Changes in body mass index and risk of adolescent psychopathology: a longitudinal cohort study.

BACKGROUND: Abnormal body mass index (BMI) has been associated with development of psychopathology. This association in children is well documented, for both overweight and underweight children. However, the association between change in BMI and the development of psychopathology has been less investigated. AIM: To investigate the association between change in BMI between childhood and adolescence and psychopathology in adolescence. METHODS: Data from the Growing Up in Ireland cohort were used. We investigated the '98 cohort (also known as the child cohort) at age 9/13. BMI, defined using internationally recognised definitions as underweight, healthy or overweight, was used as the exposure, and abnormal Strength and Difficulties Questionnaire scores were used as the outcome. Logistic regression was undertaken for the analysis. All analyses were adjusted for confounders. RESULTS: A change to overweight from healthy BMI was significantly associated with increased risk of psychopathology (adjusted OR 1.66; 95% CI 1.19-2.32). Both change from underweight to healthy (adjusted OR 0.12; 95% CI 0.03-0.43) or from overweight to healthy (adjusted OR 0.47; 95% CI 0.79-0.8) was associated with a significantly reduced risk of developing psychopathology. DISCUSSION: As a child's BMI returns to within the healthy range, their risk of adolescent psychopathology is reduced. Interventions to restore healthy BMI, in both underweight and overweight, children may reduce their risk of adolescent psychopathology.

Special Issue: Psychosis from early intervention to treatment resistance.

Psychotic disorders are central to mental health service provision and a common theme of academic research programmes in Ireland, which explore the neurobiological and psychosocial risk factors underpinning the development and progression of these illnesses. While we await the discovery of novel pharmacological treatment targets for psychotic disorders, it is important to employ our existing management strategies to optimal effect. In this special issue on psychosis, a selection of clinical research studies and reviews from Irish researchers, and often of Irish populations, are brought together which span the trajectory of psychotic illness from early intervention to treatment resistance. The topics include the characteristics and course of first episode psychosis cohorts, real-world evaluation of early intervention services, management strategies for treatment resistant schizophrenia and neurobiological research into social stress. The current editorial provides an overview of these papers and highlights the initial steps of the Irish Psychosis Research Network towards developing an integrated clinical research network focusing on the treatment and research into psychotic disorders.

Identification of a plasma signature of psychotic disorder in children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

The identification of an early biomarker of psychotic disorder is important as early treatment is associated with improved patient outcome. Metabolomic and lipidomic approaches in combination with multivariate statistical analysis were applied to identify plasma alterations in children (age 11) (38 cases vs 67 controls) and adolescents (age 18) (36 cases vs 117 controls) preceeding or coincident with the development of psychotic disorder (PD) at age 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC). Overall, 179 lipids were identified at age 11, with 32 found to be significantly altered between the control and PD groups. Following correction for multiple comparisons, 8 of these lipids remained significant (lysophosphatidlycholines (LPCs) LPC(18:1), LPC(18:2), LPC(20:3); phosphatidlycholines (PCs) PC(32:2; PC(34:2), PC(36:4), PC(0-34-3) and sphingomyelin (SM) SM(d18:1/24:0)), all of which were elevated in the PD group. At age 18, 23 lipids were significantly different between the control and PD groups, although none remained significant following correction for multiple comparisons. In conclusion, the findings indicate that the lipidome is altered in the blood during childhood, long before the development of psychotic disorder. LPCs in particular are elevated in those who develop PD, indicating inflammatory abnormalities and altered phospholipid metabolism. These findings were not found at age 18, suggesting there may be ongoing alterations in the pathophysiological processes from prodrome to onset of PD.

Proteomic analysis of the postsynaptic density implicates synaptic function and energy pathways in bipolar disorder.

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders such as schizophrenia and bipolar disorder. We enriched for this anatomical structure in the anterior cingulate cortex of 16 bipolar disorder samples and 20 controls from the Stanley Medical Research Institute. Unbiased shotgun proteomics incorporating label-free quantitation was used to identify differentially expressed proteins. Quantitative investigation of the PSD identified 2033 proteins, among which 288 were found to be differentially expressed. Validation of expression changes of DNM1, DTNA, NDUFV2, SEPT11 and SSBP was performed by western blotting. Bioinformatics analysis of the differentially expressed proteins implicated metabolic pathways including mitochondrial function, the tricarboxylic acid cycle, oxidative phosphorylation, protein translation and calcium signaling. The data implicate PSD-associated proteins, and specifically mitochondrial function in bipolar disorder. They relate synaptic function in bipolar disorder and the energy pathways that underpin it. Overall, our findings add to a growing literature linking the PSD and mitochondrial function in psychiatric disorders generally, and suggest that mitochondrial function associated with the PSD is particularly important in bipolar disorder.

Reduced protein synthesis in schizophrenia patient-derived olfactory cells.

Human olfactory neurosphere-derived (ONS) cells have the potential to provide novel insights into the cellular pathology of schizophrenia. We used discovery-based proteomics and targeted functional analyses to reveal reductions in 17 ribosomal proteins, with an 18% decrease in the total ribosomal signal intensity in schizophrenia-patient-derived ONS cells. We quantified the rates of global protein synthesis in vitro and found a significant reduction in the rate of protein synthesis in schizophrenia patient-derived ONS cells compared with control-derived cells. Protein synthesis rates in fibroblast cell lines from the same patients did not differ, suggesting cell type-specific effects. Pathway analysis of dysregulated proteomic and transcriptomic data sets from these ONS cells converged to highlight perturbation of the eIF2α, eIF4 and mammalian target of rapamycin (mTOR) translational control pathways, and these pathways were also implicated in an independent induced pluripotent stem cell-derived neural stem model, and cohort, of schizophrenia patients. Analysis in schizophrenia genome-wide association data from the Psychiatric Genetics Consortium specifically implicated eIF2α regulatory kinase EIF2AK2, and confirmed the importance of the eIF2α, eIF4 and mTOR translational control pathways at the level of the genome. Thus, we integrated data from proteomic, transcriptomic, and functional assays from schizophrenia patient-derived ONS cells with genomics data to implicate dysregulated protein synthesis for the first time in schizophrenia.

Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia.

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and N-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all P<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13,689 cases and 18,226 controls show significant association of HIST1H1E and MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Clathrin-mediated endocytosis (CME) is the best-characterized mechanism governing cellular membrane and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the clathrin interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes and aberrant neurodevelopment are all influenced by clathrin-dependent processes, and that other cellular trafficking mechanisms previously linked to psychoses interact with the clathrin interactome in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of the clathrin interactome may offer fruitful opportunities for novel treatments of schizophrenia.

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression.

The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n=10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P<0.001), BASP1 (40% difference; P<0.05) and LAMP (22% difference; P<0.01)) and BPD (STXBP1 (31% difference; P<0.001), BASP1 (23% difference; P<0.01) and LAMP (20% difference; P<0.01)) in the Stanley brain series (n=20 per group). Further validation in dlpfc from the Harvard brain subseries (n=10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P<0.0001), BASP1 (14% difference; P<0.0001) but not LAMP (20% difference; P=0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

A proteomic investigation of similarities between conventional and herbal antidepressant treatments.

Increasing clinical evidence for the effectiveness of herbal antidepressants has led to investigations at the molecular level. Using two-dimensional gel electrophoresis, this study investigated similarities in protein expression between clomipramine, St John's wort and a Chinese herbal formula, xiao-yao-san, often used in mood disorder treatment. HT22 cells, derived from a mouse hippocampal cell line, were treated for 24 h, and protein expression was compared with that of the untreated cells (n = 4/group). Forty-three protein spots were found to be significantly differentially expressed (P < 0.05) in more than one of the treatment groups. Twenty-nine of these were identified using mass spectrometry. The most affected proteins were those involved in the cytoskeleton and energy metabolism, and an up-regulation of vimentin by all three treatments was confirmed by Western blotting. This study provides preliminary evidence for multiple common molecular targets between conventional and alternative antidepressants, which appear to collectively affect neuronal plasticity.

Evidence for reduced neuronal somal size within the insular cortex in schizophrenia, but not in affective disorders.

The insular cortex is a paralimbic area of the brain thought to have important roles in sensory integration, auditory hallucinations and language. Both structural and functional MRI studies have revealed that this brain area is abnormal in both size and activity in schizophrenia. Further investigation of this region at the cellular level in schizophrenia has not been carried out. In the current study, we conducted a stereological examination of neuronal and glial size and density in layers 2 and 3 of the dorso-caudal region of the insular cortex in 15 schizophrenic, 15 bipolar, 15 unipolar and 15 control patients. These cortical layers are candidate layers based on previous cytoarchitectual investigations. Statistical analysis (ANCOVA, correcting for pH, post-mortem interval and age) showed decreased neuronal volume in layer 2 in schizophrenia (p=0.0008, 16.2% mean reduction). No other significant changes were observed. This study thus provides the first evidence of cytoarchitectural abnormality of the insular cortex in the pathophysiology of schizophrenia but not mood disorders. Further work is needed to investigate the molecular basis for this neuronal abnormality in schizophrenia in order to elucidate its role in the pathophysiology of schizophrenia.

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder.

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

Density and distribution of white matter neurons in schizophrenia, bipolar disorder and major depressive disorder: no evidence for abnormalities of neuronal migration.

The neurodevelopmental hypothesis of schizophrenia suggests that this disorder may result from a disruption of normal brain development. While widely cited, neuropathological evidence for this is far from conclusive. Alterations in the density and position of white matter neurons have been previously described in the frontal and temporal lobes and have led to suggestions that abnormal neuronal migration may play a role in the aetiology of schizophrenia. However, these findings have not been replicated. Furthermore, developmental abnormalities may not be specific to schizophrenia. The aim of this study was to examine the density and spatial pattern distribution of white matter neurons in psychiatric and control subjects using sophisticated computerised image analysis techniques. White matter neurons immunoreactive for microtubule associated protein-2 were quantified in the frontal lobe in schizophrenia, bipolar disorder, major depressive disorder and matched controls (each group n = 15). Analysis showed that the density and spatial distribution of white matter neurons did not differ significantly between the control and psychiatric groups. This study cannot replicate the earlier findings of white matter abnormalities in schizophrenia and finds no evidence for abnormal brain development in any of the disorders studied.

Glial cell abnormalities in major psychiatric disorders: the evidence and implications.

Recent quantitative post-mortem investigations of the cerebral cortex have convincingly demonstrated cortical glial cell loss in subjects with major depression. Evidence is also mounting that glial cell loss may also be a feature of schizophrenia. These findings coincide with a re-evaluation of the importance of glial cells in normal cortical function. In addition to their traditional roles in neuronal migration and inflammatory processes, glia are now accepted to have roles in providing trophic support to neurons, neuronal metabolism, and the formation of synapses and neurotransmission. Consequently, reduced cortical glial cell numbers could be responsible for some of the pathological changes in schizophrenia and depression, including reduced neuronal size, reduced levels of synaptic proteins, and abnormalities of cortical neurotransmission. Additionally, as astrocytes provide the energy requirements of neurons, deficient astrocyte function could account for aspects of the functional magnetic imaging abnormalities found in these disorders. We discuss the possible basis of glial cell loss in these disorders and suggest that elevated levels of glucocorticoids, due to illness-related stress or to hyperactivity of the hypothalamic-pituitary-adrenal may down-regulate glial activity and so predispose to, or exacerbate psychiatric illness through enhanced excitotoxicity. The potential therapeutic impact of agents which up-regulate glial activity or normalise glial cell numbers is also discussed.

Focal cortical dysplasia: a neuropathological and developmental perspective.

Focal cortical dysplasia (FCD) is a rare, sporadic disorder which is a recognised cause of chronic epilepsy. It is proposed to result from disordered neuronal migration and differentiation and has characteristic histological features which include disturbed cortical lamination, large abnormal neurons and the presence of large balloon cells with glassy eosinophilic cytoplasm and pleomorphic eccentric nuclei. These latter express both glial and neuronal markers indicative of abnormal neuroglial differentiation. In this paper we review the current literature on the neuropathology of FCD and discuss potential mechanisms. We focus on growth factors, signalling pathways and candidate genes with known roles in Drosophila and vertebrate brain development that could be responsible for the developmental brain changes seen in FCD. At issue are the factors that influence cell fate and differentiation and which regulate neural migration. Some of the molecular pathways, such as those involving the Notch and the Wnt pathways have particularly important roles in neuroglial differentiation in vertebrates, and these are proposed as potential candidates.