R. Swami Nathan

Effect of age and sex on cortisol secretion in depressives and normals

The mean 24-hour plasma level of cortisol with plasma sampling every 20-30 minutes was determined in 32 normal women aged 12-73, 40 normal men aged 10-55, 21 depressed women aged 20-61, and 11 depressed men aged 22-66. The mean levels of cortisol were higher in the group of depressives compared with the controls. Cortisol levels showed a significant linear correlation with age in normal women but not in normal men. Both depressed women and men had a significant linear increase of cortisol levels with age. The finding that age substantially contributes to increased levels of cortisol calls for cautious interpretation of any data concerning that hormone when the variable of age is not adequately controlled. Furthermore, aging and depression may have some underlying mechanisms whose elucidation may contribute to the understanding of the pathophysiology of vulnerability to affective disorders.

Amitriptyline versus haloperidol in borderlines: final outcomes and predictors of response

The authors report the final results of a 4-year study of amitriptyline and haloperidol in 90 symptomatic borderline inpatients. Medication trials were double-blind and placebo controlled and lasted 5 weeks. Haloperidol (4-16 mg/day) produced significant improvement over placebo in global functioning, depression, hostility, schizotypal symptoms, and impulsive behavior. Significant effects of amitriptyline (100-175 mg/day) were generally limited to measures of depression. Factor analysis identified three symptom change patterns: a global depression, hostile depression, and schizotypal symptom pattern. Medication effects favoring haloperidol were most prominent for hostile depression. Variables predicting favorable response to haloperidol included severity of schizotypal symptoms, hostility, and suspiciousness. Schizotypal symptoms and paranoia predicted poor outcome on both depression patterns with amitriptyline. Placebo effects were most prominent on acute state symptoms, with severe character traits predicting poor response.

Clomipramine and EEG sleep in depression

Recent studies with clomipramine (CMI) have demonstrated that a pulse-loading approach is associated with a rapid improvement in symptomatology in the absence of continuous treatment. In the present study, sleep changes were evaluated to ascertain the rapidity of clomipramines effect on electroencephalographic sleep, especially rapid eye movement (REM) and delta wave sleep measures. Clomipramine produced rapid changes in sleep with reduced sleep continuity and almost complete suppression of REM sleep as well as a redistribution of slow wave sleep. Delta waves during sleep were also found to be shifted to the earlier part of the night and increased in intensity. Spectral analysis revealed an increase in power in the delta frequency range that was correlated with clinical responsiveness. These studies point toward a role for clomipramine in the rapid treatment of depression and confirm that sleep physiology may be a good predictor of antidepressant action.

Relative insulin insensitivity and cortisol secretion in depressed patients

Relative insulin insensitivity occurs in a substantial portion of patients with major endogenous depressions, and about half such cases also hypersecrete cortisol in the afternoon and evening. This study assessed the relation between these two abnormalities in 16 patients with major endogenous depression. Over several days, insulin tolerance tests (ITTs) were performed in the morning and evening, and measures of cortisol secretion taken: plasma cortisol at 0800, 1600, and 2300 hours, both before and after dexamethasone; baseline cortisol before ITTs; and mean 24-hour plasma cortisol concentrations (in 10 cases). After clinical recovery, some of these patients had repeat ITTs (n = 10) and repeat predexamethasone and postdexamethasone cortisol assessments (n = 9). Additionally two control groups of 15 normal subjects and of 12 schizophrenic patients received morning ITTs. None of the control subjects manifested insulin insensitivity. However, during illness, 8 of the 16 depressed patients manifested relative insulin insensitivity (glucose drop less than 50%, glucose nadir greater than 50 mg/dl); compared to the insulin responsive depressed group, the insensitive group had insignificantly greater afternoon and evening cortisol secretion by nearly all indices. After clinical recovery, hypoglycemic response for the entire group was significantly greater than during illness; this improvement was accounted for by the increased insulin responsivity of the previously insulin resistant subgroup. There was also substantial plasma cortisol reduction in the previously insulin resistant group after clinical recovery, but not in the insulin sensitive group.

The dexamethasone suppression test in depressive illness: clinical correlates.

Abstract Clinical correlates of endogenous depression which may be associated with dexamethasone resistance have been evaluated by many investigators and found to be inconclusive. The authors investigated in 40 endogenously depressed patients the relationship of the dexamethasone suppression test (DST) and various clinical correlates - SADS scales, Research Diagnostic Criteria (RDC) depressive subtypes, family history from the FHRDC, responsivity to antidepressant treatment, etc. Dexamethasone resistance was found to be significantly associated with psychotic and bipolar depression but unrelated to the other clinical correlates examined. These findings are limited to the 2 mg DST; clinical correlates associated with non-suppression to dexamethasone may be related to the dose of dexamethasone.

Endocrine responses to thyrotropin-releasing hormone in major depressive disorders

The endocrine response to thyrotropin-releasing hormone (TRH) was studied in severely endogenously depressed patients during illness (n = 21) and after recovery (n = 18). The thyroid-stimulating hormone (TSH) response to TRH was blunted (deltaTSH less than 5 microIU/ml) in over one third of depressives during illness and remained blunted in most even after recovery. There was no correlation between multiple measures of cortisol secretion (the mean 24-hour plasma cortisol, dexamethasone suppression test, and plasma cortisol during the TRH procedure) and the TSH response during illness and after recovery. The TSH and prolactin (PRL) responses to TRH, as well as the baseline PRL, were significantly lower during illness. The role of possible abnormalities in dopamine and/or serotonin in depression contributing to these endocrine disturbances is discussed.

DIURNAL CORTISOL RESPONSES TO DEXTROAMPHETAMINE IN NORMAL SUBJECTS

Abstract (1) Dextroamphetamine, in doses of 0.1 and 0.15 mg/kg, was administered intravenously morning and evening to normal young men and postmenopausal women, and plasma cortisol responses were assessed. (2) There were no differences in cortisol responses between the young men and older women at either dose. (3) The higher dose elicited a significant and reliable acute cortisol release, while the lower dose did not. (4) In the evening, 0.15 mg/kg amphetamine elicited a larger cortisol increase from baseline than the same dose in the morning. (5) Within morning or evening periods, baseline cortisol values were not significantly correlated with magnitude of cortisol responses, although trends for inverse correlations were observed. (6) It is suggested that these normal diurnal differences in the acute cortisol response to amphetamine may be related to a corresponding rhythm in the responsitivity to amphetamine of neuroendocrine neurotransmitters. (7) The previously reported abnormal cortisol response to amphetamine in a group of endogenous depressives probably is not primarily related to variables of age, sex or baseline cortisol level.

The prolactin response to intravenous dextroamphetamine in normal young men and postmenopausal women

Abstract D-amphetamine was administered intravenously in doses of 0.1 mg/kg and 0.15 mg/kg to normal young men and postmenopausal women in both morning and evening. No suppression of PRL secretion after amphetamine was found, and, in the postmenopausal women, no significant change in PRL levels in any dose or time condition occured. However, a significant and relatively consistent PRL release was induced in the young men in the evening by the higher dose. This latter response suggests that, in humans, dextroamphetamine can actually stimulate prolactin perhaps by a mechanism other than alteration in dopaminergic tone.

Dopaminergic factors in human prolactin regulation: A pituitary model for the study of a neuroendocrine system in man

This study in normal male subjects further investigates the effects of dopaminergic-antidopaminergic interactions as manifested by the prolactin response to dopamine and neuroleptic drugs. Incremental doses of dopamine hydrochloride (4 μg/min, 15 μg/min, 60 μg/min, 300 μg/min) were infused fused at a constant rate over 90–120 min after a fixed dose of a neuroleptic drug (sufficient for about half of the maximal prolactin response) had been given IV. A dose of dopamine in the order of 15–60 μg/min appeared to match the “los” of endogenous dopaminergic inhibition due to the antidopaminergic effect of the neuroleptic drug. The lactotrophic cells of the pituitary gland are suggested to serve as a model in man for the study of some basic neurohormonal mechanisms.

Prolactin responses to haloperidol in normal young women

The prolactin (PRL) responses to intramuscular haloperidol (HPD) (0.5, 1.0, and 1.5 mg) were evaluated in six normal premenopausal women during the follicular and luteal phases of their menstrual cycles. These were compared to the PRL responses to these doses of HPD in normal young men. PRL responses to HPD did not differ between the follicular and luteal phases. The mean log-transformed PRL response to the lowest HPD dose (0.5 mg) in women was less than that in the men, but the women had greater PRL responses than the men to the higher haloperidol doses (1.0 mg and 1.5 mg).