Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10-5 and c.2702T > G [p.V901G], MAF 2.51 × 10-3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10-8), viability (P = 8.9 × 10-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

The characteristics of psychotic features in bipolar disorder.

BACKGROUND: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors. METHODS: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models. RESULTS: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (ß = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (ß = 0.09, t = 3.04, p = 0.002). CONCLUSIONS: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome.

BACKGROUND: We previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors. AIM: To verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients. METHODS: Monocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) α and GRß, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage. RESULTS: As compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRα and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found. CONCLUSION: T cell deficits most likely are a trait phenomenon of BD, since they have also been found in the other cohorts of BD patients and in bipolar offspring. Monocytes of this cohort showed an anti-inflammatory set point, suggesting that pro- and anti-inflammation are state characteristics of BD. The monocyte gene profile indicated an increased CAC activity; the question arises whether this is due to putative vessel damage in these relatively old patients with a high prevalence of the MetS.

Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes.

INTRODUCTION: Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients. METHODS: Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers. RESULTS: In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women. CONCLUSION: Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness.

Metabolic syndrome in patients with bipolar disorder: comparison with major depressive disorder and non-psychiatric controls.

OBJECTIVE: We aimed to investigate the prevalence of the metabolic syndrome (MetS) and its individual components in subjects with bipolar disorder (BD) compared to those with major depressive disorder (MDD) and non-psychiatric controls. METHODS: We examined 2431 participants (mean age 44.3±13.0, 66.1% female), of whom 241 had BD; 1648 had MDD; and 542 were non-psychiatric controls. The MetS was ascertained according to NCEP ATP III criteria. Multivariable analyses were adjusted for age, sex, ethnicity, level of education, smoking status and severity of depressive symptoms, and in the case of BD subjects, also for psychotropic medication use. RESULTS: Subjects with BD had a significantly higher prevalence of MetS when compared to subjects with MDD and non-psychiatric controls (28.4% vs. 20.2% and 16.5%, respectively, p<0.001), also when adjusted for sociodemographic and lifestyle factors (OR 1.52, 95% CI: 1.09-2.12, p=0.02 compared to MDD; OR 1.79, 95% CI: 1.20-2.67, p=0.005 compared to non-psychiatric controls). The differences between BD subjects with controls could partly be ascribed to a higher mean waist circumference (91.0 cm vs. 88.8, respectively, p=0.03). In stratified analysis, the differences in the prevalence of MetS between patients with BD and MDD were found in symptomatic but not in asymptomatic cases. CONCLUSION: This study confirms a higher prevalence of MetS in patients with BD compared to both MDD patients and controls. Specifically at risk are patients with a higher depression score and abdominal obesity.

Predictors of the onset of manic symptoms and a (hypo)manic episode in patients with major depressive disorder.

OBJECTIVE: One third of patients with a major depressive episode also experience manic symptoms or, even, a (hypo)manic episode. Retrospective studies on the temporal sequencing of symptomatology suggest that the majority of these patients report depressive symptoms before the onset of manic symptoms. However, prospective studies are scarce and this study will, therefore, prospectively examine the onset of either manic symptoms or a (hypo)manic episode in patients with a major depressive disorder. In addition, we will consider the impact of a large set of potential risk factors on both outcomes. METHODOLOGY: Four-year follow-up data were used to determine the onset of manic symptoms as well as a CIDI-based (hypo)manic episode in a large sample (n = 889, age: 18-65 years) of outpatients with a major depressive disorder and without manic symptoms at baseline. Baseline vulnerability (i.e., sociodemographics, family history of depression, childhood trauma, life-events) and clinical (i.e., isolated manic symptoms, depression characteristics, and psychiatric comorbidity) factors were considered as potential risk factors. RESULTS: In our sample of depressed patients, 15.9% developed manic symptoms and an additional 4.7% developed a (hypo)manic episode during four years. Baseline isolated manic symptoms and comorbid alcohol dependence predicted both the onset of manic symptoms and a (hypo)manic episode. Low education only predicted the onset of manic symptoms, whereas male gender, childhood trauma and severity of depressive symptoms showed strong associations with, especially, the onset of (hypo)manic episodes. CONCLUSIONS: A substantial proportion (20.6%) of patients with a major depressive disorder later developed manic symptoms or a (hypo)manic episode. Interestingly, some identified risk factors differed for the two outcomes, which may indicate that pathways leading to the onset of manic symptoms or a (hypo)manic episode might be different. Our findings indirectly support a clinical staging model.

Effects of mood state on divided attention in patients with bipolar disorder: evidence for beneficial effects of subclinical manic symptoms.

A relatively small number of studies have been dedicated to the differential effects of the current mood state on cognition in patients with a bipolar disorder (BD). The aim of the current study was to investigate the effect of current mood state on divided attention (DA) performance, and specifically examine possible beneficial effects of the (hypo-) manic state. Over a maximum period of 24 months, medication use, divided attention test (a subtest of the Test for Attentional Performance (TAP)) was assessed every 6 months in 189 outpatients with BD. Data were analyzed with multilevel regression analysis (i.e. linear mixed models). DA performance varied considerable over time within patients. Corrected for psychotropic medication a significant quadratic relationship between manic symptoms and DA performance was found, with mild hypomanic symptoms having a positive influence on divided attention scores and moderate to severe manic symptoms having a negative influence. No association between depressive symptoms and DA performance was found. In future research on mania and cognition as well as in the clinical practice both the beneficial and negative effects of mania should be taken into account.

The Mood Disorder Questionnaire (MDQ) for detecting (hypo)manic episodes: its validity and impact of recall bias.

BACKGROUND: Bipolar disorders often remain unrecognized in clinical practice, which may be a consequence of imprecise recall of manic symptoms earlier in life. This study will therefore examine the validity of the widely-used Mood Disorder Questionnaire (MDQ) in detecting a (hypo)manic episode and explore the impact of recall bias. METHODS: As an indication of impairments in recalling manic symptoms, we examined the long-term reliability of the MDQ after two years of follow-up in a sample of 2087 persons. Then, the validity of the MDQ was tested against the gold standard of a CIDI-based DSM-IV (hypo)manic episode. Its performance was compared for detecting a lifetime episode (at T1) versus a recent episode in the past two years (at T2). RESULTS: The long-term reliability of the MDQ was limited as the correct recall of individual items ranged from 44.6% to 68.8% after two years. The overall validity of the MDQ in detecting a lifetime (hypo)manic episode was limited and no adequate cut-off point with acceptable sensitivity and specificity could be identified. However, the MDQ accurately detected a recent episode with a sensitivity of 0.83 and a specificity of 0.82 for the standard and optimal cut-off point of ≥ 7. Taking into account two additional MDQ questions on clustering in time and severity of problems decreased its validity. LIMITATIONS: Patients with a primary, clinical diagnosis of bipolar disorder were excluded. CONCLUSIONS: The MDQ accurately detected recent (hypo)manic episodes, but imprecise recall may result in a limited performance for episodes earlier in life.

Long-term cortisol in bipolar disorder: associations with age of onset and psychiatric co-morbidity.

INTRODUCTION: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to play a role in the pathogenesis of bipolar disorder (BD). Conflicting results have been reported when saliva or serum was used to measure cortisol levels. A recently developed method is to measure cortisol in scalp hair, with 1cm of scalp hair representing 1 month. We studied whether there are differences in long-term hair cortisol levels between BD patients and healthy individuals and whether there are associations between hair cortisol and disease characteristics. METHODS: Hair samples were collected in 100 BD patients and 195 healthy controls. Long-term cortisol levels were determined in 3 cm hair segments. Saliva samples were collected on two consecutive evenings. Documented disease characteristics were disease state, age of onset and psychiatric co-morbidity. RESULTS: Hair cortisol levels were not statistically different in BD patients compared to healthy controls (p=0.233) and were not associated with the disease state at the moment of sample collection (p=0.978). In the subgroup of patients with age of onset ≥ 30 years, hair cortisol levels were significantly elevated compared to the subgroup with age of onset <30 years and to healthy controls (p=0.004). Psychiatric co-morbidity was associated with elevated cortisol levels (44.87 versus 31.41 pg/mg hair; p=0.021), with the exclusion of panic disorder, which was associated with decreased cortisol levels (22.13 versus 34.67 pg/mg hair; p=0.019). CONCLUSIONS: Elevated long-term cortisol levels might play a role in a subgroup of patients with BD. There may be differences in pathogenesis of younger and older onset BD suggesting two different disease entities.