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.

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

OBJECTIVE: To identify the early signs of mood disorder development, specifically bipolar disorder (BD), in a population at familial risk for BD. METHOD: The sample included 107 Dutch adolescent bipolar offspring (age 12-21) followed into adulthood (age 22-32). Lifetime DSM-IV axis I diagnoses were examined at baseline, 1-, 5-, and 12- year follow-up. Symptoms were assessed at baseline on a 3-point Likert scale at baseline with the K-SADS-PL and were analyzed using symptom and sum scores. As observed in previous studies, BD typically starts with other mood disorders. Therefore, the sample was stratified in offspring with a mood diagnosis (n = 29) and without (n = 78) at baseline. RESULTS: Subthreshold manic experiences proved the strongest predictor of BD conversion (n = 10; HR2.16, CI95% 1.23-3.78). At symptom level, elated mood, decreased need of sleep, racing thoughts, suicidal ideation, and middle insomnia were significantly associated with BD conversion. Depressive symptoms proved the strongest predictor for first mood episode onset (n = 28; HR1.27, CI95% 1.02-1.58). CONCLUSION: This study extends our knowledge of prodromal manifestations of BD in a high-risk population. Although preliminary, findings of this study provide potential targets for early identification and underscore the importance of detailed assessment of manic symptomatology in 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.

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.

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.

The seroprevalence of antithyroid peroxidase antibodies in bipolar families and bipolar twins: results from two longitudinal studies.

BACKGROUND: Previous studies of our group among bipolar offspring and bipolar twins showed significant higher prevalence's and levels of antithyroid peroxidase antibodies (TPO-Abs) in offspring and co-twins (without a mood disorder) compared to controls, suggesting that TPO-Abs might be considered as vulnerability factor (trait marker) for BD development. OBJECTIVES: Here we elucidate, in the same cohorts, but now after 12- and 6-year follow-up, whether TPO-abs should be considered as a 'trait' marker for BD. The present study aims to investigate whether TPO-Abs (1) are stable over time, (2) are associated with lithium-exposure, (3) share a common genetic background with BD and are related to psychopathology. RESULTS: In bipolar offspring and twins, the prevalence of TPO-Abs is stable over time (r s = .72 p < .001 resp. r s = .82, p < .001) and not associated with lithium use. At follow-up, an increased prevalence of TPO-abs was again observed in bipolar offspring (10,4% versus 4%) and higher TPO-abs titers were still present in co-twins of bipolar cases compared to control twins [mean 1.06 IU/ml (SD .82) versus mean .82 IU/ml (SD .67)], although statistical significance was lost. CONCLUSIONS: Although our results show a trend toward an increased inherited risk of the co-occurrence of BD and thyroid autoimmunity, large-scale studies can only draw final conclusions. Nationwide epidemiological and GWAS studies reach such numbers and support the view of a possible common (autoimmune) etiology of severe mood disorders and chronic recurrent infections and autoimmunity, including thyroid autoimmunity.