Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample.

Background: Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. Methods: We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. Results: The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide-significant (p < 5 × 10-8) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10-10), the AKAP6 gene (rs3784187, p = 1.2 × 10-8), and near the MFSD1 gene (rs340315, p = 4.5 × 10-8). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). Conclusions: In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.

Antidepressant prescriptions and associated factors in men with prostate cancer and their female partners.

PURPOSE: To estimate the risk of first-time antidepressant prescriptions as a proxy for depression or anxiety and associated risk factors in patients with prostate cancer and their female partners. METHODS: We followed all men (n = 25,126) and their female cohabiting partners (n = 8785) without a history of cancer or antidepressants from the Danish Diet, Cancer and Health cohort from 1997 to 2014 or 2010, respectively. We estimated the cumulative incidence of first-time antidepressant prescriptions in men with prostate cancer compared with cancer-free men and their respective female partners, using the Danish National Prescription Registry. Sociodemographic, lifestyle-related, and clinical risk factors were assessed using Cox regression models. RESULTS: A total of 1828 men were diagnosed with prostate cancer of whom 15% received antidepressants. The unadjusted hazard ratio of antidepressant prescription was 2.18 (95%CI, 1.92, 2.48) for men with prostate cancer and 1.27 (95%CI, 0.87, 1.85) for their partners, compared with cancer-free men and their partners, respectively. After adjusting for sociodemographic, lifestyle-related, and comorbidity factors, this risk was 2-fold to 4-fold increased among patients, but not significantly increased among partners. Significant risk factors among patients were curative and palliative treatment (vs. active surveillance and watchful waiting), nonlocalized disease, and short education. CONCLUSIONS: Men with prostate cancer have a higher risk of receiving antidepressant medication than cancer-free men. Clinical characteristics can help clinicians in identifying patients at a high risk of depression or anxiety. IMPLICATIONS FOR CANCER SURVIVORS: Men with prostate cancer who experience symptoms of depression or anxiety should seek professional help early on. Patient education could aid in raising awareness and reducing the stigma associated with mental disorders.

Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population.

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (ß = -.07; SE = .02; P = .002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Genetic variants in 5-HTTLPR, BDNF, HTR1A, COMT, and FKBP5 and risk for treated depression after cancer diagnosis.

BACKGROUND: The role of gene-environment interactions in the pathogenesis of depression is unclear. Previous studies addressed vulnerability for depression after childhood adversity and stressful life events among carriers of numerous specific genetic variants; however, the importance of individual genetic variants, the environmental exposures with which they interact, and the magnitude of the risk conveyed by these interactions remain elusive. METHODS: We included 7,320 people with a first primary cancer identified in the prospective Diet, Cancer and Health study in an exposed-only cohort study. The mean age of the individuals was 68 years (5th, 95th percentiles: 58, 78) at cancer diagnosis. Using Cox regression models and cumulative incidence plots, we analyzed the associations between genetic variants in 5-HTTLPR, BDNF, HTR1A, COMT, and FKBP5 and use of antidepressants as well as hospital contact for depression after diagnosis of cancer. RESULTS: Overall, we observed no statistically significant associations, with nonsignificant hazard ratio estimates for use of antidepressants of 0.95-1.07. CONCLUSIONS: This study of elderly people indicates that it is unlikely that the investigated genetic variants are clinically relevantly associated with depression after diagnosis of cancer. The mechanisms for gene-environment interactions in younger individuals are probably different, and we advise caution in extrapolating our results to early life stress. However, conclusion from the present study might be generalizable to elderly persons exposed to other stressful life events.

First use of antidepressant medication in male partners of women with breast cancer in Denmark from 1998 to 2011.

OBJECTIVE: A diagnosis of breast cancer disrupts the life of the patient, but also the partner may experience adverse psychological effects. We examined partners' risk for first use of antidepressant medication, as a proxy for pharmacologically treated depression. METHODS: By linkage of national registers, we identified 1 420 592 depression-free men living with a cancer-free female partner in 1998 to 2011. During follow-up, breast cancer was diagnosed in female partners of 26 256 men. In Poisson regression models, we estimated the rate ratios for first use of antidepressant medication compared to partners of breast cancer-free women. Cox regression analyses examined associations between exposed partners' sociodemographic characteristics, somatic comorbidity, death of female partner, and first use of antidepressant medication. RESULTS: Male partners of women with breast cancer had an increased rate ratio of 1.08 (95% CI, 1.03-1.13) for first use of antidepressant medication compared to the background population, corresponding to excess absolute risk of 12 cases per 10 000 person-years. This increased risk persisted throughout 14 years of follow-up. Higher age, shorter education, somatic comorbidity, and death of female partner were associated with increased risk among men whose partner had breast cancer. CONCLUSION: The modest, but long term, increased risk for first use of antidepressant medication calls for attention by health care professionals to symptoms of depression among partners of breast cancer patients.

Survival After Early-Stage Breast Cancer of Women Previously Treated for Depression: A Nationwide Danish Cohort Study.

Purpose The aim of this nationwide, register-based cohort study was to determine whether women treated for depression before primary early-stage breast cancer are at increased risk for receiving treatment that is not in accordance with national guidelines and for poorer survival. Material and Methods We identified 45,325 women with early breast cancer diagnosed in Denmark from 1998 to 2011. Of these, 744 women (2%) had had a previous hospital contact (as an inpatient or outpatient) for depression and another 6,068 (13%) had been treated with antidepressants. Associations between previous treatment of depression and risk of receiving nonguideline treatment of breast cancer were assessed in multivariable logistic regression analyses. We compared the overall survival, breast cancer-specific survival, and risk of death by suicide of women who were and were not treated for depression before breast cancer in multivariable Cox regression analyses. Results Tumor stage did not indicate a delay in diagnosis of breast cancer in women previously treated for depression; however, those given antidepressants before breast cancer had a significantly increased risk of receiving nonguideline treatment (odds ratio, 1.14; 95% CI, 1.03 to 1.27) and significantly worse overall survival (hazard ratio, 1.21; 95% CI, 1.14 to 1.28) and breast cancer-specific survival (hazard ratio, 1.11; 95% CI, 1.03 to 1.20). Increased but nonsignificant estimated risks were also found for women with previous hospital contacts for depression. In subgroup analyses, the association of depression with poor survival was particularly strong among women who did not receive the indicated adjuvant systemic therapy. Conclusion Women previously treated for depression constitute a large subgroup of patients with breast cancer who are at risk for receiving nonguideline breast cancer treatment, which probably contributes to poorer overall and breast cancer-specific survival.

Increased risk for depression after breast cancer: a nationwide population-based cohort study of associated factors in Denmark, 1998-2011.

PURPOSE: To investigate the risk for first depression, assessed as incident hospital contacts for depression and incident use of antidepressants, among women with breast cancer. PATIENTS AND METHODS: Danish national registries were used to identify 1,997,669 women with no diagnosis of cancer or a major psychiatric disorder. This cohort was followed from 1998 to 2011 for a diagnosis of breast cancer and for the two outcomes, hospital contact for depression and redeemed prescriptions for antidepressants. Rate ratios for incident hospital contacts for depression and incident use of antidepressants were estimated with Poisson regression models. Multivariable Cox regression was used to evaluate factors associated with the two outcomes among patients with breast cancer. RESULTS: We identified 44,494 women with breast cancer. In the first year after diagnosis, the rate ratio for a hospital contact for depression was 1.70 (95% CI 1.41 to 2.05) and that for use of antidepressants was 3.09 (95% CI 2.95 to 3.22); these rate ratios were significantly increased after 3 and 8 years, respectively. Comorbidity, node-positive disease, older age, basic and vocational educational levels, and living alone were associated with use of antidepressants. CONCLUSION: Women with breast cancer are at long-term increased risk for first depression, including both severe episodes leading to hospital contact and use of antidepressants. Clinicians should be aware that the risk is highest in women with comorbid conditions, node-positive disease, and age of 70 years or more. We found no clear association between type of surgery or adjuvant treatment and risk for depression.

Factors associated with the prescription of antidepressive medication to breast cancer patients.

UNLABELLED: We evaluated factors associated with use of antidepressant medication subsequent to a diagnosis of breast cancer. We also evaluated the effect of participation in a cancer rehabilitation program on use of antidepressants. MATERIAL AND METHODS: We conducted a register-based cohort study of 1 247 women with breast cancer diagnosed between 1998 and 2006 who attended a week-long rehabilitation program and a comparison group of 2 903 women who did not attend the program matched through the registers of the Danish Breast Cancer Cooperative Group. The associations between breast cancer-related, treatment-related, and sociodemographic factors and use of antidepressants were evaluated in multivariate Cox proportional hazard models separated on use of antidepressants before diagnosis of breast cancer. RESULTS: The mean follow-up for the 4 150 women in the study was 3.3 years (5-95% range, 0.3-7.0 years) and 1 020 (25%) were users of antidepressants after diagnosis of breast cancer. Among women who had not used antidepressants before their breast cancer, the diagnosis of a new primary cancer increased the adjusted hazard ratio (HR) to 3.34 (95% CI, 1.50-7.76), and recurrence of breast cancer increased the HR for first use of antidepressants to 2.56 (95% CI, 1.86-3.52). Unemployment was associated significantly with use of antidepressants, whereas having no children living at home, lower income, and the number of tumor-positive axillary lymph nodes were of borderline significance. No effect of the rehabilitation program was observed on first use of antidepressants after breast cancer. DISCUSSION: Diagnosis of a new cancer or recurrence of breast cancer considerably increased the rate of use of antidepressants. Sociodemographic rather than disease- or treatment-related characteristics at the time of diagnosis were associated with first use of antidepressants after a breast cancer diagnosis.