Jan-Gustaf Ljunggren

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.

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.

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.

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.

PINEAL-HYPOTHALAMIC-PITUITARY FUNCTION IN PATIENTS WITH DEPRESSIVE ILLNESS

The pineal-hypothalamic-pituitary function was investigated in twelve patients with major depressive illness. The laboratory investigation included analysis of Cortisol, prolactin and melatonin diurnal rhythms as well as the TSH response to TRH and the Cortisol response to dexamethasone administration. The results showed that the patients could be divided into three groups, each containing four patients, according to their Cortisol response to dexamethasone. A correlation between the Cortisol response after dexamethasone and the Cortisol/melatonin ratio at night time before the dexamethasone suppression test was found. Analyses of the diurnal rhythms showed that the patients with no Cortisol-response to dexamethasone administration showed the highest Cortisol and lowest melatonin and prolactin levels. This group of patients did not show any suppression of prolactin after dexamethasone in contrast to the other two groups. Only two patients showed a blunted TSH response to TRH administration, however one of these was receiving thyroxine medication. The serum Cortisol: melatonin ratio at 02 hr was significantly higher in the group of patients showing no Cortisol suppression to dexamethasone compared to the other groups. No gross clinical difference was found between the groups. It is concluded that patients with no Cortisol response to dexamethasone may have an enhanced CRF production secondary to a subfunction of a proposed pineal factor inhibiting CRF.

Unaltered 24 h serum PRL levels and PRL response to TRH in contrast to decreased 24 h serum TSH levels and TSH response to TRH in major depressive disorder

ABSTRACT— The 24 h serum levels of prolactin (PRL) and thyrotropin (TSH) assessed at ten different time points and the PRL and TSH responses to TRH administration (ΔPRL, ΔTSH) were investigated in 26 inpatients meeting the RDC criteria for an acute major depressive disorder. Fourteen of these patients were reinvestigated in a state of partial or complete remission. Comparison between the patients during both relapse and remission and 23 healthy controls showed no differences in the paramenters reflecting the 24 h PRL levels or ΔPRL. However, significantly lower 24 h TSH levels and ΔTSH were found in the patient group in the acute phase. Antidepressant medication, sedatives or the outcome of the dexamethasone test did not significantly influence the PRL levels or ΔPRL. Both the patient group and the controls revealed normal sleep associated PRL release indicating unaltered serotoninergic and/or dopaminergic neurotransmission regulating the PRL secretion. The present results indicate a selective disturbance affecting the pituitary TSH secretion, and are consistent with our hypothesis that the mechanism behind the decreased TSH levels and the impaired TSH response to TRH in acute major depressive disorder involves a down‐regulation of the pituitary TRH receptors.

Release of corticotropin after administration of corticotropin-releasing hormone in depressed patients in relation to the dexamethasone suppression test.

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 μg 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.

Serum dopamine-β-hydroxylase activity in patients with major depressive disorders

ABSTRACT The dopamine‐β‐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.