Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology.

Omics methodologies are widely used in toxicological research to understand modes and mechanisms of toxicity. Increasingly, these methodologies are being applied to questions of regulatory interest such as molecular point-of-departure derivation and chemical grouping/read-across. Despite its value, widespread regulatory acceptance of omics data has not yet occurred. Barriers to the routine application of omics data in regulatory decision making have been: 1) lack of transparency for data processing methods used to convert raw data into an interpretable list of observations; and 2) lack of standardization in reporting to ensure that omics data, associated metadata and the methodologies used to generate results are available for review by stakeholders, including regulators. Thus, in 2017, the Organisation for Economic Co-operation and Development (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) launched a project to develop guidance for the reporting of omics data aimed at fostering further regulatory use. Here, we report on the ongoing development of the first formal reporting framework describing the processing and analysis of both transcriptomic and metabolomic data for regulatory toxicology. We introduce the modular structure, content, harmonization and strategy for trialling this reporting framework prior to its publication by the OECD.

A systematic review of illness perception interventions in type 2 diabetes: Effects on glycaemic control and illness perceptions.

AIMS: This systematic review sought to synthesize the evidence regarding the effectiveness of illness perception interventions compared with control conditions at changing illness perceptions and improving glycaemic control in individuals with type 2 diabetes. METHODS: Seven electronic databases were searched between October 2018 and May 2020. Randomized controlled trials that tested interventions informed by the Common-Sense Model in adults with type 2 diabetes, and measured illness perceptions and glycaemic control at pre- and post-intervention were included. The Cochrane risk of bias tool was used to assess risk of bias. RESULTS: A total of 4095 articles were identified, of which nine randomized control trials (2561 participants) across 12 publications were included in this review. Findings showed that all the illness perception domains were modified in at least one trial, with the exception of cyclical timeline perceptions. Coherence, personal control, treatment control and chronic timeline perceptions were the most frequently modified perceptions. Glycaemic control demonstrated an improvement in the intervention group compared to the control group at 3 and 6 months post-intervention in two trials. Risk of bias assessment showed high risk of bias especially for the blinding of participants and the personnel domain. CONCLUSIONS: There is limited evidence that interventions informed by the Common-Sense Model can improve glycaemic control in individuals with type 2 diabetes through changing inaccurate illness perceptions. Recommendations for future research are to tailor intervention content based on baseline perceptions, measure the emotional and causal domains, and involve family members in the intervention. (PROSPERO registration: CRD42019114532).

How Patient Perceptions Shape Responses and Outcomes in Inherited Cardiac Conditions.

At least one-third of adults living with an inherited cardiac condition report clinically-significant levels of psychological distress. Poorer health-related quality of life compared with population norms is also consistently reported. These outcomes are associated with younger patient age, having an implantable cardioverter defibrillator, and receipt of uncertain clinical test results, and can influence self-management behaviours, such as adherence to potentially critical life-preserving medications. According to the Common Sense Model of Illness, people use information from multiple sources to 'make sense' of their health condition, and how they conceptualise the condition can strongly influence adaptation and coping responses. Previous studies with people with inherited cardiac conditions show that illness perceptions, such as greater perceived consequences and a poorer understanding of the condition, are associated with greater psychological distress and poorer adherence to medication. The Common Sense Model provides one potential framework for identifying patients who may be more vulnerable to adverse health outcomes, and for developing early interventions to reduce the physical and psychosocial burden of these conditions. Interventions based on the Common Sense Model have successfully improved physical and psychosocial outcomes associated with other cardiac conditions, and could be tailored for use with patients with an inherited cardiac condition (ICC).

Internet use by older adults with bipolar disorder: international survey results.

BACKGROUND: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. METHODS: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. RESULTS: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. CONCLUSIONS: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

The impact of illness perceptions and disease severity on quality of life in congenital heart disease.

BACKGROUND: Despite an increasing prevalence of adults living with a CHD, little is known about the psychosocial impact of CHD. We sought to investigate the relative impact of disease severity and patients' perceptions about their condition on depression, anxiety, and quality of life over a period of a year. METHODS: A total of 110 patients aged over 16 years completed an initial questionnaire containing measures for anxiety, depression, quality of life, and illness perceptions when they attended the Adult Congenital Heart Disease Clinic. Cardiologists rated the patients' disease severity and illness course. A year later, patients were invited to complete the same measures. Regression analyses were performed to determine the relative impact of illness perceptions and disease severity on psychological outcomes a year later. RESULTS: At baseline, 23% of the study population had depressive symptoms and 30% had elevated trait anxiety. After controlling for associations with disease-related variables, illness perceptions explained 28% of the variance in depression, 40% anxiety, and 27% overall quality of life at baseline. Baseline illness perceptions bivariately predicted quality of life, cardiac anxiety, and depression 1 year later, and regression analyses controlling for other factors showed that they were significant predictors of outcomes 1 year later. CONCLUSION: Symptoms of depression and anxiety are common among adults with CHD. Patients' illness perceptions are related to psychological outcomes, especially cross-sectionally. Future research could investigate whether an intervention to discuss patients' perceptions about their CHD can improve mental health and quality of life.

Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment.

OBJECTIVE: Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li). METHODS: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction. RESULTS: The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls. CONCLUSIONS: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study.

BACKGROUND: Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity. METHODS: To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy. RESULTS: We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t41 = -3.44, corrected p < 0.01) or control participants (t35 = -2.91, corrected p < 0.05), who did not differ from the Li group (t46 = -0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = -0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74). LIMITATIONS: Study limitations include the crosssectional design and exposure to other medications. CONCLUSION: Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.

Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. I. Classification, burden and principles of management.

BACKGROUND: Major depressive disorder (MDD) is one of the most burdensome illnesses in Canada. The purpose of this introductory section of the 2009 revised CANMAT guidelines is to provide definitions of the depressive disorders (with an emphasis on MDD), summarize Canadian data concerning their epidemiology and describe overarching principles of managing these conditions. This section on "Classification, Burden and Principles of Management" is one of 5 guideline articles in the 2009 CANMAT guidelines. METHODS: The CANMAT guidelines are based on a question-answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to the Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included evidence and expert clinical support. RESULTS: Epidemiologic data indicate that MDD afflicts 11% of Canadians at some time in their lives, and approximately 4% during any given year. MDD has a detrimental impact on overall health, role functioning and quality of life. Detection of MDD, accurate diagnosis and provision of evidence-based treatment are challenging tasks for both clinicians and for the health systems in which they work. LIMITATIONS: Epidemiologic and clinical data cannot be seamlessly linked due to heterogeneity of syndromes within the population. CONCLUSIONS: In the eight years since the last CANMAT Guidelines for Treatment of Depressive Disorders were published, progress has been made in understanding the epidemiology and treatment of these disorders. Evidence supporting specific therapeutic interventions is summarized and evaluated in subsequent sections.

The human cost of not achieving full remission in depression.

Depression is among the most disabling and costly illnesses in the world. Despite good short-term efficacy outcomes in the treatment of depression, long-term outcomes remain disappointing. Depression continues to be missed or underdiagnosed and undertreated, and comorbidities are frequently not identified. Of particular concern is the low rate of depression treated to full remission. Treating only to response leaves patients with residual depressive symptoms and an increased risk of a recurrent or chronic course. Anything less than full remission should be considered a treatment failure. This article examines the substantial psychiatric, medical, functional, and economic costs associated with not achieving remission. Available pharmacoeconomic data and randomized, controlled clinical trials published in the last 5 years identified through Medline searches with terms including burden, cost, economics, serotonin reuptake inhibitors (also, specific agents), venlafaxine, nefazadone, mirtazapine, psychotherapy, remission, and depression were reviewed. One of the limiting factors to this review is that few trials have compared the effects of various antidepressant strategies on clinically relevant outcomes such as depression-free days and patient productivity, making the full benefit of remission more difficult to measure. Patients who fail to achieve a full remission have a more recurrent and chronic course, increased medical and psychiatric comorbidities, greater functional burden, and increased social and economic costs. Cost-effective treatment for depression includes antidepressant therapies with higher remission rates. Antidepressants with a dual mechanism of action and combination therapies are associated with higher remission rates, more depression-free days, reduced pain-symptom morbidity, reduced health service utilization, and improved productivity.