Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test

The 24 hr profiles of melatonin and cortisol in serum, morning levels of ACTH in plasma, and the dexamethasone suppression test (DST) were investigated in 32 acutely ill patients with a RDC diagnosis of major depressive disorder, 24 patients with a history of longlasting unipolar or bipolar major depressive disorder studied in remission, and 33 healthy subjects. A significant decrease in maximum nocturnal melatonin level (MTmax) was found in the acutely ill depressed patients with abnormal DST compared to both those with normal DSTs and the healthy subjects. The MTmax levels were unaltered when these patients were reinvestigated in remission. A decrease of MTmax was also seen in the group of unipolar and bipolar patients studied in remission. Low nocturnal melatonin is proposed to be a trait marker for major depressive disorder and depressive states with abnormalities in the hypothalamic--pituitary--adrenal (HPA) axis. A significant decrease of ACTH levels at 0800 hr after dexamethasone administration the preceding evening was found in the healthy subjects, the unipolar--bipolar patients in remission, and the acutely ill depressed patients with normal DSTs, but was not found in the acutely ill depressed patients with abnormal DSTs. These findings support the hypothesis that pituitary ACTH regulation is altered in depressed patients with abnormal DST. Morning plasma ACTH before the administration of dexamethasone did not significantly differ between the acutely ill depressed patients with abnormal DSTs, normal DSTs, the patients with unipolar--bipolar disease in remission, or the healthy subjects. Thus, the abnormalities in the HPA axis in depresséd patients are proposed to be due to a hypersecretion of corticotrophin releasing factor (CRF) with a subsequent stimulus-induced pituitary desensitization. A significant decrease of melatonin after dexamethasone was seen at 0800 hr in the unipolar--bipolar patients in remission as well as in the healthy subjects, at 1600 hr and 2200 hr in the acutely ill depressed patients in remission, but not at 0800 hr in the acutely ill depressed patients in relapse. A significant regression was found between MTmax levels and the degree of non-suppression of cortisol at 0800 hr in the DST in the acutely ill depressed patients both in relapse and in remission. Melatonin thus is proposed to be an inhibiting factor for CRF during depression. A trend to a phase-advance of cortisol nadir and melatonin peak was seen in the acutely ill depressed patients with abnormal DST, possibly indicating an involvement of the suprachiasmatic nuclei in the hypothalamus.     

Daily profiles of melatonin, cortisol and gonadotropins in 8 adolescents with anorexia nervosa

From a biological study of 8 patients with anorexia nervosa and an analysis of the daily profiles of gonadotropins, cortisol and melatonin, the authors discuss the possible relationship between anorexia nervosa and affective disorders. At the initial phase of the illness, plasmatic levels of FSH, LH and oestradiol were very low. 24-hour plasma cortisol values were comparable with those of a depressive population; when weight loss was equal to or higher than 25% of the initial weight, there was no suppression by dexamethasone. The daily profile of melatonin was maintained, with melatonin plasma levels significatively higher than in a control group of depressed patients.     

Nocturnal melatonin and cortisol secretion in newly admitted psychiatric inpatients

Summary Melatonin secretion has been suggested as a marker of both circadian and noradrenergic dysfunction in affective disorders. Seventy-two newly admitted psychiatric inpatients [49 with major depressive disorder (MDD), 12 with schizophrenia, and 11 with intermittent depressive disorder (IDD)] underwent neuroendocrine screening at 0200, 0800, 1600 and 2300 hours prior to and the day following dexamethasone administration. All groups showed a drop in cortisol following dexamethasone. Dexamethasone nonsuppression was found in 20 of 49 patients with MDD, in none of the schizophrenics and in none of those with intermittent depressive disorder. Mean melatonin levels decreased significantly after the administration of dexamethasone across all four groups. Overall, the schizophrenic group had a significantly greater mean melatonin level than each of other three groups, whereas the three depressive groups did not differ significantly from one another. Only at 2300 hours did both the schizophrenic group and the MDD patients with normal dexamethasone suppression show significantly greater melatonin levels than the MDD patients with dexamethasone nonsuppression or the IDD group. The observed trend for a low circadian melatonin profile in IDD patients with superimposed personality disorders is puzzling.     

Bulimia, bulimia-anorexia and nocturnal secretion of melatonin and cortisol

The authors compared nocturnal variations of melatonin (MT) and cortisol levels in subjects with bulimia (n = 12), 6 with a normal body weight and 6 with anorexia nervosa, as well as 6 control subjects. The hypothesis, formulated for anorexia nervosa, that a decrease of noradrenergic activity induces a decrease of pineal activity, therefore a decrease of melatonin secretion, was not confirmed by our study. Moreover, in subjects with bulimia in the absence of anorexia nervosa, no significant decrease of nocturnal melatonin secretion was reported. Significant differences were due to cortisol variations when comparing MTmax/Cmin ratios. Melatonin did not add any complementary biological cue for diagnostic assessment for subjects with eating disorder and depression. The results of this study suggest that melatonin does not appear to be a useful biological marker in bulimia.     

The relationship between the pineal gland and the pituitary--adrenal axis in health, endocrine and psychiatric conditions

Evidence is reviewed in favour of a close relationship between the pineal hormone, melatonin and ACTH--cortisol in man. Subgroups of patients with Cushing's disease as well as with major depressive disorder have low levels of nocturnal serum melatonin. Depressed patients with an abnormal dexamethasone suppression test (DST) have lower melatonin levels than do patients with a normal DST. Low melatonin levels may be a genetic trait marker for vulnerability to depression. The mechanism may be related to increased corticotropin-releasing factor (CRF), secondary to hypofunction of a pineal factor which physiologically inhibits CRF.     

Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects

Serum melatonin levels over a 24 hr period were studied in 30 acutely ill patients with major depressive episode, 24 patients with a history of unipolar or bipolar major affective disorder in remission and 33 healthy subjects. A significant negative correlation (-0.45) between body height and maximum nocturnal serum melatonin level was found. Maximum serum melatonin levels during the night were lower in both patient groups than in the healthy controls. No difference was found between maximum nocturnal serum melatonin levels in 26 patients investigated when ill and again in remission. We thus propose low nocturnal melatonin to be a trait-dependent marker for major depressive disorder. A difference in the morning but not night melatonin levels was found between samples taken during the dark, winter season versus samples taken during the bright, spring-summer season. Melatonin levels were not lower in females than in males, when melatonin levels were adjusted for body height. Similar results were found when the nocturnal areas under the curve for melatonin were analyzed.     

The 24-hour profile of plasma prolactin in men with major endogenous depressive illness

Plasma prolactin (PRL) levels were measured at 15-minute intervals for 24 hours in 18 men suffering from major endogenous depressive illness and in 7 age-matched healthy men. Eleven of the 18 depressed patients were restudied during clinical remission following either electroconvulsive therapy or treatment with amitriptyline hydrochloride. During the acute phase of the illness, the unipolar depressed patients had fragmented patterns of PRL secretion with an early timing of the nocturnal secretory phase of PRL, which started, on the average, 2 hours earlier than in healthy subjects. Moreover, the amplitude of the circadian variation of PRL was reduced in these patients, with subnormal PRL levels occurring during the midsleep period. This latter abnormality was also observed in bipolar patients, who had otherwise normal PRL profiles. These lower midsleep PRL concentrations were associated with a significant increase in the amount of time spent awake during the same period. Antidepressant treatment did not consistently correct the abnormalities in the patterns of PRL release observed during the acute phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation may be found in men with endogenous depressive disorders. In contrast to disturbances of the corticotropic and somatotropic axes, these abnormalities of PRL secretion may still be present during clinical remission following antidepressant treatment.     

Serum melatonin and urinary 6-sulfatoxymelatonin in major depression

In this study, serum melatonin and urinary 6-sulfatoxymelatonin (aMT6s) were measured in 14 major depressive inpatients, compared to 14 matched controls according to age, gender, season and hormonal treatment in women. Moreover, the relationship between serum melatonin and urinary aMT6s levels was analysed in the two groups. Results indicated that the two groups of subjects showed a clear melatonin rhythm without significant difference in the mean level of melatonin or aMT6s, in the area under the curve of melatonin or in the melatonin peak. However, the time of the nocturnal melatonin peak secretion was significantly delayed in depressive subjects as compared to healthy controls. Moreover, the depressed patients showed urinary aMT6s concentrations enhanced in the morning compared to night time levels, while these concentrations were lowered from the night to the morning in the control group. These results suggest that the melatonin production is phase-shifted in major depression.     

Neuroendocrine aspects of primary endogenous depression. XI. Serum melatonin measures in patients and matched control subjects.

To ascertain the extent of dysregulation of melatonin secretion in endogenous depression, we measured nocturnal and diurnal serum melatonin concentrations in 38 depressed patients (23 women and 15 men) who had primary, definite endogenous depression according to the Research Diagnostic Criteria and in 38 individually matched normal control subjects. Previous reports have suggested that such patients may have reduced nocturnal melatonin secretion, often in conjunction with increased hypothalamic-pituitary-adrenal cortical axis activity. This has been considered as a possible reflection of reduced noradrenergic activity in depression. Compared with their matched controls, the depressed patients showed a trend toward a significantly elevated average nocturnal melatonin concentration that was accounted for primarily by the 14 premenopausal women--the postmenopausal female and male depressive patients did not differ significantly from their respective controls. The average diurnal melatonin concentration also showed a trend toward being higher in both the female and male depressed patients. The melatonin measures were not consistently related to any of the previously reported hypothalamic-pituitary-adrenal cortical axis measures in these subjects. Our findings thus failed to confirm a "low melatonin syndrome" or an inverse relationship between nocturnal melatonin and nocturnal cortisol concentrations in depression. This discrepancy may be related to methodologic differences among studies; our data are in accord with those findings of the one other reported study in which normal controls were individually matched to patients on variables that were known to influence melatonin secretion. Most of the studies, including ours, have been cross-sectional.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dexamethasone suppression test and depressive symptoms in bereaved children: a preliminary report

Eighteen bereaved children and adolescents were assessed using the dexamethasone suppression test (DST) and the Diagnostic Interview for Children and Adolescents 4 weeks following parental death. Thirty-nine percent had a positive (nonsuppressed) DST. DST-positive subjects reported more DSM-III-R depressive symptoms (6.3 +/- 2.9 vs. 3.9 +/- 2.7, means +/- SD) than DST-negative subjects. Most frequently reported symptoms included dysphoria, loss of interest, sleep disturbance, appetite disturbance, psychomotor disturbance, and morbid and suicidal ideation. Post-dexamethasone cortisol levels were significantly correlated with the total number of depressive symptoms and suicidal ideation.     

The metyrapone test in schizophrenic patients and healthy subjects

The metyrapone test, a useful and reliable procedure for assessing hypothalamic-pituitary-adrenocortical (HPA) axis function, was applied to schizophrenic patients and healthy controls. 4 out of 18 patients had subnormal responses to metyrapone whereas there were no such cases in the 22 control subjects. 1 schizophrenic patient and 3 control subjects had high normal responses to metyrapone. The relationship with the dexamethasone suppression test was found to be complex. These preliminary results suggest that the HPA axis activity patterns in psychiatric illness may be more complicated than previously reported.     

Immunoreactive somatomedin B is increased in serum in patients with major depressive disorder

Serum levels of immunoreactive somatomedin B (RIA-B) were investigated in patients with major depressive disorder both in the acute state and during remission at 8 h and 22 h and at 22 h after the dexamethasone suppression test. Elevated levels of RIA-B at 8 h and at 22 h after the dexamethasone suppression test were found consistently in the patient group compared with the healthy controls. No indication was obtained that the patients' clinical condition or depressive symptomatology as revealed by their CPRS score, psychotropic medication or TSH, prolactin, melatonin or cortisol levels was significantly related to the RIA-B levels.     

Nocturnal cortisol and melatonin secretion in primary insomnia

The present study investigated evening and nocturnal serum cortisol and melatonin concentrations in patients with primary insomnia to test if this clinical condition is accompanied by an increase of cortisol secretion and a simultaneous decrease of nocturnal melatonin production. Ten drug-free patients (4 males, 6 females) with primary insomnia (mean age+/-S.D.: 39.2+/-9.1 years) and 10 age- and gender-matched healthy controls participated in the study. All subjects spent three consecutive nights in the sleep laboratory with polysomnography. Measurement of cortisol and melatonin (from 19:00 h to 09:00 h) was performed prior to and during the last laboratory night. Contrary to expectation, cortisol secretion did not differ between healthy controls and insomniac patients. On the other hand, nocturnal melatonin production was significantly diminished in insomniac patients. Polysomnographically determined sleep patterns, in contrast to subjective ratings of sleep, demonstrated only minor alterations of sleep in the insomniac group. The lack of increased cortisol secretion in the patients with primary insomnia indicates that results from studies on the biological consequences of experimental sleep loss in healthy subjects cannot be applied to primary insomnia in general, especially if there are only minor objective sleep alterations. In spite of the negligible objective sleep disturbances in the present sample, nocturnal melatonin production was reduced, which tentatively suggests a role for this hormone in primary insomniacs. The pathophysiological significance of this finding is, however, still a matter of debate.     

Psychoneuroendocrinology of depression

Abnormalities in neuroendocrine regulation are widespread in depressive illness. In this article, abnormalities found in five different endocrine systems are evaluated. There has been a wide-spread use of the dexamethasone suppression test in investigation of depressed patients. Use of this test as a diagnostic test for melancholia may be confounded because abnormalities are found in overlapping illnesses such as Alzheimer's disease or anorexia nervosa as well as in a variety of other conditions such as fasting. However, this test has promise in monitoring clinical status in patients who have an abnormal DST. Abnormalities found in the TRH test and in growth hormone regulation are of limited use clinically, but point to underlying biologic abnormalities. Aberrent regulation of prolactin is now well established, but this hormone has been investigated to a limited extent and warrants further investigation. There is currently a good deal of interest in the pineal hormone melatonin. Reduction in the normal nocturnal peak is found in depressed patients and there is an increase in nocturnal melatonin levels found in patients during treatment with desipramine. Bipolar patients are reported to be abnormally sensitive to melatonin suppression by light. This finding points to the abnormality in the photoperiodic regulation of the pineal output in these patients. Further refinement of neuroendocrine approaches to the investigation of depression should be very productive.     

Neuroendocrine probes as biological markers of affective disorders: new directions

Numerous endocrine abnormalities are found in depressive illness and, among these, several have been proposed as useful markers in diagnosis, prediction of treatment response, monitoring treatment outcome or in understanding of etiology. This paper reviews five endocrine systems--the hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, growth hormone regulation, prolactin regulation and pineal function, in which such abnormalities have been reported. The dexamethasone suppression test (DST) results are affected by a variety of other diseases and confounding conditions. Furthermore, variability in dexamethasone availability has recently been shown to be an important factor, influencing post-DST cortisol levels. Refined tests, taking into account all these factors, or alternative tests of hypothalamic-pituitary-adrenal function may lead to improved clinical utility. Pineal function is now the focus of considerable investigation. Low nocturnal output of melatonin is found in unipolar and bipolar affective disorder and is normalized by treatment with antidepressant drugs which block re-uptake of noradrenaline. These findings support the hypothesis of noradrenergic abnormality in depression. In seasonal affective disorder there is evidence for a phase delay in the melatonin rhythm which may be a key factor in the seasonal disorder. Effective light therapy causes a phase advance in the abnormal melatonin rhythm. Whether the normalization of the melatonin rhythm is instrumental in producing the antidepressant effect is yet to be determined. There are wide spread neuroendocrine abnormalities in depressive illness. These abnormalities encompass many different pituitary hormones, as well as the pineal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia

Disturbances in the hypothalamo-pituitary-adrenal (HPA) and other endocrine axes were assessed in 24 women with bulimia and healthy controls. Overnight blood samples for measuring nocturnal plasma cortisol, prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were obtained at 30-min intervals. A 1.5 mg dexamethasone suppression test (DST) and a TRH-test were performed. Patients were monitored closely while their nutritional intake was recorded over 21 days. Compared with healthy controls, nocturnal cortisol plasma levels were not elevated in the bulimics. There was a trend toward insufficient cortisol suppression in the DST in patients with bulimia, which was most pronounced in patients with signs of restricted caloric intake. Plasma dexamethasone levels were significantly reduced in bulimics compared with healthy controls. There was a trend for blunted thyrotropin stimulating hormone (TSH) responses to thyrotropin releasing hormone (TRH) in bulimia. The prolactin response to TRH was significantly reduced in bulimics with a history of anorexia nervosa. Plasma LH and plasma FSH were significantly reduced in bulimics with signs of reduced caloric intake [low T3, high levels of beta-hydroxy-butyric acid (BHBA), reduced daily caloric intake, high number of fasting days] as compared with healthy controls. Bulimics with high BHBA levels had significantly reduced nocturnal prolactin plasma levels. Results show that multiple neuroendocrine disturbances exist in bulimia in a milder form than in anorexia nervosa. Evidence for the impact of caloric intake on endocrine functions is presented. Endocrine dysfunctions in our bulimic sample did not show a positive association with the presence of depressive symptoms.     

Laughter elevates the levels of breast-milk melatonin

OBJECTIVE: Patients with atopic eczema (AE) often complain of sleep disturbance. Melatonin is involved in sleep, and the levels of blood melatonin in patients with AE are decreased in comparison to healthy subjects. However, the levels of breast-milk melatonin had only been reported in healthy subjects. Laughter increased natural killer cell activity in blood and free radical-scavenging capacity in saliva in healthy subjects. Thus, the effect of laughter on the levels of breast-milk melatonin was studied in mothers with AE. Moreover, the effect of feeding with breast milk after laughter on allergic responses in infants was studied. METHODS: Forty-eight infants aged 5-6 months were enrolled. All of the infants had AE and were allergic to latex and house dust mite (HDM). Half (n=24) of the mothers of these infants were patients with AE, while another 24 mothers were healthy subjects. The mothers viewed either an 87-min humorous DVD (Modern Times, featuring Charlie Chaplin) or an 87-min nonhumorous weather information DVD at 2000 h. After viewing, breast milk was collected sequentially from 2200, 2400, 0200, 0400 to 0600 h. The levels of breast-milk melatonin were measured. In addition, skin wheal responses to HDM and histamine were studied in infants. RESULTS: Laughter caused by viewing a humorous DVD increased the levels of breast-milk melatonin in both mothers with AE and healthy mothers. In addition, allergic responses to latex and HDM of infants were reduced by feeding with breast milk after laughter of mothers with AE or of healthy mothers. CONCLUSION: Laughter increased the levels of breast-milk melatonin in both mothers with AE and healthy mothers, and feeding infants with increased levels of melatonin-containing milk reduced allergic responses in infants. Thus, laughter of mothers may be helpful in the treatment of infants with AE.     

Changes in melatonin levels but not cortisol levels are associated with depression in patients with eating disorders

Disturbances were studied in the nocturnal circadian pattern of serum melatonin and plasma cortisol levels in 33 female patients with an eating disorder (anorexia nervosa, n = 11; bulimia nervosa, n = 12; or both, n = 10) and in ten female control subjects of comparable age. Blood samples were obtained hourly from 8 PM to 6 AM under controlled darkness. Serum melatonin levels in all patient groups were initially similar to those of control subjects. When patients were divided according to depression status, those with concurrent major depression had significantly lower nocturnal melatonin values than the nondepressed group. Weight did not appear to influence melatonin levels. In contrast, all patient groups had significantly higher nocturnal levels of plasma cortisol than control subjects, and neither weight nor depression separated patient groups on profiles of plasma cortisol.     

Electrodermal activity in relation to cortisol dysregulation in depressive patients

Electrodermal activity (EDA), basal morning plasma cortisol, outcome of the dexamethasone suppression test (DST), and nocturnal urinary cortisol excretion were studied in a somewhat confined number of originally 59 depressive patients and 59 matched healthy subjects. The patients showed nocturnal hypercortisolism. According to the DST, EDA and cortisol dysregulation were unrelated. In the total patient group, the correlations between EDA and cortisol in plasma and in urine were small and insignificant. However, in suicide attempters, in nonsuicidal patients, and in the healthy subjects, complex patterns of correlations were found between tonic electrodermal activity, electrodermal responsivity, basal morning plasma cortisol, and nocturnal urinary cortisol. Some inconsistencies in the patterns may be explained by differences in the sampling of data. Future research should try to delineate possible relationships between EDA and hormones on all levels of the hypothalamic-pituitary-adrenocortical axis.     

Abnormal nocturnal melatonin secretion and disordered sleep in abstinent alcoholics.

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