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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation.
We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV.
We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males.
We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.
The etiology of schizophrenia (SZ) is proposed to include an interplay between a genetic risk for disease development and the biological environment of pregnancy and birth, where early adversities may contribute to the poorer developmental outcome. We investigated whether a history of birth asphyxia (ASP) moderates the relationship between intracranial volume (ICV) and intelligence in SZ, bipolar disorder (BD) and healthy controls (HC).
Two hundred seventy-nine adult patients (18–42 years) on the SZ and BD spectrums and 216 HC were evaluated for ASP based on information from the Medical Birth Registry of Norway. Participants underwent structural magnetic resonance imaging (MRI) to estimate ICV and intelligence quotient (IQ) assessment using the Wechsler Abbreviated Scale of Intelligence (WASI). Multiple linear regressions were used for analyses.
We found a significant three-way interaction (ICV × ASP × diagnosis) on the outcome variable, IQ, indicating that the correlation between ICV and IQ was stronger in patients with SZ who experienced ASP compared to SZ patients without ASP. This moderation by ASP was not found in BD or HC groups. In patients with SZ, the interaction between ICV and a history of the ASP was specifically related to the verbal subcomponent of IQ as measured by WASI.
The significant positive association between ICV and IQ in patients with SZ who had experienced ASP might indicate abnormal neurodevelopment. Our findings give support for ICV together with verbal intellectual abilities as clinically relevant markers that can be added to prediction tools to enhance evaluations of SZ risk.
Uncertainty exists about what causes brain structure alterations associated with schizophrenia (SZ) and bipolar disorder (BD). Whether a history of asphyxia-related obstetric complication (ASP) – a common but harmful condition for neural tissue – contributes to variations in adult brain structure is unclear. We investigated ASP and its relationship to intracranial (ICV), global brain volumes and regional cortical and subcortical structures.
A total of 311 patients on the SZ – BD spectrum and 218 healthy control (HC) participants underwent structural magnetic resonance imaging. They were evaluated for ASP using prospective information obtained from the Medical Birth Registry of Norway.
In all groups, ASP was related to smaller ICV, total brain, white and gray matter volumes and total surface area, but not to cortical thickness. Smaller cortical surface areas were found across frontal, parietal, occipital, temporal and insular regions. Smaller hippocampal, amygdala, thalamus, caudate and putamen volumes were reported for all ASP subgroups. ASP effects did not survive ICV correction, except in the caudate, which remained significantly smaller in both patient ASP subgroups, but not in the HC.
Since ASP was associated with smaller brain volumes in all groups, the genetic risk of developing a severe mental illness, alone, cannot easily explain the smaller ICV. Only the smaller caudate volumes of ASP patients specifically suggest that injury from ASP can be related to disease development. Our findings give support for the ICV as a marker of aberrant neurodevelopment and ASP in the etiology of brain development in BD and SZ.
Recently there has been a renewed interest in defining the boundaries and subdomains of the negative syndrome in schizophrenia and new scales have been asked for. Apathy is one of the symptoms in focus. The Apathy Evaluation Scale (AES) with its clinical version (AES-C) is one of the most used scales in an interdisciplinary context, but it has never previously been used in a population with first episode psychosis. The main aims of this study were to examine the psychometric properties of the AES-C and its relationship to the Positive and Negative Syndrome Scale (PANSS).
A total of 104 patients with first episode psychosis from the ongoing Thematic Organized Psychosis Research (TOP) study were included.
A factor analysis of the AES-C identified three subscales: Apathy, Insight and Social Contacts. Only the Apathy subscale showed satisfactory psychometric properties and showed acceptable convergent and discriminate properties by correlating strongly with the apathy-related items of the PANSS.
This study shows that the AES-C measures more than one dimension. The main factor, the Apathy subscale, can however be used to assess apathy in first episode psychosis patients in the ongoing work of refining the subdomains of the negative syndrome.
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).
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.
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.
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.
We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls.
Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples.
Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10−5), vanillylmandelic acid (VMA, p = 4.5×10−5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10−5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals.
Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.
Inflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account.
We investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured in n = 992 patients (SCZ, AFF), and n = 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels.
CXCL16 (p = 0.03) and sIL-2R (p = 7.8 × 10−5) were higher, while sCD14 (p = 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p = 0.04) and sIL-2R (p = 1.1 × 10−5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p = 0.001) and lower sCD14 (p = 0.002) remained, also in SCZ (sIL-2R, p = 3.0 × 10−4 and sCD14, p = 0.01). The adjustment revealed lower ALCAM levels (p = 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels.
The results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.
Patients with psychiatric conditions are often referred for a brain scan during the course of their diagnostic workup.
The aim of our study is to determine frequency and type of organic brain pathology, the relationship to age, gender and psychiatric diagnosis.
We investigated magnetic resonance imaging and computed tomography brain scans from consecutively referred patients over a 10-year period (January 2002-December 2011). The reasons for referral, estimated psychiatric diagnosis, and the pathology discovered for each patient were registered.
A total of 34% of patients demonstrated organic brain pathology, of which 32.8% were considered clinically relevant. This represents a higher frequency of relevant pathology than reported in healthy subjects. Age (P < 0.001) and diagnosis (P = 0.016) were the most important determinants for frequency of pathological findings.
Brain imaging in clinical psychiatry resulted in approximately 30% positive findings mainly associated with increasing pathologies with age, but also with diagnosis.
Declaration of interest
Both T.O.D. and M.K.B. have received honorary from Novartis for scientific lectures about multiple sclerosis. M.K.B. also received honoraria from Biogen for scientific lectures. The other authors have no conflicts of interest.
Common variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear.
To identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls.
VRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels.
We found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10–12), bipolar disorder (P<10–12) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified.
Altered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.
Negative symptoms in schizophrenia have been associated with structural and functional alterations of the amygdala. We hypothesised that there would be between-group differences in amygdala volume and neural activation patterns during processing of affective stimuli among patients with schizophrenia and healthy controls. We further hypothesised correlations between neuroimaging metrics and clinical ratings of negative symptoms in patients with schizophrenia.
We used structural and functional magnetic resonance imaging to assess volume and neural activation of the amygdala in 28 patients with schizophrenia and 28 healthy controls.
We found no between-group differences in amygdala volume or neural activation. However, we found a significant negative correlation between emotional blunting and neural activation in the left amygdala during processing of positive affect. We also found a significant negative correlation between stereotyped thinking and the volume of right amygdala.
Our findings implicate the amygdala in a subgroup of negative symptoms in schizophrenia that are characterised by reduced expression with blunted affect and stereotyped thinking.
ANK3 gene variants have consistently been associated with
bipolar spectrum disorder and schizophrenia spectrum disorder. However, the
relevance of its encoded protein, ankyrin-3, in these disorders remains
elusive. Here, we show that ANK3 gene expression in blood
is significantly increased in bipolar disorder and schizophrenia compared
with healthy controls. Additionally, we identified potential cis-acting
expression quantitative trait loci located close to the transcription start
site of one of the isoforms of the gene. These findings suggest that
ANK3 mRNA is an interesting marker for further
investigation of the underlying mechanisms in psychotic disorders.
Schizophrenia and bipolar disorder are severe mental disorders with
overlapping genetic and clinical characteristics, including cognitive
impairments. An important question is whether these disorders also have
overlapping neuronal deficits.
To determine whether large-scale brain networks associated with working
memory, as measured with functional magnetic resonance imaging (fMRI),
are the same in both schizophrenia and bipolar disorder, and how they
differ from those in healthy individuals.
Patients with schizophrenia (n = 100) and bipolar
disorder (n = 100) and a healthy control group
(n = 100) performed a 2-back working memory task
while fMRI data were acquired. The imaging data were analysed using
independent component analysis to extract large-scale networks of
Similar working memory networks were activated in all groups. However, in
three out of nine networks related to the experimental task there was a
graded response difference in fMRI signal amplitudes, where patients with
schizophrenia showed greater activation than those with bipolar disorder,
who in turn showed more activation than healthy controls. Secondary
analysis of the patient groups showed that these activation patterns were
associated with history of psychosis and current elevated mood in bipolar
The same brain networks were related to working memory in schizophrenia,
bipolar disorder and controls. However, some key networks showed a graded
hyperactivation in the two patient groups, in line with a continuum of
neuronal abnormalities across psychotic disorders.
As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.
Recientemente ha aumentado el interés por definir los límites y subdominios del síndrome negativo de la esquizofrenia y se han buscado nuevas escalas. La apatía es uno de los síntomas analizados. La Escala de Evaluacion de la Apatía (AES) con su version clínica (AES-C) es una de las escalas más usada en un contexto interdisciplinario, pero no se ha usado antes en poblaciones con el primer episodio de psicosis. Los objetivos principales de este estudio fueron examinar las propiedades psicométricas de la AES-C y su relación con la Escala de Síndrome Positiva y Negativa (PANSS).
Se incluyeron 104 pacientes con un primer episodio de psicosis del estudio de Investigación Tematicá Organizada de la Psicosis (TOP).
En el análisis de los factores de la AES-C se identificaron tres subescalas: Apatía, Percepción y Contactos Sociales. Sólo la subescala de Apatía exhibió propiedades psicométricas satisfactorias y propiedades convergentes y discriminatorias aceptables por correlación fuerte con los apartados del PANSS relacionados con la apatía.
Este estudio demuestra que la AES-C mide mas de una dimensión. Sin embargo, el factor principal, la subescala de la Apatía, puede usarse para evaluar la apatía en pacientes con un primer episodio de psicosis con el fin de refinar la evalaución de los subdominios del síndrome negativo.