuroendocrinal study of depression in male epileptic patients

Endocrine changes are reported in both epilepsy and depression. The interrelationships between mood, epilepsy, and endocrine changes are not well characterized. The authors included 40 epileptic patients (20 depressed, 20 nondepressed) and 20 healthy subjects. All patients had an electroencephalogram, and were given the Hamilton Rating Scale for Depression. All subjects were tested for serum levels of cortisol, prolactin, testosterone, and thyroid hormones. Patients were medication-free. Patients had elevated prolactin and cortisol and reduced serum testosterone relative to control subjects. Depressed patients had higher cortisol levels than nondepressed. Data suggest that the effects of epilepsy and depression on cortisol, but not other hormones, may be additive.     

Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine

There is evidence that the abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic alpha 2-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the alpha 2-antagonist yohimbine suggests a relative subsensitivity of postsynaptic alpha 2-adrenergic receptors in depression.     

Neuroendocrine (HPA axis) and clinical correlates during fluvoxamine and amitriptyline treatment

The effect of amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) axis activity was compared with that of fluvoxamine in 38 patients suffering from DMS-IV major depressive disorder. Basal plasma adrenocorticotropic hormone and cortisol levels were determined in the so-called "observation window" of an hour (08:00-09:00 h), and cortisol levels were determined again at 20:00 h. Clinical and biochemical assessments were performed before therapy (T0), at day 14 (T14), and at day 42 (T42) of the course of antidepressant treatment. At T0, neuroendocrine parameters did not differ in patients from those in controls, except for the ratio between cortisol levels at 20:00 h and the mean level of the "window" (ratio F20/F8), which was significantly higher, suggesting a dysregulation of the circadian pattern of cortisol. Although a decrease in the ratio F20/F8 was already apparent at T14 of both treatments, the repeated measures analysis of variance failed to demonstrate a significant variation with time (T0, T14, and T42) and with treatment (amitriptyline and fluvoxamine) for any hormonal measure. At T42, both treated groups showed a similar level of clinical improvement. Our results did not demonstrate any effect of antidepressant therapy on the cortisol circadian rhythm abnormality.