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A multivariate approach using pattern recognition method was applied on a multivariable data set from patients with affective disorders comprising biological and clinical variables. The depressed patients were rated according to 23 items of the comprehensive psychopathological rating scale (CPRS). Variables of importance were selected and clusters of patients were found by combining monoamine oxidase, melatonin and post-dexamethasone cortisol with symptoms of psychomotor retardation and agitation. Patients were distributed with high scores of agitation in the extreme of one direction and with high scores of retardation in the opposite direction. By using the combined clinical and biological variables, a diagnostic subcategory with latent bipolar disorder was identified. Two clusters of unipolar patients, one with low melatonin and low psychomotor retardation scores, and one with high melatonin and high psychomotor retardation scores, were found. Identification of a patient group with latent bipolar disorder may have potential therapeutic value since bipolar patients should be taken care of by a specialist in psychiatry, avoid tricyclic antidepressant therapy and may be candidates for lithium treatment.

The effect of bright light on cortisol and the relationship between melatonin and cortisol were studied in 63 depressed patients (42 patients with a seasonal pattern and 21 patients with a non-seasonal pattern). The patients were matched for age, time of treatment and severity of depression. Before and after light treatment the severity of the depression was rated with the Comprehensive Psychopathological Rating Scale (23 items) and the Hamilton Depression Rating scale (18 items), and serum cortisol and melatonin were drawn at nine time-points between 20.00 and 08.00 hours. Two hours of light treatment (350 cd m-2) was given daily for 10 days either in the morning (06.00-08.00 hours) or in the evening (18.00-20.00 hours). As reported earlier, patients with a seasonal pattern improved significantly more than patients with a non-seasonal pattern of depression, and no significant differences were found between the treatment efficacy of morning compared to evening light. A cosinor analysis showed that the cortisol batyphase was significantly advanced by morning light, but was not delayed by evening light. A delay in batyphase cortisol showed a weak significant correlation with a decrease in the absolute and relative sum of scores. The batyphase of cortisol occurred approximately 3 h earlier than the acrophase of melatonin. Of the changes in the melatonin acrophase 43% were reflected in a change of cortisol batyphase, indicating a hierarchical relationship with melatonin as the co-ordinating hormone transducing part of the information of the external light to the phase position of cortisol. No significant differences between patients with a seasonal or a non-seasonal pattern were seen in mesor, amplitude or batyphase of cortisol before treatment, and no significant changes in mesor or amplitude were seen as a result of light treatment.

Platelet monoamine oxidase activity (MAO), melatonin and cortisol post-dexamethasone suppression test (DST) were examined in 28 patients with major affective disorder and in 20 controls. MAO activity was lower and cortisol post-dexamethasone was higher in depressed patients. Platelet MAO activity and cortisol in depressed and controls yielded high sensitivity (90%) and specificity (89%). The patients were re-examined after 10 years and categorized into affective psychosis or neurotic depression (ICD-9). Multidimensional analysis identified one subgroup coinciding in 92% with affective psychosis and another subgroup coinciding in 87% with neurotic depression. Combination of MAO, melatonin and post-DST cortisol may be useful in the diagnosis of subgroups of depressed patients and in choice of therapy.

The possible hypersecretion involvement of corticotropin-releasing hormone (CRH) in the pathophysiology of hypothalamic-pituitary-adrenocortical axis disturbances in patients with major depressive episode and with an abnormal dexamethasone suppression test (DST) was investigated. The corticotropin (ACTH) and cortisol response to the injection of 45 micrograms of synthetic human CRH at 1630 were analyzed in 24 inpatients with normal (suppressors) or abnormal (nonsuppressors) DST. The outcome of the DST was analyzed using 3 cut-off points for the cortisol levels. The clinical assessments included two rating scales. The results showed that nonsuppressors had a significantly lower ACTH response to CRH stimulation than suppressors at all cut-off points (calculated as net area under the curve and as the difference between the peak and the baseline level) despite no significant differences in the severity of depression.

Blood levels of melatonin, serotonin, cortisol, prolactin, and serotonin uptake by platelets were measured at 08:00, 14:00, 20:00, 02:00, and 08:00 hours in 10 healthy men who ranged in age from 27 to 35 years. The Km values of serotonin active transport by platelets were significantly correlated with melatonin blood levels. There were no other significant correlations. The secretion of steroid hormones and prolactin showed an increase at 02:00 hours; levels of prolactin decreased at 08:00 hours, but steroid levels continued to rise. This finding suggests either a direct effect of melatonin on serotonin active transport or the influence of the suprachiasmatic nucleus on serotonin uptake by platelets. It is also possible that there is a simultaneous decrease in serotonin uptake and decline from peak levels of melatonin due to the rise in steroid secretion.

The metyrapone-test was used to study the influence of pituitary-adrenal activity on the pineal function in man. We recorded in blood the circadian rhythmicity of melatonin, ACTH and cortisol and the excretion of melatonin, cortisol and Porter-Silber chromogens in urine before, during and after the administration of 750 mg metyrapone every 4 h during 24 h in two healthy volunteers and in two patients with asymptomatic, moderate hyperparathyroidism and a prolactin-secreting microadenoma, respectively. The present study confirmed our previous report on an increased excretion of melatonin per 24 h and per mmol creatinine during the administration of metyrapone. The excretory maximum preceded the maximal ACTH-adrenal response. Serum melatonin remained unchanged during the administration of metyrapone. A second finding was depressed serum melatonin the night after the test in the subjects with the most marked ACTH-cortisol response following the metyrapone-test indicating suppression of melatonin secretion when ACTH-cortisol secretions were increased. A third finding was a late increase in diuresis appearing the day after metyrapone-administration while glomerular filtration rates did not show significant alterations. Thus, it is shown that the metyrapone-induced cortisol inhibition stimulates both ACTH and melatonin secretion, while high ACTH and cortisol levels are accompanied by reduced S-melatonin levels.

Thirty-three patients with major depressive illness were treated with electroconvulsive therapy (ECT) and plasma adrenocorticotropin (ACTH), and cortisol levels were measured 30 min before and 1, 5, 15, 30 and 60 min after ECT. There was an immediate release of ACTH with a maximum after 5 min. The maximum cortisol plasma levels were measured 30 min after ECT. No change in ACTH and cortisol concentrations was seen in control experiments when the patients received only anaesthesia. ACTH release was seen in patients treated with ECT in the morning and in the evening. In 15 patients the levels were studied at the first and sixth (last) ECT. ACTH and cortisol levels were significantly higher after the first ECT as compared with the sixth. This alteration in ACTH release might reflect ECT-induced changes in the central monoaminergic transmission with stimulation of beta-adrenergic pathways leading to inhibition of ACTH-release.

Psychiatric symptoms in primary hyperparathyroidism (PHPT) are usually characterized as depressive. In this study 13 patients with PHPT and six control patients with atoxic nodular goiter underwent psychiatric ratings with the comprehensive psychopathological rating scale (CPRS) the day before surgery. The 21 items in this scale were grouped into clusters. The ratings were repeated after successful removal of a parathyroid adenoma. Diurnal serum concentrations of cortisol, melatonin and prolactin were studied pre- and postoperatively in eight of the patients. Patients with PHPT had significantly higher CPRS total scores, 8.5 +/- 1.3, compared with goiter controls, 1.9 +/- 0.8, and showed a significant improvement of psychiatric symptoms after excision of the parathyroid adenoma, to 3.3 +/- 0.9. The preoperative diurnal and peak levels of cortisol and melatonin were higher (P less than 0.05) than after surgery. Serum melatonin fell to levels lower than those in healthy controls. Correlations were found between some clusters or items and cortisol or melatonin. Serum prolactin levels were normal and unaltered by parathyroid surgery. It is concluded that patients with PHPT show well defined psychiatric symptoms many of which are correlated to alterations in serum cortisol and melatonin accompanying PHPT. The improvement of symptoms seen after successful surgery further suggests that PHPT is associated with a specific psychiatric disorder similar to but distinguishable from major depressive disorder.

The cyclic nature of cluster headache warranted a study of the 24-hour rhythms of serum cortisol and melatonin. They were both altered during cluster periods as compared with periods of remission and healthy controls. The 24-hour mean and maximal cortisol levels were higher and the timing of the cortisol minimum was delayed as compared to the same patients in remission. Although there was no relation between the cortisol and melatonin levels and headaches, the rise of cortisol following many attacks might in part represent an adaptive response to pain. The nocturnal melatonin maximum was lower during cluster periods than in remission. This finding, and the dysautonomic signs during attacks, may reflect a change of the vegetative tone in a hyposympathetic direction.

The aim of the present study was to determine the diurnal secretion of melatonin, cortisol, prolactin, and calcitonin during chronic parathyroid hormone-dependent hypercalcemia. Eight women, aged 40-76 years, with primary hyperparathyroidism (PHPT) were studied before and after surgical removal of a parathyroid adenoma. The hormone concentrations in blood were determined at 08, 12, 16, 22, 02, 04, and 06 h. Concomitantly, the excretion of melatonin and cortisol in urine between 07-19 h and 19-07 h, and the clearance of calcium and creatinine were measured. Nyctohemeral serum prolactin and calcitonin were unaffected by moderate parathyroid hormone-dependent hypercalcemia. In contrast, serum cortisol and melatonin were significantly higher during active disease than after surgical cure. Mean 24-h variation of serum cortisol was 349 +/- 34 nmol/liter vs. 223 +/- 17 nmol/liter and mean serum melatonin was 0.13 +/- 0.04 nmol/liter vs. 0.06 +/- 0.02 nmol/liter. Endogenous creatinine clearance was similar before and after surgery, while the clearance of melatonin and cortisol significantly increased after surgery, indicating an increased tubular reabsorption of both hormones during active disease. Fasting morning glucose concentrations were also significantly decreased after successful surgery, 6.1 +/- 0.6 vs. 5.2 +/- 0.5 mmol/liter. It is suggested that the relative hypercortisolism may be the cause of the glucose intolerance in primary hyperparathyroidism. Three to 4 months after surgical cure the serum melatonin levels were significantly lower than those seen in age-matched controls, indicating a melatonin insufficiency in patients successfully treated for PHPT. The meaning of this finding is not yet understood but might be of importance in the development of primary hyperparathyroidism.

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.

The pathophysiology behind the abnormalities of the hypothalamic pituitary adrenal cortex axis found in patients with major depressive disorder was studied by the use of the vasopressin test. The response of plasma adrenocorticotropin (ACTH) and cortisol to the injection of 10 IU lysine-vasopressin (LVP) was investigated in 18 patients meeting the DSM-III criteria for major depressive episode. The response was correlated to the outcome of the dexamethasone suppression test (DST) with the use of two different cut-off points, 139 nmol/l and 200 nmol/l respectively. The results show that no significant difference was found in ACTH or cortisol response between patients having a normal or abnormal DST. The results do not seem to support the hypothesis that the abnormalities of the hypothalamic pituitary adrenal cortex axis involve a hypersecretion of corticotropin-releasing factor (CRF) and a subsequent desensitization of the corticotrophs to CRF-stimulated ACTH release.