Heterogeneity in Long-term Trajectories of Depression: A Review and Application of Group-based Trajectory Modeling

Objective: The goal of this dissertation was to study heterogeneity in long-term (i.e. 5+ year) trajectories of depression over time using group-based trajectory modeling – a statistical method designed to identify unobserved classes of individuals with different trajectory patterns. Paper 1 reviews studies that used group-based trajectory models (Latent Class Growth Analysis (LCGA) and Growth Mixture Modeling (GMM)) to examine heterogeneity in long-term trajectories of depressive symptoms (Chapter 2). In paper 2 we used LCGA to examine patterns and predictors of 10-year trajectories of inpatient and outpatient MDD treatment among patients with earlier onset (< 60) MDD (Chapter 3). In paper 3 we used LCGA to examine patterns and predictors of 5-year trajectories of inpatient and outpatient MDD treatment in late-onset (≥ 60) cases (Chapter 4). Methods: Papers 2 and 3 used data from the Danish registers. The study sample in paper 2 consisted of 14,564 individuals born between 1935 and 1994. The study sample in paper 3 consisted of 12,200 individuals born between 1898 and 1947. Only individuals with no record of bipolar disorder or psychotic illness were eligible for inclusion in the study samples. Trajectories were estimated with LCGA using PROC TRAJ in SAS 9.4. Results: We identified 4 classes with distinct trajectory patterns: early recovery, prolonged initial illness, later recurrence and chronic illness. Similar patterns were observed in early and late-onset cases, however the proportions of individuals in the prolonged initial illness and chronic illness classes were higher in late-onset cases. In cases with onset before 60, parental history of depression and anxiety predicted membership in the later recurrence class, while parental history of psychotic illness predicted membership in the chronic illness class. In late-onset cases, past history of dementia predicted membership in the prolonged initial illness and chronic illness classes. Conclusions: The majority of MDD cases in Denmark have a positive prognosis, however a significant minority of cases experience prolonged periods of illness. Demographic variables, characteristics of the initial diagnosis and parental history of psychiatric diagnoses predict course trajectory class membership. Differences in observable course trajectories may be indicative of underlying differences in genetic or biological etiology

Polygenic liabilities and treatment trajectories in early-onset depression: a Danish register-based study.

BACKGROUND: The clinical course of major depressive disorder (MDD) is heterogeneous, and early-onset MDD often has a more severe and complex clinical course. Our goal was to determine whether polygenic scores (PGSs) for psychiatric disorders are associated with treatment trajectories in early-onset MDD treated in secondary care. METHODS: Data were drawn from the iPSYCH2015 sample, which includes all individuals born in Denmark between 1981 and 2008 who were treated in secondary care for depression between 1995 and 2015. We selected unrelated individuals of European ancestry with an MDD diagnosis between ages 10-25 (N = 10577). Seven-year trajectories of hospital contacts for depression were modeled using Latent Class Growth Analysis. Associations between PGS for MDD, bipolar disorder, schizophrenia, ADHD, and anorexia and trajectories of MDD contacts were modeled using multinomial logistic regressions. RESULTS: We identified four trajectory patterns: brief contact (65%), prolonged initial contact (20%), later re-entry (8%), and persistent contact (7%). Relative to the brief contact trajectory, higher PGS for ADHD was associated with a decreased odds of membership in the prolonged initial contact (odds ratio = 1.06, 95% confidence interval = 1.01-1.11) and persistent contact (1.12, 1.03-1.21) trajectories, while PGS-AN was associated with increased odds of membership in the persistent contact trajectory (1.12, 1.03-1.21). CONCLUSIONS: We found significant associations between polygenic liabilities for psychiatric disorders and treatment trajectories in patients with secondary-treated early-onset MDD. These findings help elucidate the relationship between a patient's genetics and their clinical course; however, the effect sizes are small and therefore unlikely to have predictive value in clinical settings

Bipolar disorder and depression in early adulthood and long-term employment, income, and educational attainment : A nationwide cohort study of 2,390,127 individuals

Background Mood disorders are known to be associated with poor socioeconomic outcomes, but no study has examined these associations across the entire worklife course. Our goal was to estimate the associations between bipolar disorder and depression in early adulthood and subsequent employment, income, and educational attainment. Methods We conducted a nationwide prospective cohort study including all individuals (n = 2,390,127; 49% female) born in Denmark between 1955 and 1990. Hospital-based diagnoses of depression and bipolar disorder before age 25 were obtained from the Danish psychiatric register. Yearly employment, earnings, and education status from ages 25 to 61 were obtained from the Danish labor market and education registers. We estimated both absolute and relative proportions. Results Population rates of hospital-diagnosed depression and bipolar between ages 15-25 were 1% and 0.12%, respectively. Compared to individuals without mood disorders, those with depression and particularly bipolar disorder had consistently poor socioeconomic outcomes across the entire work-life span. For example, at age 30, 62% of bipolar and 53% of depression cases were outside the workforce compared to 19% of the general population, and 52% of bipolar and 42% of depression cases had no higher education compared to 27% of the general population. Overall, individuals with bipolar disorder or depression earned around 36% and 51%, respectively, of the income earned by individuals without mood disorders. All associations were smaller for individuals not rehospitalized after age 25. Conclusions Severe mood disorders with onset before age 25, particularly bipolar disorder, are associated with persistent poor socioeconomic outcomes across the entire work-life course.Peer reviewe

Heterogeneity in Long-term Trajectories of Depression: A Review and Application of Group-based Trajectory Modeling

Objective: The goal of this dissertation was to study heterogeneity in long-term (i.e. 5+ year) trajectories of depression over time using group-based trajectory modeling – a statistical method designed to identify unobserved classes of individuals with different trajectory patterns. Paper 1 reviews studies that used group-based trajectory models (Latent Class Growth Analysis (LCGA) and Growth Mixture Modeling (GMM)) to examine heterogeneity in long-term trajectories of depressive symptoms (Chapter 2). In paper 2 we used LCGA to examine patterns and predictors of 10-year trajectories of inpatient and outpatient MDD treatment among patients with earlier onset (< 60) MDD (Chapter 3). In paper 3 we used LCGA to examine patterns and predictors of 5-year trajectories of inpatient and outpatient MDD treatment in late-onset (≥ 60) cases (Chapter 4). Methods: Papers 2 and 3 used data from the Danish registers. The study sample in paper 2 consisted of 14,564 individuals born between 1935 and 1994. The study sample in paper 3 consisted of 12,200 individuals born between 1898 and 1947. Only individuals with no record of bipolar disorder or psychotic illness were eligible for inclusion in the study samples. Trajectories were estimated with LCGA using PROC TRAJ in SAS 9.4. Results: We identified 4 classes with distinct trajectory patterns: early recovery, prolonged initial illness, later recurrence and chronic illness. Similar patterns were observed in early and late-onset cases, however the proportions of individuals in the prolonged initial illness and chronic illness classes were higher in late-onset cases. In cases with onset before 60, parental history of depression and anxiety predicted membership in the later recurrence class, while parental history of psychotic illness predicted membership in the chronic illness class. In late-onset cases, past history of dementia predicted membership in the prolonged initial illness and chronic illness classes. Conclusions: The majority of MDD cases in Denmark have a positive prognosis, however a significant minority of cases experience prolonged periods of illness. Demographic variables, characteristics of the initial diagnosis and parental history of psychiatric diagnoses predict course trajectory class membership. Differences in observable course trajectories may be indicative of underlying differences in genetic or biological etiology

Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study

textabstractObjective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders. Design Population based cohort study. Setting Danish national registers. Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×10 6 person years at risk. Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy). Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models. Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group. Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive