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Background. This study addresses the complex relationship between cognitive function and the course of depression. Method. A sample of patients (n=73) in a depressive episode (major depression or bipolar disorder) was tested with a comprehensive battery of attention and executive tasks at both admission and discharge. In addition, response to pharmacological treatment and remission was assessed with standardized rating scales. Nineteen patients, recovered from depression, were re-investigated 6 months after discharge to determine whether specific cognitive parameters were related to subsequent relapse. Results. On admission, patients were impaired in almost all cognitive tasks. At discharge, we found a significant reduction in psychopathology, but only marginal cognitive improvements. Non-responders after 4 weeks of antidepressive medication and subjects who did not achieve remission prior to discharge were specifically impaired in divided attention on admission (p<0·05). In addition, a trend was found for the association between impaired divided attention at discharge and an elevated risk to relapse (p<0·10). Conclusions. We observed generalized cognitive impairment in most cognitive domains in acute depression. Cognitive impairments were still within abnormal ranges at discharge but less distinct. Divided attention performance predicted response to treatment, remission of symptoms, and risk to relapse. Impaired divided attention capacity can be explained either by reduced attentional resources or impaired activation and/or top-down control of attentional resources by the central executive.

The most consistent biological findings in patients with depression are abnormalities in the hypothalamic–pituitary–adrenal (HPA)-axis, which can be measured using the combined dexamethasone-suppression/CRH-stimulation (Dex-CRH) test. The reactivity of the HPA-axis in this test, however, ranges over several orders of magnitude in depressed patients with comparable severity of symptoms. In this present study, we investigate which factors influence the magnitude of the response in the Dex-CRH test in 235 acutely depressed in-patients. We first examined the effects of common confounders shown to influence the HPA-axis, such as caffeine and nicotine consumption, acute stressors during the test, weight, gender, and age. Of all these variables, only female sex and nicotine consumption were positively correlated with the cortisol or ACTH response, respectively. As for the effects of psychopharmacological treatment, only the intake of carbamazepine and the fact of having relapsed under an established pharmacotherapy significantly increased the response in the Dex-CRH test, whereas the presence or absence of antidepressant treatment, the type of antidepressant treatment, or the number of ineffective antidepressant treatment trials during the index episode up to admission did not have any effect. We also found a positive correlation of the number of previous episodes, the overall HAM-D score and the severity of somatic/vegetative symptoms with the results in the Dex-CRH test. These results underline that in depressed patients this test is not majorly influenced by disease-unrelated factors. In addition, current antidepressant treatment does not appear to affect test outcome in the absence of clinical response. The influence of the number of previous episodes and relapse under pharmacotherapy suggests that HPA-axis reactivity may be altered by repetitive states of hypercortisolemia or continuous antidepressant treatment. Finally, more severe vegetative symptoms are associated with an enhanced HPA-axis activity.

Long QT syndrome (LQTS) refers to a group of \"channelopathies\"-disorders that affect cardiac ion channels. The \"family\" concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470+ allelic mutations induce loss-of-function in the passage of mainly K+ ions, and gain-of-function in the passage of Na+ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with subpopulation depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A S1102Y in African Americans, show racial-ethnic specificity. At least nine genetic polymorphisms may enhance susceptibility to drug-induced arrhythmia (an \"acquired\" form of LQTS). Studies have generally demonstrated greater QT prolongation and more severe outcomes among adult females. Gene-gene interactions, e.g., between SCN5A Q1077del mutations and the SCN5A H558B polymorphism, have been shown to seriously reduce ion channel current. While phenotypic ascertainment remains a mainstay in the clinical setting, SSCP and DHPLC-aided DNA sequencing are a standard part of mutational investigation, and direct sequencing on a limited basis is now commercially available for patient diagnosis.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

Depression frequently co-occurs with somatization, and somatic complaints have been reported as a vulnerability marker for affective disorders observable before disease onset. Somatization is thought to result from an increased attention to somatic sensations, which should be reflected in long-latency somatosensory evoked electroencephalogram (EEG) potentials (SSEPs) at the physiological level. Previous studies revealed that SSEPs are altered in depressed patients and suggested late SSEP components as vulnerability markers for affective disorders. Neurotransmitters such as serotonin, γ-aminobutyric acid (GABA) and the neuropeptide substance P may play an important role for both affective disorders and somatosensory processing. Method We investigated the associations between SSEPs and polymorphisms within candidate genes of the serotonergic, GABAergic as well as the substance P system in subjects at high risk for affective disorders. The sample was composed of high-risk families participating in the Munich Vulnerability Study and genetic association analyses were calculated using qfam (family-based association tests for quantitative traits) implemented in PLINK 1.05. We observed significant associations (false discovery rate <0.05) withstanding correction for multiple testing between late SSEP components (response strength 170-370 ms after stimulation) and four single nucleotide polymorphisms within the GABA transaminase (ABAT) gene region coding for a protein responsible for GABA degradation. No effects were found with the classical disease trait approach, suggesting SSEP marker specificity of the observed associations. Our findings point to a possible role of ABAT gene-regulated GABA catabolism for an altered processing of somatosensory stimuli as a potential vulnerability marker for affective disorders.

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality 1 as well as the treatment of depression 2 . To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Decreased feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system as revealed by the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH) test has been documented in the vast majority of patients with affective disorders. This finding was interpreted as a failure at the level of the glucocorticoid receptor (GR)-mediated feedback action, which apparently fails to restrain HPA activity in the presence of elevated plasma corticosteroid levels. To test this hypothesis we conducted the DEX/CRH test using increasing doses of DEX in order to establish a dose-response relationship. We used three different DEX doses (0.75, 1.5, 3.0 mg) in three groups of depressed patients and controls. As expected, increasing DEX doses were associated with decreasing amounts of adrenocorticotropin (ACTH) and cortisol being released after CRH injection. However, dose-response curves for both plasma ACTH and cortisol concentrations were shifted to higher area under the curve (AUC) values among patients compared to controls. Pretreatment with 0.75 and 1.5 mg DEX produced significantly higher AUC values for both plasma ACTH and cortisol values among patients. These differences became less obvious with the higher DEX doses, indicating that the dose of 1.5 mg used in the majority of clinical studies so far is well suited to differentiate between healthy controls and patients. The reported data here are consistent with the hypothesis that an altered GR capacity or function underlies the exaggerated HPA activity in depression.

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 p.m. and CRH stimulation at 3 p.m. on the next day). Twenty-four patients were re-assessed after response was determined or, in cases of non-response, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale (HDRS 17-item version). Response was defined as a ΔHDRS of ⩾50% and an endpoint score of < 10. Patients had a significantly higher ACTH and cortisol response to CRH stimulation during lithium augmentation compared with the values at baseline. There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation. This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline. Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change. This effect might be explained by the serotonergic effects of lithium.

Studies have long established that children with disabilities are disproportionately criminally victimised. According to research children with intellectual disabilities are almost four times as likely to be neglected or emotionally abused and five times as likely to be physically or sexually abused. Perhaps most astonishingly, 97–99% of abusers of victims with developmental disabilities are known and trusted by the victim. Many significant barriers exist, both real and perceived, that limit investigation and prosecution of these cases. Specific techniques must be developed to effectively interview child victims with disabilities. This presentation is designed for victim advocates, law enforcement, prosecutors, disability advocates and other criminal justice, medical and social service personnel who work with children with disabilities. Participants will develop an awareness of victimisation of children with disabilities and how assumptions and attitudes toward disability can affect the outcome of services by law enforcement and victim advocates. Additionally, the participants will be presented with information and materials on addressing access and accessibility for children with disabilities as well as develop skills for communicating effectively with individuals with autism, intellectual and other communication disabilities. Course objectives include: Participants will develop an understanding of the unique characteristics of children with disabilities that make them susceptible to abuse. Participants will develop specific communication skills to effectively interview children with autism, mental retardation, cerebral palsy and speech/language limitations. Participants will increase their knowledge regarding the identification of physical and programmatic barriers to provide more effective services to people with disabilities.