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The model of mismatch negativity (MMN) as a simple index of change detection has been superseded by a richer understanding of how this event-related potential (ERP) reflects the representation of the sound environment in the brain. Our conceptualization of why the MMN is altered in certain groups must also evolve along with a better understanding of the activities reflected by this component. The detection of change incorporates processes enabling an automatic registration of "sameness", a memory for such regularities and the application of this recent acoustic context to interpreting the present and future state of the environment. It also includes "weighting" the importance of this change to an organism's behaviour. In this light, the MMN has been considered a prediction error signal that occurs when the brain detects that the present state of the world violates a context-driven expectation about the environment. In this paper we revisit the consistent observation of reduced MMN amplitude in patients with schizophrenia. We review existing data to address whether the apparent deficit might reflect problems in prediction error generation, estimation or salience. Possible interpretations of MMN studies in schizophrenia are linked to dominant theories about the neurobiology of the illness., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Cancer incidence in schizophrenia is not increased commensurate with higher rates of risk exposures. Here we report an investigation of the DNA damage response, an anti-tumorigenic defence, in immortalised lymphoblasts from patients with schizophrenia., Methods: Unirradiated and irradiated (5Gy) lymphoblasts from schizophrenia patients (n = 28) and healthy controls (n = 28) were immunostained for the phosphorylated histone variant H2AX (γH2AX), an index of DNA double-strand breaks. Flow cytometry was used to assess cell cycle distribution and γH2AX immunofluorescence. Rate of DNA repair was quantified by determining the temporal change in γH2AX values following irradiation., Results: In unirradiated lymphoblasts, γH2AX levels were significantly increased in the schizophrenia group compared with controls (effect size = 0.86). This increase was most evident in patients with cognitive deficits. In irradiated lymphoblasts, peak radiation-induced γH2AX levels were significantly reduced in patients. No differences between patients and controls were found in the rate of DNA repair or in cell cycle distribution., Conclusions: The significant differences in DNA damage response signalling observed involve modification of histone variant H2AX and thereby implicate regulatory processes determining chromatin structure in dividing lymphoblasts from patients with schizophrenia. The role that aberrant DNA damage response signalling plays in protecting patients from cancer is unclear.

OBJECTIVES. Olfactory hallucinations (OHs) are underrepresented in conventional clinical instruments, infrequently researched, and poorly understood. To advance understanding of OHs, we examined their past-month prevalence and co-occurring symptoms in two datasets. DESIGN. One dataset comprised categorical codes and was examined using homogeneity analysis and logistic regression; the other dataset comprised numeric ratings and was examined using principal components analyses and linear regression. METHOD. The two datasets included: (1) 962 cases with Present State Examination - 9th Edition (PSE-9), codes (recoded present/absent) from the World Health Organization 10 Country (WHO-10) Study and (2) 265 cases with ratings on Scales for Assessing Positive/Negative Symptoms of Schizophrenia (SAPS/SANS). Two PSE-9 items (external- and self-smells) were recoded into a single OH item to examine consistency with the SAPS/SANS dataset, which contained a single OH item. RESULTS. Prevalence of OHs and hallucinations in other modalities differed according to the WHO-10 international centre. Across centres, OHs were present in 13% of the WHO-10 dataset, similar to the 17% prevalence rate in the SAPS/SANS dataset. Referential/control delusions and other hallucinations (particularly, somatic/tactile/gustatory hallucinations) were significant independent correlates of OHs in both datasets. OHs also co-occurred with social anxiety and depression in the WHO-10 dataset, with self-smells being particularly associated with self-depreciation. CONCLUSIONS. Sociocultural factors may modulate the self-reporting and/or detection of OHs and hallucinations in other modalities. Referential/control delusions promote the generation and/or maintenance of OHs independent of factors shared with other hallucinations. OHs and hallucinations of taste, touch, and bodily sensation frequently co-occur. Self-smells warrant sensitive probing., (©2010 The British Psychological Society.)

Aim: Clinical practice improvement carried out in a quality assurance framework relies on routinely collected data using clinical indicators. Herein we describe the development, minimum training requirements, and inter-rater agreement of indicators that were used in an Australian multi-site evaluation of the effectiveness of early psychosis (EP) teams., Methods: Surveys of clinician opinion and face-to-face consensus-building meetings were used to select and conceptually define indicators. Operationalization of definitions was achieved by iterative refinement until clinicians could be quickly trained to code indicators reliably. Calculation of percentage agreement with expert consensus coding was based on ratings of paper-based clinical vignettes embedded in a 2-h clinician training package., Results: Consensually agreed upon conceptual definitions for seven clinical indicators judged most relevant to evaluating EP teams were operationalized for ease-of-training. Brief training enabled typical clinicians to code indicators with acceptable percentage agreement (60% to 86%). For indicators of suicide risk, psychosocial function, and family functioning this level of agreement was only possible with less precise 'broad range' expert consensus scores. Estimated kappa values indicated fair to good inter-rater reliability (kappa > 0.65). Inspection of contingency tables (coding category by health service) and modal scores across services suggested consistent, unbiased coding across services., Conclusions: Clinicians are able to agree upon what information is essential to routinely evaluate clinical practice. Simple indicators of this information can be designed and coding rules can be reliably applied to written vignettes after brief training. The real world feasibility of the indicators remains to be tested in field trials.

The literature that is relevant to evaluation of treatment effectiveness is large, scattered and difficult to assemble for appraisal. This scoping review first develops a conceptual framework to help organize the field, and second, uses the framework to appraise early psychosis intervention (EPI) studies. Literature searches were used to identify representative study designs, which were then sorted according to evaluation approach. The groupings provided a conceptual framework upon which a map of the field could be drawn. Key words were cross-checked against definitions in dictionaries of scientific terms and the National Library of Medicine Medical Subject Headings (MeSH) browser. Using the final list of key words as search terms, the EPI evaluation literature was appraised. Experimental studies could be grouped into two classes: efficacy and effectiveness randomized controlled trials. Non-experimental studies could be subgrouped into at least four overlapping categories: clinical epidemiological; health service evaluations; quality assurance studies; and, quasi-experimental assessments of treatment effects. Applying this framework to appraise EPI studies indicated promising evidence for the effectiveness of EPI irrespective of study design type, and a clearer picture of where future evaluation efforts should be focused. Reliance on clinical trials alone will restrict the type of information that can inform clinical practice. There is convergent evidence for the benefits of specialized EPI service functions across a range of study designs. Greater investment in health services research and quality assurance approaches in evaluating EPI effectiveness should be made, which will involve scaling up of study sizes and development of an EPI programme fidelity rating template. The degree of complexity of the evaluation field suggests that greater focus on research methodology in the training of Australasian psychiatrists is urgently needed.

A prospective cohort study of a random sample of 1,000 Australian Army Vietnam veterans analyzed risk factors for postwar mortality using information from Army records and personal interview assessments of physical and mental health measured approximately 15 years earlier. This enabled examination of the role of combat, military service, and psychiatric status including post-traumatic stress disorder (PTSD) on postwar civilian mortality. Factors predicting mortality were identified using multivariate statistical methods including logistic and Cox regression. Mortality was associated principally with age, enlistment route (regular vs. national service conscripts), and conduct while in service in the whole cohort. Additional analysis using interview data revealed that mortality was predicted by age, smoking status, chronic diabetes, bronchitis and blood diseases, and treatment for cancer and heart disease. Psychiatric status including PTSD diagnosis was not associated with mortality. Veterans' mortality risk may be reduced by attention to smoking and alcohol both in-service and postservice.

Aim: Expert opinion holds that the rate of implementation of specialist services for first presentation psychosis in Australia is much too slow. We aimed to collect evidence regarding this view from the first national survey of adult public mental health services about their self-reported efforts to implement specialist early psychosis intervention (EPI)., Methods: Using a purpose-designed Census form for assessing EPI implementation, adult public mental health service directors throughout Australia were asked about EPI-relevant local service activities., Results: Sixty Census forms were returned (response rate = 61%), representing a total catchment population of 12.5 million people. A minority of services reported high levels of EPI implementation, which varied widely between area services and across state and territory jurisdictions. Rural and remote services were overrepresented in the lowest levels of reported EPI implementation. Only one service characteristic, the value of identifiable funding committed specifically to EPI, was predictive of level of reported EPI implementation., Conclusions: The disturbingly high levels of variability in EPI implementation across jurisdictions suggest a pressing need for a set of nationally agreed uniform EPI implementation standards. Additional specific strategies for rural and remote mental health services may be needed for these services to implement EPI.

The reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have antineoplastic effects. In this study, 6 antipsychotic agents with a range of structural and pharmacological properties (reserpine, chlorpromazine, haloperidol, pimozide, risperidone and olanzapine), were screened for their effect on the viability of cell lines derived from lymphoblastoma, neuroblastoma, non-small cell lung cancer and breast adenocarcinoma. We aimed to determine if antipsychotic drugs in general possess cancer-specific cytotoxic potential, and whether it can be attributed to a common mode of action. With the exception of risperidone, all drugs tested displayed selective inhibition of the viability of cancer cell lines compared with normal cells. Using Affymetrix expression microarrays and quantitative real-time polymerase chain reaction, we found that for the antipsychotic drugs, olanzapine and pimozide, cytotoxicity appeared to be mediated via effects on cholesterol homeostasis. The role of cholesterol metabolism in the selective cytotoxicity of these drugs was supported by demonstration of their increased lethality when coadministered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hr in time course studies, mirroring the time-dependent onset of cytotoxicity induced by the amphiphile, U18666A. On the basis of these results, we concluded that the Class II cationic amphiphilic properties of antipsychotic drugs contribute to their cytotoxic effects by acting on cholesterol homeostasis and altering the biophysical properties of cellular membranes, and that drugs affecting membrane-related cholesterol pathways warrant further investigation as potential augmentors of standard cancer chemotherapy.

The long-term health consequences of war service remain unclear, despite burgeoning scientific interest. A longitudinal cohort study of a random sample of Australian Vietnam veterans was designed to assess veterans' postwar physical and mental health 36 years after the war (2005-2006) and to examine its relation to Army service, combat, and post-traumatic stress disorder (PTSD) assessed 14 years previously (1990-1993). Prevalences in veterans (n = 450) were compared with those in the Australian general population. Veterans' Army service and data from the first assessments were evaluated using multivariate logistic regression prediction modeling. Veterans' general health and some health risk factors were poorer and medical consultation rates were higher than Australian population expectations. Of 67 long-term conditions, the prevalences of 47 were higher and the prevalences of 4 were lower when compared with population expectations. Half of all veterans took some form of medication for mental well-being. The prevalence of psychiatric diagnoses exceeded Australian population expectations. Military and war service characteristics and age were the most frequent predictors of physical health endpoints, while PTSD was most strongly associated with psychiatric diagnoses. Draftees had better physical health than regular enlistees but no better mental health. Army service and war-related PTSD are associated with risk of illness in later life among Australian Vietnam veterans.

Objective: Controversy concerning cancer incidence in schizophrenia exists because of heterogeneous study findings., Method: A meta-analysis was performed on standardized incidence ratios (SIR) of cancer in patients with schizophrenia and first-degree relatives and compared with general population samples., Results: The pooled overall cancer incidence in patients was not significantly increased (SIR = 1.05, CI 0.95-1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI 1.01-1.71), but was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. Breast cancer rates were significantly increased in female patients. The pooled overall cancer incidence in siblings (SIR = 0.89, CI 0.84-0.94) and parents (SIR = 0.90, CI 0.88-0.93) was significantly reduced. A meta-regression detected a significant relationship between cancer risk in the general population and relative risk in patients., Conclusion: The meta-analysis aided exploration of inconsistent study findings. There is a discrepancy between cancer risk exposure and cancer incidence in schizophrenia consistent with a protective effect.

Objective: This study aimed to examine the relative contributions to physical health of combat trauma exposure and posttraumatic stress disorder (PTSD), which have both been implicated separately in poorer physical health but whose unconfounded effects have not been teased out., Methods: Data from an epidemiological study of Australian Vietnam veterans, which used personal interviews and standardized physical and psychiatric health assessments, provided the means to assess the independent and joint effects of psychological trauma exposure and PTSD on a wide range of self-reported measures of physical health. Trauma exposure was measured by published scales of combat exposure and peritraumatic dissociation. Logistic regression modeling was used to assess the relative importance of trauma exposure and PTSD to health while controlling for a set of potential confounders including standardized psychiatric diagnoses., Results: Greater health service usage and more recent health actions were associated more strongly with PTSD, which was also associated with a range of illness conditions coded by the World Health Organization International Classification of Diseases, 9th Edition (asthma, eczema, arthritis, back and other musculoskeletal disorders, and hypertension) both before and after controlling for potential confounders. In contrast, combat exposure and peritraumatic dissociation were more weakly associated with a limited number of unconfounded physical health outcomes., Conclusions: This study provided evidence that PTSD, rather than combat exposure and peritraumatic dissociation, is associated with a pattern of physical health outcomes that is consistent with altered inflammatory responsiveness.

Objective: To review the first 10 years of operation of the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), Australia's first virtual research institute., Method: Narrative description of the evolution of NISAD., Results: Since inception in 1996, NISAD has developed a wide range of activities to enhance existing efforts and develop new initiatives in schizophrenia research, initially throughout New South Wales, but increasingly on a national scale. This involved the initial development of critical research infrastructure to provide the foundation, with the subsequent focus on developing a multidisciplinary programme of schizophrenia research, across the basic to applied research spectrum. While the primary focus has been the scientific domain, NISAD has also played a leading role in increasing public awareness of schizophrenia as a disease amenable to scientific investigation., Conclusion: NISAD has succeeded in building a framework to apply the latest developments in neuroscience to the study of schizophrenia and has formed a multidisciplinary network of clinicians and neuroscientists who are actively collaborating on a range of research initiatives. The 'virtual institute' structure of NISAD has proven cost-efficient and consistent with innovative thinking about research resource management.

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal dopamine D2-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D2-receptor occupancies were determined using 3H-raclopride. The doses required to achieve dopamine D2-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day.

Introduction: The aim of this study was to investigate whether there is an increased susceptibility to apoptosis in cultured fibroblasts from patients with schizophrenia., Method: Dermal fibroblasts were collected and cultured from three groups: patients with schizophrenia, patients with non-schizophrenic psychosis, and healthy comparison subjects. Susceptibility to apoptosis was measured at the level of degradation product (proportion of cells in the sub-G0 cell cycle fraction in which apoptotic bodies accumulate), pro-apoptotic effector (activated caspase-3), and molecular regulators (P53, Bax and Bcl-2). Cell lines were studied under both basal culture and cycloheximide (an apoptotic inducer) exposure conditions., Results: Consistent with increased susceptibility to apoptosis, the proportion of sub-G0 cells under basal conditions was significantly larger in the schizophrenia group, compared to the non-schizophrenic psychosis group. However when apoptosis was stimulated with cycloheximide, the schizophrenia group showed an attenuated caspase-3 response. The pattern of correlations between regulators, caspase-3 and the proportion of sub-G0 cells was different in the schizophrenia group, consistent with group-specific apoptotic pathway dysregulation., Conclusion: The study demonstrated anomalous apoptotic mechanisms in schizophrenia, which appear not to affect non-schizophrenia psychosis patients. The detection of these anomalies in fibroblasts suggests that altered apoptosis may be observable in all somatic cell types in schizophrenia.

Background: Although there is evidence that post-mortem interval (PMI) is not a major contributor to reduced overall RNA integrity, it may differentially affect a subgroup of gene transcripts that are susceptible to PMI-related degradation. This would particularly have ramifications for microarray studies that include a broad spectrum of genes., Method: Brain tissue was removed from adult mice at 0, 6, 12, 18, 24, 36 and 48 h post-mortem. RNA transcript abundance was measured by hybridising RNA from the zero time point with test RNA from each PMI time point, and differential gene expression was assessed using cDNA microarrays. Sequence and ontological analyses were performed on the group of RNA transcripts showing greater than two-fold reduction., Results: Increasing PMI was associated with decreased tissue pH and increased RNA degradation as indexed by 28S/18S ribosomal RNA ratio. Approximately 12% of mRNAs detected on the arrays displayed more than a two-fold decrease in abundance by 48 h post-mortem. An analysis of nucleotide composition provided evidence that transcripts with the AUUUA motif in the 3' untranslated region (3'UTR) were more susceptible to PMI-related RNA degradation, compared to transcripts not carrying the 3'UTR AUUUA motif. Consistent with this finding, ontological analysis showed transcription factors and elements to be over-represented in the group of transcripts susceptible to degradation., Conclusion: A subgroup of mammalian mRNA transcripts are particularly susceptible to PMI-related degradation, and as a group, they are more likely to carry the 3'UTR AUUUA motif. PMI should be controlled for in human and animal model post-mortem brain studies, particularly those including a broad spectrum of mRNA transcripts.

Background: Disturbed speech in schizophrenia may reflect pragmatic deficits of expressive language. Pragmatic comprehension deficits also occur in schizophrenia. This study investigated whether poor 'mind-reading' (i.e. a general difficulty with inferring and monitoring other people's thoughts) causes pragmatic language impairments of both expression and comprehension in patients with schizophrenia., Method: Mind-reading (or theory of mind) was tested in patients with schizophrenia and in healthy controls using a false-belief picture-sequencing task. Pragmatic comprehension skills were assessed using a test of non-literal speech interpretation. Clinical ratings of formal thought disorder (FTD) indexed the expressive language deficits of patients. To control for possible contributory effects of executive dysfunction, inhibitory control was tested using capture picture-sequences and executive-planning was tested using the Tower of London task., Results: False-belief picture-sequencing, understanding of irony and understanding of metaphors were all selectively impaired in the patients. Poor mind-reading (indexed by high error rate in sequencing false-belief stories) was associated with poor understanding of irony, but was unrelated to poor understanding of metaphors. Whereas poor appreciation of irony and poor mind-reading were associated with high ratings of positive formal thought disorder, high ratings of negative formal thought disorder were associated with poor understanding of metaphors and executive dysfunction., Conclusions: Whereas poor mind-reading may contribute to positive aspects of formal thought disorder and impaired appreciation of irony in patients with schizophrenia; negative features of formal thought disorder and poor understanding of metaphors appear better explained by abnormal semantics. Overall, the findings of this study support the view that the functional basis of formal thought disorder in schizophrenia is not unitary.

Objective: To evaluate measures of schizotypy as familial risk factors for schizophrenia with the aim of making recommendations for assessing schizotypy as part of screening procedures for identifying people at risk of schizophrenia., Method: Published studies using self-report and interview-based measures of schizotypy to assess relatives of patients with schizophrenia are reviewed. A parent study is reported evaluating the diagnostic accuracy of parental schizotypy as assessed by three questionnaire-based measures: the Chapman Perceptual Aberration and Physical Anhedonia Scales, and the Eysenck Psychoticism Scale. Group scores for these self-report ratings of 23 parent-pairs of patients with schizophrenia, 20 parent-pairs of patients with chronic nonpsychotic psychiatric disorder, and 19 parent-pairs of healthy comparison subjects are compared., Results: Consistent with published evidence that self-report measures of psychosis-proneness and schizotypy do not consistently reflect familial risk factors that are specific for schizophrenia, scores on questionnaire measures of schizotypy did not distinguish the parents of patients with schizophrenia from the parents in the other two groups., Conclusions: Interview-based assessments of schizotypy better assess familial risk factors than self-report measures of schizotypy. Questionnaire measures of schizotypy should be supplemented by interview-based assessments when screening for individuals at risk of schizophrenia.

This paper reviews the six published incidence studies of the relative risk of cancer in patients with schizophrenia compared with the general population. These studies used: incidence data, register case ascertainment, and controlled for age and sex. It is concluded that schizophrenia is associated with a lower risk of developing cancer. The role of apoptosis (programmed cell death) in cancer and brain development is briefly described. The possibility is explored that increased apoptosis may account for neurodevelopmental abnormalities as well as tumour resistance associated with schizophrenia. The authors propose that p53, a tumour suppressor gene central to regulation of apoptosis, should be investigated as a candidate susceptibility gene in schizophrenia.

Background: Previous studies have reported significant correlations, indicating an emerging relationship, between severity of auditory hallucinations and reduced size of temporal lobe cortical regions implicated in language processing. The present study used high-resolution magnetic resonance imaging (MRI) scanning, along with assessment of functional lateralization via a dichotic listening task (DLT), to extend these findings., Methods: Thirty patients with schizophrenia and a history of auditory hallucinations participated in the study. All were completely right-handed. Eleven subjects were currently hallucinating at the time of the study. Volumetric T1-weighted MRI scans were obtained and regions of interest were manually traced using the BRAINS package (Andreasen et al 1993). Whole brain, bilateral temporal lobe, and anterior superior temporal gyrus volumes were calculated. Subjects completed a binaural consonant-vowel DLT., Results: Increased severity of hallucinatory experience was significantly associated with smaller left anterior superior temporal gyrus volumes. Current hallucinators demonstrated a reduction in right ear advantage on the DLT., Conclusions: The results suggest that auditory hallucinations are subserved by a trait-like dysfunction in language-related neural networks, of which the superior temporal cortex forms one component. The findings are also consistent with theories proposing abnormal lateralization in the etiology of auditory hallucinations.

The effect of d-amphetamine on selective attention in humans was investigated by measuring event-related potentials (ERPs) during a complex auditory selective attention task (CSAT). The CSAT required subjects to make a button press response to infrequent target tones presented amongst tones that varied in pitch (high vs. low), location (left vs. right ear) and duration (51 ms vs. 102 ms). Healthy subjects completed the CSAT under three conditions: placebo, 10 mg and 20 mg d-amphetamine, at least one week apart. D-amphetamine produced a significant dose response increase in hit-rate and decrease in reaction time without changing false alarm rate. D-amphetamine reduced late PN to location irrelevant stimuli and pitch irrelevant stimuli in both the attended and unattended location. The effect of d-amphetamine was interpreted as a decrease in the maintenance of the attentional trace to irrelevant stimuli. However, these changes were accompanied by some evidence of processing of stimulus features in the unattended location. These results suggest that d-amphetamine improves selective attention, and decreases the maintenance of attention to irrelevant stimuli.

Rationale: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia., Objective: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs)., Methods: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task., Results: Confirming our previous results, S2 processing is "accentuated" by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets ("prepulse-induced non-target positivity"; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts "S2 accentuation" associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP., Conclusions: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation.

Reliability, specificity, and validity of three event-related potential (ERP) indices of non-attended and attended auditory information processing [the mismatch negativity (MMN), the novelty-P3a and the target-P3b] were assessed in 21 healthy subjects and 25 schizophrenic patients while performing a visual discrimination task (Ignore condition) and, subsequently, an auditory discrimination task (Attend condition). Re-test reliability, as measured in a subset of 10 healthy subjects and 9 patients respectively, ranged from r=0.4 to r=0.8. In both groups P3a was found to be smaller in the Ignore than in the Attend condition. Patients had significantly larger P3a amplitudes than healthy subjects while their MMN and P3b amplitudes were smaller. Two ERP factors were extracted in healthy subjects: (1) 'novelty reaction' with high loading scores for P3a and (2) 'deviant detection' with high loading scores for MMN. P3b was predominantly loading on the first factor thus confirming partly overlapping P3a and P3b generators. However, considerable variance was also shared by the second factor, particularly in patients. External validity of the ERP factors was confirmed post hoc. Particularly ERP indices of deviant detection were found to be associated with negative symptoms. In order to assess further clinical relevance, therapy response to clozapine was followed-up over 3 yr in a sub-sample of 17 patients. Poor treatment response was associated with high Novelty Factor scores and large P3a amplitudes whereas good response was associated with high Deviant Factor scores and relatively intact MMN. It is concluded that ERP abnormalities provide a severity index of brain impairment and a measure of predicting therapeutic outcome.

There are several reports that performance-based measures as well as symptom ratings improve with clozapine in patients with schizophrenia who previously responded poorly to typical neuroleptic treatment. It is not clear whether improved cognitive function following initiation of clozapine is simply related to relief of psychotic symptoms and extrapyramidal side-effects associated with prior use of typical neuroleptics, or reflects another dimension of the greater efficacy of clozapine compared with typical neuroleptics. To elucidate this issue and better specify the cognitive changes associated with use of clozapine, the authors have assessed cognitive function psychometrically and using event-related potentials (ERPs), pre- and 8-12 wk post-initiation of clozapine treatment. Patients were rated on the BPRS, the SAPS and the SANS and completed a number of tests tapping aspects of frontal lobe function. ERP recordings were conducted using an auditory task twice, which was repeated under passive and active attention conditions. It was found that clozapine differentially affects tests reflecting executive and planning function, and not stimulus-driven cognitive functions. The results were not consistent with the hypothesis that these effects were simply due to relief of medication side-effects but could be related to the D(1) receptor antagonist actions of clozapine.

Haloperidol is widely considered a reference standard in antipsychotic therapy and is commonly used in comparative studies of the efficacy and safety of antipsychotic medication. Comparative clinical trials have shown that the novel antipsychotic agent risperidone tends to have greater efficacy (i.e., clinical response defined as a > or = 20% reduction in total scores on the Positive and Negative Syndrome Scale) than haloperidol in patients with chronic schizophrenia and poses less risk of extrapyramidal symptoms (EPS). We used DerSimonian and Laird's random-effects model to analyze pooled patient data from available randomized, double-masked, comparative trials of risperidone and haloperidol in patients with schizophrenia treated for at least 4 weeks at recommended doses. The purpose of the analysis was to determine whether there are significant overall differences in the rates of patient clinical response, prescription of anticholinergic agents, and treatment dropout. Six of the nine trials revealed in a literature search met all criteria for inclusion in the meta-analysis. The meta-analysis showed that in patients with chronic schizophrenia, risperidone therapy is associated with significantly higher response rates, significantly less prescribing of anticholinergic medication, and significantly lower treatment dropout rates than haloperidol. These results demonstrate the greater treatment efficacy associated with risperidone compared with haloperidol and suggest both a lower incidence of EPS and improved treatment compliance.

Australia and Canada are currently the only Western nations with government guidelines for analyzing the cost-effectiveness of drugs. We used guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee to construct a model for comparing the cost-effectiveness of risperidone and haloperidol over a 2-year period in patients with chronic schizophrenia. Use of clozapine was also included in the analysis as an alternative treatment given to patients who proved unresponsive to therapy with haloperidol or risperidone. Results are expressed in Australian dollars. Cost-effectiveness was determined by using decision-analytic modeling to compare clinical outcomes and costs. The analytic model contained a decision tree for each of the compared agents that tracked the distribution of patients between treatment outcome pathways (i.e., scenarios). Distributions were based on probabilities derived from our meta-analysis results reported elsewhere and from other sources. Each scenario had an associated monetary cost that included all significant direct costs (i.e., hospital costs; outpatient costs; and the cost of drugs, the services of health care professionals, and government-subsidized hostel accommodation). The cost for a given outcome was the sum of costs for all scenarios leading to that outcome. Cost-effectiveness was expressed as the total cost per favorable outcome. The definition of a favorable outcome was one in which the patient was in a response phase at the end of the 2-year period. The probability of a patient experiencing a favorable outcome at the end of 2 years was 78.9% for risperidone versus 58.9% for haloperidol. The total cost of treatment for 2 years was $15,549.00 for risperidone versus $18,332.00 for haloperidol. The expected cost per favorable outcome was $19,709.00 for risperidone and $31,104.00 for haloperidol. Risperidone was more cost-effective than haloperidol and therefore was "dominant" in pharmacoeconomic terms because it produced a higher proportion of favorable outcomes at lower cost. Sensitivity analysis showed that the difference in clinical response rate was a key determinant of cost-effectiveness.

The mentalising abilities of schizophrenic patients and normal controls were tested using picture sequencing and story-telling tasks that required subjects to infer causal mental states in story characters, and a recall task that required subjects to dissociate subjective mental states from objective realities. Selective mentalising deficits were found in some patients. For other patients, general sequencing errors, "sensory" mentalising, and poor recall of symbolic representations suggested more profound problems. Task results were best accounted for by dissociable cognitive abnormalities, rather than graded dysfunction of a central mentalising mechanism. Symptom profiles of patient subgroups and correlations between task measures and clinical ratings linked these cognitive abnormalities to specific symptoms. General sequencing difficulty was associated with both poverty symptoms and reality distortion, suggesting that two mechanisms may underpin such errors: one, inability to manipulate symbolic representations, being linked to poverty; the other, failure to critically evaluate plausible cause-and-effect, being linked to reality distortion. There was some evidence that defective self-monitoring underpins thought disorder. Impaired metarepresentation was linked to the autisticlike symptoms of flat affect, social dysfunction, and alogia, rather than reality distortion. Implications of these findings are discussed with respect to theoretical and methodological issues confronting current schizophrenia research.

This study examines the effect of decreased catecholamine transmission on event-related potential (ERP) indices of selective attention. Intravenous clonidine (1.5 micrograms/kg Catapres), droperidol (15 micrograms/kg Droleptan), or placebo were administered to healthy adult males prior to performance of a multidimensional auditory selective attention task (SAT) in which dichotically presented sequences of tone pips varied on dimensions of location (left or right ear), pitch (high or low), and duration (short or long). Subjects were required to make a button press response to infrequent "target" stimuli that matched a prespecified stimulus on the three dimensions. ERPs were recorded during the task. Clonidine led to a significant increase of processing negativity (PN) over 200-400 ms at the irrelevant location. Droperidol led to a significant increase in reaction time (RT), a significant decrease in hit rate, and an attenuation of PN over the 200- to 400-ms and 400- to 700-ms epochs. Neither substance led to a significant change in P3 amplitude. The role of catecholamines in the selective attention subprocesses of "tuning" and "switching" is discussed.

Objective: There is increasing acceptance that schizophrenia is associated with a generalised disorder in cortical neurodevelopment. The aim of this paper is to review the evidence that this disorder may be accounted for by abnormalities in mechanisms mediated by the main family of excitatory neuroreceptors in cortical brain systems, the N-methyl-D-aspartate (NMDA) glutamatergic receptors., Method: The neurobiological evidence is presented for an abnormality in cortical development related to synaptic pathology in schizophrenia. The unique functions of the NMDA receptor in information processing are described, especially its role in learning and memory, and in neural plasticity and brain development. It is argued that the cellular and molecular mechanisms which underlie learning and memory also govern normal brain development. Studies examining abnormalities in glutamatergic transmission in schizophrenia are reviewed., Results: There is a substantial literature in support of the possibility that NMDA receptor abnormalities may be involved in the neurodevelopmental predisposition to schizophrenia, as well as in symptom production., Conclusions: Research to determine the role of the NMDA receptor in the pathophysiology of schizophrenia is warranted and now feasible. To be successful, this research will require the application of molecular biology techniques to postmortem brain tissue studies, in addition to traditional histochemical approaches.

This study investigated immune activation, as measured by production of interleukin-2 (IL-2) and soluble interleukin-2 receptors (sIL-2R) from stimulated lymphocytes, in schizophrenia and schizophreniform disorder. The study included 13 neuroleptic-free patients, 13 medicated patients and 13 age- and sex-matched control subjects. Production of IL-2 and sIL-2R by peripheral blood mononuclear cells (PBMCs) was measured after in vitro stimulation with phytohaemagglutinin (PHA). Patients' symptoms were rated on the Scales for Assessment of Positive (SAPS) and Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS). IL-2 production by stimulated lymphocytes was significantly elevated in neuroleptic-free patients compared with both medicated patients and control subjects. IL-2 production was inversely correlated with the SAPS subscales of bizarre behaviour and formal thought disorder. The pattern of increased IL-2 production is in contrast to previous findings in patients with schizophrenia. Significant associations with clinical rating scores suggest that IL-2 production may vary in different biological subgroups of schizophrenia and schizophreniform disorder.

Schizophrenic patients reportedly have a deficit in the control of sensitivity to auditory stimuli as shown by the P50 auditory evoked potential wave in a conditioning-testing paradigm that measures suppression of response to a repeated stimulus. Although this finding has been replicated by several US laboratories, one European group has not found differences between schizophrenic patients and normal control subjects. In the present study, investigators in the Schizophrenia Research Center at the Prince of Wales Hospital in Sydney, Australia, selected 22 normal control subjects, 11 acutely ill schizophrenic inpatients, and 11 clinically stable schizophrenic outpatients. Both schizophrenic groups were treated with similar doses of classical neuroleptic medications. Evoked potentials were recorded by an investigator from the US laboratory that initially reported the difference; five averages, each the response to 32 stimulus pairs, were recorded from each subject. The normal control subjects demonstrated significantly more suppression of the P50 response to the repeated stimuli than the schizophrenic groups, as previously reported. There were no significant changes in the suppression measure over the five trials. The suppression of the P50 wave by schizophrenic outpatients was somewhat greater than that by schizophrenic inpatients, but both schizophrenic groups had decreased suppression, compared with the normal subjects. The mean P50 suppression for five averages was successfully used in a logistic regression to classify subjects as normal or schizophrenic. This method was more accurate than attempts to classify subjects with only one average. The mean amplitude of the initial conditioning response did not differ between groups. Schizophrenic patients had slightly shorter mean latencies. There was no direct relationship of P50 suppression to measures of clinical psychopathology.

Objective: The multiple disorders of selective attention found in schizophrenia could be secondary to disturbances in sensory processing. The authors investigated this possibility by using an event-related potential index of auditory sensory memory, called "mismatch negativity.", Method: Medicated (N = 11) and neuroleptic-free (N = 11) patients with schizophrenia and patients with bipolar affective disorder (N = 11) were compared with age- and sex-matched healthy comparison subjects. Auditory stimuli were presented while the subjects were distracted with an attention-demanding visual task. Event-related potentials were elicited by infrequently occurring auditory stimuli (deviants) and by regularly presented auditory stimuli (standards), which differed slightly in duration. The difference in amplitude between the event-related potentials elicited by the deviant and standard stimuli was the mismatch negativity., Results: The amplitude of the mismatch negativity was significantly lower in both groups of schizophrenic patients than in the healthy comparison subjects. Mismatch negativity amplitude was significantly correlated with ratings of negative schizophrenic symptoms but not with positive symptoms. Compared with the matched comparison subjects, the bipolar affective disorder patients did not show lower amplitude of mismatch negativity. There was a significant negative correlation between age and mismatch negativity amplitude., Conclusions: The abnormal auditory sensory memory processing indicated by low mismatch negativity amplitude in the schizophrenic patients cannot be accounted for by neuroleptic medication status. Because this abnormality was significantly related to measures of negative symptoms only, it may be a chronicity marker or reflect a predisposition to the development to schizophrenia. These findings implicate the auditory cortex in the pathophysiology of schizophrenia.

Event-related potentials (ERPs) were recorded while schizophrenic patients and healthy controls read congruous and incongruous sentences in anticipation of a memory test. The schizophrenic group performed more poorly in both recognition memory and cued recall tests. The two groups did not differ in the amplitude of the N400 component of the ERP but the difference between the ERPs to congruous and incongruous sentences persisted longer in the schizophrenic sample. The schizophrenic sample also showed reduced parietal positivity and a reduced effect of congruity on the late positive component that follows N400. Within the schizophrenic sample, measures of attentional impairment and positive thought disorder were correlated with mean amplitude of both the N400 and the subsequent positivity. The results imply that the structure and spread of activation within semantic memory is not impaired in schizophrenia. Rather, impairments appear to lie in processes required to integrate activated information with the current context.

Romney (J. Nerv. Ment. Dis. 178:481-486, 1990) performed a meta-analysis of studies examining psychometrically assessed "thought disorder" in the relatives of schizophrenics. He concluded that thought disorder was more prevalent in the relatives of schizophrenics than control subjects. The present review focuses on only those studies that measured "allusive thinking" using the Lovibond-Rapaport Object Sorting Test in parents of schizophrenics. Even when the meta-analysis included this more limited number of studies, it demonstrated that the parents of schizophrenics were 2.42 times more likely to obtain high scores on the Object Sorting Test, confirming replication of the original McConaghy (J. Neurol. Neurosurg. Psychiatry 22:243-246, 1959) finding. This effect remained significant when the original study was excluded from the meta-analysis. The predictive strength of parental Object Sorting Test score as a familial risk factor for the development of schizophrenia is discussed.

Loosening of thinking as assessed by the Object Sorting Test (OST) has been found in a percentage of normal subjects but in a higher percentage of schizophrenics, and is familially transmitted in both groups. Loosening of thinking in normal subjects is not associated with evidence of impaired function or increased psychopathology, and in recognition of this, it was termed allusive thinking rather than thought disorder. Both OST-assessed loosening and concreteness of thinking were found to be present independently in a high percentage of schizophrenics, so that both were considered to contribute to schizophrenic thought disorder. The presence of OST-assessed loosening in schizophrenics would, therefore, be predicted to correlate partially rather than totally with measures of schizophrenic thought disorder. It has been suggested that OST-assessed loosening in normal subjects is due to a genetically determined reduction in strength of an inhibitory process that limits the spread of activation of semantic associations and results in a predisposition to schizophrenia. The brain event-related potential P300, which is, in part, under genetic control, may index this inhibitory process. Therefore, it was predicted that in normal subjects, P300 would correlate with OST-assessed loosening of associations. If schizophrenic thought disorder is due to a further weakening of this inhibitory process, it can be predicted that P300 in schizophrenics correlates only weakly with OST-assessed loosening of thinking, but more strongly with schizophrenic thought disorder. In a study in which P300 was elicited using a difficult selective attention task with 15 unmedicated schizophrenics and 22 healthy subjects, all three predictions were supported.

Reduced amplitude of the P300 component of the event-related potential (ERP) has frequently been reported in schizophrenic patients and their first-degree relatives. The present study examined the relationship between this ERP measure of attentional processing and loosening of associations in normal university students (termed "allusive thinking"). Among male subjects, scores reflecting increased conceptual loosening, measured using the Lovibond scoring method for the Goldstein-Scheerer Object Sorting Test (OST), were significantly correlated with smaller P300 amplitude recorded during an auditory target detection task. There was no association between OST score and either performance of the target detection task or self-reported psychopathology. It is suggested that reduced P300 amplitude could reflect altered attentional processing in individuals with a constitutional trait factor of thought disorder.

Attentional dysfunctions in schizophrenia were investigated using a sentence priming task. Schizophrenic patients and healthy control subjects were presented with sentences to which they were required to make a response based on either semantic or physical stimulus features. Schizophrenics' behavioural responses were slower than those of controls, particularly when attending to semantic relationships, but their performance was no less accurate. Both the P300 and the N400 components of the event-related potentials (ERPs) recorded to the sentence completions were attenuated in the schizophrenic sample. The results are interpreted in terms of a deficit in the active maintenance of semantic information in memory and the integration of new information with this representation.

The present study examined long-term repetition effects on human auditory event-related potentials (ERPs). ERPs were recorded from subjects performing the same multidimensional auditory selective attention task on six separate occasions spaced one week apart. The task required subjects to attend to tones that varied along the dimensions of location (L), pitch (P), and duration (D) and to detect prespecified target (L + P + D +) combinations of these attributes. Processing negativity (PN) between 100-400 ms did not change in amplitude or onset latency as a function of repeated experience with the task. In contrast, two measures of "very late" PN were reduced with practice. Specifically, the location effect measured over the 400-700-ms epoch was significant only for Weeks 1 and 2, and the separation of the L + P + D- ERP from other D- ERPs, measured over the 700-1000-ms epoch, was significantly reduced from Week 1 to Week 2. A late negative component (700-1000 ms) elicited by correctly identified targets increased between Weeks 1 and 2, consistent with subjects adopting the strategy of rehearsal of the target itself rather than the L + P + D- standard. P2 amplitude increased significantly for all standards, possibly due to decreased latency jitter in later weeks. N1 latency became significantly shorter over weeks, reflecting either increasing confidence in stimulus discrimination with repeated testing or the overlapping of an unchanging N1 with an increasing P2.

Brain ERPs were recorded in ten unmedicated schizophrenic patients and age- and sex-matched healthy controls during a multidimensional listening task. Patients showed a marked reduction in a long-duration attention-related negative ERP component, termed 'processing negativity' (PN), which was elicited by attended stimuli. The amplitude of PN was significantly correlated with SANS and SAPS scores of schizophrenic symptoms. The P300 component was also reduced in amplitude in patients, and was significantly correlated with SANS ratings of negative thought disorder. These findings provide neurophysiological evidence of impairment in the maintenance of selective attention and the cognitive processes associated with target detection among schizophrenic patients. The reduced PN in schizophrenics implicates frontostriatal pathways in the aetiology of attentional deficits in schizophrenia.

Auditory event-related potentials (ERPs) from a multidimensional selective attention task were recorded from 10 unmedicated schizophrenic patients and 10 age- and sex-matched healthy controls. Tone pip stimuli varying on the dimensions of pitch (high or low) and location (left or right ear) formed four 'channels' of stimuli: left low, left high, right low, and right high. The pitch difference was considerably more difficult to discriminate than the location difference. Subjects were instructed to pay attention to a designated channel and press a button whenever they detected a long-duration, rare target tone that occurred amongst frequent short-duration standard tones. There were a number of differences between unmedicated schizophrenics and controls in processing negativity elicited by standard tones. There was no evidence of hierarchical processing of stimulus dimensions in the early processing negativity component, and the late frontal component was virtually absent in schizophrenics. Furthermore, there was evidence that in schizophrenics the processing of the location dimension was delayed for standard tones having the same pitch as the target. The P300 component to attended target tones was substantially reduced in schizophrenics over parietal sites but there was no difference between the two groups over frontal sites. The results are interpreted in terms of multiple attentional deficits in schizophrenics that are indicative of a failure in the planning and execution of selective listening strategies. Such a failure may result from a dysfunction in the prefrontal regions of the brain.

Auditory evoked potentials were recorded in healthy medical students who were grouped according to whether they obtained a high or low score on an Object Sorting Test (OST), on which schizophrenics also obtain high scores. High-OST scoring male students compared to Low-OST scoring male students showed reduced P200 latency. This finding was replicated in a second study of medical students. The authors believe these results support the hypothesis that schizophrenic thought disorder and an equivalent loosening of thinking in nonschizophrenic populations (allusive thinking) have a neurophysiological basis in common, namely a relative weakness of inhibition operating on cortical and subcortical structures.

In an attempt to replicate findings reported by Slade (1976), 12 hallucinating and 12 non-hallucinating shcizophrenic subjects were compared on tests of verbal ability, personality and mental imagery variables and the Verbal Transformation Effect. No significant differences between the groups was demonstrated. When the data from both groups of schizophrenics were combined, a significant correlation was found between 2 measures of the Verbal Transformation Effect and the P-score of the Eysenck Personality Questionnaire.

Jones and Miller (1981) reported that schizophrenics could be distinguished from healthy controls by latency differences in their ipsilateral and contralateral somatosensory evoked potentials (SEPs), considered a measure of corpus callosum conduction time. Subsequent replication studies failed to follow the method of the original study. The present study represents a precise replication. An additional control for contamination of SEPs by an auditory stimulus generated by the vibrotactile stimulus was used. Ipsilateral SEP activity was identified but poor definition of a positive peak in the range of interest prevented measurement of peak latency. Evidence was advanced to suggest that such ipsilateral potentials result from activity at the vertex. It was concluded that this method is inappropriate for the investigation of interhemispheric transmission.

A significant negative correlation between platelet monoamine oxidase (MAO) activity, a stable peripheral enzyme measure under genetic control, and sensation seeking, as measured using the Zuckerman Sensation Seeking Scale (SSS), has been reported for male subjects in several studies. As tobacco smoking has been related to both these measures, in the present study correlations were calculated among smoking and non-smoking male university students. Platelet MAO activity was negatively correlated with the Disinhibition and Total scales of the SSS. These correlations were not significantly different in smokers and non-smokers. The results are discussed in terms of recent evidence of reduced platelet MAO activity in psychiatric patients.