Effectiveness of Criminal Justice Liaison and Diversion Services for Offenders With Mental Disorders: A Review

Objective: The authors evaluated and synthesised the best-available evidence relating to the effectiveness of CJLD service models with respect to changes in mental health status and/or criminal recidivism.Methods: Research examining the effectiveness of CJLD services when compared to traditional Criminal Justice System (CJS) responses was reviewed and systematically appraised according to Campbell/Cochrane guidelines. Key outcomes included a reduction in offending and post-intervention changes in mental health. Results: Comprehensive searches of published and unpublished literature identified 6571 studies which varied considerably in terms of their methodological approach and overall quality. Ten studies met the inclusion criteria. The synthesised findings indicated that, when compared to traditional CJS outcomes, CJLD services appeared to be effective in terms of identifying MDOs and impacting positively on criminal justice and mental health outcomes.Conclusions: Although the evidence may be deemed to be moderate in terms of methodological rigour, overall, the findings suggest that CJLD services can be beneficial. The effectiveness of services depends upon the model of service delivery, the availability of community services and the engagement of MDOs.The successful implementation of CJLD services requires a clearer recognition of the importance of system of care principles.

Assessment of factors that influence physician decision making regarding medication use in patients with dementia at the end of life

Objective
This study aimed to evaluate the extent to which patient-related factors and physicians' country of practice (Northern Ireland [NI] and the Republic of Ireland [RoI]) influenced decision making regarding medication use in patients with end-stage dementia.

Methods
The study utilised a factorial survey design comprising four vignettes to evaluate initiating/withholding or continuing/discontinuing specific medications in patients with dementia nearing death. Questionnaires and vignettes were mailed to all hospital physicians in geriatric medicine and to all general practitioners (GPs) in NI (November 2010) and RoI (December 2010), with a second copy provided 3 weeks after the first mailing. Logistic regression models were constructed to examine the impact of patient-related factors and physicians' country of practice on decision making. Significance was set a priori at p ≤ 0.05. Free text responses to open questions were analysed qualitatively using content analysis.

Results
The response rate was 20.6% (N = 662) [21.1% (N = 245) for GPs and 52.1% (N = 38) for hospital physicians in NI, 18.3% (N = 348) for GPs and 36.0% (N = 31) for hospital physicians in RoI]. There was considerable variability in decision making about initiating/withholding antibiotics and continuing/discontinuing the acetylcholinesterase inhibitor and memantine hydrochloride, and less variability in decision making regarding statins and antipsychotics. Patient place of residence and physician's country of practice had the strongest and most consistent effects on decision making although effect sizes were small.

Conclusions
Further research is required into other factors that may impact upon physicians' prescribing decisions for these vulnerable patients and to clarify how the factors examined in this study influence prescribing decisions.

Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease

Prefibrillar assembly of amyloid-ß (Aß) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aß synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aß 1–42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aß 1–42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aß oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aß oligomers in normal rats. SEN1576 bound to monomeric Aß 1–42, protected neuronal cells exposed to Aß 1–42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.

Molecular Validation of the Schizophrenia Spectrum

Background: Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum? Methods: The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = s) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929). Results: The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample. Conclusions: In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.

Common variant at 16p11.2 conferring risk of psychosis

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).

Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families

A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions. As this dysregulation could arise from abnormal expression of D2 dopamine receptors, the D2 receptor gene (DRD2) on chromosome 11q is a candidate locus for schizophrenia. We tested whether allelic variation at DRD2 and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined by DSM-III-R. Evidence of linkage was assessed using varying definitions of illness and modes of transmission. Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q around DRD2 could be strongly excluded. Assuming genetic heterogeneity, variation at the DRD2 locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models. The DRD2 linkage in fewer than 25% of these families could not be excluded under any of the models tested. Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at the DRD2 locus or other genes in the surrounding chromosomal region.

Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families

This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues.

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families:evidence for possible etiologic heterogeneity

The authors sought to determine whether the clinical manifestations of schizophrenia and other psychotic disorders are correlated in affected sibling pairs.

Support for a possible schizophrenia vulnerability locus in region 5q22-31 in Irish families

In our genome scan for schizophrenia genes in 265 Irish pedigrees, marker D5S818 in 5q22 produced the second best result of the first 223 markers tested (P = 0.002). We then tested an additional 13 markers and the evidence suggests the presence of a vulnerability locus for schizophrenia in region 5q22-31. This region appears to be distinct from those chromosome 5 regions studied in two prior reports, but the same as that producing positive results in the report by Wildenauer and colleagues found elsewhere in this issue. The largest pairwise heterogeneity LOD (H-LOD) score was found with marker D5S393 (max 3.04, P = 0.0005), assuming a narrow phenotypic category, and a genetic model with intermediate heterozygotic liability. In marked contrast to the H-LOD scores from our sample with markers from the regions of interest on chromosomes 6p and 8p, expanding the disease definition to include schizophrenia spectrum or nonspectrum disorders produced substantially smaller scores, with a number of markers failing to yield positive values at any recombination fraction. Using multipoint H-LODS, the strongest evidence for linkage occurs under the narrow phenotypic definition and recessive genetic model, with a peak at marker D5S804 (max 3.35, P = 0.0002). Multipoint nonparametric linkage analysis produced a peak in the same location (max z = 2.84, P = 0.002) with the narrow phenotypic definition. This putative vulnerability locus appears to be segregating in 10-25% of the families studied, but this estimate is tentative. Comparison of individual family multipoint H-LOD scores at the regions of interest on chromosomes 6p, 8p and 5q showed that only a minority of families yield high lod scores in two or three regions.

Longitudinal study of interpersonal dependency in female twins

Interpersonal dependence is thought to be important in a number of physical and psychological disorders. There are several developmental theories that suggest environmental influences in childhood are important.

Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families

Schizophrenia is clinically heterogeneous. Recent linkage studies suggest that multiple genes are important in the etiology of schizophrenia. The authors examined the hypothesis of whether the clinical variability in schizophrenia is due to genetic heterogeneity.

Sibling correlation of deficit syndrome in the Irish study of high-density schizophrenia families

The deficit syndrome is a subtype of schizophrenia characterized by primary and enduring negative features of psychopathology. It appears to reflect a distinct subtype within the syndrome of schizophrenia. Little is known about the familial or genetic aspects of the deficit syndrome. The purpose of this study was to determine whether deficit versus nondeficit subtypes are correlated in sibling pairs affected with schizophrenia.

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families

The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia. Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed. SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative. These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews. Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects. This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele. We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.