Manon Hillegers

A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes.

CONTEXT Mood disturbances are associated with an activated inflammatory response system. OBJECTIVE To identify a discriminating and coherent expression pattern of proinflammatory genes in monocytes of patients with bipolar disorder. DESIGN A quantitative polymerase chain reaction (Q-PCR) case-control gene expression study on purified monocytes of bipolar patients, the offspring of bipolar patients, and healthy control participants after having selected 22 discriminating inflammatory genes using whole genome analyses. SETTING Academic research setting in The Netherlands. PATIENTS Forty-two bipolar patients with 25 healthy controls, 54 offspring of a bipolar parent (13 had a mood disorder and 3 developed one during follow-up), and 70 healthy children underwent Q-PCR. MAIN OUTCOME MEASURE Inflammatory gene expression levels in monocytes. RESULTS We detected in the monocytes of bipolar patients a coherent mutually correlating set (signature) of 19 aberrantly expressed (P < .01) messenger RNAs of inflammatory (PDE4B, IL1B, IL6, TNF, TNFAIP3, PTGS2, and PTX3), trafficking (CCL2, CCL7, CCL20, CXCL2, CCR2, and CDC42), survival (BCL2A1 and EMP1), and mitogen-activated protein kinase pathway (MAPK6, DUSP2, NAB2, and ATF3) genes. Twenty-three of 42 bipolar patients (55%) had a positive signature test result vs 7 of 38 healthy controls (18%) (positive test result: positivity for PDE4B, ie, a messenger RNA 1 SD higher than the mean level found in healthy controls, plus 25% of the other genes with similar positive findings). Positive signature test results were also present in 11 of 13 offspring with a mood disorder (85%), 3 of 3 offspring developing a mood disorder (100%), and 17 of 38 euthymic offspring (45%) vs 13 of 70 healthy children (19%). Lithium carbonate and antipsychotic treatment downregulated the gene expression of most inflammatory genes. CONCLUSIONS The monocytes of a large proportion of bipolar patients and offspring of bipolar parents showed an inflammatory gene expression signature. This coherent set of genes opens new avenues for biomarker development with possibilities for disease prediction in individuals genetically at risk and for the subclassification of bipolar patients who could possibly benefit from anti-inflammatory treatment.

Prevalence of Psychopathology in Children of a Bipolar Parent

OBJECTIVE To determine psychopathology in adolescent children of a bipolar parent living in the Netherlands, using multiple sources of information (self-, parent, and teacher reports). METHOD Problem behavior in 140 offspring (aged 12-21 years) of 86 bipolar parents was assessed with the Child Behavior Checklist (CBCL), the Teachers Report Form (TRF), and the Youth Self-Report (YSR) between 1997 and 1999. All adolescents, bipolar parents, and their available spouses were interviewed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). RESULTS Higher problem scores were found for 8 of the 11 CBCL scales for girls and 4 of the 11 CBCL scales for boys, compared with a Dutch normative sample, and 1 Young Adult Self-Report (YASR) scale for girls compared with an American normative sample. Lower problem scores were found on 4 YSR and 4 YASR scales for boys, 1 TRF scale for girls, and 1 TRF scale for boys. The prevalence of current DSM-IV diagnoses in the offspring was 29% and of life-time DSM-IV diagnoses, 44%. CONCLUSIONS The prevalence of problem behavior and DSM-IV diagnoses found in our sample did not support the notion that the level of psychopathology in children aged 12 to 21 years of bipolar parents is highly elevated. This study, similar to prior studies, suffers from lack of information on the representativeness of the sample and a rather low response rate.

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.

Functional differences in emotion processing during adolescence and early adulthood.

Adolescence is a transitional period between childhood and adulthood and is characterized by emotional instability. Underlying this behavior may be an imbalance between the limbic subcortical areas and the prefrontal cortex. Here, we investigated differences in these regions during adolescence and young adulthood. Fifty subjects aged 10 to 24 viewed and rated neutral, negative, and positive pictures (IAPS: International Affective Picture System), while being scanned with functional MRI. Only those trials in which there was a match between the subjects response and the IAPS rating were included in the analyses. Task performance (matching accuracy, reaction times) did not differ across age. Activity in the amygdala and hippocampus decreased with age when processing emotional salient stimuli versus neutral stimuli. In contrast, activation in the ventrolateral prefrontal cortex increased with age. Importantly, we show for the first time that these age-related changes are paralleled by an increase in functional coupling of the amygdala and hippocampus with the orbitofrontal cortex and ventrolateral prefrontal cortex. These findings are in line with the general notion that brain development from childhood to adulthood is characterized by a gradual increase in frontal control over subcortical regions. Understanding these developmental changes is important as these may underlie typical adolescent behavior.

Psychopathology in the adolescent offspring of bipolar parents.

BACKGROUND The aim of this study was to determine the prevalence and 14-months incidence of psychopathology in adolescent offspring of a bipolar parent. METHOD Parent, teacher and self-report rating scales and Kiddie-SADS were used to assess 132 13-23-year-old offspring of bipolar parents. RESULTS Compared to the general population, there were few differences between rating scale scores for bipolar offspring and problem scores for normative adolescents. Of the sample 49% had a lifetime psychiatric disorder, most commonly (33%) a mood disorder. LIMITATIONS There was no suitable control group and there are no comparison data for psychiatric diagnoses (DSM-IV), based on semi-structured interviews in the adolescent age group in the Netherlands. CONCLUSIONS The overall level of psychopathology of bipolar offspring was not particularly elevated, but when there were more problems, they tended to be mood disorders.

Frontostriatal activity and connectivity increase during proactive inhibition across adolescence and early adulthood

During adolescence, functional and structural changes in the brain facilitate the transition from childhood to adulthood. Because the cortex and the striatum mature at different rates, temporary imbalances in the frontostriatal network occur. Here, we investigate the development of the subcortical and cortical components of the frontostriatal network from early adolescence to early adulthood in 60 subjects in a cross‐sectional design, using functional MRI and a stop‐signal task measuring two forms of inhibitory control: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping). During development, reactive inhibition improved: older subjects were faster in reactive inhibition. In the brain, this was paralleled by an increase in motor cortex suppression. The level of proactive inhibition increased, with older subjects slowing down responding more than younger subjects when anticipating a stop‐signal. Activation increased in the right striatum, right ventral and dorsal inferior frontal gyrus, and supplementary motor area. Moreover, functional connectivity during proactive inhibition increased between striatum and frontal regions with age. In conclusion, we demonstrate that developmental improvements in proactive inhibition are paralleled by increases in activation and functional connectivity of the frontostriatal network. These data serve as a stepping stone to investigate abnormal development of the frontostriatal network in disorders such as schizophrenia and attention‐deficit hyperactivity disorder. Hum Brain Mapp 35:4415–4427, 2014.

Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents

BACKGROUND Studies are inconsistent as to whether patients with bipolar disorder are more frequently affected by autoimmune thyroiditis. AIM To study the prevalence of autoimmune thyroiditis in offspring of bipolar patients. METHOD In 1998 140 children (age 12-21 years) of bipolar parents were evaluated psychiatrically using the K-SADS-PL and blood was drawn to determine thyroperoxidase antibodies (TPO-Abs) and serum TSH. Blood samples of high school students (aged 12-19 years, n=77) and young adults (aged 20-35 years, n=52) were used as comparisons. At follow-up the offspring were psychiatrically evaluated and tested for TPO-Abs and TSH twice (14 months and 55 months after enrollment). RESULTS TPO-Abs were predominantly found in female bipolar offspring, who had a significantly higher prevalence of positive TPO-Ab titers (9 out of 57 female offspring subjects) as compared to the female high school and young adult comparisons (4 out of 103 female control subjects). In TPO-Ab positive offspring (n=11) a raised prevalence of 55% of thyroid failure (i.e. a raised serum TSH or l-thyroxine treatment) was evident. TPO-Ab positive offspring did not show a raised prevalence of mood disorders (or any psychopathology) as compared to the TPO-Ab negative offspring. CONCLUSION Our study suggests that bipolar offspring are more vulnerable to develop thyroid autoimmunity independently from the vulnerability to develop psychiatric disorders.

Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor

Cortisol and corticosterone act on the appraisal process, which comprises the selection of an appropriate coping style and the encoding of the experience for storage in the memory. This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus. Limbic MR is down‐regulated by chronic stress and during depression but induced by antidepressants. Increased MR activity inhibits hypothalamic‐pituitary‐adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping. Cortisol and emotion‐cognition are affected by MR gene haplotypes based on rs5522 and rs2070951. Haplotype 1 (GA) moderates the effects of (early) life stressors, reproductive cycle and oral contraceptives. MR haplotype 2 (CA) is a gain of function variant that protects females against depression by association with an optimistic, resilient phenotype. Activation of MR therefore may offer a target for alleviating depression and cognitive dysfunction. Accordingly, the MR agonist fludrocortisone was found to enhance the efficacy of antidepressants and to improve memory and executive functions in young depressed patients. In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower affinity glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation. In this MR:GR regulation, the MR is an important target for promoting resilience.

Different developmental trajectories for anticipation and receipt of reward during adolescence.

Typical adolescent behaviour such as increased risk-taking and novelty-seeking is probably related to developmental changes in the brain reward system. This functional MRI study investigated how brain activation related to two components of reward processing (Reward Anticipation and Reward Outcome) changes with age in a sample of 39 children, adolescents and young adults aged 10-25. Our data revealed age-related changes in brain activity during both components of reward processing. Activation related to Reward Anticipation increased with age, while activation related to Reward Outcome decreased in various regions of the reward network. This shift from outcome to anticipation was confirmed by subsequent analyses showing positive correlations between age and the difference in activation between Reward Anticipation and Reward Outcome. The shift was predominantly present in striatal regions and was accompanied by a significant effect of age on behaviour, with older participants showing more response speeding on potentially rewarding trials than younger participants. This study provides evidence for functional changes in the reward system which may underlie typical adolescent behaviour.

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.