Four days of citalopram increase suppression of cortisol secretion by prednisolone in healthy volunteers.

RATIONALE: Chronic antidepressant treatment increases glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, and thus reduces HPA axis activity, in depressed patients and healthy controls. In contrast, acute antidepressant treatment induces an activation of basal HPA axis activity. OBJECTIVES: We examined the effects of 4 days of treatment with the selective serotonin reuptake inhibitor, citalopram, on basal salivary cortisol and on suppression of salivary cortisol by prednisolone. METHODS: We used a single-blind, placebo-controlled, repeated-measure design. Salivary cortisol was measured from 0900 to 1700 hours. In the first phase of the study, basal salivary cortisol secretion was measured on 2 study days, before and after 4 days of treatment with citalopram (orally, 20 mg/day). In the second phase, salivary cortisol secretion after suppression by prednisolone (5 mg, given at 2200 hours the night before) was measured on 2 study days, again before and after 4 days of treatment with citalopram (orally, 20 mg/day). Eight volunteers participated to the study. RESULTS: Citalopram increased basal salivary cortisol in the morning (0900-1100 hours) by approximately 47% (P=0.003). Moreover, citalopram increased suppression by prednisolone in the morning (0900-1100 hours): suppression was approximately 22% before citalopram and 45% after citalopram (P=0.05). CONCLUSIONS: Citalopram increases glucocorticoid-mediated negative feedback on the HPA axis after as little as 4 days of treatment. This effect could be due to an increased function of the corticosteroid receptors. Our findings further support the notion that one of the mechanisms by which antidepressants exert their therapeutic effects is by normalizing HPA axis hyperactivity in depressed patients.

Neural abnormalities during cognitive generation of affect in treatment-resistant depression.

BACKGROUND: Dysfunctions in brain regions known to be involved in affect and mood states are thought to be implicated in depression and may have a role in determining the type and symptoms of this illness. METHODS: Functional magnetic resonance imaging was used to elucidate neural correlates of cognitive generation of affect, using a previously published paradigm of evoking affect with picture-caption pairs, in patients with unipolar, treatment-resistant depression. RESULTS: Compared with control participants, patients showed relatively decreased response in the anterior cingulate (rostral; right) with both negative and positive picture-caption pairs and in the medial frontal gyrus and hippocampus (all left) with positive picture-caption pairs. They demonstrated increased response in the inferior (right) and middle temporal gyri (left) with negative picture-caption pairs, and in the parahippocampal gyrus (right), inferior frontal gyrus (left), subgenual cingulate (right), striatum (right), and brain stem (left) with positive picture-caption pairs. CONCLUSIONS: Reduced medial/middle prefrontal and hippocampal activity may account for positive affect disturbances and temporal lobe hyperactivity for negative affect disturbances in treatment-resistant depression. The results also corroborate previous observations from resting positron emission tomography studies and further elucidate the association between hypoactive rostral cingulate and nonresponsiveness to treatment in depression.

Estrogen administration does not reduce the rate of recurrence of affective psychosis after childbirth.

BACKGROUND: High rates of postpartum relapse occur in women with histories of bipolar or schizoaffective disorder. These relapses may be triggered by the postdelivery fall in circulating estrogen through alteration of central neurotransmitter (especially dopaminergic) systems. This study tested the hypothesis that estrogen administration after childbirth would prevent postpartum relapse and would alter dopamine receptor sensitivity. METHOD: Twenty-nine pregnant women with a Research Diagnostic Criteria diagnosis of hypomania (bipolar II), mania (bipolar I), or schizoaffective disorder participated in an open clinical trial. Three transdermal dose regimens of estrogen (17beta-estradiol) were tested. Starting doses were 200 (N = 13), 400 (N = 3), and 800 (N = 13) micro g/day, beginning within 48 hours after delivery and reduced by one half every 4 days for a total of 12 days. On the fourth day after starting estradiol therapy (before relapse occurred), subjects participated in a neuroendocrine challenge test that measured the sensitivity of the central nervous system (tubero-infundibular) dopaminergic system (plasma prolactin and growth hormone responses to apomorphine). RESULTS: Estradiol at all dose regimens did not reduce the rate of relapse. However, of the 12 women who relapsed, those who had taken the highest dose of estradiol (800 micro g/day) needed less subsequent psychotropic medication (fewer chlorpromazine equivalents) and were discharged sooner than those who had taken either of the 2 lower doses. No differences in neuroendocrine responses to apomorphine were detected between women receiving the high-dose and the lower-dose regimens. CONCLUSION: The results do not support the hypothesis that a fall in circulating concentrations of estrogens precipitates relapse in subjects at risk of postpartum affective psychosis. The use of prophylactic estrogen in such circumstances is therefore highly questionable.

A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis.

We have developed a suppressive test for the hypothalamic-pituitary-adrenal (HPA) axis using prednisolone, which is similar to endogenous glucocorticoids. We used a single-blind, repeated-measure design in healthy volunteers. In the first phase of the study, we compared placebo or prednisolone 2.5 mg, 5 mg, or 10 mg; in the second phase of the study, we compared placebo or prednisolone 5 mg or dexamethasone.5 mg. On the following day, we collected plasma and salivary cortisol levels from 9 AM to 5 PM. Maximal average prednisolone plasma levels (at 9 AM after the 10-mg dose) were 30 to 35 ng/mL. At all doses, prednisolone caused a larger suppression of salivary cortisol (approximately 20% after 2.5 mg, 30% to 35% after 5 mg, and 70% to 75% after 10 mg) than of plasma cortisol (approximately 5% after 2.5 mg, 10% after 5 mg, and 35% after 10 mg). Dexamethasone.5 mg gave 80% suppression of plasma cortisol and 90% suppression of salivary cortisol. Plasma and salivary cortisol levels were more consistently correlated in each subject after prednisolone than after dexamethasone. We propose that prednisolone at the 5-mg dosage (which gave partial HPA suppression), together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid-mediated negative feedback in large samples of patients with psychiatric disorders.

Vasoconstrictor response to topical beclomethasone in major depression.

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been frequently described in depression. Due to the closed-loop nature of the HPA axis, one possible cause of this overactivity may be a defect in negative feedback regulation, in particular an abnormality of the glucocorticoid receptor (GR). In the present study, the vasoconstrictor response to the topical glucocorticoid, beclomethasone, was used to examine GR function in depression. Topical beclomethasone was applied in four concentrations (10 microl each of 3, 10, 30 and 100 microg/ml) to the forearms of 22 subjects with major depression and their age- and sex-matched controls. Skin blanching responses were compared between the depressed and control groups and, within the depressed group, on the basis of the modified dexamethasone suppression test (DST), between cortisol suppressors and non-suppressors. Depressed subjects demonstrated a significantly reduced vasoconstrictor response compared to controls (P=0.0001). No difference was detected between cortisol suppressors and non-suppressors in their skin blanching responses. These findings suggest that peripheral GR function is abnormal in depression but that the reduced vasoconstrictor response to beclomethasone is not necessarily a secondary effect of hypercortisolaemia or HPA axis overactivity.

Information processing deficits in withdrawing alcoholics.

Prepulse inhibition (PPI) of the acoustic startle response (a reduction in response to an intense, startling stimulus (the pulse) if preceded by 30-150 ms by a weaker, non-startling stimulus) is an established model to index information processing deficits in thought-disordered schizophrenic patients. The present study aimed to investigate the influence of alcohol withdrawal on the PPI effect. Eight withdrawing alcoholic patients underwent testing for PPI of the acoustic startle response (defined as percentage reduction of the response over pulse-alone stimulus; prepulses 15 dB above the background) on three occasions (1, 3 and 7 days following the last drink). The results demonstrated remarkably low levels of PPI on days 1 and 3, with this being very robust in three patients who had a history of delirium tremens; there was a trend towards normalization of PPI on day 7. This study, although preliminary, suggests strongly that there is a deficit in the filtering of sensory information in alcohol-dependent patients undergoing alcohol withdrawal. This was most apparent in those with a history of delirium tremens. Further studies are needed to define the cause and chronicity of these deficits.

Salivary cortisol measurements during a medically assisted alcohol withdrawal.

Previous studies using plasma cortisol estimations have suggested that hypothalmo-pituitary-axis (HPA) activation occurs in alcohol-dependent patients during alcohol withdrawal. The present study set out to confirm this finding using salivary cortisol assays, which are a better indicator of plasma free cortisol, the fraction which exerts its physiological effects. Nine alcohol dependent patients provided four saliva samples (at 10 a.m., 2 p.m., 6 p.m. and 10 p.m.) on days 1, 3 and 7 of a medically assisted alcohol withdrawal (corresponding to 1, 3 and 7 days following the last drink, respectively).Withdrawal symptom severity, craving and mood disturbance were also measured. A group of non-alcohol-dependent individuals, without psychiatric or medical disorder, gave four samples at the same times on one day only. Mean daily cortisol levels in our alcohol-dependent population, as calculated by the area under the curve (AUC), decreased significantly over time (mean AUC (nmol/l/hour) on day 1 = 149, on day 7 = 85.7, p = 0.009) and were significantly higher than controls on each day (mean AUC in controls = 28.3, p = 0.001). The cortisol response showed a similar temporal trend to withdrawal symptom severity and mood disturbance. This is consistent with previous studies measuring plasma cortisol in alcohol withdrawal. However, the magnitude of the effect in our study was greater, and in contrast to some previous studies, levels were far from normal by day 7. The comparatively low cortisol response in our one mildly dependent patient suggests that there may be a relationship between dependence severity and the size of the cortisol response to withdrawal. Salivary cortisol sampling could prove to be a useful prognostic tool, with implications for subsequent withdrawal symptom severity, mood disturbances, risk of relapse and alcohol-related cognitive decline. There are implications for developing new treatments for alcohol withdrawal but more studies are needed.