ABSTRACT
The effect of early-life vulnerability factors on the subsequent pathophysiology of severe mood disorders has yet to be fully elucidated. This study examines the relationship between early adverse life experience, family history and hypothalamic-pituitary-adrenal (HPA) axis function. Childhood trauma questionnaire (CTQ) scores, family history data and the cortisol response to the dexamethasone/corticotrophin releasing hormone (dex/CRH) test were examined in 40 patients with severe mood disorder. Normative data for the CTQ was also obtained. The study demonstrated that mood disorder patients reporting high levels of childhood emotional neglect (n = 26) had an HPA axis response which did not differ from controls, whereas patients reporting low levels (n = 19) had an enhanced response (p = 0.011). A positive family history of mood disorder further enhanced this response. These data suggest that early adverse life events and genetic susceptibility have dissociable effects on glucocorticoid receptor-mediated negative feedback of the HPA axis in adult patients with severe mood disorders.
ABSTRACT
High cortisol levels are found in severe mood disorders, particularly bipolar disorder. Hypercortisolaemia may cause or exacerbate both neurocognitive impairment and depressive symptoms. We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder. To test this hypothesis, 20 bipolar patients were treated with 600 mg/day of the corticosteroid receptor antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind crossover design. Over the total 6 weeks of the study, neurocognitive and neuroendocrine function were evaluated at baseline, days 21 and 42. Mood symptoms were evaluated weekly. Nineteen subjects completed the protocol; there were no drop-outs due to adverse events. Following treatment with mifepristone, selective improvement in neurocognitive functioning was observed. Spatial working memory performance was significantly improved compared to placebo (19.8% improvement over placebo). Measures of verbal fluency and spatial recognition memory were also improved after mifepristone. Beneficial effects on mood were found; Hamilton Depression Rating Scale scores were significantly reduced compared to baseline (mean reduction of 5.1 points) as were Montgomery-Asberg Depression Rating Scale scores (mean reduction of 6.05 points). No significant change occurred after placebo. These data require replication but provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder.
Subject(s)
Affect/drug effects , Bipolar Disorder/drug therapy , Bipolar Disorder/psychology , Cognition/drug effects , Hormone Antagonists/therapeutic use , Mifepristone/therapeutic use , Adult , Attention/drug effects , Cross-Over Studies , Double-Blind Method , Female , Humans , Hydrocortisone/blood , Learning/drug effects , Male , Memory, Short-Term/drug effects , Middle Aged , Psychiatric Status Rating Scales , Psychomotor Performance/drug effects , Receptors, Glucocorticoid/antagonists & inhibitors , Space Perception/drug effects , Treatment Outcome , Verbal Learning/drug effectsABSTRACT
RATIONALE: Enhancement of dopamine (DA) release by corticosteroids may be of aetiological importance in substance misuse. OBJECTIVES: To examine the effect of sub-chronic administration of hydrocortisone on the response to amphetamine in healthy male volunteers. METHODS: Following baseline assessment, 20 volunteers were pretreated for 7 days with 20 mg of hydrocortisone or placebo at 0800 hours and 2000 hours in a double-blind, random order, cross-over design prior to receiving 0.15 mg/kg metamphetamine intravenously. Blood samples for cortisol and prolactin were taken every 15 min. Subjects also underwent tests of neuropsychological function including sustained attention using the rapid visual information processing test (RVIP), which has been shown to be sensitive to changes in DA function. RESULTS: Metamphetamine produced a substantial reduction in prolactin levels, and increased subjective mood ratings of "mind-race" and "buzz". Sub-chronic hydrocortisone administration had no effect on these neuroendocrine responses, subjective mood changes or neurocognitive performance on a task of sustained attention (RVIP). CONCLUSIONS: Despite measurable changes in neuroendocrine and affective functioning in response to metamphetamine, pretreatment with hydrocortisone did not significantly affect any of the variables measured. This suggests that this model of DA function is not affected by this regimen of corticosteroid administration.
