Beyond the Window of Risk? The Dutch Bipolar Offspring Study: 22-Year Follow-Up.

OBJECTIVE: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet, it remains unknown how this risk continues into middle adulthood. We aim to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. METHOD: This study reports on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants, established in 1997. Offspring (n=100; mean age of 38.28 years, SD=2.74) of parents with BD-I or BD-II were assessed at baseline, 1-, 5-, 12-, and 22-year follow-up. RESULTS: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence=11-13%; BD-I=4%; BD-II=7%). Lifetime prevalence of any mood disorder is 65%, for major depressive disorder (MDD) 36%, and for recurrent mood episodes 37%. Prevalence of MDD more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20-25 years (38-46%) subsiding to 29-35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. CONCLUSION: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Emerging psychopathology and clinical staging in adolescent offspring of parents with bipolar disorder or schizophrenia-A longitudinal study.

OBJECTIVES: Offspring of parents with bipolar disorder (BDo) and schizophrenia (SZo) are at increased risk for these disorders and general psychopathology. Little is known about their (dis)similarities in risk and developmental trajectories during adolescence. A clinical staging approach may help define the developmental course of illness. METHODS: The Dutch Bipolar and Schizophrenia Offspring Study is a unique cross-disorder and prospective cohort study, established in 2010. In total, 208 offspring (58 SZo, 94 BDo, and 56 control offspring [Co]) and their parents participated. Offspring were 13.2 years (SD = 2.5; range: 8-18 years) at baseline and 17.1 years (SD = 2.7) at follow-up (88.5% retention rate). Psychopathology was assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version, and Achenbach System of Empirically Based Assessment parent-, self- and teacher-reports. Groups were compared on (1) the presence of categorical psychopathology, (2) timing and development of psychopathology using a clinical staging perspective, and (3) dimensional psychopathology using a multi-informant approach. RESULTS: SZo and BDo showed more categorical psychopathology and (sub)clinical symptoms, as compared to Co. SZo have, compared to BDo, an increased risk for developmental disorders, a younger age of onset, and more (sub)clinical symptoms of the mood and behavioral spectrum as reported by multiple informants. CONCLUSIONS: Our study shows that the phenotypical risk profile overlaps between SZo and BDo, although an earlier onset of developmental psychopathology was found specifically in SZo, suggesting of a potentially different ethiopathophysiology. Longer follow-up and future studies are needed.

Functional outcomes across development in offspring of parents with bipolar disorder.

OBJECTIVE: Whereas the risk and course of psychopathology in offspring of parents with bipolar disorder (BD) have been the primary focus of high-risk offspring studies to date, functional outcomes have not been given much attention. We present a systematic review of functional outcomes and quality of life (QoL) across development in offspring of parents with BD and aim to explore the role of offspring psychopathology in these outcomes. METHOD: We searched Embase, MEDLINE, PsycINFO, Web of Science, Cochrane Central, and Google Scholar from inception to June 24, 2022, for studies referring to functional outcomes (global, social, academic or occupational) or QoL in offspring of parents with BD. RESULTS: From the 6470 records identified, 39 studies were retained (global = 17; social = 17; school = 16; occupational = 3; QoL = 5), including 13 studies that examined multiple domains. For all domains, high heterogeneity was found in study methods and quality. Only 56 % of studies adjusted for offspring psychopathology, impeding interpretation. Global and social functioning generally seemed to be impaired among older offspring (>16 years). Academic performance appeared to be unaffected. School behavior, occupational functioning, and QoL showed mixed results. Offspring psychopathology is associated with social functioning, but the relationship of offspring psychopathology with other domains is less clear. CONCLUSION: Studies on functional outcome in offspring of parents with BD show predominantly mixed results. Inconsistent adjustment of psychopathology and age limits conclusive interpretation. Functional outcomes should be prioritized as research topics in high-risk studies and the potential associations between familial risk status, offspring psychopathology, and age may inform prevention strategies.

Resilience and mental health in children and adolescents: an update of the recent literature and future directions.

PURPOSE OF REVIEW: In order to promote optimal development of children and adolescents at risk for psychiatric disorders, a better understanding of the concept resilience is crucial. Here, we provide an overview of recent work on clinical and epidemiological correlates of resilience and mental health in children and adolescents. RECENT FINDINGS: Our systematic literature search revealed 25 studies that unanimously show that higher levels of resilience are related to fewer mental health problems, despite the heterogeneity of study populations and instruments. Correlates of resilience included multisystem factors, such as social, cultural, family and individual aspects, which is in line with the multisystem approach as described by recent resilience theories. Longitudinal studies are scarce but confirm the dynamical character of resilience and mental health. The application of longitudinal studies and innovative measurement techniques will improve our understanding on the cascade effects of stressors on resilience and mental health outcomes. SUMMARY: Resilience is strongly associated with mental health in children and adolescents and deserves a more prominent role in research, prevention programs and routine clinical care. Including social, cultural and family context in the evaluation of resilience is of great value, as this can identify targets for early and preventive interventions.

Editorial: The Early Phenotype of Bipolar Disorder?

In patients with bipolar disorder (BD), there is often a substantial delay before diagnosis and accurate treatment initiation. This delay is associated with a poorer outcome and stresses the importance of early recognition. As BD runs in families, longitudinal studies on children of parents with BD can provide information on the onset and early trajectories of BD. In the past 3 decades, a number of longitudinal studies on offspring of parents with BD have been initiated. With a typical age of onset in late adolescence, most of these studies started in adolescence. Thus far, these studies have shown that 13% to 25% of these children develop BD, they are predominantly at risk for developing mood disorders (>50%), and BD typically starts with a (mild) depressive episode followed by (sub)clinical mania.1 Less is known about the preschool-age period, when preventive interventions hold promise for preserving typical development. In this issue, Birmaher and colleagues2 present findings of their longitudinal study on preschool-aged offspring of parents with BD with a follow-up into early adolescence. Accordingly, this study adds an important piece to the existing literature about the offspring of parents with BD, but also fuels the ongoing debate on pediatric BD.

Brain-derived neurotrophic factor in bipolar disorder: Associations with age at onset and illness duration.

Bipolar disorder (BD) is a heterogeneous disorder that contains neurodevelopmental differences. Defining homogeneous subgroups of BD patients by using age at onset (AAO) as a specifier may promote the classification of biomarkers. This study compares peripheral BDNF levels between pediatric and adult BD patients to investigate the associations between BDNF levels, AAO, and illness duration. We enrolled two groups of euthymic patients, those with pediatric BD (n = 39) and those with adult BD (n = 31), as well as a group of healthy controls (HCs) (n = 90). Participants were assessed using clinical measures and BDNF serum levels were obtained using ELISA. We observed that BDNF levels were comparable between adult BD and HCs, but were clearly lower in pediatric BD than in HCs. In adult BD with AAO ≥30 years, BDNF levels were significantly higher than in adult BD with AAO <30 years. In pediatric BD, patients with prepubertal-onset had higher BDNF levels than those with pubertal-onset. BDNF levels demonstrated the accuracy of being able to distinguish pediatric BD from healthy controls in a receiver operating characteristic (ROC) curve analysis (area under the curve [AUC] = 0.792). In adult BD, higher BDNF levels were associated with later disease onset, but this was not the case in pediatric BD. Finally, reduced BDNF levels were associated with illness duration in adult BD. The findings indicate that BDNF levels in BD patients are associated with AAO. BDNF may, therefore, potentially serve as a developmental marker in BD, when AAO is taken into account.

Traumatic experiences, family functioning, and mood disorder development in bipolar offspring.

OBJECTIVES: Studies in children of patients affected with bipolar disorder (BD; bipolar offspring) are at high risk to develop mood disorders. Our aim is to investigate how environmental factors such as childhood trauma and family functioning relate to the development of mood disorders in offspring at familial risk for BD. DESIGN: The current study is part of a longitudinal prospective cohort study among offspring of parents with BD. METHODS: The current study is part of the Dutch Bipolar Offspring Study, an ongoing prospective cohort study among adolescent offspring of a parent with BD. Bipolar offspring were psychiatrically evaluated at baseline and at 1-, 5-, and 12-year follow-up. Complete follow-up data over de 12-year follow-up were available for 102 offspring. Childhood trauma was measured with the Childhood Trauma Questionnaire (CTQ) and filled out by the offspring. Family functioning was reported by the mother with the 130-item Questionnaire for Family Problems (QFP). RESULTS: Emotional maltreatment was significantly associated (HR = 1.82, CI 1.18-2.82, p = .007) with mood disorder onset in bipolar offspring. No association was found with the family functioning total score (HR = 1.04, CI 0.94-15, p = .085) nor its subscales. CONCLUSIONS: The current study suggests that emotional maltreatment is associated with mood disorder development in bipolar offspring. Remarkably, the association of offspring-reported emotional maltreatment and mood disorder onset was not reflected in parent-reported family functioning (e.g., support and communication, openness or involvement). Possible explanations are discussed and warrant further study. PRACTITIONER POINTS: Offspring of bipolar patients are at increased risk of developing mood disorders across the life-time. Emotional trauma contributes to the likelihood of developing mood disorders in bipolar offspring. In the daily treatment of bipolar patients having children, attention should be given to parental style and difficulties. Further research using multiple informant methods on childhood trauma an family functioning is needed to further disentangle the effects of these variables on the onset of psychopathology in bipolar offspring.

The Dutch Bipolar Offspring Study: Cognitive Development and Psychopathology.

Various aspects of the relationship between cognitive impairment and bipolar disorder are not clear yet. This study examines cognitive and educational functioning prospectively in offspring at familial risk for bipolar disorder, in order to improve our understanding of the association between cognitive functioning and psychopathology. Bipolar offspring (N = 92) from the prospective Dutch bipolar offspring study were evaluated at adolescence and adulthood for IQ estimate, educational achievement and development of any psychiatric disorder. The main outcome was IQ estimate after 12 years of follow-up (offspring mean age 28 years). Generalized estimating equation (GEE) analyses showed that any lifetime DSM-IV axis I diagnosis was related to a lower cognitive outcome at adulthood as compared to unaffected bipolar offspring. No specific association was found for type of diagnosis. Early onset psychopathology (diagnosis at or before age 15 years) was significantly related to lower IQ estimate at adulthood, indicating a sensitive period for neurocognitive development.

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, ß=-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.

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.

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

OBJECTIVES: 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. METHODS: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1ß (IL-1ß), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls. RESULTS: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages. CONCLUSIONS: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value.

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

OBJECTIVES: 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. METHODS: Monocyte quantitative polymerase chain reaction and symptom data from 64 patients with BD were collected from three Dutch studies. Regression analyses were performed to analyze the various associations between pro-inflammatory gene expression and clinical features, from which feature-expression heat maps were drawn. RESULTS: No associations were found between pro-inflammatory gene expression and lifetime psychotic symptoms, whereas a positive association was identified between subcluster 2 genes and manic symptoms. For several subcluster 1a genes, a negative association was found with age at onset. For most subcluster 2 genes, a positive association was found with the duration of illness. Current use of antidepressants and of anti-epileptic agents was associated with subcluster 2 gene expression, and current use of lithium and antipsychotic agents with subcluster 1a gene expression. CONCLUSIONS: Our hypothesis that lifetime psychotic features would be associated with pro-inflammatory monocyte gene expression was not confirmed. In an explorative analysis we found: (i) a possible relationship between pro-inflammatory gene expression and manic symptomatology; (ii) a differential immune activation related to age at onset and duration of illness; and (iii) support for the concept of an immune suppressive action of some of the mood-regulating medications.

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.