Is cannabis a risk factor for suicide attempts in men and women with psychotic illness?

OBJECTIVE: To investigate whether recent cannabis use by men and women with psychotic disorders was associated with increased risk of suicide attempt, and to determine associated factors, stratified by sex. METHODS: Data from 1065 men and 725 women interviewed in the Australian national survey of psychosis were analysed to model separately, for each sex, the impact of daily, casual or no past-year cannabis use and other risk factors including age, on a past-year suicide attempt. RESULTS: In the past year, 168 (9.4%) participants attempted suicide. Unadjusted analyses showed daily cannabis users of both sexes had significantly increased odds of attempting suicide compared to non-users. After adjusting for confounding factors, this relationship was no longer significant. Depression had the strongest association with attempting suicide for both sexes. Sex differences in other risk factors were observed. In post hoc analysis, daily cannabis use was associated with higher odds of attempting suicide in older men compared to non-users; this was not found in younger men or women. CONCLUSIONS: Associations between past-year cannabis use and suicide attempts were confounded by other factors (depression, loneliness, homelessness and hallucinations). The possibility of greater risk of suicidal behaviour with regular cannabis use for older men should be considered.

[Multi-centre clinical assessment of the Russian language version of the Diagnostic Interview for Psychoses]. / Mnogotsentrovoe klinicheskoe issledovanie russkoiazychnoi versii diagnosticheskogo interv'iu dlia psikhozov.

OBJECTIVES: The Diagnostic Interview for Psychoses (DIP) was developed to enhance the quality of diagnostic assessment of psychotic disorders. The aim of the study was the adaptation of the Russian language version and evaluation of its validity and reliability. MATERIAL AND METHODS: Ninety-eight patients with psychotic disorders (89 video recordings) were assessed by 12 interviewers using the Russian version of DIP at 7 clinical sites (in 6 cities of the Russian Federation). DIP ratings on 32 cases of a randomized case sample were made by 9 interviewers and the inter-rater reliability was compared with the researchers' DIP ratings. Overall pairwise agreement and Cohen's kappa were calculated. Diagnostic validity was evaluated on the basis of comparing the researchers' ratings using the Russian version of DIP with the 'gold standard' ratings of the same 62 clinical cases from the Western Australia Family Study Schizophrenia (WAFSS). RESULTS: The mean duration of the interview was 47±21 minutes. The Kappa statistic demonstrated a significant or almost perfect level of agreement on the majority of DIP items (84.54%) and a significant agreement for the ICD-10 diagnoses generated by the DIP computer diagnostic algorithm (κ=0.68; 95% CI 0.53,0.93). The level of agreement on the researchers' diagnoses was considerably lower (κ=0.31; 95% CI 0.06,0.56). The agreement on affective and positive psychotic symptoms was significantly higher than agreement on negative symptoms (F(2,44)=20.72, p<0.001, η2=0.485). The diagnostic validity of the Russian language version of DIP was confirmed by 73% (45/62) of the Russian DIP diagnoses matching the original WAFSS diagnoses. Among the mismatched diagnoses were 80 cases with a diagnosis of F20 Schizophrenia in the medical documentation compared to the researchers' F20 diagnoses in only 68 patients and in 62 of the DIP computerized diagnostic outputs. The reported level of subjective difficulties experienced when using the DIP was low to moderate. CONCLUSION: The results of the study confirm the validity and reliability of the Russian version of the DIP for evaluating psychotic disorders. DIP can be recommended for use in education and training, clinical practice and research as an important diagnostic resource.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

The structure of schizotypal personality traits: a cross-national study.

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.

On the interconnectedness and prognostic value of visual and auditory hallucinations in first-episode psychosis.

BACKGROUND: Visual hallucinations (VH) are common symptoms in schizophrenia and other psychoses. An understanding of their cross-sectional and longitudinal patterns of association with auditory hallucinations (AH) is essential for developing accurate models of hallucinatory phenomena. OBJECTIVE: This study presents the most comprehensive examination of the association between VH and AH, and its change over time, in 1303 individuals with first-episode psychosis (FEP) and 469 individuals with chronic schizophrenia. METHOD: The samples included data from the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders and the Western Australian Family Study of Schizophrenia (WAFSS). Standardized assessment of symptoms and functioning were used to examine the clinical profile and symptom co-occurrence of hallucinations over time. RESULTS: VH were approximately half as frequent as AH, almost always co-occurred with AH, and tended to be linked to a more severe psychopathological profile. AH and VH at baseline also predicted higher disability, risk of relapse and duration of psychosis after 1 and 2 years, especially when occurring in combination. CONCLUSIONS: The findings point to three hallucination 'subtypes' with different symptom profile. The VH+AH combination signals greater psychopathology and a less favourable prognosis, than hallucinations occurring in isolation, and no hallucinations. This conclusion points to one common mechanism for all hallucinations, which can separate into distinct pathways and modalities. For a more complete clinical picture, clinicians should carefully probe for both auditory and VHs in presenting patients.

Psychosis prevalence and physical, metabolic and cognitive co-morbidity: data from the second Australian national survey of psychosis.

BACKGROUND: There are insufficient data from nationwide surveys on the prevalence of specific psychotic disorders and associated co-morbidities. METHOD: The 2010 Australian national psychosis survey used a two-phase design to draw a representative sample of adults aged 18-64 years with psychotic disorders in contact with public treatment services from an estimated resident population of 1 464 923 adults. This paper is based on data from 1642 participants with an International Classification of Diseases (ICD)-10 psychotic disorder. Its aim is to present estimates of treated prevalence and lifetime morbid risk of psychosis, and to describe the cognitive, physical health and substance use profiles of participants. RESULTS: The 1-month treated prevalence of psychotic disorders was 3.10 cases per 1000 population aged 18-64 years, not accounting for people solely accessing primary care services; lifetime morbid risk was 3.45 per 1000. Mean premorbid intelligence quotient was approximately 0.5 s.d.s below the population mean; current cognitive ability (measured with a digit symbol coding task) was 1.6 s.d.s below the population mean. For both cognitive tests, higher scores were significantly associated with better independent functioning. The prevalence of the metabolic syndrome was high, affecting 60.8% of participants, and pervasive across diagnostic groups. Of the participants, two-thirds (65.9%) were current smokers, 47.4% were obese and 32.4% were sedentary. Of the participants, half (49.8%) had a lifetime history of alcohol abuse/dependence and 50.8% lifetime cannabis abuse/dependence. CONCLUSIONS: Our findings highlight the need for comprehensive, integrative models of recovery to maximize the potential for good health and quality of life for people with psychotic illness.

ENDOPHENOTYPE FINDINGS AND PSYCHOSIS PROFILE OF SCHIZOPHRENIA IN MONGOLIA / Шинэ санаа Шинэ нээлт

BACKGROUND: The Western Australian Family Study of Schizophrenia (WAFSS) has conducted genetic epidemiology studies of schizophrenia in Australia for two decades. Recently the WAFSS practices were adopted at the National Centre for for Mental Health in Mongolia, with a view tocollecting comparable data. Like the cited projects (supra), we are cognizant of the dangers of multi site data collection. We replicate common practices, such as training manuals and common site training and refreshment (CCRN WHO training centre). However in international (possibly multilingual) collection and pooling, identical assessment is difficult, it is impossible to replicate endophenotype instructions verbatim (Calkins 2007), and identical recording equipment may not be available indisparate sites. At the very least the data must be compared separately, with the option of weighting,before the pooling for genetic analysis. The use of endophenotypes (Gottesman& Gould) is well established in schizophrenia research for genetic analysis () as well as in more general neuroscience biomarker approaches. The use of electrophysiological markers, and particularly Event-Related Potentials (ERPs) is a well developedaspect of this approach (BraffDL, 2007, TuretskyBI, 2009). Electrophysiological endophenotypes include (inter alia) the Mismatch Negativity (MMN), P50 suppression ratio (P50), auditory oddball P300 (P300), and Antisaccade (AS) tasks. In this study, we seek to follow the multi centre quality assurance examples for pooled data on a smallerscale. This report details the validation of compatibility between the Western Australian Family Study of Schizophrenia (WAFSS) dataset (Perth, Australia), and a pilot dataset from the National Centre for Mental Health (NCMH) in Ulaanbaatar, Mongolia. The working hypothesis is that the psychiatric and endophenotype profiles in the two datasets are sufficiently similar to allow data ompatibility for genetic analysis.METHODS: The Mongolian version of the DIP was developed as part of a joint genetic investigation of schizophrenia between the Centre for Clinical Research in europsychiatry (CCRN) in Perth Western Australia, and the National Center of Mental Health (NCMH) in Ulaanbaatar, Mongolia.The DIP is a semi-structured interview for psychosis for use in epidemiological and clinical settings (CastleD, 2006). It is designed to provide a diagnosis, as well as to assess symptom profiles (present state, past year and lifetime), social functioning, disablement, and service utilisation. It was developed specifically for the National Mental Health Survey – Low Prevalence (Psychotic) Disorders Study(Jablensky et al, 1999, 2000), and has been translated to Italian (RossiA, 2010), Norwegion (SkorvenCS, 2010), and to Mongolian in 2012. The process started with the translation of the original English language version (Castle et al., 2006) by an experienced bilingual psychiatrist (GE) from the NCMH whose native language was Mongolian. Layout and formatting of the document were preserved. It was then back-translated by a non medical,tertiary educated professional, whose native language is Mongolian, but is now resident in Perth. The back-translation was reviewed by an original author (AJ) and experienced practitioners (GP). Grammatical and syntactical discrepancies were resolved directly with the original translator. Event Related Potentials To replicate the WAFSS ERP approach at NCMH, a new portable ERP recording system was deployed. This decision was based on several considerations: a) the WAFSS system could not be taken out of service; b) an identical system could not be replicated due to the age of the components; c) an equivalent system would be too substantial for easy, cost effective transport; d) the system was expected to be used in multiple sites in Mongolia; e) the same system was expected to be used in other Australian projects.The Portable ERP system uses NuAmps, with a hardware selected reference at the FPz location. While the ear references A1 and A2 were recorded, the mathematically re-referenced data is not the same as directly linking ears. (Citation ****). Instead the data was analysed as recorded, with cognizance traces (instead of 20) could not be used. This marks a variation from the original WAFSS processing. Instead of artifact rejection on any trace, only the relevant trace (Fz, Cz, Pz) was used for each ERP (MMN, P50, P300). Endophenotypes The ERP endophenotypes are clearly continous variables, and analysed with general linear modelling. Two tailed significance testing was used for between cohort comparisons, since there is no a priori indication which cohort would have the higher values. Single tailed testing was used in comparing Proband (Pb) and Control (Ctl) groups within the same cohort, as thedirection of any difference is well established.RESULTS: DIP The structure of the diagnostic module (DIP-DM) follows the Operational Criteria for Psychosis, OPCRIT, version 3.31 (McGuffin et al., 1991; Williams et al., 1996) 90-item checklist. It can be used to generate diagnoses according to the criteria of ICD-10 (World Health Organization, 1993); DSM-IV (American Psychiatric Association, 1994); the Research Diagnostic Criteria (Spitzer et al., 1978), and others. The summary of diagnoses (ICD-10 and DSM-IV) generated for each cohort are shown in Figure 1. Diagnostic distribution (%) of 30 interviewed cases from NCMH and 201 cases from the WAFSS cohorts, according to the DIP diagnostic algorithm, by diagnostic classification system. To facilitate omparisons between different criteria systems, Castle (2006) escribes aggregated diagnostic classification descriptors (with reservations) that are used in Figure 1. Greater detail of the DIP responses that support these descriptors is shown for similiarly aggregated questions in Figure 2. aMicrovolts for MMNAmp and P300Amp, numeric forothers.bFor MMN, P50, and AS, but not P300, the raw mean (notabsolute value) for the Pb and Fm groups are higher thanthat of the Ctl group. cEqual variances not assumed.Endophenotype values were each significantly “worse” inthe proband group of the NCMH cohort, for MMN (t=1.65;p=0.05), P300 (t=-2.02; p=0.02) and AS (t=2.12; p=0.02).The comparable values from the WAFSS cohort showed thesame behaviour for MMN (t=4.52; p<0.01), P300 (t=-3.35;p<0.01) and AS (t=3.93; p<0.01). The P50 endophenotypedid not show a significant difference between clinical groups in either NCMH (t=0.20) or WAFSS (t=1.12) cohort. DISCUSSION: This comparison has shown that there is not a significant difference (α= 0.05) between the NCMH and WAFSSpopulations (patient and control). This outcome is deemed sufficient to allow pooled analysis of genetic and electrophysiological data in future studies. It is acknowledged that the outcome does not show that the two populations are the same. Questions of international comparison (McGrathJJ, 2006) in incidence and prevalence, of mental illness and particularly of schizophrenia are eschewed. These were not the purpose of the study. Our experience from this study, as distinct from analysis, is that situational variation in equipment, protocol and recruitment likely outweigh any cultural differencesin epidemiology. The absolute value of the lectrophysiologicalendophenotypes was different between the two sites, butthe relative values were the same. The control group showed“better” responses than the patient group, with similareffect size. Moreover, the patient clinical profile was also slightly different. The incidence of neuroleptic medication was a substantial uncontrolled factor. The question becomes how to deal with these differences.In combining population groups, the data can be discarded,equalized, or transformed. Describe each. We seek to standardize comparisons between populations by transforming data by scaling prior to genetic analysis.Absolute value The raw amplitude data for both ERP eatures (MMN, P300) is significantly lower from the Mongolian cohort in both Patient and Control groups. Endophenotype characteristics.ScalingWhile the difference in absolute values precludes directlycombining data from different cohorts, the consistentendophenotype characteristics allows one possiblemethod to further genetic investigation of continuousendophenotype variables. The results are expected toderive from a combination of technical, situational, clinicaland endophenotype factors. Each of these factors could befurther investigated individually. However, if a combinedendophenotype analysis is even theoretically acceptable,then the endophenotypebehaviour in different cohorts hasto be defined as identical, and the standardized measuresfrom equivalent Control groups must be equal. If the WAFSScontrol group is considered as the standard in this study, then the scaling factors for the NCMH cohort are 13.5 (MMN), 1.0 (P50), 2.5 (P300) and 0.6 (AS).SUMMARY: The consistency in endophenotypebehaviour betweencohorts legitimizes the application of the genetic approachin Mongolia. DNA extraction and analysis for this cohort iscontinuing and, although for smaller numbers, preliminaryresults can be compared with the Australian cohort.

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.

Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

A whole-of-population study of the prevalence and patterns of criminal offending in people with schizophrenia and other mental illness.

BACKGROUND: Large epidemiological studies are needed to better understand the prevalence and profile of offending by people with mental illness. This study used a whole-of-population design to examine the prevalence, type and pattern of offending across all psychiatric diagnoses, including schizophrenia, compared to the general population. Method We used whole-of-population longitudinal record-linked data for a cohort of all Western Australians born 1955-1969 to determine arrest history over the period 1985-1996 and to ascertain recorded history of psychiatric illness. Of the cohort, 116 656 had been arrested and 40 478 were on the psychiatric case register. RESULTS: The period prevalence of arrest for people with any psychiatric illness was 32.1%. The highest arrest prevalence, by diagnostic category, was for substance use disorders (59.4%); the prevalence for schizophrenia was 38.7%. Co-morbid substance use disorders significantly increased risk of arrest in people with schizophrenia. The prevalence of mental illness among offenders was 11.1%: 6.5% of offenders had substance use disorders and 1.7% had schizophrenia. For the majority of offenders with a psychiatric illness, first arrest preceded first contact with mental health services; for schizophrenia only, this proportion was increasing over time. The mean percentage annual change in the number of arrests during 1985-1996 rose significantly for offenders with a psychiatric illness other than schizophrenia and dropped significantly for those with no mental illness. Compared to non-psychiatric offenders, offenders with schizophrenia were more likely to offend alone, to offend in open places and to target strangers. CONCLUSIONS: Our findings open the way to an informed approach to the management of offenders with mental illness.

The disease entity in psychiatry: fact or fiction?

BACKGROUND: The current debate concerning the forthcoming revisions of the International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM) lacks sufficient historical perspective on groundwork concepts in psychiatry, such as the nature of the disease entity, categorical typologies, dimensional models and their validity and utility. OBJECTIVE: To offer an overview of the evolution and metamorphoses of the conceptual basis of classification in psychiatry, with particular focus on psychotic disorders. METHOD: Discursive, proceeding from history of ideas to a critique of present dilemmas. RESULTS: Much of the present-day discussion of basic issues concerning the classification of mental disorders is a replay of debates that took place in the earlier periods of scientific psychiatry. CONCLUSION; The mainstream nosological paradigm adopted in psychiatry since early 20th century is in need to be critically examined and transcended with the help of concepts and methodological tools available today.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.

Polymorphisms associated with normal memory variation also affect memory impairment in schizophrenia.

Neurocognitive dysfunction is a core feature of schizophrenia with particularly prominent deficits in verbal episodic memory. The molecular basis of this memory impairment is poorly understood and its relatedness to normal variation in memory performance is unclear. In this study, we explore, in a sample of cognitively impaired schizophrenia patients, the role of polymorphisms in seven genes recently reported to modulate episodic memory in normal subjects. Three polymorphisms (GRIN2B rs220599, GRM3 rs2189814 and PRKCA rs8074995) were associated with episodic verbal memory in both control and patients with cognitive deficit, but not in cognitively spared patients or the pooled schizophrenia sample. GRM3 and PRKCA acted in opposite directions in patients compared to controls, possibly reflecting an abnormal brain milieu and/or adverse environmental effects in schizophrenia. The encoded proteins balance glutamate signalling vs. excitotoxicity in complex interactions involving the excitatory amino acid transporter 2 (EAAT2), implicated in the dysfunctional glutamatergic signalling in schizophrenia. Double carrier status of the GRM3 and PRKCA minor alleles was associated with lower memory test scores and with increased risk of schizophrenia. Single nucleotide polymorphism (SNP) rs8074995 lies within the PRKCA region spanned by a rare haplotype associated with schizophrenia in a recent UK study and provides further evidence of PRKCA contribution to memory impairment and susceptibility to schizophrenia. Our study supports the utility of parsing the broad phenotype of schizophrenia into component cognitive endophenotypes that reduce heterogeneity and enable the capture of potentially important genetic associations.

Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition.

Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate.

Kraepelin's concept of psychiatric illness.

Emil Kraepelin fundamentally shaped our current psychiatric nosology. Although much has been written about his diagnostic formulations, less is known about his views on the fundamental nature of psychiatric illness and the goals of psychiatric nosology. We focus on his writings from 1896 to 1903 but also review his inaugural lecture in Dorpat in 1887 and his last two papers, published in 1919­1920. Kraepelin hoped for a ' natural ' classification of psychiatric illness but realized that the level of etiologic knowledge required to undergird this effort was not feasible in his own lifetime. This did not stop him, however, from developing a pragmatic approach based on his clinical method of careful description with detailed follow-up, coupled with the available fallible tools of pathological anatomy and, by 1919, genetics and biochemistry. Kraepelin saw psychiatric disorders as multifactorial, arising from the difficult to untangle action and interaction of internal and external causes. He was aware of the problem of defining the boundaries of illness and health but knew this was not unique to psychiatry. Contrary to his stereotype, he was sensitive to the importance of personality factors in psychiatric illness and advocated for their investigation. He also recognized the limitations of his ' clinical method' and was especially critical of classifications based on single prominent symptoms. Ultimately, Kraepelin was a skeptical realist when it came to psychiatric nosology. His goal of developing a consistent ' natural ' classification of the major mental disorders has yet to be attained, but his ' research agenda' remains central to psychiatry to the present day.

'Social dysmetria' in first-episode psychosis patients.

OBJECTIVE: The 'embodied cognition' hypothesis suggests a close relationship between internal self-representations and the outward expression of social behaviours and emotions. Given self-awareness disturbances in patients with first-rank symptoms (FRS), we hypothesized that these patients would show abnormal social behaviours. In this study, we examined the social interactive skills of patients with first-episode psychosis during an interview, together with changes in performance over time. METHOD: We analysed previously unreported data from 227 patients with first-episode psychosis (90 with, and 137 without, FRS) who took part in the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders. They were assessed on the Psychological Impairment Rating Schedule (PIRS) and examined again after 2 years. RESULTS: A principal component analysis on the Psychosocial Impairment Rating Schedule produced two factors (interactive skills; withdrawal from interactions). Patients with FRS showed greater impairments in the domain linked to 'interactive skills', which remained 2 years after the first experience of a psychotic illness. These findings were not explained by clinical characteristics, or presence of non-FRS delusions. CONCLUSION: Self-awareness deficits, as indexed by the FRS symptom cluster, are linked to deficits in social interactive behaviours. These abnormalities are indicative of 'social dysmetria' in this group, which involves difficulties conveying motor aspects of behaviours, volition and affect to facilitate mutual communication. These findings point to the utility of behavioural assessment scales in clinical and research settings.

Subtyping schizophrenia: implications for genetic research.

Phenotypic variability and likely extensive genetic heterogeneity have been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. The inconsistent results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype suggest that the current broad concept of schizophrenia does not demarcate a homogeneous disease entity. Approaches involving subtyping and stratification by covariates to reduce heterogeneity have been successful in the genetic study of other complex disorders, but rarely applied in schizophrenia research. This article reviews past and present attempts at delineating schizophrenia subtypes based on clinical features, statistically derived measures, putative genetic indicators, and intermediate phenotypes, highlighting the potential utility of multidomain neurocognitive endophenotypes.