The influence of psychiatric comorbidity on the dexamethasone/CRH test in major depression

BackgroundThe outcome of the dexamethasone/corticotropin-releasing-hormone (DEX/CRH) test in depressed patients is heterogeneous. The present study investigated whether comorbidity of anxiety or somatoform disorders might be an explaining factor for this finding.MethodsThe DEX/CRH test was administered in 36 pure major depressive outpatients, 18 major depressive outpatients with a comorbid anxiety and/or somatoform disorder, and 43 healthy controls. Patients were free of psychotropic medication. Group differences in responsivity to the DEX/CRH test were analysed.ResultsDepressive patients with comorbidity showed a significant lower cortisol response compared to pure depressive patients (p = 0.04) and controls (p = 0.003). Group differences between MDD patients with and without comorbidity in cortisol responses disappeared after adjustment for post-DEX cortisol concentrations (p = 0.34).ConclusionsAn enhanced suppression of cortisol to 1.5 mg DEX is present in a subgroup of depressed patients with psychiatric comorbidity. Distinct hypothalamic-pituitary-adrenal (HPA) axis dysfunctions are revealed when comorbidity is taken into account.     

A comparison of methods for assessing hypothalamic-pituitary-adrenal (HPA) axis activity in asthma patients treated with inhaled corticosteroids

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an accepted indicator of potential side effects from inhaled corticosteroids. Although cortisol monitoring is frequently used to detect changes in HPA axis activity, the optimal method for identifying the subset of asthma patients on inhaled steroids who experience severe cortisol suppression of potential clinical significance has not been established. The objective of this study was to compare several methods for assessing HPA axis activity in asthma patients taking inhaled corticosteroids. After screening, 153 patients with mild to moderate asthma were randomly assigned to receive inhaled fluticasone propionate (110, 220, 330, or 440 microg bid), flunisolide (500 microg or 1000 microg bid), or one of two control regimens (prednisone or placebo) for 21 days. Salivary (8 a.m.) and urinary (24-h) cortisol determinations were compared against 22-hour area under the serum cortisol concentration-time curve (AUC0-22 h) measured at baseline and on day 21. Comparisons were also made against 8 a.m. serum cortisol. A significant positive correlation was found between AUC0-22 h of serum cortisol and 8 a.m. serum cortisol level (r = 0.5140; p = 0.0001). The AUC0-22 h of serum cortisol was weakly correlated with 24-hour urinary cortisol levels, both corrected (r = 0.4388; p = 0.0001) and uncorrected (r = 0.3511; p = 0.0001) for creatinine excretion. The 8 a.m. salivary cortisol level correlated positively with the 8 a.m. serum cortisol level (r = 0.5460; p = 0.0001). Salivary cortisol was both sensitive and specific for the detection of a 50% decline in AUC0-22 h of serum cortisol. Cortisol reductions of this magnitude have been observed following repeated use of inhaled steroids. Because it is noninvasive, salivary cortisol measurement offers distinct advantages as a screening method for detecting pronounced HPA axis suppression in asthma patients receiving corticosteroid therapy.     

Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: implications for pathogenesis of affective disorders.

To investigate the neuroendocrine alterations linked to inborn emotionality in two Wistar rat lines selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, we administered the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. DEX (12:00 M. (noon); 30 microg/kg) resulted in a significantly less efficient suppression of the diurnal increase in the circulating corticotropin (ACTH) levels in the male HAB rats than in the male LAB rats. In addition, plasma ACTH and corticosterone responses to subsequent CRH (7:30 P.M.; 50 ng/kg) were significantly higher in male HAB rats. The rise in ACTH after CRH in the DEX-pretreated male HAB rats points toward an enhanced activity and involvement of endogenous vasopressin synthesized in the hypothalamic paraventricular nucleus (PVN) and acting at pituitary corticotrope cells. We tested this hypothesis by in situ hybridization and in vivo microdialysis, and found an increase in both basal synthesis and release of vasopressin within the PVN of the male HAB rats. As expected, pretreatment with a selective vasopressin type 1 receptor antagonist abolished the CRH-stimulated increase in ACTH secretion in the DEX-pretreated male HAB rats. The results indicate that vasopressin-mediated effects are critically involved in the profound disturbance of the hypothalamic-pituitary-adrenocortical system in male HAB rats, thus revealing striking parallels to the neuroendocrine situation in human depression.     

Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia.

The effectiveness of selective serotonin reuptake inhibitors for depression in remitted schizophrenia has not been clearly demonstrated. A randomized, double-blind, prospective placebo-controlled study was performed of 48 subjects meeting DSM-IV criteria for both schizophrenia in remission and for a major depressive episode. Twenty-seven patients were randomized to placebo and 21 to sertraline. All subjects had a 1-week anticholinergic phase before randomization. The treatment duration was 6 weeks. Sertraline was started at 50 mg/day; this could be increased to 100 mg after 4 weeks for an inadequate response. There were no statistically significant differences in symptoms between the two groups at randomization. There were no differences in outcome between treatment groups. In both groups, between 40% and 50% of subjects showed a 50% reduction in depression score. This study does not provide support for the efficacy of sertraline in the treatment of depression in remitted schizophrenia. The small sample size limits the strength of the conclusions that can be drawn from this study. The study design called for a sample size of 96 on the basis of an expected placebo response rate of 30%. Recruitment for the study was difficult because of the placebo design. The placebo response was 50%. Clinicians and patients underestimate the strength of the placebo response and may overestimate the risk of participating in such a study. Testing the efficacy of widely accepted but poorly evaluated treatments should be a research priority. Future studies require a larger sample size and longer duration of treatment.     

Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression.

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 P.M. and CRH stimulation at 3 P.M. on the next day). Twenty-four patients were re-assessed after response was determined or, in cases of non-response, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale (HDRS 17-item version). Response was defined as a DeltaHDRS of > or =50% and an endpoint score of < 10. Patients had a significantly higher ACTH and cortisol response to CRH stimulation during lithium augmentation compared with the values at baseline. There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation. This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline. Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change. This effect might be explained by the serotonergic effects of lithium.     

HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment.

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or 'core' schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.     

Long-term treatment with moclobemide. An open-label, non-comparative, multiple-distributed study in patients with a major depressive episode as defined by DSM-III

Evaluation of 247 patients receiving long-term moclobemide treatment showed that it was effective as an antidepressant, as measured both by decrease in HAMD mean total score and the doctor's evaluation of therapeutic effect. In patients who had been treated for 6 months or less, results were less favourable (ratings of very good or good in 31.5%, compared with 81.3% in patients treated for more than 6 months). This was due to a higher number of drop-outs, as a result of insufficient efficacy in the first 6 months. In those patients who responded favourably, 9.2% relapsed within 6 months of commencing treatment; of the remaining responders, 16% relapsed during months 7–12. In terms of the doctor's evaluation of side-effects, tolerability was very good or good in 88.2%.     

The dexamethasone suppression test (1 mg and 2 mg) in major depression: illness versus recovery

This study reexamined the 1 mg and 2 mg DST in endogenous depression. Two groups of depressives were evaluated during illness and shortly after clinical recovery; one group with the 2 mg DST (N = 29) and another with the 1 mg DST (N = 16). The 2 mg DST was found to be a reliable state marker: all nonsuppressors during illness (N = 9) became suppressors after recovery. In contrast, the 1 mg DST was not a useful state marker: over 50% of the nonsuppressors during illness remained nonsuppressors after clinical recovery. A discussion of these discrepant findings dependent on the dose of dexamethasone is presented. This study suggests that although most psychiatric investigations are utilizing the 1 mg DST, the 2 mg DST should be reexamined.     

Effects of acute and chronic administration of mu- and delta-opioid agonists on the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat.

The control of hypothalamic-pituitary-adrenocortical (HPA) activity by opioids seems to involve stimulatory and inhibitory pathways. The purpose of the present study was to determine the acute and chronic effects of selective mu- and delta-opioid agonists, administered centrally (i.c.v.) on pituitary-adrenocortical activity in the rat. The mu-agonist DAGO ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin; 0.75 nmol i.c.v.) and the delta-agonist DPDPE ([D-Pen2,5]enkephalin; 194 nmol i.c.v.) both stimulated corticosterone release when administered acutely. Chronic administration of DAGO and DPDPE resulted in the development of tolerance to their neuroendocrine effects. These data suggest that both mu- and delta-opioid receptors are involved in the regulation of HPA activity under physiological conditions and during opiate abuse.     

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.     

Phosphatidylethanol in blood (B-PEth): a marker for alcohol use and abuse

Phosphatidylethanol (PEth) represents a group of glycerophospholipid homologues where ethanol by phospholipase D has been bound at the position that normally contains an amino-alcohol. Since the formation of PEth is specifically dependent on ethanol, the diagnostic specificity of PEth as an alcohol biomarker is theoretically 100%. The half-life of PEth in blood is approximately 4 days. The amount of alcohol consumed correlates to blood concentration of PEth and PEth has been shown to be a more sensitive indicator of alcohol consumption than traditional alcohol markers, such as CDT (carbohydrate-deficient transferrin), GGT (γ-glutamyl transferase), and MCV (mean corpuscular volume) or a combination of these. Almost all clinical data so far available are based on a high performance liquid chromatography (HPLC) method with limited analytical sensitivity. With the advent of methods with considerably higher analytical sensitivity (e.g. mass spectrometric methods), clinical sensitivity will increase correspondingly. The possibility of determining very low concentrations of PEth by new sensitive analytical techniques may, however, have both ethical and legal consequences that have to be considered.     

Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder

The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.     

Some milestones in in vitro organ Toxicity Assessment. The Kidney as a Case Study

The expression of target organ toxicity ranges from subtle abnormalities of cellular organelles to permanent loss of organ function. The selective targeting of chemicals for discrete regions and cell types of a given organ is frequently due (besides some pharmacodynamic mechanisms) to the fact that target cells may express unique biochemical or functional characteristics predisposing them to chemically induced injury. In vitro models commonly used in target organ toxicity tests include perfused organ preparations, isolated tissue preparations, single-cell suspensions and tissue culture systems. Although these systems have proved their usefulness for acute toxicity tests, there is still a great need for in vitro models to be used for chronic toxicity tests. Among the systems listed above, the single-cell culture technique may be adapted to long-term study requirements. The example of kidney proximal tubules is taken to illustrate the necessity for extensive characterization of the actual capacities of the models in term of phenotypic profiling, energy status, drug detoxication activities, specific transport systems and organ-specific differentiated functions. LLC-PK1, LLC-RK1, NRK and OK cell lines are compared with primary cultures of rat, rabbit and human proximal tubule cells. The importance of the cell culture environment on the cell phenotypic profile, and its subsequent response pattern to toxicant exposure, are described using gentamicin and platinum derivatives as examples. In terms of experimental strategy, choice of cell type, choice of species of origin, choice of doses, choice of duration, continuous or discontinuous exposure, and whether to study the recovery phase, are crucial issues for designing models mimicking more closely the in vivo situation. The identification of relevant endpoints, allowing discrimination between general cell toxicity and specific organ toxicity, has not been sufficiently explored in vitro. Scientifically based endpoints referring to the background studies conducted by biochemists or physiologists should be selected and included in experimental designs dealing with organ toxicology in vitro. Conceptually, relevant specific target-organ toxicity could be investigated by the use of multiple cell types and by analysis of the difference in concentration between the cytotoxic concentration threshold and the specific endpoint alteration threshold.     

Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression.

Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported on the effects of rapid dietary TRP depletion in psychiatric patients; this study extends those reports and summarizes the effects of rapid TRP depletion on mood in depressed patients. One hundred and fifteen depressed (according to DSM-III-R) patients (69 drug free and symptomatic; 46 in clinical remission after antidepressant treatment) received tryptophan depletion testing in a double-blind, placebo-controlled, crossover fashion. Of 69 symptomatic, drug-free, depressed patients, 30 percent were unchanged the day of the tryptophan-free drink (TFD), but became clinically less depressed the day after the TFD. Although 80 percent of monoamine oxidase inhibitor- or fluvoxamine-treated patients experienced a depressive relapse during TRP depletion testing, only 18 percent of desipramine-treated patients relapsed. Brain 5-HT function may be intimately involved in the modulation of some affective states and in the mechanism of action of some antidepressant medications.