Afternoon plasma cortisol in depressed patients: A measure of diagnosis or severity?

Plasma cortisol concentration was measured at 20 min intervals from 3 p.m. (1500 hrs) to 6 p.m. (1800 hrs) in 26 hospitalized patients classified according to the Newcastle Index as endogenously depressed (n = 16) or non-endogenously depressed (n = 10). When examined in depressed state, before treatment, maximum, mean and range of plasma cortisol concentration in this time interval was significantly higher in the endogenously depressed patients than in the non-endogenously depressed patients (p less than 0.01-0.02). The diagnostic identification of endogenous depression on the basis of these cortisol concentration measurements was at least as good as that reported by others using post-dexamethasone cortisol levels. The plasma cortisol levels (maximum, mean) and fluctuations (range) correlated significantly with the degree of depression (Hamilton Depression Scale), and differences in severity of depression could explain most of the differences in cortisol levels between the two diagnostic groups. Nine patients were reexamined after 3-12 months in a non-depressed state, and all unipolar endogenously depressed patients (n = 6) then had clearly reduced cortisol levels and fluctuations.     

Saliva cortisol levels following dexamethasone administration in endogenously depressed patients

Saliva and serum cortisol levels were measured in 11 patients with primary major depression, endogenous subtype, and in 9 control subjects before and 8, 16, and 24 hours after dexamethasone administration (1.0 mg p.o.). Six of the 20 subjects had post-dexamethasone serum cortisol concentrations greater than 50 ng/ml and thus were considered “escapers” from dexamethasone suppression. These six subjects also had saliva cortisol concentrations which were significantly elevated compared to those of the suppressors. Measurement of saliva cortisol holds promise as a non-invasive technique for assessing CNS-pituitary-adrenal function in endogenously depressed patients.     

Plasma acth and cortisol levels in depressed patients: Relation to dexamethasone suppression test

Blood samples collected from normal subjects and newly hospitalized depressed patients at 8 AM on the day before and at 8 AM and 4 PM the day after receiving dexamethasone, 1 mg orally at 11 PM, were analyzed for ACTH and cortisol. The mean plasma ACTH values of these two groups were not significantly different at any of the times, while the cortisol levels of the depressed patients were significantly higher than those of the normal subjects at 8 AM pre-dexamethasone (P<0.001). There was no correlation between plasma ACTH and cortisol values in either group. The cortisol responses to dexamethasone in depressed patients revealed two subgroups. In one subgroup, the cortisol was suppressed as much as in normal subjects, but in the other, cortisol levels were not suppressed. The post-dexamethasone ACTH rebounded at 4 PM in the latter subgroup to higher values than in the subgroup with suppressed cortisol levels and in the normal subjects. After dexamethasone, the ACTH values were negatively correlated with plasma cortisol only in the normal subjects (P<0.01), not in the depressed patients. These results indicate that ACTH levels do not account for the elevated cortisol and the failure of dexamethasone to suppress cortisol levels in some depressed patients.     

Antepartum Depression Severity is Increased During Seasonally Longer Nights: Relationship to Melatonin and Cortisol Timing and Quantity

Current research suggests that mood varies from season to season in some individuals, in conjunction with light-modulated alterations in chronobiologic indices such as melatonin and cortisol. The primary aim of this study was to evaluate the effects of seasonal variations in darkness on mood in depressed antepartum women, and to determine the relationship of seasonal mood variations to contemporaneous blood melatonin and cortisol measures; a secondary aim was to evaluate the influence of seasonal factors on measures of melancholic versus atypical depressive symptoms. We obtained measures of mood and overnight concentrations of plasma melatonin and serum cortisol in 19 depressed patients (DP) and 12 healthy control (HC) antepartum women, during on-going seasonal variations in daylight/darkness, in a cross-sectional design. Analyses of variance showed that in DP, but not HC, Hamilton Depression Rating Scale (HRSD) scores were significantly higher in women tested during seasonally longer versus shorter nights. This exacerbation of depressive symptoms occurred when the dim light melatonin onset, the melatonin synthesis offset, and the time of maximum cortisol secretion (acrophase) were phase-advanced (temporally shifted earlier), and melatonin quantity was reduced, in DP but not HC. Serum cortisol increased across gestational weeks in both the HC and DP groups, which did not differ significantly in cortisol concentration. Nevertheless, serum cortisol concentration correlated positively with HRSD score in DP but not HC; notably, HC showed neither significant mood changes nor altered melatonin and cortisol timing or quantity in association with seasonal variations. These findings suggest that depression severity during pregnancy may become elevated in association with seasonally related phase advances in melatonin and cortisol timing and reduced melatonin quantity that occur in DP, but not HC. Thus, women who experience antepartum depression may be more susceptible than their nondepressed counterparts to phase alterations in melatonin and cortisol timing during seasonally longer nights. Interventions that phase delay melatonin and/or cortisol timing—for example, increased exposure to bright evening light—might serve as an effective intervention for antepartum depressions whose severity is increased during seasonally longer nights.     

Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test

Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism.     

The occurrence, synthesis and metabolism of 5-hydroxytryptamine and 5-hydroxytryptophan in the cestode Hymenolepis diminuta: a high performance liquid chromatographic study

The biosynthesis and metabolism of 5-hydroxytryptamine (serotonin; 5-HT) in the cestode Hymenolepis diminuta was investigated by High Performance Liquid Chromatography (HPLC). Incubation of intact H. diminuta in [3H]tryptophan resulted in substantial radioactivity recovered in 5-HT, 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA). Furthermore, the tissue levels of 5-HT and 5-HTP, as determined by HPLC with electrochemical detection, were significantly depressed when the animals were deprived of tryptophan. On the other hand, the tissue levels of 5-HTP were significantly increased following incubation with the 5-HTP decarboxylase inhibitor m-hydroxybenzylhydrazine. The synthesis and metabolism of 5-HT are discussed in the light of 5-HT as a physiological transmitter in H. diminuta.     

血清连蛋白、高迁移率族蛋白B1水平与双相障碍患者认知功能和肠道菌群相对丰度的相关性分析

摘要 目的：探讨血清连蛋白、高迁移率族蛋白B1（HMGB1）水平与双相障碍患者认知功能和肠道菌群相对丰度的相关性。方法：选取2018年5月～2021年5月北京回龙观医院收治的80例双相障碍患者,其中狂躁发作43例,抑郁发作37例,分别作为狂躁组、抑郁组,取同期于我院体检的健康志愿者62例作为对照组。比较三组血清连蛋白、HMGB1水平,并采用重复性成套神经心理状态测验（RBANS）评估三组认知功能。收集受试者的粪便标本,经聚合酶链反应（PCR）与测序技术分析肠道菌群相对丰度。利用Pearson线性相关检验分析血清连蛋白、HMGB1水平与RBANS评分及肠道菌群相对丰度的相关性。结果：狂躁组、抑郁组血清连蛋白、HMGB1水平高于对照组,即刻记忆、言语功能、注意、延时记忆、视觉广度评分及RBANS总分均低于对照组（P＜0.05）。狂躁组、抑郁组拟杆菌纲、拟杆菌目相对丰度均低于对照组,大肠埃希菌种相对丰度高于对照组,且狂躁组青春双歧杆菌相对丰度高于对照组、抑郁组,抑郁组青春双歧杆菌相对丰度低于对照组,抑郁组毛螺菌属相对丰度高于狂躁组与对照组（P＜0.05）。血清连蛋白与拟杆菌纲、拟杆菌目呈负相关,与大肠埃希菌种呈正相关（P＜0.05）,但与RBANS总分无相关性（P＞0.05）。血清HMGB1与RBANS总分、拟杆菌纲、拟杆菌目呈负相关,与大肠埃希菌种呈正相关（P＜0.05）。结论：双相障碍患者的血清连蛋白、HMGB1水平增高,其中连蛋白与患者认知功能异常无明显关联,而HMGB1与认知功能异常有关,且二者均会影响患者的肠道菌群变化。     

Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression

To investigate whether depression is accompanied by changes in diurnal rhythms of free estradiol and cortisol in different phases of the menstrual cycle, we measured these two hormone levels in saliva samples collected every 2 h for 24 h from 15 healthy normally cycling women and 12 age-matched normally cycling women suffering from major depression taking antidepressants. The assessments were repeated four times over one menstrual cycle: during menstruation and in the late follicular/peri-ovulating, early to mid-luteal and late luteal phases, respectively. Quantification with a nonlinear periodic regression model revealed distinct diurnal rhythms in free estradiol and free cortisol in all subjects. For the diurnal cortisol rhythm, significant differences were found in the peak-width and ultradian amplitude among different menstrual phases, both in controls and depressed patients, while no significant differences were found between the two groups. The diurnal estradiol rhythm, on the other hand, was quite consistent among different menstrual phases within both groups, while the depressed patients had overall larger amplitudes than controls, which is negatively correlated with disease duration. Significant positive correlations between the two hormone rhythms were found for 24-h mean level (mesor), peak, and trough in late luteal phase, and for ultradian harmonics in early to mid-luteal phase in controls, but only for ultradian harmonics in late follicular/peri-ovulating phase and for acrophase in the menstruation phase in depressed patients. A sub-analysis was also performed in patients who received Fluoxetine (n = 7). The findings implicate a close correlation between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, both of which may be involved in depression.     

Unrecognised depression in general practice.

Patients attending their general practitioner were screened and a group with unrecognised major depressive disorder identified. This group was interviewed and the findings compared with those in a group of patients recognised correctly as depressed by their general practitioners. Half of the patients with severe depression screened in their doctors'' waiting rooms went unrecognised, and they differed in few ways from those who were recognised. The differences found were that the patients with unrecognised depression were less obviously depressed and their illness had lasted longer. Physical illness was present in nearly 30% of patients in the unrecognised group, and the depression seemed related to it. Patients with unrecognised depression were more likely to have feelings other than those of normal sadness and more likely to respond with change of mood to intercurrent events. These data suggest that patients might benefit if general practitioners were better trained to recognise depression, although it is not known whether treatment would be effective.     

Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients

3H-Lysergic acid diethylamide (3H-LSD) binding, a putative measure of 5-HT2 receptor binding, was studied in the blood platelets of 29 depressed patients and 24 normal controls. The Bmax (maximum number of 3H-LSD binding sites) in the blood platelets of depressed patients was significantly greater than that of normal volunteers. This increase in Bmax was due to an increase in female depressed patients only. Bmax was significantly lower in female compared to male normal controls but there was no difference between male and female depressed patients. There was also no difference in Kd (an inverse measure of affinity of 3H-LSD binding to its sites) between normal controls and depressed patients. The correlations between Bmax of 3H-LSD binding and the Bmax of the 3H-imipramine binding site or the Vmax of 5-HT uptake sites were not significant. The role of serotonergic processes in the psychobiology of depression is discussed.     

The effects of injections of D,L-5-hydroxytryptophan on the efflux of endogenous serotonin and 5-hydroxyindoleacetic acid from a synaptosomal fraction.

Abstract— The effects of i.p. injections of SO mg/kg d,l-5-hydroxytryptophan (5-HTP) and saline alone on the in uitro release of endogenous serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were studied using preparations of axon terminals (P₂ isolated from the telencephalon of rats. The level of 5-HT was 2-fold greater and the level of 5-HIAA was 5-fold greater in the P₂ fraction isolated from rats given the d,l-5-HTP injection than from rats given saline injections. At 37°C the in vitro efflux of 5-HT and 5-HIAA from the P₂ fractions of animals injected with 5-HTP 30min before killing was approx 3 times higher than the saline control group. The amount of 5-HT and 5-HIAA released at 37°C was 3–5 times higher than the amount released at 0°C for both the 5-HTP and saline injected rats. Increasing the concentration of potassium ions in the media to 55 mm significantly increased the release of 5-HT but not 5-HIAA in both groups of animals. The amount of 5-HT released by 55mm-K⁺ was about 2-fold higher from the P₂ fraction isolated from rats given 5-HTP injections with respect to those given saline injections. The potassium stimulated release of 5-HT was calcium dependent. The data thus indicate that injection of 50 mg/kg d,l-5-HTP in rats can cause an increase in the level of 5-HT and 5-HIAA in a crude synaptosomal fraction and that as a result of this increase, there is a temperature dependent increased release of 5-HT and 5-HIAA under normal resting membrane conditions. There is also an increased release of 5-HT as a result of membrane depolarizing conditions induced by elevated potassium levels which is calcium dependent.     

Behavioral depression in pigeons following L-tryptophan administration

Since elevations of serotonin (5-HT) content in brain have been related to the behavioral depression which follows administration of 5-hydroxytryptophan (5-HTP) to pigeons emitting a food-reinforced learned response, injections of L-tryptophan (100, 200, and 300 mg/kg I.M.), which is partially metabolized to 5-HT, were given to pigeons working on the same behavioral schedule. Qualitatively similar, but shorter, periods of disrupted behavior followed. As is also the case with 5-HTP, pretreatment with 50 mg/kg iproniazid, a monoamine oxidase inhibitor, increases the duration of behavioral depression following L-tryptophan. Pretreatment with 10 mg/kg Lilly 110140, a new highly selective inhibitor for uptake of 5-HT into synaptosomes, also enhanced L-tryptophan induced depression. Initial neurochemical studies indicate that the elevated levels of 5-HT in the telencephalon after an injection of L-tryptophan follow the time course of the depressed behavior. These data support the suggestion that the release of 5-HT plays a role in certain types of behavioral depression.     

A study on the blunted natural killer cell activity in severely depressed patients.

Recently, some investigators have established a blunted natural killer cell activity (NKCA) in severely depressed patients. In order to replicate these findings NKC cytotoxicity assays--on fresh cell suspensions in human plasma and fetal calf serum--were performed in healthy controls and depressed inpatients. Instead of the commonly used 51Cr-release assay we have used a fluorescent NKC cytotoxicity assay, which allows a greater sensitivity. We observed a significantly blunted NKCA in melancholic patients as compared with healthy controls and minor depressives, whilst simple major depressives exhibited an intermediate position. NKC cytotoxicity assays in fetal calf serum were significantly and negatively correlated with the severity of illness. We were unable to establish any relationship between NKCA and measures of hypothalamic-pituitary-adrenal-axis function, such as baseline, postdexamethasone plasma cortisol and 24 hr urinary cortisol secretion. In addition, we did not find any effects of dexamethasone administration (1 mg orally) on NKCA.     

Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression

The FK506 binding protein 51 or FKBP5 has been implicated in the regulation of glucocorticoid receptor (GR) sensitivity, and genetic variants in this gene have been associated with mood and anxiety disorders. GR resistance and associated stress hormone dysregulation are among the most robust biological findings in major depression, the extent of which may be moderated by FKBP5 polymorphisms. FKBP5 mRNA expression in peripheral blood cells (baseline and following in vivo GR stimulation with 1.5 mg dexamethasone p.o.) was analyzed together with plasma cortisol, ACTH, dexamethasone levels and the FKBP5 polymorphism rs1360780 in 68 depressed patients and 87 healthy controls. We observed a significant (P = 0.02) interaction between disease status and FKBP5 risk allele carrier status (minor allele T) on GR‐stimulated FKBP5 mRNA expression. Patients carrying the risk T allele, but not the CC genotype, showed a reduced induction of FKBP5 mRNA. This FKBP5 polymorphism by disease status interaction was paralleled by the extent of plasma cortisol and ACTH suppression following dexamethasone administration, with a reduced suppression only observed in depressed patients carrying the T allele. Only depressed patients carrying the FKBP5 rs1360780 risk allele showed significant GR resistance compared with healthy controls, as measured by dexamethasone‐induced FKBP5 mRNA induction in peripheral blood cells and suppression of plasma cortisol and ACTH concentrations. This finding suggests that endocrine alterations in depressed patients are determined by genetic variants and may allow identification of specific subgroups .     

Predictors of the Onset of Manic Symptoms and a (Hypo)Manic Episode in Patients with Major Depressive Disorder

Objective

One third of patients with a major depressive episode also experience manic symptoms or, even, a (hypo)manic episode. Retrospective studies on the temporal sequencing of symptomatology suggest that the majority of these patients report depressive symptoms before the onset of manic symptoms. However, prospective studies are scarce and this study will, therefore, prospectively examine the onset of either manic symptoms or a (hypo)manic episode in patients with a major depressive disorder. In addition, we will consider the impact of a large set of potential risk factors on both outcomes.

Methodology

Four-year follow-up data were used to determine the onset of manic symptoms as well as a CIDI-based (hypo)manic episode in a large sample (n = 889, age: 18–65 years) of outpatients with a major depressive disorder and without manic symptoms at baseline. Baseline vulnerability (i.e., sociodemographics, family history of depression, childhood trauma, life-events) and clinical (i.e., isolated manic symptoms, depression characteristics, and psychiatric comorbidity) factors were considered as potential risk factors.

Results

In our sample of depressed patients, 15.9% developed manic symptoms and an additional 4.7% developed a (hypo)manic episode during four years. Baseline isolated manic symptoms and comorbid alcohol dependence predicted both the onset of manic symptoms and a (hypo)manic episode. Low education only predicted the onset of manic symptoms, whereas male gender, childhood trauma and severity of depressive symptoms showed strong associations with, especially, the onset of (hypo)manic episodes.

Conclusions

A substantial proportion (20.6%) of patients with a major depressive disorder later developed manic symptoms or a (hypo)manic episode. Interestingly, some identified risk factors differed for the two outcomes, which may indicate that pathways leading to the onset of manic symptoms or a (hypo)manic episode might be different. Our findings indirectly support a clinical staging model.     

Formation of biogenic amines by isolated kidneys of spontaneously hypertensive rats

Kidneys form dopamine (DA) from L-dopa and serotonin from L-5-hydroxytryptophan (L-5-HTP) via aromatic L-amino acid decarboxylase. We compared the ability of isolated perfused kidneys from adult (20-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) to form these biogenic amines. Renal vascular resistance (RVR) was greater in perfused kidneys from SHR (n = 10) than WKY (n = 8) (p less than 0.01). Slight decreases in RVR were observed during L-dopa infusion but these were unrelated to DA formation. L-Dopa infusion was associated with greater DA output in SHR than WKY in both the renal venous and urinary effluents although the latter did not achieve statistical significance. L-5-HTP increased RVR to a greater degree in SHR than WKY kidneys. This was associated with larger quantities of serotonin in the urinary and venous effluents and greater pressor responses to exogenous serotonin in SHR than WKY kidneys; however, either parameter alone was not significantly increased. Our findings do not support a deficiency of intrarenal DA formation as a pathogenic factor for hypertension in SHR. Biogenic amine formation is as great if not greater in SHR than WKY kidneys and appears to contribute largely to the greater increases in renal resistance seen in SHR kidneys on infusion of L-5-HTP. Enhanced renal serotonin formation may elevate blood pressure, whereas enhanced renal DA formation would favor blood pressure lowering, perhaps as a compensatory mechanism.     

The effects of smoking on ACTH and cortisol secretion

The relationship among changes in plasma nicotine, ACTH, and cortisol secretion after smoking were investigated. Ten male subjects smoked cigarettes containing 2.87 mg nicotine and 0.48 mg nicotine. No rises in cortisol or ACTH were detected after smoking 0.48 mg nicotine cigarettes. Cortisol rises were significant in 11 of 15 instances after smoking 2.87 mg nicotine cigarettes, but ACTH rose significantly in only 5 of the 11 instances where cortisol increased. Each ACTH rise occurred in a subject who reported nausea and was observed to be pale, sweaty, and tachycardic. Peak plasma nicotine concentrations were not significantly different in sessions when cortisol rose with or without ACTH increases, but cortisol increases were significantly greater in nauseated than in non-nauseated smokers. Our data suggest that smoking-induced nausea stimulates cortisol release by stimulating ACTH secretion and that cortisol secretion in non-nauseated smokers may occur through a non-ACTH mechanism. It is not clear whether nicotine or some other stimulus inherent in smoking is responsible for cortisol secretion without ACTH secretion.     

Increased basal plasma vasopressin-neurophysin in mania

Basal plasma vasopressin-neurophysin (hNpI) was estimated in 50 drug-free neuropsychiatric patients classified according to the Research Diagnostic Criteria. The hNpI concentration was higher in the 5 manics (0.76 +/- 0.15 ng/ml) than in the 16 schizophrenics (0.53 +/- 0.08), 12 minor depressed (0.54 +/- 0.06) and 17 major depressed (0.48 +/- 0.10; p less than 0.05). Thus, those results confirm our initial observation of an increased vasopressinergic function in the manic compared to the depressed phase in one bipolar patient. Whether this increase in the vasopressin release is a consequence of the neuropsychiatric disorders or initiates and/or participates in their pathophysiology remains to be elucidated. The hypothetic consequence on water metabolism of such an increase remains also to be defined.     

Precursor utilization of 5-hydroxytryptophan for 5-hydroxytryptamine biosynthesis in isolated and perfused rabbit and rat lungs

The present study was designed to investigate whether lungs can utilize 5-hydroxytryptophan (5-HTP), formed elsewhere and transported, for the synthesis of 5-hydroxytryptamine (5-HT). [14C]5-HTP uptake was 7.7 +/- 1.1 and 3.9 +/- 0.2% by rabbit and rat lungs, respectively, after 1 h of perfusion with 10 microM [14C]5-HTP. There was an increase in the lung uptake of [14C]5-HTP when the lungs were preperfused with 0.5 mM chlorphentermine (CP) and the uptake was low when the lungs were preperfused with 0.1 mM hydroxybenzylhydrazine dihydrochloride (HBH). The perfusate concentration of 5-hydroxyindole acetic acid (5-HIAA) increased significantly (3-4 micrograms/100 mL) during rabbit lung perfusion with 10 microM [14C]5-HTP and this did not change significantly when the lungs were preperfused with 0.5 mM CP. However, 5-HT increased with time in the perfusate. 5-HT, but not 5-HIAA, was detected in the perfusate and increased with time of perfusion when the rat lungs were perfused either with 10 microM 5-HTP or with 0.5 mM CP and 10 microM 5-HTP. However, no metabolites were detected in either the rabbit lung or rat lung perfusates when they were preperfused with 0.1 mM HBH. Lung contents of 5-HT and 5-HIAA were significantly higher in the rat lungs and only 5-HIAA increased in rabbit lungs after 1 h of perfusion with 10 microM 5-HTP. Preperfusion with 0.5 mM CP resulted in a greater increase in the 5-HT content of both rabbit and rat lungs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamic-Pituitary Function in Depressive Illness: Insensitivity to Hypoglycaemia

The insulin tolerance test was performed in 16 severely depressed patients on admission to hospital and after treatment with electric convulsion therapy. The mean plasma cortisol response to hypoglycaemia was significantly impaired before treatment, particularly in the patients who also showed resistance to dexamethasone suppression. The results are consistent with hypothalamic-pituitary insensitivity to hypoglycaemia in these subjects.