The origin and course of schizophrenia: implications for clinical practice.

The authors first review current evidence concerning abnormalities of brain structure and function in schizophrenia and interpret them within a "network" pathophysiological model of the disorder. This information is then placed within a contemporary neurodevelopmental framework that "roots" the illness in adverse events during early pregnancy, which result in a developmentally compromised nervous system. They then consider the controversy as to whether the subsequent expression of psychosis reflects an active morbid process and, in a more general sense, whether the disorder is characterized by subsequent progression and clinical deterioration.

Investigation of the apolipoprotein-L (APOL) gene family and schizophrenia using a novel DNA pooling strategy for public database SNPs.

We performed an extensive genetic association study of the six known apolipoprotein-L (APOL) genes and schizophrenia (SZ) using a novel DNA pooling strategy. The APOL genes are both positional and functional candidate genes for SZ. This gene family maps to chromosome 22q12.

Epidemiology of first-episode psychosis: illustrating the challenges across diagnostic boundaries through the Cavan-Monaghan study at 8 years.

The epidemiology of first-episode psychosis is poorly understood because of the paucity of systematic studies, yet it constitutes the fundamental basis for understanding the disorder and the foundations on which clinical, biological, therapeutic, and long-term outcome studies are built. A particular need is to clarify the diagnostic breadth of first-episode psychosis and, on this basis, to undertake systematic comparisons across representative populations of the psychoses, to include comparisons with first-episode mania. Considered here is the new generation of prospective studies that may be able to inform in some way on these issues.

Ethological resolution of behavioural topography and D1-like versus D2-like agonist responses in congenic D5 dopamine receptor mutants: identification of D5:D2-like interactions.

The phenotypic ethogram of congenic dopamine D(5) receptor "knockout" mice was evaluated. Each individual topography of behaviour within the natural repertoire was assessed over the extended course of initial exploration of and subsequent habituation to the environment, and following challenge with a series of D(1)-like agonists. Over initial exploration, D(5)-null mice evidenced a modest reduction in locomotion and a modest increase in sifting.

Topographical effects of D1-like dopamine receptor agonists on orofacial movements in mice and their differential regulation via oppositional versus synergistic D1-like: D2-like interactions: cautionary observations on SK&F 82958 as an anomalous agent.

Using a novel procedure, the regulation of individual topographies of orofacial movement in the mouse by oppositional versus cooperative/synergistic D1-like: D2-like dopamine receptor interactions was studied. The D1-like agonists SK&F 38393 and SK&F 83959 each induced vertical, but not horizontal, jaw movements, together with tongue protrusions and incisor chattering; however, SK&F 82958 induced a different profile which, consistent with other neurochemical and neurophysiological studies, suggests that this agent shows anomalous properties relative to other D1-like agonists. When given alone, the D2-like agonist quinpirole reduced horizontal jaw movements and incisor chattering.

Systematic comparison of subjective and objective measures of quality of life at 4-year follow-up subsequent to a first episode of psychosis.

There is enduring debate about the validity of subjective measures of quality of life derived from people with psychiatric disorders and particularly from those with psychosis. We evaluated patients with established psychosis 4 years after their first episode. We compared subjective and objective measures of quality of life and evaluated the influence of insight on the individual's interpretation of their quality of life.

D1-like dopamine receptor-mediated function in congenic mutants with D1 vs. D5 receptor "knockout".

Current understanding of the functional roles of individual dopamine D1-like [D1, D5] and D2-like [D2L/s, D3, D4] receptor subtypes remains incomplete. In particular, the lack of pharmacological agonists and antagonists able to distinguish between D1 and D5 receptors means that any differential roles in the regulation of behavior are poorly understood. Mutant mice with targeted gene deletion ("knockout") of individual dopamine receptor subtypes offer an important alternative approach to resolving these functional roles.

Neurological soft signs and dermatoglyphic anomalies in twins with schizophrenia.

Schizophrenia is associated with altered neural development. We assessed neurological soft signs (NSS) and dermatoglyphic anomalies (total a-b ridge count (TABRC) and total finger ridge count) in 15 pairs of twins concordant and discordant for schizophrenia. Within-pair differences in both NSS and TABRC scores were significantly greater in discordant compared to concordant monozygotic pairs.

Longitudinal assessment of psychopathological domains over late-stage schizophrenia in relation to duration of initially untreated psychosis: 3-year prospective study in a long-term inpatient population.

There remains uncertainty regarding any progressive nature of psychopathology and cognitive dysfunction in late-stage schizophrenia, and whether duration of initially untreated psychosis (DUP) might be associated with such 'progression'. This study examines longitudinally, over 3 years, the psychopathology and neuropsychology in 82 inpatients with DSM-IV schizophrenia, many of whom were admitted in the pre-neuroleptic era. Increase in executive dysfunction exceeded that in general cognitive impairment.

Ethologically based resolution of D2-like dopamine receptor agonist-versus antagonist-induced behavioral topography in dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa "knockout" mutants congenic on the C57BL/6 genetic background.

Given the critical role of dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) in the regulation of dopaminergic function, DARPP-32-null mutant mice congenic on the inbred C57BL/6 strain for 10 generations were examined phenotypically for their ethogram of responsivity to the selective D2-like receptor agonist RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine) and the selective D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide), using procedures that resolve all topographies of behavior in the natural repertoire. After vehicle challenge, levels of sniffing and rearing seated were reduced in DARPP-32 mutants; the injection procedure seems to constitute a "stressor" that reveals phenotypic effects of DARPP-32 deletion not apparent under natural conditions. Topographical effects of 0.

Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).

Context: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study.

Objectives: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype.

SK&F 83822 distinguishes adenylyl cyclase from phospholipase C-coupled dopamine D1-like receptors: behavioural topography.

Effects of SK&F 83822 [3-allyl-6-chloro-7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine], an agonist at dopamine D1-like receptors which stimulate adenylyl cyclase but not phosphoinositide hydrolysis, were studied topographically so as to clarify differences between these receptors in the regulation of behaviour. Using cloned receptors, SK&F 83822 showed high, selective affinity for dopamine D1 and D5 over D2, D3, D4 and several non-dopamine receptors. SK&F 83822 induced little intense grooming, but readily induced sniffing, locomotion and rearing; seizures were evident at higher doses, characterised by tonic convulsions, forepaw myoclonus and explosive hyperlocomotion.

3D morphometrics of craniofacial dysmorphology reveals sex-specific asymmetries in schizophrenia.

Over early fetal life cerebral and craniofacial morphogenesis proceed in embryological intimacy. Therefore, craniofacial shape differences between schizophrenia patients and controls are informative of developmental disturbance(s) in cerebral-craniofacial morphogenesis. 3D craniofacial coordinates were calculated from interlandmark distances for 169 patients with DSM-III-R schizophrenia and 78 matched normal controls.

Schizophrenia, schizoaffective and bipolar disorder within an epidemiologically complete, homogeneous population in rural Ireland: small area variation in rate.

While a controversy has endured as to whether schizophrenia evidences the geographical variations in rate that characterise essentially all medical conditions, even less is known of such fundamental aspects of the epidemiology of schizoaffective and bipolar disorder. Within an ethnically and socioeconomically homogeneous region of rural Ireland, population 29,542, several methodological refinements were adopted to seek an epidemiologically complete population of 'all' cases of these disorders, with each potential case interviewed and diagnosed. Prevalence and morbid risk were calculated over the region as a whole and for each of the 39 constituent District Electoral Divisions [DEDs], by place at birth and by place at onset.

Confirmation and refinement of an 'at-risk' haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus.

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample.

Confirming RGS4 as a susceptibility gene for schizophrenia.

A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia.

Doorway states in the gamma decay-out of the yrast superdeformed band in 59Cu.

The decay-out process of the yrast superdeformed band in 59Cu has been investigated. The firm determination of spin, parity, excitation energy, and configuration of the states involved in this process constitutes a unique situation for a detailed understanding of the decay-out mechanism. A theoretical model is introduced that includes a residual interaction and tunneling matrix element between bands, calculated in the configuration-dependent cranked Nilsson-Strutinsky model.

Prospective evaluation of neurological soft signs in first-episode schizophrenia in relation to psychopathology: state versus trait phenomena.

Background: Although patients with schizophrenia have increased rates of neurological soft signs, few studies have examined prospectively their trait or state characteristics in relation to psychopathology.

Method: In a prospective study of 97 patients with first-episode schizophrenia (DSM-IV criteria) we assessed neurological soft signs and psychopathology at presentation and at 6 month follow-up for 73 cases. To establish whether soft signs were associated with variations in clinical state, neurological soft signs were measured using two validated examinations (Neurological Evaluation Scale and Condensed Neurological Examination); psychopathology was assessed using the Positive and Negative Syndrome Scale.

Comparative phenotypic resolution of spontaneous, D2-like and D1-like agonist-induced orofacial movement topographies in congenic mutants with dopamine D2 vs. D3 receptor "knockout".

Using a novel system, the role of D2-like dopamine receptors in distinct topographies of orofacial movement was assessed in mutant mice with congenic D2 vs. D3 receptor knockout, and compared with findings in D1A mutants. Under spontaneous conditions, D2 mutants evidenced increased vertical jaw movements and unaltered horizontal jaw movements, with reductions in tongue protrusions and incisor chattering; in D3 mutants, only incisor chattering was reduced.

Prefrontal, accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors.

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v.

Topographical Assessment of Ethological and Dopamine Receptor Agonist-Induced Behavioral Phenotype in Mutants with Congenic DARPP-32 'Knockout'.

Congenic (10 backcrosses into C57BL/6J) mutants with targeted gene deletion of DARPP-32, a neuronal phosphoprotein regarded as an essential mediator of the biological effects of dopamine (DA), were assessed phenotypically using an ethologically based approach that resolves all topographies of behavior in the mouse repertoire. Over initial exploration, female, but not male, DARPP-32 mutants evidenced increased locomotion and decreased grooming, while a decrease in rearing seated was evident in mutants of both genders; continuing assessment over several hours did not reveal additional phenotypic effects. Following challenge with the nonselective DA receptor agonist apomorphine, low doses were associated with reduced levels of sniffing, grooming, total rearing, and rearing seated in DARPP-32 mutants relative to wildtypes; this would suggest some role for DARPP-32 in mediating the biological effects of presynaptic D(2)-like autoreceptor or inhibitory postsynaptic D(2)-like receptor activation.

Neurochemical changes in dopamine D1, D3 and D1/D3 receptor knockout mice.

Neurochemical changes were examined in dopamine D1 receptor knockout (D1(-/-)), dopamine D3 receptor knockout (D3(-/-)) and dopamine D1/D3 receptor double knockout (D1(-/-)D3(-/-)) mice. The level of dopamine D1- and D2-like receptors and gamma-aminobutyric acid (GABA(A)) receptor was assessed by ligand autoradiography and dopamine D1- and D2 receptor, enkephalin, dynorphin and substance P transcripts measured by in situ hybridization. D1(-/-) mice had normal GABA(A) receptor levels, reduced dynorphin and substance P, and increased enkephalin mRNA and dopamine D2-like binding.

Relationship of orofacial movements to behavioural repertoire as assessed topographically over the course of 6-month haloperidol treatment followed by 4-month withdrawal.

Rationale: Late-onset vacuous chewing movements (VCMs) arise in a significant proportion of rats treated chronically with conventional antipsychotic drugs. Given their common action to block dopamine D2-like receptors, VCMs may be related to changes in dopaminergic function; if so, other typical dopamine-mediated behaviours might be altered also.

Objective: To examine this hypothesis, behavioural repertoire was studied topographically over the course of chronic treatment and withdrawal.

Essential conservation of D1 mutant phenotype at the level of individual topographies of behaviour in mice lacking both D1 and D3 dopamine receptors.

Rationale: In the absence of agonists and antagonists evidencing appropriate selectivities, individual and interactive properties of D(1) and D(3) dopamine receptors would be illuminated most powerfully by their co-deletion.

Objectives: To define and contrast the behavioural phenotype of D(1)/D(3) double knockout mice in comparison with wild types, and with individual D(1) and D(3 )mutants.

Methods: Behavioural phenotype was characterised using an ethologically based topographical technique.

Prospective analysis of premature mortality in schizophrenia in relation to health service engagement: a 7.5-year study within an epidemiologically complete, homogeneous population in rural Ireland.

While premature death in schizophrenia is well recognised, mortality risk has received little longitudinal study in relation to population representativeness and patient engagement with health services. Within a rural Irish catchment area of socioeconomic, ethnic and geographical homogeneity and low residential mobility, an epidemiologically complete population of 72 patients with schizophrenia was followed up over 7.5 years in order to quantify mortality prospectively.