Gunther Meinlschmidt

Plasma oxytocin concentration during pregnancy is associated with development of postpartum depression

Postpartum depression (PPD) affects up to 19% of all women after parturition. The non-apeptide oxytocin (OXT) is involved in adjustment to pregnancy, maternal behavior, and bonding. Our aim was to examine the possible association between plasma OXT during pregnancy and the development of PPD symptoms. A total of 74 healthy, pregnant women were included in this prospective study. During the third trimester of pregnancy and within 2 weeks after parturition, PPD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Blood samples for plasma OXT assessment were collected in the third trimester. Following the literature, participants with postpartum EPDS scores of 10 or more were regarded as being at risk for PPD development (rPPD group). In a logistic regression analysis, plasma OXT was included as a potential predictor for being at risk for PPD. Results were controlled for prepartal EPDS score, sociodemographic and birth-outcome variables. Plasma OXT concentration in mid-pregnancy significantly predicted PPD symptoms at 2 weeks postpartum. Compared with the no-risk-for-PPD group, the rPPD group was characterized by lower plasma OXT concentrations. To our knowledge, this is the first study to show an association between prepartal plasma OXT concentration and postpartal symptoms of PPD in humans. Assuming a causal relationship, enhancing OXT release during pregnancy could serve as a potential target in prepartum PPD prevention, and help to minimize adverse effects of PPD on the mother–child relationship.

Sensitivity to Intranasal Oxytocin in Adult Men with Early Parental Separation

BACKGROUND Central oxytocin (OT) is critically involved in mediating social bonding and protecting against stress, depression, and anxiety. In animal models, early social experiences induce changes in central OT systems. In humans, early parental separation (EPS) increases the risk for emotional disorders in adulthood. We examined neuroendocrine responses to intranasal OT administration in men with EPS and healthy control subjects as an estimate of central OT sensitivity. METHODS Salivary cortisol concentrations were measured in 9 healthy men with EPS and 10 control subjects before and after double-blind intranasal administration of placebo and OT (24 IU Syntocinon). RESULTS Relative to placebo, intranasal OT resulted in attenuated cortisol decreases in EPS subjects compared with control subjects. CONCLUSIONS These preliminary results may suggest altered central sensitivity to the effects of OT after EPS. Future studies should replicate these results and scrutinize the role of OT in mediating risk versus resilience to psychopathology after early social adversity.

Epidemiology of the association between somatoform disorders and anxiety and depressive disorders: an update.

Objective: To review the available epidemiological evidence on associations between somatoform disorders with anxiety and depressive disorders. Results: Clinical and population-based studies have found that the co-occurrence of some types of somatoform disorders (e.g., somatization disorder, somatic-symptom-index (SSI)4,6, and pain disorder) and anxiety and depressive disorders is common. These findings may suggest either a causal relationship between these disorders or that they share some common etiological factors. For other forms of somatoform disorders, empirical evidence about co-occurrence is even thinner or not available at all, especially from non-western settings. Conclusion: Some implications of how these findings, or the absence of them, can help us understand better the etiology of somatoform disorders and improve the classification of mental disorders as a whole are discussed. DSM = Diagnostic and Statistical Manual of Mental Disorders; DIS = Diagnostic Interview Schedule; ECA = Epidemiological Catchment Area Program; FGD = functional gastrointestinal disorders; GAD = general anxiety disorder; OR = odds ratio; PTSD = posttraumatic stress disorder; SSI = Somatic Symptom Index.

Selective amnesic effects of oxytocin on human memory

The neuropeptide oxytocin is essential for mammalian parturition and lactation. Recent animal studies suggest that oxytocin is also implicated in the central nervous control of behavior including learning and memory. There has been little investigation, however, of the impact of oxytocin on human memory. The purpose of this study was to investigate the effect of a single dose of intranasal oxytocin on implicit and explicit memory in humans. In a placebo-controlled, double-blind study, 38 healthy men were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before the study phase (incidental learning). Memory was measured using three different memory tests: an implicit perceptual test (word stem completion), an implicit conceptual test (category-cued semantic association), and an explicit test (cued recall). Due to the reproductive-biological role of oxytocin and the impact of adequate environmental conditions for the stimulation of behavioral effects of oxytocin known from animal research, we used semantic word stimuli with reproduction-related vs. neutral meaning. Oxytocin significantly impaired recall performance as compared with placebo treatment irrespective of the meaning of words in the cued recall test. In the implicit conceptual test, characterized by a deepened information processing, compared with placebo, oxytocin significantly impaired only the overall generation of associated target words with reproduction relevant meaning, whereas no significant difference between oxytocin and placebo was obtained for neutral words. These findings concur with data from animal research suggesting that central oxytocin selectively influences memory performance depending on the kind of memory test used and, more importantly, the psychobiological relevance of stimuli.

Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF ) after acute psychosocial stress

Environmentally induced epigenetic alterations are related to mental health. We investigated quantitative DNA methylation status before and after an acute psychosocial stressor in two stress-related genes: oxytocin receptor (OXTR) and brain-derived neurotrophic factor (BDNF ). The cross sectional study took place at the Division of Theoretical and Clinical Psychobiology, University of Trier, Germany and was conducted from February to August 2009. We included 83 participants aged 61–67 years. Thereof, 76 participants completed the full study procedure consisting of blood sampling before (pre-stress), 10 min after (post-stress) and 90 min after (follow-up) the Trier social stress test. We assessed quantitative DNA methylation of whole-blood cells using Sequenom EpiTYPER. Methylation status differed between sampling times in one target sequence of OXTR (P<0.001): methylation increased from pre- to post-stress (P=0.009) and decreased from post-stress to follow-up (P<0.001). This decrease was also found in a second target sequence of OXTR (P=0.034), where it lost statistical significance when blood cell count was statistically controlled. We did not detect any time-associated differences in methylation status of the examined BDNF region. The results suggest a dynamic regulation of DNA methylation in OXTR—which may in part reflect changes in blood cell composition—but not BDNF after acute psychosocial stress. This may enhance the understanding of how psychosocial events alter DNA methylation and could provide new insights into the etiology of mental disorders.

Decreased cortisol awakening response after early loss experience

Early loss experience (ELE) due to death or separation is a major risk factor for the development of several psychiatric and physical disorders in adulthood. Few studies have focused on the effects of ELE on neuroendocrine systems, which might mediate this risk in part. The goal of this study was to evaluate salivary cortisol responses to awakening in individuals with and without ELE. A total of 95 healthy college students (29 men, 66 women) completed a questionnaire on ELE and were instructed to collect saliva immediately after awakening and 30 min later. Fifty-five of the 95 subjects reported having experienced the separation or divorce of their parents and/or the death of a close relative before the age of 14 years. Subjects with such ELE exhibited decreased salivary cortisol responses to awakening compared to subjects without ELE (net increase: 4.78 nmol/l versus 9.83 nmol/l; t93 = 2.88, p = 0.005). The effect was most pronounced in individuals who experienced multiple types of ELE, while there were no sex differences. In conclusion, ELE appears to be associated with decreased salivary cortisol responses to awakening. Low cortisol awakening responses are believed to reflect altered dynamics of the hypothalamic-pituitary-adrenal (HPA) axis, possibly conferring risk for certain stress-related disorders.

Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder ☆

In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system. However, few studies have investigated molecular signaling pathways known to critically regulate inflammation. Additionally, the relationship between inflammatory function and immune cell glucocorticoid sensitivity has not been extensively explored in PTSD. Nuclear factor-κB (NF-κB) pathway activity was examined in peripheral blood mononuclear cells obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls (ages 19-48) using DNA-binding ELISA. Glucocorticoid sensitivity of monocytes in whole blood was measured as the concentration of dexamethasone needed to suppress in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production by 50% (DEX IC(50)). Women with PTSD displayed increased NF-κB pathway activity compared to controls (t [34]=2.45, p=0.02) that was positively correlated with PTSD severity (determined by PTSD symptom severity scale) (r(s)=0.39, p=0.02). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC(50) (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants (r=0.66, p<0.001). These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.

Helplessness: a systematic translational review of theory and evidence for its relevance to understanding and treating depression.

Helplessness is a major concept in depression and a major theme in preclinical and clinical depression research. For example, in rodents and humans, the learned helplessness (LH) effect describes a specific deficit in behaviour to control aversive stimuli that is induced by prior exposure to uncontrollable aversive stimuli. The LH effect is objective and valid in that the cause of the behavioural deficit, namely uncontrollability, is clear; furthermore, the deficit induced is underlain by emotional, motivational and cognitive processes that are relevant to depression psychopathology. As a further example, helplessness, hopelessness, external locus of control and causal attribution are inter-related and major themes in psychological theories (primarily cognitive theories) of depression. Despite this broad interest in helplessness, it can be argued that its potential usefulness as a scientific and clinical concept has so far not been investigated optimally, including with respect to its application in research aimed at development of improved anti-depressant pharmacotherapy. The first aim of this review was to describe and integrate the psychological evidence and the neurobiological evidence for the LH effect in rodents and healthy humans and for helplessness in depressed patients. The second aim was to conduct three systematic reviews, namely of rodent studies of the LH effect, rodent studies of effects of psychopharmacological agents on the LH effect, and human studies of efficacy of pharmacotherapeutic and psychotherapeutic treatment on helplessness in depressed patients. With respect to the first aim, the major findings are: the specificity of the LH effect in otherwise non-manipulated rodents and healthy humans has been under-estimated, and the LH effect is a specific learned aversive uncontrollability (LAU) effect. There is theoretical and empirical support for a model in which a specific LAU effect induced by a life event of major emotional significance can function as an aetiological factor for generalised helplessness which can in turn function as an aetiological and maintenance factor for depression. However, to date such models have focused on cognitive mediating processes whereas it is emotional-motivational-cognitive processes (as proposed for the LAU effect) that need to be invoked and understood. The evidence is for analogous neural processes underlying the LAU effect in rodents and healthy humans and helplessness in depression, with the ventro-medial prefrontal cortex exhibiting aversive uncontrollability-dependent activity. With respect to the second aim, the major findings are: the LAU effect is demonstrated quite consistently using a number of different paradigms in rat but is poorly studied in mouse. The rat LAU effect can be reversed by chronic administration of monoamine reuptake inhibitors. The effects of antidepressants on human helplessness have been scarcely studied to-date. The major conclusion is that the LAU effect and generalised helplessness constitute major neuropsychological concepts of high value to future translational research aimed at increased understanding of depression and development of novel, improved antidepressant treatments.

HPA Axis Reactivity and Lymphocyte Glucocorticoid Sensitivity in Fibromyalgia Syndrome and Chronic Pelvic Pain

Objective: Chronic pelvic pain (CPP) and fibromyalgia syndrome (FMS) have been associated with hypothalamic-pituitary-adrenal (HPA) axis alterations, i.e., mild hypocortisolism and enhanced feedback sensitivity. We tested the hypothesis of reduced cortisol release in response to a psychosocial stressor and pharmacological stimulation. Furthermore, glucocorticoid (GC) sensitivity was evaluated. Methods: Plasma total and salivary-free cortisol concentrations were measured in response to a standardized social laboratory stressor, the Trier Social Stress Test, and to adrenocorticotropin (ACTH)1–24 stimulation. In the Trier Social Stress Test, we additionally measured ACTH. GC sensitivity was measured by dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in whole blood. Results: There were no HPA axis alterations in women with CPP (N = 18) in these tests. Patients with FMS (N = 17) showed lower total cortisol release in response to the social stressor and exogenous ACTH, but normal free cortisol and ACTH levels compared with controls (N = 24). GC sensitivity was similar in all groups. Conclusions: Our results suggest normal HPA responses to stress and ACTH stimulation in patients with CPP but reduced adrenal reactivity in patients with FMS, namely in total cortisol release. Free cortisol on the other hand was unaltered, possibly reflecting an adaptation to reduced circulating total cortisol. FMS = fibromyalgia syndrome; CPP = chronic pelvic pain; HPA = hypothalamic-pituitary-adrenal; TSST = Trier Social Stress Test; ACTH = adrenocorticotropin; GC = glucocorticoid; GR = glucocorticoid receptor; BMI = body mass index; LPS = lipopolysaccharide; IL-6 = interleukin-6; TNF-&agr; = tumor necrosis factor-alpha.

Effects of Intrauterine Exposure to Synthetic Glucocorticoids on Fetal, Newborn, and Infant Hypothalamic-Pituitary-Adrenal Axis Function in Humans: A Systematic Review

BACKGROUND Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits.