Sex differences in response to psychopharmacological interventions in humans.
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Biomedical subjects
Publications and source records attributed to R S Nathan.
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Twelve healthy chronic schizophrenic patients were treated with the long-acting oral dopamine (DA) receptor blocker penfluridol (100 mg orally) for 6 weeks. Plasma prolactin (PRL) levels were measured during insulin-tolerance tests (ITT) performed at the end of the drug-free period (7-10 days) and during weeks 1 and 6 of penfluridol treatment. Simultaneous PRL and penfluridol plasma levels were determined just prior to, and at 8, 72 and 120 h after penfluridol administration during weeks 1, 5, and 6. During penfluridol treatment women (N = 4) had a greater increase in their maximal PRL increments after ITT as compared to the men (N = 8). Analyses of (peak) plasma penfluridol and PRL concentrations 8 h after penfluridol administration revealed a trend towards lower plasma penfluridol levels during weeks 5 and 6 and significantly higher PRL levels in women compared to men during weeks 1 (P less than 0.01), 5 (P less than 0.02), and 6 (P less than 0.02). The consistent sex-related differences in the PRL responses to DA blockade, and to insulin-induced hypoglycemia and in the penfluridol plasma levels in our study support the view that sex-related changes need to be considered not only in the hormonal responses to various pharmacological agents, but also in the assessment of the plasma levels of these drugs.
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The authors studied the relationship of plasma cortisol secretion and REM period latency in 25 patients with endogenous depression. The 8 patients (32%) with cortisol hypersecretion had a significantly shortened REM period latency in comparison with the 17 with normal cortisol secretion. Furthermore, an extremely short REM latency (20 minutes or less) occurred almost exclusively in those with cortisol hypersecretion. The authors discuss possible neurotransmitter disturbances responsible for these abnormalities and the clinical implications of these findings.
The human growth hormone (HGH) response to dextroamphetamine sulfate (doses, 0.1 and 0.15 mg/kg) was determined in both the morning and evening in patients with endogenous and atypical depression and in normal young men and normal postmenopausal women. Although the HGH response was found to be reduced in endogenously depressed postmenopausal women, it was equally reduced in normal postmenopausal women and in patients with atypical depression. Depressed and normal men had larger HGH responses, but there were no differences between depressed and normal men. These results do not confirm an earlier report that the reduced HGH response to dextroamphetamine is specific to endogenous depression. The results do suggest the importance to control for other variables in studies of HGH responses in psychiatric patients.
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Bolus injections of synthetic thyrotropin-releasing hormone (TRH) were administered to five young normal men in the morning (0900 hr) and the evening (1800 hr) on different days. Frequent blood samples for prolactin (PRL) and TSH analyses were collected before and after TRH infusion. Although there were no differences between the morning and the evening basal PRL levels, a significantly greater PRL response to TRH in the evening was observed (delta PRL, a.m. vs p.m., p less than 0.025). Since TRH stimulates PRL through a direct effect on the pituitary, our data suggest that there is a diurnal variation in the pituitary lactotroph responsiveness to TRH. On the other hand, a.m. and p.m. basal and TRH-stimulated TSH responses were virtually identical.
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Dextroamphetamine hydrochloride was administered intravenously (IV) in the morning and evening to 22 unmedicated patients with severe endogenous depressions and 18 normal control subjects. While the normal subjects generally had a sharp increase in plasma cortisol level by 30 minutes after drug administration, two thirds of the depressed patients showed instead a paradoxical suppression of cortisol levels by 60 minutes. Discrimination between normal subjects and depressives was greatest in the evening. These results are consistent with other reports of abnormal cortisol responses in depressed patients to smaller IV doses of dextroamphetamine and larger doses of methamphetamine hydrochloride. A defect in activation or noradrenergic alpha receptors may account, in part, for the abnormal cortisol responses. The dextroamphetamine cortisol test in other patient populations requires study before its diagnostic use in endogenous depression can be established.
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 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.
The prolactin (PRL) response to 0.5 mg i.m. of reserpine was compared to 0.5 mg i.m. of haloperidol in eight young men. The fact that reserpine was found to be a potent releaser of PRL--significantly greater than haloperidol--suggests a major role of storage pool dopamine in regulating PRL Secretion. Since the PRL response to neuroleptics is highly correlated with clinical potency, reserpine could be a potent antipsychotic, and further clinical trials are indicated.
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Twenty-five unmedicated hospitalized patients, ages 26-64, with severe major depressive disorders, endogenous subtype, were evaluated both clinically and endocrinologically. Although measures reflecting cortisol secretion did not correlate with symptom dimensions and diagnostic subtypes, we did find a significant relationship between cortisol secretion and age during endogenous depressive illness; this included the mean 24 hour plasma cortisol, assessed by sampling every 30 minutes for 24 hours, as well as other single plasma cortisol assessments on other days. After clinical recovery, when plasma cortisol levels returned to normal, there was no significant relationship between cortisol secretion and age. Replication is required of this apparent interaction among age, depressive illness, and cortisol secretion. The result may relate to the proposed role of brain noradrenalin in tonically inhibiting cortisol secretion, the decline of hypothalamic noradrenalin with age, and the hypothesized deficit in depressive illness.