Age Trajectories of the Structural Connectome in Child and Adolescent Offspring of Individuals With Bipolar Disorder or Schizophrenia.

Background: Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at elevated risk of developing psychiatric illness owing to both genetic predisposition and increased burden of environmental stress. Emerging evidence indicates a disruption of brain network connectivity in young offspring of patients with bipolar disorder and schizophrenia, but the age trajectories of these brain networks in this high-familial-risk population remain to be elucidated. Methods: A total of 271 T1-weighted and diffusion-weighted scans were obtained from 174 offspring of at least 1 parent diagnosed with bipolar disorder (n = 74) or schizophrenia (n = 51) and offspring of parents without severe mental illness (n = 49). The age range was 8 to 23 years; 97 offspring underwent 2 scans. Anatomical brain networks were reconstructed into structural connectivity matrices. Network analysis was performed to investigate anatomical brain connectivity. Results: Offspring of parents with schizophrenia had differential trajectories of connectivity strength and clustering compared with offspring of parents with bipolar disorder and parents without severe mental illness, of global efficiency compared with offspring of parents without severe mental illness, and of local connectivity compared with offspring of parents with bipolar disorder. Conclusions: The findings of this study suggest that familial high risk of schizophrenia is related to deviations in age trajectories of global structural connectome properties and local connectivity strength.

In this article, we show that child and adolescent offspring of parents with schizophrenia had different patterns in the development of their brain's structural connections compared with offspring of parents with bipolar disorder and offspring of parents without these conditions. The findings of this long-term study indicate that having a family history of schizophrenia is associated with changes over time during adolescence in the overall organization of the brain's structural network.

Non-linear development of brain morphometry in child and adolescent offspring of individuals with bipolar disorder or schizophrenia.

Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at increased risk of developing psychopathology. Structural brain alterations have been found in child and adolescent offspring of patients with bipolar disorder and schizophrenia, but the developmental trajectories of brain anatomy in this high-familial-risk population are still unclear. 300 T1-weighted scans were obtained of 187 offspring of at least one parent diagnosed with bipolar disorder (n=80) or schizophrenia (n=53) and offspring of parents without severe mental illness (n=54). The age range was 8 to 23 years old; 113 offspring underwent two scans. Global brain measures and regional cortical thickness and surface area were computed. A generalized additive mixed model was used to capture non-linear age trajectories. Offspring of parents with schizophrenia had smaller total brain volume than offspring of parents with bipolar disorder (d=-0.20, p=0.004) and control offspring (d=-0.22, p=0.005) and lower mean cortical thickness than control offspring (d=-0.23, p<0.001). Offspring of parents with schizophrenia showed differential age trajectories of mean cortical thickness and cerebral white matter volume compared with control offspring (both p's=0.003). Regionally, offspring of parents with schizophrenia had a significantly different trajectory of cortical thickness in the middle temporal gyrus versus control offspring (p<0.001) and bipolar disorder offspring (p=0.001), which was no longer significant after correcting for mean cortical thickness. These findings suggest that particularly familial high risk of schizophrenia is related to reductions and deviating developmental trajectories of global brain structure measures, which were not driven by specific regions.

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.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Brain structure, IQ, and psychopathology in young offspring of patients with schizophrenia or bipolar disorder.

BACKGROUND: Studying offspring of schizophrenia (SZo) and bipolar disorder patients (BDo) provides important information on the putative neurodevelopmental trajectories underlying development toward severe mental illnesses. We compared intracranial volume (ICV), as a marker for neurodevelopment, and global and local brain measures between SZo or BDo and control offspring (Co) in relation to IQ and psychopathology. METHODS: T1-weighted magnetic resonance imaging (MRI) brain scans were obtained from 146 participants (8-19 years; 40 SZo, 66 BDo, 40 Co). Linear mixed models were applied to compare ICV, global, and local brain measures between groups. To investigate the effect of ICV, IQ (four subtests Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale-III) or presence of psychopathology these variables were each added to the model. RESULTS: SZo and BDo had significantly lower IQ and more often met criteria for a lifetime psychiatric disorder than Co. ICV was significantly smaller in SZo than in BDo (d = -0.56) and Co (d = -0.59), which was largely independent of IQ (respectively, d = -0.54 and d = -0.35). After ICV correction, the cortex was significantly thinner in SZo than in BDo (d = -0.42) and Co (d = -0.75) and lateral ventricles were larger in BDo than in Co (d = 0.55). Correction for IQ or lifetime psychiatric diagnosis did not change these findings. CONCLUSIONS: Despite sharing a lower IQ and a higher prevalence of psychiatric disorders, brain abnormalities in BDo appear less pronounced (but are not absent) than in SZo. Lower ICV in SZo implies that familial risk for schizophrenia has a stronger association with stunted early brain development than familial risk for bipolar disorder.