Psychiatry - Research Publications
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ItemPeripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia(FRONTIERS MEDIA SA, 2017-11-06)Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.
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ItemThe impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes(SPRINGERNATURE, 2015)BACKGROUND: Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group. METHODS: A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups. RESULTS: A total of 157 patients (29%) classified as 'preserved' performed within one s.d. of control means in all cognitive domains. Patients classified as 'deteriorated' (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as 'compromised,' performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures. CONCLUSIONS: In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group.
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ItemMeta-analysis reveals associations between genetic variation in the 5′ and 3′regions of Neuregulin-1 and schizophrenia(SPRINGERNATURE, 2017-01-17)Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5' and 3' regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5'-end and two (rs2954041 and rs10503929) near the 3'-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5' and 3' ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1's role in the pathophysiology of schizophrenia.
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ItemElevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients(NATURE PUBLISHING GROUP, 2017-12-11)Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFβ (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-β1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFβ (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.
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ItemWidespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group(SPRINGERNATURE, 2018-05)The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
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ItemDevelopment and validation of a mental health screening tool for asylum-seekers and refugees: the STAR-MH(BMC, 2018-03-16)BACKGROUND: There is no screening tool for major depressive disorder (MDD) or post-traumatic stress disorder (PTSD) in asylum-seekers or refugees (ASR) that can be readily administered by non-mental health workers. Hence, we aimed to develop a brief, sensitive and rapidly administrable tool for non-mental health workers to screen for MDD and PTSD in ASR. METHODS: The screening tool was developed from an extant dataset (n = 121) of multiply screened ASR and tested prospectively (N = 192) against the M.I.N.I. (Mini International Neuropsychiatric Interview) structured psychiatric interview. Rasch, Differential Item Functioning and ROC analyses evaluated the psychometric properties and tool utility. RESULTS: A 9-item tool with a median administration time of six minutes was generated, comprising two 'immediate screen-in' items, and a 7-item scale. The prevalence of PTSD &/or MDD using the M.I.N.I. was 32%, whilst 99% of other diagnosed mental disorders were comorbid with one or both of these. Using a cut-score of ≥2, the tool provided a sensitivity of 0.93, specificity of 0.75 and predictive accuracy of 80.7%. CONCLUSIONS: A brief sensitive screening tool with robust psychometric properties that was easy to administer at the agency of first presentation was developed to facilitate mental health referrals for asylum-seekers and new refugees.
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ItemMuscarinic M1 receptor sequence: Preliminary studies on its effects on cognition and expression(ELSEVIER, 2012-06)It has been reported that people with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism of the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test than those who are heterozygous. We investigated whether CHRM1 sequence is associated with impaired executive function, a common problem in schizophrenia. We sequenced the CHRM1 using peripheral DNA from 97 people with schizophrenia who completed the Wisconsin Card Sorting Test, a verbal fluency test and the National Adult Reading Test. Clinical severity was assessed using the Positive and Negative Syndrome Scale. To determine whether CHRM1 sequence affected receptor expression, we used post-mortem data, from another cohort, to investigate associations between CHRM1 sequence and mRNA levels. On the Wisconsin Card Sorting Test, 267C/C participants with schizophrenia made more perseverative errors (p<0.05) and perseverative responses (p<0.05) than 267C/A participants. Genotype had no effect on verbal fluency (p=0.8) or National Adult Reading test (p=0.62). Cortical CHRM1 mRNA levels did not vary with gene sequence (p=0.409). The clinical study supports the proposal that CHRM1 sequence is associated with alterations in some aspects of executive function. However, the post-mortem study indicates this is not simply due to altered expression at the level of mRNA, suggesting this sequence alteration may affect the functionality of the CHRM1.
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ItemSensory integration deficits support a dimensional view of psychosis and are not limited to schizophrenia(NATURE PUBLISHING GROUP, 2017-05-09)Visual dysfunction is commonplace in schizophrenia and occurs alongside cognitive, psychotic and affective symptoms of the disorder. Psychophysical evidence suggests that this dysfunction results from impairments in the integration of low-level neural signals into complex cortical representations, which may also be associated with symptom formation. Despite the symptoms of schizophrenia occurring in a range of disorders, the integration deficit has not been tested in broader patient populations. Moreover, it remains unclear whether such deficits generalize across other sensory modalities. The present study assessed patients with a range of psychotic and nonpsychotic disorders and healthy controls on visual contrast detection, visual motion integration, auditory tone detection and auditory tone integration. The sample comprised a total of 249 participants (schizophrenia spectrum disorder n=98; bipolar affective disorder n=35; major depression n=31; other psychiatric conditions n=31; and healthy controls n=54), of whom 178 completed one or more visual task and 71 completed auditory tasks. Compared with healthy controls and nonpsychotic patients, psychotic patients trans-diagnostically were impaired on both visual and auditory integration, but unimpaired in simple visual or auditory detection. Impairment in visual motion integration was correlated with the severity of positive symptoms, and could not be accounted for by a reduction in processing speed, inattention or medication effects. Our results demonstrate that impaired sensory integration is not specific to schizophrenia, as has previously been assumed. Instead, sensory deficits are closely related to the presence of positive symptoms independent of diagnosis. The finding that equivalent integrative sensory processing is impaired in audition is consistent with hypotheses that propose a generalized deficit of neural integration in psychotic disorders.
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ItemExploring the moderating effects of dopaminergic polymorphisms and childhood adversity on brain morphology in schizophrenia-spectrum disorders(ELSEVIER IRELAND LTD, 2018-11-30)Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.
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ItemSelective impairment of global motion integration, but not global form detection, in schizophrenia and bipolar affective disorder(Elsevier, 2016-03-01)Recent evidence suggests that schizophrenia is associated with impaired processing of global visual motion, but intact processing of global visual form. This project assessed whether preserved visual form detection in schizophrenia extended beyond low-level pattern discrimination to a naturalistic form-detection task. We assessed both naturalistic form detection and global motion detection in individuals with schizophrenia spectrum disorder, bipolar affective disorder, and healthy controls. Individuals with schizophrenia spectrum disorder and bipolar affective disorder were impaired relative to healthy controls on the global motion task, but not the naturalistic form-detection task. Results indicate that preservation of visual form detection in these disorders extends beyond configural forms to naturalistic object processing.