In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Reduced levels of circulating adhesion molecules in adolescents with early-onset psychosis.

It is suggested that neurodevelopmental abnormalities are involved in the disease mechanisms of psychotic disorders. Although cellular adhesion molecules (CAMs) participate in neurodevelopment, modulate blood-brain barrier permeability, and facilitate leukocyte migration, findings concerning their systemic levels in adults with psychosis are inconsistent. We examined plasma levels and mRNA expression in peripheral blood mononuclear cells (PBMCs) of selected CAMs in adolescents with early-onset psychosis (EOP) aged 12-18 years (n = 37) and age-matched healthy controls (HC) (n = 68). EOP patients exhibited significantly lower circulating levels of soluble platelet selectin (~-22%) and soluble vascular cell adhesion molecule-1 (~-14%) than HC. We found no significant associations with symptom severity. PSEL mRNA expression was increased in PBMCs of patients and significantly negatively correlated to duration of illness. These findings suggest a role for CAMs in the pathophysiology of psychotic disorders.

Exploring white matter microstructure and the impact of antipsychotics in adolescent-onset psychosis.

White matter abnormalities are well-established in adult patients with psychosis. Less is known about abnormalities in the rarely occurring adolescent early onset psychosis (EOP). In particular, whether antipsychotic medication might impact white matter microstructure is not known. Using 3T diffusion weighted imaging, we investigated differences in white matter microstructure and the impact of antipsychotic medication status in medicated (n = 11) and unmedicated (n = 11) EOP patients relative to healthy controls (n = 33), aged between 12-18 years. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication in patients. We found significantly lower FA in the left genu of the corpus callosum, the left anterior corona radiata (ACR) and the right superior longitudinal fasciculus in EOP patients relative to healthy controls. AD values were also lower in the left ACR, largely overlapping with the FA findings. Mean FA in the left ACR was significantly associated with antipsychotic medication status (Cohen's d = 1.37, 95% CI [0.01, 2.68], p = 0.008), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region hypothesized to contribute to the etiology of psychosis. Replications are warranted to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure in adolescent-onset psychosis.

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia: A comparison among participants between 2 and 53 years.

Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2-53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age-and gender-adjusted vitB12 z-scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z-score: 0.30) than in HC (316 pmol/L, z-score: 0.06, P < .01) and schizophrenia (306 pmol/L, z-score: -0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age-and gender-adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z-scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.

Microstructural White Matter and Links With Subcortical Structures in Chronic Schizophrenia: A Free-Water Imaging Approach.

Schizophrenia is a severe mental disorder with often a chronic course. Neuroimaging studies report brain abnormalities in both white and gray matter structures. However, the relationship between microstructural white matter differences and volumetric subcortical structures is not known. We investigated 30 long-term treated patients with schizophrenia and schizoaffective disorder (mean age 51.1 ± 7.9 years, mean illness duration 27.6 ± 8.0 years) and 42 healthy controls (mean age 54.1 ± 9.1 years) using 3 T diffusion and structural magnetic resonance imaging. The free-water imaging method was used to model the diffusion signal, and subcortical volumes were obtained from FreeSurfer. We applied multiple linear regression to investigate associations between (i) patient status and regional white matter microstructure, (ii) medication dose or clinical symptoms on white matter microstructure in patients, and (iii) for interactions between subcortical volumes and diagnosis on microstructural white matter regions showing significant patient-control differences. The patients had significantly decreased free-water corrected fractional anisotropy (FAt), explained by decreased axial diffusivity and increased radial diffusivity (RDt) bilaterally in the anterior corona radiata (ACR) and the left anterior limb of the internal capsule (ALIC) compared to controls. In the fornix, the patients had significantly increased RDt. In patients, positive symptoms were associated with localized increased free-water and negative symptoms with localized decreased FAt and increased RDt. There were significant interactions between patient status and several subcortical structures on white matter microstructure and the free-water compartment for left ACR and fornix, and limited to the free-water compartment for right ACR and left ALIC. The Cohen's d effect sizes were medium to large (0.61 to 1.20, absolute values). The results suggest a specific pattern of frontal white matter axonal degeneration and demyelination and fornix demyelination that is attenuated in the presence of larger structures of the limbic system in patients with chronic schizophrenia and schizoaffective disorder. Findings warrant replication in larger samples.

Negative and disorganized symptoms mediate the relationship between verbal learning and global functioning in adolescents with early-onset psychosis.

Neurocognitive deficits are associated with impaired global functioning and psychotic symptoms. However, whether symptoms can mediate the relationship between neurocognition and global functioning in adolescent psychosis is unclear. Here, we investigated if symptoms assessed with the Positive And Negative Syndrome Scale (PANSS), mediated the relationship between neurocognitive performance and global functioning in adolescents with non-affective early-onset psychotic disorders (EOP). Sixty-one adolescent EOP patients (age 12-18 years) from 2 Norwegian clinical cohorts were included. Linear regression models were applied to investigate associations between neurocognitive domains from the MATRICS Consensus Cognitive Battery (MCCB) and global functioning. PANSS symptoms were analyzed using the Wallwork/Fortgang five-factor model. Using the INDIRECT macro for SPSS, mediation effects were tested using bootstrapping with 95% bias corrected confidence intervals. Verbal learning was positively associated with global functioning (P < 0.001) and negatively associated with the disorganized symptom factor (P = 0.002), controlling for age, sex and cohort. Testing of indirect effects, controlling for age, sex and cohort, showed that the Negative (point estimate = 1.56, 95% CI 0.22, 3.47) and Disorganized (point estimate = 1.24, 95% CI 0.05, 3.69) symptom factors significantly mediated the relationship between verbal learning and global functioning. We found that verbal learning, negative and disorganized symptoms influenced global functioning in adolescents with EOP, while reality-distorted positive symptoms did not. These results suggest that assessing these domains in EOP is helpful for planning treatment and rehabilitation programs focusing on functional outcome.

Obstetric complications and intelligence in patients on the schizophrenia-bipolar spectrum and healthy participants.

BACKGROUND: Whether severe obstetric complications (OCs), which harm neural function in offspring, contribute to impaired cognition found in psychiatric disorders is currently unknown. Here, we sought to evaluate how a history of severe OCs is associated with cognitive functioning, indicated by Intelligence Quotient (IQ). METHODS: We evaluated the associations of a history of OCs and IQ in 622 healthy controls (HC) and 870 patients on the schizophrenia (SCZ) - bipolar disorder (BIP) spectrum from the ongoing Thematically Organized Psychosis study cohort, Oslo, Norway. Participants underwent assessments using the NART (premorbid IQ) and the WASI (current IQ). Information about OCs was obtained from the Medical Birth Registry of Norway. Multiple linear regression models were used for analysis. RESULTS: Severe OCs were equally common across groups. SCZ patients with OCs had lower performances on both premorbid and current IQ measures, compared to those without OCs. However, having experienced more than one co-occurring severe OC was associated with lower current IQ in all groups. CONCLUSIONS: Severe OCs were associated with lower IQ in the SCZ group and in the BIP and HC groups, but only if they had experienced more than one severe OC. Low IQ might be a neurodevelopmental marker for SCZ; wherein, severe OCs influence cognitive abilities and increase the risk of developing SCZ. Considering OCs as a variable of neurodevelopmental risk for severe mental illness may promote the development of neuroprotective interventions, improve outcome in vulnerable newborns and advance our ability to make clinical prognoses.

Lipid alterations in adolescents with early-onset psychosis may be independent of antipsychotic medication.

BACKGROUND: Dyslipidemia and insulin resistance (HOMA-IR) are cardiovascular risk factors prevalent in patients with psychosis. Whether these factors are intrinsic or affected by lifestyle or antipsychotic medication (AP) is unclear. Therefore, we investigated lipid profiles, HOMA-IR, and psychotic phenotypes in patients aged 12-18 years with early-onset psychosis (EOP) with and without AP exposure. METHOD: We measured fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), triglycerides (TG), insulin, and glucose in patients with EOP (n = 39) and healthy controls (HC) (n = 66). Diet information was not available. Negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We used univariate analysis of variance to compare TC/HDL-C ratios and TG and HOMA-IR values, controlling for body mass index (BMI) and AP exposure. We assessed the explained variance of having EOP using multiple regression analysis. RESULTS: Patients with and without AP exposure had significantly higher TC/HDL-C (p = 0.003, p = 0.029) and TG values (p < 0.001, p = 0.021) than HC. Significantly increased HOMA-IR scores were found only in AP-exposed patients (p = 0.037). EOP significantly increased the explained variance for TC/HDL-C and TG, but not for HOMA-IR. Patients with a PANSS negative score > 21 had significantly higher levels of TG than those with low scores (p = 0.032). CONCLUSION: Our results suggest that lipid alterations predate AP treatment in adolescents with EOP. Higher levels of negative symptoms and AP further increase metabolic risk. The preliminary findings propose that subclinical dyslipidemia may be intrinsic to EOP.

Increased interleukin 18 activity in adolescents with early-onset psychosis is associated with cortisol and depressive symptoms.

OBJECTIVE: Evidence indicates that the pathophysiology of adult psychosis involves immune dysregulation, but its associations with stress are often not considered. The inflammatory cytokine interleukin (IL)-18, which is elevated in adult schizophrenia, is suggested to be sensitive to stress. We compared the associations of IL-18 with cortisol and clinical variables in adolescents with early-onset psychosis (EOP) aged 12-18 years and age-matched healthy controls (HC). METHOD: We measured serum IL-18, IL-18 binding protein (IL-18BP), IL-18 receptor accessory protein (IL-18RAP), IL-18 receptor 1 (IL-18R1) and cortisol, and calculated the IL-18/IL-18BP ratio in patients (n = 31) and HC (n = 60). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale and depressive symptoms by the Mood and Feelings Questionnaire-Child version (MFQ-C). Bivariate correlation analysis was used to explore relationships between IL-18/IL-18BP ratio and cortisol, depression and other clinical characteristics. Hierarchical multiple linear regression analysis was used to assess their individual contributions to the variance of the IL-18/IL-18BP ratio. RESULTS: Patients had significantly higher IL-18 levels and IL-18/IL-18BP ratios than HC, but similar IL-18BP, IL-18RAP and IL-18R1. Both cortisol (R2 change = 0.05) and the MFQ-C score (R2 change = 0.09) contributed significantly to the variance in IL-18/IL-18BP ratios after controlling for confounders. CONCLUSION: We found increased IL-18 system activity in adolescents with EOP. Cortisol and depressive symptoms each contributed to the variance in the IL-18/IL-18BP ratio. Our findings support activation of inflammatory pathways in adolescent psychosis and suggest interactions between stress, inflammation and depressive symptoms in EOP.

Healthy Adolescent Performance With Standardized Scoring Tables for the MATRICS Consensus Cognitive Battery: A Multisite Study.

OBJECTIVE: The aim of this study was to develop standardized scores and scoring tables for test performance in healthy adolescents for the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for each year from 11 to 19 years of age, by sex, with T scores and percentile ranks. METHODS: A total of 502 healthy participants (aged 11-19 years) from 7 cohorts from Ireland, Norway, Sweden, and United States, were included in this multisite study. Regression-predicted means for the MCCB tests, except the social cognition subtest, were calculated using the MCCB test scores as outcome variables and age, age2, sex, age × sex as predictors. The regression-predicted means for each combination of age and sex were added with the residuals from the entire cohort to yield the expected distribution of that group. Age effects were examined using regression models with age and age2 as predictors. Sex differences were examined using Student's t-tests. RESULTS: Significant positive age effects were found for all tests, except for the Brief Visuospatial Memory Test, revised (BVMT-R; measure of visual learning). Females performed significantly better than males on BACS Symbol coding (measure of speed of processing) and BVMT-R, while males performed significantly better than females on NAB Mazes (measure of reasoning and problem solving). Based on the regression-predicted distributions of scores, 19 standardized scoring tables for each test and domain were created. CONCLUSIONS: With the results from this study, we have developed an accessible standardized data set of healthy adolescent test performance for the MCCB.

Vitamin D, Folate and the Intracranial Volume in Schizophrenia and Bipolar Disorder and Healthy Controls.

Vitamin D and folate deficiency are considered risk factors for schizophrenia and bipolar disorders, but it is unknown how vitamin D and folate influence the growing brain, cranium or the clinical phenotype. Serum vitamin D and folate levels are in part genetically regulated. We investigated whether adult vitamin D and folate levels are associated with the intracranial volume (ICV) under the hypothesis that developmental vitamin D or folate levels influence neurodevelopment and that current levels are associated with ICV. Ninety patients with severe mental disorders and 91 healthy controls underwent 3 T magnetic resonance imaging and serum sampling. Multiple linear regression was used to assess the contribution of serum vitamin D, folate and patient-control status on ICV. We show that vitamin D levels were within lower range for patients and controls (48.8 ± 22.1 nmol/l and 53.4 ± 20.0 nmol/l, respectively). A significant positive association was found between vitamin D and ICV (p = 0.003, r = 0.22), folate was trend-significantly associated with ICV. Folate and vitamin D were significantly associated (p = 0.0001, r = 0.28). There were nonsignificant patient-control differences and no interaction effects. The results suggest that Vitamin D is associated with ICV as detected in the adult. Further studies are warranted for replication and to investigate possible mechanisms and genetic associations.

[The ward atmosphere and satisfaction in four psychogeriatric wards]. / Postmiljø og trivsel ved fire alderspsykiatriske avsnitt.

BACKGROUND: We wanted to investigate the treatment milieu in two psychogeriatric hospitals by use of the Ward Atmosphere Scale (WAS), a self-report questionnaire that has been used in studies of the treatment climate in several psychiatric wards. MATERIAL AND METHODS: 22 patients and 54 staff members in four psychogeriatric wards rated the WAS. The staff's perception of the working environment was also examined (the Working Environment Scale, WES-10). RESULTS: Both patients and staff had higher scores for "order and organization" and lower scores for "anger and aggressive behaviour" than mean scores of the Norwegian normative sample of wards (mainly for patients with psychosis). Three wards obtained higher patient scores for "support" and three obtained lower ones for "staff control". The psychogeriatric patients seemed to be more satisfied with the wards in general and with the staff, whereas the staff's satisfaction and evaluation of the working environment was similar to that of the Norwegian normative sample. INTERPRETATION: The common trend of the four wards, convincingly shows that the psychogeriatric ward atmosphere differs from that of the wards mainly for psychotic patients. The WAS seemed to be suitable to describe this environment.