Lithium in drinking water and incidence of suicide:A nationwide individual-level cohort study with 22 years of follow-up

Suicide is a major public health concern. High-dose lithium is used to stabilize mood and prevent suicide in patients with affective disorders. Lithium occurs naturally in drinking water worldwide in much lower doses, but with large geographical variation. Several studies conducted at an aggregate level have suggested an association between lithium in drinking water and a reduced risk of suicide; however, a causal relation is uncertain. Individual-level register-based data on the entire Danish adult population (3.7 million individuals) from 1991 to 2012 were linked with a moving five-year time-weighted average (TWA) lithium exposure level from drinking water hypothesizing an inverse relationship. The mean lithium level was 11.6 μg/L ranging from 0.6 to 30.7 μg/L. The suicide rate decreased from 29.7 per 100,000 person-years at risk in 1991 to 18.4 per 100,000 person-years in 2012. We found no significant indication of an association between increasing five-year TWA lithium exposure level and decreasing suicide rate. The comprehensiveness of using individual-level data and spatial analyses with 22 years of follow-up makes a pronounced contribution to previous findings. Our findings demonstrate that there does not seem to be a protective effect of exposure to lithium on the incidence of suicide with levels below 31 μg/L in drinking water

Reducing the rate and duration of Re-ADMISsions among patients with unipolar disorder and bipolar disorder using smartphone-based monitoring and treatment -- the RADMIS trials: study protocol for two randomized controlled trials

Abstract Background Unipolar and bipolar disorder combined account for nearly half of all morbidity and mortality due to mental and substance use disorders, and burden society with the highest health care costs of all psychiatric and neurological disorders. Among these, costs due to psychiatric hospitalization are a major burden. Smartphones comprise an innovative and unique platform for the monitoring and treatment of depression and mania. No prior trial has investigated whether the use of a smartphone-based system can prevent re-admission among patients discharged from hospital. The present RADMIS trials aim to investigate whether using a smartphone-based monitoring and treatment system, including an integrated clinical feedback loop, reduces the rate and duration of re-admissions more than standard treatment in unipolar disorder and bipolar disorder. Methods The RADMIS trials use a randomized controlled, single-blind, parallel-group design. Patients with unipolar disorder and patients with bipolar disorder are invited to participate in each trial when discharged from psychiatric hospitals in The Capital Region of Denmark following an affective episode and randomized to either (1) a smartphone-based monitoring system including (a) an integrated feedback loop between patients and clinicians and (b) context-aware cognitive behavioral therapy (CBT) modules (intervention group) or (2) standard treatment (control group) for a 6-month trial period. The trial started in May 2017. The outcomes are (1) number and duration of re-admissions (primary), (2) severity of depressive and manic (only for patients with bipolar disorder) symptoms; psychosocial functioning; number of affective episodes (secondary), and (3) perceived stress, quality of life, self-rated depressive symptoms, self-rated manic symptoms (only for patients with bipolar disorder), recovery, empowerment, adherence to medication, wellbeing, ruminations, worrying, and satisfaction (tertiary). A total of 400 patients (200 patients with unipolar disorder and 200 patients with bipolar disorder) will be included in the RADMIS trials. Discussion If the smartphone-based monitoring system proves effective in reducing the rate and duration of re-admissions, there will be basis for using a system of this kind in the treatment of unipolar and bipolar disorder in general and on a larger scale. Trial registration ClinicalTrials.gov, ID: NCT03033420 . Registered 13 January 2017. Ethical approval has been obtained

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Cohort Profile:Stratifying Resilience and Depression Longitudinally (STRADL): a questionnaire follow-up of Generation Scotland: Scottish Family Health Study (GS:SFHS)

Funding: STRADL is supported by the Wellcome Trust through a Strategic Award (reference 104036/Z/14/Z). The Chief Scientist Office of the Scottish Government Health Department (CZD/16/6) and the Scottish Funding Council (HR03006) provided core support for Generation Scotland. A.M.M. is supported by the Dr Mortimer and Theresa Sackler Foundation. D.J.M. is supported by an NRS Fellowship, funded by the CSO. J.S., J.M.W., K.L.E., D.J.P., I.J.D. and A.M.M. are members of the Centre for Cognitive Ageing and Cognitive Epidemiology which also supports I.J.D.; funding from the Medical Research Council and Biotechnology and Biological Sciences Research Council is gratefully acknowledged (MR/K026992/1). Acknowledgments: We would like to express gratitude to all individuals who have taken part in both GS:SFHS and STRADL, and the entire project team including academic researchers, administrative staff, research managers and statisticians. Conflict of interest: The authors declare that they have no conflicting interests.Peer reviewedPublisher PD

Minimum taxes and repeated tax competition

An agreement about a lower bound for admissible tax rates can reduce the equilibrium tax rate (and thus welfare) in tax competition among fully symmetric countries. This is shown in an infinitely repeated game where the stage game describes the standard tax competition model with source-based taxes and symmetric countries. Repeated interaction may allow countries to sustain cooperation through implicit contracts. Lower bounds on tax rates ('minimum taxes') restrict the ability of countries to punish deviators. This makes cooperation harder to sustain. The introduction of a lower bound on feasible tax rates may thus harm all countries

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project

Objective: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. Method: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. Results: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge ‘impairment’ (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. Conclusion: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically

Genetic Polymorphisms of CYP2E1, GSTP1, NQO1 and MPO and the Risk of Nasopharyngeal Carcinoma in a Han Chinese Population of Southern China

<p>Abstract</p> <p>Background</p> <p>Southern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China.</p> <p>Methods</p> <p>Five single nucleotide polymorphisms (SNPs) of <it>CYP2E1</it>-rs2031920, <it>CYP2E1</it>-rs6413432, <it>GSTP1</it>-rs947894, <it>MPO</it>-rs2333227 and <it>NQO1</it>-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 controls (phase I cohort). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm our results, sixteen tag SNPs for <it>GSTP1</it>, <it>MPO</it>, <it>NQO1 </it>(which 100% covered these genes), and 4 functional SNPs of <it>CYP2E1 </it>were genotyped in another cohort of 213 NPC cases and 230 controls (phase II cohort).</p> <p>Results</p> <p>No significant associations in NPC risk were observed for the five polymorphisms tested in the phase I cohort. In an additional stratified analysis for phase I, there was no significant association between cases and controls in NPC high risk population (EBV/IgA/VCA positive population). Analysis of 14 tagging SNPs within the same genes in an independent phase II cohort were in agreement with no SNPs significantly associated with NPC.</p> <p>Conclusions</p> <p>Our results suggest that polymorphism of <it>CYP2E1</it>, <it>GSTP1</it>, <it>MPO </it>and <it>NQO1 </it>genes does not contribute to overall NPC risk in a Han Chinese in southern China.</p

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD