Reduced Anxiety and Depression-Like Behaviours in the Circadian Period Mutant Mouse Afterhours

Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans

Medication beliefs, treatment complexity, and non-adherence to different drug classes in patients with type 2 diabetes

AbstractObjectiveTo assess the relationship of patients' medication beliefs and treatment complexity with unintentional and intentional non-adherence for three therapeutic groups commonly used by patients with type 2 diabetes.MethodsSurvey data about adherence (Medication Adherence Report Scale) and beliefs about medicines (Beliefs about Medicines Questionnaire) were combined with prescription data from the Groningen Initiative to ANalyse Type 2 diabetes Treatment (GIANTT) database. Patients were classified as being adherent, mainly unintentional non-adherent, or partly intentional non-adherent per therapeutic group (glucose-, blood pressure-, and lipid-lowering drugs). Treatment complexity was measured using the Medication Regimen Complexity Index, which includes the dosage form, dosing frequency and additional directions of taking the drug. Analyses were performed using Kruskal–Wallis and Mann–Whitney U-tests.ResultsOf 257 contacted patients, 133 (52%) returned the questionnaire. The patients had a mean age of 66years and 50% were females. Necessity beliefs were not significantly different between the adherers, mainly unintentional non-adherers, and partly intentional non-adherers (differences smaller than 5 points on a scale from 5 to 25). For blood pressure-lowering drugs, patients reporting intentional non-adherence had higher concern beliefs than adherers (8 point difference, P=0.01). Treatment complexity scores were lower for adherers but similar for mainly unintentional and partly intentional non-adherers to glucose- and blood pressure-lowering drugs.ConclusionTreatment complexity was related to non-adherence in general. Beliefs about necessity were not strongly associated with non-adherence, while patients' concern beliefs may be associated with intentional non-adherence. However, the role of these determinants differs per therapeutic group

HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner

Health-Related Quality of Life in Relation to Obesity Grade, Type 2 Diabetes, Metabolic Syndrome and Inflammation

Health-related quality of life (HR-QoL) may be compromised in obese individuals, depending on the presence of other complications. The aim of this study is to assess the effect of obesity-related conditions on HR-QoL. These conditions are i) grade of obesity with and without type 2 diabetes (T2D), ii) metabolic syndrome (MetS), and iii) level of inflammation.From the Dutch LifeLines Cohort Study we included 13,686 obese individuals, aged 18-80 years. HR-QoL was measured with the RAND 36-Item Health Survey which encompasses eight health domains. We calculated the percentage of obese individuals with poor HR-QoL, i.e. those scoring below the domain and sex specific cut-off value derived from the normal weight population. Logistic regression analysis was used to calculate the probability of having poor domain scores according to the conditions under study.Higher grades of obesity and the additional presence of T2D were associated with lower HR-QoL, particularly in the domains physical functioning (men: odds ratios (ORs) 1.48-11.34, P<0.005, and women: ORs 1.66-5.05, P<0.001) and general health (men: ORs 1.44-3.07, P<0.005, and women: ORs 1.36-3.73, P<0.001). A higher percentage of obese individuals with MetS had a poor HR-QoL than those without MetS. Furthermore, we observed a linear trend between inflammation and the percentage of obese individuals with poor scores on the HR-QoL domains. Individuals with MetS were more likely to have poor scores in the domains general health, vitality, social functioning and role limitations due to emotional problems. Obese women with increased inflammation levels were more likely to have poor scores on all domains except role limitations due to emotional problems and mental health.The impact of obesity on an individual's quality of life is enhanced by grade of obesity, T2D, MetS and inflammation and are mainly related to reduced physical health. The mental well-being is less often impaired

Is digital cognitive behavioural therapy for insomnia effective in treating sub-threshold insomnia: A pilot RCT

Objective/Background: CBT for insomnia (CBT-I) is useful for many. It is currently unknown if those with sub-threshold insomnia also benefit. Here we assessed whether CBT-I is both feasible and acceptable in participants with sub-threshold insomnia. The primary aims were to evaluate participation rates and treatment acceptability, and to establish an effect size for symptom improvement. Patients/Methods: A total of 199 female participants (Mage 20 ± 5 years) took part. Following baseline assessments, participants were randomly allocated to either a 6-week digital CBT-I intervention or a 6-week session control group receiving puzzles. Additional assessments were performed 3-weeks, 6-weeks, and 6-months later. Results: Participation in each survey wave did not differ between the groups (ps > .140), though adherence to weekly tasks was lower in the CBT-I group, p = .02. Treatment acceptability was high (M (SD) = 33.61 (4.82), range 6 – 42). The CBT-I group showed greater improvement in insomnia symptoms at the end of the intervention compared to the control group (p = .013, d = 0.42), with significant variation in outcome (M = 4.69, SD = 5.41). Sub-threshold participants showed a similar pattern of results, whilst those meeting insomnia criteria showed a smaller between-group difference. CBT-I led to improvements in anxiety, paranoia and perceived stress between baseline and end of intervention. Changes in insomnia symptoms were mediated by cognitions about sleep and somatic pre-sleep arousal. Conclusions: CBT-I provides a benefit even in sub-threshold insomnia. CBT-I may be useful as an early preventative intervention to tackle sleep problems before they manifest as chronic insomnia

DNA methylation of FKBP5 and response to exposure-based psychological therapy

Differential DNA methylation of the HPA-axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences, and may play a role in how well people respond to psychological treatments. Participants (n=111) received exposure-based CBT for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (β=-4.26, p=3.90x10-4), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p=0.045), but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure-based CBT. In addition, there was suggestive evidence that allele-specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences