Oral Presentations

RELATIONSHIP BETWEEN REDUCED ERYTHROCYTE MEMBRANE FATTY ACIDS AND TRANSITION TO PSYCHOSIS IN ULTRA-HIGH RISK INDIVIDUALS

G.P. Amminger^1,2 , M.R. Schäfer¹, K. Papageorgiou¹, M. Kornsteiner³, P.D. McGorry², G.E. Berger^2,4

¹ Department of Child- and Adolescent Psychiatry, Medical University Vienna

² ORYGEN Research Centre (incorporating EPPIC), University of Melbourne, Australia

³ Department of Nutritional Sciences, University of Vienna, Austria

⁴ University Hospital Basel, Department of Psychiatry, Basel, Switzerland

Introduction: Reduced erythrocyte membrane fatty acids, particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), and an elevated omega-6:omega-3 ratio have been described in different stages of schizophrenia including drug-naive first episode samples. No study has yet examined (1) the erythrocyte fatty acid composition in the prodromal phase of psychosis, or (2) the relationship between fatty acids and transition to psychosis in ultra-high risk individuals.

Methods: The study sample comprised 81 UHR individuals (according to criteria of Yung et al., 1998) (mean age = 16.4, SD = 2.1 years) who participated in a RCT of omega-3 fatty acids vs. placebo (ClinicalTrials.gov number, NCT00396643). Baseline measures included the PANSS, the MADRS, and the GAF. Erythrocyte membrane fatty acids were determined at baseline using gas chromatography. The primary outcome of interest, conversion to psychosis was operationally defined using cut-off points on the PANSS (4 or more on hallucinations, 4 or more on delusions and 5 or more on conceptual disorganisation), the frequency of symptoms (at least several times a week), and their duration (more than 1 week). Correlational analysis was used to detect associations between fatty acid levels and psychiatric measures at baseline. Cox regression analysis was used to investigate the predictive validity of baseline fatty acid levels for psychosis status at 12 month follow-up.

Results: Correlational analysis revealed statistically significant associations between both low DHA (p < 0.05) and high n-6:n-3 ration (p < 0.01) with more severe negative symptoms. In addition, low trans-vaccenic acid was significantly associated with more severe PANSS global symptoms. 13 of 81 (16.0%) individuals converted to psychosis within the follow-up period. Cox regression analysis controlling for effects of treatment revealed low baseline trans-vaccenic acid as a significant predictor of transition to psychosis among investigated fatty acids in UHR individuals (p < 0.05), while both DHA and AA did not predict transition.

Conclusions: The findings suggest that abnormal membrane phospholipid metabolism may contribute to the onset of psychosis in UHR individuals.

DOES THE N170 REFLECT REDUCED STRUCTURAL ENCODING OF FACES IN SCHIZOTYPAL PERSONALITY?

Rachel Batty¹ , Susan Rossell¹, Andrew Francis²

¹ Alfred Psychiatry Research Centre, The Alfred Hospital, Monash University, Melbourne, Australia

² RMIT University, Bundoora, Australia

Background: It has been argued that deficits in facial affect discrimination in schizophrenia may reflect a more general underlying visual processing deficit, that is, inadequate configural processing.

Aims: Configural processing was assessed behaviourally using two stimuli types. Additionally, we recorded the N170 ERP component (the N170 is considered to reflect the process of encoding face information to form a structural representation). The aim was to examine whether configural processing was different in persons with high schizotypy.

Method: Two stimulus types were presented in both an upright and inverted orientation; Mooney stimuli which offer configural (holistic) information, and photographic stimuli which offer both featural and configural, these were compared with non-face stimuli. Participants were required to make face or non-face judgements. Healthy individuals (N = 28), who were assigned to either high or low schizotypy extremes defined by the Oxford Liverpool Inventory of Feelings and Experiences, were tested (O:LIFE; Mason, Claridge & Jackson, 1995).

Results: Accuracy and reaction times did not differentiate the schizotypy groups, however high schizotypy showed significantly reduced N170 amplitudes to both face orientations, relative to the low group.

Conclusion: These data suggest that the proposed generalised face processing deficiency in schizophrenia may be attributable to deficits at the structural encoding stage. Furthermore, this deficiency does not seem to be the result of inhibited featural or configural information processing in particular.

GLUTATHIONE AND OXIDATIVE STRESS; NEW MECHANISMS OF DISEASE AND NEW THERAPEUTIC OPPORTUNITIES.

Michael Berk

University of Melbourne

Introduction: There is evidence of dysregultation of oxidative defences in schizophrenia. Glutathione is the brains principal antioxidant, and levels of glutathione are decreased in schizophrenia. Polymorphisms of genes in the synthesis of glutathione are risk factors for schizophrenia. N-acetyl cysteine (NAC) is a tolerable, available safe, orally bioavailable precursor of glutathione.

Methods: This is a randomised, double-blind, multicentre, placebo-controlled study, of 140 people with schizophrenia who were treated with NAC (1g BID), as an add-on to standard antipsychotic medication. The trial duration was 24 weeks, followed by a 4 week washout. Outcomes included the Clinical Global Impression (CGI) Severity and Improvement scales, the Positive and Negative Symptoms Scale (PANSS) and measures of general functioning and extrapyramidal side effects rating scores.

Results: NAC treatment led to a significant improvement over the study period in the CGI-Severity and CGI-Improvement scores compared to placebo treatment. NAC treatment was associated with a significantly greater improvement compared to placebo treatment on PANSS Negative, General and Total scores at endpoint. There was in addition a significant improvement in akathisia. Effect sizes at endpoint were in the moderate range.

Conclusion: The results of this study suggest that NAC is a novel and effective augmentation strategy for schizophrenia, and suggests that oxidative biology and glutathione deficiency play a role in the pathophysiology of schizophrenia.

OLFACTORY IDENTIFICATION DEFICITS REFLECT STABLE ORBITOFRONTAL NEURAL COMPROMISE FOLLOWING A FIRST EPISODE OF PSYCHOSIS: FURTHER RESULTS FROM THE EPPIC-MEDIUM TERM FOLLOW-UP STUDY

Warrick Brewer, Kelly, B., Stephen Wood, Lisa Henry, Michael Harris, Christos Pantelis, Bowden, S. Patrick McGorry

Objective: Previous investigation reveals stable olfactory identification deficits (OID) at 6 months following first onset of psychosis (Brewer et al, [2001]), and more recently, in an ultra-high-risk group that later developed a schizophrenia spectrum disorder (Brewer et al, [2003]). OID may implicate more generalised difficulties in affect regulation, and may be associated with developmental arrest in prefrontal brain regions. As a potential premorbid marker of transition to schizophrenia, we have been exploring the utility of OID in mapping functional compromise of limbic-prefrontal pathways, particularly in orbitofrontal regions, particularly as this may be important for tracking the relative integrity of circuitry implicated in the course of psychosis following early onset.

Method: In this study we sought to investigate longitudinal change in olfactory identification in first episode psychosis patients using the University of Pennsylvania Smell Identification Test (UPSIT).

Results: Data from 22 patients and 9 controls (mean time between assessments = 83.4 months, range = 61.4–97.4 months) showed no change in performance over time.

Conclusions: These data support our previous longitudinal study and suggest that there is no change in OFC mediated OID with continued psychotic illness. Interaction between OFC and other neural networks implicated in the degenerative aspects of schizophrenia requires further exploration. The findings are discussed in the context of utilising olfactory models of function to track emerging onset of psychopathology as stable OID may place patients at risk for ‘growing into deficit’ as neurodevelopmental arrest becomes more apparent with age.

ADOLESCENT INTERPRETATION OF SELF-REPORTED PSYCHOTIC-LIKE EXPERIENCES (PLEs)

Joe Buckby^1,2, Margaret Ross^1,2, Jaymee Ryan^1,2, Barnaby Nelson^1,2, Gennady Baksheev^1,2, Alison Yung^1,2

¹ ORYGEN Youth Health, Melbourne, Australia

² Department of Psychiatry, University of Melbourne, Australia

Background: The use of questionnaires in psychiatric research allows for a cost-effective way to acquire large samples. Much of the research into subclinical expressions of psychotic symptoms, or psychotic-like experiences (PLEs) has been done with self-report instruments such as the Community Assessment of Psychic Experiences (CAPE). However, despite having good psychometric properties, these instruments evidence high false positive rates with respect to the prediction of psychosis. Additionally, there is only moderate agreement between interview-rated and self-reported PLEs. It is therefore important to determine the extent to which questionnaire-elicited PLEs accurately reflect the constructs we seek to measure.

Methods: 112 young people (Mean age = 18.6 years) completed a diagnostic interview plus questionnaire battery. In addition, participants completed a semi-structured interview that assessed their interpretation of the 20 positive symptom items of the CAPE.

Results: On average, participants only correctly interpreted two thirds of CAPE items (65.5%). There was a significant range however, with some items showing good interpretation (eg. ‘believing in witchcraft’, 99.1%) while others were misinterpreted by the majority of the sample (eg. ‘people are not what they seem to be’, 26.8%). There were no significant demographic predictors of the proportion of items correctly interpreted.

Discussion: Adolescents do not interpret self-reported PLEs as well as needed by researchers. There is a clear need to develop measures that are specifically targeted to young people and which will be well interpreted in order to gain a more thorough understanding of the prevalence and sequelae of PLEs.

ACUTE ADMISSIONS BY PATIENTS WITH SCHIZOPHRENIA: RISK AND RECOVERY PROFILES, ADVERSE INCIDENTS, AND RE-ADMISSION

Vaughan Carr^1,2 , Terry Lewin^1,2, Ketrina Sly¹, Agatha Conrad¹, Srinivasan Tirupati^1,2, Martin Cohen^1,2, Philip Ward^2,3, Tim Coombs⁴

¹ Centre for Brain and Mental Health Research, University of Newcastle and Hunter New England Mental Health, Newcastle, Australia

² Schizophrenia Research Institute, Sydney, Australia

³ School of Psychiatry, University of NSW, Australia

⁴ Australian Mental Health Outcomes and Classification Network, NSW Institute of Psychiatry, Parramatta, Australia

Objective: This paper reports findings from a multi-centre service evaluation (11 acute psychiatric units), with a specific focus on the characteristics and recovery trajectories of schizophrenia patients.

Method: Previously, we have reported on the pressures faced by these units and adverse incident rates (Carr et al., [2008]), but not patient-level risk, recovery and re-admission profiles. Comparisons are reported between the first 1,000 schizophrenia patients (subgroup S) and those admitted during the same period with either bipolar (subgroup B, N = 335), or depression or adjustment disorder (subgroup C, N = 879).

Results: Schizophrenia patients were younger and more likely to be unmarried males. Reportable aggression rates were similar, but there were differences in minor aggression (S,B > C) and absconding (B > C), with a gradient in the overall likelihood of adverse incidents (B:51.1% > S:36.7% > C:17.4%). Despite length of stay variations (S:19.52, B:18.97, C:10.64 days), there were comparable shift-level profiles with respect to PRN medications, staff contacts, and therapy engagement, although the schizophrenia patients had fewer visitors. Observed mental state was consistent with expectations (withdrawal: S,C > B; disinhibition: B > S>C; psychosis: S,B > C; cognitive impairment: S > C). There were also differences in perceived risk, both on admission (suicide: S,B < C; self-harm: S,B < C; harm to others: S,B > C; absconding: S,B > C) and at discharge (self-harm: S,B < C; aggression: S > B,C; disinhibition: S,B > C; medication non-compliance: S,B > C). However, the subgroups experienced similar re-admission rates (28 days: 13.0%; 6 months: 26.9%).

Conclusions: By improving our understanding of the determinants and outcomes of acute psychiatric admission, we may be able to achieve a better balance between risk management and the delivery of targeted interventions.

THE AUSTRALIAN PSYCHOSIS RESEARCH NETWORK (APRN): A NATIONAL TRANSLATIONAL RESEARCH PROPOSAL

Stanley Catts, APRN Steering Committee

University of Queensland

Background: Compared with other leading public health probems, research capacity for schizophrenia and bipolar disorder is grossly under-developed. Also, there are unacceptible delays in applying research discovery to routine clinical practice. Stakeholders have expressed concern with the apparent lack of effect of research upon clinical outcomes.

Methods: Interdisciplinary consensus-building processes were supported in order to draft a national psychosis research strategy. Review of the management literature was undertaken to identify an appropriate organisational structure within which to implement the strategy.

Results: A translational research framework which linked epidemiological, genetic, neuroscience and drug design research to the development of novel therapeutics and clinical pratice improvement was the preferred research program option and a national collaborative structured network was deemed the optimal governance model.

Conclusion: Australia is well-positioned to make a world-leading contribution to finding ways to prevent and cure schizophrenia and bipolar disorder but only with new sources of recurrent funding in the order of $20 million annually.

OBSTETRIC RISK FACTORS FOR SCHIZOPHRENIA: IDENTIFYING NEUROLOGICAL DAMAGE AND/OR HYPOXIA IN INFANTS USING POPULATION DATABASES.

Maxine Croft^1,2 , Vera Morgan¹, Giulietta Valuri¹, Carol Bower², Steve Zubrick², Assen Jablensky¹

¹ School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia

² Centre for Child Health Research, University of Western Australia, Perth, Australia

Introduction: Genetic inheritance interacting with environmental exposures such as obstetric complications may increase infants’ risk of newborn encephalopathy (NE) and/or subsequent schizophrenia [1, 2, 3, 4, 5]. Identifying mechanisms in the causal pathway to schizophrenia such as perinatal brain damage, hypoxia, and hypoxic-ischemic related complications offers preventive opportunities but poses two challenges: (1) how to use routinely collected datasets to ascertain infants exposed to such damage; and (2) how to identify NE cases from these data. A clinical study of WA infants born during 1980 to 2001, by Badawi [1] defined new criteria for identifying NE cases.

Method: A record linkage cohort study (N = 6303) compared children born 1980–92 in Western Australia to mothers with schizophrenia or affective psychosis to children born to mothers with no record of a psychiatric illness [5]. Several computer algorithms were written to identify infants with NE using data on the WA databases.

Results: Identifying hypoxia and/or perinatal brain damage according to definitions by Cannon [2], Jones [3] or Zornberg [4] resulted in 994 (15.9%) infants who met the criteria set by any one of these studies. Badawi's [1] criteria for NE identified 37 (0.6%) infants.

Conclusion: Over-ascertainment of the incidence of NE can occur, depending upon which case selection criteria are used. Future work will use Badawi's clinical study, of infants born in WA during 1980 to 2001 [1], to validate the identification of NE cases by computer algorithms.

SCHIZOPHRENIA: SEX STEROID EFFECTS AND MECHANISMS OF ACTION

George Fink, Avril Pereira, Suresh Sundram

Mental Health Research Institute of Victoria, Parkville 3052, Victoria, Australia

Gender differences in schizophrenia together with the fact that psychotic symptoms in women are commonly associated with low estradiol plasma concentrations led to the hypothesis that estrogen may protect against psychosis [9–11]. This hypothesis receives support from the fact that estradiol seems to be effective as an adjunct to antipsychotic therapy [4].

Our studies in an acute experimental rat model showed that estradiol-17 beta and testosterone (by way of its aromatase conversion to estradiol) selectively induce expression of the serotonin-2A receptor (5-HT2AR) and the serotonin transporter (SERT) genes and protein in forebrain regions that in the human are involved in cognition, mood and mental state[9–11]. PET studies with [18F] –altanserin demonstrated that estradiol also induces 5-HT2AR concentrations in human frontal cortex [5]. Estradiol also modulates dopamine 2 receptors (D2R) in striatum [6]. Since the D2R is a molecular target for all antipsychotics, and the 5-HT2AR is a target of most atypical antipsychotics, the psychoprotectant action of estradiol could be explained by its effect on the D2R, 5-HT2AR and the SERT, which affects 5-HT2AR receptor density. The actions of estradiol on the 5-HT2AR and SERT are mediated by nuclear estradiol receptors [2], [3]. However, extragenomic mechanisms may also be involved especially with respect to the D2R, and so here we explore the possible role of ERK signaling [7] which is known to be involved in fast (∼secs) estradiol action. Work on ERK signaling and beta-estradiol receptor ligands may lead to alternative strategies for adjunct antipsychotic therapy.

APPLICATIONS OF BRAIN STIMULATION IN THE TREATMENT OF SCHIZOPHRENIA

Paul B Fitzgerald

Alfred Psychiatry Research Centre

The Alfred and Monash University School of Psychology, Psychiatry and Psychological Medicine Victoria, Australia

Schizophrenia remains a disorder which is poorly understood and for which we have only partially effective treatments. Although transcranial magnetic stimulation (TMS) techniques are best known for their use in the treatment of depression, a significant body of research has developed around the use of TMS to study schizophrenia and potentially modulate the symptoms of this disorder.

Two main therapeutic applications of TMS in schizophrenia have been evaluated. First, over 10 studies have used low frequency stimulation applied to temporoparietal cortex to target refractory auditory hallucinations. The majority of these studies have demonstrated therapeutic benefit for this technique and efficacy has been supported by a positive meta-analysis. A second approach has utilised high-frequency stimulation applied to prefrontal cortex in the treatment of negative and possibly cognitive symptoms. Although these studies are far less consistent, a number have shown significant therapeutic effects despite a short duration of treatment and relatively low dose of stimulation applied.

This research suggests that TMS has the capacity to ameliorate the frequency and intensity of hallucinations and may have possible benefits in improving negative symptoms. Further research is required to understand the link between symptoms and some of the core physiological deficits in this disorder and to better refine treatment paradigms. In addition to TMS, a number of other brain stimulation techniques are being evaluated for their therapeutic potential in psychiatric disorders and may have relevance for schizophrenia but their role will require systematic evaluation.

ADEPT: A DEFINITIVE ESTROGEN PATCH TRIAL

Jayashri Kulkarni¹ , Caroline Gurvich¹, Ling Mu¹, Stella Chaviaras², Saji Damodaran², Katherine Roberts³, Michael Berk³, Anthony de Castella¹, Paul Fitzgerald¹, Henry Burger⁴

¹ The Alfred Psychiatry Research Centre, The Alfred and Monash University School of Psychology, Psychiatry and Psychological Medicine, Melbourne, Australia

² Department of Clinical and Biomedical Sciences, Barwon Health and University of Melbourne, Melbourne, Australia

³ Clinical Trials Research Group, Dandenong Hospital and Monash University School of Psychology, Psychiatry and Psychological Medicine, Melbourne, Australia

⁴ Prince Henry's Institute, Monash Medical Centre, Melbourne, Australia

Introduction: Accumulating evidence suggests estrogens may have therapeutic effects in severe mental illnesses, including schizophrenia, via neuromodulatory and neuroprotective activity. The aim of the current study was to compare the effectiveness of adjunctive transdermal estradiol to adjunctive placebo in the treatment of acute psychotic symptoms.

Methods: Women of childbearing age with a diagnosis of schizophrenia or schizoaffective disorder were invited to participate in this 8-week three-arm (100 mcg/day adjunctive transdermal estradiol, 200 mcg/day adjunctive transdermal estradiol, or adjunctive transdermal placebo) double-blind, placebo controlled study. All patients continued to receive standard antipsychotic treatment whilst in the trial. Psychopathology and mood was assessed at baseline then at days 7, 14, 28 and 56 using the PANSS and MADRS rating scales. Estrogen, progesterone, and gonadotropin levels were assessed at baseline and days 28 and 56. Cognitive functioning (RBANS) was assessed at baseline and repeated on day 56.

Results: Preliminary results on psychopathology, hormone levels and cognitive ratings will be presented.

Conclusions: Our previous studies have indicated that women receiving 100mcg transdermal estradiol improved significantly more than women receiving placebo, in terms of positive, negative and general psychopathology symptoms. The findings from this multisite ‘proof-of-concept’ study will determine whether estradiol can be used as an adjunctive treatment of psychotic symptoms in women with schizophrenia. This research is supported by The Stanley Medical Research Institute.

ACCULTURATION IS ASSOCIATED WITH THE PREVALENCE OF TARDIVE DYSKINESIA AND AKATHISIA IN COMMUNITY TREATED PATIENTS WITH SCHIZOPHRENIA

Tim Lambert^4,5 , Suresh Sundram^1,2,3, Danijela Piskulic^1,3

¹ Northern Psychiatry Research Centre and Northern Area Mental Health Service

² Mental Health Research Institute

³ Department of Psychiatry University of Melbourne, Melbourne, Australia

⁴ Department of Psychological Medicine

⁵ Brain and Mind Research Institute, University of Sydney, Sydney, Australia

Introduction: Antipsychotic drug induced movement disorders (ADIMD) remain problematic in clinical practice despite the introduction of second generation antipsychotic drugs [1]. Ethnicity is a risk factor for tardive dyskinesia (TD) and other ADIMD, however, it is unclear whether this association is mediated through genetic, environmental or cultural factors individually or in combination. This pilot study aimed to explore this interaction by determining if acculturation in migrant groups contributed to the prevalence of ADIMD.

Method: Culturally diverse but relatively genetically homogeneous (white Caucasian) patients with schizophrenia (n = 40) treated at a single community mental health clinic were recruited. Subjects were assessed for the presence of ADIMD using the Simpson-Angus scale for Parkinsonism, Barnes Akathisia Rating Scale and the Abnormal Involuntary Movement Scale and for their level of acculturation (Multicultural Acculturation Questionnaire-MAQ).

Results: Twenty-three patients rated positive for TD (mean 4.5, s.d. 4.2) using Glazer-Morgenstern criteria; 22 patients had akathisia (4.6, 4.0) and 34 patients had Parkinsonism (6.6, 3.7). The mean MAQ score was 75.1 (21.6) ranging from 24–100. Higher levels of acculturation correlated with an increased prevalence of TD (Spearman's rho 0.374, p < 0.01) and akathisia (Spearman's rho 0.355, p < 0.01) but not Parkinsonism. The level of acculturation significantly predicted TD (B = 1.10, s.e.=0.51, Wald 4.65, p < 0.05).

Conclusion: This study identifies for the first time that acculturation significantly contributes to the prevalence of TD and akathisia but not Parkinsonism in culturally diverse migrant populations and must be accounted for when explaining ethnic variation in rates of ADIMD.

DELUSIONS AND REASONING ANOMALIES IN SCHIZOPHRENIA

Robyn Langdon^1–4 , Philip B. Ward^3,4, Max Coltheart¹

¹ Macquarie Centre for Cognitive Science, Macquarie University, NSW, Australia

² Schizophrenia Research Institute, NSW, Australia

³ Schizophrenia Research Unit, Sydney South West Area Health, NSW, Australia

⁴ School of Psychiatry, University of New South Wales, NSW, Australia

Introduction: Three reasoning anomalies have been identified in deluded and delusion-prone people: 1) a jumping-to-conclusions (JTC) bias; 2) excessive attributional biases; and 3) theory-of-mind (ToM) deficits. We examined the relations between these three anomalies in the same samples of people with schizophrenia and healthy controls so as to evaluate their functional independence.

Method: 35 patients with schizophrenia (30 of whom were acutely delusional) and 34 healthy controls completed 2 probabilistic-reasoning tasks, 3 ToM tasks, and an attributional style questionnaire (which assessed levels of externalising and personalising bias). State and trait levels of delusional ideation were also assessed.

Results: Compared to controls, patients showed (a) a JTC bias and a bias to ‘overadjust’ when confronted with a change of evidence on probabilistic-reasoning tasks, (b) an excessive externalizing bias, and (c) ToM deficits. Probabilistic-reasoning and ToM measures intercorrelated and were associated with delusion-proneness, while attributional-bias scores were independent of the other task measures. Personalizing bias associated more specifically with paranoid ideation across the clinical and nonclinical samples.

Conclusions: Findings suggest that a common underlying mechanism in schizophrenia contributes to the anomalies on probabilistic-reasoning and ToM tasks which have been associated with delusional ideation. We conceive of this mechanism as an impairment of the normal capacity to inhibit ‘perceived reality’, a capacity which may have evolved as a part of the ‘social brain’ to facilitate the understanding of other minds.

PSYCHIATRIC CHARACTERISTICS AND SCHIZOTYPAL PERSONALITY TRAITS YOUNG ADULTS WITH VELO-CARDIO-FACIAL SYNDROME

Kathryn Leadbeater¹ , Ulrich Schall^1,2,3, Linda Campbell^1,2,3

¹ Centre for Brain and Mental Health Research, University of Newcastle, NSW Australia

² Schizophrenia Research Institute

³ Hunter Medical Research Institute

Aims: Velo-cardio-facial syndrome is a common genetic syndrome and the third highest known risk factor for schizophrenia. Approximately 30% of the VCFS population develops schizophrenia in early adulthood. However, many behavioural problems are present in the population. This data was collected as part of an ongoing study seeking to identify predictors of psychosis and other psychiatric disorders in young people with VCFS.

Methods: Behavioural and psychiatric data (including DSM-IV interviews, quality of life and Raine's Schizotypal Personality Questionnaire (SPQ)) for 17 subjects with VCFS and 10 healthy controls were analysed.

Results: In the VCFS group, most (12 out of 17) were diagnosed with a mild intellectual disability according to the DSM-IV criteria. Several met thresholds for diagnosis with attention deficit (hyperactivity) disorder (5), oppositional defiant disorder (3), obsessive compulsive disorder (3), trichotillomania (1), panic disorder (1), generalized anxiety disorder (1), and schizophrenia (1). Many also had sub-threshold psychiatric comorbidities. The VCFS group had significantly lower GAFs and higher schizotypal scores than controls.

Conclusions: The VCFS group had a wide range of behavioural and psychiatric problems. Future analyses will relate this information to structural brain anatomy, cognition and genotype in order to attempt to identify any potential precursors of psychoses. All participants will be followed up annually to track their mental health status.

Supported by NH&MRC NHMRC ref 455624

EMOTION RECOGNITION TRAININING IN SCHIZOPHRENIA: FUNCTIONAL PREDICTORS AND GENERALIZABILITY

Pamela Marsh¹, Melissa Green^2,3 , Anthony Harris⁵, Tamara Russell^1,4, Max Coltheart¹

¹ Macquarie Centre for Cognitive Science, Macquarie University, Sydney, Australia

² School of Psychiatry & Black Dog Institute, University of New South Wales, Sydney, Australia

³ National Alliance for Research on Schizophrenia and Depression, USA

⁴ Schizophrenia Research Institute, Sydney, Australia

⁵ Discipline of Psychological Medicine, University of Sydney, Sydney, Australia

Background: Impaired emotion perception is associated with poor social functioning in schizophrenia. Emotion recognition training (ERT) improves recognition of facial emotions for up to one month. We investigated whether baseline neurocognitive and social functioning predicted ERT efficacy, and whether improvements generalise to face stimuli not used in training.

Method: Thirty-nine participants with schizophrenia received ERT using the Micro-Expression Training Tool (METT; Ekman, 2003); twenty-two completed followed-up assessments at one week and one month post-training. Emotion recognition was assessed pre- and post-training using METT faces and other faces not used in training. Measures of social functioning (including researcher-scored and self-report measures) and working memory (WM) were assessed at baseline (pre-training).

Results: Recognition of METT faces improved immediately post-ERT; Improved recognition of other faces was evident at one week and one month post-training (n = 22). Improved recognition of METT faces was associated with better WM and higher (researcher-scored) interpersonal functioning; improved recognition of other faces was associated with higher (self-rated) interpersonal functioning.

Conclusions: Improved emotion recognition generalises to faces not used in ERT. Improvements continue for one month post-training. Baseline social and cognitive functioning predicts the efficacy of METT training.

A DOUBLE BLIND, PLACEBO-CONTROLLED RANDOMIZED TRIAL OF LOW-DOSE RISPERIDONE, COGNITIVE-BEHAVIOUR THERAPY, AND SUPPORTIVE THERAPY IN YOUNG PEOPLE WITH SUBTHRESHOLD SYMPTOMS AT INCIPIENT RISK OF PSYCHOTIC DISORDER: TWELVE-MONTH OUTCOME DATA

Patrick D McGorry, Lisa J Phillips, Barnaby Nelson, Shona M Francey, Steven Leicester, Hok Pan Yuen, Magenta B Simmons, Carrie Stanford, Kathryn Baker, Catharine McNab, Annette Thampi, G Paul Amminger, Alison R Yung

Introduction: Intervention during the prodromal phase of psychotic disorders is aimed at delaying or preventing the onset of psychosis in high risk patients. The PACE Clinic has recently completed an RCT under double blind conditions comparing the effectiveness of low-dose risperidone (0.5-2.0 mg/day) and CBT-based psychological treatment versus placebo and CBT-based psychological treatment versus placebo and a control psychological treatment (supportive therapy).

Method: The trial consisted of a 12-month treatment phase and a 12-month follow up phase. The primary outcome was the rate of transition to psychosis. Secondary outcomes included improvement on measures of symptoms, distress, functioning and quality of life. 115 participants (mean age = 18.13 years, male = 40%) meeting ultra-high risk (UHR) criteria were randomized to the three treatment groups. A further 78 participants were not randomized but consented to research monitoring.

Results: 23 participants transitioned to first episode psychosis (FEP) with number of days to transition ranging from 16 to 1343 days. A survival analysis yields the following estimates of the 12-month transition rates: risperidone + CBT group, 14% (s.e. 6%), placebo + CBT group, 10% (s.e. 5%), placebo + supportive therapy group, 22% (s.e. 9%), monitoring group, 9% (s.e. 4%). The differences in rates of transition to psychosis were not significant, either between the treatment groups (p = 0.65) or between all four groups (p = 0.61). Analysis of symptom and functioning measures is currently underway.

Conclusions: The lack of difference in onset of FEP between the treatment groups indicates that minimal, less intensive treatments may be sufficient as a first step in the UHR population.

DETERMINANTS OF ADVERSE PSYCHIATRIC OUTCOMES FOR HIGH RISK CHILDREN OF MOTHERS WITH SCHIZOPHRENIA AND OTHER PSYCHOSES: THE ROLE OF ENVIRONMENTAL AND FAMILIAL RISK FACTORS

Vera Morgan¹ , Steve Zubrick², Carol Bower², Maxine Croft¹, Giulietta Valuri¹, Jenny Griffith¹, Assen Jablensky¹

¹ School of Psychiatry and Clinical Neuroscience, University of Western Australia, Perth, Australia

² Institute for Child Health Research, Perth, Australia

Introduction: This study is designed to untangle genetic and environmental contributions to risk of adverse psychiatric outcomes in genetically high risk children of women with psychoses.

Method: We linked the Statewide midwives register (308,022 births) and psychiatric case register (79,599 women) and identified 3174 high risk children born 1980-1992 to mothers on the psychiatric register with schizophrenia, bipolar disorder, and unipolar depression, and a comparison group of 3129 children born to mothers with no psychiatric history. Psychiatric histories for mothers, fathers and children were extracted, and data collected on obstetric complications and other morbidities. Cox regression which permits the modelling of time-to-event data in the presence of censored cases was used for analysis.

Results: Of 6303 children, 750 had had a psychiatric contact: 18.1% of schizophrenia offspring, 20.1% of bipolar offspring, 16.0% of unipolar offspring and 5.6% of comparison children. Maternal psychiatric status, pregnancy complications and labour/delivery complications were independently associated with the risk of psychiatric illness in children. The number with a diagnosis of psychosis was small (57 children), affecting 3.1% of schizophrenia offspring, 1.2% of bipolar offspring, 0.9% of unipolar offspring and 0.4% of comparison children. Maternal schizophrenia (OR 8.0, CI 3.6–18.2) and bipolar disorder (OR 2.6, CI 1.1–6.0) but not unipolar depression (OR 2.2, CI 0.9–5.4) were associated with risk of psychoses. There was no significant effect for pregnancy (OR 1.3, CI 0.7–2.4), labour/delivery (OR 1.3, CI 0.8–2.3) or neonatal complications variables (OR 0.9, CI 0.5–1.7).

Conclusion: Further analysis using a dataset under construction and consisting of half a million children is warranted.

THE “PRAECOX” FEELING AS A PREDICTOR OF PSYCHOTIC DISORDER IN THE ULTRA HIGH RISK (“PRODROMAL”) POPULATION

Barnaby Nelson, Alison Yung

ORYGEN Youth Health Research Centre, Department of Psychiatry, University of Melbourne, Melbourne, Australia

Introduction: There is empirical support for the notion that schizophrenia can be identified by an experienced psychiatrist through intuitive clinical processes, based on an impression of “strangeness” and interpersonal “distance” from the patient (the “praecox” feeling). However, this has not been evaluated as a potential predictive tool. This study investigated the predictive validity of the “praecox” feeling in an “ultra-high risk” (UHR) sample, a clinical population identified by symptomatology and/or genetic risk to be at high risk of onset of psychotic disorder.

Method: After first contact with a UHR patient, experienced clinicians used a dichotomous scale to rate whether they thought the patient would develop first episode psychosis (FEP).

Results: The sample consisted of 168 UHR patients (mean age = 18.34). Clinicians expected 22% (N = 37) of the sample to develop FEP. 12 cases (7.1%) transitioned to FEP over 12-months. The sensitivity of the “praecox” feeling was .83, specificity was .83, PPV was .27 and NPV.98.

Discussion: These data indicate that the “praecox” feeling, even by experienced clinicians, is a poor indicator of whether UHR patients will progress to psychotic disorder over the short term. The strong NPV may have been due to the low transition rate. The findings indicate the importance of continuing to research predictors psychosis onset in high-risk samples. They also demonstrate that clinicians should not assume that they “know” when someone will develop psychosis, and highlight that caution should be employed in the pre-emptive prescription of anti-psychotics to UHR individuals.

ARE ALL PSYCHOTIC LIKE EXPERIENCES BAD NEWS? 12 MONTH OUTCOMES OF PSYCHOTIC LIKE EXPERIENCES IN A COMMUNITY SAMPLE OF ADOLESCENTS

Margaret L Ross^1,2 , Joe Buckby^1,2, Gennady Baksheev^1,2, Elizabeth Cosgrave¹, Kathryn Baker¹, Jaymee Ryan^1,2, Alison Yung^1,2

¹ ORYGEN Youth Health – Research Centre Melbourne, Victoria, Australia

² Department of Psychiatry, University of Melbourne, Victoria, Australia

Introduction: Studies investigating psychotic like experiences (PLE) in community samples have reported contrary results, with some suggesting that PLE may be benign and not associated with any psychiatric difficulties, while others report that PLE are associated with problems with functioning and other symptoms, and may be risk factors for onset of psychiatric disorders. Further, it remains unclear whether all PLEs are the same, or whether subtypes are associated with psychiatric problems and may be risk factors for disorder. We previously identified 4 subtypes of PLE in a community sample of adolescents: Bizarre Experiences (BE), Persecutory Ideation (PI) Perceptual Abnormalities (PA), and Magical Ideation (MT). BE, PI and PA were significantly associated with depression, and poor functioning, yet MT appeared to be more benign. This study aims to examine the longitudinal outcome of these subtypes over 1 year

Method: 652 secondary school students completed baseline assessments including the Community Assessment of Psychic Experiences (CAPE), and were followed-up one year later.

Results: Baseline PLEs significantly predicted the presence of psychiatric diagnoses suicidality, psycho-social functioning, ultra high risk (UHR) status, and depressive symptomatology at one-year follow-up. Baseline PI, BE, and PA were significantly related to these poor outcomes, but MT less so.

Discussion: The presence of PLE's appear to heighten the risk of later development of Axis I disorders particularly mood and anxiety disorders, psychopathology, suicidality and poor functioning. Though PLEs are associated with a range of negative outcomes, it may be that some types of PLEs particularly MT may not be as detrimental.

DECREASED LEVELS OF [³H]PIRENZEPINE BINDING IN BRODMANN'S AREA 6 FROM SUBJECTS WITH SCHIZOPHRENIA IS NOT ASSOCIATED WITH CHANGES IN THE TRANSCRIPTION FACTOR SP1 OR BACE1

Elizabeth Scarr^1,2 , Andrew Soulby^1,3,4, Geneviève Evin⁵, Brian Dean^1,5–7

¹ The Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute, Parkville, Australia

² Centre for Neuroscience, University of Melbourne, Parkville, Australia

³ Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia

⁴ School of Biomedical Sciences, University of Nottingham, Nottinghamshire, UK

⁵ Department of Pathology, University of Melbourne, Parkville, Australia

⁶ Department of Psychiatry, University of Melbourne, Parkville, Australia

⁷ Department of Psychological Medicine, Monash University, Clayton, Australia

Decreased muscarinic M1 receptor (CHRM1) mRNA was reported in Brodmann's area (BA) 6 from subjects with schizophrenia. We extended this study by measuring levels of CHRM1 ([³H]pirenzepine binding), CHRM3 ([³H]4-DAMP binding), the transcription factor SP1 and the CHRM1 downstream target BACE1 in BA 6 from subjects with schizophrenia and control subjects.

Radioligand binding was quantified using in situ radioligand binding with autoradiography and, in a cohort of subjects, membrane enriched fraction ([³H]pirenzepine binding). Levels of SP1 and BACE1 were measured by Western blotting.

[3H]pirenzepine binding to tissue sections (Binding layer 1: p < 0.01; Binding layer 2: p < 0.001) and membrane enriched fraction (p < 0.05) were decreased in schizophrenia. Levels of [³H]4-DAMP binding, SP1 and BACE1 were not altered in subjects with the disorder.

This study shows a decrease in levels of CHRM1 in BA 6 from subjects with schizophrenia; since CHRM1 and BA 6 are important in maintaining normal cognitive function, these data support the hypothesis that decreased levels of cortical CHRM1 may contribute to the cognitive deficits associated with schizophrenia. Our findings on BACE1 suggest that the schizophrenia phenotype reported in BACE − /− mice are not simply due to a lack of cortical BACE1.

DECREASED CORTICAL MUSCARINIC RECEPTORS DEFINE A SUB-GROUP OF SUBJECTS WITH SCHIZOPHRENIA.

Elizabeth Scarr^1–2 , Tiffany F. Cowie³, Stravoula Kanellakis³, Suresh Sundram^{4,6, 7}, Christos Pantelis^5,8 Brian Dean^2–5

¹ Centre for Neuroscience, The University of Melbourne, Victoria,

² Rebecca L. Cooper Research Laboratories, Mental Health Res. Inst., Victoria

³ Department of Pathology, The University of Melbourne, Victoria

⁴ Department of Psychiatry, The University of Melbourne, Victoria

⁵ Department of Psychological Medicine, Monash University, Victoria

⁶ Molecular Psychopharmacology, Mental Health Research Institute, Victoria

⁷ Northern Psychiatry Res. Centre, The Northern Hospital, Victoria

⁸ Melbourne Neuropsychiatry Centre, The University of Melbourne, Victoria

Schizophrenia is widely acknowledged as being a syndrome, consisting of an undefined number of diseases probably with differing pathologies. Although studying a syndrome makes the identification of an underlying pathology more difficult; neuroimaging, neuropsychopharmacological and postmortem brain studies all implicate muscarinic acetylcholine receptors (CHRM) in the pathology of the disorder. We have established that the CHRM1 is selectively decreased in the dorsolateral prefrontal cortex of subjects with schizophrenia. To expand this finding, we wanted to ascertain whether decreased cortical CHRMs might i) define a sub-group of schizophrenia and/or ii) be related to CHRM1 genotype. We assessed cortical [³H]pirenzepine binding and sequenced the CHRM1 in 80 subjects with schizophrenia and 74 age sex matched control subjects. Kernel density estimation showed that [³H]pirenzepine binding in BA 9 divided the schizophrenia, but not control, cohort into two distinct populations. One of the schizophrenia cohorts, comprising 26% of all subjects with the disorder, had a 74% reduction in mean cortical [³H]pirenzepine binding compared to controls. We suggest that these individuals make up “muscarinic receptor deficit schizophrenia” (MRDS). The MRDS could not be separated from other subjects with schizophrenia by CHRM1 sequence, gender, age, suicide, duration of illness or any particular drug treatment. Being able to define a sub-group within schizophrenia using a central biological parameter is a pivotal step towards understanding the biochemistry underlying at least one form of the disorder and may represent a biomarker that can be used in neuroimaging.

A GENOME WIDE LINKAGE SCAN IN 124 SCHIZOPHRENIA AFFECTED SIB-PAIR FAMILIES FROM INDONESIA REVEALS GENOME WIDE SIGNIFICANCE FOR A LOCUS ON CHROMOSOME 3P

Sibylle G Schwab^1,2,3 , Clarissa Ganda^1,2, Irmansyah⁴, Heriani⁴, Agung AAA Kusumawardhani⁴, Ika Widyawati⁴, Nurmiati Amur⁴, Martina W Nasrun⁴, Dieter B Wildenauer^1,5

¹ School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia

² Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Australia

³ School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

⁴ Department of Psychiatry, University of Indonesia, Jakarta, Indonesia

⁵ Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Mt Claremont, Australia

Introduction: Involvement of genetic factors in the etiology of schizophrenia has been suggested for a long time. It is assumed that an oligo- or polygenic mode of inheritance with varying influences of different sets of genes is most likely. We have collected a sample of sib-pairs affected with schizophrenia from Indonesia, in order to investigate possible population specific influences for development of schizophrenia.

Methods: The sample consisted of 152 families from Indonesia with two or more schizophrenia affected offspring, including parents and unaffected siblings. The sample is suitable for linkage and association studies. Genotyping was performed at the NHLBI Mammalian Genotyping Service at Marshfield Research Organization using the Screening Set 16 comprising 402 short tandem repeat polymorphisms. Multipoint sib-pair analysis was carried out using the program GENEHUNTER version 2.1.

Results: After extensive error checking, we were able to include 124 of the original 152 affected sib-pair families for final linkage analysis. Multipoint sib-pair analysis was carried out by estimation of maximum likelihood lod scores (MLS). A genome wide significant MLS of 3.76 was obtained for chromosome 3p26.2–25.3. Additional loci were detected on chromosomes 1p12 (MLS = 2.35), 5q14.1 (MLS = 1.56) and 10q (MLS = 1.17). These loci had been implicated in previous linkage studies.

Conclusion: Our study detected a region on chromosome 3p with genome wide significant linkage. This region will serve as starting point for the identification of susceptibility genes in the Indonesian population.

QUANTIFYING THE DEVELOPMENT OF WHITE MATTER ABNORMALITIES IN PSYCHOSIS

Marc L Seal¹ , Po Yin Tang¹, Mark Walterfang¹, Murat Yücel^1,2, Stephen J Wood¹, Gregor E Berger^2,3, Patrick McGorry², Christos Pantelis¹

¹ Melbourne Neuropsychiatry Centre, The University of Melbourne, Victoria, Australia

² ORYGEN Research Centre, The University of Melbourne, Parkville, Victoria, Australia

³ Department of Research & Education, The Schloessli Clinic, Oetwil am See, Zuerich, Switzerland

Introduction: The transition to psychosis is associated with a range of diffuse cortical changes. While there is growing evidence of white matter impairment in chronic schizophrenia the development of this neuropathology and the implications of abnormal white matter remain unclear. This study used Diffusion Tensor Imaging (DTI) to measure white matter health in vivo across the course of the illness.

Method: DTI data was acquired from two clinical samples of different duration of illness (First Episode Psychosis & Chronic Schizophrenia) and age matched healthy control participants. The groups were compared on four key measures of diffusivity [Fractional Anisotropy (FA), Axial Diffusivity (AD), Radial Diffusivity (RD) and Intervoxel Coherence (IC)] to and from functional areas of the auditory cortex.

Results: Age-related differences in diffusivity were identified between diagnostic groups in measures of temporal lobe diffusivity (FA, AD and RD). No significant age-related changes were found in IC.

Conclusions: Overall, this study did not find differences on a range diffusivity measures in a group of FEP subjects and age matched controls. This suggests that the white matter abnormalities observed in the older chronic group are not evident in the early stages of the illness.

COMORBIDITY IN EARLY PSYCHOSIS: RURAL CANADIAN EARLY PSYCHOSIS INTERVENTION EXPERIENCE

Amresh Shrivastava¹ , Diana Handsaeme², Robbie Campbell³

¹ Assistant professor, Department of Psychiatry, University of Western Ontario, Physician, Early psychosis Program Regional Mental Health care Associate Scientist, Lawson Health Research Institute, London, ON, Canada

² Case manager, R.N. CPMHN (C); Canadian Mental health Association, Elgin

³ Associate Professor & Chief, assessment program, regional Mental Health care, London, ON, Canada

Introduction: Comorbidity in psychosis is a major issue-affecting outcome of treatment, is prevalent in about 50% patients on axis I, II & III. Though conventionally substance abuse is excluded while establishing the diagnosis, still cannabis and other substance are found widely prevalent in the population of schizophrenia. Cannabis is particular interest because of its association with causation of psychosis. The present study is targeted to find out prevalence and impact of cannabis is newly developing ‘early intervention’ program in a rural community of Ontario, Canada.

Methodology: This is a cross sectional, Naturalistic, cohort study. The subjects enrolled in past one year in early intervention program were recruited. A semi-structured clinical study tool was used.

Results: Twenty-six patients enrolled in the study showed a mean age 22 years (range 16–26 SD. 4) with duration of illness 26 months (range 8–38 months, SD = 3) & Duration of untreated psychosis as 17 months (range 4 to 20 months SD = 2). Comorbidity of 61.5% was found on axis I & 26.9% on axis II. Commonest Comorbidity was cannabis in 42% followed by personality disorder in 29% and depression 23%. 46% patients had two diagnoses on axis 15% and I three diagnoses.

Conclusion: The short study reconfirms presence of Comorbidity and highlights need for tailoring intervention programs toward it. Success of early psychosis programs without resources of dealing with addictions and personality disorder will remain compromised.

THE ROLE OF EFFORT, COGNITIVE EXPECTANCY APPRAISALS AND COPING STYLE IN THE MAINTENANCE OF THE NEGATIVE SYMPTOMS OF SCHIZOPHRENIA

Mike Startup, Rachel Avery, Karen Calabria

School of Psychology, University of Newcastle, Australia

Background: Negative symptoms have long been recognised as core features of schizophrenia. They refer to the loss of, or reduction in, normal functions or behaviours. They are associated with poor social functioning, and poor quality of life. Despite their clinical importance, there is no consensus among researchers on the causes of these impairments and explanatory variables individually have tended to account for little of the variance in the severity of these symptoms.

Aims: To assess the role of psychological factors, specifically effort, coping, and negative expectancy appraisals, in addition to executive functioning and depression, in accounting for negative symptoms broadly defined.

Method: Fifty inpatients with acute non-affective psychosis participated in a study with a cross-sectional design.

Results: All of the psychological variables had significant partial correlations with some of the measures of negative symptoms when depression was controlled. A series of multiple regression analyses indicated that executive functioning only made a significant unique contribution to the prediction of affective flattening, whereas psychological factors made unique contributions to the variance in each of the negative symptom subscales apart from affective flattening, as well as to the negative symptom total score, accounting for 9 to 19% of the variance.

Conclusion: In addition to neuropsychological variables, psychological variables are important for understanding negative symptoms in acute schizophrenia.

INVESTIGATION OF ASSOCIATIONS BETWEEN SINGLE NUCLEOTIDE POLYMORPHISMS OF THE MUSCARINIC 1 RECEPTOR GENE AND COGNITIVE DEFICITS IN SCHIZOPHRENIA

Suresh Sundram^1,2 , Azita Khademy-Deljo^1,2, Tiffany Cowie¹, Elizabeth Scarr², Danijela Piskulic², Christos Pantelis³, Brian Dean³

¹ Mental Health Research Institute of Victoria

² Northern Psychiatry Research Centre

³ The University of Melbourne

Introduction: Negative symptoms and cognitive deficits are the major predictors of functional outcome in schizophrenia. Current antipsychotic treatments are not effective in treating cognitive dysfunction. In understanding the etiology of cognitive deficit in schizophrenia the acetylcholine Muscarinic 1 Receptor (M1R) has emerged as an attractive target of investigation.

Aim: To investigate associations between CHRM1 single nucleotide polymorphisms (SNPs) and cognitive and clinical characteristics in schizophrenia.

Method: 59 patients with schizophrenia aged 18–60 with a National Adult Reading Test (NART) score greater than 75 completed The Wisconsin Card Sorting Test (WCST), Controlled Oral Word Association Test (COWAT) and Positive and Negative Syndrome Scale (PANSS). DNA was extracted from whole blood for genotypic analysis.

Results: Subjects with the C267C/C1353C genotype made significantly more perseverative error than subjects with C267A/C1353T genotype (t = 2.4, p=.02)

Discussion: Our study, in part, replicates a similar previous finding regarding the CHRM1 c.267C > A/C.1353C > T haplotype and perseveration (Liao et al, 2003) but contradicts with this study's findings regarding concept formation. As an interim independent replication, it further supports the role of the M1R in cognitive dysfunction in schizophrenia and enhances its attraction as a candidate molecular target for the development of cognitive remediation therapies in schizophrenia.

THE DIFFERENTIAL EFFECT OF CLOZAPINE COMPARED TO OTHER ANTIPSYCHOTIC DRUGS IN CORTICAL AND STRIATAL CELL SIGNALLING: A NOVEL ANTIPSYCHOTIC DRUG MECHANISM?

Suresh Sundram², Avril Pereira¹ , A Sugiharto¹, George Fink¹

¹ Mental Health Research Institute, Melbourne, Australia

² Northern Psychiatry Research Centre, Melbourne, Australia

Antipsychotic drugs (APD) have limited and variable efficacy in treating positive psychotic symptoms. The atypical APD clozapine appears demonstrably effective in a proportion of these treatment resistant cases. The mechanism through which clozapine exerts this quality is unknown but may involve alternate cell signalling systems. A potential candidate is the mitogen activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade that links GPCR and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. We previously reported in vitro that clozapine and other APD acutely inhibit ERK activation but only clozapine stimulated ERK with sustained treatment. This stimulation was mediated by the epidermal growth factor (EGF) receptor (ErbB1). We have extended our findings in-vivo examining if clozapine, haloperidol, quetiapine and aripiprazole differentially modulate the EGF-ERK1/2 pathway in prefrontal cortex (PFC) and striatum of C57Bl/6 mice following acute treatment. ERK1/2 phosphorylation was inhibited by clozapine at 20 and 60 min followed by subsequent activation at 8 hrs and normalization of the pERK1 response at 24 hours. This in-vivo clozapine-induced ERK activation was significantly reduced by the EGF receptor inhibitor, AG1478, in both brain regions (PFC clozapine 8 hrs: 144.7±7.4% vs clozapine + AG1478 8 hrs: 46.7±10.7%, p < 0.001). Differential patterns of activation were noted with the other APD tested, in particular, haloperidol significantly stimulated pERK1 in striatum for up to 8 hrs. Clozapine recruitment of ErbB1 signalling to activate ERK1/2 may warrant investigation as a novel antipsychotic drug target for treatment resistant patients.

COMPUTERIZED COGNITIVE REMEDIATION IN THE REAL WORLD: IMPROVED COGNITIVE PERFORMANCE AND QUALITY OF LIFE RATINGS

Philip B. Ward¹ ; Lucy Albertella¹; Megan Still¹, Pamela K Ward²

¹ Schizophrenia Research Unit, Sydney South West Area Health Service, Sydney, NSW, Australia

² School of Psychiatry, University of New South Wales, Sydney NSW, Australia

Introduction: Cognitive impairments are core and enduring features of schizophrenia, and severity of cognitive impairment has been found to be a major determinant of overall disability in people with schizophrenia. Recent research shows that cognitive training, including computer-assisted cognitive skills training (COGPACK), improves schizophrenia-associated cognitive impairment (Sartory et al, [2005])

Methods: COGPACK was compared with a typing training program that involves a similar level of computer interaction, but did not specifically address a wide range of cognitive domains. Patients were selected who met the following criteria; age 17–65, adequate English language abilities, no current history of substance abuse, willing to attend a MHS facility in which COGPACK or typing training is provided twice weekly (1 hours sessions) for eight weeks. Participants were randomly assigned to either COGPACK or typing groups, and pre- and post-tested using the MATRICS™ Consensus Cognitive Battery (MCCB™; Nuechterlein and Green, [2004]). Self-rated quality of life by was measured using the WHO-QoL-BREF.

Results: Patients assigned to COGPACK significantly improved in 2 of the MCCB domain scores (working memory and visual learning p < 0.01) and the overall composite T-score. Improved ratings for the psychological and environmental domains of the WHO-QoL were also found for the COGPACK Group. Significant changes were not found in the typing group for any measure.

Conclusions: COGPACK improved neurocognitive function and self-rated quality of life. A high level of acceptance by the target group, low cost, and simple operational requirements make if feasible for widespread use in public mental health settings.

CHILDHOOD BEHAVIOURAL AND EMOTIONAL ANTECEDENTS OF NON-AFFECTIVE PSYCHOSIS IN A 21 YEAR BIRTH COHORT STUDY

Joy Welham¹ , James Scott^2,3, Gail Williams⁴, Jake Najman⁴, William Bor⁵, Michael O'Callaghan⁴, John McGrath^1,2,6

¹ Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD 4076, Australia

² Department of Psychiatry, University of Queensland, St Lucia, QLD 4072, Australia

³ Child & Youth mental Health Service, Royal Children's Hospital, Herston, QLD, 4029 Australia

⁴ School of Population Health, University of Queensland, Herston QLD 4029 Australia

⁵ Mater Children's Hospital, South Brisbane, Australia QLD 4101 Australia

⁶ Queensland Brain Institute, University of Queensland, QLD 4072 Australia

Background: Individuals who develop nonaffective psychoses may display subtle deviations in behaviour during childhood and adolescence. This study explored the antecedents of nonaffective psychosis in an Australian birth cohort utilizing the Child Behavioral Checklist (CBCL) and the Youth Self Report (YSR).

Methods: Based on a birth cohort of 3801 young adults, psychopathology was assessed at years 5 and 14 using the CBCL and/or YSR. Screen-positive non-affective psychosis (SP-NAP) was assessed at year 21 by the Composite International Diagnostic Interview, or a self-report checklist. The association between childhood symptoms and SP-NAP was examined using logistic regression.

Results: Sixty subjects from the cohort were classified as SP-NAP. SP-NAP in boys predicted higher scores: (a) on year 5 CBCL ‘Total’, ‘Aggression’ and ‘Social, Attention and Thought’ scores; (b) on year 14 CBCL ‘Social’, ‘Attention’ and ‘Delinquency’ scores, and (c) YSR ‘Total’ and many YSR subscores. These associations were less clear for girls. At year 14, hallucinations predicted SP-NAP for both sexes. Boys with high ‘Total’ scores at both years 5 and 14 had a 5-fold risk of SP_NAP; boys and girls whose ‘Social, Attention and Thought’ scores either increased or remained high from years 5 to14 had a 3- to 13-fold risk.

Conclusions: Young adults who screen positive for non-affective psychosis show increased psychopathology during childhood and adolescence. This included hallucinatory experiences at year 14. We identified for the first time that the psychopathological trajectory of children who go on to develop schizophrenia anticipates the heterogeneity associated with the full clinical syndrome.

STRESS RELATED PSYCHOLOGICAL FACTOR AND PSYCHOSIS: PRELIMINARY RESULTS FROM SHARP STUDY

Y Yun^1,2, R Parslow¹, B Garner^1,2, L Phillips¹, C Phassouliotis¹, C Markulev², C Leong¹, S Bendall^1,2, G Berger^1,3, P McGorry^1,2

¹ University of Melbourne, Melbourne, Australia

² ORYGEN Research Centre, Melbourne, Australia

³ University Hospital Basel, Department of Psychiatry, Switzerland

Introduction: SHARP (Stress, HPA function And Related Psychosis) is a project to investigate the relationship among childhood trauma, stress, coping, psychopathology, HPA function, neuro-cognition, brain structure and medical compliance in the first episode psychotic (FEP) population. This poster is the results about trauma, stress, coping and psychopathology.

Method: 45 first episode psychosis drug naïve or early treated patients and 40 matched healthy controls were recruited from the ORYGEN Youth Health in Melbourne, Australia. Their psychopathology (BPRS, SANS, HAMA and HAMD), social function (GAF and SOFAS), medical compliance (Clinical rating scale, Drug attitude Inventory), NEO personality inventory, trauma (Childhood Trauma Questionnaire and List of Threatening Experiences) and Stress and coping (Coping Inventory for Stressful Situations, Daily Hassles Scale, Perceived Stress Scale and Connor-Davidson Resilience Scale) were measured at baseline and after 12 weeks follow up.

Conclusion: FEP with childhood traumatic history might experiences more hassle, more severe hassles and perceived more stress when they were suffering from the psychosis, also might report more negative symptom.

Results:

1. Daily hassle is positively correlated to perceived distress at baseline. The bigger change of hassle total score and severity of hassle is linked to the more severe negative symptoms at follow up.

2. Perceived stress at baseline is correlated to less severe negative symptom, higher hassle and hassle severity and poor clinical rating score.

3. Higher CTQ is linked to higher baseline hassle total score, severity of hassle and higher perceived stress. It also related to lower negative group.

VALIDATION OF “PRODROMAL” CRITERIA TO DETECT INDIVIDUALS AT ULTRA HIGH RISK OF PSYCHOSIS: 2 YEAR FOLLOW UP

Alison Yung, Barnaby Nelson, Carrie Stanford, Magenta Simmons, Elizabeth Cosgrave, Eoin Killackey, Lisa Phillips, Joe Buckby, Andreas Bechdolf

Orygen Research Centre

Background: Identification of individuals “prodromal” for schizophrenia and other psychotic disorders relies on criteria that predict onset within a brief period. Previous trials and biological research have been predicated on the view that certain “ultra high risk” (UHR) criteria detect “the prodrome”, but there is a need to test the validity of these criteria. Also, it may be the fact of seeking help from a UHR service, rather than the UHR criteria per se, which predicts onset of psychosis.

Aim: To assess the predictive validity of the UHR criteria in a clinical population. A secondary aim was to assess clinicians’ ability to detect UHR criteria.

Method: Presence of UHR criteria was determined in 292 individuals at baseline. At 2 year follow up the number of new cases of psychotic disorder was assessed in those meeting and not meeting the UHR criteria.

Results: Help-seeking per se was not a risk factor for development of psychotic disorder, rather it was the UHR+ status at baseline that predicted psychosis onset within 2 years. The transition rate of 16% was much lower than in initial cohorts (over 40%). Clinicians frequently missed UHR + ve individuals and failed to diagnose the UHR criteria in others.

Conclusions: Although young help-seekers meeting UHR criteria are at greater risk of psychotic disorder than those who do not meet them, caution is needed in their management, since a high transition rate can no longer be assumed. Training with a structured assessment tool may aid clinicians in detecting the UHR criteria.