Søren Dinesen Østergaard

The WHO-5 Well-Being Index: A Systematic Review of the Literature

Background: The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well-being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. Methods: We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. Results: A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. Conclusions: The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields.

Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study

BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals. METHODS By use of the Danish national registers, we followed up 1·92 million individuals, including 32,061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD. FINDINGS During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10,000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70-2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93-3·27), and it was 1·58 (1·21-2·03) for those aged 6-17 years, and 4·25 (3·05-5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11-1·98), and was higher in girls and women (2·85, 1·56-4·71) than in boys and men (1·27, 0·89-1·76). INTERPRETATION ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents. FUNDING This study was supported by a grant from the Lundbeck Foundation.

Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders: A Nationwide Study

IMPORTANCE Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. OBJECTIVE To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. DESIGN Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91, 637 people having hospital contacts for mood disorders. MAIN OUTCOMES AND MEASURES The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. RESULTS A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. CONCLUSIONS AND RELEVANCE Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.

The heterogeneity of the depressive syndrome: when numbers get serious.

The current criteria for major depression (1) have been criticized for the heterogeneity of the clinical syndrome they define. This has led to suggestions of alternative classifications, most recently by G. Parker in this journal (2). According to the critics, the polymorphic syndrome is partly to blame for the fact that the treatment of depression still has not moved beyond the trial and error approach and that the genetics and neurobiology underlying the depressive disorder still remain largely unknown and without practical significance (3). Two of the most interesting studies on major depression, conducted within recent years, reflect this problem:

Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides

The neural cell adhesion molecule (NCAM) plays a key role in neural development, regeneration, and learning. In this study, we identified a synthetic peptide-ligand of the NCAM Ig1 module by combinatorial chemistry and showed it could modulate NCAM-mediated cell adhesion and signal transduction with high potency. In cultures of dissociated neurons, this peptide, termed C3, stimulated neurite outgrowth by activating a signaling pathway identical to that activated by homophilic NCAM binding. A similar effect was shown for the NCAM Ig2 module, the endogenous ligand of NCAM Ig1. By nuclear magnetic resonance spectroscopy, the C3 binding site in the NCAM Ig1 module was mapped and shown to be different from the binding site of the NCAM Ig2 module. The C3 peptide may prove useful as a lead in development of therapies for neurodegenerative disorders, and the C3 binding site of NCAM Ig1 may represent a target for discovery of nonpeptide drugs.

Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks

Insulin is thought to elicit its effects by crosslinking the two extracellular α-subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.

Register-based studies of mental disorders

Introduction: Denmark has been pioneering international psychiatric register research for decades. In this article we review central publications, by Danish and international authors, based on data from the Danish Psychiatric Central Research Register and other related registers. Research topics: Our aim was to describe the history, development and achievements of psychiatric research, based on the Danish national registers. The studies considered in this review can be categorized as follows: i) health service research, mainly studies on prevalence and incidence, ii) studies on the outcome of mental disorders, iii) studies on the aetiology of mental disorders. Conclusion: Studies based on Danish registers have provided significant contributions to international psychiatric research. The major advantage of the registers is that they cover the entire population, which makes the conduction of nationwide population-based studies possible. Furthermore, all information in the registers is connected to each citizen’s unique personal identification number, which enables linkage between various registers and biobanks. Such linkage studies have provided important knowledge on the aetiology of mental disorders. Despite inherent limitations about internal and external validity, the Danish national registers have been extremely valuable to international psychiatric research and will continue to play an important role in years to come.

Evidence against protein kinase B as a mediator of contraction-induced glucose transport and GLUT4 translocation in rat skeletal muscle.

Both insulin and muscle contraction stimulate glucose transport activity. However, contraction stimulation does not involve the insulin signalling intermediate phosphatidylinositol 3‐kinase (PI 3‐kinase). Protein kinase B (PKB) has recently been identified as a direct downstream target of PI 3‐kinase in the insulin signalling pathway. We have examined here whether the two stimuli share PKB as a convergent step in separate signalling pathways. Insulin stimulates both glucose transport, GLUT4 cell‐surface content and PKB activity (by 4–6‐fold above basal) in a wortmannin‐sensitive manner in in vitro incubated rat soleus muscles. By contrast, muscle contraction, which stimulates glucose transport and the cell surface content of GLUT4 by 3‐fold above basal levels, had no effect on PKB activity. These data demonstrate that PKB is not a mediator of contraction‐induced glucose transport and GLUT4 translocation.

Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with 64Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion

Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy. Methods: To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with 64Cu (64Cu-DOTA-AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with 18F-FDG uptake, and finally the correlation between sensitivity toward 5-fluorouracil therapy and uPAR expression level was investigated. Results: The uPAR-targeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of 64Cu-DOTA-AE105 and uPAR expression was found (R2 = 0.73; P < 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of 64Cu-DOTA-AE105, compared with that of 18F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using 64Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting. Conclusion: Our results clearly demonstrate that the peptide-based PET tracer 64Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy.

Peptomers: A Versatile Approach for the Preparation of Diverse Combinatorial Peptidomimetic Bead Libraries

This report describes a versatile approach in thegeneration of peptidomimetic bead libraries. Themethod is based on the preparation of peptide–peptoidhybrids using the portioning–mixing procedure, whichgives diverse peptidomimetic bead libraries composedof peptides, peptoids and peptide–peptoid hybrids. Weterm these peptomers, from peptide–peptoidhybrid polymers. The synthesis of the peptomersis easily accomplished by adapting the peptoidsynthesis strategy, in which a primary amine reactswith bromoacetic acid, and we combine this methodologywith conventional peptide synthesis. The sequence ofthe active compound is deduced by conventionalmicrosequencing using Edman degradation chemistry,thus avoiding the synthesis of a coding structure orthe addition of molecular tags. We demonstrate theutility of the peptomer approach by the synthesis ofa bead library together with the identification ofnovel peptidomimetic ligands binding to themacromolecular targets streptavidin and the insulin receptor.