Higher overcommitment to work is associated with higher plasma cortisol but not ACTH responses in the combined dexamethasone/CRH test in apparently healthy men and women.

BACKGROUND: Overcommitment (OC) is a pattern of excessive striving that has been associated with alterations in the hypothalamus-pituitary-adrenal (HPA) system. To investigate whether overcommitment is associated with alterations in HPA system function we measured cortisol and adrenocorticotropin (ACTH) release in response to the combined dexamethasone/CRH test. METHODS: We recruited 92 men and 108 women of a wide range of OC scores including the minimum (6) and maximum (24) of possible OC scores (mean+/-SEM: 13.25+/-.27). We repeatedly measured plasma cortisol and ACTH levels in the combined dexamethasone/CRH test after injection of 100mul CRH preceded by administration of 1.5mg dexamethasone the night before. Moreover, we assessed depressive symptoms (Beck Depression Inventory, BDI) and work stress (effort-reward-imbalance, ERI). RESULTS: Independent of age and gender, higher OC was associated with higher repeated cortisol (interaction time-by-OC: p=.014, f=.15) but not ACTH (p=.22) secretion in the combined dexamethasone/CRH test. Similarly, higher cortisol (beta=.16, p=.029, R(2)=.02) but not ACTH (p=.47) increase following CRH injection was predicted by higher OC. Depressive symptoms (BDI score) and work stress scores (effort-reward-ratio) did not relate to neuroendocrine responses to the dexamethasone/CRH test. Controlling for depressive symptoms and work stress scores in addition to age and gender did not change results. OC was not associated with ACTH or cortisol pre-test levels. DISCUSSION: Whereas OC was not associated with alterations in negative feedback sensitivity after dexamethasone administration, our findings indicate that with increasing OC scores, a higher reactivity of the adrenal cortex together with a normal reactivity of the pituitary is observed following subsequent stimulation by CRH injection.

Treatment with a CRH-1-receptor antagonist (R121919) does not affect weight or plasma leptin concentration in patients with major depression.

Weight gain during treatment with psychotropic drugs is frequently observed and is assumed to be responsible for non-compliance and for an elevated risk to develop a number of somatic co-morbidities including cardiovascular disorders and type 2 diabetes. Absence of weight inducing effects is therefore a major objective for the development of new compounds. Recently, R121919, the first corticotropin releasing hormone receptor 1 (CRH1R) antagonist, was tested in major depression. Clinical efficacy, safety, and tolerability of this compound could be demonstrated. Since CRH is discussed to be involved in the regulation of appetite and weight, directly and via interaction with leptin, CRH1R antagonists are suspected to influence body weight. Effects of 30 days of treatment with the CRH1R antagonist R121919 on weight and leptin levels in 20 patients suffering from major depression were investigated. No significant weight changes during treatment with R121919 were observed. Furthermore, noeffects on plasma leptin concentrations were found. We conclude that treatment with the CRH1R antagonist R121919 does not affect weight or plasma leptin concentrations in patients with major depression. Together with previous findings indicating safety, tolerability, and clinical efficacy CRH1R antagonists are highly promising as a new treatment option in depression.

Improvement of working but not declarative memory is correlated with HPA normalization during antidepressant treatment.

Previous research demonstrated that depression is associated with hyperactivity of the hypothalamus-pituitary-adrenocortical (HPA) system after stimulation. There is also strong evidence that the modulation of corticosteroids in the brain induces memory dysfunction which represents core features of depression. Antidepressant treatment with serotonin reuptake inhibitors (SSRIs) alleviates both dysfunctions. Thus, these previous observations propose a correlation between treatment induced changes of the endocrinological response of the HPA system to challenge with dexamethasone and CRH and changes of memory functions during antidepressant treatment. This study explores the relationship between depression, memory functions and the responsiveness of the HPA system as assessed by the combined DEX/CRH test during antidepressant treatment in n = 64 patients with major depression during a four weeks treatment with citalopram. We found that treatment induced changes of the cortisol response pattern in the DEX/CRH test were correlated with improvement of working memory but not so with episodic memory, sustained attention or global severity of depression. We suggest that improvement of working memory is more sensitive to the changes of hormones of the HPA system (e.g. cortisol) than other cognitive functions and the global severity of depression.

Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects.

A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.

Clinical and neurobiological effects of tianeptine and paroxetine in major depression.

Selective serotonin reuptake inhibitors (SSRIs) are widely used as effective pharmacological agents to treat depressive disorders. In contrast to the SSRIs, which block the presynaptic serotonin (5-HT) transporter and by this route increase the concentration of serotonin in the synaptic cleft, the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission. Both SSRIs and tianeptine are clinically effective; however, their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission. To better understand the differences between these two opposite pharmacological modes of action, we compared the changes induced by tianeptine and paroxetine on psychopathology, the hypothalamic-pituitary-adrenocortical (HPA) system, and cognitive functions in a double-blind, randomized, controlled trial including 44 depressed inpatients over a period of 42 days. Depressive symptomatology significantly improved in all efficacy measures, with no significant differences between tianeptine and paroxetine. There was a trend toward better response to the SSRI among women. Assessment of the HPA system showed marked hyperactivity before the beginning of treatment, which then normalized in most of the patients, without significant differences between the two antidepressants. Cognitive assessments showed no significant differences between the two drugs investigated. The results of the current study suggest that the initial effect, i.e., enhancement or decrease of 5-HT release, is only indirectly responsible for antidepressant efficacy, and they support the notion that downstream adaptations within and between nerve cells are crucial. The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest.