ASPR Symposium Presentations

ARS01 INTERNATIONAL SOCIETY FOR THE STUDY OF PERSONALITY DISORDERS SYMPOSIUM ON PERSONALITY DISORDERS

Andrew Chanen, Richard Bell, Jennifer Boldero, Carol Hulbert, Martina Jovev, Janine Stevenson

This symposium brings together researchers affiliated with the International Society for the Study of Personality Disorders. It canvasses current personality disorder research from classification through to social cognition, psychopathology and clinical phenomenology

THE CONTRIBUTIONS OF PERSONALITY AND SELF-ESTEEM TO OVERT AND COVERT NARCISSISM

Jennifer Boldero, Carol Hulbert, Chay Miang, Jamie Lim, Benjamin Wright, Safiye Aytekin, Hailey Meaklim

Introduction: The study of narcissism is under-represented in clinical research. However, there is evidence that narcissism is a dimensional disorder, with sub-clinical levels being found in non-clinical populations In addition, despite the emerging consensus that two distinct facets of narcissism exist – an overt (grandiose) facet and a covert (vulnerable) facet with different characteristics, it remains unclear whether they are two separate personality subtypes, two ends of an adjustment continuum, or two co-existing facets manifesting in different situations. The present two studies were designed to examine these propositions in non-clinical samples, by investigating the structure of overt and covert narcissism in terms of basic personality profiles, and explicit and implicit self-esteem.

Method: Participants completed a battery of online inventories and tasks assessing overt narcissism, covert narcissism, the Five Factor Model of personality, and explicit self-esteem and implicit self-esteem. Correlational and multiple regression analyses were used to examine the relationships between overt-covert narcissism and the constructs of interest.

Results: In both studies overt and covert narcissism had different patterns of predictors. Overt narcissism was best predicted by high Extraversion, low Agreeableness, high Openness to Experience and high Conscientiousness, while covert narcissism was best predicted by high Neuroticism and low Agreeableness. Overt narcissism was associated with high explicit self-esteem and low implicit positive self-esteem, whereas covert narcissism was associated with high implicit positive self-esteem and low explicit self-esteem.

Conclusions: The results support the view that overt and covert narcissism are distinct subtypes that are associated with different personality and self-esteem profiles, rather than two ends of a continuum or co-existing facades manifesting in different situations. The implications of the findings are discussed.

THE INFLUENCE OF THE LEVEL OF MEASUREMENT ON THE STRUCTURE OF PERSONALITY DISORDERS

Richard Bell, Martina Jovev, Andrew Chanen, Carol Hulbert, Henry J. Jackson

Structural models for the personality disorders began with the DSM trio of odd, dramatic, and anxious, but have been extended to consider classification under other models such as the five-factor model of personality, or models retaining the discrete 11 or 12 personality disorders. There has been no compelling evidence for any of these models. Data collected with the SCID-II from 342 persons with varying levels of borderline personality disorder were used to examine these competing models at the 12 levels of disorder trait scores and 93 individual symptom items. Unlike Axis-I disorders where similar structures are found at both the syndrome and individual item level, personality disorder structure is show to be affected by the level at which these disorders are measured.

APPRAISAL OF SOCIAL THREAT IN FIRST PRESENTATION BORDERLINE PERSONALITY DISORDER

Martina Jovev, Andrew Chanen, Tina Proffitt, Sue Cotton, Max Coltheart, Melissa Green, Henry Jackson

Borderline personality disorder (BPD) is characterized by persistent problems in interpersonal relationships, self-image, affect and impulsivity, with the first symptoms often appearing in adolescence. Emotional dysfunction contributes to maladaptive interactions, elicits negative responses from others and fails to elicit positive responses to generate much needed support. This pilot study aims to investigate how young people (aged 15-24) with BPD respond to faces/words conveying socially threatening information, e.g., anger, rejection. It involves comparison of 20 participants with BPD to 20 non-clinical community participants on measures of social-threat processing, neuropsychological and psychosocial function. Given the interpersonal problems and the salience of emotional factors in BPD, the importance of social emotion processes in adaptive functioning can be explored by studying aspects of social cognition. As a first study of its kind, it will lead to better understanding of the key factors underpinning development of BPD and aid promotion of early-intervention programs aimed at recovery and improving mental health. The preliminary results will be presented as part of the BPD in Youth symposium.

SCREENING FOR BORDERLINE PERSONALITY DISORDER IN OUTPATIENT YOUTH

Andrew Chanen, Martina Jovev, Danica Djaja, Emma McDougall, Hok Pan Yuen, David Rawlings, Henry Jackson

Background: Young people with borderline personality disorder (BPD) commonly seek help but often go unrecognized. Screening offers a means of identifying individuals for more detailed assessment for early intervention and for research.

Aims: This study compared the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Borderline Personality Questionnaire (BPQ), the BPD items from the International Personality Disorder Examination Screening Questionnaire and the BPD items from the Structured Clinical Interview for DSM-IV Axis II disorders (SCID-II) Personality Questionnaire.

Method: 101 outpatient youth (aged 15-25 years) completed the screening measures and were interviewed, blind to screening status, with the SCID-II BPD module. The screening measures were re-administered two weeks later to assess test-retest reliability.

Results: All four instruments performed similarly but the BPQ had the best mix of characteristics, with moderate sensitivity (0.68), the highest specificity (0.90), high negative predictive value (0.91) and moderate positive predictive value (0.65). Compared to the other three instruments, the BPQ had the highest overall diagnostic accuracy (0.85), a substantially higher kappa (0.57) with the criterion diagnosis, the highest test-retest reliability (ICC = 0.92) and the highest internal consistency (? = 0.92). The only clear difference to emerge in the Receiver Operator Curve (ROC) analysis was that the BPQ significantly outperformed the MSI (p = 0.05).

Conclusion: Screening for BPD in outpatient youth is feasible but is not a replacement for clinical diagnosis.

THE CONTRIBUTION OF AVOIDANT PERSONALITY TRAITS AND BEHAVIOURS TO THE PREDICTION OVER TIME OF SEVERITY AND LETHALITY OF SELF HARM IN PEOPLE WITH PERSONALITY DISORDER

Carol Hulbert, Rosemary Thomas

Despite widespread recognition of the prominence and risks associated with self harm in the context of borderline personality disorder (BPD), there has been remarkably little theoretically-based empirical investigation of such behaviours. In their recent review of this area, Chapman et al (2006) proposed an experiential avoidance model that emphasized the negatively reinforcing role of self harm via the reduction of unwanted painful intra personal experiences. Consistent with this model, a sample of women with BPD, long histories of unsuccessful treatment attempts and high levels of self harm were found to have prominent avoidant personality disorder (PD) traits and a reliance of avoidant coping mechanisms (Hulbert & Thomas, 2007). The present study aimed to investigate the relationship between severity and lethality of self harm and BPD/ avoidant PD comorbidity and avoidant coping in 78 participants with severe PD and high levels of self harm. For a subsample of participants (n = 41), the predictive power of avoidant traits and behaviours was assessed at two time points over a six month period. Preliminary data analysis has returned results consistent with Chapman and others model, indicating that experiential avoidance contributes to the severity and maintenance of self harm. The clinical and theoretical implications of the results of this study will be discussed.

INTERACTION BETWEEN AGE, PERSONALITY DISORDER AND COPING STRATEGIES IN PSYCHIATRIC INPATIENTS

Janine Stevenson

Introduction: It is well known that comorbid personality disorder (PD) impedes recovery from an axis I disorder. One of the ways it does so is explored in this paper, which looks at ways of coping with ilness employed by psychiatric inpatients at Westmead and Prince of Wales Hospitals.

Aims: To explore the differences in coping behaviours between psychiatric inpatients with and without comorbid PD.

Method: The COPE (a questionnaire eliciting coping strategies used) was administered to 62 consecutive admissions to adult and psychogeriatric units at Westmead and POW Hospitals. Comorbid PD was determined by the SCID II questionnaire. A battery of questionnaires was also used to determine outcome.

Results: Adult non personality disordered patients employed “active”, adaptive coping strategies (education), whereas personality disordered patients employed “passive”, maladaptive coping stategies (denial, projection).Conclusions: The ability to cope with a major psychiatric disorder is impaired in patients with comorbid PD. Recovery is delayed and hindered, relapse and recurrence more common.

ARS02 CINP SYMPOSIUM 2007

Brian Dean, Trevor Norman, Elizabeth Thomas, Elizabeth Scarr, Murray Cairns, Suresh Sundram, Angela Dean

This Symposium will address broad issues facing psychiatric researchers. All presenters are active researchers, members of the CINP and will review their own work; hence Dr Elizabeth Thomas, an Assistant Professor in the Department of Molecular Biology at The Scripps Research Institute, CA, USA will seek to translate findings from gene expression studies into hypotheses about the pathological bases of psychiatric disorders such as schizophrenia and bipolar disorder, as well as the mechanisms of action of antipsychotic drugs. Dr Elizabeth Scarr, the Ronald Phillip Griffiths Research Fellow at the University of Melbourne and the recipient of a NARSAD Young Investigators Award, will review her latest research into the neurochemical changes associated with schizophrenia and bipolar disorder. Dr Murray Cairns, a Senior Research Officer for the Schizophrenia Research Institute, will discuss how changes in endogenous non-coding RNA expression influences the pattern and timing of gene expression in schizophrenia which appear to have an important role in brain development. A/Prof Suresh Sundram, Head of Molecular Psychopharmacology at the Mental Health Research Institute and Director of the Northern Psychiatry Research Centre and Clinical Services in the Northern Area Mental Health Service will report on his research into the biological basis and treatment of psychotic disorders with a particular focus in schizophrenia. Finally, Dr Angela Dean, a NHMRC Research Fellow at the Kids in Mind Research Unit, Mater Child & Youth Mental Health Services will discuss her research program in clinical psychopharmacology in children and adolescents, with an emphasis on aggression and related behaviours.

IDENTIFYING DIFFERENCES IN GENE EXPRESSION IN POSTMROTEM CNS FROM SUBJECTS WITH SCHIZOPHRENIA: EFFECTS OF DURATION OF ILLNESS

Elizabeth Thomas

Schizophrenia is a heterogeneous psychiatric disorder that presents with variable symptomatology and unpredictable treatment response. Additionally, major diversity exists in the disease outcome after initial diagnosis. The molecular differences that occur during disease progression and the basis for its heterogeneity are not known. We hypothesize that these features of the disease are governed by distinct gene expression profiles. We have profiled genome-wide RNA expression patterns from prefrontal cortex of 64 individual subjects, 32 schizophrenic subjects with durations of illness ranging from 2 to 53 yrs, and 32 matched controls. We find that gene expression profiles change dramatically over the course of illness, with the greatest gene expression differences occuring in subjects with short-term illness. We have also investigated disease heterogeneity among schizophrenic subjects and can detect several modules of co-expressed genes corresponding to subgroups of subjects throughout disease progression. Pathways enrichment analyses reveal that each subgroup is associated with distinct pathways dysfunction. Our findings indicate that the molecular basis for schizophrenia changes with course of illness and that the distinct molecular signatures can be identified among all subjects. These molecular subgroups might represent bona fide “subtypes” of schizophrenia, each of which might be associated with different symptomatology and follow a different trajectory of outcome.

A MUSCARINIC RECEPTOR DEFICIT ENDOPHEOTYPE OF SCHIZOPHRENIA

Elizabeth Scarr

Schizophrenia is a syndrome consisting of an, as yet undefined, number of diseases. Despite this hindrance, neuropsychopharmacological, neuroimaging and postmortem studies on brain tissue all suggest that deficits in levels of muscarinic acetylcholine receptors contribute to the pathology of the disorder. We have now assessed cortical [3H]pirenzepine binding in 80 subjects with schizophrenia and 74 age sex matched control subjects. Using this unique data set we have shown, by kernel density estimation, that [3H]pirenzepine binding (CHRM1/4) separates the schizophrenia cohort into two distinct populations. Significantly, one population has a marked reduction in binding compared to controls. Neither schizophrenia population were defined by a CHRM1 genotype, have altered rates of suicide nor appear to have received different anticholinergic or antipsychotic medications. These data suggest that markedly decreased levels of cortical CHRM1/4 define a distinct endophenotype of schizophrenia. This is an extremely significant advance given the premise that defining specific endophenotypes of schizophrenia will be a pivotal step towards understanding the biochemistry underlying at least one form of the disorder.

GENE EXPRESSION, EPIGENETIC INFLUENCE AND THE DEVELOPMENT OF SCHIZOPHRENIA

Murray Cairns

During the development of the brain, regulatory factors that influence the spatial and temporal expression of genes involved in neural processes, such as cell division, migration, branching and connectivity have special significance. Subtle changes in the activity of these regulatory influences can simultaneously affect the expression of many target genes, which could potentially result in neurodevelopmental dysfunction leading to disorders such as schizophrenia. Efforts to understand gene regulation in schizophrenia have largely centered on the activity and expression of coding genes, however, in this study we turned our attention to the expression of small RNA molecules known as micro RNAs (miRNA). These non-coding RNA molecules negatively regulate the expression of target genes by specifically guiding cellular gene silencing machinery to their 3’ untranslated regions (UTR), through a mechanism known as post-transcriptional gene silencing (PTGS). For the purpose of high throughput analysis of mature miRNA expression, a custom micro array platform was established and used it to examine miRNA expression in both schizophrenia and control subjects from postmortem cortical grey matter dissected from two brain regions. This analysis revealed significant differential expression of a number of miRNAs. In most cases these changes were supported by quantitative PCR analysis. The implication of these findings are substantial, as each of the altered miRNAs are predicted to regulate many target genes with significance to the development of schizophrenia. To gather greater insight into the biological significance of these findings, we established a molecular and cellular assay system capable of exploring the consequences of these changes. This system enabled the intracellular concentrations of particular miRNAs to be manipulated, allowing the identification molecular targets through gene expression profiling.

INVESTIGATING TREATMENT RESISTANCE AND COGNITIVE DYSFUNCTION AS COMPONENT FACTORS IN SCHIZOPHRENIA

Suresh Sundram

A whole of disorder approach in investigating schizophrenia has met with limited success in elucidating its aetiology. An alternative is to disaggregate the disorder into syndromal components that would permit more focussed examination of specific putative factors. This process has been fruitful, for example, in identifying the Val108/158Met single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene as being associated with working memory and executive function, cognitive processes disturbed in schizophrenia. Using this approach we investigated if clozapine, the only antipsychotic drug effective in treatment resistant schizophrenia, was differentially interacting with neuronal signalling pathways. Our data support an interaction between clozapine and the epidermal growth factor (EGF) system in frontal cortical neuronal signalling to the MAPK/ERK (Mitogen Activated Protein Kinase/Extracellular Signal Regulated Kinase) cascade. This highlights EGF signalling as a target system in examining treatment resistant schizophrenia and clozapine response. Cognitive dysfunction, as above, is another proposed component of schizophrenia and data implicate a number of potential aetiological factors. The muscarinic M1 receptor is both decreased in relevant frontal cortical regions in schizophrenia and is involved in cognitive functioning making it a robust aetiological candidate. Our preliminary data supports an association between the synonymous A267C SNP in the CHRM1 gene and perseverative errors in the Wisconsin Card Sort Test in people with schizophrenia. Taken together, our findings support disaggregating schizophrenia into syndromal clusters that permit more tractable, focussed investigations.

RESPONDING THERAPEUTICALLY TO ACUTE AGRESSION IN CHILDREN AND ADOLESCENTS

Angela Dean

Behavioural problems in children and adolescents are the “new morbidities” in paediatrics-children in western countries are more likely to die from injuries, violence or suicide than infectious disease. Aggression is one of the most common symptoms in child and adolescent mental health clinics-approximately 50% of all young people presenting to mental health services exhibit aggressive behaviours. Aggression in childhood is associated with poor educational achievement, increased risk of psychopathology in later life, reduced employment, social isolation, crime and suicide. There is a growing body of evidence to support the effectiveness of specific psychological and pharmacological treatments for aggression in young people. This presentation will review recent research findings on a little researched area-acute management of aggressive behaviour within an inpatient environment. Since fear of violence may impair access to inpatient services for aggressive young people, effective aggression management in this context is crucial. Findings from a series of studies will be presented, which have examined patterns of aggressive behaviour in an inpatient environment, identifying high risk patients, behavioural management and pharmacological management of aggression. These findings indicate that mental health interventions can improve outcomes for aggressive young people, and will be discussed within the broader context of optimising pharmacological treatments for aggressive young people.

ARS03 OPTIMISING TMS TREATMENT IN DEPRESSION

Paul Fitzgerald, Colleen Loo, Gregory Price, Joseph Lee

Introduction: Transcranial magnetic stimulation (TMS) is a non-invasive means of stimulating nerve cells in superficial areas of the brain, utilising a pulsing magnetic field generated by a coil held close to the scalp. TMS has been shown to safely influence mood, motor and cognitive functioning, with the site of the stimulation, its frequency and intensity determining its effects. Over the last 12 years, repetitive TMS (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) has been actively investigated as an alternative intervention for patients with treatment resistant depression (TRD). Most trials have suggested that active rTMS has greater antidepressant efficacy than placebo, but concerns regarding response rates and clinical relevance of results continue to be expressed.

Aim: Enhance response to rTMS and improve selection of patients likely to respond to treatment.

Method: Novel stimulation approaches are currently being investigated in order to enhance the clinical efficacy of the treatment. These include greater treatment frequency, right sided or bilateral stimulation, neuronavigational techniques to target the treatment site, priming of the brain to respond to rTMS with high frequency pulses, variation in pulse waveform, and utilising EEG as an interactive part of the rTMS treatment and in monitoring its effects. A number of these approaches have been assessed and data from these studies will be reviewed in the symposium.

Results and conclusions: This research suggests that it appears possible to enhance rTMS treatment methods in ways that will make clinical utilization of the technique possible.

ENHANCING RTMS WITH NOVEL UNILATERAL AND BILATERAL STIMULATION METHODS

Paul B. Fitzgerald

Introduction: Recently studies appear to have confirmed that standard left-sided repetitive Transcranial Magnetic Stimulation (rTMS) has antidepressant efficacy but that the degree of clinical effect may be somewhat limited. Promising data is emerging suggesting that other stimulation approaches, including right unilateral, sequential bilateral and priming stimulation, may have equal or potentially greater effects. Further, more accurate targeting of treatment site utilising recently developed neuro-navigational techniques may enhance treatment efficacy.

Aims: To assess capacity to enhance the clinical efficacy of rTMS through evaluation of neuro-navigational techniques for localising the dorsolateral prefrontal cortex, the use of high frequency pulses to prime the brain for responding to right side low frequency stimulation, and the efficacy of sequential bilateral stimulation.

Methods: Results of recent investigations of these novel rTMS delivery approaches, including three double-blind, randomised controlled studies conducted at the Alfred Psychiatry Research Centre in Melbourne, will be reviewed.

Results: The use of neuro-navigational methods to better localize dorsolateral pre frontal cortex appears to enhance response to rTMS treatment in depression. Low intensity high-frequency priming stimulation appears to enhance the response to low-frequency right-sided rTMS. Sequentially combined high frequency left-side and low frequency right-side rTMS has substantial treatment efficacy in patients with treatment resistant depression.

Conclusions: Further rTMS research should actively investigate novel stimulation approaches before high frequency left-sided stimulation is accepted as the standard approach in order to optimise the delivery of rTMS in the treatment of depression.

OPTIMISING TRANSCRANIAL MAGNETIC STIMULATION (TMS) TREATMENT FOR DEPRESSION

Colleen Loo

Introduction: Numerous sham-controlled and open label studies have shown that repetitive TMS (rTMS) has antidepressant efficacy, i.e. is statistically superior to placebo. However, in some studies, the magnitude of the clinical improvement and number of responders has been small. Various strategies to enhance the antidepressant efficacy of rTMS have been explored and some of these will be discussed.

Aims: The following approaches to increase the effect of rTMS will be discussed: variations in stimulus parameters (intensity, frequency), bilateral stimulation, multiple daily treatment sessions, selection of pulse waveform.

Methods: Relevant studies in the literature will be reviewed, including results of two sham-controlled trials (bilateral rTMS, twice daily rTMS) and a study of the effects of stimulus waveform conducted at the University of NSW (Sydney).

Results: Simultaneous bilateral prefrontal rTMS was not effective. Approximately one-third of patients responded after a two-week course of twice-daily rTMS, with further response on continued treatment. Monophasic pulse rTMS was more effective in creating lasting changes in cortical excitability than biphasic pulse rTMS.

Conclusions: Multiple sessions of rTMS daily provided an effective treatment and may be better than once daily treatment. rTMS with a monophasic waveform may be more effective in treating depression. Two weeks of rTMS is insufficient for maximal clinical response.

THE UTILISATION OF EEG/QEEG TO OPTIMISE THE EFFICACY OF RTMS IN THE TREATMENT OF DEPRESSION

Joseph Lee, Gregory Price

Background: EEG monitoring during rTMS treatment is an important safety precaution, but also provides ongoing physiological detail that may be integrated into the clinical treatment. The technique of linking stimuli to the background EEG was developed in ERP field, and we report the application of this process to rTMS stimuli. In addition, EEG topographic information has previously been used as a predictor of the degree of treatment response to medication. We likewise report how the EEG varies with rTMS and explore how these changes may be useful as an adjunct assessment of efficacy.

Method: A standard treatment of 5 seconds at 10Hz was compared with interactive treatment that applies TMS stimuli when a selected pattern is detected in the background EEG. The methods are compared in terms of clinical ratings (HamD21, BDI) after a four-week treatment. Relative spectral power in the alpha and low beta bands, and coherence between left and right prefrontal cortex were compared with clinical assessments.

Results: There was a combined improvement, regardless of treatment type, in HamD21 and in BDI scores, although no adjustment was made for placebo effects. The improvement in HamD21 score with interactive treatment was more than for standard treatment, as well as in BDI.

Conclusion: The use of EEG in rTMS stimulus delivery may lead to greater improvement in clinical scores than the standard treatment. Additionally, the use of EEG as an indicator of the immediate physiological state has the potential to provide a short-term correlate of the clinical state.

ARS04 DRUGS OF ABUSE AND PSYCHIATRIC ILLNESS: LESSONS FROM ANIMAL MODELS

Maarten van den Buuse, Tim Karl, Andrew J. Lawrence, Jennifer L. Cornish, Daryl Eyles, Anthony J. Hannan

Illicit drug use is a major problem in society today. The cost of drug use to the community includes direct components in terms of expenditure for law enforcement, medical treatments and welfare, but there is also a very large indirect cost in terms of emotional suffering and loss of quality of life which is difficult to quantitate. In addition to direct mortality and morbidity, many illicit drugs are risk factors for the development of psychiatric illness, such as psychosis and anxiety disorders, and cognitive deficits. More basic research is clearly needed to further our understanding of the effects of drugs of abuse in humans and studies on animal models form an important part of this research. This symposium brings together six experts in this field.

Dr Tim Karl will address effects of cannabis-like drugs and amphetamine in a mouse model with altered function of neuregulin-1, which has been identified as a susceptibility gene in schizophrenia. Prof. Andrew Lawrence will address long-term behavioural consequences of amphetamines when administered in adolescence. Dr. Jennifer Cornish will address the long-term effect of the administration of'ecstasy', methamphetamine and alcohol on anxiety and social interaction and will describe exacerbated behavioural changes after drug combinations. A/Prof. Maarten van den Buuse will show how serotonin in the dorsal hippocampus plays a modulatory role in the effects of several drugs of abuse, such as phencyclidine ('Angel Dust'), ketamine (‘special K'), metamphetamine ('Ice'), amphetamine (‘speed') and cocaine. Dr. Daryl Eyles will review how environmental changes in the early stages of development may alter responses to drugs in adulthood. Finally, Dr. Antony Hannan will show how changes in the immediate environment alter behaviour and may reverse deficits induced by genetic factors. This'environmental enrichment' may also be useful in chronic drug-induced behavioural changes.

Animal model studies may lead to a better understanding of the neurobiology of drugs of abuse in humans and the resulting possible development of psychiatric illness. The research in animal models could result in new clinical approaches and influence policy decisions.

DRUGS OF ABUSE IN A GENETIC MOUSE MODEL FOR TRANSMEMBRANE DOMAIN NEUREGULIN 1

Tim Karl, A. A. Boucher, L. Duffy, J. Micheau, P. R. Schofield, J. C. Arnold

Introduction and aim: Abuse of psychoactive drugs may precipitate schizophrenia in individuals with a genetic vulnerability to the disease. As neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia, we were interested in the neurobehavioural effects of amphetamine (AMP) and the psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), on heterozygous transmembrane domain Nrg1 mutant mice (Nrg1 HET).

Method: Nrg1 HET and wild type-like (WT) littermates were treated acutely with either amphetamine (0 or 5 mg/kg) or THC (0, 5 or 10 mg/kg) before being tested for locomotion, anxiety, prepulse inhibition (PPI) and working memory. C-Fos expression analysis determined neuronal correlates for the behavioural effects of THC.

Results: Acute AMP treatment induced similar locomotor hyperactivity and disruptions of PPI as well as working memory performance in mutant and WT mice. However, Nrg1 HETs were more sensitive to the locomotor suppressant actions of THC and expressed a greater THC-induced enhancement in%PPI compared to WT mice. Mutants were also more susceptible to the anxiogenic effects of THC. Consistent with Nrg1 hypomorphs exhibiting a schizophrenia-related phenotype, these mice expressed greater basal c-Fos levels in the shell of the nucleus accumbens and the ventrolateral septum (LSV). THC selectively increased c-Fos expression in the LSV, the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus of mutant mice.

Conclusion: These data suggest an interaction between Nrg1 and THC but not AMP in the CNS. It appears that variation in Nrg1 alters the sensitivity to the behavioural effects of cannabinoids but not amphetamine.

BEHAVIOURAL CONSEQUENCES OF AMPHETAMINE ADMINISTRATION IN JUVENILE RATS

Andrew J. Lawrence, T. Featherby

Introduction and aim: Adolescence is a critical period of vulnerability in the context of addiction. The present study aimed to characterise whether amphetamine exposure in juvenile rats results in long term consequences on affective and/or cognitive behavioural patterns into adulthood.

Methods: Male Sprague-Dawley rats (3-4 weeks) were treated daily with saline (1ml/kg, i.p.) or d amphetamine sulfate (10mg/kg, i.p.) for ten days, assessed through a range of behavioural tests, and compared to an adult cohort. To assess drug-seeking in adult rats previously administered with amphetamine during periadolescence, rats were treated as above and 4 weeks later implanted with jugular catheters and trained to self administer cocaine (0.3mg/kg/infusion, I.V).

Results: Treatment with amphetamine in adolescent rats revealed a deficit in time spent in the novel arm on a 6 hour retrial in a Y-maze (p < 0.01). The amphetamine pre-treatment group took significantly less days to achieve criterion for maintenance of cocaine self-administration, than did controls (p < 0.05). No significant difference was apparent in motivation to self-administer cocaine. Following 3 weeks of abstinence, both pre-treatment groups reinstated significantly above previously established response levels. The amphetamine pre-treated rats displayed a greater persistence of cocaine-seeking behaviour under reinstatement.

Conclusion: Colectively, these data suggest juvenile administration of amphetamine can cause disruptions in response to novelty. These cognitive deficits appear unique to rats treated during adolescence and apparently do not occur in adulthood. Additionally, persistent sensitization to amphetamine administered during the juvenile stage of development could contribute to a prediposition to relapse behaviour.

ECSTASY, ‘ICE’ AND POLYDRUG USE: LONG-TERM BEHAVIOURAL EFFECTS IN RATS

J. L. Cornish, K. J. Clemens, N. Kraushaar, G. E. Hunt, I. S. McGregor

Introduction: The widespread use of ±3,4 methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) and methamphetamine (‘Ice’) is a growing concern in our society. Recent reports have shown that approximately 20% of 20-29 year olds have tried either drug (National Drug Strategy Household Survey, 2004), making Australia one of the top two countries for MDMA and methamphetamine use (United Nations Report, 2003). Furthermore, many Ecstasy pills sold in Australia contain a high percentage of methamphetamine (Australian Illicit Drug Report, 2001-2002). While the prevalence to take these drugs is on the increase, the neurobiology of these drugs and the psychiatric illness resulting from their repeated use is not well understood.

Aim: Our aim was to determine the long-term behavioural effects of MDMA and methamphetamine administration.

Methods: By using animal models of drug administration, we measured the long-term effect of the administration of MDMA or methamphetamine on anxiety levels in the rat. The long-term behavioural effects of combined MDMA and methamphetamine or methamphetamine and alcohol use were also measured.

Results: Several weeks after drug administration, MDMA use resulted in increased general anxiety and decreased social interaction in rats. Methamphetamine administration increased anxiety levels which where exacerbated by co-administration with either MDMA or alcohol.

Conclusions: The repeated use of MDMA, methamphetamine or drug combinations produces long-term behavioural changes, reflected as an increase in anxiety in our animal models. By using animal models we may better understand the neurobiology of substituted amphetamine use and the resulting development of psychiatric illness. Support: NH&MRC and Macquarie and Sydney University R&D.

MODULATION OF THE ACTION OF PSYCHOSTIMULANT DRUGS OF ABUSE BY SEROTONIN IN THE HIPPOCAMPUS: IMPLICATIONS FOR PSYCHOSIS

Maarten Van den Buuse, W. Adams

Introduction: Both serotonin (5-HT) and the hippocampal formation are implicated in the pathophysiology of psychiatric disorders. The hippocampus is rich in serotonergic innervation and interacts with the mesolimbic dopamine system, the locus of action of many psychostimulant and hallucinogenic drugs of abuse.

Aim: We investigated the effect of selective serotonin depletion in the dorsal and ventral hippocampus of rats on locomotor hyperactivity responses to phencyclidine (PCP), ketamine, amphetamine, methamphetamine, MDMA and cocaine.

Method: Isoflurane-anaesthetized male Sprague-Dawley rats were stereotaxically microinjected with the serotonin-specific neurotoxin, 5,7-DHT, into either the dorsal or ventral hippocampus (DH and VH, respectively). Two weeks later, locomotor activity was measured for 90 minutes following psychostimulant treatment.

Results: DH serotonin depletion markedly enhanced PCP- (0.5, 2.5 mg/kg) and ketamine-induced (6.25, 12.5, 25 mg/kg) hyperlocomotion. In contrast, it caused a slight reduction of methamphetamine effects (1, 3 mg/kg) while responses to amphetamine and MDMA were unchanged. The effect of DH serotonin depletion on cocaine-induced hyperlocomotion was complex and included both reduced (at 5 mg/kg) and enhanced (at 20 mg/kg) components. VH serotonin depletion had no effect on any of the psychostimulant responses.

Conclusions: These results suggest that serotonin in the DH differentially modulates the expression of psychostimulant and hallucinogenic drug-induced hyperlocomotion, depending on the pharmacology of the drug. Since psychostimulant-induced locomotor hyperactivity in rats is used as a model of aspects of psychosis, these findings may further our understanding of serotonergic/hippocampal mechanisms involved in the development of psychotic disorders as well as drug abuse.

THE DEVELOPMENTAL ENVIRONMENT AND DOPAMINE SIGNALLING IN THE OFFSPRING

Darryl Eyles, T. Burne, J. McGrath

No model in animals can ever hope to replicate the complexity of the course of schizophrenia within patients. Traditionally pharmacological animal models using agents such as amphetamine were employed for therapeutic drug development. The use of dopaminergic agents is based on the aetiological assumption that dopamine signalling is abnormal in this disorder. These models however are guilty of their overly simplistic dopamine-in/dopamine-out rationale. Developmental models of schizophrenia display better construct validity for this disorder than the more traditional pharmacological models given the widely-held belief that schizophrenia is a disease of abnormal brain development. They have been essential in clarifying the biological plausibility of epidemiological risk factors and refining candidacy. Although the neurochemistry of this disorder in patients is unknown and likely to be complex, abnormalities in dopamine signalling remain a corner stone for both disease treatment and aetiology.

The speaker will describe findings from a number of developmental exposures that amongst other outcomes all appear to produce disturbances in dopamine signalling in the adult. Whilst some of these models (bilateral hippocampal lesion and disrupted neurogenesis) produce an impressive array of cognitive, behavioural and molecular brain changes they are of little aetiological relevance to the disorder. Now more biologically plausible models (prenatal infection, prenatal stress, prenatal anoxia and low maternal vitamin D) are emerging that not only produce many of these same abnormalities in adult animals but converge with regards to abnormal dopamine signalling in adult offspring.

GENE-ENVIRONMENT INTERACTIONS MEDIATING EXPERIENCE-DEPENDENT PLASTICITY IN PSYCHIATRIC DISORDERS

Anthony J. Hannan, C. E. McOmish, E. Burrows, L. Gray, M. Howard, Elizabeth Scarr, Brian Dean, Maarten Van den Buuse

Introduction: Not only cellular and molecular mediators are involved in the pathogenesis of schizophrenia, but also environmental modulators and associated gene-environment interactions. Phospholipase C-beta1 (PLC-beta1) is a rate limiting enzyme implicated in postnatal cortical development and neuronal plasticity. PLC-beta1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia.

Methods: We have behaviourally phenotyped PLC-beta1 knockout mice, performed environmental and drug manipulations, and analysed specific neurotransmitter receptors using radioligand autoradiography.

Results: PLC-beta1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Environmental enrichment provides increased sensory, cognitive and motor stimulation. The locomotor hyperactivity and sensorimotor gating deficits in PLC-beta1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore clozapine but not haloperidol (atypical and typical antipsychotics respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor expression in the neocortex and hippocampus.

Conclusions: Thus we have described a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions. These findings also have implications for understanding molecular mediators and environmental modulators in other disorders of brain development.

ARS05 NHMRC ENABLING GRANTS – TRANSFORMING THE PSYCHIATRIC RESEARCH CAPABILITY WITHIN AUSTRALIA

Brian Dean, Catriona McLean, Vaughan Carr, Carmel Loughland, Doebrich Markus, Paul Tooney

Two NHMRC Enabling Grants have been awarded that will transform the landscape within Australia in which psychiatry research will be carried out. One of these enabling grants, awarded in the first round in 2004, was to support and expand the operation of the National Network of Brain Banks. Part of the mission of the Network is to collect CNS tissue postmortem from subjects with psychiatric disorders and to make this tissue available for research into the pathology of these disorders. The second grant, awarded in 2006, was to support the activity of the Australian Schizophrenia Research Bank with its mission to linked clinical, cognitive, neuroanatomical and genetic data on 1000 subjects with schizophrenia and there first degree relatives. Once established DNA, clinical and neuroimaging data and will be available to support the identification of candidate genes schizophrenia. These two programs are clearly going to significantly advance the capability of researchers to study the underlying pathology of schizophrenia. In the Symposium speakers will outline the structure and operation of the National Network of Brain Banks and the Australian Schizophrenia Research Bank and will highlight areas of research that these facilitates will support.

THE AUSTRALIAN BRAIN BANK NETWORK

Catriona McLean

The Australian Brain Bank Network (ABBN) represents a national platform which encompasses brain collections is New South Wales, Queensland, South Australia, Victoria and Western Australia. Through this collaboration, the ABBN continues to provide Australian and international researchers with clinically and neuropathologically well-characterised human brain tissue on which they can conduct research. The ABBN has over 1,500 cases available for research, with 219 new brain and/or brain and spinal cord donations in the last twelve months. The donations included such disorders as Alzheimer's disease, Depression, Frontotemporal dementia, Huntington's disease, Motor neuron disease, Multiple sclerosis, Parkinson's disease, schizophrenia, alcohol related disorders, control ‘normal’ cases and other neurological and psychiatric disorders. During 2006-2007 as a result of the research outcomes utilising ABBN tissue, 67 Australian and international journal article and conference publication were published, 72 oral and 68 poster presentations were presented at various Australian and international neuroscience conferences.

THE USE OF HIGH THROUGHPUT SCREENING TECHNOLOGIES AND HUMAN POSTMORTEM CNS TISSUE TO UNDERSTAND THE PATHOLOGY OF PSYCHIATRIC DISEASES

Brian Dean

Combining the use of postmortem CNS and high throughput screening technologies is impacting on our understanding of the pathological processes that underlie schizophrenia. Initially, the use of differential display technologies that allowed a comparison of levels of mRNA across disease cohorts began to suggest unexpected changes in biochemical pathways previously not thought to be involved in the pathology of psychiatric diseases. Subsequently, many microarray studies have confirmed and expanded the finds on gene expression to suggest a role for energy and metabolism abnormalities, the synapse, signal transduction and transcription regulatory factors in the pathology of schizophrenia. Now proteomic studies are begin to unravel changes in the CNS of subjects with psychiatric disorders by examining levels of thousands of proteins in postmortem CNS from subjects with those disorders. These data will be reviewed as an example as to how the availability of suitable postmortem CNS tissue can facilitate understanding the causes of psychiatric diseases.

AN OVERVIEW OF THE AUSTRALIAN SCHIZOPHRENIA RESEARCH BANK: LINKING BRAIN FUNCTION AND STRUCTURE WITH GENETICS IN A LARGE SAMPLE OF SCHIZOPHRENIA CASES AND CONTROLS

Vaughan Carr, U. Schall, P. Michie, R. Scott, A. Jablenski, B. Mowry, S. Catts, F. Henskens, C. Pantelis

The Australian Schizophrenia Research Bank (ASRB) is a multi-site collaboration of scientists across four Australian States supported principally by a NH&MRC Enabling Grant and a grant from the Pratt Foundation to establish a national database of 2,000 schizophrenia cases and 2,000 healthy matched controls for the purpose of identifying key genetic risk factors for schizophrenia and their relationships to clinical phenomena, neuropsychological function and brain structure. The means for establishing the network that underpins the ASRB are described together with an account of the organisational structure and systems of governance that have been established. Since the database and genetics samples are to be made available to scientists wishing to test scientific hypotheses using the resources of the ASRB, bioinformatics systems have had to be developed and methods for accessing data and samples established. Recruitment has commenced and progress towards achieving the targets of the ASRB will be presented. In addition, an outline of some of the problems encountered in initiating and maintaining this facility will be discussed as well as some of the solutions identified in meeting the formidable challenges presented by such a large scale muli-site collaboration of this nature. The ASRB promises to be an important national resource for helping to elucidate the genetics of schizophrenia and potential schizophrenia endophenotypes.

THE NATIONAL RECRUITMENT AND ASSESSMENT OF PEOPLE WITH SCHIZOPHRENIA: THE ASRB EXPERIENCE

Carmel Loughland, V. Carr, P. Michie, H. Stain, J. Badcock, A. Jablenski, C. D. Draganic, T. J. Lewin, U. Schall, R. Scott, B. Mowry, S. Catts, F. Henskens, C. Pantelis

Introduction: This paper reports on the development of a national recruitment and clinical assessment strategy by the Australian Schizophrenia Research Bank (ASRB). The aim of this strategy is to ensure a representative sample of people with schizophrenia and to collect comprehensive, cross-referenced clinical, cognitive, genetic, brain imaging and linked data.

Method: The ASRB recruitment targets are 2000 people with schizophrenia and 2000 healthy, non-psychiatric controls. Using a three pronged approach, schizophrenia subjects will be recruited from various settings. To recruit people in the community, a successful TV and radio community service advertisement campaign was developed and a national 1800 telephone number established. The assessment battery includes the Diagnostic Interview for Psychosis (DIP: Castle et al, 2005), Neurological Evaluation Scale (Buchanan & Heinrichs, 1989), Wechsler Test of Adult Reading (WTAR-Wechsler, 2001), Wechsler Abbreviated Scale of Intelligence (WASI-Wechsler, 1999), Repeatable Battery for Assessment of Neuropsychological Status (RBANS – Randolph et al, 1998), Letter Number Sequencing (Wechsler, 1997), Controlled Oral Word Association Test (Spreen & Benton, 1969), Global Assessment of Functioning (GAF-American Psychiatric Association, 2000), and the Schizotypal Personality Questionnaire (Raine et al., 1991). In addition, a blood sample and structural MRI scan are collected.

Results: Over 2000 people have registered with the ASRB using the 1800 number. A proportion of these people have been assessed using the ASRB assessment battery.

Conclusion: The ASRB is the first Australian research facility to develop a national recruitment and clinical assessment strategy in schizophrenia.

A NATIONAL ‘VIRTUAL BRAIN BANK’ FOR MORPHOMETRIC PHENOTYPING OF SCHIZOPHRENIA

Markus Doebrich, P. Rasser, T. Budd, M. Seal, G. De Zubicaray, K. McMahon, U. Schall

This paper reports on the development of a national ‘Virtual Brain Bank’ as part of the Australian Schizophrenia Research Bank (ASRB). The aim is to collect high-resolution magnetic resonance (MRI) data of the brain for morphometric phenotyping of schizophrenia. The ASRB recruitment targets 2,000 people with schizophrenia and 2,000 healthy, non-psychiatric control subjects. A substantial proportion of these recruits will undergo MPRAGE and DTI scanning on 1.5 Tesla Siemens Avanto MRI scanners in Brisbane, Melbourne, Newcastle, Perth and Sydney. Various quality control measures have been implemented to allow for multi-site data collection and analyses, which will include voxel-based morphometry, gyral pattern averaging and tractography. A central data depository has been developed and established in Newcastle. MPRAGE sequences have been implemented and tested at all collection sites. DTI sequences will be phased in by December 2007. The national ‘Virtual Brain Bank’ will allow a detailed analysis of the morphometric characteristics of brains from a large representative sample of people with schizophrenia in order to comprehensively study associations of morphometric brain data with clinical, cognitive, and genetic data.

THE AUSTRALIAN SCHIZOPHRENIA RESEARCH BANK: A BIOLOGICAL REPOSITORY FOR STUDIES OF THE GENETIC BASIS OF SCHIZOPHRENIA

Paul Tooney, R. Scott, A. Jablenski, B. Mowry, C. Pantelis, C. Loughland, V. Carr

Whilst it is widely accepted that genetic factors play an important role in the aetiology of schizophrenia, the exact nature of the genetic component still remains to be determined. Studies of genetically complex disorders like schizophrenia require large sample sizes, especially when considering the feasibility of undertaking genome-wide single nucleotide polymorphism (SNP) association studies. The Australian Schizophrenia Research Bank (ASRB) was officially launched in May 2007 with the aim of recruiting 2000 participants with schizophrenia and 2000 controls across Australia. In addition to clinical and cognitive assessments and structural MRI scans, each participant will be asked to provide a blood sample for genetic analysis. DNA, RNA, plasma, serum and immortalised lymphocytes will be stored from each participant. The ASRB samples will be provided to researchers for ethically approved projects investigating the genetics and biomarkers for schizophrenia. The ASRB will provide researchers with the opportunity to further characterize and define the genetic basis of schizophrenia by supporting a significant clinically well characterised biological repository for studies into the genetics of this disease.