Multiple hormonal responses to insulin-induced hypoglycemia in depressed patients and normal volunteers

Studies have shown that some depressed patients may demonstrate multiple hormonal response abnormalities after a neuroendocrine challenge test; this finding has suggested the strategy of measuring several hormones after an insulin tolerance test. The authors gave insulin tolerance tests to 72 depressed patients and 51 age- and sex-matched healthy volunteer control subjects and measured glucose, cortisol, prolactin, and human growth hormone (GH) responses. Although there were no differences between patients and control subjects in the mean decrease in glucose levels after the insulin tolerance test, depressed men demonstrated significantly lower prolactin and GH levels after the test.     

Abnormal neuroendocrine responsivity to acute i.v. clomipramine challenge in depressed patients

The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.     

Prediction of depressive relapse in remitted bipolar patients using corticotrophin-releasing hormone challenge test

Abnormalities in corticotrophin (ACTH) and Cortisol levels before and after corticotrophin-releasing hormone (CRH) stimulation have been reported in depressed bipolar patients. The ACTH and free Cortisol response to the injection of 100 ug of synthetic human CRH and plasma cortisol-binding globulin (CBG) levels were measured in 42 lithium-treated patients suffering from RDC bipolar-I disorder in remission, and in 21 age- and sex-matched control subjects. A 1-year follow-up was conducted in order to assess any possible relationship between outcome and the hormonal response. Bipolar patients showed higher baseline and peak ACTH concentrations than controls. A lower net area under the ACTH concentration curve after CRH stimulation predicted depressive relapse within 6 months by multiple regression analysis. The CRH challenge test could be a potentially good predictor of depressive relapse in remitted bipolar patients.     

Neuroendocrine measures in psychiatric patients: course and outcome with ECT

Measures of neuroendocrine function--plasma cortisol and its response to dexamethasone, and plasma thyroid-stimulating hormone (TSH) and its response to thyrotropin-releasing hormone (TRH)--were employed in 50 hospitalized male veteran psychiatric patients with diagnoses of unipolar or bipolar melancholia, secondary depression, or schizophrenia. Of 20 cases of unipolar melancholia, 17 (85%) exhibited hypercortisolism; 14 (70%) failed to suppress plasma cortisol after dexamethasone; and 4 (31%) of 13 tested had an abnormal TSH response to intravenous TRH. Two patients with secondary depression also exhibited hypercortisolism; no other patients evinced abnormal neuroendocrine test results. These measures were repeated in 14 unipolar depressed patients after a course of electroconvulsive therapy (ECT). Improvement in psychopathology was directly related to normalization of measures of hypothalamic-pituitary-adrenal (HPA) function. The TSH response to TRH was not systematically altered. After a followup period of 1 to 9 months, there was a good correlation between the measures of HPA function and the clinical outcome. These findings encourage further study of HPA function measures as outcome criteria for depressed patients receiving ECT.     

Associations among dexamethasone non-suppression and TRH-induced hormonal responses: increased specificity for melancholia?

TRH-induced thyrotropin (TSH), prolactin (PRL), and growth hormone (GH) responses were investigated together with a dexamethasone suppression test in female psychiatric inpatients with major melancholic depression (n = 21), schizophrenic disorder (n = 20), alcohol dependence (n = 11), and adjustment disorder with predominantly depressed mood (n = 13), as well as in 15 healthy women. Abnormal responses for all four endocrine variables were noted most frequently in melancholia; however, a significant number of the non-depressed patients also had abnormal hormonal responses in the individual test. The association of two or three abnormalities proved to be quite specific for the melancholic group. There were no statistically significant differences in TRH-induced TSH responses among the patient subgroups. Non-suppression of cortisol after dexamethasone was associated with blunted TSH-responses only in melancholia. There was a tendency for non-suppressor schizophrenics to show more abnormal GH-responses to TRH administration.     

Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects

OBJECTIVE: This study was designed to compare central serotonergic function in depressed patients and healthy comparison subjects by examining neuroendocrine and mood responses to intravenous L-tryptophan. METHOD: One hundred twenty-six drug-free patients with DSM-III-R major depression (109 unipolar, 17 bipolar; 68 melancholic, 58 nonmelancholic; 28 psychotic, and 98 nonpsychotic patients) and 58 healthy comparison subjects participated. After an overnight fast, subjects received an intravenous infusion of L-tryptophan, 7 g. Blood was obtained for determination of serum prolactin, serum growth hormone (GH), and plasma tryptophan levels. Visual analogue scales were used to assess mood. RESULTS: Prolactin responses were blunted in nonmelancholic and higher in melancholic and psychotic depressed patients, while GH responses were blunted in combined unipolar, nonmelancholic, and nonpsychotic depressed patients. Controlling for baseline biological, clinical, and demographic factors eliminated the higher prolactin response in the melancholic and psychotic patients, attenuated the blunted GH response in the unipolar patients, and revealed a blunted GH response in the melancholic patients. Patients and comparison subjects differed on five of 13 mood responses, primarily because of baseline differences. CONCLUSIONS: These findings are consistent with previous studies demonstrating blunted neuroendocrine responses to intravenous L-tryptophan in depression. Restriction of these findings to specific subtypes of depression may reflect a differential role of serotonergic abnormalities in these subtypes.     

Neuroendocrine strategies in affective disorders

1. 1. Neuroendocrine strategies in affective disorders have explored both resting values of hormones and hormonal responses to stimuli such as hypoglycemia, TRH, LHRH, dexamethasohe, methadone and morphine. The abnormalities established to date have involved growth hormone, cortisol and TSH responses in particular. Prolactin has not been investigated to the same extent. We therefore describe several prolactin studies exemplifying selected neuroendocrine strategies.

2. 2. Our studies of prolactin responses included acute cases of either primary or secondary depression, stabilized bipolar patients, and healthy controls both off and on lithium. We found prolactin response to hypoglycemia significantly reduced in primary but not secondary depressions.

3. 3. Lithium administration led to flattened prolactin responses to hypoglycemia in stabilized bipolar patients but not in healthy controls. The flattened response in patients was observed already after 3 weeks of lithium, and remained flattened after years of treatment. The findings suggest a greater degree of prolactin reponse reduction in those patients showing most pronounced stability on lithium treatment.

Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers

Abnormalities in several hypothalamic-pituitary-target organ axes in depression may reflect alterations in central neurotransmitter receptor function. As the alpha 2-adrenergic receptor has been implicated in a variety of neuroendocrine abnormalities in depression, we assessed the role of alpha 2-adrenoceptor dysfunction in mediating response abnormalities of growth hormone, cortisol, and prolactin after intravenous clonidine administration (an alpha 2-adrenergic receptor agonist) in 18 patients with major depression (12 with melancholic features, 6 without melancholic symptoms) and 9 healthy volunteers. In particular, we examined the hypothesis that these abnormalities might be more evident in patients with DSM-III melancholic depression. After clonidine, the mean growth hormone response was significantly lower in melancholic depressives compared to controls (p = 0.02), and the shape of the growth hormone response profile was also significantly different in melancholic patients (p = 0.04). There was an overall decrease in the mean cortisol concentration after clonidine in melancholic patients and control subjects (p = 0.02), as well as a larger cumulative prolactin response in melancholic patients compared to those without melancholic features (p = 0.02). The present results confirm prior observations of a blunted growth hormone response after clonidine and suggest that alterations in alpha 2-adrenergic receptor activity might also contribute to several neuroendocrine abnormalities in patients with melancholic depression.     

Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites.

The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.     

Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function

OBJECTIVE: Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function. METHODS: Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined. RESULTS: Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients' post-dexamethasone cortisol correlated with WM commission errors (r(s) = 0.64, p = 0.0006). No such relationship was evident in controls. CONCLUSION: Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function.     

Crossed acoustic response combined with visual and somatosensory evoked responses in the diagnosis of multiple sclerosis.

The crossed acoustic response, (CAR), a recently introduced test of brainstem function, has been studied in 66 patients with multiple sclerosis and 53 control subjects, and compared with conventional visual and somatosensory evoked responses (VER, SER). A latency abnormality was found in the CAR in 73% of patients, in the VER in 63%, and in the SER in 37%. Abnormalities have been related to the presence or absence of clinically detectable signs. All three responses detected subclinical lesions by showing abnormality in a proportion of multiple sclerosis patients who had no corresponding abnormal clinical signs (CAR 69%, VER 42%, SER 29%). The best diagnostic combination of responses was VER and CAR. Ninety per cent of patients had at least one of these two responses abnormal.     

Psychoimmunoendocrine aspects of panic disorder.

Immunological, neuroendocrine and psychological parameters were examined in 14 psychophysically healthy subjects and in 17 panic disorder patients before and after a 30-day course of alprazolam therapy. T lymphocyte proliferation in response to the mitogen phytohemagglutinin, lymphocyte beta-endorphin (beta-EP) concentrations, plasma ACTH, cortisol and beta-EP levels were examined in basal conditions and after corticotropin-releasing hormone (CRH) stimulation. Cortisol inhibition by dexamethasone (DST) and basal growth hormone (GH) and prolactin levels were also examined. Depression, state or trait anxiety, anticipatory anxiety, agoraphobia, simple and social phobias, severity and frequency of panic attacks were monitored by rating scales. The immune study did not reveal any significant difference between patients and controls, or any effect of alprazolam therapy. The hormonal data for the two groups were similar, except for higher than normal basal ACTH and GH plasma levels, lower than normal ratios between the ACTH and cortisol responses to CRH, and blunted DST in some patients. All the impairments improved after alprazolam therapy, in parallel with decreases in anxiety and in severity and frequency of panic attacks.     

Lithium effects on neuroendocrine function

1. We studied growth hormone and prolactin responses to insulin hypoglycemia and TSH responses to TRH in symptom-free bipolar patients and healthy controls.

2. There were no significant differences in prolactia and growth hormone responses to hypoglycemia between stabilized bipolar patients and healthy controls, both tested medication-free. When lithium was administered to both groups, only bipolar patients showed a dramatic reduction in prolactin and growth hormone responses.

3. Both bipolar patients in remission and healthy controls showed an increase of TSH response to TRH when treated with lithium in comparison with the testings before lithium administration.

4. The subjects, both patients and volunteers, showed a comparable degree of hypoglycemia on and off lithium.

5. The observed difference in responsivenes s of bipolar patients warrants further systematic investigation and offers interesting possibilities for practical utilization.     

Neuroendocrine effects of intravenous clomipramine in depressed patients and healthy subjects.

OBJECTIVE: Neuroendocrine challenge paradigms have been used to asses serotonergic systems in depression, but limitations in the specificity of many of these tests have been noted. In this study, the neuroendocrine responses to acute intravenous administration of the serotonin (5-HT) reuptake inhibitor clomipramine were assessed in depressed patients and matched control subjects. METHODS: Thirty hospitalized patients who met DSM-III-R criteria for major depression, and 30 healthy control subjects who were matched for age, sex, and season of year for the time of study, received 12.5 mg of intravenously administered clomipramine. RESULTS: The depressed patients demonstrated significant blunting of prolactin responses to clomipramine, as well as trends toward blunted ACTH and cortisol responses. There was no difference between the patient and control groups in growth hormone responses, plasma clomipramine levels, or self-reports of side effects. CONCLUSIONS: These data support the hypothesis that depressed patients have abnormal neuroendocrine responses to the intravenous administration of the 5-HT reuptake inhibitor clomipramine. Further study is required to delineate the mechanisms responsible for the abnormal response to intravenously administered clomipramine in depression.     

The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.     

Blunted ACTH and cortisol response to afternoon tryptophan infusion in euthymic bipolar patients

The serotonin precursor tryptophan was used to test neuroendocrine responses in remitted bipolar patients and controls. Tryptophan was administered in the afternoon when spontaneous cortisol secretion is lower than in the morning. Following pilot studies at various doses, 50 mg/kg L-tryptophan was given i.v. over 20 min to 11 patients and 14 controls. Controls demonstrated cortisol release, whereas the response curve for patients was indistinguishable from placebo. Differences between groups were significant at 15, 30, and 45 min. Changes in adrenocorticotropic hormone were consistent with those in cortisol. Prolactin and growth hormone levels increased in both patients and controls following tryptophan. Higher doses caused gastrointestinal upset in some subjects.     

Neuroendocrine interrelationships in major depressive disorder

The authors administered the thyrotropin-releasing hormone (TRH) stimulation test and the dexamethasone suppression test (DST) to 54 patients who met DSM-III criteria for major depressive disorder and to 19 nondepressed patients. A blunted thyrotropin (TSH) response to TRH injection was noted in 18 depressed patients (33%) but in no nondepressed patients. An escape from dexamethasone suppression was noted in 23 depressed patients (43%) but in only 2 nondepressed patients (11%). The combined sensitivity of the DST and the TRH test in identifying major depressive disorder was 67% with 92% specificity. Only 6 depressed patients (11%) had abnormal responses to both the DST and the TRH test, suggesting that the hypothalamic-pituitary-adrenal axis dysregulation and hypothalamic-pituitary-thyroid axis dysregulation are independent phenomena. These findings support the combined use of these neuroendocrine tests in clinical practice.     

Neuroendocrine studies in dementia patients: responses of plasma GH and PRL following bromocriptine administration

Bromocriptine stimulates growth hormone (GH) secretion at the hypothalamus and suppresses prolactin (PRL) secretion at the pituitary level. We administered bromocriptine to 30 patients with dementia of the Alzheimer type (DAT), 30 patients with multi-infarct dementia (MID) and 22 age matched healthy controls, and compared response patterns of GH and PRL. Incomplete PRL suppressive responses (suppression rate < 50%) were seen in 36.7% of DAT patients and in 30.0% of MID patients, indicating that both groups had the same degree of pituitary dysfunctions. Blunted GH responses (< 5 ng/ml) were seen in 93.3% of DAT patients, in 63.3% of MID patients and in 31.8% of the controls. The results indicate that neuroendocrine regulation of GH is more selectively and severely damaged in DAT patients than in MID patients at the hypothalamus.     

Cardiovascular autonomic function in multiple sclerosis

In this study blood pressure (BP) and heart rate (HR) responses to standing and HR responses to deep breathing were assessed in 34 patients with clinically definite multiple sclerosis (MS) and 63 healthy subjects. Normal ranges, which were clearly age related for both HR responses, were obtained. The BP response to standing was abnormal in 13% of the MS patients, these patients demonstrating significant postural hypotension. The HR response to standing was abnormal in 28% of the MS patients, with a normal initial increase in heart rate and a significantly reduced reflex bradycardia. On deep breathing 36% of MS patients showed abnormal HR changes. The resting HR did not differ between both groups. Abnormalities of one or more tests were found in 53% of the MS patients. No relationship was found between abnormal cardiovascular autonomic responses and the symptoms, duration, severity and progression of the disease. Based on clinical and magnetic resonance imaging findings no indications were found for localisation of the autonomic disturbances in the brainstem. It is suggested that at least a part of the cardiovascular autonomic lesions in MS is located outside the brainstem, i.e. in supramedullary reflex pathways or in the spinal cord.     

Growth hormone and other hormonal responses to clonidine in melancholic and nonmelancholic depressed subjects and controls.

To study putative differences in central neurotransmitter function in depressive subtypes, growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin responses to the alpha 2-noradrenergic receptor agonist clonidine (1.3 micrograms/kg i.v.) were examined in 26 subjects with major depression, 13 of whom had melancholia. The responses of 10 of these endogenous/melancholic subjects were compared with those of 10 controls who were matched to the patients on age, sex, and menopausal status. In 15 of the depressed subjects, prolactin and cortisol responses to the putative serotonergic agonist fenfluramine were also examined to test for associations between these challenges. There were no significant differences in any of the responses between melancholic and nonmelancholic depressive subgroups after controlling for age and sex. With the exception of a greater reduction in ACTH in the endogenous/melancholic subjects, there were also no significant differences in hormonal responses between these patients and controls. There was, however, a significantly greater reduction in systolic blood pressure in the control subjects. There were no significant correlations between the responses to clonidine and fenfluramine. The findings suggest that clonidine at a dosage of 1.3 micrograms/kg is neither able to differentiate reliably between depressive subtypes nor to differentiate reliably between depressed and control subjects.