PP01 - The development, design, and testing of a peer support intervention in youth being discharged from a first episode psychosis clinic
Jo Robinson, Annie Bruxner, Susy Harrigan, Sarah Bendall, Eoin Killackey, Vitoria Tonin, Melissa Thurley, Shona Francey, Alison Yung
Orygen Youth Health Research Centre, University of Melbourne, Melbourne, Australia
Aim: This presentation will describe the development of a randomised control trial (RCT) testing the feasibility and effects of a peer support intervention in individuals being discharged from a mental health service following a first episode psychosis (FEP).
Background: Young people with FEP are prone to high risk outcomes at the time of discharge.
Method: An 18 month RCT with 6 month intervention will be piloted with 36 participants aged between 15 and 24 who are facing discharge from a specialised clinic for FEP at Orygen Youth Health. 18 participants will receive the intervention plus treatment as usual (TAU) while the remaining 18 will receive TAU (control group).
Intervention: Each participant will be allocated a peer support worker (PSW) for 6 months. PSWs will offer 2 hours of contact per fortnight and will engage the participant and support them in their transition to their new treating service via in-reach and out-of-service contact. PSWs may accompany participants to the new service, assist them with session attendance, understanding local and broader health services, and motivating the participant to develop supports and contacts for the future.
Results: Results are unavailable as data collection has not commenced.
Conclusion: It is anticipated that this pilot study will provide some indication as to what supports young people require at the time of discharge and whether or not it is realistic to expect other young people to provide this.
PP03 - The efficacy of the social cognition and intervention training (SCIT) programme for individuals with schizotypal personality features: Preliminary findings
Raymond C. K. Chan
1,2, Xiao-jing Gao3, Xiao-yan Li4, Yong-yu Deng5, Ya Wang1,2
1
Neuropsychology and Applied Cognitive Neuroscience Lab, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
2
Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
3
Sun Yat-Sen University, Guangzhou, China
4
Hebei Engineering and Technical College, Hebei, China
5
Zhongkai University of Agriculture and Technology, Guangzhou, China
Background: The purpose of this study was to explore the efficacy of an intervention specifically designed to help these students with schizotypal personality disorder (SPD) proneness to better cope with problems in their lives.
Methods: Three hundred college students were recruited to complete three questionnaires, which focus on their SPD symptoms, emotional experiences and general healthy conditions. Twelve students with SPD proneness according to the Schizotypal Personality Questionnaire (SPQ) were then invited to participate in our newly developed cognitive-behavioral course, mainly adapted from the Social Cognition and Interpersonal Training (SCIT). Assessments were done at pre- and post-training periods and also three months after the completion of the training programme.
Results: Significant correlations were found between SPD symptoms and general healthy condition (p<0.01), and the experiencing frequency of ten negative emotions (p<0.01). Significant improvement was not only observed in various outcomes immediately after the completion of the intervention but also extended to a 3-month post-intervention period. Their general healthy conditions also became better at three months after the completion of the training than the post-training periods (p<0.05).
Conclusions: The present study provided preliminary findings on the suitability and efficacy of the newly developed emotional and interpersonal relationship programme for university students with SPD proneness in mainland China.
PP04 - The dynamics of medication-taking adherence from the perspective of Taiwanese patients with schizophrenia
Ying-tzu Chang
1, Shu-gin Tao2, Chao-lin Lu3
1
Buddist Tzu Chi College of Technology, Hualien, Taiwan
2
Buddist Tzu Chi General Hospital, Hualien, Taiwan
3
Hualien Armed Forces General Hospital, Hualien, Taiwan
Background: Non-adherence to anti-psychotics has consistently been of concern to psychiatric professionals. With the promotion of the concept of adherence rather than compliance, schizophrenic patients are encouraged to actively participate in the decision to take medication. Psychiatric nurses are required not only to explore the patients’ experience of medication-taking but also to understand the processes by which patients start, maintain and stop taking their own medication in order to enhance anti-psychotic adherence. A number of qualitative researches have explored the reasons why people start and stop their medication from the viewpoint of schizophrenic patients. However, very few of these studies have examined how patients with schizophrenia maintain their medication-taking adherence. Therefore this study aims to explore the dynamics of medication-taking adherence from the perspective of Taiwanese patients with schizophrenic once they have consistently established adherent behaviour.
Method: In this qualitative study, ten clients with schizophrenia were recruited from the day care centre of a military hospital in eastern Taiwan. Each client was on average interviewed 3 times and for 30-45 minutes on each occasion. Audio tape was used to record the information during the interviews. The data was analysed by a content analysis method.
Results: Four themes were identified: the desire to stay well, deep gratitude for family support, the hope of leading a normal life and satisfaction with life during periods of stability.
Conclusion: The results will hopefully assist nurses to develop strategies to maintain patients’ adherent behaviour and to reduce the rate of relapse.
PP06 - Relationship between hospital admissions and different levels of risk for psychosis
Agatha M. Conrad
1, Terry J. Lewin1,2,3, Vaughan J. Carr1,3, Ulrich Schall1,3, Sean Halpin1,2, Ketrina A. Sly1
1
Centre for Brain and Mental Health Research, Hunter New England Mental Health and the University of Newcastle
2
Psychological Assistance Service, Hunter New England Mental Health
3
Schizophrenia Research Institute, Sydney, Australia
Background: The Psychological Assistance Service (PAS, Newcastle) is a community-based service specializing in assessments and interventions for young people at risk of psychosis.
Method: Recently, we conducted a layered service audit of all presentations to PAS during the past ten years. This project will provide valuable information about: the socio-demographic and clinical characteristics of PAS clients, together with their estimated risk status; and patterns of hospital admissions and community contacts in the years subsequent to PAS presentation.
Results: Between Jan. 1997 and Dec. 2007, PAS staff saw approximately 1,875 clients, comprising 2,207 presentations, 59.8% by males and 40.2% by females. The average age of presenting clients was 18.79 years (SD = 4.54). At the preliminary assessment, 64.9% of presentations were identified as ‘possible risk (for psychosis)’, 29.8% as ‘low risk’, and 5.3% had ‘unknown status’. Two-thirds of those identified with a ‘possible risk’ (67.8%, N=972) had a detailed assessment/review, of whom 21.1% (N = 205) were identified as ‘ultra high risk’ for psychosis, while 18.6% (N = 181) were experiencing their first episode, and 17.1% (N = 167) had an existing psychosis. Among those with another disorder (39.3%, N = 382), the highest rates were for depression (16.9%) and personality disorder (8.4%). Approximately one-quarter of PAS clients (24.3%) had at least one subsequent admission involving a drug and alcohol disorder. Admissions involving other disorders included: 16.5% for schizophrenia, 13.6% for depression, 10.7% for personality disorders, and 6.8% for bipolar disorder.
Conclusion: Relationships will be reported between the various categorisations of initial risk status at presentation to PAS and subsequent hospital admissions and community contacts. We thank the Australian Rotary Health Research Fund for their support.
PP07 - Associations between perinatal complications and clinical, neurological and cognitive outcomes in adults with schizophrenia: A preliminary analysis from ASRB Queensland
Sandra Diminic
1,2, Anna Stiller1,2, Bryan Mowry3,4, Stanley Catts2,5 and the Australian Schizophrenia Research Bank collaborative team.
1
Australian Schizophrenia Research Bank,
Schizophrenia Research Institute, Sydney, Australia
2
Discipline of Psychiatry, University of Queensland, Brisbane, Australia
3
Queensland Centre for Mental Health Research, Brisbane, Australia
4
Queensland Brain Institute, University of Queensland, Brisbane, Australia
5
Mental Health Service, Royal Brisbane & Women's Hospital, Brisbane, Australia
Background: There are well established associations between perinatal adverse events and schizophrenia. This study aimed to confirm these associations in the schizophrenia patient cohort recruited at the Brisbane site of the Australian Schizophrenia Research Bank (ASRB).
Methods: Self-reported developmental history and assessment of negative symptoms (SANS), neurological soft signs (NES), and cognitive (RBANS) and psychosocial (GAF) function were obtained from adult patients with schizophrenia. A binary variable based on items of obstetric complications was constructed. Patients were divided into those with and without perinatal adverse events (PAE). Exploratory bivariate analysis was conducted.
Results: Presence of PAE was positively associated with NES score (p<.001) and negatively associated with Total RBANS score (p<.05) and GAF ratings (p<.01). PAE was not significantly related to SANS scores but power consideration may have worked against detecting this relationship.
Conclusions: These preliminary results replicate well-established associations between clinical correlates of schizophrenia and perinatal complications. Our preliminary findings reflect the international literature and support the soundness of the ASRB recruitment and assessment procedures.
PP08 - Sodium valproate in schizophrenia/schizoaffective disorder: A critical review of existing literature
Vikas Garg
1, Narinder Panesar1, Nagesh Pai1, Saaish Raghavan2
1
South Eastern Illawarra Health Service, University of Wollongong, Illawarra Health Medical Research Institute
2
South Eastern Illawarra Area Health Service
Background: The diagnostic distinction most predictive of response to pharmacological treatment, according to available controlled studies, is between mood disorders with psychotic features and disorders in which psychosis persists in the absence of mood syndromes The treatment of acute mania and schizophrenia overlap considerably in terms of the typical and atypical neuroleptics, but begin to diverge with the recognized mood stabilizers for bipolar affective illness lithium, carbamazepine, and valproate which are substantially less effective in schizophrenia than in affective illness. Polypharmacy is a critical issue in the treatment of schizophrenia. Citrome et al. [1] reported that 43.4% of the inpatients diagnosed as having schizophrenia received a mood stabilizer. There are few controlled studies of the newer thymoleptic agents such as sodium valproate or of the newer antidepressants such as selective serotonin reuptake inhibitors in schizophrenic and schizoaffective patients. The aim of this article is to provide a debate regarding the usefulness of sodium valproate as an adjunct to schizophrenia spectrum disorders
Methods: Relevant literature review shall be conducted
Results: The current understanding for Valproate usage shall be discussed.
Conclusion: Sodium Valproate is used more often in schizophrenia and schizoaffective disorder, in spite of lack of appropriate evidence.
Reference
1. Citrome L et al. Psychiatr. Serv. 2000;51:634–638.
PP09 - Kristina's story (antipsychotic medication use during pregnancy)
Heather Gilbert, Jayashri Kulkarni
Monash Alfred Psychiatry Research Centre, The Alfred Hospital and School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia
Background: The opportunity and means with which to maintain optimum health and wellbeing throughout pregnancy are both desired and expected in our ‘civilised’ communities, as are optimal outcomes at the time of delivery, for both mother and baby. This coincides with the expectation that all women will maintain the ability to take care of their baby, no matter what their situation, including women who experience mental illness and who are prescribed antipsychotic medication during pregnancy. Currently, mental illness is treated with antipsychotic medication, however research in this area is both limited and inconclusive regarding the effect of this medication upon fetal development and maternal wellbeing.
Method: ‘Kristina's Story’ is a case study highlighting her journey through pregnancy and the postnatal phase. Kristina has bipolar affective disorder, for which she is prescribed quetiapine. She is a participant in The National Register of Antipsychotic Medication in Pregnancy (NRAMP), which tracks the progress and wellbeing of mother and baby during pregnancy and for 12 months postnatally, for mothers who take antipsychotic medication during pregnancy.
Results: Details of Kristina's pregnancy, mental health issues, hospitalisation, medication use and outcomes for mother and baby will be discussed.
Conclusion: Kristina returns to good health and delivers a healthy baby. Her inclusion in NRAMP will assist the development of evidence-based guidelines for the best use and effect of antipsychotic medication during pregnancy, thereby helping to improve the quality of life for present and future generations.
Acknowledgments: We gratefully acknowledge the generous support of AstraZeneca, Janssen-Cilag, Mayne Pharmaceuticals and the Australian Rotary Health Research Fund.
PP11 - The National Register of Antipsychotic Medication In Pregnancy (NRAMP): The first one hundred babies
Jayashri Kulkarni, Heather Gilbert, Caroline Gurvich, Stuart Lee, Natasha Marston, Kay McCauley, Anthony de Castella
Monash Alfred Psychiatry Research Centre, The Alfred Hospital and School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia
Background: As any literature review will show, current data on the use of antipsychotic medication during pregnancy is limited. By establishing The National Register of Antipsychotic Medication in Pregnancy (NRAMP), we aim to provide evidence-based guidelines to assist clinicians in making informed decisions for the best use and effect of antipsychotic medication during pregnancy, birth and for one year postnatally.
Method: NRAMP is an Australia-wide, observational study involving women who are taking, or have taken, antipsychotic medication during pregnancy. Information is collected during regular interviews throughout the pregnancy and for the first year postnatally, and includes demographic, social, medical, psychiatric, medication and obstetric history, as well as information on the general health and wellbeing for both mother and baby.
Results: This study is current and ongoing. Results for the first 100 babies born to mothers consented to take part in NRAMP will be presented, in relation to medications and mother/baby outcomes.
Conclusion: The resultant evidence-based guidelines arising from The National Register of Antipsychotic Medication (NRAMP) have the potential to provide regular contemporary updates to clinical treating teams as they manage women in this vulnerable population group. We plan to fill a void in mental health services where currently there is a distinct lack of information available for treating clinicians, with regard to providing the safest and most timely care of women who take antipsychotic medication during pregnancy.
Acknowledgments: We gratefully acknowledge the generous support of AstraZeneca, Janssen-Cilag, Mayne Pharmaceuticals and the Australian Rotary Health Research Fund.
PP12 - A meta-review of the environmental risk factors and antecedents in schizophrenia
Sandra L. Matheson
1,2, Alana M. Shepherd1, Kristin Laurens1,2, Vaughan J. Carr1,2
1
Schizophrenia Research Institute, Darlinghurst, Sydney, Australia
2
School of Psychiatry, University of New South Wales, Randwick, Sydney, Australia
Background: The impact of environmental risk factors and the presence of antecedents of schizophrenia remain unclear. This meta-review aims to summarize and quality assess the available evidence from systematic reviews with meta-analysis in this area to compare effect sizes and identify gaps in the evidence in this area.
Methods: Medline, CINAHL, Current Contents and PsycINFO were searched, supplemented by hand-searching. Included are systematic reviews with meta-analysis, reporting results separately for schizophrenia spectrum disorders. Reviews published prior to 2000, treatment guidelines, overviews, and reviews with a high possibility of reporting bias (as per PRISMA) were excluded. All included reviews’ reporting was quality assessed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, and data quality was assessed using GRADE guidelines for consistency, precision and directness. Data extraction and quality assessment were completed by two independent reviewers.
Results: The searches identified 451 results (less duplicates) of which 13 meet inclusion criteria. A further seven reviews have been identified via hand-searching and other sources. Results are currently being collated and will be presenting in order of magnitude of risk.
Conclusions: There appears to be a paucity of evidence in this area from well-conducted systematic reviews, particularly relating to antecedents of schizophrenia.
PP13 - Childhood adversity in a schizophrenia population: Data from the Australian Schizophrenia Research Bank (ASRB)
Kathryn McCabe
1,2, Jason Bridge1,2, Carmel Loughland1,2, Vaughan Carr1,3
1
Schizophrenia Research Institute, Sydney, New South Wales, Australia
2
University of Newcastle / Centre for Brain and Mental Health Research, Newcastle, New South Wales, Australia
3
School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
Objective: Childhood adversity is strongly associated with later psychological difficulties and mental health problems. However, little is known about the impact of childhood adversity on the course and outcomes in schizophrenia. The present study investigated the prevalence of childhood adversity in schizophrenia and explored its contribution to clinical and neurocognitive profile.
Method: Participants were recruited through the Australian Schizophrenia Research Bank (ASRB). Childhood adversity along with socio-demographic questions, medical and family history, neurological evaluation (NES), neuropsychological assessment and cognitive performance measures (WTAR, WASI, RBANS, LNS, COWAT), a diagnostic interview to confirm (or screen for) diagnosis, symptoms (SANS) and general functioning (GAF) ratings were all assessed.
Results: The sample consisted of 364 people with schizophrenia (mean age =39.87, SD=11.37) and 196 healthy controls (mean age =37.01, SD=13.24). Comparisons were also made with another Australian sample (ROSE SAMPLE). Compared to the R&R sample, the ASRB control group had a greater proportion of people reporting incidents of childhood adversity. For the ASRB sample, the schizophrenia subjects reported a higher proportion of any childhood adversity (cases=91.5%, controls=76.5%) and a greater number of multiple adversities (case mean=5.2; control mean=2.7) compared to the controls. Clinical and neuropsychological associations were explored between schizophrenia subjects with and without multiple incidents of childhood adversity.
Conclusion: This study provides for the first time data from a large Australian schizophrenia sample describing the incidence and impact of childhood adversity on the development and course of psychiatric disorder
PP15 - The metabolic syndrome among people with serious mental illness: What action we need to take?
Narinder Panesar
South Eastern Sydney Illawarra Area Health Service and University of Wollongong, Wollongong, New South Wales, Australia
Background: The metabolic syndrome is especially common in people with severe mental illness (SMI) and it describers a cluster of cardiovascular disease (CVD) risk factors. CVD is the leading natural cause of death in schizophrenia. The aim of the symposium is to identify the prevalence of metabolic syndrome among the in-patient mental health rehabilitation population.
Methods: The International Diabetic Federation (IDF) defines the metabolic syndrome as central obesity plus any two of hyperglycaemia, hypertriglyceridaemia, low HDL cholesterol or hypertension. All 20 patients were screened according to the definition criteria of metabolic syndrome set by the International Diabetic Federation. The prevalence of metabolic syndrome was calculated to be 50% among all patients. Of this group men (40%) were significantly more affected than women (10%).
Conclusion and recommendation: Each person with SMI within the health system should be offered an annual physical assessment for metabolic syndrome and CVD risk factors. People with the metabolic syndrome or with one or more of its parameters should receive prompt preventative intervention. To reduce the morbidity and mortality of people with SMI, health care professionals need to embrace a truly holistic approach to patient care that includes mental health, physical health and lifestyle management.
PP16 - A guide to pharmacological treatment for severe behavioural disturbance of adults in psychiatric in-patient settings in a regional area
Narinder Panesar
South Eastern Sydney Illawarra Area Health Service; Illawarra Health Medical Research Institute; University of Wollongong, Wollongong, New South Wales, Australia
Background: Acute behavioural disturbance is one of the commonest scenarios on acute psychiatric in-patients settings. The management of a disturbed behaviour depends upon the underlying cause. To de-escalate such a behaviour emergency treatment is required to prevent further risk to the person and others by maintaining a safe environment. This paper will guide a simple one page evidence based pharmacological treatment of short term management of acute disturbed or violent behaviour in an emergency setting.
Method: The acute disturbed behaviour on in-patients settings could be due to various reasons in context of mental illness or disorder, personality disorder, substance misuse and physical illness. The Rapid Tranquillisation (RT) should only be used if other interventions like appropriate psychological interventions have failed to de-escalate violent behaviour. The aim of treatment should be treating the underlying cause of acute disturbed behaviour rather than over sedating patients, masking their symptoms which may result in delaying appropriate assessment and treatment. The commonest medication use to manage acute disturbed behaviour is one of the benzodiazines with or without antipsychotic medication and intense monitoring of physical observations after RT.
Conclusion: To manage acute disturbed behaviour a comprehensive assessment and treatment by the experienced and trained multi disciplinary team is mandatory. The concise and precise one page guidance will assist the staff to manage patients with acute disturbed behaviour. RT is a treatment of last resort of acute violent behaviour rather than management of underlying condition.
PP17 - Diagnostic and treatment challenges of negative symptoms in schizophrenia
Narinder Panesar, Vikas Garg, Nagesh Pai
South Eastern Sydney Illawarra Area Health Service; Illawarra Health Medical Research Institute; University of Wollongong, Wollongong, New South Wales, Australia
Background: Negative symptoms (NSs) are a major contributor to the poor quality of life people with schizophrenia and are the most important cause of long-term disability. Recent evidence has shown that 15-25% of people with schizophrenia experience NSs which warrant treatment. The purpose of this paper is to address issues of diagnostic and treatment challenges of NSs.
Method: NSs are multifactorial in origin and it is difficult to differentiate between primary and secondary NSs. The primary NSs or ‘deficit symptoms’ are due to underlying disorder whereas secondary NSs are secondary to positive psychotic symptoms, extra-pyramidal side effects of anti psychotic medication, depression and catatonia. Andreasen includes NSs of affective flattening, alogia, avolition, anhedonia, and attention, which in turn are defined by a number of symptoms as reflected by the Scale for the Assessment of Negative Symptoms (SANS). It is difficult to differentiate between NSs and that of depression. Amongst all atypical antipsychotics clozapine has a good effect on the secondary NSs but not on primary. Other specific psychosocial interventions have some beneficial effects on NSs include cognitive remediation, CBT, social skills training and group therapies involving multiple families.
Conclusion: NSs are hard to define as they are more subjective than the presence of positive symptoms. They are nonspecific and may mimic depression. Accurate assessment of NSs requires robust standard rating scales. More research is required to understand the psychopathology of NSs and to find out more efficacious interventions of their management.
PP18 - Clinical course and analysis of nine fatal cases of clozapine-induced myocarditis in comparison with 66 surviving cases
Kathlyn J. Ronaldson
1, Andrew J. Taylor2, Paul B. Fitzgerald3, Duncan J. Topliss4, John J. McNeil1
1
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
2
The Heart Centre, Alfred Hospital, Melbourne, Australia
3
Monash Alfred Psychiatry Research Centre, Alfred Hospital, Melbourne, Australia
4
Department of Endocrinology and Diabetes, Alfred Hospital, Melbourne, Australia
Background: Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of nine fatal cases of myocarditis with clozapine and identify factors associated with fatality.
Method: Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports.
Results: The fatal cases of myocarditis occurred 1996-2006 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and for none was myocarditis suspected pre-death. Duration of clozapine was 14-33 days for the fatal cases. Comparison with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (67% vs 26%; p < 0.02) and duration of clozapine was significantly longer for fatal cases (20.8 vs 17.0 days; p < 0.006). Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004).
Conclusions: Routine monitoring for myocarditis for the first four weeks of clozapine with or without symptoms of illness, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.
PP19 - Predicting antipsychotic plasma concentrations before titrating the dose: A population pharmacokinetic study
Hiroyuki Uchida
1,2, David C. Mamo2,3, Bruce G. Pollock2,3, Benoit H. Mulsant2,3, Takefumi Suzuki1,2,3, Koichiro Watanabe1, Robert R. Bies2,4
1
Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan
2
Centre for Addiction and Mental Health, Toronto, Canada
3
University of Toronto, Department of Psychiatry, Toronto, Canada
4
Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, Indiana, US
Background: Due to a high interindividual variability in peripheral pharmacokinetic parameters, robustly predicting antipsychotic plasma concentrations before changing a dose for each individual has been a challenge. Therefore, dose adjustment has been performed, relying on a trial-and-error strategy that carries a risk of relapse and adverse effects.
Methods: Two plasma samples for the measurement of risperidone and 9-hydroxyrisperidone concentrations were collected at two separate given time points from patients with schizophrenia (DSM-IV). Subsequently, we collected another sample, following a dosage change. A plasma concentration associated with the dosage change was predicted in a blinded fashion, using the two samples collected at the baseline dose, intervals between last dose and blood draw, and subjects’ demographic information with a previously established population pharmacokinetic model for risperidone, using NONMEM. Accuracy of the predictions was then evaluated.
Results: 29 subjects participated in this study (mean±SD age=59±15; 22 men; 6 Caucasians and 23 Asians). The mean (95% CI) prediction errors and root squared prediction errors (ng/ml) were as low as 0.8 (−0.3–1.9) and 4.4 (2.8–6.0) for risperidone and 2.7 (0.9–4.5) and 7.1 (5.4–8.8) for 9-hydroxyrisperidone. The observed and predicted concentrations of risperidone and 9-hydroxyrisperidone were highly correlated (r=0.93, p<0.0001 and r=0.92, p<0.0001, respectively).
Conclusions: Antipsychotic plasma concentrations could be predicted before a dosage change. Taken together with the close relationship among plasma concentration, dopamine D2 receptor occupancy, and clinical effects (Uchida et al. submitted), these findings suggest that individualized dosing with the measurement of antipsychotic plasma concentrations could become a real potential clinical application.
PP20 - Prospective memory in schizophrenia and their non-psychotic first-degree relatives
Ya Wang
1,2, Raymond C.K. Chan1,2, Jifang Cui3, Yongyu Deng4, Jia Huang1,2, Huijie Li2, Chao Yan1,2,5, Ting Xu1,2,5, Zheng Ma6, Xiaohong Hong7, Zhanjiang Li6, David Shum8
1
Neuropsychology and Applied Cognitive Neuroscience Laboratory, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
2
Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
3
Institute of Developmental Psychology, Beijing Normal University, Beijing, China
4
Guangdong Vocational College of Mechanical and Electrical Technology, Guangzhou, China
5
Graduate School of Chinese Academy of Sciences, Beijing, China
6
Beijing Anding Hospital, Capital Medical University, Beijing, China
7
Mental Health Center, Shantou University, Shantou, China
8
School of Psychology and Griffith Institute for Health and Medical Research, Griffith University, Brisbane, Australia
Background: Prospective memory (PM) refers to the ability to execute a delayed intention at the right moment. Although a number of studies have found PM impairment in patients with schizophrenia, very little is known about the PM performance in non-psychotic relatives of these patients. The current study aimed to explore the PM performance in non-psychotic first-degree relatives of schizophrenic patients.
Methods: Three groups of participants (25 patients with schizophrenia, 25 non-psychotic first-degree relatives of these patients & 25 healthy controls) were administered three PM tasks (time-, event-, and activity-based) and a set of neurocognitive tests.
Results & Conclusions: Results showed that patients with schizophrenia performed significantly worse on PM measures than controls and non-psychotic relatives of schizophrenia, these relatives performed better than patients but worse than controls, with a similar pattern found in other cognitive measures. Together with findings of previous studies, results of the current study suggest that PM may be a potential endophenotype for schizophrenia.
PP21 - Relationships of demographic characteristics, symptomatology, retrospective and prospective memory, executive functioning and intelligence with social functioning in schizophrenia
Yu-Tao Xiang
1,2, David Shum3, Helen F. K. Chiu1, Wai-Kwong Tang1, Gabor S. Ungvari4
1
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
2
Beijing Anding Hospital, Capital Medical University, Beijing, China
3
School of Psychology and Griffith Institute for Health and Medical Research, Griffith University, Brisbane, Queensland, Australia
4
Graylands Hospital, Perth, Australia
Background: To date there is few studies exploring the independent associations of social functioning with prospective and retrospective memory in schizophrenia. The purpose of this study was to explore the influence of socio-demographic and clinical factors and neurocognitive variables (viz., prospective and retrospective memory, executive functioning and intelligence) on social functioning in Chinese schizophrenia patients.
Methods: One hundred and ten Chinese schizophrenia patients formed the study sample. Patients’ clinical condition and social functioning were evaluated with the Brief Psychiatric Rating Scale (BPRS) and the Functional Needs Assessment (FNA), respectively. Three prospective memory tasks (viz., time-, event- and activity-based), three tests of executive functioning (viz., Design Fluency Test [DFT], Tower of London [TOL], and the Wisconsin Card Sorting Test [WCST]), one test of intelligence (viz., Raven's Progressive Matrices) and two retrospective memory tasks (viz., immediate and delayed recall conditions of the Logical Memory subtest) of the Wechsler Memory Scales-Revised [WMS-R]) were administered to all patients.
Results: Correlational analyses indicate that higher education, better performance on the WCST (categories completed) and the Logical Memory subtests (delayed and immediate) of the WMS-R significantly correlated with better social functioning while lower WCST score (preservative errors) and more severe negative symptoms were associated with poorer social functioning. Multiple linear regression analysis revealed that higher education and lower WCST score (preservative errors) independently contributed to better social functioning.
Conclusions: Neither psychotic symptoms nor most aspects of the cognitive state, including prospective memory contributed to better social functioning.
PP22 - Cigarette smoking, psychopathology, and cognitive function in first-episode drug naïve schizophrenia: A case-control study
Meihong Xiu, Dachun Chen, Xiangyang Zhang
Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing, PR China
Background: Patients with chronic schizophrenia have substantially higher smoking rates than the general population or patients with other severe mental illnesses, but first-episode, drug-naive patients with schizophrenia have received little systemic study.
This study examined smoking rates, the effects of smoking on the symptoms and cognitive function in Chinese first episode schizophrenic patients using a cross-sectional and case-control design.
Method: Two hundred forty-four first-episode drug-naïve schizophrenic patients and 256 gender, age and education matched healthy controls completed a detailed cigarette smoking questionnaire, the Fagerstrom Test for Nicotine Dependence (FTND), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients were also rated on the Positive and Negative Symptom Scale (PANSS).
Results: The rate and quantity of smoking were not significantly different compared to the general population. Smokers scored higher on the PANSS positive symptom subscale and total score. There were no significant associations between cognitive function and smoking in either schizophrenia or in healthy controls.
Conclusions: In contrast to previous studies in chronic patients, the first-episode and drug-naive schizophrenic patients did not smoke more frequently than the general population. Individuals with psychotic disorders who smoked did not exhibit greater cognitive impairment or enhancement than those who did not smoke. However, smoking may have other detrimental effects on the process of psychotic illness, especially on positive symptoms.
PP23 - Cognition in transmembrane domain Neuregulin 1 mutant mice
Rose Chesworth
1,5, Liesl Duffy1,2, Emily Cappas1,2, Donna Lai3, Aurelie Boucher1,4, Tim Karl1,2,5
1
Schizophrenia Research Institute, Sydney, Australia
2
Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, Australia
3
School of Medical Sciences, University of Sydney, Australia
4
Department of Pharmacology, University of Sydney, Australia
5
Neuroscience Research Australia, Sydney, Australia
Background: Neuregulin 1 (NRG1), which has been implicated in the development of schizophrenia, is expressed widely throughout the brain and influences key neurodevelopmental processes such as myelination and neuronal migration. The heterozygous transmembrane domain Nrg1 mutant mouse (Nrg1 TM HET) exhibits a neurobehavioural phenotype relevant for schizophrenia research, characterized by the development of locomotor hyperactivity, social withdrawal, increased sensitivity to environmental manipulation, and changes to the serotonergic system. However, there is only limited data are available on the learning and memory performance of Nrg1 TM HET mice.
Methods: We conducted a comprehensive examination of these mice and their wild type-like littermates in a variety of paradigms, including fear conditioning, radial arm maze, Y maze, object exploration and passive avoidance.
Results: Male neuregulin 1 hypomorphic mice displayed impairments in the novel object recognition and fear conditioning tasks, including reduced interest in the novel object and reduced fear conditioning to a context, but not a discrete cue. These cognitive deficits were task-specific, as no differences were seen between mutant and control mice in spatial learning (i.e. radial arm maze and Y maze) for both working and reference memory measures, or in the passive avoidance paradigm.
Conclusion: These findings indicate that neuregulin 1 plays a moderate role in cognition and present further behavioural validation of this genetic mouse model for the schizophrenia candidate gene neuregulin 1.
PP24 - Repeated adolescent restraint stress triggers enhanced anxiety-related behaviour and PPI deficits on heterozygous Neuregulin 1 mice
Tariq Chohan
1,2, Areeg Hamdi1,2, Aurelie Boucher1, Adena Spiro1,2, Max Bennett1, Jonathon Arnold1,2
1
Brain and Mind Research Institute, Sydney, NSW, Australia
2
Department of Pharmacology, Sydney, NSW, Australia
Background: Stress has been proposed to trigger schizophrenia (SCZ) in genetically vulnerable individuals [1]. A leading candidate for genetic susceptibility to SCZ is Neuregulin 1 (NRG1) [2]. The present study utilised an Nrg1 heterozygous (HET) mouse model of SCZ to examine whether repeated stress during adolescence, a period of increased vulnerability to psychosis, could accelerate or accentuate the SCZ phenotype of Nrg1 HET mice which typically occurs at 5-6 months of age.
Methods: Adolescent Nrg1 HET and wild-type (WT) mice were subjected to 30 min restraint stress (S) or no stress (NS), daily for 14 days. On days 1 and 14, immediately after stress exposure, animals were first tested in animal models of anxiety (elevated plus maze then light-dark emergence test) before being assessed for changes in sensory motor gating as measured in the prepulse inhibition (PPI) paradigm.
Results: Restraint stress did not affect anxiety-related behaviour or PPI on day 1 in either WT or Nrg1 HET mice. While 14 days of repeated stress exposure initially increased anxiety-related behaviour in both genotypes, a more prolonged anxiety reaction was observed in Nrg1 HET compared to WT mice.
Conclusions: Partial deletion of Nrg1 confers greater vulnerability to stress-induced anxiety-related behaviour and attentional dysfunction. The impact of stress on Nrg1 HET mice appeared transient and did not trigger an earlier expression of the SCZ phenotype in these animals.
References
1. van Winkel R et al. Schizophr. Bull. 2008;34:1095–1105.
2. Stefansson H et al. Am. J. Hum. Genet. 2002;71:877–892.
PP25 - No change in 3H-Ifenprodil binding sites for the NR2B subunit in the prefrontal cortex in schizophrenia
Amy E. Dawson
1,2, Kelly A. Newell1,2, Xu-Feng Huang1,2
1
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia
2
Schizophrenia Research Institute, Darlinghurst, Sydney, Australia
Background: NMDA receptor hypofunction during early brain development has been linked to schizophrenia and alterations in NMDA receptor proteins have been found in schizophrenia brain tissue. The NR2B subunit may be particularly important in schizophrenia aetiology as it is highly expressed during early brain development and it is concentrated in the frontal cortex of the adult brain, a region highly implicated in schizophrenia pathology. This study aimed to determine whether NR2B protein levels are altered in the prefrontal cortex of schizophrenia patients.
Methods: Post-mortem human brain tissue (BA46) from 37 schizophrenia and 37 control subjects, matched for age, gender and post-mortem interval was obtained from the NSW Tissue Resource Centre. Quantitative receptor autoradiography was used to determine the level of 3H-Ifenprodil binding to NR2B protein in the tissue samples. NR2B binding was visualised using a Beta-Imager (Biospace) and quantified using Betavision+ software.
Results:
3H-Ifenprodil binding to the NR2B subunit was homogeneously distributed throughout all layers of BA46 in both schizophrenia and control subjects. However, there was no difference in NR2B binding levels between the schizophrenia and control cases (t= −0.263, p= 0.735). There were no significant correlations between NR2B binding levels and average daily or lifetime antipsychotic drug dose suggesting medication did not influence the result.
Conclusion: These results suggest no change in NR2B levels in BA46 in schizophrenia. While this is the first time NR2B binding has been examined in the prefrontal cortex in schizophrenia, our findings are similar to NR2B immunoblotting results in BA46 [1].
Reference
1. Kristiansen LV et al. Mol. Psychiatr. 2006;11:737–747.
PP26 - Effects of typical and atypical antipsychotics on the expressions of Neuregulin 1 and ErbB4 receptors
Bo Pan1, Xu-Feng Huang1,2, Chang-Hua Hu1,3, Mei Han1,2, Chao Deng
1,2
1
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia
2
Schizophrenia Research Institute, Darlinghurst, NSW, Australia
3
School of Pharmaceutical Sciences, Southwest University, Chongqing, China
Background: Neuregulin 1 (NRG1) gene has been identified as a candidate gene for schizophrenia. NRG1 signals mainly through stimulating ErbB4 receptors. Previous studies have showed that NRG1 and ErbB4 receptors were dysregulated in the brains of schizophrenia patients. On the other hand, the expressions of NRG1 and ErbB4 could respond to the treatment of antipsychotic drugs. This study aimed to investigate the effects of chronic antipsychotic treatment on the expression of NRG1 and ErbB4 receptors.
Methods: Female Sprague–Dawley rats were treated orally with three antipsychotic drugs – haloperidol (0.3 mg/kg/day), olanzapine (1.5 mg/kg/day), aripiprazole (2.25 mg/kg/day), or vehicle for 12 weeks. Western blotting was performed to examine the protein expression levels of three types of NRG1 (Type I, II, III) and ErbB4 receptors in the prefrontal cortex (PFC), cingulate cortex (CG), hippocampus, and hypothalamus.
Results: After 12-week treatment with antipsychotic drugs, both aripiprazole and haloperidol significantly decreased the expressions of ErbB4 receptor and all three types of NRG1 in the PFC. NRG1 type I expression was also decreased by aripiprazole in the CG. There was no significant change in the hippocampus. In the hypothalamus, aripiprazole significantly decreased the protein levels of ErbB4 receptor and NRG1 type II and III; and haloperidol reduced NRG1 type II expression.
Conclusion: Antipsychotics have differential effects on regulating NRG1 and ErbB4 receptor in various brain regions, which may contribute to the antipsychotic therapeutics in treating schizophrenia.
PP27 - Abnormal long-range neural synchrony in a neurodevelopmental animal model of schizophrenia
Desiree. D. Dickerson, David. K. Bilkey
Department of Psychology, University of Otago, Dunedin, New Zealand.
Background: The temporal coordination, or synchrony, of neural firing is believed to underlie the integration of information between and within neural networks in the brain. Abnormal synchronisation of neural activity between distal brain regions has been proposed to underlie the core symptomatology in schizophrenia.
Methods: We examined whether abnormal synchronisation occurs between the medial prefrontal cortex (mPFC) and the hippocampus (HPC), two brain regions implicated in schizophrenia pathophysiology, using the Maternal Immune Activation (MIA) animal model. This model of schizophrenia is induced through injection of the synthetic viral mimic polyriboinosinic-polyribocytidylic acid (Poly I:C) in pregnant rat dams and is based on epidemiological evidence that shows an increased risk of schizophrenia in adulthood following prenatal exposure to infection. Power and coherence were determined from the electroencephalogram (EEG), and neuronal synchrony to underlying EEG activity was examined in freely-moving adult MIA and control offspring.
Results: In utero exposure to maternal immune activation produced significant reductions in both EEG coherence and neuronal phase synchronisation between the HPC and mPFC across the theta, beta, and low-gamma frequency ranges. This occurred despite no change in local power in the mPFC or dorsal HPC. Further, firing within a putative population of theta modulated, gamma-entrained mPFC neurons was also reduced in MIA animals.
Conclusion: The results indicate that synchronous communication between the HPC and mPFC is disrupted in the MIA model. This model, therefore, provides a neurodevelopmental platform for exploring the neural mechanisms underlying the disruption of synchrony in schizophrenia.
PP28 - The dopamine-mediation of perception hypothesis and the implications for schizophrenia
Jan A. Golembiewski
University of Sydney, Sydney, Australia
Background: Following Kapur's hypothesis [1] that schizophrenia is the intensification of phenomenological experience caused by the upregulation of dopamine, a survey of observed dopamine responses to phenomenal information was conducted.
Method: An integrative study.
Results: When considered in the light of the ecological theory of perception (ETP) [2] and global workspace theory (GBT) [3] Kapur's hypothesis makes sense: Both the ETP and the GBT require an agent to attribute salience to perceptual information in order to filter an infinite array of available information and usefully sort information by importance. Dopamine may be the primary agent for this purpose. Thus perception itself is suspected as being a dopamine-mediated, and the symptoms and signs of schizophrenia may therefore be the result of dopamine dysfunction.
Conclusions: The application of both ETP and GBT to the dopamine hypothesis gives the hypothesis a much-needed causal mechanism and the confluence of these theories also provides ETP with a neurological perceptual filter. This paper provides a compelling model for schizophrenia; a hypothesis that ties perceptual theory to Kapur's concept of dopamine-mediated salience.
References
1. Kapur S. Am. J. Psychiatr. 2003;160:13–23.
2. Gibson JJ. The Ecological Approach to Visual Perception. Boston: Houghton Mifflin, 1979.
3. Baars BJ et al. Trends Cogn. Sci. 2003;7:166–172.
PP29 - Behavioural pharmacology of clozapine in a NMDA-antagonist rat model of schizophrenia
Anand Gururajan, Daniel T. Malone, David A. Taylor
Medicinal Chemistry & Drug Action, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
Background: Schizophrenia is debilitating psychiatric disorder characterised by the presence of positive (eg. hallucinations) and negative symptoms (eg. social withdrawal). In a preclinical setting, we are able to model this symptomology in rats with the use of MK-801, a non-competitive NMDA-receptor antagonist. MK-801 disrupts prepulse inhibition (PPI) of the acoustic startle response (ASR), increases locomotor activity and also produces social withdrawal in rats. Clozapine is a clinically established atypical antipsychotic which reportedly improves positive and negative symptoms with no extra-pyramidal side-effects. In this study, we evaluated the efficacy of clozapine to reverse MK-801-induced behavioural dysfunctions.
Method: Following a 4-day acclimatisation to the holding room, Sprague-Dawley rats were familiarised with the startle chamber on day 5 and tested for PPI on day 6 following injection of vehicle or clozapine and vehicle or MK-801. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following injection of vehicle or clozapine and vehicle or MK-801.
Results & Conclusion: Results showed clozapine (1, 3, 10 mg/kg) by itself had no effect on PPI, decreased ASR, social behaviour and locomotor activity. Clozapine failed to reverse MK-801 (0.3, 0.6 mg/kg) induced deficits in PPI and social withdrawal but did reverse MK-80- induced-hyperactivity. While overall these results appear to partially at odds with the clinical evidence that supports of the effectiveness of clozapine in reversing psychotic-like symptoms, it is possible that MK-801 does not produce the appropriate neuropathology that is susceptible to the antipsychotic effects of clozapine.
PP30 - Genetic variations in dopaminergic systems, cognition and schizophrenia
Caroline Gurvich, Susan Rossell, Paul Fitzgerald, Jayashri Kulkarni
Monash Alfred Psychiatry Research Centre, School of Psychology and Psychiatry, The Alfred Hospital and Monash University
Background: Cognitive deficits are central to many neuropsychiatric disorders, including schizophrenia. In particular, impairments in higher-order thought processes have been well documented in schizophrenia, and have a significant impact on quality of life and functional outcome. Extensive research has demonstrated that the prefrontal cortex plays a central role in various aspects of higher order cognitive functions. Dopamine is critically involved in the modulation of prefrontally mediated cognitive functioning. Of particular interest are the recent studies indicating that genetic factors affect dopamine flux in prefrontal cortex.
Method: We review the rapidly evolving literature exploring the association between gene polymorphisms and cognitive dysfunction in schizophrenia. We particularly focus on the various genes that are known to modulate the balance of dopamine in the prefrontal cortex and influence cognitive processing (e.g. the COMT gene).
Results: The genetic mechanisms contributing to dopaminergic modulation are complex. Nevertheless, there is evidence that variations in single genes impact a variety of core cognitive processes, including verbal working memory and executive functions like inhibition and switching, that are dependent upon the prefrontal cortex.
Conclusion: Recent advances in genetics research, demonstrating that a single functional polymorphism can significantly impact dopaminergic systems that modulate prefrontal brain networks during cognitive processing, have generated much excitement and are of significant interest in attempting to understand higher order cognitive processes, in healthy individuals as well as neuropsychiatric disorders, such as schizophrenia.
PP31 - Effects of antipsychotic drugs on muscarinic M1 receptors in the rat brain
Mei Han
1,2, Xu-Feng Huang1,2, Chao Deng1,2
1
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia
2
Schizophrenia Research Institute, Sydney, Australia
Background: Previous studies on post-mortem brain tissue suggested decrease or no change in the expression of muscarinic M1 receptors in various brain regions in schizophrenia. However, the effects of antipsychotic drugs on the expression of M1 receptors have not been well understood. This study examined the M1 receptor binding density in the rat brain following antipsychotic treatments.
Methods: Female Sprague Dawley rats were treated with aripiprazole, olanzapine, haloperidol or vehicle (control) for 1 or 12 weeks. [3H] pirenzepine was used to examine muscarinic M1 receptor binding sites.
Results: Aripiprazole significantly increased M1 receptor density in the core of the accumbens nucleus (23%, AcbC) compared to controls after 1 week treatment. Aripiprazole also significantly increased M1 receptor density in the hippocampal CA1 region after 1 and 12 weeks of treatments (17% and 22%, respectively). Olanzapine significantly increased M1 receptor density in the AcbC (29%) and the CA1 region (24%) after 12 weeks of treatment. Haloperidol significantly increased M1 receptor density in the CA1 region (13%) only after 1 week treatment.
Conclusions: All three antipsychotic drugs examined in this study showed an effect to increase M1 receptor binding density in various brain regions, which suggests that therapeutic effects of antipsychotics may partially act through the muscarinic M1 receptors in the limbic regions of the brain.
PP32 - Characterization of a novel hERG potassium channel isoform upregulated in schizophrenia patients
Juliane Heide
1,2, Stefan A. Mann1, Jamie I. Vandenberg1,2
1
Victor Chang Cardiac Research Institute, Sydney, Australia
2
Schizophrenia Research Institute, Sydney, Australia
Background: Recently, Weinberger and colleagues found an association between a single nucleotide polymorphism (SNP) in the second intron of the KCNH2 gene and schizophrenia [1]. The KCNH2 SNP results in increased expression of an alternatively spliced isoform of the human ether-a-go-go-related (hERG-1) potassium channel (referred to as hERG-3.1) in the prefrontal cortex and hippocampus. Intriguingly, the vast majority of antipsychotics, which block dopamine receptors as their major therapeutic mechanism, also inhibit hERG K+ channels. This raises the possibility that, in patients who have increased levels of hERG-3.1, treatment with antipsychotics could exacerbate, or ameliorate, symptoms of the disease. Accordingly, the aim of this study was to characterize the gating properties of the novel hERG-3.1 isoform and investigate the effects of antipsychotic drugs on this isoform.
Methods: hERG K+ channel currents were recorded from Chinese hamster ovary cells, stably expressing hERG-1 or transiently transfected with the hERG-3.1 isoform, using the whole-cell voltage clamp technique.
Results & Conclusions: hERG channels can exist in one of three main gating states, a closed state, an open state or an inactivated state (another non-conducting state that is distinct to the closed state). Transitions between theses states are voltage dependent. We found that the hERG-3.1 isoform has faster deactivation kinetics compared to the hERG-1 isoform, similar to that reported by Huffaker et al. In addition we found that the hERG-3.1 isoform has reduced inactivation. Preliminary data suggests that haloperidol, a typical antipsychotic, binds with a lower affinity to hERG-3.1 than to hERG-1.
Reference
1. Huffaker SJ et al. Nat. Med. 2009;15:509–518.
PP33 - Enriched environment provides neuroprotection via BDNF mediated PI3 kinase pathway activation
Vishal Jain, G. Ilavazhagan
Defence Institute of Physiology and Allied Sciences, Delhi, India
Background and Purpose: Environmental enrichment has numerous beneficial effects on brain and behavior. Several studies have investigated its effect on functional recovery following experimental models of stroke and traumatic brain injury. At the behavioral level, enriched environment enhances learning and memory, reduces memory decline in aged animals, decreases anxiety and increases exploratory activity. Our previous findings showed that enriched environment provide neuroprotection through neurotrophins against hypobaric hypoxia mediated cell death. The present study therefore aimed at exploring the involvement of possible neurotrophin and its signaling cascade.
Methods: Behavioral study was assessed by Morris Water Maze training, Golgi cox, biochemical estimations of various oxidative stress markers and antioxidant status was performed to study level of oxidative stress. Stereotaxical administration of blockers. Expression of different proteins was also assessed by Immunohistological and molecular techniques.
Results: Hypobaric hypoxia leads to neural death in rat hippocampus and cause memory impairment whereas housing in enriched environment significantly decreases neural death as evident from biochemical, immunohistological and molecular studies. Out of all possible neurotrophins BDNF plays major role in enriched environment mediated neuroprotection. BDNF known to work through PI3K and ERK mediated survival cascade. In the present study we showed that BDNF mainly work through PI3K mediated Akt activation leads to neuronal survival. We also observed that CREB may play an important role in regulation of this cascade.
Conclusions: Enriched environment provided neuroprotection against hypoxia mediated cell death and also improved learning and memory. BDNF plays a major role in survival and work through PI3K pathway. CREB may be a key player as a regulatory factor in this cascade.
PP34 - Studying the ‘two-hit’ hypothesis of schizophrenia in mice: Role of brain-derived neurotrophic factor (BDNF)
Maren Klug
1,2, Kwok Ho Christopher Choy1,3, Rachel Hill1, Maarten van den Buuse1,3
1
Mental Health Research Institute of Victoria, Parkville, Australia
2
Swinburne University of Technology, Melbourne, Australia
3
Department of Pharmacology, University of Melbourne, Australia
Background: Epidemiological studies have suggested that schizophrenia is caused by an early disruption, such as a genetic deficit or environmental stress, which increases vulnerability to late factors, such as drug abuse or social stress, i.e. the ‘two-hit’ hypothesis. We aimed to study the combined effect of reduced BDNF levels and postnatal stress on short-term spatial memory.
Methods: Female and male BDNF heterozygous (Het) mice and control wild-type mice (WT) were chronically treated with corticosterone (CORT) from 6-9 weeks of age. The mice were behaviourally tested in the Y-maze paradigm at 11 weeks of age. Protein levels for BDNF and its receptor, TrkB, were determined in hippocampus by Western Blot.
Results: Control groups, i.e. WT, WT receiving CORT, or BDNF Het mice, showed intact short-term spatial memory in the Y-maze, as evidenced by a significant preference to spend time in the novel arm one- or two hours after the 2-arm pre-exposure. In contrast, male CORT-treated BDNF Het mice showed no preference for the novel arm, suggesting disrupted short-term spatial memory. This disruption was not seen in female ‘two-hit’ mice. Male and female BDNF Het mice showed the expected reduction of BDNF levels while TrkB levels did not differ. CORT treatment did not affect either BDNF or TrkB levels.
Conclusion: CORT treatment induced a disruption of Y-maze spatial memory in male BDNF Het mice but did not affect BDNF or TrkB levels indicating that the ‘two-hit’-induced spatial memory disruption is mediated by other factors.
PP35 - Gene expression analysis of treatment-Naïve schizophrenia patients
Nishantha Kumarasinghe2,3,4,5, Ulrich Schall2,3,4, Natalie Beveridge1,3,4, Erin Gardiner1,3,4, Paul Tooney
1,3,4
1
School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Australia
2
School of Medicine and Public Health, Faculty of Health, University of Newcastle, Australia
3
Priority Research Centre for Brain and Mental Health Research, University of Newcastle and Hunter Medical Research Institute, Newcastle Australia
4
Schizophrenia Research Institute, Sydney, Australia
5
University of Sri Jayewardenepura, Colombo, Sri Lanka
Background: Distinct gene expression profiles can be detected in peripheral blood lymphocytes (PBLs) in patients with schizophrenia when compared to controls [1]. The current study investigated potential drug treatment confounds.
Methods: Ten treatment-naöve patients with confirmed diagnosis of schizophrenia (DSM-IV) were recruited from the National Institute of Mental Health (Angoda, Sri Lanka). Blood was obtained before and 6 weeks after initiating antipsychotic drug treatment. Eleven healthy community volunteers from the University Family Practice Centre (University of Sri Jayewardenepura, Sri Lanka) served as control group. Samples were hybridized to Illumina HumanHT-12 expression bead chips and genome-wide expression profiles of 48,803 transcripts (25,202 genes) compared between groups by Significance of Microarrays (SAM).
Results: Of the 10,207 genes expressed in PBLs, SAM analysis indentified 219 up- and 426 down-regulated genes prior to antipsychotic treatment (P<0.05). Comparison of before and after antipsychotic treatment resulted in 7 up-regulated genes at P<0.05. Of 31 upregulated genes identified at P<0.1, 10 of these genes were identified as down-regulated prior to treatment. Comparison of controls to patients after treatment identified 108 genes with altered expression.
Conclusions: We identified 645 genes with altered expression in treatment-naïve schizophrenia patients. Antipsychotic drug treatment restored 10 initially downregulated genes to control levels. These findings suggest altered PBL gene expression profiles in schizophrenia can be detected that are not driven by drug treatment, however such drug treatment generally stabilises gene expression to control levels.
Supported by the World Health Organisation, the University of Newcastle, and the Schizophrenia Research Institute.
References
1. Bowden N et al. Schizophr. Res. 2006; 82: 175–183.
PP36 - Non-invasive quantification of carotenoid antioxidant in schizophrenic patients
Han Chern Loh, Tze Jen Chow
Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Jalan Genting Kelang, Setapak, 53300 Kuala Lumpur, Malaysia
Background: The imbalance in oxidative stress and antioxidant defense system is hypothesised in the pathogenesis of many chronic diseases. Higher levels of antioxidant could boost up immune system by neutralising the damaging free radicals. Thus, antioxidants are reported as antidotes to counteract oxidative stress and improve disease condition, where carotenoids could serve as a reliable indicator of overall antioxidant level in human. This study investigated the association of carotenoid antioxidant levels in schizophrenic patients.
Methods: A total of 524 schizophrenic subjects from Hospital Bahagia Ulu Kinta, Malaysia and 488 healthy controls were recruited in this study. Skin carotenoid levels were measured using a non-invasive laser spectroscopic technique, Raman spectroscopy. Gender and age factor was not associated with carotenoid level.
Results: Among patient group, carotenoid level analysis of subtypes, antipsychotic drug treatments, and duration of illness show no significant association to schizophrenia. However, the overall results showed statistically significant (P<0.01) lower level of carotenoid in patient compared to control, suggesting schizophrenic patient to have higher oxidative stress.
Conclusions: Omitting factors such as dietary diet and smoking habit that differentiate between patients and controls, antipsychotics treatment was suggested to be the possible cause of reduced antioxidant level in schizophrenia.
PP37 - Effects of cannabidiol in heterozygous Neuregulin 1 transmembrane domain mutant mice
Leonora E. Long
1,2,3, Rose Chesworth1,2, Xu-Feng Huang1,4, Iain S. McGregor5,6, Jonathon C. Arnold1,6,7, Tim Karl1,2, 3
1
Schizophrenia Research Institute, Sydney, NSW, Australia
2
Neuroscience Research Australia, Sydney, NSW, Australia
3
Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
4
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia
5
School of Psychology, University of Sydney, Sydney, NSW, Australia
6
Brain and Mind Research Institute, Sydney, NSW, Australia
7
Department of Pharmacology, University of Sydney, NSW, Australia
Background: Cannabidiol (CBD), a non-psychotropic cannabis constituent, exerts anxiolytic- and some antipsychotic-like effects. We investigated whether CBD would reverse some of the behavioural abnormalities of heterozygous transmembrane domain neuregulin 1 mutant (Nrg1 HET) mice, which have partial face, predictive and construct validity for schizophrenia.
Methods: Adult (21 weeks) male Nrg1 HET mice and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. Behavioural tests for locomotor activity [open field test], anxiety-like behaviour (light-dark test), working memory [novel object recognition test], social interaction and sensorimotor gating [prepulse inhibition (PPI)] were applied after acute and chronic treatment and 48 h after treatment withdrawal.
Results: While CBD had no overall effect on locomotor activity, the baseline hyperactivity observed in Nrg1 HET mice was not observed after chronic treatment with 50 or 100 mg/kg CBD. Chronic treatment with CBD (1 and 100 mg/kg) exerted an anxiolytic-like effect in WT mice only, while chronic CBD (50 and 100 mg/kg) enhanced social interaction in Nrg1 HET mice only. There were no effects of genotype or CBD on working memory. Startle response and PPI were reduced in vehicle-treated Nrg1 HET mice after treatment withdrawal. Acute CBD (100 mg/kg) increased the startle response in WT and Nrg1 HET mice and enhanced PPI in Nrg1 HET mice only.
Conclusions: The effects of CBD on anxiety- and schizophrenia-related behaviours are dependent on treatment dose and duration. A mutation in the Nrg1 transmembrane domain may confer increased sensitivity to some of these effects.
PP38 - How is Neuregulin 1 “knocked out” in the Nrg1 transmembrane domain heterozygous “knock-out” mouse?
Leonora E. Long
1,2,3, Elisabeth Frank1,4, Xu-Feng Huang1,4, Tim Karl1,2,3, Cynthia Shannon Weickert1,2,3
1
Schizophrenia Research Institute, Sydney, NSW, Australia
2
Neuroscience Research Australia, Sydney, NSW, Australia
3
Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
4
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia
Background: Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene. The neuregulin 1 transmembrane (TM) domain heterozygous mutant (Nrg1 HET) mouse models some behavioural and neurochemical features of schizophrenia. However, the effect of the heterozygous TM domain mutation on the expression of the various Nrg1 exons is unknown. We examined Nrg1 mRNA in the frontal cortex of Nrg1 HET mice, predicting firstly that they would show reduced expression of the intracellular domain, which is downstream from the TM domain mutation. Secondly, we predicted that expression of the upstream extracellular bioactive epidermal growth factor-like domain would be unaltered.
Methods: Using probes for the intracellular and extracellular domains of Nrg1, mRNA concentrations were measured using quantitative RT-PCR in frontal cortex homogenates from Nrg1 HET and wild type-like (WT) mice.
Results:
Nrg1 HET mice show reduced concentration (ng/μl: mean + SEM) of mRNA for the intracellular domain (1.4 + 0.08) compared with WT (1.8 + 0.07). Expression of extracellular domain mRNA is unchanged (Nrg1 HET: 1.5 + 0.08; WT: 1.6 + 0.08).
Conclusions: The absence of change in mRNA encoding the extracellular portion of Nrg1 coupled with reduced expression of the TM and intracellular domains suggests that the Nrg1 HET mouse makes increased amounts of soluble forms of Nrg1. This model may be useful for modelling increases in “soluble” NRG1 isoforms observed in schizophrenia and could also serve as a model of reduced NRG1-mediated back signalling to the nucleus. These findings should be considered when interpreting observations of the phenotype of this animal model.
PP39 - Inverse relationship between serum testosterone level and severity of psychotic symptoms in males with chronic schizophrenia
Loretta Moore
1,2, Richard Morris1,2,3, Ans Vercammen1,2,3, Rhoshel Lenroot2,3, Brooke L. Short2,3,4, Maryanne O’Donnell4, Jayashri Kulkarni5, Vaughan J. Carr1,3, Cynthia Shannon Weickert1,2,3, Thomas W. Weickert1,2,3
1
Schizophrenia Research Institute, Sydney, Australia
2
Neuroscience Research Australia, Sydney, Australia
3
School of Psychiatry, University of New South Wales, Sydney, Australia
4
Kiloh Centre, Prince of Wales Hospital, Sydney, Australia
5
Monash Alfred Psychiatric Research Centre, Melbourne, Australia
Background: In accordance with a hypothesis of a dysfunctional hypothalamic-pituitary-gonadal axis as contributing to schizophrenia disease expression, previous studies have shown an inverse relationship between testosterone levels and negative symptom severity in males with schizophrenia; however, others report an inverse relationship between testosterone and only moderate to severe negative symptoms. Our study sought to assess the relationship between serum testosterone levels and psychotic symptoms in males with schizophrenia.
Methods: Fifteen male outpatients with chronic schizophrenia (24 – 49 years of age) receiving antipsychotic medication were assessed using the Positive and Negative Syndrome Scale (PANSS). Circulating serum testosterone levels were also collected.
Results: Although all patients were receiving antipsychotics, there was no significant difference between positive (mean = 16.5, SD = 3.8) and negative (mean = 15.1, SD = 7.1) symptoms scores, t(15) = .93, ns. Serum testosterone levels showed a mild correlation with age (r = -.31, n.s.) and no correlation with daily chlorpromazine equivalent dose (r = -.04, n.s.). Applying a partial correlation accounting for age revealed strong, significant inverse correlations between serum testosterone levels and PANSS positive (r = -.71), negative (r = -.54), symptoms and general psychopathology (r = -.63) scores, (all p's <.05), such that individuals with lower serum testosterone levels had more severe symptoms.
Conclusions: The study supports previous findings of an inverse relationship between severity of negative symptoms and serum testosterone levels. The strong inverse relationship between serum testosterone levels and PANSS positive symptom and general psychopathology scores warrants further investigation with a larger sample.
PP40 - Upregulation of Dicer and microRNA expression in the dorsolateral prefrontal cortex (Brodmann's Area 46) in schizophrenia
Danielle Santarelli
1,2,3, Natalie Beveridge1,2,3, Paul Tooney1,2,3, Murray Cairns1,2,3
1
Schizophrenia Research Institute, Sydney, NSW, Australia
2
School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, Callaghan, NSW, Australia
3
Hunter Medical Research Institute, New Lambton, NSW, Australia
Background: Schizophrenia expression studies report a common trend for global downregulation of gene expression. MicroRNA (miRNA) are endogenous non-coding RNA molecules that can each potentially regulate up to thousands of genes, and are essential factors in mediating healthy neurodevelopment. We hypothesised that abnormal miRNA levels contribute to the complex global changes in gene expression that underlie the pathophysiology of schizophrenia.
Methods: Using a commercial bead array platform, we investigated miRNA expression in 74 samples of postmortem dorsolateral prefrontal cortex (Brodmann's Area 46) (n=37 matched pairs schizophrenia/schizoaffective disorder and controls). A subset of differentially expressed miRNA and genes in the miRNA biogenesis pathway was also analyzed using Q-PCR. Gene targets of significantly different miRNA were predicted and pathways analysis performed.
Results: Microarray analysis reported a global upregulation of 18 miRNA in schizophrenia. miR-328 was significantly upregulated by real time RT-PCR, along with the miRNA biogenesis gene DICER. Trends for upregulation of DGCR8 and Drosha mRNA were also apparent. Target and pathways analysis provide insight into the potential cellular effects – with particular enrichment of miRNA targets in focal adhesion, axon guidance and long term potentiation.
Conclusions: These results provide additional evidence to previous investigations in Brodmann's Area 9 and superior temporal gyrus tissue that have also shown altered miRNA expression, likely caused by changes in miRNA biogenesis, in the complex pathophysiology of schizophrenia.
PP41 - Plasma interleukin-6 and granulocyte-colony stimulating factor are differentially expressed in the Neuregulin-1 knockout mouse model of schizophrenia following immune stimulation
Peta Snikeris
1,2, Xu-Feng Huang1,2, Elisabeth Frank1,2
1
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, NSW 2522, Australia
2
Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
Background: Schizophrenia is a devastating brain disorder; disease mechanisms, however, remain unknown. Recent evidence suggests the involvement of immune factors in schizophrenia aetiology, with patients showing altered cytokine levels in the blood and brain. We therefore investigated immune parameters in the Neuregulin-1 heterozygous knockout (Nrg1 KO) mouse model of schizophrenia following a chronic immune stimulus.
Methods: We challenged Nrg1 KO mice and wild type littermates (WT) with a chronic immune stimulus (B16F0 murine melanoma cell line; n=8). After 10 days, animals were sacrificed and blood and brains were collected. Plasma cytokine levels were quantified using a multi-plex bead based array (Milliplex, Millipore) measured on a Luminex100.
Results & Conclusions: We found an approximate 3-fold increase in the up-regulation of plasma IL-6 following immune stimulation in Nrg1 KO compared to WT mice. In addition, plasma G-CSF levels were 2-times higher in Nrg1 KO mice following immune challenge, while no increase was seen in WT mice. Both IL-6 and G-CSF can cross the blood-brain-barrier and are also produced by cells of the CNS, indicating their potential role in the brain. Cytokine levels in the brain are yet to be measured. Together, these alterations indicate a dysregulation of the cytokine response in Nrg1 KO mice as comparably observed in schizophrenia patients. With additional links between IL-6, G-CSF and schizophrenia-relevant neurotransmitter systems, these data provide a basis for future research into the psychopathological potential of a dysregulated neuro-immune system in schizophrenia.
PP42 - Female Neuregulin 1 hypomorphic mice display wild type-like responses to thc but display subtle startle and locomotor habituation deficits
Jarrah Spencer
1,2, Mohammed Kashem3, Leonora Long4,5, Iain McGregor3, Tim Karl4,5, Jonathon Arnold1,2,4
1
Department of Pharmacology, University of Sydney, Australia
2
Brain and Mind Research Institute, Camperdown, Australia
3
School of Psychology, University of Sydney, Australia
4
Schizophrenia Research Institute, Darlinghurst, Australia
5
Neuroscience Research Australia, Randwick, Australia
Background: Neuregulin 1 (Nrg1) has been linked by a number of human epidemiological studies to schizophrenia susceptibility. Previous characterization of mice with a heterozygous knockout of Nrg1 has revealed a number of schizophrenia relevant phenotypic behaviors, including altered response to cannabinoids.
Methods: Adult female Nrg1 heterozygous (Nrg1 HET) and wild type-like (WT) mice were treated daily for 21 days with the principle psychotropic constituent of cannabis, Δ9-tetrahydrocannabinol (THC). We measured locomotor activity, anxiety, prepulse inhibition, novel object recognition following acute and repeated THC exposure and after a 21 day drug washout. In addition hippocampal cytosolic protein expression is being analysed.
Results: No genotypic difference in the response to 10 mg/kg THC was observed at any timepoint. Significant locomotor suppression was observed for both genotypes after acute and repeated THC administration. After washout locomotor activity remained constant in vehicle-treated Nrg1 HET mice whilst decreasing in vehicle-treated WT mice, indicating reduced habituation in the Nrg1 HET mice. No prepulse inhibition deficits were shown within this study; however in vehicle treated mice there was an acute trend towards inhibited sensitization to the acoustic startle response.
Conclusions: Our results confirm previously reported habituation deficits in Nrg1 hypomorphs and suggest a promising line of enquiry regarding altered sensitization to acoustic startle response. The locomotor suppression induced by the dose of THC administered abolished any measurable genotypic differences in response. Proteomic analysis of the hippocampi of THC-treated Nrg1 HET mice may assist in identifying altered neuronal protein expression explaining previous findings of altered response to cannabinoids.
PP43 - Feasibility of imaging the ontogeny of CB1 receptors in adolescent and adult rats in vivo with [18F]MK 9470 and PET: A pilot study
Mathieu Verdurand
1,2, Vu Nguyen2, Daniela Stark2, David Zahra2, Marie-Claude Gregoire2, Ivan Greguric2, Katerina Zavitsanou1,2
1
Schizophrenia Research Institute, Sydney, Australia
2
ANSTO Life Sciences, Sydney, Australia
Background: Evidence suggests that cannabinoid CB1 receptors (CB1R) play a role in psychosis. In vivo studies of CB1R in both humans and animal models have been hampered by the lack of suitable radioligands. In the present animal study, we assessed the ontogeny of CB1R in adolescence and adulthood in vivo with Positron Emission Tomography (PET) and [18F]MK9470, a selective high-affinity radioligand for CB1R.
Methods: [18F]MK9470 was labeled with high specific activity (4000Ci/mmole). One adolescent (35 days) and one adult (70 days) old male Wistar rats were investigated with our Inveon PET/CT (Siemens). A 60-min PET scan was started at the same time of [18F]MK9470 injection with a low mass (0.07 ± 0.007 nmoles). Images were reconstructed, coregistered with CT and spatially normalized to a home-made atlas of rat brain. Standardized Uptake Values (SUV) were calculated for 12 regions of interest, based on the last 20 min of each scan, as a measure of CB1R binding.
Results: Levels of CB1R binding (SUV) were concordant with the literature. Overall, the adult rat showed a statistically significant increase in CB1R binding compared to the adolescent, with the biggest increase in the Striatum (+58.8%, p<0.01) and the lowest in the Cerebellum (+23.4%, p<0.001).
Conclusion: This study confirms the feasibility of examining the ontogeny of CB1Rs in vivo with PET. These results will be consolidated by the investigation of 6 animals in each population and will provide the basis for future longitudinal in vivo studies looking at CB1R expression in animal models of psychosis.
Merck & Co., Inc is acknowledged for the availability of the precursor for [
18
F]MK9470.
PP44 - Olanzapine decreases POMC mRNA expression and M3 receptor binding density in the hypothalamus and brainstem: Pathway for weight gain side-effect?
Katrina Weston-Green
1,2, Xu-Feng Huang1,2, Chao Deng1,2
1
Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, 2522, NSW, Australia
2
Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010, NSW, Australia
Background: Molecular pathways regulating appetite and body weight are important in understanding the mechanisms of olanzapine-induced metabolic dysfunction. The potent anorexigen pro-opiomelanocortin (POMC) is expressed in the hypothalamus and brainstem, key brain regions for controlling energy homeostasis. Olanzapine is a muscarinic M3 receptor (M3R) antagonist and antipsychotic affinity to M3R can be used to predict weight gain liability. M3R are co-expressed on POMC neurons but their role is unclear.
Methods: Rats were treated with olanzapine (0.75, 1.5, 3.0, 6.0mg/kg/day, orally 3x/day) or vehicle (control) (n=12/group) for 14-days. POMC mRNA expression and M3R binding density (n=6/group) were measured in the hypothalamic arcuate nucleus (Arc) and the dorsal vagal complex (DVC) of the brainstem. Correlations between POMC mRNA, M3R binding density, weight gain and food intake were examined.
Results: Olanzapine significantly decreased POMC mRNA expression in the Arc (1.5-6.0mg/kg/day), but not the DVC. M3R binding density in the Arc and DVC increased (1.5-6.0mg/kg/day). Body weight and food intake increased. POMC mRNA expression in the Arc negatively correlated to M3R binding in the Arc and body weight, but not food intake.
Conclusion: Olanzapine decreased POMC mRNA expression in the Arc, and increased M3R binding density in the Arc and DVC. Increased M3R binding density may be a compensatory up-regulation due to olanzapine antagonism. The minimum dosage required to induce changes in this animal model was 1.5mg/kg/day olanzapine. Olanzapine-induced weight gain may result from decreased anorexigenic POMC in the Arc and increased M3R, however further studies are required to elucidate the exact mechanisms.
PP45 - Abnormal hippocampal function as a result of maternal immune activation (MIA) in rats
Amy Wolff, Kirsten Cheyne, David Bilkey
Psychology Department, University of Otago, Dunedin, New Zealand
Background: Cognitive impairments are a key aspect of schizophrenia and may result from impaired contextual processing. The hippocampus processes contextual information, and hippocampal function is abnormal in schizophrenia. Our study examined hippocampal function in rats using the maternal immune activation (MIA) animal model to examine the link between exposure to prenatal infection and schizophrenia.
Method: MIA involves a single administration of a cytokine inducer (poly I:C) to pregnant rats during mid-gestation. Offspring were tested on behavioural tasks that are sensitive to hippocampal damage. Recordings of hippocampal neurons were conducted in a separate group of freely-moving animals.
Results: In a novel context, MIA offspring showed more rapid within-trial habituation of rearing than control animals (p < 0.05), suggesting that contextual information about a novel experience is encoded abnormally. MIA animals also displayed a post pubertal onset of open field hyper-locomotion. MIA offspring also showed reduced object exploration (p < 0.001) and the proportion of time exploring novel rather than familiar objects was less than in controls (p < 0.05). Neural activity was indicative of abnormal hippocampal processing, with cells in MIA offspring displaying a lower average firing rate (p < 0.01) and smaller place fields (p = 0.05) than controls.
Conclusions: This range of effects has not previously been observed in the MIA rat model. They are linked, however, in that they have previously been associated with hippocampal dysfunction. This is consistent with the hypothesis that abnormalities in the hippocampus may underlie the cognitive impairments observed in schizophrenia.
PP46 - Δ9-tetrahydrocannabinol but not olanzapine induces adipocyte hypertrophy and macrophage infiltration: Attenuating actions of co-administered cannabidiol
Alexander Wong
1, Nathan Gunasekaran1, Charlotte Klein2,4, Jane Radford3, Iain McGregor2, Jonathon Arnold1
1
Department of Pharmacology, University of Sydney, Australia
2
Department
of Psychology, University of Sydney, Australia
3
Department
of Pathology, University of Sydney, Australia
4
University of Bremen, Germany
Background: The main psychoactive constituent Δ9-tetrahydrocannabinol (THC) promotes adipocyte hypertrophy and macrophage infiltration. Another major constituent of cannabis, cannabidiol (CBD) might alter the action of THC. Here we aim to observe whether adipocytes of rats treated with cannabidiol (CBD) prior to THC administration display any attenuation or additive promotion of THC-related adipocyte cell hypertrophy and macrophage infiltration. Olanzapine has been shown to promote metabolic syndrome in humans. We additionally aim to determine whether this atypical antipsychotic drug similarly alters adipocyte morphology and inflammatory status.
Methods: 8-9 week old male Australian Albino Wistar rats were injected with ascending doses of THC, CBD + THC or vehicle solution. The rats were sacrificed at three weeks and fat pads collected and analysed for changes in cell sizes and macrophage infiltration. A pilot study into adipocyte morphology changes was also conducted with female Sprague-Dawley rats treated with vehicle or 3 mg/kg olanzapine for 15 days before being sacrificed and fat pads collected and analysed.
Results: THC treated rats showed significant increases in cell size and macrophage infiltration, whereas CBD + THC treated rats showed an attenuation of both THC's cell hypertrophic effect and macrophage infiltration. Olanzapine treated SD rats showed no significant changes in either cell size or macrophage infiltration.
Conclusions: Our results confirm THC's promotion of adipocyte cell hypertrophy and macrophage infiltration. Interestingly, pre-treatment of CBD attenuated both cell hypertrophy and macrophage infiltration, leading to the theory that CBD may be inhibiting or at least competing for uptake into adipose tissue.
PP47 - Cortical thinning in diagnostic sub-groups of first-episode psychosis
Brendan R.E. Ansell
1, Dominic B. Dwyer1, Patrick D. McGorry2, Tina M. Proffitt2, Dennis Velakoulis1, Christos Pantelis1, Stephen J. Wood1
1
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia
2
Orygen Youth Health Research Centre, University of Melbourne, Melbourne, Australia
Background: To date, studies of differences in cortical thickness underlying different diagnostic sub-groups in first-episode psychosis have been limited. Despite clinical differences in subjects in diagnostic sub-groups such as schizophreniform and affective psychoses, the underlying neurobiology is less well understood. This study aimed to investigate regions of cortical thinning in first-episode patients in the clinical diagnostic groups of schizophrenia/schizoaffective, schizophreniform, affective psychosis, and a composite group of other psychoses.
Methods: 162 first-episode psychosis patients (33.3% females) and 87 controls (36.8% females) were recruited and imaged at 1.5T. The first-episode diagnostic sub-groups consisted of 46 schizophrenia or schizoaffective patients (26.1% female), 57 schizophreniform (26.3% female), 34 affective psychosis (47.1% female), and 25 patients with other diagnosed psychoses (44% female). Magnetic resonance images were automatically analysed using a surface-based approach, and the average cortical thickness of each sub-group was compared to controls.
Results: All sub-groups displayed cortical thinning of the medial frontal cortex compared to controls. Specific reductions were found in the temporal poles and right insula of schizophrenia/schizoaffective patients, the superior frontal cortex in the schizophreniform and affective psychosis groups, and in the right insula in the group characterised by heterogeneous psychotic diagnoses.
Conclusions: Despite the consistency of medial frontal cortex thinning in all patient groups, distinct differences were found between different diagnostic categories when compared to controls. These results may be reflective of the clinical similarities and differences between the groups.
PP48 - Symptom misattribution in first-episode psychosis: A cortical thickness and diffusion tensor imaging tractography study
Lisa Buchy
1,2,3, Yasser Ad-Dab'bagh4,5, Ashok Malla2,6, Claude Lepage3, Michael Bodnar1,2,3, Ridha Joober2,6, Karine Sergerie1,3, Alan Evansc, Martin Lepage1,2,3,6
1
Brain Imaging Group, Douglas Mental Health University Institute, 6875 LaSalle Blvd., Verdun, Quebec, Canada, H4H 1R3
2
Prevention and Early Intervention Program for Psychoses, Douglas Mental Health University Institute, 6875 LaSalle Blvd., Verdun, Quebec, Canada, H4H 1R3
3
Department of Neurology & Neurosurgery, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4
4
Department of Psychiatry, University of Ottawa, 1145 Carling Avenue, Ottawa, Ontario, Canada, K1Z 7K4
5
Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada, K1H 8L1
6
Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada, H3A 1A1
Introduction: Poor insight is a central clinical characteristic of psychosis. In a previous work, we observed cortical thinning in prefrontal and temporal cortices in association with hallucination and delusion misattribution in people with a first-episode psychosis. The current investigation aimed to replicate our previous findings, and explore whether fronto-temporal dysconnectivity is evident in patients with hallucination and delusion misattribution.
Methods: Thirty-eight patients with a first-episode psychosis (FEP) were rated on the misattribution of hallucination and delusions items of the Scale for assessment of Unawareness of Mental Disorder. Participants were assessed with magnetic resonance imaging. Scores on the two misattribution items were first regressed on cortical thickness at 40 962 vertices across the cortical mantle (CIVET pipeline). Second, misattribution of hallucination and delusion scores were correlated with diffusion tensor imaging tractography-determined fractional anisotropy (FA) in two tracts connecting frontal and temporal regions: the superior longitudinal fasciculus (SLF) and uncinate fasciculus (UNC), as well as the fornix.
Results: Misattribution of hallucinations associated with thinning in the left DLPFC (BA9) and left middle temporal gyrus (BA21), and to lower FA values in left SLF, left UNC and left fornix. Misattribution of delusions associated with thinning in the right inferior temporal cortex (BA20), and to lower FA values in right SLF, bilateral UNC and bilateral fornix.
Conclusions: The results support the hypothesis that in people with a first-episode psychosis hallucination and delusion misattribution are associated with fronto-temporal dysconnectivity. The results also suggest the existence of partially separable neural systems underlying attribution of specific symptoms in FEP.
PP49 - Automatic brain morphometry used to identify first episode schizophrenia
Dominic B. Dwyer
1, Brendan R.E. Ansell1, Patrick D. McGorry2, Tina M. Proffitt2, Dennis Velakoulis1, Christos Pantelis1, Stephen J. Wood1
1
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia
2
Orygen Youth Health Research Centre, University of Melbourne, Melbourne, Australia
Background: Automated brain morphometry presents a promising opportunity to explore early markers of disease. The aim of this study was to employ automatic methods to identify regions that best discriminate first episode schizophrenia patients from controls.
Methods: Magnetic resonance images were acquired from 31 (8 female) first-episode schizophrenia patients and 62 (23 female) controls. Measurements of 67 neuroanatomic regions of interest (ROI) were used to identify first episode patients. Regions demonstrating an area under the receiver operating characteristic curve (AUC) above 0.7 were entered into a stepwise regression.
Results: Stepwise regression with 11 retained ROIs identified the left inferior parietal thickness, left bank of the superior temporal sulcus, and the left hippocampus as significant independent contributors. Together, the selected regions demonstrated an AUC of .84 (specificity 88%, sensitivity 63%).
Conclusions: The use of exploratory automatic techniques identified regions consistent with research literature. Discrimination accuracy was below previously published data utilizing manual measurements. The strengths and limitations of exploratory automatic techniques are discussed.
PP50 - Corpus callosum size reductions in schizophrenia: Is there a sex difference?
Swu Chyi Gan
1, Simon Lowes Collinson1, Wai Yen Chan2, Guo Liang Yang3, Jimin Liu3, Kang Sim4
1
Department of Psychology,
National University of Singapore, Singapore
2
Research Division, Institute of Mental Health, Singapore
3
Biomedical Imaging Laboratory, Singapore Bioimaging Consortium, Agency for Science, Technology, and Research, Singapore
4
Department of General Psychiatry, Institute of Mental Health, Singapore
Background: Previous accounts of similarities in symptoms exhibited by schizophrenia patients and those with agenesis of the corpus callosum (CC) [1] suggest a link between schizophrenic symptoms and CC abnormalities. It is still unclear whether a sex difference exists in the size of the CC in patients with schizophrenia, though sex differences have been reported in healthy individuals [2]. This study investigates whether a sex difference exists in the schizophrenia population relative to healthy controls, with respect to CC size.
Methods: Seventy-two schizophrenia patients (54 males and 18 females) and 58 healthy controls (35 males and 23 females) underwent magnetic resonance imaging and the volumes of 5 CC segments, anterior to posterior, were acquired. Separate 2 [diagnosis: patients versus controls] x 2 [sex: males versus females] ANCOVAs (analysis of covariance) were then performed.
Results: ANCOVAs revealed marginally significant main effects for diagnosis in total CC, central CC and mid-posterior CC volumes. The same main effect was significant in the mid-anterior CC volume. Patients show reduced volumes in these CC segments compared to controls. The interaction between sex and diagnosis, and the main effect for sex were not significant.
Conclusions: CC regions consisting of motor and sensory fibres were smaller in patients, possibly explaining the motor and sensory deficits frequently observed. There was no sex difference in CC volume nevertheless. Hence, the CC is probably not directly responsible for any sex difference observed in symptomatology and course of illness in schizophrenia.
References
1. Motomura N et al. Psychiatry Clin. Neurosci. 2002;56:199–202.
2. Leonard CM et al. Cereb. Cortex 2008;18:2920–2931.
PP51 - Auditory mismatch negativity and long-term cannabis use
Lisa-marie Greenwood
1, Stuart Johnstone1, Rodney Croft1, Juanita Todd2,3,4, Pat Michie2,3,4, Nadia Solowij1,4
1
School of Psychology, University of Wollongong
2
School of Psychology, University of Newcastle
3
Priority Research Centre for Brain and Mental Health, University of Newcastle
4
Schizophrenia Research Institute, NSW, Australia
Background: Similarity between cognitive impairments and subclinical psychotic symptoms associated with long-term cannabis use and schizophrenia suggests an overlapping pathology. Auditory mismatch negativity (MMN) is a vulnerability marker of schizophrenia that is highly dependent on the glutamatergic system and N-methyl-D-asparate receptors (NMDARs). Exogenous cannabinoids have been found to disrupt regulatory mechanisms of the glutamatergic, GABAergic and endocannabinoid systems and acute cannabinoid administration has been shown to modulate MMN. Little research has examined the effects of regular cannabis use on MMN and how neural alterations resulting from long-term cannabis use interact with vulnerability markers of schizophrenia.
Methods: A cross-sectional design will compare MMN in long-term regular cannabis users (n∼20) with healthy age and gender matched non-user controls (n∼20). A multi-feature paradigm with duration, frequency and intensity deviants will be employed. Participants will also complete standardised tests of memory and attention. Cannabis users will be required to abstain from cannabis for 12-24 hours before testing.
Results: MMN amplitude and latency and cognitive measures will be compared between groups using ANOVA. It is hypothesised that long-term cannabis users will show significant reduction in MMN amplitude when compared to controls. Relationships between MMN amplitude and outcome measures of psychological tests and various cannabis use parameters will be examined in correlational analyses.
Conclusion: The association between cannabis use and the development of schizophrenia is complex. Further detailed understanding of the vulnerability markers pertinent to the precipitation of psychosis by cannabis is urgently required. This study will help to clarify the neurobiological role of cannabis as a precipitator of psychosis.
PP53 - A combined ERP-fMRI study of cognitive control in schizophrenia
Frini Karayanidis1,2, Sharna Jamadar1,2, Pat Michie
1,2
1
Centre for Brain and Mental Health Research, University of Newcastle, Australia
2
Schizophrenia Research Institute, Darlinghurst, Australia
Background: Individuals with schizophrenia consistently show deficits in cognitive control across a range of paradigms. The ability to flexibly switch between simple tasks is considered to be a hallmark of cognitive control, however previous studies of task-switching ability in schizophrenia have shown that patients are able to switch tasks as effectively as controls. We examined event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) in task-switching in individuals with schizophrenia and controls (n=12/group) to examine processes underlying task-switching performance.
Methods: Participants switched randomly between two tasks using informative and non-informative cues. Informative cues allowed advance preparation for an upcoming switch or repeat trial, whereas non-informative cues did not.
Results: Patients and controls did not differ in RT switch cost or reduction in switch cost with preparation. ERPs associated with advance preparation to switch were intact in patients, however ERPs related to post-stimulus and response activation processes were significantly reduced relative to controls. In fMRI data, patients showed increased switch-related activity in the dorsolateral prefrontal cortex (DLFPC) and posterior parietal cortex (PPC) relative to controls.
Conclusions: Intact preparation-related ERPs suggests patients were able to effectively prepare for the task-switch, however impaired post-stimulus and pre-response ERPs suggests patients had difficulty in implementing the task-set. These findings are consistent with the proposal that DLPFC and PPC hyperfunction in schizophrenia is indicative of a compensatory mechanism [1]. We argue that these high-functioning patients adopt such compensatory mechanisms to overcome difficulties with response implementation and thereby achieve behavioural outcomes comparable to controls.
Reference
1. Quintana J et al. Biol. Psychiatry 2003;53:12–24.
PP54 - Neurophysiological biomarkers of early schizophrenia and affective spectrum psychosis
Manreena Kaur, Daniel F. Hermens, Ian B. Hickie
Brain and Mind Research Institute, University of Sydney, Australia
Background: Mismatch negativity (MMN) is a neurophysiological indicator of the brain's ability to extract relevant information from an irrelevant background. The P3a orienting response often accompanies MMN in deviance detection paradigms. Both MMN and P3a have been described as reliable biomarkers of schizophrenia. Despite claims that MMN impairments are specific to schizophrenia, there have been few studies which have examined this biomarker in other types of psychoses. This study examines the MMN/P3a complex in individuals with schizophrenia-versus affective-spectrum first-episode psychosis (FEP).
Methods: Fifty-three young people (18-29 yrs) were assessed: 15 diagnosed with schizophrenia-spectrum FEP; 15 with affective-spectrum FEP; and 25 healthy controls. To elicit MMN/P3a, a two-tone passive auditory oddball paradigm with 8% duration deviants was used; event-related potentials were recorded at frontal, central and temporal sites.
Results: Both FEP groups showed a reduced central MMN/P3a and a reduced left temporal MMN compared to controls. However, there were subtle differences at frontal and right temporal sites. Schizophrenia-FEP showed the largest impairment in frontal MMN/P3a; whereas the affective-FEP showed the largest reduction in right temporal MMN.
Conclusions: This study provides evidence of neurobiological markers in young people with schizophrenia and affective spectrum psychoses. Subtle differences, according to the brain region involved, emerged to suggest that these early psychoses subgroups may differ in fundamental pre-attentive/deviance detection processes. The MMN/P3a may have utility in differentiating subtypes of psychosis at early stages.
PP55 - Potentiated automatic memory in schizophrenia appears task invariant
Daria Korobanova
1, Richard J. Linscott1,2
1
Department of Psychology, University of Otago, Dunedin, New Zealand
2
Department of Psychiatry and Psychology, Maastricht University, Maastricht, the Netherlands
Background: The study of rudimentary cognitive processes such as automatic memory (AM) in schizophrenia offers insights into the neuropathological basis of this disorder. Evidence on the relation between schizophrenia and AM appears equivocal. Methodological differences among previous studies [1–3] may have contributed to the ambiguity of current evidence for potentiated AM in schizophrenia. Our aim was to determine whether schizophrenia is associated with potentiated AM when methodological differences are addressed. It was hypothesized that schizophrenia is associated with impaired controlled memory (CM) and potentiated AM.
Method: There were 20 participants with schizophrenia and 20 without. They all completed the Word Stem Completion Task (WSCT), as well as clinical and validation measures.
Results: When the unadjusted estimates of AM and CM were compared between the groups, the statistical analysis revealed that participants with schizophrenia had impaired CM and potentiated AM when compared to participants without schizophrenia.
Conclusion: This finding is consistent with the view that verbal processing of semantic information is disinhibited in schizophrenia. It also implies that findings of increased spreading activation in schizophrenia as observed in semantic priming studies are not confined to those paradigms or tasks. It is possible that the combined finding of altered automatic processes in semantic spreading and memory indicates a fundamental loosening or slippage of activation in verbal processing in schizophrenia.
References
1. Balsa F et al. Revista de Psicopatologia y Psicologia Clinica 2002; 7:45–60.
2. Kazes M et al. Neuropsychology 1999;13:54–61.
3. Linscott RL et al. Neuropsychology 2001;15:576–585.
PP56 - The Australian Schizophrenia Research Bank (ASRB): Demographic, clinical and neuropsychological profile of participants with schizophrenia
Vaughan Carr1,2, Carmel Loughland
1,2, Kathryn McCabe1,2, Aslan Nasir1,2, Stanley Catts1,5, Assen Jablensky1,4, Frans Henskens1,2, Patricia Michie 1,2, Bryan Mowry1,5, Christos Pantelis1,6, Ulrich Schall1,2, Paul Tooney1,2, Rodney Scott1,2,3
1
Schizophrenia Research Institute, Sydney, New South Wales, Australia
2
University of Newcastle/Centre for Brain and Mental Health Research, Newcastle, New South Wales
3
University of Queensland/Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
4
University of Western Australia/Centre for Clinical Research in Neuropsychiatry, Perth, Western Australia
5
University of Melbourne/Melbourne Neuropsychiatry Centre, Melbourne, Victoria,
6
School of Psychiatry, University of New South Wales, Sydney, New South Wales
Background: The Australian Schizophrenia Research Bank (ASRB) was established in 2007 to collect linked clinical, cognitive, neuroimaging and genetic data in people with schizophrenia and matched controls, and is the first of its kind developed in Australia.
Methods: Participants were assessed using a comprehensive assessment battery developed based on advice from a collaboration of schizophrenia research specialists. The three-hour battery consists of socio-demographic questions including medical and family history, neurological evaluation (NES), neuropsychological assessment and cognitive performance measures (WTAR, WASI, RBANS, LNS, COWAT), a diagnostic interview that includes drug and alcohol history (DIP) [1] to confirm (or screen for) diagnosis, ratings for symptoms (SANS) and general functioning (GAF), and questionnaires of childhood adversity, personality disorder (IPDE) and psychosis proneness (SPQ).
Results: The sample currently comprises 550 people with schizophrenia (mean age=39.66 years; SD=10.98) and 250 healthy controls (mean age=37.37 years; SD=13.14). Compared to the controls, the schizophrenia sample had a higher proportion of males (cases 66.80%; controls 46.40%), fewer living in married or de facto relationships (cases 15.80%; controls 53.60%) and fewer years of education (cases 12.93, SD = 2.91; controls 15.13, SD = 3.14). Schizophrenia participants also had lower premorbid IQ (cases 103.17, SD=13.17; controls 111.83, SD=8.76), current IQ (cases 102.29, SD=15.62; controls 118.24, SD=10.20) and RBANS scores (cases 82.55, SD = 15.59; controls 96.24, SD =15.88) consistent with performance reported previously for Australian samples [2].
Discussion: These findings are broadly consistent with those reported previously in the Australian Low Prevalence Disorders Study [3], suggesting the ASRB sample is broadly representative of people with schizophrenia living in Australia. The ASRB is a unique schizophrenia resource that is accessible to approved Australian researchers in 2010 and international scientists in 2011.
References
1. Castle DJ et al. Psychol. Med. 2006;36:69–80.
2. Loughland CM et al. Schizophr. Res. 2007;89:232–242.
3. Jablensky A et al. Aust. N.Z. J. Psych. 2000;34:221–236.
PP57 - Brain tissue donations support schizophrenia research
Toni McCrossin
1, Nina Sundqvist1,2, Donna Sheedy1, Jillian Kril1
1
University of Sydney, Sydney, Australia
2
Schizophrenia Research Institute, Sydney, Australia
Introduction: Research aimed at understanding the underlying pathogenesis of psychiatric disorders has expanded over the years to include application of a range of technologies to post mortem human brain tissue. Brain donations facilitated by the NSW Tissue Resource Centre (TRC) at the Discipline of Pathology, University of Sydney, are via both post-mortem and prospective donor programs.
Aim: To review the outcomes of prospective brain donors programs of the TRC.
Method: Quantitative analysis of donor programs and associated research.
Results: The Schizophrenia Research Institute launched the Gift of Hope Brain Donor Program (GoH) in 1998, and invited those with schizophrenia to register. In addition, the Using our Brains Donor Program (UoB) was launched in 2002 to invite those in the community who are free from neurological and psychiatric disease to donate. The GoH has 574 registrations of interest. The UoB has had over 2000 enquires and 911 people have now consented. Of these donors 612 have had neuropsychological assessments. To date, 84 collections have been made through these programs. Both programs have assisted with the facilitation of 46 research projects worldwide which are focused on schizophrenia.
Conclusion: The support of the community at large has allowed the collection of cases to form important cohorts for research into schizophrenia.
PP58 - Auditory mismatch negativity and event-related potential recovery in the wistar rat
Tamo Nakamura
1,2,3,4, Patricia T. Michie1,2,3,4, William R. Fulham2,3,4,5, Michael Hunter1,2, Timothy W. Budd1,2,3,4, Juanita Todd 1,2,3,4, Ulrich Schall2,3,4,5, Deborah M. Hodgson1,2,3,4
1
School of Psychology, The University of Newcastle, Callaghan, Australia
2
Priority Centre for Brain & Mental Health Research, The University of Newcastle, Callaghan, Australia
3
Schizophrenia Research Institute, Darlinghurst, Australia
4
Hunter Medical Research Institute, Newcastle, Australia
5
School of Medicine and Public Health, The University of Newcastle, Callaghan, Australia
Background: Auditory event related potentials (ERPs) can be used to study intermediate phenotypes of schizophrenia. Mismatch negativity (MMN) is generated when the auditory system detects a change in a regular and rapid sequence of background sounds. MMN is the result of an automatic memory-based comparison process that detects a discrepancy between the neural representations of the regularity of recent stimulation and the deviant sound. Auditory ERP sensitivity to stimulus onset asynchrony (SOA) reflects changes in cortical excitability following repeated stimulation. In schizophrenia, reductions in MMN (suggested as the most robust physiological marker of the disorder) and N1 ERP recovery are observed. The aim of this research is to develop rodent models of MMN and ERP recovery.
Methods: Deviance-related ERPs were recorded in awake rats (n = 5 – 6) using a duration deviance paradigm, a frequency deviance paradigm and variable SOA paradigms, all modelled after paradigms used in human studies to characterise MMN and N1 ERP recovery.
Results: MMN was observed in both duration and frequency deviance paradigms with long duration and high frequency stimuli. The high frequency deviant elicited a negative shift with an earlier onset latency than the long duration deviant. ERP peak amplitudes were sensitive to variations in SOA, providing a basis for identifying the rat homologue of the human N1 ERP component.
Conclusion: If the pattern of results holds with data from additional animals, MMN in particular and ERP recovery in animals may be useful tools to investigate the aetiology of schizophrenia and treatment efficacy.
PP59 - Cannabis use in first episode psychosis and the mismatch negativity
Nicole Pesa
1, Daniel Hermens2, Robert Anthony Battisti2,3, Juanita Todd4,5,6, Pat Michie4,5,6, Nadia Solowij1,6
1
School of Psychology, University of Wollongong, Wollongong, Australia.
2
Brain and Mind Research Institute, University of Sydney, Sydney, Australia.
3
National Cannabis Prevention & Information Centre, University of New South Wales, Sydney, Australia.
4
School of Psychology, University of Newcastle.
5
Priority Research Centre for Brain and Mental Health, University of Newcastle.
6
Schizophrenia Research Institute, NSW, Australia.
Background: Mismatch Negativity (MMN) is dependent on the glutamatergic system and N-methyl-D-aspartate receptors (NMDAR) are critically involved in the generation of MMN. Deficient NMDAR-dependent neurotransmission has been indicated in contributing to the robust MMN deficits found in schizophrenia. Cannabinoids have been demonstrated to modulate NMDAR activity. No studies to date have investigated MMN in patients with schizophrenia or First Episode Psychosis (FEP) and comorbid cannabis use. This study aims to investigate the effects of regular cannabis use on the MMN in a sample diagnosed with FEP.
Methods: MMN will be compared in a sample of FEP patients with cannabis use (n=12) and FEP patients without cannabis use (n=12) using a multi-feature paradigm (varying in duration, frequency, and intensity deviants). Standardised cognitive tests of memory and attention will also be administered. FEP patients with cannabis use will be required to abstain from cannabis for at least 12 hours prior to testing.
Results: MMN amplitude and latency differences between patient groups will be interpreted as the additive effects of cannabis use. Correlation analyses will explore relationships between MMN and cognitive measures, positive/negative symptoms, duration of illness, and various cannabis use parameters.
Conclusions: The results of this study will further inform our understanding of MMN early in the course of psychotic illness and the impact of regular cannabis use on this vulnerability marker for schizophrenia. They will also shed light on the impact of cannabis use on the functionality of the glutamatergic system and its role as a component cause of psychosis.
PP60 - Australian Brain Bank supports research to detect molecular and histological changes in schizophrenia
Julia Stevens
1, 2, Donna Sheedy2, Jillian Kril2
1
Schizophrenia Research Institute, Sydney, Australia
2
University of Sydney, Sydney, Australia
The NSW Tissue Resource Centre (TRC) is a human brain bank, located at the University of Sydney and supported by the Schizophrenia Research Institute. It provides brain tissue for schizophrenia research.
Aim: To collate the research outcomes of all schizophrenia-related studies where TRC cohorts have been used.
Method: Peer-reviewed publications that were generated from studies using TRC schizophrenia brain tissue during the period 1998 – 2009 were examined and the outcomes collated. For each manuscript the anatomical region(s) studied, methods used and results were summarised. Tissue request information during this time period was also reviewed.
Results: Forty-six projects headed by 28 researchers were supported by the TRC during the 12-year period. Frozen tissue was requested in 67% of studies. Of the 34 journal articles published, 50% of experimental techniques used were focused on proteomics or gene expression profiling. Frontal regions (including prefrontal cortex, BA9, BA4 and motor frontal cortex) were requested in 25% of the studies. Significantly altered binding densities and protein/RNA expression levels were found for 8 of the regions studied in schizophrenia cases compared to controls. These regions were; frontal, anterior cingulate, posterior cingulate, superior temporal and, visual cortices, amygdala, corpus callosum and cerebellum.
Conclusion: This overview highlights the importance of a large schizophrenia cohort and the demand for high quality frozen tissue. The availability of the cohort to researchers worldwide will continue to assist in the detection and characterisation of genes of interest in schizophrenia.
PP62 - Functional correlates of the non self-serving attributional bias: A pilot study
Renate Thienel
1,2,3, Katharina Pauly4, Thilo Kellermann4, Tilo Kircher5
1
Priority Centre for Brain and Mental Health Research, University of Newcastle, Australia
2
Schizophrenia Research Institute, Darlinghurst, Australia
3
Hunter Medical Research Institute, Newcastle, Australia
4
Dept. of Psychiatry and Psychotherapy, University of Aachen, Germany
5
Dept. of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany
Background: Humans use causal attributions to infer the cause of events in their social world. Attributions may be internal (attributing the event's causation to oneself) or external (attributing the causation to another person or situational factors). Some studies demonstrated an association between persecutory delusions and exaggerated externality when attributing causes for negative events while most attribution research has tested the link between depression or anxiety and an attenuated self-serving bias (SSB) [1]. SSB is the tendency to excessively attribute positive events to internal and negative events to external causes.
Methods: Thirteen healthy men (26 ± 7 yrs., IQ: 113 ± 17) performed an event related attributional bias paradigm (80 visually presented statements) while assessed with functional Magnetic Resonance Imaging (3 T). ANOVA was performed using SPM5 (P<0.01 at voxel level, Monte-Carlo-corrected P<0.05, ≥ 26 continuous voxels).
Results: The fMRI data revealed increased BOLD for the interaction representing a ‘non self-serving bias’ (attributing negative events internally and positive events externally) bilaterally in the superior medial gyrus, middle cingulate cortex, right middle frontal gyrus, posterior cingulate cortex and angular gyrus and left superior frontal and medial gyrus.
Discussion/Conclusions: Under non self-serving conditions, our data partly confirmed previous work [2], which has previously been associated with depression [1] where subjects demonstrate the tendency to attribute the causation of negative events to themselves and positive events to others.
References
1. Jolley S et al. Behav. Res. Therap. 2006;44:1597–1607.
2. Blackwood et al. NeuroImage 2003;20:1076–1085.
PP63 - Inhibition of response to emotional words elicits attenuated neural responses in schizophrenia
Ans Vercammen
1,2, Richard Morris1,2, Melissa J. Green2,3, Rhoshel Lenroot1,2, Loretta Moore1, Brooke L. Short2,4, Jayashri Kulkarni5, Vaughan J. Carr2,3, Cynthia Shannon Weickert1,2,3, Thomas W. Weickert1,2,3
1
Neuroscience Research Australia, Randwick, NSW, Australia
2
School of Psychiatry, University of New South Wales, Randwick, NSW, Australia
3
Schizophrenia Research Institute, Darlinghurst, NSW, Australia
4
Kiloh Centre, Prince of Wales Hospital, Sydney, Australia
5
Monash Alfred Psychiatric Research Centre, Melbourne, Vic, Australia
Background: Disruptions of response inhibition constitute one of the most characteristic neurocognitive deficits related to prefrontal cortex dysfunction in schizophrenia. People with schizophrenia also display impairments in identifying emotions (e.g. facial expressions). We used an affective go/no-go task to investigate the interaction between cognitive-executive and affective processing.
Methods: fMRI scans were obtained in 13 people with schizophrenia and 16 healthy adults, while responding to target words of a pre-specified valence and inhibiting responses to distracters of other valences. Four conditions (neutral targets with positive or negative distracters, and negative or positive targets with neutral distracters) were presented in a pseudo-randomized block design.
Results: In healthy adults, inhibition of negative stimuli revealed activation in a predominantly right hemispheric network: middle and superior frontal gyrus, lateral inferior frontal gyrus, cingulate, insula, and angular gyrus, whereas inhibition of positive stimuli caused deactivation of the anterior cingulate. In people with schizophrenia, neither contrast revealed significant clusters, though at a lower threshold patients did show activity in portions of the network identified in healthy adults. Two sample T-tests revealed significantly increased activation in the right superior/middle frontal region and left insula when inhibiting negative stimuli, and enhanced deactivation in the mid-cingulate gyrus when inhibiting positive stimuli in controls relative to schizophrenia.
Conclusions: People with schizophrenia showed attenuated neural responses in the frontal cortex, a region contributing to response inhibition, and the insula, implicated in facilitating interference resolution for emotional information. These findings are suggestive of aberrant interactions between cognitive and affective processing streams in schizophrenia.
