E. Mesman

The Dutch Bipolar Offspring Study: 12-Year Follow-Up

OBJECTIVE Offspring of bipolar parents have a genetically increased risk of developing mood disorders. In a longitudinal study, the authors followed a bipolar offspring cohort from adolescence into adulthood to determine the onset, prevalence, and early course of mood disorders and other psychopathology. METHOD The Dutch bipolar offspring cohort is a fixed cohort initiated in 1997 (N=140; age range at baseline, 12-21 years). Bipolar offspring were psychiatrically evaluated at baseline and at 1-, 5-, and 12-year follow-ups. Of the original sample, 77% (N=108) were followed for the full 12 years. RESULTS Overall, 72% of the bipolar offspring developed a lifetime DSM-IV axis I disorder, 54% a mood disorder, and 13% bipolar spectrum disorders. Only 3% met DSM-IV criteria for bipolar I disorder. In 88% of the offspring with a bipolar spectrum disorder, the illness started with a depressive episode. In total, 24% of offspring with a unipolar mood disorder developed a bipolar spectrum disorder over time. Mood disorders were often recurrent (31%), were complex (comorbidity rate, 67%), and started before age 25. CONCLUSIONS Even after 12 years of follow-up, from adolescence into adulthood, bipolar I disorder was rare among bipolar offspring. Nevertheless, the risk of developing severe and recurrent mood disorders and other psychopathology was high. Future follow-up of this and other adult bipolar offspring cohorts is essential to determine whether recurrent mood disorders in bipolar offspring reflect the early stages of bipolar disorder.

Relationship between clinical features and inflammation related monocyte gene expression in bipolar disorder - towards a better understanding of psychoimmunological interactions

Existing and previously published datasets were examined for associations between illness and treatment characteristics and monocyte pro‐inflammatory gene expression in patients with bipolar disorder (BD). We hypothesized a priori that increased monocyte pro‐inflammatory gene expression would be found more frequently in patients with a lifetime history of psychotic symptoms.

Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring : a follow-up study from adolescence into adulthood

There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro‐immune changes in a prospective study on children of patients with bipolar disorder.

Categorical and dimensional psychopathology in Dutch and US offspring of parents with bipolar disorder: A preliminary cross-national comparison

OBJECTIVE Accumulating evidence suggests cross-national differences in adults with bipolar disorder (BD), but also in the susceptibility of their offspring (bipolar offspring). This study aims to explore and clarify cross-national variation in the prevalence of categorical and dimensional psychopathology between bipolar offspring in the US and The Netherlands. METHODS We compared levels of psychopathology in offspring of the Pittsburgh Bipolar Offspring Study (n=224) and the Dutch Bipolar Offspring Study (n=136) (age 10-18). Categorical psychopathology was ascertained through interviews using the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS-PL), dimensional psychopathology by parental reports using the Child Behavior Checklist (CBCL). RESULTS Higher rates of categorical psychopathology were observed in the US versus the Dutch samples (66% versus 44%). We found no differences in the overall prevalence of mood disorders, including BD-I or -II, but more comorbidity in mood disorders in US versus Dutch offspring (80% versus 34%). The strongest predictors of categorical psychopathology were maternal BD (OR: 1.72, p<.05), older age of the offspring (OR: 1.19, p<.05), and country of origin (US; OR: 2.17, p<.001). Regarding comorbidity, only country of origin (OR: 7.84, p<.001) was a significant predictor. In general, we found no differences in dimensional psychopathology based on CBCL reports. LIMITATIONS Preliminary measure of inter-site reliability. CONCLUSIONS We found cross-national differences in prevalence of categorical diagnoses of non-mood disorders in bipolar offspring, but not in mood disorder diagnoses nor in parent-reported dimensional psychopathology. Cross-national variation was only partially explained by between-sample differences. Cultural and methodological explanations for these findings warrant further study.

The role of life events and psychological factors in the onset of first and recurrent mood episodes in bipolar offspring: results from the Dutch Bipolar Offspring Study.

BACKGROUND Life events are an established risk factor for the onset and recurrence of unipolar and bipolar mood episodes, especially in the presence of genetic vulnerability. The dynamic interplay between life events and psychological context, however, is less studied. In this study, we investigated the impact of life events on the onset and recurrence of mood episodes in bipolar offspring, as well as the effects of temperament, coping and parenting style on this association. METHOD Bipolar offspring (n = 108) were followed longitudinally from adolescence to adulthood. Mood disorders were assessed with: the Kiddie Schedule of Affective Disorders and Schizophrenia - Present and Lifetime Version or the Structured Clinical Interview for DSM-IV Axis I disorders; life events with the Life Events and Difficulties Schedule; and psychological measures using the Utrecht Coping List, Temperament and Character Inventory and short-EMBU (memories of upbringing instrument). Anderson-Gill models (an extension of the Cox proportional hazard model) were utilized. RESULTS Life events were associated with an increased risk for first and, although less pronounced, subsequent mood episodes. There was a large confounding effect for the number of previous mood episodes; findings suggest a possible kindling effect. Passive coping style increased the risk of mood episode onset and recurrent episodes, but also altered the effect of life events on mood disorders. Harm avoidance temperament was associated with mood episode recurrence. CONCLUSIONS Life events are especially a risk factor in the onset of mood disorders, though less so in recurrent episodes. Psychological features (passive coping and harm-avoidant temperament) contribute to the risk of an episode occurring, and also have a moderating effect on the association between life events and mood episodes. These findings create potential early intervention strategies for bipolar offspring.

A dynamic course of T cell defects in individuals at risk for mood disorders.

OBJECTIVES T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.

Childhood trauma and HPA axis functionality in offspring of bipolar parents

Children of a parent with bipolar disorder (bipolar offspring) have an increased risk for mood disorders. While genetic factors play a significant role in this population, susceptibility to environmental stress may also significantly contribute to this vulnerability for mood disorders. Childhood trauma has consistently been found to increase the risk for mood disorders, with persisting consequences for hypothalamic-pituitary-adrenal (HPA) axis functionality. However, it is currently unknown whether childhood trauma specifically affects HPA axis activity in individuals with a familial risk for bipolar disorder. Therefore, we investigated the effects of childhood trauma on daytime and evening cortisol levels and dexamethasone suppression in bipolar offspring (N=70) and healthy controls (N=44). In our study we found no significant differences in daytime and evening cortisol levels as well as dexamethasone suppression between bipolar offspring and healthy controls (all p-values>0.43). In contrast, childhood trauma differentially affected daytime cortisol levels in the bipolar offspring compared to healthy controls (childhood trauma X bipolar offspring interaction, β=-7.310, p=0.0414) with an effect of childhood trauma on daytime cortisol in bipolar offspring at trend level (p=0.058). In the bipolar offspring group, lifetime or current psychiatric diagnoses, and stressful life events separately did not affect cortisol levels or dexamethasone suppression (all p-values>p=0.50). These findings were independent of current or lifetime psychiatric diagnosis. In conclusion, trauma-related changes in daytime HPA axis activity appear to be a specific trait in bipolar offspring who have increased risk for mood disorders compared to healthy individuals.

Baseline dimensional psychopathology and future mood disorder onset: findings from the Dutch Bipolar Offspring Study

To identify the early signs of mood disorder development, specifically bipolar disorder (BD), in a population at familial risk for BD.

Validation of the Seven Up Seven Down Inventory in bipolar offspring: screening and prediction of mood disorders. Findings from the Dutch Bipolar Offspring Study

OBJECTIVE To validate the Seven Up Seven Down (7U7D), an abbreviated version of the General Behavior Inventory (GBI), as screener for mood disorders and test its ability to predict mood disorders over time in individuals at risk for bipolar disorder (BD). METHODS Bipolar offspring (n=108) were followed from adolescence into adulthood and assessed at baseline, 1-, 5- and 12 years follow-up (T1-T4 respectively). Offspring were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime Version, Structured Clinical Interview for DSM-IV Axis I Disorders and the GBI. RESULTS Performance of the GBI and 7U7D was functionally similar for the depression (7D) scale, but variable for the mania (7U) scale. As screener for mood disorders (T4), the 7D showed fair diagnostic efficiency (area under the curve (AUC) 0.68, p<0.01, OR 1.53, 95% CI 1.15-2.03). The discriminative validity for BD and unipolar disorder was only close to significant (7D AUC 0.66, p=0.078; 7U AUC 0.67, p=0.067). In terms of prediction of mood disorder onset between T1 and T4, the 7D, but not the 7U, was associated with new onset (AUC 0.67, p<0.05; HR 1.14, 95% CI 1.07-1.23). The 7U7D did not achieve significant prediction of BD. LIMITATIONS Relative small sample size and limited generalizability. CONCLUSIONS Based on the current study, the 7U7D shows limited potential as screening instrument for mood disorders in bipolar offspring. The clinical utility of the 7U7D needs further exploration for use in clinical and research settings.

Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age

Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.