Sociodemographic, mental health, and physical health factors associated with participation within re-contactable mental health cohorts: an investigation of the GLAD Study.

BACKGROUND: The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants. METHODS: In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey (aim one). Subsequently, we used a zero-inflated negative binomial regression to examine whether these factors were also related to participation in the COPING follow-up surveys (aim two). RESULTS: For aim one, older age, female gender identity, non-binary or self-defined gender identities, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey, and current or ex-smoking were associated with a reduced odds. For aim two, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. Lower educational attainment, higher alcohol consumption at the GLAD Study sign-up, ex-smoking, and self-reported attention deficit hyperactivity disorder had negative relationships. CONCLUSIONS: Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Factors associated with participation may vary depending on study design. Researchers should examine the barriers and mechanisms underlying participation bias in order to combat these issues and address recruitment biases in future studies.

The efficacy and tolerability of pharmacologically active interventions for alcohol-induced hangover symptomatology: a systematic review of the evidence from randomised placebo-controlled trials.

AIMS: To compare quantitatively the efficacy and tolerability of pharmacologically active interventions in the treatment and prevention of alcohol-induced hangover. METHODS: Systematic review of placebo-controlled randomised trials in healthy adults that evaluated any pharmacologically active intervention in the treatment or prevention of hangover. We searched Medline, Embase, PsycINFO and CENTRAL from database inception until 1 August 2021. The primary efficacy outcome was any continuous measure of overall hangover symptoms and the primary tolerability outcome the number of people dropping out because of adverse events (AEs). Quality was assessed using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. RESULTS: A total of 21 studies were included reporting on 386 participants. No two studies reported on the same intervention; as such, meta-analysis could not be undertaken. Methodological concerns and imprecision resulted in all studied efficacy outcomes being rated as very low quality. When compared with placebo, individual studies reported a statistically significant reduction in the mean percentage overall hangover symptom score for clove extract (42.5% vs 19.0%, P < 0.001), tolfenamic acid (84.0% vs 50.0%, P < 0.001), pyritinol (34.1% vs 16.2%, P < 0.01), Hovenia dulcis fruit extract (P = 0.029), L-cysteine (P = 0.043), red ginseng (21.1% vs 14.0%, P < 0.05) and Korean pear juice (41.5% vs 33.3%, P < 0.05). All studied tolerability outcomes were of low or very low quality with no studies reporting any drop-outs because of AEs. CONCLUSIONS: Only very low quality evidence of efficacy is available to recommend any pharmacologically active intervention for the treatment or prevention of alcohol-induced hangover. Of the limited interventions studied, all had favourable tolerability profiles and very low quality evidence suggests clove extract, tolfenamic acid and pyritinol may most warrant further study.

Stoma Formation in Crohn's Disease and the Likelihood of Antidepressant Use: A Population-Based Cohort Study.

BACKGROUND & AIMS: The impact of a temporary or permanent stoma on mental health in Crohn's Disease (CD) is unknown. The aim was to examine the association between intestinal surgery and stoma formation and subsequent antidepressant medication (ADM) use. METHODS: Using the Clinical Practice Research Datalink, we identified individuals with CD who underwent intestinal surgery between 1998-2018. We excluded individuals with a prescription for an ADM in the 6 months before surgery. Individuals were stratified into three groups: no stoma, temporary stoma, and permanent stoma. We used Kaplan-Meier curves to examine initiation of ADM after intestinal surgery and Cox regression to identify risk factors for ADM use after intestinal surgery. RESULTS: We identified 1,272 cases of CD undergoing their first intestinal surgery. Of these, 871 (68.5%) had no stoma, 191 (15.0%) had a temporary stoma and 210 (16.5%) had a permanent stoma. The 10-year cumulative incidence of ADM use was 26.4%, 33.4% and 37.3% respectively. Individuals with a permanent stoma were 71% more likely to receive an ADM than those with no stoma (HR 1.71, 95% CI 1.20-2.44). Individuals with a temporary stoma reversed within 12 months had a similar likelihood of ADM use to those without stoma formation (HR 0.99, 95% CI 0.64-1.53) whereas temporary stoma formation with late reversal after 12 months was associated with significantly greater likelihood of ADM use (HR 1.85, 95% CI 1.15-2.96). CONCLUSIONS: Permanent stomas and temporary stomas with late reversal surgery are associated with increased ADM use after intestinal surgery, likely associated with increased anxiety and depression.

Depressive symptoms during early adulthood and the development of physical multimorbidity in the UK: an observational cohort study.

BACKGROUND: An understanding of whether early-life depression is associated with physical multimorbidity could be instrumental for the development of preventive measures and the integrated management of depression. We therefore aimed to map out the cumulative incidence of physical multimorbidity over adulthood, and to determine the association between the presence of depressive symptoms during early adulthood and the development of physical multimorbidity in middle age. METHODS: In this observational cohort study, we used pooled data from the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS). Cohort waves were pooled in each decade of adult life available (when cohort members were aged 26 years in the BCS and 23 years in the NCDS [baseline]; 34 years in the BCS and 33 years in the NCDS [age 34 BCS/33 NCDS]; 42 years in the BCS and NCDS [age 42 BCS/NCDS]; and 46 years in the BCS and 50 years in the NCDS [age 46 BCS/50 NCDS]). We included participants who had completed the nine-item Malaise Inventory at baseline, and did not have a history of physical multimorbidity, any physical multimorbidity at baseline, or the presence of depressive symptoms before the development of physical multimorbidity. The presence of depressive symptoms was determined using the nine-item Malaise Inventory (cutoff score ≥4). Physical multimorbidity was defined as having at least two measures of any of the following ten self-reported groups of long-term conditions: asthma or bronchitis; backache; bladder or kidney conditions; cancer; cardiovascular conditions; convulsions or epilepsy; diabetes; hearing conditions; migraine; and stomach, bowel, or gall conditions. Cumulative incidence (with 95% CI) of physical multimorbidity was calculated for each decade considered after baseline, with physical multimorbidity being assessed as both a dichotomous and categorical variable. The association between depressive symptoms and the development of physical multimorbidity was assessed using adjusted relative risk ratios (with 95% CIs). FINDINGS: Analyses included 15 845 participants, of whom 4001 (25·25%; 95% CI 24·57-25·93) had depressive symptoms at baseline and 11 844 (74·75%; 74·07-75·42) did not. The cumulative incidence of physical multimorbidity (dichotomous) ranged over the study period from 2263 (18·44%; 95% CI 17·75-18·14) of 12 273 participants at age 34 BCS/33 NCDS, to 4496 (42·90%; 41·95-43·85) of 10 481 participants at age 46 BCS/50 NCDS, and was consistently higher in participants with depressive symptoms at baseline. The adjusted relative risk of physical multimorbidity was higher in participants with depressive symptoms than in those without and remained stable over the study period (adjusted relative rate ratio 1·67, 95% CI 1·50-1·87, at age 34 BCS/33 NCDS; 1·63, 1·48-1·79, at age 42 BCS/NCDS; and 1·58, 1·43-1·73, at age 46 BCS/50 NCDS). INTERPRETATION: The presence of depressive symptoms during early adulthood is associated with an increased risk of the development of physical multimorbidity in middle age. Although further research about the drivers of this relationship is needed, these results could help to enhance the integrated management of individuals with depressive symptoms and the development of preventive strategies to reduce the effect and burden of physical multimorbidity. FUNDING: UK Medical Research Council and Guy's Charity.

Genetic risk for severe COVID-19 correlates with lower inflammatory marker levels in a SARS-CoV-2-negative cohort.

OBJECTIVES: It remains unknown how inflammatory marker levels differ amongst individuals susceptible to coronavirus disease 2019 (COVID-19), prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the onset of the cytokine storm. We used genetic risk scores to model how susceptibility to severe COVID-19 correlates with baseline levels of 35 inflammatory markers, by testing their impact in a SARS-CoV-2-negative population cohort. Because of the established effects of age and body mass index on severe COVID-19 risk, we further considered how these variables interacted with genetic risk to affect inflammatory marker levels. METHODS: We accessed data on 406 SARS-CoV-2-negative individuals as part of a UK population study. Multiplex electrochemiluminescence methods were applied to blood serum, and 35 inflammatory markers were assayed. Corresponding genotype data, alongside results from a large genome-wide association study of severe COVID-19, allowed us to construct genetic risk scores and to test their impact on inflammatory protein levels. RESULTS: Our results revealed that a higher genetic risk for severe COVID-19 was associated with lower blood levels of interferon gamma (IFN-γ), vascular endothelial growth factor D (VEGF-D) and tumor necrosis factor alpha (TNF-α). Inflammatory profiles of those with high genetic risk increasingly diverge from the norm in association with age and obesity. CONCLUSION: Our results support the theory that individuals at risk of severe COVID-19 have a deficient innate immunity marked by reduced levels of inflammatory markers at baseline, including IFN-γ, VEGF-D and TNF-α. We hypothesise that a secondary overactive adaptive immune response may subsequently explain the high levels of cytokines observed in SARS-CoV-2-positive COVID-19 patients.

Elevated C-Reactive Protein in Patients With Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK Biobank.

OBJECTIVE: The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank. METHODS: This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status. RESULTS: CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels >3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors. CONCLUSIONS: The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.

Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case-control study.

OBJECTIVE: Depression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD. DESIGN: We conducted a nested case-control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn's disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5-5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status. RESULTS: We identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38). CONCLUSIONS: Depression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD.

High-frequency follow-up studies in musculoskeletal disorders: a scoping review.

OBJECTIVES: This scoping review identifies research in musculoskeletal disorders that uses high frequency follow-up of symptoms. The aim was to investigate whether symptom variability is investigated as a predictor of disease outcome and how intensive follow-up methods are used in musculoskeletal research. METHODS: Embase, MEDLINE and PsycInfo were searched using OVID, and the Institute of Electrical and Electronic Engineers was also searched using the Institute of Electrical and Electronic Engineers Xplore search engine. Studies were systematically reviewed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses, but no meta-analysis was done because the priority in this study is to identify gaps in available literature. RESULTS: Twenty-one papers were included. There was a mean of 54 patients per study (s.d. of 27.7). Two-thirds of the papers looked at how a symptom influences another in the short-term (subsequent assessment in the same day or next day), but none looked at the long-term. Only one study considered symptom variability investigating how higher variability in pain (defined by the s.d.) is associated with higher average pain severity and lower average sleep quality. CONCLUSION: The methodology of musculoskeletal disorder research has changed from completing paper booklets to using electronic data capture (smartphones). There has also been a trend of collecting more intensive longitudinal data, but very little research utilizes these data to look at how symptom variability affects symptom outcomes. This demonstrates a gap in research where furthering understanding of this will help clinicians decide on the most important symptom to address in future patients.

Association Between Lifetime Affective Symptoms and Premature Mortality.

Importance: Associations between affective symptoms and mortality have been evaluated, but studies have not examined timing or cumulative exposure to affective symptoms over the life course. Objectives: To examine how lifetime accumulation and timing of affective symptoms are associated with mortality and identify potential explanatory factors. Design, Setting, and Participants: Data were obtained from the MRC National Survey of Health and Development (1946 British birth cohort), a socially stratified, population-based sample originally consisting of 5362 singleton births in England, Wales, and Scotland during March 1946. The cohort has been followed up 24 times, most recently in 2014-2015. Eligible participants included those flagged for mortality with affective symptom data available at a minimum of 3 time points (n = 3001). Data analysis was conducted from July 2016 to January 2019. Exposures: Affective symptoms were assessed at ages 13 to 15 years (teacher-rated questionnaire), 36 years (Present State Examination clinical semistructured interview), 43 years (Psychiatric Symptom Frequency questionnaire), and 53 years (General Health Questionnaire-28). Case-level affective symptoms were determined by those scoring in the top 16th percentile (ie, suggestive of a clinical diagnosis). Main Outcomes and Measures: Mortality data were obtained from the UK National Health Service Central Register from age 53 to 68 years. Results: Of 3001 study members (1509 [50.3%] female, 1492 [49.7%] male), 235 individuals (7.8%) died over a 15-year follow-up. After adjustment for sex, those who experienced case-level affective symptoms 1, 2, and 3 to 4 times had 76%, 87%, and 134% higher rates of premature mortality, respectively, compared with those who never experienced case-level symptoms. Case-level symptoms in adolescence only (ages 13-15 years) were associated with a 94% increased rate of mortality, which was unexplained after full adjustment for covariates (hazard ratio, 1.73; 95% CI, 1.10-2.72). Associations between participants with case-level symptoms multiple (2-4) times and mortality were predominately explained by adult health indicators and behaviors. For example, associations for those with case-level symptoms 3 to 4 times were most strongly attenuated by number of health conditions (32.1%), anxiolytic use (28.4%), lung function (24.6%), physical activity (23.9%), smoking (24.6%), antidepressant use (20.1%), diet (16.4%), pulse rate (12.7%), and adult social class (11.2%). Conclusions and Relevance: Lifetime accumulation of affective symptoms may be associated with an increased rate of mortality, with explanatory pathways dependent on the duration and timing of symptoms. Future research into causal pathways and potential points of intervention should consider affective symptom history.

The behavioral, cellular and immune mediators of HIV-1 acquisition: New insights from population genetics.

Millions are exposed to the human immunodeficiency virus type 1 (HIV-1) every year, but not all acquire the virus, suggesting a potential role for host genetics in the moderation of HIV-1 acquisition. Here, we analyzed summary statistics from the largest genome-wide association study of HIV-1 acquisition to-date, consisting of 6,334 infected patients and 7,247 population controls, to advance our understanding of the genetic mechanisms implicated in this trait. We found that HIV-1 acquisition is polygenic and heritable, with SNP heritability estimates explaining 28-42% of the variance in this trait at a population level. Genetic correlations alongside UK Biobank data revealed associations with smoking, prospective memory and socioeconomic traits. Gene-level enrichment analysis identified EF-hand calcium binding domain 14 as a novel susceptibility gene for HIV-1 acquisition. We also observed that susceptibility variants for HIV-1 acquisition were significantly enriched for genes expressed in T-cells, but also in striatal and hippocampal neurons. Finally, we tested how polygenic risk scores for HIV-1 acquisition influence blood levels of 35 inflammatory markers in 406 HIV-1-negative individuals. We found that higher genetic risk for HIV-1 acquisition was associated with lower levels of C-C motif chemokine ligand 17. Our findings corroborate a complex model for HIV-1 acquisition, whereby susceptibility is partly heritable and moderated by specific behavioral, cellular and immunological parameters.

Characteristics, comorbidities, and correlates of atypical depression: evidence from the UK Biobank Mental Health Survey.

BACKGROUND: Depression is a heterogeneous disorder with multiple aetiological pathways and multiple therapeutic targets. This study aims to determine whether atypical depression (AD) characterized by reversed neurovegetative symptoms is associated with a more pernicious course and a different sociodemographic, lifestyle, and comorbidity profile than nonatypical depression (nonAD). METHODS: Among 157 366 adults who completed the UK Biobank Mental Health Questionnaire (MHQ), N = 37 434 (24%) met the DSM-5 criteria for probable lifetime major depressive disorder (MDD) based on the Composite International Diagnostic Interview Short Form. Participants reporting both hypersomnia and weight gain were classified as AD cases (N = 2305), and the others as nonAD cases (N = 35 129). Logistic regression analyses were conducted to examine differences between AD and nonAD in depression features, sociodemographic and lifestyle factors, lifetime adversities, psychiatric and physical comorbidities. RESULTS: Persons with AD experienced an earlier age of depression onset, longer, more severe and recurrent episodes, and higher help-seeking rates than nonAD persons. AD was associated with female gender, unhealthy behaviours (smoking, social isolation, low physical activity), more lifetime deprivation and adversity, higher rates of comorbid psychiatric disorders, obesity, cardiovascular disease (CVD), and metabolic syndrome. Sensitivity analyses comparing AD persons with those having typical neurovegetative symptoms (hyposomnia and weight loss) revealed similar results. CONCLUSIONS: These findings highlight the clinical and public health significance of AD as a chronic form of depression, associated with high comorbidity and lifetime adversity. Our findings have implications for predicting depression course and comorbidities, guiding research on aetiological mechanisms, planning service use and informing therapeutic approaches.

Extent of disease at first cancer presentation and previous anxiety and depressive symptoms: the HUNT study.

BACKGROUND: Depressive symptoms are associated with higher cancer mortality, whereas anxiety symptoms are associated with lower than expected risk. AIMS: This study aimed to investigate the prospective association between depressive/anxiety symptoms and the extent of disease (EOD) of first cancer at diagnosis. METHOD: Prospective population-based study conducted from the second wave of the Nord-Trøndelag Health (HUNT) study. Of 65 000 residents comprehensively interviewed and examined for health status, 407 received first lifetime cancer diagnoses 1-3 years later, ascertained from the Cancer Registry of Norway, and had EOD recorded. Patients with localised disease or regional/distant spread at cancer diagnosis were analysed for earlier depressive/anxiety symptoms ascertained by the Hospital Anxiety and Depression Scale in HUNT. RESULTS: Beyond-local EOD was present in 59.8% of those with neither anxiety nor depression, in 76.6% of those with depression alone (odds ratio, 2.20; 1.08-4.49), in 39.3% of those with anxiety alone (odds ratio, 0.44; 0.20-0.96) and in 57.7% of those with both anxiety and depression (odds ratio, 0.92; 0.41-2.06). After adjustment for demographic and health status, and cancer type, these associations were marginally stronger, but no longer statistically significant (odds ratios, 2.26; 0.84-6.11; 0.43; 0.15-1.26; and 1.00; 0.98-1.03, respectively). CONCLUSIONS: In people who develop cancer, beyond-local EOD at diagnosis was more common in people with previous depression and less common in people with previous anxiety; however, independence from confounding factors could not be concluded.

The association between emotional eating and depressive symptoms: a population-based twin study in Sri Lanka.

This study investigated the genetic and environmental contributions to emotional overeating (EOE) and depressive symptoms, and their covariation, in a Sri-Lankan population, using genetic model-fitting analysis. In total, 3957 twins and singletons in the Colombo Twin and Singleton Study-Phase 2 rated their EOE behaviour and depressive symptoms, which were significantly associated (men: r = 0.11, 95% confidence interval (CI) 0.06-0.16, women: r = 0.12, 95% CI 0.07-0.16). Non-shared environmental factors explained the majority of variance in men (EOE e2 = 87%, 95% CI 78-95%; depressive symptoms e2 = 72%, 95% CI 61-83%) and women (EOE e2 = 76%, 95% CI 68-83%; depressive symptoms e2 = 64%, 95% CI 55-74%). Genetic factors were more important for EOE in women (h2 = 21%, 95% CI 4-32%) than men (h2 = 9%, 95% CI 0-20%). Shared-environmental factors were more important for depressive symptoms in men (c2 = 25%, 95% CI 10-36%) than women (c2 = 9%, 95% CI 0-35%). Non-shared environmental factors explained the overlap between depressive symptoms and EOE in women but not in men. Results differed from high-income populations, highlighting the need for behavioural genetic research in global populations.

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Inflammatory profiles of severe treatment-resistant depression.

BACKGROUND: Treatment-resistant depression (TRD) contributes substantially to the burden of mood disorders and is undoubtedly an important subpopulation in whom there are clear unmet treatment needs. Despite a paucity of research focusing specifically on TRD, recent studies indicate that inflammatory activity may be particularly elevated in these patients. METHODS: 36 patients with TRD were investigated longitudinally before and after undertaking a specialist inpatient treatment program. 27 inflammatory proteins were compared between patients and a matched sample of non-depressed controls, as well as between treatment responders and non-responders. Treatment outcomes were calculated from depression severity scores before and after admission, and at a long-term follow-up 3-12 months after discharge. RESULTS: TRD patients had higher levels of numerous inflammatory proteins than controls, and elevated interleukins 6 and 8, tumour necrosis factor, c-reactive protein and macrophage inflammatory protein-1 were associated with poorer treatment outcomes. A separate set of proteins (either anti-inflammatory in nature or attenuated at baseline) showed increases during treatment, regardless of clinical response. Participants with the greatest elevations in inflammation tended to be older, more cognitively impaired and more treatment-resistant at baseline. LIMITATIONS: The small sample and large number of comparisons examined in this study must be taken into account when interpreting these results. CONCLUSIONS: However, this study provides empirical support for theories that more severe, chronic or treatment-resistant depressive disorders are associated with dysregulated inflammatory activity. If a predictor or predictors of response in TRD are established, improved and targeted care might be more reliably provided to this vulnerable population.

Genetic Risk for Psychiatric Disorders and Telomere Length.

Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample. Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking). Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ≤ 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ≤ 0.05). Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants.

Antidepressants for the treatment of depression in people with cancer.

BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have been shown to have a negative impact in terms of quality of life, compliance with anti-cancer treatment, suicide risk and likely even the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results. OBJECTIVES: To assess the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage). SEARCH METHODS: We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 6), MEDLINE Ovid (1946 to June week 4 2017), Embase Ovid (1980 to 2017 week 27) and PsycINFO Ovid (1987 to July week 4 2017). We additionally handsearched the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug-approving agencies for published, unpublished and ongoing controlled trials. SELECTION CRITERIA: We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis). DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a form specifically designed for the aims of this review. The two authors compared the data extracted and then entered data into Review Manager 5 using a double-entry procedure. Information extracted included study and participant characteristics, intervention details, outcome measures for each time point of interest, cost analysis and sponsorship by a drug company. We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We retrieved a total of 10 studies (885 participants), seven of which contributed to the meta-analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update we included one additional unpublished study. These new data contributed to the secondary analysis, while the results of the primary analysis remained unchanged.For acute-phase treatment response (6 to 12 weeks), we found no difference between antidepressants as a class and placebo on symptoms of depression measured both as a continuous outcome (standardised mean difference (SMD) -0.45, 95% confidence interval (CI) -1.01 to 0.11, five RCTs, 266 participants; very low certainty evidence) and as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants; very low certainty evidence). No trials reported data on follow-up response (more than 12 weeks). In head-to-head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, showing no difference between these two classes (SMD -0.08, 95% CI -0.34 to 0.18, three RCTs, 237 participants; very low certainty evidence). No clear evidence of a beneficial effect of antidepressants versus either placebo or other antidepressants emerged from our analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low certainty evidence). In terms of dropouts due to any cause, we found no difference between antidepressants as a class compared with placebo (RR 0.85, 95% CI 0.52 to 1.38, seven RCTs, 479 participants; very low certainty evidence), and between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the certainty (quality) of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity. AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo. On the basis of these results, clear implications for practice cannot be deduced. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. To better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.

Depression and anxiety symptom trajectories in coronary heart disease: Associations with measures of disability and impact on 3-year health care costs.

BACKGROUND: As mortality from coronary heart disease (CHD) falls, years lived with disability increase. Depression and anxiety are known indicators of poor outcomes in CHD, but most research has measured distress symptoms at one time point, often following acute events. Here we consider the long-term trajectories of these symptoms in established CHD, and examine their association to distinct measures of disability and impact on costs. METHODS AND RESULTS: 803 patients with diagnosis of CHD were recruited from primary care, and completed detailed assessments every 6months for 3years. Latent class growth analysis (LCGA) was used to identify 5 distinct symptom trajectories based on the Hospital Anxiety and Depression Questionnaire (HADS): 'stable low', 'chronic high', 'improving', 'worsening', and 'fluctuating'. The 'chronic high' group had highest association with reporting of chest pain (RRR 5.8, CI 2.9 to 11.7), smoking (2.9, 1.1 to 6.3), and poorer physical (0.88, 0.83-0.93) and mental (0.78, 0.73-0.84) quality of life. The 'chronic high' and 'worsening' trajectories had significantly higher health-care costs over the 'stable low' trajectory (107.2% and 95.5% increase, respectively). In addition, our trajectories were the only significant variable associated with increased health-care costs across the 3years. CONCLUSIONS: Symptoms of depression and anxiety are highly prevalent in stable CHD patients, and their long-term trajectories are the single biggest driver of health care costs. Managing morbidity in these patients, in which depression and anxiety play a key role in, should become the primary focus of policy makers and future clinical trials.

Smoking and common mental disorders in patients with chronic conditions: An analysis of data collected via a web-based screening system.

OBJECTIVE: Smoking is the largest preventable cause of death and disability in the UK and remains pervasive in people with mental disorders and in general hospital patients. We aimed to quantify the prevalence of mental disorders and smoking, examining associations between mental disorders and smoking in patients with chronic physical conditions. METHOD: Data were collected via routine screening systems implemented across two London NHS Foundation Trusts. The prevalence of mental disorder, current smoking, nicotine dependence and wanting help with quitting smoking were quantified, and the relationships between mental disorder and smoking were examined, adjusting for age, gender and physical illness, with multiple regression models. RESULTS: A total of 7878 patients were screened; 23.2% screened positive for probable major depressive disorder, and 18.5% for probable generalised anxiety disorder. Overall, 31.4% and 29.2% of patients with probable major depressive disorder or generalised anxiety disorder respectively were current smokers. Probable major depression and generalised anxiety disorder were associated with 93% and 44% increased odds of being a current smoker respectively. Patients with depressive disorder also reported higher levels of nicotine dependence, and the presence of common mental disorder was not associated with odds of wanting help with quitting smoking. CONCLUSION: Common mental disorder in patients with chronic physical health conditions is a risk factor for markedly increased smoking prevalence and nicotine dependence. A general hospital encounter represents an opportunity to help patients who may benefit from such interventions.

Sociodemographic, lifestyle, and psychosocial determinants of hair cortisol in a South London community sample.

OBJECTIVE: Hypothalamic-pituitary-adrenal (HPA) measures are crucial for research into stress and stress-related disorders. Most HPA measures fluctuate depending on diurnal rhythms and state confounders. Hair cortisol concentrations (HCC) are less susceptible to such fluctuations, but less is known about trait-like confounders. Using a community sample, we tested the relationship between HCC and a range of variables including demographic variables, hair treatment, and medication, as well as psychosocial variables, namely childhood trauma, critical life events, and depressive symptoms. METHODS: Hair samples were collected from 144 individuals from the South East London Community Health (SELCoH) study. Childhood trauma, life events, and depressive symptoms were measured, together with age, sex, ethnicity, relationship status, educational attainment, employment status, occupational social class, hair washing frequency, hair treatments, season reflected in the hair sample, hazardous drinking, smoking, medication intake, and body mass index. Hair samples reflecting the past 3 months were collected and analysed using immunoassays. First, correlations (continuous variables) and simple linear regressions (dichotomous variables) were conducted to identify sociodemographic, hair-related, and lifestyle determinants of HCC. Next, multiple linear regressions were conducted to test the relationship between psychosocial variables and HCC when controlling for the identified confounders. RESULTS: Age (r=-0.17, p=0.050), White British ethnicity (ß=-0.19, p=0.023), heat-based treatments (ß=-0.22, p=0.010), and winter season (ß=-0.18, p=0.024) were associated with lower HCC, whereas summer season (ß=0.24, p=0.024), painkillers (ß=0.25, p=0.003), anxiolytics/antidepressants (ß=0.21, p=0.014), and hormonal contraceptives (ß=0.27, p=0.006) were associated with higher HCC. Controlling for these confounders, physical neglect during childhood (ß=-0.17, p=0.057), war-related experiences (ß=0.20, p=0.027), separation (ß=0.18, p=0.054), and being the victim of a serious crime (ß=-0.17, p=0.062) were linked with altered HCC. CONCLUSION: Our findings suggest that variation in HCC occurs according to sociodemographic, hair-related, and lifestyle variables, and that certain associations between stress and altered HCC can only be revealed when accounting for these confounders.