Acute Stress-Induced Coagulation Activation in Patients With Remitted Major Depression Versus Healthy Controls and the Role of Stress-Specific Coping.

BACKGROUND: Depressed patients have an increased risk of myocardial infarction, for which acute stress is a frequent trigger. Prothrombotic changes could be one involved mechanism that can be modulated by psychological coping. PURPOSE: We examined the effects of remitted major depression and situation-specific coping strategies on stress-induced coagulation activation. METHODS: Forty patients with remitted depression and 23 healthy controls underwent the Trier Social Stress Test, rating applied coping strategies thereafter. Blood was sampled at baseline and 15 and 45 min poststress to measure fibrinogen, von Willebrand factor (VWF) and D-dimer. Coagulation activation over time was quantified as area under the curve (AUC) with respect to baseline activity. Standardized z-scores of individual coagulation AUC measures were added up to a prothrombotic index. RESULTS: Stress provoked significant VWF (p = .024) and D-dimer (p = .002) responses. Remitted depressed patients used positive distraction coping more frequently than controls did (p = .030). Coagulation AUC measures were similar in both groups. In all participants, higher positive coping total (p = 0.009), driven by devaluation/defense (p = .022) and distraction (p = .004) coping, was associated with a lower prothrombotic index. In controls, but not in remitted depressed patients, higher positive coping total (p = .008), driven by higher devaluation/defense (p = .010) and distraction (p = .023) coping, was associated with lower VWF AUC. CONCLUSIONS: Despite the use of favorable coping strategies in a specific stress situation, remitted depressed patients may benefit less from a positive effect of positive situational coping on coagulation activation than controls. Such a mechanism could partially explain the increased risk of myocardial infarction in depressed individuals.

Evidence for an enhanced procoagulant state in remitted major depression.

OBJECTIVES: Hypercoagulability is one mechanism to explain the increased risk of incident atherothrombotic disease in patients with major depressive disorder (MDD). We examined whether patients with remitted MDD show an enhanced procoagulant state. METHODS: 63 individuals (median age 35 years, 59% women), 40 with a DSM-IV diagnosis of remitted MDD, made by a clinical interview, and 23 healthy controls provided blood samples for the measurement of fibrinogen, D-dimer, von Willebrand factor, and plasminogen activator inhibitor-1. Standardised z-scores of plasma levels of these haemostatic factors were added to form a procoagulant index (PCI) as the primary outcome variable. Self-ratings of residual depressive symptoms and trait anxiety were also obtained. RESULTS: Compared with controls, remitted MDD patients had higher PCI (p = 0.013, Cohen's d = 0.69) and fibrinogen (p = 0.001, d = 0.91), controlling for age, sex, body mass index, smoking and C-reactive protein. There were no significant associations of the PCI and individual haemostatic molecules with age of MDD onset, time since the last MDD episode, the number of previous MDD episodes and residual depressive symptoms. Additional adjustment for anxiety symptoms did not change these results. CONCLUSIONS: Remitted MDD is associated with an enhanced procoagulant state. Hypercoagulability seems more a trait than a state characteristic of depression.

Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.

FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

BACKGROUND: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. METHODS: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. RESULTS: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. CONCLUSIONS: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

Transgender transitioning and change of self-reported sexual orientation.

OBJECTIVE: Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A common reason for this phenomenon is not known. METHODS: We included 115 transsexual persons (70 male-to-female "MtF" and 45 female-to-male "FtM") patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation. RESULTS: In total, 32.9% (n = 23) MtF reported a change in sexual orientation in contrast to 22.2% (n = 10) FtM transsexual persons (p = 0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males ( = androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p = 0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p =0.05). CONCLUSION: In line with earlier reports, we reveal that a change in self-reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individual's biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon.

Increased HPA axis response to psychosocial stress in remitted depression: the influence of coping style.

The aim of the study was to examine the modulating effects of coping style on the response to psychosocial stress in remitted major depression (MD) and healthy controls. Thirty-three participants with a lifetime history of MD, who were in remission, and 32 age- and gender-matched healthy controls were recruited from a longitudinal-epidemiological study, in which the presence or absence of mental disorders was prospectively ascertained. Participants (aged 30-41 years) underwent two consecutive Trier Social Stress Tests (TSSTs). Subjects with a lifetime history of MD showed larger plasma ACTH and cortisol concentrations in response to both TSSTs, confirming a disturbed hypothalamic-pituitary-adrenal (HPA) axis regulation. Moreover, the MD group reported less positive, adaptive coping strategies and more negative, maladaptive strategies than the control group. The amount of negative coping predicted the size of the plasma cortisol response in the combined group. Our results demonstrate the importance of psychological coping strategies for the investigation of HPA axis response in depression.

Psychopathological profiles in transsexuals and the challenge of their special status among the sexes.

OBJECTIVE: Investigating psychopathological profiles of transsexuals raises a very basic methodological question: are control groups, which represent the biological or the phenotypic sex, most suited for an optimal evaluation of psychopathology of transsexuals? METHOD: Male-to-female (MtF) (n=52) and female-to-male transsexuals (FtM) (n=32), receiving cross-sex hormone treatment, were compared with age matched healthy subjects of the same genetic sex (n=178) and with the same phenotypic sex (n=178) by means of the Symptom Check List-90-Revisited instrument (SCL-90-R). We performed analyses of covariance (ANCOVA) to test for group and sex effects. Furthermore, we used a profile analysis to determine if psychopathological symptom profiles of transsexuals more closely resemble genotypic sex or phenotypic sex controls. RESULTS: Transsexual patients reported more symptoms of psychopathological distress than did healthy control subjects in all subscales of the SCL-90-R (all p<0.001), regardless of whether they were compared with phenotype or genotype matched controls. Depressive symptoms were more pronounced in MtF than in FtM (SCL-90-R score 0.85 vs. 0.45, p = 0.001). We could demonstrate that FtM primarily reflect the psychopathological profile of biological males rather than that of biological females (r = 0.945), while MtF showed a slightly higher profile similarity with biological females than with biological males (r = 0.698 vs. r = 0.685). CONCLUSION: Our findings suggest that phenotypic sex matched controls are potentially more appropriate for comparison with the psychopathology of transsexual patients than are genetic sex matched controls.

Stress response regulation in panic disorder.

Panic disorder is a frequent and disabling mental disorder characterized by recurrent periods or abrupt surges of intense fear or discomfort, the panic attacks. The clinical phenomenology of panic attacks suggests a prominent role of a disturbed stress response regulation in the aetiopathology of this disorder. We summarize the results of challenge tests of the hypothalamus-pituitary-adrenocortical (HPA) axis in panic disorder and give an overview of studies using psychosocial challenge paradigms. The results of HPA axis challenge tests suggest an increased expression of the hypothalamic neuropeptides, but an intact negative feedback inhibition at the level of the pituitary. Psychosocial challenge tests give evidence for dissociation between the subjective stress response and the HPA axis response in panic disorder, which might be the result of an over-focussed self-monitoring leading to an enhanced stress perception despite normal HPA axis activation. We integrated these findings in a cognitive stress control model suggesting that panic disorder patients develop efficient strategies to control the somatic stress response despite a hypothalamic hyperdrive of the HPA axis. To employ these strategies at the right time, patients acquired an enhanced perception of stress symptoms, leading to the reported dissociation of the subjective and HPA axis response. It can be inferred from these findings that cognitive behavioral therapy addressing over-focussed self-monitoring and maladaptive control strategies in combination with pharmacological treatment against over-expression of the hypothalamic neuropeptides should be an effective treatment in severe forms of panic disorder, which corresponds with recent treatment guidelines.