Dexamethasone/corticotropin-releasing Hormone Research Articles

Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of α₂-adrenoceptor (ADRA2A –1291C→G) and the β₂-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A –1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders.

Suppressed Neuroendocrine Stress Response in Depressed Women on Job-Stress-Related Long-Term Sick Leave: A Stable Marker Potentially Suggestive of Preexisting Vulnerability

We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed women on job-stress-related long-term sick leave (LTSL). This unexpected finding prompted the question of whether HPA axis hypofunction in this group results from stress exposure or reflects preexisting vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA axis reactivity in these subjects. We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA axis reactivity in 29 patients and 27 control subjects after 12 months of follow-up. Clinical status and cognitive performance was also retested. Despite marked clinical improvement and normalization of initially observed impairments in attention and working memory, marked HPA axis hyporeactivity persisted in patients. A high test-retest correlation was found both at the level of corticotropin (R = .85, p < .001) and cortisol (R = .76, p < .001) responses. Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independent of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA axis hyporeactivity may reflect a preexisting vulnerability in these subjects.

Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol – A double-blind multicenter trial

Background Patients with delusional depression are difficult to treat. The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder. The major neurobiological effect of trimipramine is the inhibition of the hypothalamic–pituitary–adrenocortical (HPA) system. In delusional depression HPA overactivity is more distinct than in other subtypes of depression. HPA suppression is thought to contribute to the action of trimipramine. Methods In a double-blind, randomized, placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol. Dosage was increased stepwise from 100 mg up to 400 mg trimipramine and from 100 mg up to 200 mg amitriptyline combined with 2 mg up to 7.5 mg haloperidol. The average dose of trimipramine was higher than that of amitriptyline throughout the trial. During sixth week mean dosage (±standard deviation) were 356.1 ± 61.2 mg trimipramine, 184.0 ± 23.6 mg amitriptyline and 6.3 ± 1.8 mg haloperidol. During six weeks psychometric assessments were performed weekly. For HPA monitoring a dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed before active medication and at the end of treatment. Additionally tolerability was monitored by ECG, EEG assessment of extrapyramidal symptoms and akathisia, clinical laboratory routine and recording of blood pressure and heart rate. Adverse events were documented. Results 94 patients were enclosed into the study. The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group. The decrease of the Hamilton depression (HAMD) score (24 items) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol. Twenty-eight patients (84.84%) in the trimipramine arm and 17 patients (70.83%) in the amitriptyline/haloperidol arm were responders (HAMD ⩽ 50%). Remission (HAMD < 8) was found in 18 (54.55%) patients after trimipramine and in 11 (45.83%) patients after amitriptyline/haloperidol. No significant differences were found concerning response and remission. The cortisol and ACTH response in the Dex/CRH test decreased between days 1 and 42 in both groups. Serious side effects were not reported. Conclusion In all, trimipramine monotherapy appears to be an effective treatment in delusional depression.

Childhood Parental Loss and Adult Hypothalamic-Pituitary-Adrenal Function

Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function that could predispose to the development of psychiatric disorders. Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared with a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, parental care, gender, and age on the hormone responses to the Dex/CRH test. Parental loss was associated with increased cortisol responses to the test, particularly in men. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. Adrenocorticotropic hormone responses to the Dex/CRH test did not differ significantly as a function of parental loss. These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.

Cortisol and ACTH responses to the Dex/CRH Test: Influence of temperament

Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated-measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test ( F(1, 58) = 4.86, p < .05). The GLM for novelty seeking and cortisol response also showed a main effect ( F(1, 58) = 5.28, p < .05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking ( F(4, 53) = 3.37, p < .05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.

Longitudinal neuroendocrine changes assessed by dexamethasone/CRH and growth hormone releasing hormone tests in psychotic depression

Although psychotic depression has been reported to exhibit a greater degree of dysregulation of hypothalamic-pituitary-adrenocortical (HPA) function than non-psychotic depression, little is known concerning hypothalamic-pituitary-somatotropic (HPS) function in psychotic depression and how neuroendocrine function changes after treatment. To investigate the longitudinal changes in HPA and HPS system function in psychotic depression, we performed repeated dexamethasone/corticotropin releasing hormone (DEX/CRH) tests and growth hormone (GH) releasing hormone (GHRH) tests in inpatients with major depressive disorder. The psychotic depression group exhibited greater elevation of ACTH responses to the DEX/CRH test and stronger decreases in GH responses to the GHRH test than the non-psychotic depression group at admission. At discharge, the neuroendocrine responses to the DEX/CRH test of the psychotic depression group were still stronger than those of the non-psychotic depression group, though there were no significant differences in severity of depression between the groups. There were significant longitudinal changes in neuroendocrine responses to the DEX/CRH test between admission and discharge. The psychotic depression group exhibited increased GH responses to GHRH at discharge compared with those at admission, whereas no significant longitudinal change in GH response was found in the non-psychotic depression group. Consequently, there were no significant differences in GH responses to GHRH between the psychotic and non-psychotic depression groups at discharge. The results of GHRH test showed no significant relationships with severity of depression except psychotic features and the results of the DEX/CRH test. Our findings suggest that the HPS axis may be associated with psychotic features rather than general severity of depression. Further longitudinal studies are needed to clarify the role of HPS function in psychotic depression and whether sustained dysregulation of HPA function in psychotic depression is associated with a poor outcome after discharge.

Differences in the response to the combined DEX-CRH test between PTSD patients with and without co-morbid depressive disorder

Neuroendocrine studies have shown profound alterations in HPA-axis regulation in posttraumatic stress disorder (PTSD). Based on baseline assessments and the response to dexamethasone, a hypothalamic overdrive with enhanced glucocorticoid feedback inhibition has been suggested. The dexamethasone-corticotrophin releasing hormone (DEX-CRH) test has shown to be a more sensitive test to assess HPA-axis dysregulation in major depression and therefore may provide a useful test tool to probe HPA-axis regulation in PTSD. To evaluate the effect of PTSD on HPA-axis regulation, we compared the response to a DEX-CRH test between male veterans with PTSD (n=26) and male veterans, who had been exposed to similar traumatic events during their deployment, without PTSD (n=23). Patients and controls were matched on age, year and region of deployment. Additionally, we compared the response of PTSD patients with (n=13) and without co-morbid major depressive disorder (MDD) (n=13). No significant differences were observed in ACTH and cortisol response to the DEX-CRH test between patients and controls. PTSD patients with co-morbid MDD showed a significantly lower ACTH response compared to patients without co-morbid MDD. The response to the DEX-CRH test did not correlate with PTSD or depressive symptoms. The DEX-CRH test did not reveal HPA-axis abnormalities in PTSD patients as compared to trauma controls. PTSD patients with a co-morbid MDD showed an attenuated ACTH response compared to PTSD patients without co-morbid MDD, suggesting the presence of subgroups with different HPA-axis regulation within the PTSD group. Altered sensitivity of the CRH receptors at the pituitary or differences in AVP secretion might explain these differences in response.

Enhanced Suppression of Adrenocorticotropic Hormone and Cortisol Responses to Hypothalamic-Pituitary-Adrenal Function and Thyrotropin-Releasing Hormone Tests after Stressful Life Events in Patients with Major Depressive Disorder

Background: It is commonly believed that there exists a relationship between the outcome of thyrotropin-releasing hormone (TRH) test, the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test and stressful life events (SLEs) in major depressive disorder. Objective: SLEs influence the TRH and DEX/CRH tests in major depressive disorder when administered at the time of admission and improvement. Methods: The TRH and DEX/CRH tests were administered to patients hospitalized for major depressive disorders – on the 4th through the 7th hospital day and at the time of improvement. We measured ΔMAX TSH, ΔMAX ACTH, ACTH AUC, ΔMAX cortisol, cortisol AUC, ΔMAX ACTH/ΔMAX TSH and ΔMAX cortisol/ΔMAX TSH. Results: SLEs were significantly negatively associated with ΔMAX ACTH, ACTH AUC and cortisol AUC at the time of admission. However, these relationships lost significance at the time of improvement. The sample (41 patients at the time of admission, 18 patients at the time of improvement) was relatively small, which may have contributed to false-negative results. Conclusion: SLEs may be negatively associated with the outcome of the DEX/CRH tests in major depressive disorder. The hypothalamic-pituitary-adrenal axis in the DEX/CRH test was modulated by SLEs.

Temperament and response to the Trier Social Stress Test

The personality characteristics behavioural inhibition and neuroticism have been associated with mood and anxiety disorders and, in some studies, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We recently reported that low levels of Novelty Seeking were associated with elevated plasma cortisol responses to the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test in healthy adults with no psychiatric disorder. The present study tested the association between temperament and HPA axis function in the same group of subjects using a standardized psychosocial neuroendocrine stress test. Subjects completed diagnostic interviews, questionnaires, and the Trier Social Stress Test (TSST). Novelty Seeking was inversely associated with plasma cortisol concentrations at baseline and throughout the TSST, but was not related to adrenocorticotropic hormone (ACTH) levels. Results of this study extend our previous finding in the Dex/CRH test to a psychosocial stress test. Future investigations are needed to replicate these findings and further elucidate how temperament and personality are linked to HPA function.

Temperament and hypothalamic–pituitary–adrenal axis function in healthy adults

Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.

HPA axis functioning associated with transition to psychosis: Combined DEX/CRH test

We investigated functioning of the hypothalamic–pituitary–adrenal (HPA) axis in 12 young people at ultra high risk for developing psychosis, using the combined dexamethasone corticotrophin releasing hormone (DEX/CRH) test. Over a two year period, three of the 12 participants developed an acute psychosis. Descriptive analysis of the data indicated that contrary to expectations, participants who did not make the transition to psychosis had on average higher cortisol levels at the latter stages of the test, as well as a greater severity of depression and anxiety symptoms, than participants who subsequently developed psychosis. These preliminary results suggest that dysregulated HPA-axis functioning in individuals at high risk for psychosis may be associated more with comorbid depression symptoms than factors specifically related to the process of emerging psychosis illness.

Glucocorticoids and Relapse of Major Depression (Dexamethasone/Corticotropin-Releasing Hormone Test in Relation to Relapse of Major Depression)

Knowledge of pathogenic mechanisms and predictors of relapse in major depressive disorder is still limited. Hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation is thought to be related to the development and course of depression. We investigated whether dexamethasone/corticotropin-releasing hormone (DEX/CRH) test parameters were related to the occurrence of relapse in 45 outpatients with clinically remitted major depression. The DEX/CRH test was administered before and after 8 weeks of antidepressant treatment. Posttreatment maximal adrenocorticotropic hormone (ACTH) and maximal cortisol levels, as well as delta ACTH and delta cortisol levels, were significantly higher (all p < .05) among patients who relapsed (n = 22) compared with patients in whom no relapse occurred (n = 23). Higher posttreatment maximal cortisol response on the DEX/CRH test was associated with shorter "relapse-free survival" (p = .05). In outpatients with clinically remitted major depression, higher posttreatment maximal cortisol levels on the DEX/CRH test were associated with relapse of major depression.

Changes of Sleep Architecture, Spectral Composition of Sleep EEG, the Nocturnal Secretion of Cortisol, ACTH, GH, Prolactin, Melatonin, Ghrelin, and Leptin, and the DEX-CRH Test in Depressed Patients during Treatment with Mirtazapine

The noradrenergic and specific serotoninergic antidepressant mirtazapine improves sleep, modulates hormone secretion including blunting of hypothalamic-pituitary-adrenocortical (HPA) activity, and may prompt increased appetite and weight gain. The simultaneous investigation of sleep electroencephalogram (EEG) and hormone secretion during antidepressive treatment helps to further elucidate these effects. We examined sleep EEG (for later conventional and quantitative analyses) and the nocturnal concentrations of cortisol, adrenocorticotropin (ACTH), growth hormone (GH), prolactin, melatonin and the key factors of energy balance, ghrelin, and leptin before and after 28 days of treatment of depressed patients (seven women, three men, mean age 39.9+/-4.2 years) with mirtazapine. In addition, a sleep EEG was recorded at day 2 and the dexamethasone-corticotropin-releasing hormone (DEX-CRH) test was performed to assess HPA activity at days -3 and 26. Psychometry and mirtazapine plasma concentrations were measured weekly. Already at day 2, sleep continuity was improved. This effect persisted at day 28, when slow-wave sleep, low-delta, theta and alpha activity, leptin and (0300-0700) melatonin increased, and cortisol and ghrelin decreased. ACTH and prolactin remained unchanged. The first two specimens of GH collected after the start of quantitative EEG analysis were reduced at day 28. The DEX-CRH test showed, at day 26, a blunting of the overshoot of ACTH and cortisol found at day -3. The Hamilton Depression score decreased from 32.1+/-7.3 to 15.5+/-6.7 between days -1 and 28. A weight gain of approximately 3 kg was observed. This unique profile of changes is compatible with the action of mirtazapine at 5-HT-2 receptors, at presynaptic adrenergic alpha 2 receptors, at the HPA system, and on ghrelin and leptin.

HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures

To examine the clinical effects of electroconvulsive therapy (ECT) on depressed patients with medication treatment failures, we investigated the alterations in hypothalamic-pituitary-adrenocortical (HPA) function and regional cerebral metabolism rate of glucose (rCMRGlu) after ECT in these patients. Before and after ECT, the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test was administered to seven patients who were referred for ECT. In the same patients, (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was also assessed. Cortisol response in the DEX/CRH test significantly decreased after a successful ECT. A significant hypometabolism in various frontal regions and hypermetabolism in the parietal regions of these patients when compared with controls remained after ECT. Depressed patients who failed trials of antidepressant medication showed a remission with ECT that was accompanied by resolution of HPA dysregulation. However, measures of cerebral brain metabolism did not resolve.

Fatigue and Regulation of the Hypothalamo-Pituitary-Adrenal Axis in Multiple Sclerosis

Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation. To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS. A prospective survey. Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany. Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment. Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test. The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test. In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.

Simultaneous use of thyrotropin-releasing hormone test and combined dexamethasone/corticotropine-releasing hormone test for severity evaluation and outcome prediction in patients with major depressive disorder

We performed a prospective study designed to examine whether or not evaluation of the severity and prediction of treatment outcome in major depressive disorder would be enabled by simultaneous use of the thyrotropin-releasing hormone (TRH) test and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test. We studied consecutive patients hospitalized for major depressive disorder. The patients received the TRH test and the DEX/CRH test on the 4th through the 7th hospital days and at the time of improvement. None of the indices in these tests at the time of admission correlated with the Hamilton rating scale for depression (HRSD) or the Global Assessment for Function (GAF). However, since the ΔMAXACTH, ACTHAUC, ΔMAXcortisol, and CortisolAUC showed significant decreases at the time of improvement compared with the time of admission, suggesting that the DEX/CRH test can be a state marker. ΔMAXTSH showed no significant change. Prediction of improvement within 3 months after admission was not possible with either test alone. However, the quotient which divided ΔMAXACTH by ΔMAXTSH was predictive of clinical improvement with a sensitivity of 50% and a specificity of 100%. The simultaneous use of the TRH test and the DEX/CRH test seems to provide a more useful biological marker than the separate use of either test alone in patients with major depressive disorder.

The biochemical investigation of Cushing syndrome

Cushing syndrome is an insidious illness that warrants an early diagnosis to avoid the effects of prolonged hypercortisolism. The variability in the clinical features of the disease and the occasional inconsistencies between different biochemical tests performed to identify it render the diagnosis challenging. In this paper the author discusses the various biochemical tests that are useful for the diagnoses of Cushing syndrome and Cushing disease, with an emphasis on the respective sensitivities and specificities of these tests. The measurement of evening salivary cortisol and the combined low-dose dexamethasone-corticotropin-releasing hormone stimulation test have improved overall sensitivity and specificity in the evaluation of Cushing syndrome and Cushing disease.

High neuroticism and depressive temperament are associated with dysfunctional regulation of the hypothalamic-pituitary-adrenocortical system in healthy volunteers.

Elevated neuroticism, depressive temperament and dysfunctional regulation of the hypothalamic-pituitary-adrenocortical (HPA) system are considered as risk factors for unipolar depression. An interaction of these vulnerability factors was suggested, but controversially discussed. In absence of other informative studies we set out for a replication test and for elucidation of the underlying mechanism. Ninety-two subjects recruited in the community-performed assessments of personality and temperament as well as measurement of HPA function with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Cortisol levels subsequent to Dex/CRH challenge were associated with neuroticism; high-neuroticism subjects revealed a higher HPA activation. This difference was mainly because of male subjects >/=25 years. A similar relationship was observed for depressive temperament. This constellation may propose that HPA dysregulation is the endocrinological basis for neuroticism and depressive temperament; this result supports the view that distinct personality factors and HPA vulnerability interact in mediating depression.

Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder

Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression, knowledge of factors related to response remains scanty. Findings with the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are associated with response to treatment with a tricyclic antidepressant. This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder. The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks. Response status was assessed weekly using the Hamilton Rating Scale for Depression. For multivariate prediction, a logistic regression analysis was performed. Eleven (37%) patients responded to lithium augmentation within 4 weeks. Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test, but results were not statistically significant. However, non-responders had a statistically significant higher cortisol/ACTH peak ratio (3.43±1.75) compared to responders (2.18±1.38) ( P=0.027). This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH. A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders. In conclusion, results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation. The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group, because chronic depression is known to cause enlargement of the adrenal gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.

Born to be Anxious: Neuroendocrine and Genetic Correlates of Trait Anxiety in HAB Rats

This review summarises behavioural, neuroendocrine, and genetic characteristics of Wistar rats bred for either high (HAB) or low (LAB) anxiety-related behaviour. Compared to LABs, HAB animals show signs of extreme trait anxiety in a variety of behavioural tests; they further prefer passive coping strategies, indicative of a genetically linked depression-like behaviour, and show signs of increased stress vulnerability. All behavioural parameters associated with trait anxiety are robust and consistent. Resembling psychiatric patients, HAB rats respond to exposure to ethologically relevant stressors with a hyper-reactivity of the hypothalamic-pituitary-adrenal axis and show a pathological outcome of the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) challenge test. Experimental evidence indicates that over-expression and -release of vasopressin in the hypothalamic paraventricular nucleus is responsible for these behavioural and neuroendocrine phenomena, making the neuropeptide gene a candidate gene of trait anxiety/depression. Indeed, preliminary molecular genetic approaches succeeded in identifying polymorphisms in the promoter structure of the vasopressin gene. This may have implications for understanding the molecular basis for individual variations in trait anxiety and for psychopathology.