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

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

BackgroundSystematic studies on the outcome of treatment-resistant depression are scarce.AimsTo describe the longer-term outcome and predictors of outcome in treatment-resistant depression.MethodOut of 150 patients approached, 118 participants with confirmed treatment-resistant depression (unipolar, n= 7; 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).ResultsThe 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 (MAOl) 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.ConclusionsAlthough 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.</jats:sec

Doping Test Results Dependent on Genotype of UGT2B 17, the Major Enzyme for Testosterone Glucuronidation

Running title: UGT2B17 and testosterone doping Key terms: UGT2B17 deletion polymorphism, T/E ratio, testosterone doping, testosterone enanthate, glucuronidation, urinary excretion Number of words (abstract): 247 Number of words (text): 3460 Number of tables and figures: 3, 3 The authors have nothing to disclose. Abstract Context: Testosterone abuse is conventionally assessed by the urinary testosterone/ epitestosterone (T/E) ratio, levels above 4.0 being considered suspicious. The large variation in testosterone glucuronide (TG) excretion and its strong association with a deletion polymorphism in the UGT2B17 gene challenge the accuracy of the T/E ratio test. Objective: To investigate whether genotype based cut-off values will improve the sensitivity and specificity of the test. Design: Open 3-armed comparative study. Participants: 55 healthy male volunteers with either two, one or no allele (ins/ins, ins/del or del/del) of the UGT2B17 gene. Intervention: A single intramuscular dose of 500 mg testosterone enanthate. Main outcome measures: Urinary excretion of TG after dose and the T/E ratio during 15 days. Results: The degree and rate of increase in TG excretion rate was highly dependent on the UGT2B17 genotype with a 20-fold higher average maximum increase in the ins/ins group compared to the del/del group. Forty percent of the del/del subjects never reached the T/E ratio of 4.0 on any of the 15 days after the dose. When differentiated cut-off levels for the del/del (1.0) and the other genotypes (6.0) were applied, the sensitivity increased substantially for the del/del group and false positives in the other genotypes were eliminated. Conclusion: Consideration of the genetic variation in disposition of androgens will improve the sensitivity and specificity of the testosterone doping test. This is of interest not only for combatting androgen doping in sports, but also for detecting and preventing androgen abuse in the society

Doping Test Results Dependent on Genotype of UGT2B 17, the Major Enzyme for Testosterone Glucuronidation

Running title: UGT2B17 and testosterone doping Key terms: UGT2B17 deletion polymorphism, T/E ratio, testosterone doping, testosterone enanthate, glucuronidation, urinary excretion Number of words (abstract): 247 Number of words (text): 3460 Number of tables and figures: 3, 3 The authors have nothing to disclose. Abstract Context: Testosterone abuse is conventionally assessed by the urinary testosterone/ epitestosterone (T/E) ratio, levels above 4.0 being considered suspicious. The large variation in testosterone glucuronide (TG) excretion and its strong association with a deletion polymorphism in the UGT2B17 gene challenge the accuracy of the T/E ratio test. Objective: To investigate whether genotype based cut-off values will improve the sensitivity and specificity of the test. Design: Open 3-armed comparative study. Participants: 55 healthy male volunteers with either two, one or no allele (ins/ins, ins/del or del/del) of the UGT2B17 gene. Intervention: A single intramuscular dose of 500 mg testosterone enanthate. Main outcome measures: Urinary excretion of TG after dose and the T/E ratio during 15 days. Results: The degree and rate of increase in TG excretion rate was highly dependent on the UGT2B17 genotype with a 20-fold higher average maximum increase in the ins/ins group compared to the del/del group. Forty percent of the del/del subjects never reached the T/E ratio of 4.0 on any of the 15 days after the dose. When differentiated cut-off levels for the del/del (1.0) and the other genotypes (6.0) were applied, the sensitivity increased substantially for the del/del group and false positives in the other genotypes were eliminated. Conclusion: Consideration of the genetic variation in disposition of androgens will improve the sensitivity and specificity of the testosterone doping test. This is of interest not only for combatting androgen doping in sports, but also for detecting and preventing androgen abuse in the society.