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Ninety patients with major depressive disorder were classified according to seasonal (n = 68, 50 women) or nonseasonal (n = 22, 17 women) pattern according to DSM-III-R. They were also clinically evaluated and rated before and after morning (0600-0800) or evening (1800-2000) light treatment for 10 days in a room with a luminance of 350 cd/m2 (approximately 1500 lx) at eye level. Mood ratings were performed using both the Comprehensive Psychopathological Rating Scale and the Hamilton Depression Rating Scale. Depressed patients with seasonal pattern improved significantly more than those with a nonseasonal pattern suggesting a specific nonplacebo effect of light treatment in depressed patients with seasonal pattern. There were no significant differences in outcome when light treatment was given in the morning or in the evening, and not between patients with and without atypical symptoms such as carbohydrate craving or increased appetite.

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.

A potentially confounding variable inherent in studies designed to examine the effect of melatonin administration in humans is the presence of an endogenous melatonin rhythm in the experimental subjects. The effects of exogenous melatonin administration on serum hormone rhythms was recently examined in a male patient who lacked detectable circulating levels of endogenous melatonin. The patient's pineal gland had been destroyed five years previously in the course of treatment for a pineal astrocytoma. On three separate occasions, over approximately a one-year period, the patient was given daily oral melatonin replacement (2 mg/day, 1 mg/day and 0.5 mg/day). These experiments were designed to assess the effects of exogenous melatonin on serum growth hormone, prolactin, cortisol and testosterone rhythms. Analysis of blood samples collected every 2-4 hours periods both before and during melatonin replacement revealed that the exogenous melatonin rhythm was associated with improvements in self-reported sleep and mood ratings. Melatonin administration produced robust nocturnal peaks in serum growth hormone and prolactin levels immediately following ingestion of the hormone, while serum cortisol and testosterone rhythms were not influenced. These results suggest that melatonin may modulate the coordination and enhancement of selected biological rhythms in man.

The dopamine-beta-hydroxylase (DBH) activity in serum was assayed in 32 acutely ill inpatients with major disorder and in 33 healthy control subjects. Twenty-six of these patients were also studied in a state of remission. The DBH activity was compared to the serum levels (studied during a 24 h period) of T4, T3, TSH, prolactin and melatonin as well as to the outcome of the dexamethasone suppression and TRH test and to various clinical symptoms, as estimated by different rating procedures. No significant differences in DBH activity were found between the acutely ill patients, patients in remission, or normal subjects. Thus, the determination of the activity does not seem to be of practical importance as a laboratory diagnostic tool for major depressive disorder. A significant positive correlation was found between the DBH activity and the TSH levels, estimated by several parameters during the 24 h period, in the acutely ill patients, whereas no significant correlation was found in patients in remission or in the normal subjects. No significant correlation was found between the DBH activity in any group and the other laboratory or clinical parameters. The mechanism behind the significant correlation between the DBH activity and TSH levels remains to be clarified.

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 thyrotropin-releasing hormone (TRH) test was studied in 32 patients with acute major depressive disorder, 16 patients with recurrent unipolar (n = 8) or bipolar (n = 8) affective disorder in remission, and 22 healthy control subjects. Twenty-six of the 32 acutely ill patients were also studied when in remission. Outcome in these patients was correlated to serum levels of triiodothyronine (T3), 3,3',5'triiodothyronine (reverse T3), thyroxine (T4), thyroid-stimulating hormone (TSH), prolactin (PRL), melatonin, dexamethasone suppression test (DST) results, and clinical symptoms assessed by the Comprehensive Psychopathological Rating Scale (CPRS). The TSH response to TRH (delta TSH) was decreased in the acutely ill patients, but no difference was found between patients in remission and controls. The delta TSH was correlated to TSH but not to T3 and T4 levels in both acutely ill and control subjects. In the acutely ill group, delta TSH did not distinguish between patients with normal and abnormal DST results. Thus, abnormalities in the hypothalamic-pituitary-thyroid (HPT) axis are not correlated to abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, delta TSH did not differentiate between melancholic (DSM-III) and nonmelancholic patients or between patients with primary and secondary depression. No correlation was found between delta TSH and CPRS scores. Patients with observable agitation greater than 0.25 points (item range 0-3) had higher levels of delta TSH than patients with lower levels. No significant correlation was found between delta TSH and seven specific symptom clusters on the CPRS. However, there was a possible relation between low delta TSH and violent suicide attempts or suicide. PRL levels did not distinguish acutely ill patients from controls. Finally, there was no significant regression between delta TSH and melatonin levels. The decrease in delta TSH seen in the acutely ill patients was too small to be of diagnostic value as a laboratory measure differentiating acutely ill and healthy subjects. The mechanism underlying the HPT alterations in acute major depressive disorder may be a desensitization of the TRH receptor in the thyrotrophs secondary to an increased endogenous TRH stimulation.

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.

Serum levels of 3,3',5' triidothyronine (reverse T3) were investigated in 32 patients with acute major depressive disorder. Twenty-six of these patients were also studied during a state of clinical improvement. Comparison subjects were 22 healthy controls, and 16 currently euthymic patients with histories of affective disorders (8 unipolar, 8 bipolar). The laboratory investigation included the determination of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroxin-binding globuline (TBG) levels in serum. The clinical symptoms were rated by the Comprehensive Psychopathological Rating Scale (CPRS) for depressive illness (CPRS global score), as well as the sum of 10 items (CPRS 10) and 22 items (CPRS 22) measuring depression. The patients were also divided into those having a normal or abnormal response to the dexamethasone suppression test; those having melancholia or not having melancholia; and those having primary or secondary depression. No significant difference in reverse T3 levels emerged among the patients with acute major depressive disorders, the euthymic unipolar or bipolar affective disorders, and the healthy controls. There were also no significant differences between those having an abnormal or normal DST test; those having primary or secondary depression; or those having melancholia or not having melancholia. In the group of patients with acute major depressive disorder, however, a significant increase in reverse T3 levels and a significant decrease in T3 levels, but no significant difference in T4 or TSH levels, were seen in the patients with the most pronounced clinical symptoms as measured by the CPRS. The implications of these findings are discussed.

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.