Diurnal variations in endocrine and psychological responses to 0.2 mg/kg naloxone administration in patients with major depressive disorder and matched controls.

BACKGROUND: There is evidence that the endogenous opioid system (EOS) is involved in the modulation of mood and neuroendocrine function. Furthermore, the possible involvement of the EOS in major depression has been postulated, although a clear role has not been established. METHODS: The affective and endocrine responses to naloxone administration in seven female depressives and in seven matched controls and their diurnal variations were investigated. Subjects had an i.v. bolus of either 0.2 mg/kg naloxone or saline at two time points (09:00 or 18:00 h) and for 2 days in a single-blind, cross-over design. RESULTS: The basal cortisol plasma levels, both in the morning and in the afternoon, showed higher values (P<0.05) in the depressives. There was a naloxone-induced increase in the adrenocorticotrophic hormone (ACTH), cortisol, and luteinizing hormone (LH) plasma levels, plus a subjective dysphoric effect in both groups. The depressives showed a greater dysphoric effect both in the morning and afternoon (P<0.05), and a blunted cortisol response in the afternoon (P<0.05). There were no differences between groups or time of day in the ACTH or LH responses. LIMITATIONS: The sample size was small, but by studying each patient as their own control, plus a matched control for every patient, softens this effect. Finding patients with a major depressive episode free of medication is difficult, and this aspect contributes to the size of the sample. CONCLUSIONS: These results suggest that opioid mechanisms may be involved in the HPA axis changes and possibly in mood changes found in depression. The discrepancy between increased sensitivity in depression to mood changes and decreased change in cortisol may indicate a ceiling effect for the latter.

High-dose naloxone (1.0 mg/kg): psychological and endocrine effects in normal male subjects pretreated with one milligram of dexamethasone.

The possible participation of the endogenous opioid system (EOS) in the negative feedback of the hypothalamic-pituitary-adrenal axis (HPA-a) activated by low doses (1 mg) of dexamethasone (Dex) was investigated. Ten male healthy subjects (mean age 31.5 +/- 1.9 SEM) were studied on 2 separate days, in a double-blind, cross-over and placebo-controlled design. All subjects were pretreated with 1.0 mg Dex orally the night (2300 h) before both test days. On the study days, subjects were admitted at 0700 h for cannula insertion; the administration of an i.v. bolus of either naloxone (Nal) (1.0 mg/kg) or saline solution (Sal) i.v. was started at 0900 h. Before and following each infusion, mood was measured by a Visual Analogue Scales (VAS) and by the Affective Quality Scale (AQS) every 30 min and blood samples were taken at 15-min intervals. Blood pressure and heart rate were also monitored. Before Dex administration, plasma cortisol levels were within the normal range in all subjects (210.4 +/- 13 ng/ml), while after 9 h after Dex cortisol levels showed the expected significant (p < 0.01) decrease (11.5 +/- 1.9 and 15.04 +/- 0.7 ng/ml for Sal and Nal test days respectively). There were no detectable increases in plasma cortisol levels following either Nal nor Sal administration. However, there was a Nal-induced significant increase in LH (p < 0.01) thus indicating that an effective opioid blockade at the level of the hypothalamic-pituitary unit occurred. There were also a mild and selective Dex + Nal-induced dysphoric (mood factors related to subjects perception of their cognition) and bradycardic effects (p < 0.05). These results suggest that the EOS is not directly involved in the negative feedback triggered by low doses of Dex of the HPA-a, and that there might be a possible glucocorticoid-opioid interaction for the modulation of some aspects of mood.

The use of the plasma concentration-effect relationship as a tool for the study of the mechanism of action of naloxone effects on mood and endocrine function.

The relationship between naloxone-plasma concentrations and their effects on mood and endocrine function was studied. Ten healthy volunteers received 1.0 mg/kg i.v. naloxone or placebo following a randomized double-blind design. Effects on mood, determined by a visual analogue scale and luteinizing hormone (LH) and naloxone-plasma concentrations were measured at selected times. Naloxone induced significant effects on confusion, bewilderment and indifference, and an increment in LH levels. The timecourse of the responses on confusion and bewilderment was similar to that of naloxone-plasma concentration, suggesting that these effects are directly related to the action of naloxone on its receptors. Responses for indifference and LH, however, exhibited a delayed onset. This delay could be due to an indirect action, i.e. to the participation of additional physiological mechanisms in a cascade-like manner. The results show that analysis of the concentration-effect relationship can be a useful tool for understanding naloxone effects on mood and endocrine function.

Effects of naloxone on diurnal rhythms in mood and endocrine function: a dose-response study in man.

This study investigated diurnal variations in the affective and endocrine response to opioid blockade in man and whether there were effects related either to the dose of naloxone or the time of day at which it was given. Normal male subjects were given an intravenous bolus of either 0.2 mg/kg (study 1) or 1 mg/kg naloxone (study 2) or control infusions at two time points (0900 or 1800 hours) in a single-blind crossover design. Before and following each infusion, mood was measured by the Profile of Mood States (POMS) and a visual analogue scale (VAS), and blood samples taken at 15-min intervals. Cortisol, LH ACTH and vasopressin (study 2 only) were measured. Blood pressure and heart rate were also monitored. The lower dose of naloxone had no effect on overall mood (POMS), though tension and confusion were increased in the afternoon. The VAS showed increased depression in the afternoon, and heightened tension, sleepiness and reduced ability to concentrate at both times of day. The higher dose increased overall dysphoria at both time points, though the tension and depression subscales were not altered. VAS depression and tension were increased, and there were changes in sleepiness. Subjective reports showed that 45% of the subjects correctly identified the drug treatment at the lower dose compared with 89% at the higher one. ACTH increased after both doses of naloxone irrespective of time of day. Cortisol was also raised by naloxone; the effect was greater in the afternoon for the lower dose, but not the higher.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of 12-hour infusion of naloxone on mood and cognition in normal male volunteers.

The effects of a 12-hour naloxone infusion on mood, cognition, and plasma cortisol levels were evaluated in eight normal subjects. The dosage used was a 10 mg dose plus 7 mg/hr (total = 94 mg). Naloxone induced a significant rise in serum cortisol and also induced cognitive impairment, as shown by increased choice reaction time, reduced ability to recall the order of letters and numbers, and reduced accuracy of spatial orientation. The rise in cortisol induced by naloxone was significantly correlated with the rise in the Profile of Mood Scale (POMS) score, indicative of dysphoria. Finally, performance on the spatial orientation task was highly negatively correlated with the peak POMS score after naloxone. From these data and previous studies it is concluded that opioid receptors of low sensitivity to naloxone may mediate a common mechanism regulating the pituitary-adrenal axis' mood, and cognitive function during stress. Personality traits may account for the large individual variability reported in previous studies.