Childhood trauma associated with increased post-awakening cortisol in major depressive disorder.

BACKGROUND: Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma. METHODS: A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated. RESULTS: The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR. CONCLUSIONS: Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.

Comparison of hypothalamo-pituitary-adrenal function in treatment resistant unipolar and bipolar depression.

Altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this study was to test, for the first time, whether post-awakening cortisol, a highly reliable, naturalistic measure of HPA functioning, could distinguish patients with clearly defined treatment-resistant unipolar (TRUD) and bipolar depression (TRBD). A total of 37 patients with TRUD, 17 patients with TRBD, and 47 healthy controls were recruited. Areas under the curve (AUC) with respect to the ground (g) and increase (i) of post-awakening cortisol concentrations (awakening, +15, +30, +45, +60, +90 min) were measured over two days. Patients with TRUD had higher total cortisol production in the morning hours compared to controls (AUCg, p = 0.01), while they did not differ in terms of the awakening response (AUCi, p = 0.28). By contrast, subjects with TRBD had lower total cortisol when compared to controls by trend (AUCg, p = 0.07), while they did not differ in the awakening response (AUCi, p = 0.15). A direct comparison of TRUD and TRBD revealed differences in the AUCg (p = 0.003) and AUCi (p = 0.03). This finding of comparatively elevated HPA axis activity in the morning in TRUD and attenuated HPA axis activity in TRBD attests to a fundamental biological distinction between unipolar and bipolar depression. It has implications for the understanding and treatment of bipolar depression and in differentiating the two types of depression.

Fear Biases in Emotional Face Processing Following Childhood Trauma as a Marker of Resilience and Vulnerability to Depression.

There is a high prevalence of depression in adults with a history of childhood maltreatment. A negative cognitive bias is implicated in the etiology of depressive symptomatology and has also been found in physically abused children who show preferential processing of anger. However, how these biases mediate the link between childhood maltreatment and adult depression has not yet been clarified. This study involved 36 patients with depression (19 with and 17 without a history of childhood maltreatment) and 40 healthy controls (18 with and 22 without a history of childhood maltreatment). All participants were assessed using a facial emotion recognition task. Healthy individuals with a history of childhood maltreatment made significantly more errors in recognizing fear than anger. This difference between the number of errors for fear and anger was higher in healthy abused individuals than healthy nonabused individuals and depressed abused individuals. Resilient individuals with a history of childhood maltreatment but who have not developed depression show absence of a fear bias, which may help explain why they do not manifest depressive symptoms, despite their experiences of childhood maltreatment. In contrast, other individuals who become vulnerable to depression after childhood maltreatment show an amplified bias toward fear.

Long term effects of childhood trauma on cortisol stress reactivity in adulthood and relationship to the occurrence of depression.

BACKGROUND AND AIMS: Childhood trauma may have longstanding effects on individuals' propensity to react adversely to stress, and also predisposes individuals to suffer from depression. The current study aimed to examine stress reactivity in individuals with and without a history of childhood trauma by measuring cortisol responses to the passive viewing of stressful images, specifically including images relevant to childhood trauma. In addition, participants with and without a diagnosis of current depression were studied to investigate whether cortisol stress reactivity may underlie resilience or vulnerability to depression. METHODS: The study involved 17 healthy participants with and 24 without a history of childhood trauma; and 21 depressed patients with and 18 without a history of childhood trauma. Salivary cortisol was measured before, during and after participants were shown affectively laden images, including standardised scenes from the International Affective Picture System and also images suggestive of childhood abuse. Cortisol stress reactivity to the passive image viewing was compared between groups. RESULTS: In those who had experienced childhood trauma, cortisol stress responses were overall low and the same in those who were depressed and those who were not (mean stress reactivity variable - depressed: 0.8 nmol/l; non-depressed: 0.72 nmol/l). In contrast, cortisol stress reactivity was raised in depressed subjects relative to those who were not depressed in those without a history of childhood trauma (mean stress reactivity variable - depressed: 3.75 nmol/l; non-depressed: 0.1 nmol/l). CONCLUSIONS: A history of childhood trauma has longstanding effects on adulthood cortisol responses to stress, particularly in that depressed individuals with a history of childhood trauma show blunted cortisol responses. However, there were no differences between abused depressed and abused non-depressed subjects on cortisol stress responses, suggesting that such a finding does not explain subsequent susceptibility to depression. On the other hand, patients who experience depression without a history of childhood trauma show enhanced cortisol stress reactivity, which could help explain the aetiology of their depressive illnesses. Differences between the current findings and those using other pharmacological and stress challenge paradigms may relate to the type of stimuli used and to dysfunction at different levels of the hypothalamic-pituitary-adrenal (HPA) axis.

Long-term symptomatic and functional outcome following an intensive inpatient multidisciplinary intervention for treatment-resistant affective disorders.

BACKGROUND: The natural history of treatment-resistant depression (TRD) is poor, with high rates of chronicity and recurrence. We describe longer-term symptomatic and functional outcome following multimodal intensive inpatient treatment for TRD. METHODS: Symptomatic and functional outcomes were assessed in 71 participants (unipolar, n=51; bipolar, n=20) with severe TRD previously treated at a specialist inpatient unit a median of 34 months (IQR 19-52) post discharge. We looked at outcomes in defined subgroups (unipolar, bipolar and psychotic) and at symptom clusters to see whether certain aspects of depression were more resistant to treatment than others. RESULTS: Symptomatic improvement during the admission was maintained at follow up: HDRS21 scores fell from admission (median 22; IQR 19-25) to discharge (median 12; IQR 7-16) and follow-up (median 10; IQR 4-18). Overall, two-thirds of patients were judged to have a good long-term outcome, while half remained in full remission at follow-up. Outcomes were more favourable in bipolar patients, patients without a history of psychosis and patients who were discharged in remission, although a minority of responders at discharge no longer met response criteria at follow up, and conversely some patients discharged as non-responders did subsequently respond. Non-remitting depression was characterised by three main factors; anxiety, cognitive difficulties and sleep disturbance. Those who remitted had better functional outcomes as did those who had experienced a more sustained response to treatment whilst inpatients. Quality of life was poor for those who did not respond to the treatment package. LIMITATIONS: Variable follow-up length. CONCLUSIONS: This difficult-to-treat population gained long-term benefits from multidisciplinary inpatient treatment. Treatment to remission was associated with more favourable outcomes. Non-responsive depression was characterised by specific symptom clusters that might be amenable to more targeted treatments.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression.

BACKGROUND: Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS: One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS: Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS: The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS: Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

The role of mineralocorticoid receptor function in treatment-resistant depression.

BACKGROUND: Treatment-resistant depression patients show both reduced glucocorticoid receptor function and a hyperactive hypothalamic-pituitary-adrenal axis. However, few studies have examined the role of the mineralocorticoid receptor. This study aimed to evaluate the functional activity of the mineralocorticoid receptor system in regulating the hypothalamic-pituitary-adrenal axis in well-defined treatment-resistant depression patients. MATERIAL AND METHOD: We recruited 24 subjects divided into: (a) treatment-resistant depression; (b) healthy controls. We evaluated: (a) the effect of combined glucocorticoid receptor/mineralocorticoid receptor stimulation with prednisolone; (b) the effect of prednisolone with the mineralocorticoid receptor antagonist spironolactone; and (c) the effect of spironolactone alone. The response of the hypothalamic-pituitary-adrenal axis was measured using salivary cortisol and plasma levels of drugs were also measured. RESULTS: Treatment-resistant depression patients had higher cortisol compared with controls after all challenges. In controls, spironolactone increased cortisol compared to placebo. The co-administration of spironolactone with prednisolone in controls decreases the suppressive effects of prednisolone. In contrast, in treatment-resistant depression, spironolactone did not increase cortisol compared to placebo and spironolactone with prednisolone had no effect on the suppressive effects of prednisolone. Patients with treatment-resistant depression had a reduction in the conversation of spironolactone to the active metabolite canrenone. CONCLUSION: Our data confirmed that treatment-resistant depression is associated with hypercortisolism and these patients no longer show an hypothalamic-pituitary-adrenal response to the administration of a mineralocorticoid receptor antagonist, suggesting that there is a mineralocorticoid receptor malfunctioning, such as a down regulation, however, pharmacokinetics and pharmacodynamics in these subjects could also have had an effect on the lack of mineralocorticoid receptor response.

Prediction of longer-term outcome of treatment-resistant depression in tertiary care.

BACKGROUND: Systematic studies on the outcome of treatment-resistant depression are scarce. AIMS: To describe the longer-term outcome and predictors of outcome in treatment-resistant depression. METHOD: Out of 150 patients approached, 118 participants with confirmed treatment-resistant depression (unipolar, n = 77; bipolar, n = 27; secondary, n = 14) treated in a specialist in-patient centre were followed-up for between 8 and 84 months (mean = 39, s.d. = 22). RESULTS: The majority of participants attained full remission (60.2%), most of whom (48.3% of total sample) showed sustained recovery (full remission for at least 6 months). A substantial minority had persistent subsyndromal depression (19.5%) or persistent depressive episode (20.3%). Diagnosis of bipolar treatment-resistant depression and poorer social support were associated with early relapse, whereas strong social support, higher educational status and milder level of treatment resistance measured with the Maudsley Staging Method were associated with achieving quicker remission. Exploratory analysis of treatment found positive associations between treatment with a monoamine oxidase inhibitor (MAOI) in unipolar treatment-resistant depression and attaining remission at discharge and at final follow-up, and duloxetine use predicted attainment of remission at final follow-up. CONCLUSIONS: Although many patients with treatment-resistant depression experience persistent symptomatology even after intensive, specialist treatment, most can achieve remission. The choice of treatment and presence of good social support may affect remission rates, whereas those with low social support and a bipolar diathesis should be considered at higher risk of early relapse. We suggest that future work to improve the long-term outcome in this disabling form of depression might focus on social interventions to improve support, and the role of neglected pharmacological interventions such as MAOIs.

Confidence judgment in depression and dysphoria: the depressive realism vs. negativity hypotheses.

BACKGROUND AND OBJECTIVES: According to the negativity hypothesis, depressed individuals are over-pessimistic due to negative self-concepts. In contrast, depressive realism suggests that depressed persons are realistic compared to their nondepressed controls. However, evidence supporting depressive realism predominantly comes from judgment comparisons between controls and nonclinical dysphoric samples when the controls showed overconfident bias. This study aimed to test the validity of the two accounts in clinical depression and dysphoria. METHODS: Sixty-eight participants, including healthy controls (n = 32), patients with DSM-IV major depression (n = 20), and dysphoric participants with CDC-defined chronic fatigue syndrome (n = 16) performed an adjective recognition task and reported their item-by-item confidence judgments and post-test performance estimate (PTPE). RESULTS: Compared to realistic PTPE made by the controls, patients with major depression showed significant underconfidence. The PTPE of the dysphoric participants was relatively accurate. Both the depressed and dysphoric participants displayed less item-by-item overconfidence as opposed to significant item-by-item overconfidence shown by the controls. LIMITATIONS: The judgment-accuracy patterns of the three groups need to be replicated with larger samples using non-memory task domains. CONCLUSION: The present study confirms depressive realism in dysphoric individuals. However, toward a more severe depressive emotional state, the findings did not support depressive realism but are in line with the prediction of the negativity hypothesis. It is not possible to determine the validity of the two hypotheses when the controls are overconfident. Dissociation between item-by-item and retrospective confidence judgments is discussed.

Long-term impact of residual symptoms in treatment-resistant depression.

OBJECTIVE: Although commonly encountered, little work has defined the longitudinal course of treatment-resistant depression (TRD) and the influence of residual posttreatment symptoms on longer-term outcome. The aim of our study was to assess the impact of posttreatment clinical states on longer-term outcome. METHOD: Patients (n = 118) with TRD received specialist inpatient treatment and were followed-up for a median of 3 years. Longitudinal outcome dichotomized into good and poor outcome was used as the primary outcome and functional measures were used as secondary outcomes. RESULTS: Among 118 treated patients, 40 (34%) entered clinical remission, 36 (31%) entered partial remission, and 42 (37%) remained in episode at discharge. At follow-up, 35% had longitudinally defined poor outcome. Posttreatment clinical status was the main predictor of both poor and good outcome. Nearly 50% of patients achieved postdischarge recovery, and subsequently had longer-term outcome, comparable with patients discharged in remission. Patients who remained in episode posttreatment were more symptomatically and functionally impaired. CONCLUSION: Posttreatment clinical states are a useful guide to clinicians for projecting the longer-term outcome of patients with TRD. The persistence of residual or syndromal symptoms predicts a poorer longer-term outcome, whereas treatment to remission is associated with better outcomes.

Prospective evaluation of specialist inpatient treatment for refractory affective disorders.

BACKGROUND: Little data exist to inform the treatment of severe and resistant affective disorders. We report here the effectiveness of specialist multimodal inpatient treatment for refractory affective disorders. METHODS: Prospective evaluation of 225 consecutive patients admitted to the National Affective Disorders Unit between 2001 and 2008. RESULTS: Patients were highly treatment-resistant: most had already received ECT, lithium augmentation and over 10 prior treatment trials. Even so, sequential assessment with the Hamilton Depression Rating Scale found that 69% showed a clinical response (≥ 50% reduction in Hamilton score) to intensive therapy during admission; 50% continued to sustain a full response and 71% at least a partial response on discharge. Patients' self-ratings (57% very much or much improved, 24% slightly improved) and relative and referrer reports (75% and 68% respectively rated patients as improved) gave similar levels of improvement. LIMITATIONS: This was an observational study, without any untreated control group. The generalisability of the findings is limited by the highly specialised nature of the unit. CONCLUSIONS: Most patients with depression highly resistant to prior treatment respond to specialist and intensive multimodal inpatient therapy.

The prednisolone suppression test in depression: dose-response and changes with antidepressant treatment.

Depressed patients have reduced glucocorticoid receptor (GR) function, as demonstrated by resistance to the suppressive effects of the synthetic glucocorticoid hormone, and GR agonist, dexamethasone. We have developed a suppressive test with prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics, and binds to both the GR and the mineralocorticoid receptor (MR). We have found that depressed patients suppress normally to prednisolone, unless they are particularly non-responsive to treatment. In the present study, we evaluated 28 inpatients with treatment-resistant depression (TRD), and compared salivary cortisol secretion (at 0900 h, 1200 h and 1700 h) after placebo or after prednisolone (5 mg), before and after an inpatient treatment admission. Half of the patients (n=14) reached treatment response. When comparing the assessment between admission and discharge, cortisol output after placebo fell (-26% of area under the curve; p=0.024) while the output after prednisolone did not change. Moreover, there was no change in the response to prednisolone (percentage suppression) between admission at discharge, and this was not influenced by treatment response. Finally, we could confirm and extend our previously published data with prednisolone (5 mg), showing that depressed patients (n=12) and controls (n=12) suppressed equally to both 5 and 10 mg doses of prednisolone. This study suggests that the response to prednisolone is similar in depressed patients and controls at different doses of prednisolone, and does not change with symptomatic improvement. This is in contrast with findings, from us and others, using other measures of hypothalamic-pituitary-adrenal axis function, such as basal cortisol levels or the response to dexamethasone. Thus, we propose that the prednisolone suppression test may offer specific biological and clinical information, related to its action at both the GR and the MR.

Evidence for a role of progesterone in menstrual cycle-related variability in prepulse inhibition in healthy young women.

Prepulse inhibition (PPI) of the startle response is sensitive to sex, with healthy young women showing less PPI compared with age-matched men, and varies according to the menstrual cycle phase in women. Relatively less is known regarding sex and hormonal influences in prepulse facilitation (PPF). Menstrual phase-related variability in PPI is suggested to be mediated by fluctuating estrogen level, based on the observations of more PPI in women during the follicular, relative to the luteal, phase. No study has directly assessed the relationship between fluctuating hormones and PPI or PPF levels over the human ovarian cycle. To examine the roles of circulating ovarian hormones in PPI and PPF, 16 non-smoking regularly menstruating healthy women were tested during both the follicular and luteal phases on PPI and PPF and provided saliva samples for measurement of 17beta-estradiol (estrogen), progesterone and testosterone. The results showed higher levels of 17beta-estradiol and progesterone during the luteal, relative to the follicular, phase; and more PPI during the follicular phase and more PPF during the luteal phase with comparable startle amplitude and habituation during the two phases. A larger increase in progesterone was associated with a smaller decrease in PPI from the follicular to the luteal phase. No significant associations were found between changes in PPI/PPF and estrogen levels. The findings confirm lower PPI during the luteal, compared with the follicular, phase and suggest a role for progesterone, more specifically an antipsychotic-like PPI-restoration action of progesterone, during the luteal phase in PPI of young women.

Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance.

BACKGROUND: People with severe depressive illness have raised levels of cortisol and reduced glucocorticoid receptor function. AIMS: To obtain a physiological assessment of hypothalamic-pituitary-adrenal (HPA) axis feedback status in an in-patient sample with depression and to relate this to prospectively determined severe treatment resistance. METHOD: The prednisolone suppression test was administered to 45 in-patients with depression assessed as resistant to two or more antidepressants and to 46 controls, prior to intensive multimodal in-patient treatment. RESULTS: The patient group had higher cortisol levels than controls, although the percentage suppression of cortisol output after prednisolone in comparison with placebo did not differ. Non-response to in-patient treatment was predicted by a more dysfunctional HPA axis (higher cortisol levels post-prednisolone and lower percentage suppression). CONCLUSIONS: In patients with severe depression, HPA axis activity is reset at a higher level, although feedback remains intact. However, prospectively determined severe treatment resistance is associated with an impaired feedback response to combined glucocorticoid and mineralocorticoid receptor activation by prednisolone.

A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method.

OBJECTIVE: Treatment resistance is a common clinical phenomenon in depression. However, current unitary models of staging fail to represent its complexity. We aimed to devise a model to stage treatment-resistant depression, taking into account the core factors contributing to treatment failure. METHOD: We reviewed the literature to identify factors consistently associated with treatment resistance. We also analyzed data from a subgroup of patients discharged from a specialist inpatient unit for whom adequate data were obtainable. RESULTS: We present a points-based staging model incorporating 3 factors: treatment, severity of illness, and duration of presenting episode. In this model, the rating of symptom severity ranges from subsyndromal depression (score 1) to severe syndromal depression with psychosis (score 5). Antidepressant treatment is rated on a 5-point subscale based on number of medications used, while duration of the presenting episode is rated on a 3-point subscale. The overall level of resistance estimated using this model varies from minimal resistance (score of 3) to severe resistance (score of 15). The rating system allows the overall severity of treatment resistance to be summarized either as a single numeric score or under a single descriptive category. It may also be possible to specify categories (mild, moderate, and severe) based on severity of resistance. Analysis of inpatient data indicates that the factors incorporated in the model and the model itself have some predictive validity. CONCLUSION: This staging model has reasonable face and predictive validity and may have better utility in staging treatment resistance than currently available methods.

The ratio of cortisol/DHEA in treatment resistant depression.

OBJECTIVE: Hypercortisolaemia has been well described in depression and may be a factor associated with treatment resistance. The role of the more abundant adrenal steroid dehydroepiandrosterone (DHEA) has been recently investigated, with some evidence that it may have an antiglucocorticoid effect. This study measured cortisol, DHEA and their ratio in treatment resistant depression (TRD) and healthy controls and also related these measures to treatment outcome. METHOD: Plasma cortisol, DHEA and cortisol/DHEA ratio were determined at 0900h in 28 patients with TRD and 40 healthy controls. The measures were repeated following inpatient treatment in a subgroup of 21 patients and related to the outcome of such treatment. The stability of cortisol/DHEA ratios was assessed with 2 hourly samples from 0900 to 1700h in a subgroup of 15 controls. RESULTS: Basal levels of cortisol and the cortisol/DHEA ratio were higher in patients compared to controls. Whilst cortisol levels were lower after treatment, there was no relationship between cortisol levels and treatment outcome. In contrast, treatment responders had significantly lower DHEA on admission and a higher cortisol/DHEA ratio both on admission and on discharge. Cortisol/DHEA ratios were stable between 9 a.m. and 5 p.m. CONCLUSIONS: In addition to cortisol, the cortisol/DHEA ratio is raised in TRD; thus, there is no evidence that DHEA levels could negate the increased glucocorticoid activity in TRD. Patients with a more abnormal cortisol/DHEA ratio, possibly indicating greater biological dysfunction, responded preferentially to inpatient therapy, though the raised cortisol/DHEA ratio persisted after response. The cortisol/DHEA ratio is stable throughout the day and may be a more practical biological marker of TRD.

Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test.

BACKGROUND: Chronic fatigue syndrome (CFS) is associated with hypocortisolism, but it is not yet clear the extent to which enhanced negative feedback may underlie this finding. METHODS: We undertook a low-dose dexamethasone (0.5 mg) suppression test in 18 CFS patients and 20 matched, healthy controls. We measured salivary cortisol levels at 0800 h, 1200 h, 1600 h and 2000 h before and after the administration of 0.5 mg of dexamethasone. RESULTS: Basal cortisol output was raised in this group of CFS patients compared to controls. Overall, the percentage suppression following dexamethasone administration was no different between CFS (mean+/-sem: 80.4+/-4.4%) and controls (76.2+/-4.9 %). However, the sub-group of patients with CFS and comorbid depression (n=9) showed a significant hypersuppression of salivary cortisol in response to dexamethasone (89.0+/-1.9%; p<0.05 v controls). LIMITATIONS: The sub-group analysis was on small numbers and should be considered preliminary. Dexamethasone probes only glucocorticoid medicated negative feedback but does not probe mineralocorticoid feedback, the other main physiological feedback mechanism. CONCLUSION: We found partial support for the hypothesis of enhanced negative feedback in CFS but only in patients with comorbid depression and also in the context of a sample of patients with elevated basal cortisol levels, which is an atypical finding in the literature.

Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression.

Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 muM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.

A comparison of prepulse inhibition in pre- and postmenopausal women and age-matched men.

Prepulse inhibition (PPI) of the startle response is sensitive to sex with women showing less PPI compared with age-matched men and varies according to the menstrual cycle in women. Relatively less is known about sex differences in prepulse facilitation (PPF). To examine further the roles of sex and circulating sex hormones, pre- (n=20) and postmenopausal women (n=20) were compared with men of similar ages (n=17, 18-40 years; n=18, 55-69 years). All participants were assessed on PPI and PPF, and provided saliva samples for measurement of 17beta-estradiol (estrogen) and testosterone. Premenopausal women showed less PPI compared with age-matched men, with no significant difference in PPF. Postmenopausal women did not differ in PPI but showed more PPF than age-matched men. There was less PPI and PPF in older, relative to young, men; pre- and postmenopausal women did not differ significantly. PPI showed no association with the levels of sex hormones. PPF showed small positive associations with both the levels of estrogen and testosterone, especially in young men. The present findings extend recent observations in mice showing less PPI in premenopausal, but not postmenopausal, female compared with male mice of similar ages (Ison and Allen, Behav Brain Res, 2007) to humans. There appear to be no substantial relationships between individual differences in endogenous levels of sex hormones and PPI; fluctuations within an individual may have a stronger role.

Different responses to dexamethasone and prednisolone in the same depressed patients.

RATIONALE: Patients with major depression show hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear. OBJECTIVES: We have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic-pituitary-adrenal (HPA) axis in depressed patients. Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function. MATERIALS AND METHODS: We used a single-blind, repeated-measure design. We administered placebo, prednisolone (5 mg) or dexamethasone (0.5 mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers. On the following days, we collected salivary cortisol from 9:00 to 22:00. RESULTS: Depressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001). Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5 mg) was -85% in controls vs -46% in depressed patients (p=0.018). However, the same depressed patients showed normal suppression by prednisolone (5 mg): suppression was -41% in controls and -36% in depressed patients (p=0.6). CONCLUSIONS: We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.