Summary

Background

The hypothalamic-pituitary adrenal (HPA) axis is critical for biobehavioral adaptation to challenge and appears dysregulated in a range of psychiatric disorders. Its precise role in psychopathology remains unclear and discrepant and difficult to explain findings abound in the clinical literature. Basic research suggests this system is sensitive to psychosocial cues, but psychosocial milieu factors are rarely controlled or examined in psychiatric studies using biological probes of the HPA axis. To test the hypothesis that psychological factors might complicate HPA study results even in direct, pharmacological challenge paradigms, endocrine responses to corticotropin-releasing hormone (CRH) were examined under two different cognitive preparation conditions.

Methods

Healthy subjects (n=32) received standard instructions or a cognitive intervention (CI) prior to injection with CRH and placebo, given on separate days in random order. The CI combined access to control over drug exposure with novelty reduction and coping enhancement. Blood samples were obtained via intravenous catheter before and after CRH.

Results

Cognitive intervention reduced corticotropin (ACTH) levels, but only when CRH was given first (intervention by order interaction). It did not reduce cortisol response. The CI and visit (1st or 2nd) both impacted cortisol levels on placebo day.

Conclusions

Modifiable psychological factors may amplify or inhibit HPA axis activity in pharmacological activation paradigms, including CRH stimulation tests. The factors manipulated by the CI (novelty/familiarity, control and coping) may have particular salience to the HPA axis. Differential sensitivity to such factors could impact results in studies applying biological HPA probes to psychiatric populations.

Background

The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the HPA-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder.

Methods

The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m.

Results

Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to cardiovascular (CV) causes (t = 4.01, p < .001 and t = 3.03, p = .004, respectively); the 11 p.m. cortisol concentration predicted death due to suicide (t = 2.05, p = 0.048). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0) μg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6) μg/dl (t = 3.03, df = 53, p = 0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t = 2.05, p = 0.048).

Conclusions

Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.

Summary

Objective

Hormone-based contraceptives affect mood in healthy women or in women with Premenstrual Dysphoric Disorder. No study has yet examined their association with mood in women with major depressive disorder (MDD). The purpose of this study was to determine whether estrogen-progestin combination or progestin-only contraceptives are associated with depression severity, function and quality of life, or general medical or psychiatric comorbidity in women with MDD.

Methods

This analysis focused on a large population of female outpatients less than 40 years of age with non-psychotic MDD who were treated in 18 primary and 23 psychiatric care settings across the United States, using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Baseline demographic and clinical information was gathered and compared between three groups based on hormonal use: combination (estrogen-progestin)(N=232), progestin-only (N=58), and no hormone treatment (N=948).

Results

Caucasians were significantly more likely to use combined hormone contraception. Women on progestin-only had significantly more general medical comorbidities; greater hypersomnia, weight gain and gastrointestinal symptoms; and worse physical functioning than women in either of the other groups. Those on combined hormone contraception were significantly less depressed than those with no hormone treatment by the 16-item Quick Inventory of Depressive Symptomatology - Self-Rated. The combined hormone group also demonstrated better physical functioning and less obsessive-compulsive disorder comorbidity than either of the other groups.

Conclusions

Synthetic estrogen and progestins may influence depressive and physical symptoms in depressed women.

Summary

Numerous studies suggest that increased central drive to the hypothalamic-pituitary adrenal axis occurs in patients with major depression. To determine if increased central drive occurs throughout the 24H, we evaluated ACTH secretion under metyrapone blockade of cortisol production. We collected blood every 10 minutes for measurement of ACTH and data were analyzed for ACTH pulsatility using the pulse detection algorithm deconvolution. We studied 28 patients with major depression and 28 age and sex matched control subjects, of which 9 pairs were men and 19 pairs were women. We found a significant group by sex interaction with number of ACTH pulses (p=.04); depressed men showed more ACTH pulses over 24H than matched control men (p=0.02). There was also a significant sex difference in AUC pulses with men showing a smaller AUC ACTH than women. Previous analyses of these data with RM-ANOVA showed a smaller ACTH response in depressed men compared to control men. These data suggest that pulsatility and mean ACTH levels are examining different aspects of HPA axis function, and that the types of HPA axis dysregulation in depression may differ between men and women.