Growth hormone, prolactin and thyrotropin responses to gonadotropin-releasing hormone in depressed patients and healthy volunteers

Growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) release following gonadotropin-releasing hormone (GnRH) administration were examined in 56 patients with major affective disorder (37 unipolar, 19 bipolar) and 38 normal healthy subjects. There were no differences in GH, PRL or TSH responses after GnRH infusion between the patients and the normal subjects, in contrast to previously reported abnormalities in depressed patients. Serum GH concentration increased after GnRH in both normal and depressed men; serum TSH increased after GnRH in both normal women and bipolar women, but not in unipolar depressed women. Further studies comparing GnRH to saline infusion will be necessary to determine if the GH and TSH responses seen in this study are due to GnRH or result from the stress of the experimental procedures.     

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.     

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.     

Growth hormone responses to intravenous clonidine challenge correlate with behavioral irritability in psychiatric patients and healthy volunteers.

To explore the relationship between central noradrenergic receptor responsivity and indices of impulsive aggression, growth hormone responses to infusions with the alpha 2-adrenergic receptor agonist clonidine (GH[CLON]) and responses on the Buss-Durkee Hostility Inventory (BDHI) were examined in healthy male volunteers and male patients with major affective or personality disorder. GH[CLON] values were found to correlate significantly with the BDHI "Irritability" subscale in all subjects, but especially in healthy volunteer and personality disorder patients. GH[CLON] values did not correlate with the BDHI "Assault" subscale. These results suggest a role for central alpha 2-adrenergic receptor responsivity in the personality trait characterized by behavioral irritability, but not overt assaultiveness, in humans.     

Growth hormone response to clonidine in untreated depressed patients

Growth hormone (GH) responses to i.v. clonidine administration (150 micrograms) were compared in untreated depressed patients and controls. There were 8 controls (6 males, 2 females), 16 patients with a major depressive episode (8 males, 8 females), and 16 matched patients with a minor depressive episode according to Research Diagnostic Criteria. Differences in the GH response to clonidine only occurred between male patients and controls. These results suggest that endocrinological variables are important in the interpretation of this neuroendocrine test. Findings in the subgroup of unmedicated male patients with a nonendogenous major depressive episode support the hypothesis of decreased noradrenergic receptor sensitivity.     

The effects of clonidine on cardiovascular responses to standing in healthy volunteers

This study assessed the effects of clonidine on blood pressure (BP) and heart rate responses to active standing, recorded continuously using a Finapres monitor. Ten subjects were given a placebo infusion over 1 h, followed by clonidine hydrochloride 1.5 µg/kg over 2 h. During placebo and at 1, 3 and 19 h following the clonidine infusion, heart rate and blood pressure were recorded during the second half of supine rest for 10 min, active standing and quiet standing for 7 min. Clonidine did not alter the size of immediate drop in BP on standing, although the nadir was lower. BP recovery was impaired, with a loss of the usual BP overshoot in most subjects and with delays in reaching supine levels of diastolic BP (6.1 versus 9.6 s; p < 0.01) and systolic BP (8.1 versus 12.3 s; p < 0.05). The compensatory initial heart rate rise was significantly increased from 47 to 53 beats/min (p < 0.05), athough the peak rate reached was reduced from 114 to 104 beats/min (p < 0.05). These results demonstrate that impairment of central sympathetic vasomotor drive leads to a delay in BP recovery and loss of initial BP overshoot immediately after standing, together with impaired maintenance of early steady-state BP.     

Noradrenergic responses to clonidine in acute and remitted depressed male patients.

To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.     

Growth hormone, noradrenaline, blood pressure and cortisol responses to clonidine in healthy male volunteers: dose-response relations and reproducibility

The growth hormone (GH) response to clonidine (CLON) has been investigated to date mostly with CLON doses of 2.0 micrograms/kg or 150 micrograms intravenously (IV). The present study investigated GH and blood pressure (BP) responses to CLON (2.0 and 1.5 micrograms/kg IV) (Study I). Twelve healthy male volunteers were tested with the two CLON doses and saline in a cross-randomized design. Plasma GH, noradrenaline (NA) and cortisol concentrations, BP and sedation were determined. CLON (1.5 and 2.0 micrograms/kg) induced a significant dose-dependent GH increase, but only the 2.0 micrograms/kg dose differentiated GH responders from nonresponders. In contrast to GH, NA, cortisol, and BP did not differ significantly after either CLON dose. We also studied GH responses to repeated CLON stimulation (Study II). Ten healthy male volunteers were given four CLON tests (2.0 micrograms/kg) at three-week intervals. The nine volunteers who participated in both studies were investigated over a time course up to 21 months. The subjects could be classified into those who showed consistent GH responses greater than 5 ng/ml, those who showed consistent GH responses less than 5 ng/ml, and those who showed both degrees of responses.     

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.     

Panic-related responses to pentagastrin,flumazenil, and thyrotropin-releasing hormone in healthy volunteers

Thyrotropin-releasing hormone ( TRH) induces some somatic symptoms that resemble those of a panic attack, without being considered to be a laboratory panicogen in panic disorder (PD) patients. This study aimed to identify doses of TRH and the laboratory panicogens, pentagastrin and flumazenil, that would produce a similar intensity of panic-related somatic symptoms in healthy volunteers because comparison of the effects of these doses in PD patients could be used to test the hypothesis that these agents have specific panicogenic effects that are not explained solely by cognitively mediated reactions to somatic symptoms. Nine subjects were administered pentagastrin (0.2 micro g/kg) and TRH (600 or 1,200 micro g) in a double-blind, randomized order, within-subjects design. Fifteen subjects received pentagastrin (0.1 micro g/kg), TRH (600 or 1200 micro g) and flumazenil (2 mg) in a double-blind, randomized order within-subjects design. Although low dose pentagastrin (0.1 micro g/kg) induced comparable cardiorespiratory responses to those of TRH, it induced greater anxiety, suggesting that TRH would not be a credible comparator for pentagastrin in challenge studies in PD. However, TRH produced equal or greater symptom and physiological responses compared with flumazenil, suggesting that flumazenil may act as a panicogen in PD via a GABAergic mechanism rather than via a cognitively mediated response to somatic symptoms. This now requires confirmation in PD patients.     

Effect of sulpiride on plasma prolactin in healthy volunteers and depressed patients

Plasma prolactin (PRL) levels were measured before and 1, 2 and 4 h after oral administration of sulpiride (SPR) (2 mg/kg) in 91 healthy individuals (56 males and 35 females) and 36 patients with mental depression (15 males and 21 females). The identical measurements were conducted during remission in 16 available patients (9 males and 7 females) for comparison of the values during the depression and remission. During remission, the PRL values (lower in males and higher in females than the normal values), were closer to those of healthy subjects than they were during depression.     

HPA-Axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors.

2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed.

3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist.

4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), B endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values.

5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.     

Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects

Several recent investigations have raised the possibility that the sensitivity of alpha 2-adrenergic receptor may be of etiologic importance in depression. To assess whether abnormalities in presynaptic alpha 2-adrenergic receptor exist in depressed patients not taking drugs, the effects of an alpha 2 agonist, clonidine, on plasma 3-methoxy-4-hydroxyphenelethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in 15 depressed patients and 12 healthy controls of similar age. The ability of clonidine to increase growth hormone (GH) secretion was also assessed. The effect of clonidine on plasma MHPG and BP was not different between the depressed patients and controls. However, the GH response to clonidine was blunted in the depressed patients. These results suggest that in depression (1) the sensitivity of the presynaptic alpha 2-adrenergic receptor is not abnormal, and (2) the sensitivity of postsynaptic adrenergic receptors may be decreased.     

From early to late adulthood. Changes in EEG sleep of depressed patients and healthy volunteers

In order to evaluate the impact of aging on EEG sleep patterns we investigated the polysomnograms of 74 patients with major depression and 51 healthy volunteers aged 18-65 years. In most of the EEG sleep parameters, age-related changes were obvious in both the depressives and the normals. In the patients, some of these alterations occurred earlier and were more pronounced. The amount of slow-wave sleep decreased with age, but no differences were found between the depressives and the healthy volunteers at any particular age. Rapid-eye-movement (REM) latency was clearly affected by age, but there were no significant differences between patients and controls until the middle of the fourth decade of life. On the other hand, REM density measures did not vary with age and were increased in the depressives. Therefore, REM density appears to be a more likely candidate for a biologic marker for major depression than is REM latency.     

Prolactin response to thyrotropin-releasing hormone in schizoaffective depressed compared to depressed and schizophrenic men and healthy controls

Biological tests may help clarify the relationship of schizoaffective disorder to major depressive disorder (MDD) and schizophrenia (SCZ). Thyrotropin-releasing hormone (TRH), 500 micrograms, was administered intravenously to eight schizoaffective depressed (SD), ten SCZ, 23 MDD patients and 43 healthy controls (HC), all males, ages 20-66 years and drug-free. Research Diagnostic Criteria (RDC) were utilized for establishing diagnoses, Hamilton Rating Scale for Depression (HRSD) total scores were used for assessing depressive symptoms. There were no differences in dmax PRL (post-TRH prolactin peak minus baseline, mean +/- SD) amongst SD, SCZ and HC groups (27.3 +/- 5.2, 28.8 +/- 5.4 and 31.5 +/- 5.6 ng/ml respectively). Mean dmax PRL in MDD was significantly lower than each of the other three groups (17.1 +/- 2.2 ng/ml, P less than 0.05 for all). The essentially normal PRL response to TRH in SD, significantly different from MDD but similar to SCZ parallels our previous observations on the pattern of thyrotropin (TSH) response to TRH in the same diagnostic groups. These biological findings may be taken to indicate that schizoaffective disorder, depressed subtype, is closer to schizophrenia than to major depressive disorder. However, they cannot be considered definitive evidence to that effect since schizoaffective disorders are known to be quite heterogeneous, and since the utilized biological tests lack specificity.     

Cortisol, 11-deoxycortisol, and ACTH concentrations after dexamethasone in depressed patients and healthy volunteers

The 1 mg dexamethasone suppression test was used to assess pituitary-adrenal activity in 23 depressed patients and 8 healthy volunteers. At 1600h, after administration of the test dose of dexamethasone at 2300h, levels of cortisol, 11-deoxycortisol, and corticotropin were determined following a chromatographic extraction step applying highly specific radioimmunoassay techniques. Cortisol nonsuppressors had significantly increased adrenocorticotropic hormone (ACTH) values and cortisol/11-deoxycortisol ratios. The cortisol/11-deoxycortisol ratio was regarded as a measure of biologically active ACTH. The present results, which indicate a concordance of corticotropin and corticosteroid response, suggest that the parent abnormality of dexamethasone-resistant cortisol concentrations is elevation of biologically active corticotropin.     

Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients

The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirone's effects on cortisol may occur after chronic gepirone administration.     

Hormonal responses to zimelidine and desipramine in depressed patients

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.