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.

Platelet serotonergic functions and light therapy in seasonal affective disorder.

We investigated platelet 14C-serotonin uptake and platelet [3H]LSD and [3H]paroxetine binding in 11 patients with seasonal affective disorder (SAD). Patients were reinvestigated after light therapy, applied at 07.00-09.00 h for 10 consecutive days. The degree of depression was rated before and after light therapy using the Comprehensive Psychopathological Rating Scale (CPRS). Baseline data in patients were compared with data from a control group consisting of 11 age- and sex-matched healthy volunteers. Seven patients responded to light therapy with a > 50% reduction in CPRS scores. In non-responders, the reduction in CPRS was 24.7 +/- 5.5%. There was a significant inverse correlation (P = 0.014) between Km for platelet 14C-serotonin uptake and CPRS scores. Patients had significantly higher Bmax for platelet [3H]LSD binding (P = 0.04) and significantly lower Bmax for platelet [3H]paroxetine binding (P = 0.016). There was a strong, multiple correlation between Bmax for [3H]LSD, as the dependent variable, and Km, Vmax and Bmax for [3H]paroxetine binding in patients (P < 0.0001) but not in controls. Responders to light therapy had significantly higher Km (P = 0.023) and significantly lower Bmax for [3H]paroxetine binding (P = 0.028) than non-responders. Bmax for [3H]paroxetine binding increased significantly to normal levels after light therapy. The results indicate that SAD is associated with aberrations in the serotonin uptake mechanism. The enhanced 5-HT2-receptor density may reflect a consequential up-regulation.

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.

Cortisol in light treatment of seasonal and non-seasonal depression: relationship between melatonin and cortisol.

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.

Melatonin in light treatment of patients with seasonal and nonseasonal depression.

Melatonin as a marker of circadian rhythm and the effect of bright light on melatonin were studied in 63 depressed patients, 42 with a seasonal pattern and 21 with a nonseasonal pattern. The patients were matched for age, time of treatment and severity of depression. Before light treatment, blood was sampled for melatonin and depression was clinically rated with the Comprehensive Psychopathological Rating Scale and Hamilton Depression Rating Scale. Two hours of light treatment, 350 cd/m2, was given daily for 10 days 0600 to 0800 or 1800 to 2000. Of the 42 patients with seasonal depression, 26 were treated with morning light and, 16 with evening light. The melatonin amplitude was significantly decreased by light, and the melatonin phase position was advanced by morning light and delayed by evening light. All patients except for 3 in each group changed in the expected direction. Although the patients with seasonal pattern had a more favorable outcome than patients with nonseasonal pattern, there was no difference in therapeutic outcome related to the baseline melatonin phase position. The hypothesis that the short term clinical effects of light therapy either in the morning or evening are related to pretreatment melatonin levels or alteration of melatonin amplitude or phase position was not supported in the study. There was also no significant difference between the seasonal and nonseasonal patients related to the degree of light suppression of melatonin and the rebound effect of serum melatonin levels following bright level exposure between 2200 and 2300 before regular light treatment.

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 (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.

Seasonal and non-seasonal depression. A comparison of clinical characteristics in Swedish patients.

This study compares the clinical characteristics of 127 patients with major depression, 99 with a seasonal and 28 with a non-seasonal pattern. Non-seasonal depressives had significantly higher scores in the Comprehensive Psychopathological Rating Scale, and the Hamilton Depression Rating Scale. Increased appetite and carbohydrate craving, were more frequently reported among patients with a seasonal pattern. Compared to previous reports, the Swedish patients with seasonal depression had less atypical vegetative symptomatology. The symptoms sadness, suicidal thoughts, slowness of movement, gastrointestinal symptoms, and weight loss were more frequent in the patients with a non-seasonal pattern. The clinical symptomatology has a low specificity compared to the seasonal pattern in diagnosing seasonal affective disorder according to DSM-III-R for seasonal and non-seasonal patterns.

Electrodermal activity in relation to basal and postdexamethasone levels of thyroid stimulating hormone and basal levels of thyroid hormones in major depressive patients and healthy subjects.

Electrodermal activity in 50 patients with major depression and 50 matched healthy control subjects was related to basal and postdexamethasone changes in levels of thyroid stimulating hormone (TSH), basal levels of thyroid hormones, and nocturnal levels of urinary cortisol. Levels of skin conductance and thyroxine were inversely correlated in the patients, but positively correlated in the healthy subjects. Patients with blunted postdexamethasone reduction of TSH showed high rates of nonevoked electrodermal fluctuations, low TSH levels, and elevated nocturnal urinary cortisol levels.

The hypothalamic-pituitary-thyroid axis in depressive patients and healthy subjects in relation to the hypothalamic-pituitary-adrenal axis.

Serum levels of thyroid stimulating hormone (TSH), triiodothyronine (T3), free T3 index (fT3i), thyroxine (T4), and free T4 index (fT4i) were measured before and after administration of 1 mg of dexamethasone in 54 depressive patients and 54 matched healthy subjects. A followup study at a mean of 2 years was performed in 28 patients in remission. Basal TSH levels were lower and fT4i levels were higher in major depressive patients compared with healthy subjects. After dexamethasone administration, there was no significant change in any of the hormones in a subgroup of 46 major depressive patients in contrast to matched healthy subjects, who showed a significant decrease in the levels of TSH, T3, and fT3i. The magnitude of the TSH response to dexamethasone in the major depressive patients was related to the level of nocturnal urinary cortisol excretion and pathological dexamethasone suppression test results. The level of TSH in depressive patients during remission did not return to levels similar to those found in the healthy subjects.

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 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.

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 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.

Effect of a 15 minute light pulse on nocturnal serum melatonin levels in human volunteers.

Monitoring the daily melatonin rhythm during the course of phototherapy for affective disorders may be beneficial in assessing the efficacy of such treatments. It is therefore of interest to study the effects of the timing, duration, and intensity of bright light pulses on melatonin levels in normal subjects. To examine the effects of a single exposure to a brief burst of bright light on serum melatonin, groups of healthy human volunteers of both sexes were treated with a 15 minute pulse of bright light (350 cd/m2) early in the evening during the winter months. Serial blood samples were collected from each person and the effect of the light pulse on serum melatonin and cortisol levels determined. Melatonin levels were significantly but only transiently suppressed by the light pulse, while cortisol levels were not affected. These results demonstrate that short duration bright light treatments can influence the melatonin rhythm generating system in humans.

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.

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 (delta LH, delta FSH) 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 less than 0.03) higher delta FSH 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 less than 0.03) testosterone levels and increased delta FSH (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.

Adrenocorticotropin and cortisol response to lysine vasopressin in relation to the outcome of the dexamethasone suppression test in major depressive disorder.

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.

Electrodermal activity in antidepressant medicated and unmedicated depressive patients and in matched healthy subjects.

A group of 59 depressive in- and outpatients displayed statistically significantly subnormal electrodermal activity (EDA) according to the skin conductance level, the skin conductance response magnitude, the skin conductance response rate, and the index of nonresponding during neutral tone stimulation, compared to 59 mentally and somatically healthy subjects, individually matched for age and sex. Comparisons between 20 antidepressant medicated and 20 unmedicated patients, matched for age, and comparisons between 21 drug-free patients and 10 patients medicated exclusively with antidepressants yielded no statistically significant difference in any EDA variable. However, all the electrodermal central values were somewhat lower in the medicated patients, possibly an effect of greater severity of symptoms. The present and previous findings offer strong support to the hypothesis of a subnormal function of the electrodermal activity in groups of depressive patients.

Electrodermal activity in relation to diagnostic subgroups and symptoms of depressive patients.

The electrodermal activity (EDA) in 59 depressive patients was investigated during stimulation with neutral tone stimuli. The patients were classified according to six dichotomies: 1) dysthymic disorder vs major depressive episode (DSM-III); 2) melancholic vs nonmelancholic major depressive episode (DSM-III); 3) endogenous vs nonendogenous (Newcastle scale); 4) high vs low inhibition; 5) psychomotor inhibition vs agitation; and 6) indices of high vs low hypothalamic disturbance. The low EDA usually found in depressive patients seems to be more pronounced in endogenous patients and in patients with symptoms of inhibition. Relationships between indices of hypothalamic dysfunction and low EDA were found, but lacked homogeneity. Early debut and long duration of current depression were related to small magnitude of the skin conductance response.

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.

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 (delta PRL, delta TSH) 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 delta PRL. However, significantly lower 24 h TSH levels and delta TSH 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 delta PRL. 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.

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.

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 (delta 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, whereas 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 delta 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.

Serum dopamine-beta-hydroxylase activity in patients with major depressive disorders.

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.