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Objective Tinnitus can be regarded as a chronic stressor, leading to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. There is important comorbidity with anxiety, particularly panic, potentially associated with differences in HPA axis functioning and methylation patterns of HPA axis-related genes. This study examines DNA methylation of the glucocorticoid receptor gene (NR3C1) exon 1F in adults with chronic subjective tinnitus and the possible differential effect of panic. Methods In a well characterized tinnitus sample (n = 22, half of which had co-occurring panic attacks), and unaffected controls (n = 31) methylation patterns of the CpG sites were determined using pyrosequencing and compared between groups through linear mixed models. Gene expression was determined using quantitative PCR on mRNA. Results Comparing the combined tinnitus groups to the control group, no DNA methylation differences were observed; however, the tinnitus group with panic attacks showed consistently higher mean methylation values across all CpGs compared to the tinnitus-only and the control group (P = 0.03 following Tukey correction), which became even more pronounced when accounting for childhood trauma (P = 0.012). Moreover, a significant positive correlation was found between methylation of the CpG7 site and the Beck Anxiety Inventory total score (P = 0.001) in the total population. NR3C1-1F expression was not significantly different between the three groups. Conclusion Panic is associated with higher DNA methylation of the NR3C1 exon 1F in adults with chronic subjective tinnitus, consistent with the reduced negative glucocorticoid feedback and HPA axis hyperfunction observed in individuals with panic disorder.

The current article reports on perpetrator characteristics gathered in the first large-scale prevalence study on interpersonal violence against children in sport in the Netherlands and Belgium. Using retrospective web survey design, 4043 adults answered questions on their experiences in youth sport. The study looks at the number of perpetrators as well as individual descriptive characteristics (sex, age, and role in the sport organization) of perpetrators of psychological, physical and sexual violence as reported retrospectively by victim-respondents. This information was then clustered to provide an overview of the most common perpetrator profiles. Results show that in all types of interpersonal violence in sport, perpetrators are predominantly male peer athletes who frequently operate together in (impromptu) groups. Several differences between the three types of interpersonal violence are highlighted. While incidents of physical violence perpetrated by coaches tend to be less severe compared to those by other perpetrators, acts of sexual violence committed by a coach are significantly more severe. The presented findings shed new light on perpetrators of interpersonal violence in sport, nuancing the predominant belief that the male coach is the main perpetrator while providing nuanced information that can be utilized to improve prevention and child protection measures and other safeguarding initiatives in sport.

Background Although haloperidol is the most widely used drug in the treatment of delirium, evidence on the relevance of atypical antipsychotics (AAPs) is growing. Objective To review the literature on the efficacy and tolerability of AAPs in the treatment of delirium. Methods A systematic search of the literature published before April 2018 was performed on PubMed using the following search strings: “Delirium” and “Atypical antipsychotics”, “Novel antipsychotics”, “New antipsychotics”, “Quetiapine”, “Olanzapine”, “Aripiprazole”, “Risperidone”, “Paliperidone”, “Clozapine”, “Asenapine”, “Iloperidone”, “Amisulpiride”, “Ziprasidone”, “Zotepine”, “Sertindole”, “Lurasidone” or “Perospirone”. Results Twelve randomized controlled trials (RCTs) and 22 open trials were considered. Despite an overall lack of large-scale RCTs, there is some evidence supporting the efficacy of olanzapine and quetiapine in placebo controlled trials. In a recent and large RCT in elderly patients, risperidone and/or haloperidol were associated with a significantly worse outcome than placebo. While preliminary, the current comparative studies suggest that haloperidol and the AAPs olanzapine, quetiapine and risperidone are similarly effective, although treatment with AAPs is associated with a reduced incidence of extrapyramidal symptoms. Ziprasidone was not shown to be effective. No RCTs are available for other AAPs. Conclusions Although the current evidence of the efficacy and tolerability of AAPs in the treatment of delirium is limited and the heterogeneity of the data precluded a meta-analysis, olanzapine and quetiapine seem to be adequate alternatives to haloperidol, especially in patients who are vulnerable for extrapyramidal symptoms, who require sedation or who have a history of haloperidol intolerance. Evidently, larger-scale RCTs are urgently required.

Objective: The diagnoses of solvent-induced chronic toxic encephalopathy (CSE) can be supported by neuropsychological tests. However, since results not only reflect cognitive functioning but also the patients effort to perform well, this study examines to what extent underperformance impacts neuropsychological outcomes in individuals referred for suspected CSE. Methods: A retrospective study of 48 suspected CSE patients having completed ten neuropsychological tests assessing different domains of cognition. Underperformance was identified using the Amsterdam Short-Term Memory Test and the Rey 15-item Memory Test (FIT). Multiple linear regression was applied to examine the effect of insufficient effort on test performance. Results: A total of 54.1% of the patients were identified as having underperformed on one or both performance validity tests. Analyses showed a significant effect of underperformance on most tests barring letter-number sequencing. Conclusions: Most of the neuropsychological tests evaluated showed significant effects of underperformance. Performance on letter-number sequencing was not affected. In case of underperformance, the results of the neuropsychological assessment should be disregarded when weighing the final multi-disciplinary diagnosis, with the exception of letter-number sequencing.

The dysregulation of the inflammatory and neuroendocrine systems seen in major depressive disorder (MDD) may persist after remission and this is associated with a higher risk of relapse. This vulnerable subgroup may be characterized by a history of childhood trauma. In a single-blind randomized placebo-controlled crossover study, 21 women with remitted recurrent MDD and 18 healthy controls were exposed to psychosocial stress (Trier social stress test) or inflammatory stress (typhoid vaccine), or both, to investigate the effects of childhood trauma on the neuroendocrine and inflammatory responses. Childhood trauma was assessed using the Childhood Trauma Questionnaire and participants were dichotomized into a traumatized and non-traumatized group. Serum adrenocorticotropic hormone (ACTH), cortisol, interferon (IFN)-&gamma, tumor necrosis factor (TNF)-&alpha, and interleukin (IL)-6 were measured at regular intervals after each intervention. The effects of trauma, time, and intervention on these parameters were modeled by fitting linear mixed models. Childhood trauma in itself did not have a main effect on the outcome measurements. However, an interactional effect of trauma with stressor type was found in the remitted MDD group: trauma was associated with higher cortisol levels only after adding immunological to psychosocial stress, and with lower TNF-&alpha, levels in response to vaccination. This suggests the existence of a vulnerable trauma-associated MDD endophenotype.

In a recent large-scale prevalence study of interpersonal violence (IV) against child athletes in the Netherlands and Belgium we found that 9% of adult respondents who participated in organized sports before the age of 18 had experienced severe psychological violence, 8% severe physical violence, and 6% severe sexual violence in various sport settings. While the general literature has repeatedly shown that exposure to IV during childhood is associated with mental health problems in adulthood and to a lesser extent with reduced quality of life (QOL), these relationships have not been demonstrated in (former) athletes. Thus, the current study aims to assess the association of severe childhood IV in sport and adult wellbeing. Depression, anxiety, and somatization were assessed in the same general population sample (N = 4043) using the Brief Symptom Inventory (BSI-18) and QOL with the World Health Organization Quality of Life questionnaire (WHOQOL-Bref). The association between severe IV in sport and adult wellbeing was investigated using multiple linear regression while controlling for demographics, recent life events, and relatives’ psychological problems. We found severe sexual, physical, and psychological childhood IV in sport to be associated with more adult psychological distress and reduced QOL. Polyvictimization shows the strongest correlation with poorer wellbeing and QOL. Recent life events, relatives’ psychological problems, marital status, and level of education were significant covariates in the psychological symptoms and QOL assessed. We hope that these new insights prompt sport administrators to implement broad spectrum child protection measures and raise the awareness of mental health professionals about the necessity to also screen for adverse childhood experiences in the sport context.

The current article reports on the first large-scale prevalence study on interpersonal violence against children in sport in the Netherlands and Belgium. Using a dedicated online questionnaire, over 4,000 adults prescreened on having participated in organized sport before the age of 18 were surveyed with respect to their experiences with childhood psychological, physical, and sexual violence while playing sports. Being the first of its kind in the Netherlands and Belgium, our study has a sufficiently large sample taken from the general population, with a balanced gender ratio and wide variety in socio-demographic characteristics. The survey showed that 38% of all respondents reported experiences with psychological violence, 11% with physical violence, and 14% with sexual violence. Ethnic minority, lesbian/gay/bisexual (LGB) and disabled athletes, and those competing at the international level report significantly more experiences of interpersonal violence in sport. The results are consistent with rates obtained outside sport, underscoring the need for more research on interventions and systematic follow-ups, to minimize these negative experiences in youth sport.

Over the past decade, the international agenda on the prevention of child sexual harassment and abuse in sport has been strengthened by a number of general policy recommendations. Despite a growing body of literature and research about sexual harassment and abuse in sport, there is hardly any evidence-based policy and preven- tion research to guide the policy implementation process. By using the Flemish sport 15 system as its empirical focus, this article investigates the feasibility of the so-called Flag System to translate policy into practice. The Flag System is a didactic tool created to assist sport stakeholders in the assessment of sexual behaviour involving children. It is in the process of being implemented in Flanders, and preliminary findings suggest a high level of feasibility at all levels of organized sports. Demonstrating that a number 20 of inhibiting forces have effectively been reduced in Flanders, the current analysis of the process of planned change suggests that the Flag System has potential in bridging the gap between policy and practice and may also be suitable for implementation in other Western countries.

Background: The clinical presentation of panic disorder (PD) is known to be highly heterogeneous, complicating research on its etiology, neurobiological pathways, and treatment. None of the attempts to identifyPD subtypes have been independently reproduced, rendering the current literature inconclusive. Methods: Using a data-driven, case-centered approach (factor mixture modeling) on a broad range of anxiety symptoms assessed with the Beck anxiety inventory, the present study identifies PD disorder subtypes in a large (n = 658), welldocumented mixed-population sample from the Netherlands Study of Depression and Anxiety (NESDA), with subtypes being validated and detailed using a variety of clinical characteristics. Results: A three-class, one-factor model proved superior to all other possible models (Bayesian information criterion = 13,200; Lo-Mendel-Rubin = 0.0295; bootstrapped likelihood ratio test 0.0001), with the first class, a cognitive-autonomic subtype, accounting for 29.8%, the second class, the autonomic subtype, for 29.9%, and a third class, the aspecific subtype, for 40.3% of the population. The cognitive-autonomic and autonomic subtypes showed significant differences compared to the aspecific subtype (e.g., comorbidity and suicide attempts) but on severity differed between themselves only. Conclusion: Three qualitatively different PD subtypes were identified: a severe cognitive-autonomic subtype, a moderate autonomic subtype, and a mild aspecific subtype. Qualitative and quantitative differences were related to severity and clinical properties such as comorbidity, suicide attempts, sleep, and sense of mastery.

Background Antidepressant-induced hyponatremia can cause significant morbidity and mortality. It is mostly associated with the use of selective serotonin reuptake inhibitors (SSRIs), but its frequency and class specificity are uncertain. Objectives To determine the relationship between hyponatremia and antidepressants and to define the incidence and odds ratios for antidepressant classes. Methods A review of the literature prior to March 2013 was performed using Web of Science and PubMed by employing combinations of search strings “antidepressants” and antidepressant class and generic drug names with “hyponatr(a)emia,” “SIADH,” or “inappropriate ADH.” Results Overall, 21 effect studies and more than 100 case reports were considered, most concerning SSRIs. Because of variations in study designs, populations, and cutoff values, incidence rates diverged between 0.06% and 40% for SSRIs and 0.08% and 70% for venlafaxine. Although based on less solid evidence, incidence figures for mirtazapine and tricyclic antidepressants were lower. Regarding classes, odds ratios for SSRIs (1.5–21.6) were consistently higher than for tricyclic antidepressants (TCAs) (1.1–4.9). The risks associated with monoamine oxidase inhibitors, reboxetine, and bupropion could not be established owing to insufficient information. Patient risk factors included older age (odds ratios = 6.3) and concomitant use of (thiazide) diuretics (odds ratios = 11.2–13.5). Conclusion Hyponatremia is a potentially dangerous side effect of antidepressants and is not exclusive to SSRIs. Current evidence suggests a relatively higher risk of hyponatremia with SSRIs and venlafaxine, especially when combined with patient risk factors, warranting clinicians to be aware of this complication. The risks associated with mirtazapine are moderate, supporting this antidepressant as an alternative treatment for patients with (an increased risk of) hyponatremia.

Objective. Maladaptive response styles to negative affect have been shown to be associated with prospective (postpartum) depression. Whether maladaptive styles to positive affect are also critically involved is understudied, even though anhedonia (a correlate of low positive affectivity) is a cardinal symptom of depression. The present study is the first to investigate the predictive value of cognitive response styles to both negative (depressive rumination) and positive affect (dampening) for postpartum depressive symptoms. Methods. During the third trimester of pregnancy, 210 women completed self-report instruments assessing depression (symptom severity and current and/or past episodes) and scales gauging the presence of depressive rumination and dampening. Of these women, 187 were retained for postpartum follow-up, with depressive symptoms being reassessed at 12 (n = 171) and 24 (n = 176) weeks after delivery. Results. Regression analyses showed that higher levels of dampening of positive affect during pregnancy predicted higher levels of depressive symptoms at 12 and 24 weeks postpartum, irrespective of initial symptom severity, past history of depression and levels of rumination to negative affect. Prepartum trait levels of rumination, however, did not predict postpartum symptomatology when controlled for baseline symptoms and history of major depressive episode(s). Conclusions. The results of this investigation suggest that the way women cognitively respond to positive affect contributes perhaps even more to the development of postpartum depression than maladaptive response styles to negative affect. publisher: Elsevier articletitle: Turning the pink cloud grey: Dampening of positive affect predicts postpartum depressive symptoms journaltitle: Journal of Psychosomatic Research articlelink: http://dx.doi.org/10.1016/j.jpsychores.2014.04.003 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved. ispartof: Journal of Psychosomatic Research vol:77 issue:1 pages:64-69 ispartof: location:England status: published

Objective. Although the remission criteria for generalized anxiety are well defined, there is not much data available on the point prevalence of remission. The Measuring Impact of Remission in Anxiety Disorders in Belgium (MIRABEL) study is a naturalistic study designed to document the point prevalence of remission in patients treated for general anxiety and potential factors affecting this prevalence. Methods. The study population consisted of 618 adult outpatients being treated for generalized anxiety. The sample is defined by the key symptoms of generalized anxiety disorder rather than by fulfilling the exact DSM-IV-TR diagnostic criteria. Remission was defined as a Hamilton Anxiety Scale (HAM-A) score of less than or equal to 7. To reduce the interrater reliability, the HAM-A was assessed by the attending physicians who had no specific training. Factors investigated as possibly related to remission included sociodemographic, disease and treatment characteristics. Results. The point prevalence of remission in the study population was estimated at 13.3%. Remission prevalence varied with occupational status and severity of the current anxiety episode. Remission prevalence was lower in the presence of comorbidity and was proportional to the number of comorbid symptoms. Remitters took fewer medications but were treated longer. Remission prevalence was higher in patients who were taking antidepressants, but was lower in patients who were taking sedatives. Conclusions. These findings underline the poor prognosis of generalized anxiety.

INTRODUCTION: In the following article CAPRI presents its current research projects. SUBJECTS AND METHOD: The team leaders were asked to present and summarize the project they had been working on. The fields in which research was conducted are: Child and Adolescent Psychiatry, Cognitive and Psychomotor Dysfunctions in Schizophrenia, fMRI in Schizophrenia, Cognitive and Psychomotor Dysfunctions in Major Depressive Disorder, Chronic Fatigue Syndrome, Addiction Medicine and Forensic Psychiatry. RESULTS: An overview of recent and ongoing research projects is provided and the main results are summarized.

There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.

We have read the article by Neigh and Nemeroff with a lot of interest [1xReduced glucocorticoid receptors: consequence or cause of depression?. Neigh, G.N. and Nemeroff, C.B. Trends Endocrinol. Metab. 2006; 17: 124–125Abstract | Full Text | Full Text PDF | PubMed | Scopus (33)See all References[1]. The authors discussed the study by Ridder et al. [2xMice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. Ridder, S. et al. J. Neurosci. 2005; 25: 6243–6250Crossref | PubMed | Scopus (239)See all References[2] as a starting point to review the current status of the glucocorticoid receptor (GR) hypothesis of major depressive disorder (MDD). In their excellent paper, they argue that GR dysfunction might not be the primary source of the hypothalamic–pituitary–adrenal (HPA) axis dysfunction in MDD. Although we agree that several molecular mechanisms might lead to HPA axis dysfunction, we would like to draw the attention to some recent genetic studies in humans. Concerning the causal involvement of the GR in the pathogenesis of MDD, it is important to mention two studies that have been published very recently [3xGlucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. van West, D. et al. Neuropsychopharmacology. 2006; 31: 620–627Crossref | PubMed | Scopus (107)See all References, 4xPolymorphisms of the glucocorticoid receptor gene and major depression. van Rossum, E.F. et al. Biol. Psychiatry. 2006; 59: 681–688Abstract | Full Text | Full Text PDF | PubMed | Scopus (223)See all References]. Both studies are related to the ground breaking work by van Rossum et al. that was reviewed previously in Trends in Endocrinology and Metabolism [5xGenetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene. van Rossum, E.F. et al. Trends Endocrinol. Metab. 2005; 16: 445–450Abstract | Full Text | Full Text PDF | PubMed | Scopus (37)See all References[5].Our research group examined whether genetic variations in the GR-encoding gene (NR3C1, gene ID 2908) were associated with MDD, using a gene-based association analysis of single nucleotide polymorphisms (SNPs) [3xGlucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. van West, D. et al. Neuropsychopharmacology. 2006; 31: 620–627Crossref | PubMed | Scopus (107)See all References[3]. In a Belgian sample, we observed a significant association of MDD with a SNP in the promoter region (NR3C1–1, rs10482605). In a Swedish sample, there was a significant association between MDD and SNP R23K (rs6190). The two SNPs were located close to each other in the 5′ region of the gene. Interestingly, SNP R23K was shown to be associated with resistance to glucocorticoids [6xA polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. van Rossum, E.F. et al. Diabetes. 2002; 51: 3128–3134Crossref | PubMedSee all References[6], a major feature in MDD [7xThe corticosteroid receptor hypothesis of depression. Holsboer, F. Neuropsychopharmacology. 2000; 23: 477–501Crossref | PubMed | Scopus (1358)See all References, 8xGlucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Pariante, C.M. and Miller, A.H. Biol. Psychiatry. 2001; 49: 391–404Abstract | Full Text | Full Text PDF | PubMed | Scopus (667)See all References]. The proposed underlying molecular mechanism of the GR resistance caused by the R23K polymorphism is a change in balance between two translocational variants of the GR proteins (GR-A and GR-B). More precisely, R23K leads to a reduced production of the transcriptionally more active GR-B and to an increased production of the less active GR-A [9xIncreased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism. Russcher, H. et al. Mol. Endocrinol. 2005; 19: 1687–1696Crossref | PubMed | Scopus (69)See all References[9].Almost simultaneously, van Rossum et al. [4xPolymorphisms of the glucocorticoid receptor gene and major depression. van Rossum, E.F. et al. Biol. Psychiatry. 2006; 59: 681–688Abstract | Full Text | Full Text PDF | PubMed | Scopus (223)See all References[4] reported a significant association between the R23K SNP and MDD in a German population. In this study, patients who were heterozygote for the R23K SNP responded more quickly to antidepressant treatment. The authors also observed an association of MDD with BclI, a restriction length polymorphism associated with hypersensitivity to glucocorticoids. The latter finding does not match with the GR hypothesis for MDD, although the authors emphasized the tissue-specific effects of BclI. More specifically, they suggested that increased GR activation in the limbic system might also contribute to the development of MDD. Clearly, this issue requires further investigation.Taken together, these two studies on the association between polymorphisms in the GR-encoding gene and MDD provide further evidence for a role of the GR receptor in the vulnerability for MDD. It seems likely that, at least in a proportion of MDD patients, GR dysfunction is the primary source of HPA axis abnormalities.

PurposeEvidence indicates that classical antipsychotics may aggravate non-malignant and malignant catatonia (MC). Atypical antipsychotics are less likely to cause movement disorders than classical antipsychotics and they are being frequently prescribed in disorders that can be associated with catatonia. Therefore, the important question that arises is whether atypical antipsychotics have a role to play in the treatment of catatonia.Materials and methodsA Medline search was performed to locate papers on the use of atypical antipsychotics in catatonia published between 1970 and 31st December 2004.ResultsThe literature on the use of atypical antipsychotics in catatonia consists of case reports and retrospective studies. In most cases of non-MC a reduction of the catatonic symptoms is reported upon treatment with atypical antipsychotics. Cases of MC relate mainly to the neuroleptic malignant syndrome (NMS), which is considered as an iatrogenic stuporous variant of MC caused by antipsychotics.ConclusionThere are indications that atypical antipsychotics may be useful in non-MC. As a consequence, one should not only focus on the possible extrapyramidal and autonomic side effects of these drugs, but also on the possible beneficial effects on certain brain functions and on the catatonic symptomatology. However, randomized controlled trials are needed to evaluate the effect of these drugs, and caution is advisable, since cases of NMS have been linked to treatment with atypical antipsychotics. There is no evidence to prescribe atypical antipsychotics in MC.