Qualitative analysis of feasibility of recruitment and retention in a planned randomised controlled trial of a psychosocial cancer intervention within the NHS.

BACKGROUND: The randomised control trial (RCT) is the most rigorous method of evaluating interventions. Recruitment is often slower and more challenging than expected. The aim of the current paper is to understand the feasibility of recruitment within the NHS and the barriers and motivators to recruitment from the perspective of patients and healthcare professionals (HCPs). METHODS: NHS HCPs were surveyed to establish their willingness to participate. Twenty HCPs were interviewed to establish barriers and motivators to recruitment. Eleven patients were interviewed to understand their willingness to participate. Interviews were analysed using thematic analysis. RESULTS: HCP interviews identified key barriers to recruitment: practical barriers included workload and time; clinical barriers included terminology and concern that the trial implied criticism of their current practice; and patient barriers included gender and cultural factors. Motivators to recruitment included: regular communication between research and clinical teams; feedback on findings; and patient and individual benefits for clinicians. Patient interviews suggested that participation in a trial of a psychosocial intervention would strengthen existing coping skills and develop mechanisms for those who were struggling. CONCLUSIONS: Survey results demonstrated that recruitment to an RCT of a psychosocial intervention for people living with and beyond cancer would be feasible within the NHS if specific barriers are addressed. From a clinician point of view, barriers should be addressed to improve recruitment, particularly training and education of clinicians and clear communication. From a patient perspective, interventions and RCT should be tailored to target those not routinely represented in RCTs.

Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples.

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.

A survey to determine usual care after cancer treatment within the United Kingdom national health service.

BACKGROUND: Approximately one third of cancer survivors in the United Kingdom face ongoing and debilitating psychological and physical symptoms related to poor quality of life. Very little is known about current post-cancer treatment services. METHODS: Oncology healthcare professionals (HCPs) were invited to take part in a survey, which gathered both quantitative and free text data about the content and delivery of cancer aftercare and patient needs. Analysis involved descriptive statistics and content analysis. RESULTS: There were 163 complete responses from 278 survey participants; 70% of NHS acute trusts provided data. HCPs views on patient post-cancer treatment needs were most frequently: fear of recurrence (95%), fatigue (94%), changes in physical capabilities (89%), anxiety (89%) and depression (88%). A median number of 2 aftercare sessions were provided (interquartile range: 1,4) lasting between 30 and 60 min. Usually these were provided face-to-face and intermittently by a HCP. However, sessions did not necessarily address the issues HCPs asserted as important. Themes from free-text responses highlighted inconsistencies in care, uncertain funding for services and omission of some evidence based approaches. CONCLUSION: Provision of post-cancer treatment follow-up care is neither universal nor consistent in the NHS, nor does it address needs HCPs identified as most important.

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

Interrelationship of depression, stress and inflammation in cancer patients: a preliminary study.

OBJECTIVE: Depression is common in cancer patients and detrimentally affects patients' quality of life. Both depression and stress are associated with raised inflammatory marker levels. This prospective study of cancer patients focuses on childhood trauma, recent life events and inflammatory marker levels as risk factors for high post-surgery depressive symptoms. METHODS: Ninety cancer patients (56 head and neck, 34 colorectal) completed the Hospital Anxiety and Depression Scale, pre-surgery and six, 12 and 24 weeks post-surgery. Recent life events and childhood trauma were assessed at six and 12 weeks respectively. Blood samples were taken pre- and one and six weeks post-surgery to measure C-reactive protein (CRP) and pro-inflammatory cytokine levels. RESULTS: Childhood trauma and recent life events were risk factors for higher depressive symptom levels. In colorectal cancer patients, baseline CRP levels were associated with depressive symptom levels at six (p=0.008) and 12 weeks (p=0.038). Baseline and six week Tumour Necrosis Factor-alpha (TNFα) levels were significantly associated with higher depressive symptoms at later time points after adjusting for cancer-related variables. Childhood trauma was positively associated with TNFα and CRP levels in colorectal cancer patients. The associations between inflammatory markers and depressive symptoms were not significant after adjusting for childhood trauma. LIMITATIONS: Small sample size. CONCLUSIONS: Raised inflammatory mediator levels may be risk factors for depressive symptoms in colorectal cancer patients and thus worth considering as a potential therapeutic target. These pilot data support recent findings demonstrating long-term effects of childhood adversity on adult health.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

A follow-up case-control association study of tractable (druggable) genes in recurrent major depression.

The High-Throughput Disease-specific target Identification Program (HiTDIP) aimed to study case-control association samples for 18 common diseases. Here we present the results of a follow-up case-control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max-Planck Institute (MP-GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow-up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator-Activated Receptor-Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow-up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP-GSK sample. Performing Cochran-Mantel-Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP-GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis.

Adverse life event reporting and worst illness episodes in unipolar and bipolar affective disorders: measuring environmental risk for genetic research.

BACKGROUND: Studies exploring gene-environment interplay in affective disorders now include very large numbers of participants. Methods for evaluating the role of adversity in such studies need to be developed that do not rely on lengthy and labour-intensive interviews. In the present study, a brief questionnaire method for measuring 11 adverse events reported before interview and before their worst illness episodes by bipolar, unipolar and healthy control participants, participating in genetic association studies, was evaluated. METHOD: Five hundred and twelve bipolar disorder (BD) participants, 1447 participants with recurrent unipolar depression (UPD) and 1346 psychiatrically healthy control participants underwent the researcher-administered version of the List of Threatening Experiences Questionnaire (LTE-Q) for the 6 months before their worst affective episodes for UPD and BD participants, and for the 6 months before interview for the UPD participants and controls. RESULTS: UPD and BD cases were significantly more likely to report at least one event, as well as more events in the 6 months before interview and before their worst illness episodes, than healthy controls. Both manic and depressive episodes were significantly associated with adverse events in the BD cases. Depressed mood at the time of interview influenced event reporting in UPD and control participants but not the BD cases. Age was negatively correlated with the number of events reported by controls. CONCLUSIONS: The researcher-administered LTE-Q provides a measure of case-control differences for adversity that is applicable in large genetic association studies. Confounding factors for event reporting include present mood and age.

Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX-DISC1 fusion protein. We explored the TSNAX-DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX-DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX-DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX-DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

NRG1 gene in recurrent major depression: no association in a large-scale case-control association study.

The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large-scale case-control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD.

Sex, trauma, stress hormones and depression.

Although few studies dispute that there are gender differences in depression, the etiology is still unknown. In this review, we cover a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression. These include the possible role of estrogens at puberty, differences in exposure to childhood trauma, differences in stress perception between men and women and the biological differences in stress response. None of these factors seem to explain gender differences in depression. Finally, we do know that when depressed, women show greater hypothalamic-pituitary-adrenal (HPA) axis activation than men and that menopause with loss of estrogens show the greatest HPA axis dysregulation. It may be the constantly changing steroid milieu that contributes to these phenomena and vulnerability to depression.

Depression, migraine with aura and migraine without aura: their familiality and interrelatedness.

Migraine is frequently comorbid with depression. There appear to be common aetiological factors for both disorders, but the aetiology of migraine within depressed patients, in particular the significance of aura, has been little studied. A large sample of concordantly depressed sibling pairs [the Depression-Network (DeNT) sample] was assessed as having migraine with aura (MA), migraine without aura (MoA), probable migraine or no migraine according to International Headache Society guidelines. Correlations between siblings' migraine status were used to assess the nature of familial liability to migraine. A multiple threshold isocorrelational model fit best, in which different syndromes are conceptualized as different severities of one underlying dimension rather than as having separate aetiologies. Thus, MA and MoA were found to be different forms of the same disorder, with MA occupying the more extreme end of the spectrum of liability. Implications for our understanding of the relationship between migraine and depression are discussed.

No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis.

Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta-analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5-methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003, however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD.

Phantom bite revisited.

The term 'phantom bite' is used to describe an uncommon condition in which patients are preoccupied with their dental occlusion, believing that it is abnormal. The condition is remarkable for the nature of the involved explanations and interpretations that the patients give and for their persistence in trying to find a solution to what appears to be a relatively minor problem. Three clinical cases that illustrate the nature of this condition are presented and problems associated with the management of affected patients are discussed. Phantom bite can be a disabling disorder which is difficult to treat. Available evidence suggests that the symptoms cannot be improved by occlusal treatments. It is therefore essential to avoid extensive irreversible restorative treatment. General dental practitioners should refer patients for specialist opinion and management. Psychiatric assessment with recommendations for management should be obtained if possible. The prognosis is poor for symptom elimination but need not necessarily be poor for patients' overall functioning and well-being. It is suggested that emphasis should be placed on building adaptive coping skills. Further research is needed to elucidate the nature of the condition to improve treatment.