Dexamethasone fails to suppress beta-endorphin plasma concentrations in humans and rhesus monkeys.

In humans and rhesus monkeys, dexamethasone decreased concentrations of plasma cortisol but did not alter circulating beta-endorphin immunoreactivity. Contrary to current theory suggesting that pituitary beta-endorphin and adrenocorticotropic hormone are controlled by identical regulatory mechanisms for synthesis and release, our evidence suggests that in higher primates the established glucocorticoid feedback mechanism for the adrenocorticotropic hormone-cortisol system does not regulate beta-endorphin secretion in the same way.

Mood and behavioral effects of physostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol.

Administration of physostigmine to normal volunteers produced significant elevations in plasma cortisol and beta-endorphin immunoreactivity as well as alterations in mood, cognition, and behavior. These observations might be explained by a cholinergically mediated stress syndrome. However, peak elevations in plasma beta-endorphin immunoreactivity (but not in plasma cortisol) were significantly correlated with physostigmine-induced increases in depression ratings. These results suggest that a cholinergically mediated beta-endorphin pathway may be involved in the observed affective changes.

Central cholinergic stimulation causes adrenal epinephrine release.

Cholinergic drugs administered into the cerebral ventricles of animals selectively stimulate the adrenal medulla. However, the effects of central cholinergic stimulation on the sympathoadrenal system have not been studied in man. We stimulated central cholinergic activity in man by administering the cholinesterase inhibitor physostigmine to subjects pretreated with peripheral cholinergic blocking agents. A dose of 0.022 mg/kg physostigmine dramatically increased plasma epinephrine levels and slightly increased norepinephrine levels, which is consistent with selective adrenomedullary stimulation. A smaller dose of physostigmine increased epinephrine but did not alter norepinephrine levels. Subjects had increased pulse rates and blood pressures, and felt anxious while they had high plasma epinephrine levels.

The cholinergic rapid eye movement induction test with arecoline in depression.

The cholinergic rapid eye movement (REM) induction test using arecoline hydrobromide, a cholinergic muscarinic receptor agonist, was studied in patients with affective disorder and in normal controls to determine whether or not depression is associated with enhanced induction of REM sleep by muscarinic agonists. Arecoline induced REM sleep in a dose-dependent fashion in both patients and controls compared with placebo infusions. Compared with normal controls, patients entered REM sleep significantly more rapidly following intravenous administration of 1.0 mg of arecoline hydrobromide than they did following administration of 0.5 mg of arecoline hydrobromide or placebo. These results, as well as those of previous studies, support the hypothesis that patients with affective disorder show a functional supersensitive induction of REM sleep in response to muscarinic receptor agonists and may be consistent with the hypothesis that functional muscarinic receptor "up regulation" is associated with depression.

Blunted prolactin response. A neuroendocrine abnormality manifested by depressed patients.

Prolactin concentrations of 30 unmedicated psychiatric inpatients and 11 normal controls were measured at baseline and at 30 and 60 minutes after the administration of 10 mg of intramuscular methadone hydrochloride. Methadone raised the prolactin level at 60 minutes to more than twice the mean baseline level for the full subject sample. Patients with depressive disorders had lower mean basal prolactin levels than did the other subjects, and also manifested attenuated prolactin responses to methadone. Eight of 16 depressives had markedly blunted prolactin responses, a finding consistent with other studies reporting deficient responses in depression. These data are consistent with the hypothesis that the pathophysiology of depressive disorders involves dysfunctions in the anterior pituitary itself or in the hypothalamic neurotransmitter and neuromodulator systems (eg, endorphins) that regulate the secretion of prolactin and other neurohormones.

Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.

We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.

Central cardiovascular effects of physostigmine in humans.

Central cholinergic control of pulse rate and blood pressure has seldom been studied in humans. In the current study we contrasted the cardiovascular effects of the centrally acting cholinesterase inhibitor physostigmine, which increases central and peripheral acetylcholine levels, with those of saline placebo and with those of the non-centrally acting cholinesterase inhibitor neostigmine, which only increases peripheral acetylcholine levels. We found that physostigmine, in contrast to neostigmine and saline, caused significant and often profound increases in pulse rate and blood pressure levels in humans. Thus, we conclude that acetylcholine may have a role in central cardiovascular regulation in humans. We also found that administration of physostigmine may cause net increases in pulse of up to 74 beats/minute, systolic blood pressure increases of up to 50 mm Hg, and diastolic increases of up to 45 mm Hg. Such increases could be dangerous in elderly patients with concomitant cerebrovascular or coronary circulation disorders.

Diurnal variation in cerebrospinal fluid prolactin concentration of the rhesus monkey.

PRL immunoreactivity in the cerebrospinal fluid (CSF) of the rhesus monkey was found found to undergo a diurnal variation. Hourly samples of CSF from four adult male rhesus monkeys showed a mean peak PRL immunoreactivity of 6.30 +/- 2.53 ng/ml at 0200 h and a mean minimum concentration at 1500 h of 3.15 +/- .68 ng/ml. To our knowledge, this is the first report of a significant diurnal variation in the concentration of an anterior pituitary peptide hormone in CSF.

beta-Endorphin hypersecretion in depression: possible cholinergic mechanisms.

Morning plasma concentrations of beta-endorphin immunoreactivity were significantly higher in a group of depressed patients meeting the Research Diagnostic Criteria for Major Depressive disorder or Schizo-affective disorder, depressed, than in age- and sex-matched groups of normal controls and psychiatric patients without affective disorders. Furthermore, physostigmine-stimulated release of beta-endorphin immunoreactivity was also significantly greater in the depressed patients. These results provide the first evidence for elevated plasma concentrations of beta-endorphin in depression and also represent further evidence for cholinergic supersensitivity in depression. These results suggest that elevated plasma concentrations of beta-endorphin and cholinergically stimulated hypothalamic-pituitary beta-endorphin release, might potentially represent biological state or trait markers for depression.

Neuroendocrine effects of ovine corticotropin-releasing hormone in panic disorder patients.

A number of neuroendocrine abnormalities have been reported in panic disorder patients: the most extensively studied being disturbances of hypothalamic-pituitary-adrenal function (Curtis et al. 1982; Leiberman et al. 1983; Uhde et al. 1988). The recent sequencing and synthesis of corticotropin-releasing hormone now allows direct testing of pituitary responsivity to this neuropeptide in affective and panic disorder patients (Holsboer et al. 1984; Gold et al. 1986; Roy-Byrne et al. 1986; Holsboer et al. 1987; Risch et al. 1988). We report the effects of intravenously administered ovine corticotropin-releasing hormone (0.03 micrograms/kg) on plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol in a small group of panic disorder patients and age- and sex-matched normal controls.

Plasma cortisol and natural killer cell activity during bereavement.

Natural killer cell (NK) activity, which is important in the defense against tumors and viral infections, is reduced in women undergoing conjugal bereavement. The relationship between NK activity and plasma cortisol was investigated in three groups of subjects: women who were anticipating the death of their husbands, women whose husbands had recently died, and controls. Bereaved women showed reduced NK activity and increased plasma cortisol levels as compared to controls. Anticipatory bereaved women also showed significant reductions in NK activity, but had levels of plasma cortisol comparable to those of controls. The reduction of NK activity during anticipatory and actual bereavement cannot be explained solely on the basis of increased cortisol secretion.

The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group.

In order to determine the effect of an anticholinergic agent on mood and sleep, scopolamine (0.4 mg IM) was administered before bedtime for three consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison subjects. The patients had a small, statistically significant antidepressant response on the second morning of treatment. Scopolamine inhibited rapid eye movement (REM) sleep and prolonged REM latency equally in depressed patients and the normal comparison group. Partial tolerance to the REM inhibiting effect of scopolamine developed between the first and third night of treatment. A REM rebound occurred during recovery nights. These results are consistent with concepts relating central cholinergic mechanisms to the control of REM sleep. Compared with controls, patients showed a greater increase in Stage 2 and Stage 2% and a lesser and increase in Delta (Stage 3 and 4) sleep % and Stage 4% on the first night of treatment. Further, well-controlled studies are needed to determine whether anticholinergic drugs possess clinically significant antidepressant effects.

The effects of physostigmine infusion on patients with panic disorder.

Nine patients who met both DSM-III and RDC criteria for panic disorder and nine age-matched normal controls received infusions of physostigmine. The patients and normal controls did not differ in either their self-reported or the observer-reported ratings of anxiety, mood, or activation. The two subject groups also did not differ in blood pressure, pulse, or cortisol responses to physostigmine. Physostigmine did not provoke panic attacks in either the control or patients groups.

Neuroendocrine responses in psychiatric and pain patients with major depression.

Basal and postdexamethasone concentrations of cortisol and prolactin were studied in three groups of male patients: chronic pain patients with no psychiatric diagnosis (n = 12), chronic pain patients with coexisting major depression by Research Diagnostic Criteria (RDC) (n = 24), and pain-free psychiatric patients meeting RDC criteria for major depression (n = 28). Basal cortisol concentrations were significantly higher in pain-major depression and psychiatric-major depression patients compared to pain patients without psychiatric illness. The frequency of cortisol nonsuppression after dexamethasone was significantly greater in pain patients with major depression (41.7%) compared to pain patients without psychiatric disorder (8.3%), and was comparable to that of psychiatric patients (21.4%). Prolactin concentrations, but not cortisol levels, were significantly correlated with observer-rated severity of depression in pain patients. These findings suggest that cortisol and prolactin abnormalities in chronic pain may be related to psychiatric disorder rather than to pain per se, at least in male patients, and may indicate a role for cholinergic mechanisms in the interface of pain and depression.

Controlled trial of bright light for nonseasonal major depressive disorders.

Psychotropic drug-free hospitalized veterans with nonseasonal major depressive disorders or depressed forms of bipolar disorder were treated with light for 1 week. Twenty-five patients were randomly assigned to bright white light treatment (2000-3000 lux), and 26 patients were randomized to dim red light placebo control treatment. Unlike those treated with dim red light, those treated with bright white light showed declines in three measures of depression during treatment. Partial relapse appeared within 2 days. A global depression score showed a statistically significant (p = 0.02) difference favoring bright white light treatment. Two bright-light-treated patients became mildly hypomanic, but side effects were mild. Improvement was not correlated with patient expectations; indeed, patients expected somewhat greater benefit from the placebo. Patients treated in summer responded as well as those treated in winter. Baseline electroencephalogram (EEG) sleep stage data (e.g., rapid eye movement; REM latency) did not predict treatment responses. These 1-week treatment results suggest that bright light might produce benefits for patients with nonseasonal depression. Bright light should not be recommended for routine clinical application before additional assessments with longer treatment durations are done.

Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression.

To assess cellular immune status and the hypothalamic-pituitary (HP) axis in patients with major depression, we examined peripheral blood mononuclear cells (PBMC) and measured the plasma levels of cortisol, adrenocorticotropin hormone (ACTH), growth hormone (GH), and prolactin (PRL). Twenty patients with major depression were compared with 20 control subjects matched for age, sex, and race. The dose-response curves for concanavalin-A (Con-A) and phytohemagglutinin (PHA) stimulation were not significantly different between the two groups. The patients had decreased Con-A-stimulated T-lymphocyte proliferation when compared to the control subjects, but only at the lowest suboptimal concentration of Con-A. None of the four concentrations of PHA-stimulated proliferation were different between the two groups, neither was PHA-induced interleukin-2 production. Within the patient group only, plasma prolactin (PRL) correlated significantly with stimulated lymphocyte proliferation using two optimal concentrations of PHA and one optimal concentration of Con-A, when the proliferation was expressed using the stimulation index.

A controlled trial of daily left prefrontal cortex TMS for treating depression.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS: Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS: Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS: Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

Alcohol consumption, ACTH level, and family history of alcoholism.

Plasma levels of ACTH were evaluated in 18 sons of alcoholics and 18 sons of nonalcoholics before and after they consumed placebo, 0.75 ml/kg of ethanol, and 1.1 ml/kg of ethanol. The analyses revealed significant changes in ACTH levels over time, an effect of ethanol on ACTH overall, and significantly lower ACTH levels in the sons of alcoholics than in the control subjects following the high-dose ethanol challenge. The data corroborate the earlier finding that sons of alcoholics have less intense responses to ethanol and are consistent with the conclusion that changes in cortisol level associated with drinking include a pituitary response as well as effects on the adrenal glands.

Behavioral hyporeactivity to physostigmine in detoxified primary alcoholics.

Changes in anergia/inhibition, mood, and pulse rate induced by intravenous physostigmine were significantly less pronounced in 26 patients with primary alcoholism than in 36 normal control subjects. These results suggest possible abnormalities in central cholinergic functioning in primary alcoholics.

Association of beta-endorphin with specific clinical symptoms of depression.

OBJECTIVE: Abnormalities in plasma concentrations of beta-endorphin-like immunoreactivity (beta-endorphin) have been reported in depressed patients. This study was done to test the hypothesis that specific clinical characteristics of depression are associated with plasma beta-endorphin concentration. METHOD: Plasma beta-endorphin was evaluated in 20 depressed patients diagnosed according to DSM-III-R and in 23 age- and sex-matched comparison subjects, and each was evaluated with the structured Schedule for Affective Disorders and Schizophrenia (SADS). Twelve SADS items involving dysphoric mood and related symptoms were chosen for analysis. RESULTS: Within the group of all 43 subjects and within the depressed group, beta-endorphin level correlated significantly with psychic anxiety and with phobia. In the depressed group only, beta-endorphin also correlated significantly with obsessions/compulsions. Concentration of beta-endorphin was not significantly correlated with score on the Hamilton Rating Scale for Depression or Beck Depression Inventory or with scores on other SADS symptom items, including somatic anxiety, insomnia, subjective anger, overt anger, agitation, psychomotor retardation, panic attacks, appetite loss, or total weight loss. In the group of 23 comparison subjects, beta-endorphin did not correlate with Beck or Hamilton depression score or with any of the SADS clinical variables. CONCLUSIONS: High levels of plasma beta-endorphin may be associated with more severe anxiety, phobia, and obsessions/compulsions in depressed patients.