Florey Department of Neuroscience and Mental Health - Research Publications
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ItemEvaluation of an alternative model for the management of clinical risk in an adult acute psychiatric inpatient unit(WILEY, 2019-10)Despite their widespread use, typical visual observation practices are not evidence-based and adverse events - such as self-harm and absconding - still occur even under the most intense forms of observation. This study aimed to (i) develop and implement an engagement-focused systematized model of clinical risk management in an adult acute psychiatric inpatient unit; and (ii) prospectively evaluate its effect on rates of violence, self-harm, absconding, sexually inappropriate behaviour, and seclusion. A new model of engagement-focused clinical risk management was developed using a participatory action research framework and implemented in an adult acute psychiatric inpatient unit. Using a mirror-image design, rates of violence/aggression, self-harm, absconding, sexually inappropriate behaviour, and seclusion were compared before and after implementation, and staff satisfaction levels were measured. The clinical engagement-based model was introduced, and 1087 admissions before implementation (24 months) were compared with 965 admissions post-implementation (18 months). The new model was associated with significantly reduced rates of absconding (pre: 10.5/1000 occupied bed days, 95% CI [9.0, 12.1] compared with post: 6.5/1000 occupied bed days [5.2, 8.1], P < 0.001) and seclusion (pre: 43.7/1000 occupied bed days, 95% CI [40.6, 46.9] compared with post: 30.9/1000 occupied bed days [27.9, 34.1], P < 0.0001). Rates of aggression, deliberate self-harm, and sexually inappropriate behaviour were non-significantly decreased. Findings suggest that this engagement-focused model of clinical risk management in an adult psychiatric inpatient unit significantly reduced adverse patient events and was preferred by staff over current practice. Other psychiatric inpatient facilities may see a reduction in adverse events following the introduction of this well-tolerated risk management model.
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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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ItemChanges in Non-Coding RNA in Depression and Bipolar Disorder: Can They Be Used as Diagnostic or Theranostic Biomarkers?(MDPI, 2020-09)The similarities between the depressive symptoms of Major Depressive Disorders (MDD) and Bipolar Disorders (BD) suggest these disorders have some commonality in their molecular pathophysiologies, which is not apparent from the risk genes shared between MDD and BD. This is significant, given the growing literature suggesting that changes in non-coding RNA may be important in both MDD and BD, because they are causing dysfunctions in the control of biochemical pathways that are affected in both disorders. Therefore, understanding the changes in non-coding RNA in MDD and BD will lead to a better understanding of how and why these disorders develop. Furthermore, as a significant number of individuals suffering with MDD and BD do not respond to medication, identifying non-coding RNA that are altered by the drugs used to treat these disorders offer the potential to identify biomarkers that could predict medication response. Such biomarkers offer the potential to quickly identify patients who are unlikely to respond to traditional medications so clinicians can refocus treatment strategies to ensure more effective outcomes for the patient. This review will focus on the evidence supporting the involvement of non-coding RNA in MDD and BD and their potential use as biomarkers for treatment response.
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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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ItemClozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum(PERGAMON-ELSEVIER SCIENCE LTD, 2013-01-10)Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-Fos, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-Fos, clozapine elevated expression 24h after administration, a timeframe consistent with ERK activation at 8h. Alternatively, haloperidol stimulation of c-Fos levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia.
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ItemClozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugs(CAMBRIDGE UNIV PRESS, 2012-09)Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapine's action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile.