Imipramine effect on hypothalamic-pituitary-adrenal axis response to hypoglycemia.

Six control subjects underwent an insulin tolerance test before and after the administration of therapeutic doses of imipramine hydrochloride for 10 days to investigate effects of tricyclic antidepressants on hypothalamic-pituitary-adrenal axis response to hypoglycemia. The mean steady-state tricyclic blood level was 141 (SD = 66) ng/ml. Baseline levels of glucose, cortisol, and adrenocorticotropic hormone (ACTH) were not affected by the administration of imipramine. After administration of imipramine for 10 days, subjects uniformly had a significantly lower glucose nadir than before its administration (before imipramine: mean = 32 mg/dl; SD = 5; after imipramine: mean = 24 mg/dl; SD = 6). There was no difference in ACTH or cortisol response before and after the administration of imipramine. These findings suggest that imipramine hydrochloride increases sensitivity to the hypoglycemic effects of insulin, but does not alter the counterregulatory response of ACTH and cortisol.

Arecoline-associated changes in open-field behavior following swim stress in the rat. A possible relationship to water temperature.

The rat exhibits a reduction in movement in an open field following a 14-day course of forced swim stress at 12 degrees C. The decrease in movement is greater in rats receiving arecoline relative to those receiving saline prior to placement in the open field. The authors report that when water temperature is increased to 20 degrees, there is a categorical difference in the results. The saline control group exhibits a rise and the arecoline group no change in crossings.

Multiple steroid hormone levels in depressed patients and normal controls before and after exogenous ACTH.

Forty depressed patients and 36 age- and sex-matched controls were given 250 micrograms ACTH1-24 by IV bolus. Plasma steroid hormone levels were measured prior to and 60 min after ACTH administration. The depressed patients had significantly greater cortisol (F), 11-deoxycortisol (S), androstenedione (AD), and 17 alpha-hydroxyprogesterone (17 alpha-OHP) responses (delta; p less than 0.05) and a marginally greater 11 beta-hydroxyandrostenedione (11 beta-OHAD) response (delta; p = 0.091) than the controls. There was no significant difference in the corticosterone (B) response between the two groups. With the exception of 11 beta-OHAD, all the steroid hormones were significantly negatively correlated with age in the controls, but only S and AD marginally demonstrated this relationship in the depressed patients. F, S, AD, 17 alpha-OHP, and B, but not 11 beta-OHAD, were significantly positively correlated with each other in the controls, but only F was significantly correlated with AD in the depressed patients. These data suggest that the hypercortisolemia found in some depressed patients involves increased precursor and metabolite levels both at baseline and in response to exogenous ACTH, compared to controls. Furthermore, variability in these precursors is greater in depressed patients, and their relationship to age is lost. These findings are consistent with the hypothesis that adrenal products other than cortisol also could be related to affective symptoms.

Chronic swim stress enhances the motoric inhibiting effects of a muscarinic agonist.

The authors previously demonstrated that chronic inescapable swim stress and footshock increase the capacity of a fixed dose of a muscarinic agonist to produce hypothermia in the rat. This project was designed to determine whether chronic inescapable swim stress in cold water would render a low dose of a muscarinic agonist, devoid of an effect on motor behavior in the naive rat (i.e., prior to subjection to the course of swim stress), an inhibitor of mobility. The study involved two groups of rats, an experimental group which received arecoline and a control group which received saline five minutes prior to being placed in an open field. Number of crossings, the dependent variable, was measured in both groups before and after a 14-day course of twice daily inescapable swim stress of 10 minutes duration at 12 degrees C. The arecoline-treated group, as hypothesized, exhibited a significantly greater reduction in number of crossings than the saline-treated groups following the course of swim stress.

Winter depression responds to an open trial of tranylcypromine.

Seasonal affective disorder (SAD) is a disturbance of mood bearing a fixed relationship to season. Winter depression is characterized by the onset of a depressive syndrome in the fall or winter and spontaneous remission in the spring, this condition responds to full-spectrum, bright artificial light. In the first study assessing responsiveness of winter depression to a standard pharmacologic treatment for depression, the authors found that 14 patients meeting National Institute of Mental Health criteria for winter depression responded to treatment with tranylcypromine.

Simulated acute hemorrhage through lower body negative pressure as an activator of the hypothalamic-pituitary-adrenal axis.

While insulin induced hypoglycemia is the principle method of producing hypothalamic-pituitary-adrenal stress response, the mechanism by which this occurs may be different from that produced by other stressors. In a pilot study, we explored ways to standardize lower body negative pressure (LBNP), as a simulator of hemorrhage, to determine its utility for future studies of hypothalamic-pituitary-adrenal (HPA) axis function. Reduced atmospheric pressure of -40 mmHg applied at the level of the iliac crests during LBNP rapidly lowers blood pressure in most subjects, simulating acute hemorrhage. In 6 normal subjects, ACTH and cortisol values were measured before, during and after the application LBNP at 0800, 1600 and 2300 hours in the baseline state and at 1600 hours on the day following 1 mg of dexamethasone. Peak ACTH values of 60-250 pg/ml occurred 2 to 10 minutes after the cessation of the stimulus in subjects experiencing presyncope or having a systolic or diastolic blood pressure decrease of greater than 20 mmHg with a rise in pulse of 30 beats per minute or more. There was no significant difference between ACTH responses at different times of day. Peak cortisol values of 25-30 micrograms/dl occurred 15-20 minutes after cessation of the stimulus. In all subjects, administration of dexamethasone greatly attenuated the ACTH response and decreased but did not ablate the cortisol response. In conclusion, these data indicate that LBNP may be used to simulate hemorrhage as a stimulus of the HPA axis. HPA axis changes occur only when physiologic evidence of hypovolemic stress is present. Dexamethasone may be used to modulate the response to this stress paradigm.

The naturally occurring rhythm of blues: winter depression.

Winter depression, a form of seasonal affective disorder, is a common condition that increases in prevalence in northern areas and in regions with a high proportion of overcast fall and winter days. Parts of Ohio are high-risk areas given the high percentage of overcast days. Winter depression is marked by the onset of recurrent episodes of major depression each fall or winter which spontaneously remit in the spring. The depressive syndrome is often characterized by sadness, anxiety, decreased involvement in work and social activities, increased appetite, carbohydrate craving, weight gain, hypersomnia and psychomotor retardation. This syndrome often responds to treatment with two to six hours per day of full-spectrum bright artificial light. The efficacy of drugs in the treatment of this condition is now being studied at The Ohio State University. A monoamine oxidase inhibitor is effective.

Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression.

Eleven patients with major depression and 12 control subjects were administered corticotropin-releasing hormone (CRH), aqueous arginine vasopressin (AVP), and insulin hypoglycaemia (IH) to test for differences in hypothalamic-pituitary-adrenal (HPA) axis function. Patients with major depression demonstrated lower ACTH responses to CRH when compared with controls, and a trend toward such after administration of AVP. Despite lower ACTH responses in patients with depression, there were no differences in cortisol responses to these stimuli. In the CRH and AVP tests, there was no correlation between the basal cortisol and ACTH responses in either controls or patients, but in the IH test there was a negative correlation between these responses for both groups. The ACTH responses to CRH and AVP were positively correlated in controls and patients. Cortisol responses to all three provocative stimuli were positively correlated in both subject groups. These findings are consistent with the hypothesis that hypothalamic or supra-hypothalamic overactivity may be involved in the development of HPA-axis abnormalities in patients with depression.

Pathophysiology of HPA axis abnormalities in patients with major depression: an update.

Four hypotheses have been proposed to explain why nonsuppression on the dexamethasone suppression test occurs in patients with major depression. These include 1) increased metabolism of dexamethasone, 2) decreased sensitivity of pituitary glucocorticoid receptors to dexamethasone, 3) hyperresponsivity of the adrenal gland to ACTH stimulation, and 4) increased central drive of the pituitary from hypothalamic/limbic structures that overrides the action of the dexamethasone. A critical review of the literature suggests that the last hypothesis is most closely supported by the data. Despite this conclusion, factors other than depression may be involved in hypothalamic-pituitary-adrenal axis dysfunction.

HPA axis abnormalities in depressed patients with normal response to the DST.

In order to identify depressed patients with hypothalamic-pituitary-adrenal (HPA) axis abnormalities who have a normal response to the dexamethasone suppression test (DST), the authors administered a series of neuroendocrine tests including insulin-induced hypoglycemia, arginine vasopressin challenge, and a DST. Using standard sensitivity measures, as well as logistic regression, they concluded that many patients with HPA abnormalities are not identified by the DST. These findings suggest that other neuroendocrine tests, which are sensitive to HPA axis abnormalities, may be helpful in subtyping depression on the basis of HPA axis functioning.

Partial 11 beta-hydroxylase activity suppression after dexamethasone in patients with major depression.

Eleven beta-hydroxylase activity was assessed by measuring the cortisol to 11-deoxycortisol ratio in 20 control subjects, 38 patients with major depression, and five patients with Cushing's disease before and after 1 mg of dexamethasone. The mean levels of 11 beta-hydroxylase activity did not differ among groups before dexamethasone. After dexamethasone patients with Cushing's disease showed a nonsignificant increase in 11 beta-hydroxylase activity while patients with major depression and controls subjects both showed a decrease. Endogenous depressive patients were no more likely to show high 11 beta-hydroxylase activity than neurotic depressive patients; however, depressed patients with cortisol nonsuppression after dexamethasone were. Post-dexamethasone 11 beta-hydroxylase activity is positively correlated with age in both control subjects and patients with depression.

Stable adrenocorticotropin-stimulated 11-beta-hydroxylase activity but loss of age-related changes in patients with hypercortisolemia.

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushing's syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushing's patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.

Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH alpha 1-24) stimulation in major depression. Relationship to dexamethasone suppression test results.

ACTH alpha 1-24 (cosyntropin) (250 micrograms by intravenous bolus) was given to 38 medicated patients with major depressive disorder (MDD) and to 34 normal control subjects. Patients with MDD had significantly higher plasma cortisol concentrations and significantly higher increases in plasma cortisol levels 60 minutes after cosyntropin infusion than did control subjects. Patients who were nonsuppressors in the dexamethasone suppression test had significantly higher 60-minute cortisol concentrations and cortisol increases than did normal subjects and patients with MDD who were suppressors. There were significant, strongly positive correlations between cortisol secretory responses to cosyntropin and postdexamethasone cortisol concentrations in patients with MDD. These findings confirm that adrenal sensitivity to corticotropin (ACTH) is enhanced in MDD and suggest that this endocrine abnormality may be related pathophysiologically to the resistance of cortisol secretion to dexamethasone suppression.

The HPA axis response to insulin hypoglycemia in depression.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, demonstrated by failure to suppress cortisol secretion after dexamethasone, is found in approximately 50% of patients with major depression (MD). In this study, we examined the response of adrenocorticotrophic hormone (ACTH) and cortisol to insulin-induced hypoglycemia in 20 healthy controls and 18 inpatients with MD [12 dexamethasone suppressors (S) and 5 dexamethasone nonsuppressors (NS)]. After the administration of 0.15 U/kg of regular insulin, both controls and patients with MD showed an increase in plasma ACTH and cortisol levels. Controls had a significantly higher ACTH peak (p less than 0.01) and ACTH increment (p less than 0.01) than MD patients. There were no statistically significant differences between patients who were S and NS. Although baseline plasma cortisol levels were significantly higher in MD patients, there were no significant differences in the peak cortisol or increment in plasma cortisol after hypoglycemia between patients with MD and controls or between patients who were S and those who were NS. These findings suggest that a defect exists in the regulation of the HPA axis at the pituitary level in MD and that this defect is not necessarily reflected in the dexamethasone suppression status of the patient.

Stimulation of the pituitary-adrenal axis with arginine vasopressin in patients with depression.

The ACTH response to arginine vasopressin was the same in patients with depression while cortisol response was significantly greater in patients with depression when compared to the control population. These findings are consistent with the hypothesis that vasopressin corticotroph receptors are not downregulated in depression and that there is increased adrenal responsiveness in patients with depression to endogenous ACTH.

Covariation of depressive symptoms, parkinsonism, and post-dexamethasone plasma cortisol levels in a bipolar patient: simultaneous response to ECT and lithium carbonate.

A patient presented with concurrent mood congruent delusions, parkinsonism, and elevated post-dexamethasone plasma cortisol levels. This triad could result from simultaneous development of cholinergic-monoaminergic dysfunction within critical limbic and extrapyramidal loci. The magnitude of each abnormality decreased in concert during a course of electroconvulsive therapy (ECT). Remaining abnormalities disappeared during treatment with lithium. Actions of ECT and lithium on muscarinic systems are reviewed, and a strategy for testing the hypothesis that dysfunction of cholinergic-monoaminergic mechanisms develops in parallel in different neural networks is considered.

Major depression and carbon monoxide-induced parkinsonism: diagnosis, computerized axial tomography, and response to L-dopa.

A case of major depressive disorder complicated by carbon monoxide (CO)-induced Parkinson's syndrome is reported. Computerized axial tomography (CAT) revealed bilateral globus pallidus necrosis. Clinical, CAT, and neuropathological findings in other cases of CO encephalopathy with and without parkinsonism are reviewed. The utility of CAT in the diagnostic workup and in following clinical course is discussed, as are the difficulties of making a diagnosis of an antecedent primary psychiatric disorder in the presence of neurological and psychiatric sequelae of CO intoxication. There was no clinical response to a tricyclic antidepressant, but both the mood and movement disorders responded fully to L-dopa. The implications of these findings with regard to the central neurochemical pathophysiology in this patient and in major depressive disorder in general are discussed.