B. F. Kjellman

Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome

ABSTRACT Maximum nocturnal serum melatonin level (MTmax) in relation to some clinical variables was studied in 32 patients with a major depressive episode and in 33 healthy subjects with reference to the outcome of the dexamethasone suppression test (DST). Significant regressions were found between MTmax levels and clinical rating scores in CPRS, interpreted as retardation symptoms. Four healthy subjects with disposition for dysthymic reactions had subnormal MTmax levels, which differed from MTmax levels in subjects without such disposition. Patients but not the healthy subjects, who reported parental loss before 17 years of age, had subnormal MTmax levels and differed from patients with no reported parental loss. Patients with no reported suicidal behaviour in clinical history had significantly lower MTmax levels than patients with reported suicide attempts. No relations were found between low MTmax levels and diagnoses, duration of illness, reported inheritance for depressive illness or sleep disturbances. A hypothetical low melatonin syndrome in depression is proposed: 1) low nocturnal melatonin, 2) abnormal dexamethasone suppression test, 3) disturbed 24‐h rhythm of cortisol, 4) less pronounced daily and annual cyclic variation in depressive symptomatology.

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.

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.

Light treatment in seasonal and nonseasonal depression

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 (∼ 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.

Twenty‐four‐hour serum levels of TSH in affective disorders

ABSTRACT– As a part of a broad endocrine testing of patients with affective disorders the 24 h serum levels of thyrotropin (TSH) were investigated and correlated to the clinical history and disease symptoms. Thirty‐two patients with the research diagnostic criteria of major depressive disorder were investigated. Twenty‐six of these patients were reinvestigated in a state of full or partial clinical remission. Nine patients with unipolar and eight patients with bipolar affective disorders were also investigated in clinical remission. The control group comprised 32 healthy subjects. The results showed significantly lower 24 h serum levels of TSH and less variability of TSH levels during the 24 h period in the group with acute major depression compared with the controls. The 24 h serum levels of TSH normalized during clinical remission. Different subtypes of depression, different clusters of symptoms and severity of depression did not significantly correlate with the 24 h serum levels of TSH. There were also no significant correlations between abnormalities of the dexamethasone suppression test or nightly melatonin levels and the 24 h serum levels of TSH. The lower TSH levels seen in acute major depression could not be correlated to increased or decreased levels of peripheral thyroid hormones. The mechanism of the decreased 24 h serum levels of TSH is unclear. One possibility is an altered sensitivity in the thyrotrophs of the pituitary.

Serotonergic‘vulnerability’ in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram‐responders

A double‐blind study of the tryptophan depletion (TD) challenge was performed on a sample consisting of 20 patients with a major depressive disorder in clinical remission after citalopram treatment. TD was induced by the intake of 43 g of an amino acid mixture containing the five large neutral amino acids. The control group received the same mixture, to which 2.3 g tryptophan had been added. Five of the 12 challenged patients showed a worsening of depressive symptoms during the day of the test. In contrast, there was no mood alteration in the eight control patients. Baseline Cortisol levels were significantly higher in responders to TD compared to those in non‐responders and controls. Platelet serotonin‐receptor function and plasma prolactin levels were correlated. There was a significant positive correlation in the baseline data between rated mood state and plasma Cortisol and a significant inverse correlation between related mood state and plasma tryptophan concentration. Thus low mood appeared to be associated with low serotonin precursor availability as well as with high Cortisol levels.

Twenty-four-hour serum levels of T4 and T3 in relation to decreased TSH serum levels and decreased TSH response to TRH in affective disorders.

ABSTRACT The serum levels of thyroxine and triiodothyronine (T4 and T3) were investigated at 10 different time points during a 24 h period in 31 inpatients meeting the RDC criteria for acute major depressive disorder. Twenty‐three of these patients were also reinvestigated in a state of partial or complete remission. The results show that there was no significant difference in T4 or T3 levels during the 24 h period between depressed patients and 32 healthy controls despite significantly decreased TSH levels and TSH response to TRH administration (Δ TSH) in the patient group. No indications were obtained that the patients’ clinical presentation or depressive symptomatology as revealed by their CPRS scores, psychotropic medication, melatonin levels, or the outcome of the dexamethasone test, significantly influenced the T4 or T3 levels. The depressed patients who were studied longitudinally showed increased T4 levels in the acute phase compared to remission, wheras the T3 levels did not change. However, the levels of thyroid hormones were within the normal range in the acute phase as well as in remission. Furthermore, the changes in thyroid hormones between the state of relapse and remission were not significantly correlated to the corresponding increase in TSH levels and Δ TSH between the two assessments. The present results are consistent with the hypothesis that the mechanism behind the impaired TSH response to TRH in acute major depressive disorder is a downregulation of the pituitary TRH receptors.

Platelet serotonin functions in untreated major depression

The uptake of [14C]5-HT, [3H]paroxetine and [3H]LSD binding was determined in platelets from 30 untreated patients with major depression and compared with corresponding variables from 30 healthy age-, sex- and season-matched control subjects. The maximum velocity (Vmax) for the 5-HT uptake was significantly decreased in patients (P = 0.014) compared to control subjects. Depressed women had significantly lower Vmax than female control subjects. In men, Vmax did not differ between patients and control subjects. Vmax was significantly lower in male inpatients compared with male outpatients (P = 0.05). The density (Bmax) of 5-HT uptake sites was found to be significantly increased in patients (P < 0.05) compared to control subjects and male patients had significantly higher Bmax than male control subjects, but there was no difference between female control subjects and female patients. No significant difference was found in Bmax of 5-HT2-receptors between patients and control subjects. A positive correlation was found between Bmax of 5-HT2-uptake sites and the degree of anxiety and between Bmax of 5-HT2 receptors and MADRS scores. Bmax of 5-HT2-receptors was positively correlated with the degree of suicidality. The results in the present study indicate that there may be a gender difference in serotonergic dysfunction in depression.

Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin

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 patients 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.

Hypothalamic‐pituitary‐gonadal axis in major depressive disorders

The baseline LH, FSH and testosterone levels and the LH and FSH response to TRH‐LHRH administration (ΔLH, ΔFSH) were investigated in 28 patients meeting the RDC criteria for an acute major depressive disorder, and in 20 healthy persons. Twenty‐two patients were also reinvestigated in a state of complete or partial clinical remission. Cross‐sectional and longitudinal comparisons were made between the groups divided according to sex and menopausal status. After mathematical correction for age differences, the depressed males with an abnormal DST response showed significantly (P < 0.03) higher ΔFSH in the acute state compared to the controls. No relation could be established between the HPG axis hormone levels and the nocturnal serum melatonin levels or the PRL or TSH response to TRH‐LHRH administration. In the longitudinal part of the study, the depressed males with an abnormal DST response showed decreased (P < 0.03) testosterone levels and increased ΔFSH (n.s.) in the acute state compared to remission, in contrast to the males with a normal DST. The present results do not support a hypothesis regarding a stimulus‐induced down‐regulation of the pituitary LHRH receptors in our patients. The possible mechanisms by which HPA axis activation (as revealed by an abnormal DST response) could influence the HPG axis in depressed patients remain to be elucidated.