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Introduction: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses., Methods: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography., Results: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations., Conclusion: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.

Background: Elevated glucocorticoids may increase the vulnerability of the brain to the adverse effects of repeated seizures. This study tested the hypothesis that higher ambient cortisol levels would predict increased cognitive impairment in depressed patients subsequent to receiving electroconvulsive therapy (ECT) for major depression., Methods: Sixteen subjects provided three samples of saliva the day before receiving unilateral nondominant ECT. Measures of mood, global cognitive functioning, attention, executive function, verbal and visuospatial memory, and visuospatial processing speed were obtained 1 day before the first ECT and 1 day after the sixth ECT treatment. The relationship between basal salivary cortisol obtained before the first ECT treatment and the change score of each cognitive measure after the sixth ECT treatment was examined and tested with Pearson correlation coefficients., Results: Electroconvulsive therapy treatments delivered over 2 weeks resulted in a significant improvement in mood and a decline in most measures of cognitive performance. Elevated basal cortisol was associated with a greater decline in performance of executive function, visuospatial processing speed, and verbal memory., Conclusions: Although this study is limited by the small number of subjects and the high number of comparisons, all significant correlations were consistent with the hypothesis that elevated cortisol predicts a greater degree of ECT-induced cognitive impairment.

Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology.

Objective: The theoretical and empirical rationales for the potential therapeutic use of antiglucocorticoid agents in the treatment of depression are reviewed., Method: Individual case reports, case series, open-label, and double-blind, controlled trials of the usage of cortisol-lowering treatments in Cushing's syndrome and major depression are evaluated and critiqued., Results: In each of the 28 reports of antiglucocorticoid treatment of Cushing's syndrome, antidepressant effects were noted in some patients; the largest two series document a response rate of 70% to 73%. Full response, however, was at times erratic and delayed. Across the 11 studies of antiglucocorticoid treatment of major depression, some degree of antidepressant response was noted in 67% to 77% of patients. Antidepressant or antiobsessional effects of antiglucocorticoid augmentation of other psychotropic medications have also been noted in small studies of patients with treatment-resistant depression, obsessive-compulsive disorder, and schizoaffective disorder or schizophrenia., Conclusions: These promising results with antiglucocorticoid treatment must be interpreted cautiously because of the small sample sizes and heterogeneity of the studies reviewed, the bias favoring publication of positive results, and the open-label nature of most of the studies. Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions.

Background: Glucocorticoids have been linked to self-administration of a wide range of drugs in animals and are increased endogenously by chronic nicotine intake. Corticosteroids have also been shown to regulate nicotine receptor sensitivity and to be involved in behavioral sensitization to nicotine., Methods: Cortisol levels and cortisol suppression in response to dexamethasone were measured in a sample of smokers participating in a smoking cessation treatment trial., Results: Cortisol levels dropped significantly during the early quitting process (2 weeks post-quit) and returned to a level below baseline 1 month post-quit. The magnitude of the initial drop in cortisol was strongly related to post-quit distress and marginally predictive of abstinence. Neither baseline nor post-quit changes in percent cortisol suppression after dexamethasone were related to abstinence success or withdrawal distress., Conclusions: Withdrawal from cigarette smoking is marked by a reduction in cortisol levels that appears to be related to the degree of distress experienced during the early quitting period. Further work is needed to determine whether withdrawal-related cortisol changes or distress are predictive of abstinence success.

Ketoconazole, an antiglucocorticoid drug, was administered to 10 hypercortisolemic depressed patients for up to 6 weeks. Three patients dropped out because of side effects or intercurrent illness. The remaining seven had significant ketoconazole-associated decreases in serum cortisol levels and in depression ratings. Antiglucocorticoid agents may be useful probes for investigating the sequelae of hypercortisolemia in patients with major depression.

Major depressive illness is frequently associated with cortisol hypersecretion. The pathophysiologic significance of this is unknown, although it is possible that hypercortisolemia exacerbates or perpetuates depressive symptoms. In both depression and Cushing's syndrome, certain depressive symptoms are correlated with cortisol levels and, in the latter condition, therapeutic lowering of cortisol levels is associated with remission of psychiatric symptomatology. We review the behavioral effects of anticortisolemic drug administration in Cushing's syndrome and major depression. Preliminary data from small-scale studies suggest that ratings of depressive symptoms in hypercortisolemic major depression may be lowered by such interventions. Such results, if confirmed in larger scale, double-blind studies, might help clarify the role of endocrinologic disturbance in psychiatric symptomatology and might lead to the development of a novel class of antidepressant agent for hypercortisolemic depressed patients.

Severely depressed patients frequently show inadequate suppression of serum cortisol levels by dexamethasone. In a study of 15 depressed patients, we found a robust correlation between plasma levels of cortisol and 3-methoxy-4-hydroxy-phenylglycol after dexamethasone administration. These results suggest that dexamethasone resistance and adrenergic activation reflect parallel responses to illness-related stress in some depressed patients.

Disturbances of hypothalamic-pituitary-adrenal regulation are frequently observed in a subgroup of patients suffering from major depression. The mechanism of hypothesized pituitary and hypothalamic involvement in this dysregulation remains relatively uncharacterized. In this paper we investigated the response of adrenocorticotropin (ACTH), as well as cortisol, to dexamethasone inhibition and characterized the dynamic response of ACTH to a one-hour infusion of cortisol in normal subjects and patients suffering from depression. A paradoxical increase in ACTH in response to cortisol is noted in one patient.

The relationship between hypothalamic-pituitary-adrenal (HPA) dysregulation and skin conductance measures of habituation, stimulus specificity, and dishabituation was investigated in psychiatric patients exhibiting depressed affect. As a group, depressed patients showed a relative failure to dishabituate when compared with control subjects. Nonsuppression of cortisol following dexamethasone was associated with decreased response specificity as reflected in direct response measures and baseline skin conductance level. The impairment of response specificity to a novel stimulus is consistent with previous studies demonstrating a role for cortisol in the regulation of selective attention processes.

Evidence exists to suggest that there are neurochemical responses common to the development of tolerance to and dependence on a variety of psychoactive drugs. Experimental data indicates that pituitary peptides such as corticotropin and vasopressin, in addition to the endorphins, influence the development of physical dependence on either morphine or ethanol. If these findings are supported by further investigations with human subjects, various manipulations of pituitary-adrenal function, such as the administration of corticotropin and vasopressin analogs or drugs such as dexamethasone, may prove to be of clinical utility.

Although some psychiatric patients may have a disorder of hypothalamic-pituitary-adrenal (HPA) function equal in character and severity to that noted in milder cases of Cushing's disease, it is generally accepted that such patients do not show Cushingoid stigmata. This conclusion, however, appears to be based more on clinical observation than on the results of formal scientific investigation. Since some depressed patients appear to overlap with Cushing's disease patients in incidence of such signs and symptoms as amenorrhea, hypertension, sleep disturbance, and insulin resistance, we were interested in examining whether a group of psychiatric patients showing evidence of marked nonsuppression might not also show physiological changes consonant with the effect of glucocorticoid excess. Nonsuppressors selected on this basis differed slightly from a matched suppressor control group on percentage of polyneutrophils and lymphocytes in blood. A discriminant function constructed from blood sample measurements of 12 factors and systolic/diastolic blood pressure successfully predicted suppressor or nonsuppressor status in the original and in an independent group of psychiatric patients. A comparison group of Cushing's disease patients was also successfully reclassified on the basis of the discriminant function. These data are interpreted as evidence for a subtle physiological effect of HPA dysregulation and suggest that behavioral symptom complexes may be similarly shaped by changes in this neuroendocrine system. The long-term functional significance of such changes is at present speculative.

The dexamethasone suppression test (DST) has proven to be of clinical utility in the diagnosticc assessment of patients with primary endogenous depressive illness. Studies comparing individuals who show suppression of plasma cortisol after dexamethasone with those showing nonsuppression have thus far been unable to elicit clinical variables that might differentiate the two groups. Some investigators have suggested as an alternative strategy the usage of the biological variable of interest as the independent rather than the dependent variable. In this study we compared the objective and subjective characteristics of 118 psychiatric inpatients who underwent the DST and were divided on the basis of their response into suppressor and nonsuppressor categories. In the first analysis the diagnostic classification of the patient was not considered. In a secondary analysis the clinical characteristics of only those patients with primary endogenous depression are examined. The data show that independent of diagnosis nonsuppressors are noted to have a greater incidence of subjective complaints. These differences between groups are no longer evident on discharge illustrating a significantly better prognosis for the nonsuppression group.