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Background and Objectives: With 47 600 opioid-related deaths in 2017, the yearly deaths have surpassed the HIV/AIDS peak yearly death rates. Residential rehabilitation (RR) and medication-assisted treatments (MAT) are commonly utilized treatments for opioid use disorder (OUD)., Methods: All patients (n = 182) who were admitted to the Boston Veterans Health Administration for inpatient admission for medically supervised opioid withdrawal in 2015 were included. Deceased patients were matched 1:1, based on age and sex to living patients from the 182-patient cohort. Nationwide electronic medical records were analyzed from 2015 through 2018. Via multilinear regression, risk factor correlation to all-cause mortality (the dependent variable) was our main outcome. Primary risk factors included recurrent admissions for medically supervised withdrawals and exposure to RR or MAT. Secondary risk factors were opioid use traits, nonopioid drug use, partner support, education level, homelessness, and employment., Results: 18.4% (n = 34) were deceased by the time of follow-up-equivalent to 4760 deaths per 100 000 person-years. A total of 61.8% (n = 21) of these deaths were directly related to opioid use. Completion of RR correlated with lower predicted mortality (β = -8.21, P = 0.03). In contrast, attending RR but not completing correlated with higher predicted mortality rate (β = 6.51, P = 0.046). Concurrent benzodiazepine use (β = 8.99, P = 0.047), generalized anxiety disorder (β = 7.13, P = 0.03) and major depressive disorder (β = 5.44, P = 0.04) increased risk of death., Conclusion and Scientific Significance: OUD carries a shockingly high lethality in Veterans requiring inpatient admission for opioid withdrawal, particularly when there are untreated comorbid psychiatric conditions. RR and MAT are correlated to lower all-cause mortality in this population and should be highly utilized. Given the extremely high mortality, intensive system-wide interventions are needed for the care of Veterans with OUD. On the basis of the reduced predicted mortality with RR and MAT, further research into novel MATs as well as refining RR programs should be a major focus. (Am J Addict 2019;28:318-323)., (© 2019 American Academy of Addiction Psychiatry.)

Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context., (© 2014 Wiley Periodicals, Inc.)

Recent genetics research focusing on schizophrenia has led to candidate cognitive and neuroimaging variables as intermediate phenotypes or "endophenotype" markers for the illness. Among other stringent criteria, to be an endophenotype, a marker must demonstrate heritability. In an effort to explore the validity of a selection of cognitive and neuroimaging endophenotypes, the present study was designed to determine estimates of their heritability. One hundred fourteen subjects, including 27 with schizophrenia and 39 unaffected relatives from 23 multiplex schizophrenia families, participated in a comprehensive neuropsychological test battery and structural brain imaging with diffusion tensor imaging (DTI). Variables were selected if they previously have been demonstrated to show differences between people with schizophrenia and normal controls. Significant evidence of heritability was confirmed for overall cognitive function ("g"), as well as expressive and receptive language, verbal and visual memory, processing speed and cognitive inhibition. In addition, significant heritability estimates were determined for specific regions in the frontal, central, parietal, and occipital areas. These results suggest that the variables chosen may be useful endophenotypes for genetic and early detection studies, although further work with larger cohorts should be conducted to show that deficits in these functions and structures also segregate with schizophrenia within families and thus fully satisfy the definition of an endophenotype. In addition, other cognitive and neuroimaging variables that were not studied here may be candidates for schizophrenia endophenotypes.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X-Y homologous gene [Crow (1993); Lancet 342:594-598]. In particular, females with Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's syndrome (KS) who possess a supernumerary X-chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crow's prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal-occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero-posterior axis., (2008 Wiley-Liss, Inc.)

Aims: An understanding of baseline cognitive function in individuals at high genetic risk for schizophrenia could provide important information about the neurodevelopmental course of the illness and assist with early detection. In an effort to identify potential markers for the illness, this study investigates domains of neuropsychological functioning in a sample of young individuals at risk for developing schizophrenia., Methods: Twenty-two individuals with schizophrenia, 16 participants at high risk and 31 controls participated in comprehensive cognitive assessments., Results: Results support reports of a trend for high-risk participants to score intermediate to the other groups on a general cognitive battery, as well as evidencing deficits in specific skills like visual memory. The pattern appears to exist independently of and prior to the onset of prodromal symptoms., Conclusions: These findings support the hypothesis that a common cognitive pattern exists across individuals with genetic risk that may later develop into a clear psychotic illness. Further longitudinal investigation with larger cohorts is crucial to understanding these findings., (© 2008 The Authors.)

Klinefelter's Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini-Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression-cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = -0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition-gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis., (Copyright 2007 Wiley-Liss, Inc.)

An increased incidence of psychiatric and structural brain abnormalities in individuals with Klinefelter syndrome (KS, 47 XXY) could be due to the presence of extra copies of X-Y homologous genes that escape X inactivation. Of particular interest are the two brain-expressed genes Protocadherin11XY (PCDH11XY) and the Synaptobrevin-like gene (SYBL1) which have been duplicated from the X chromosome to the Y chromosome to give X-Y homologous gene pairs that are specific to modern humans. We examined the DNA of KS individuals reported recently by DeLisi et al. 2005 and determined the parental origin of the X alleles, the degree of skewed X inactivation and investigated the CpG island methylation status of PCDH11XY and SYBL1 by bisulphite sequencing and quantification of methylated HpaII sites. We used a novel method for quantification of unmethylated CpGs with the restriction enzyme McrBC which cuts methylated but not unmethylated CpGs. The results showed that KS individuals have two methylated and one unmethylated SYBL1 allele whereas PCDH11XY is unmethylated and escapes X inactivation on the extra X chromosome. Overexpression of PCDH11XY in KS is probable and variable escape from inactivation of this Homo sapiens-specific gene could account for some abnormalities in KS. The origin of the parental alleles or their preferential X inactivation was not associated with psychotic symptoms., ((c) 2006 Wiley-Liss, Inc.)

A written questionnaire about genetic testing was distributed to all registrants at The 2004 World Congress of Psychiatric Genetics, mailed to clinical psychiatrists obtained from a directory of clinicians practicing in New York City, and mailed to members of families who have multiple affected family members with schizophrenia. A total of 274 individuals responded (162 researchers, 64 clinicians, and 48 family members). This survey shows that the majority of family members who completed the questionnaire (83.3%) would want to be tested if a genetic test were to become available. Over half of the family members (56.2%) would want prenatal testing. Similarly, over half of the clinicians (56.3%) would recommend it, despite only 25% of the researchers reporting that it would be a future useful tool. All of the clinicians surveyed thought adoption agencies should inform families about a family history of schizophrenia, while only half of the researchers thought this should be done (51.9%). These differences in opinions between consumers, their clinicians, and researchers could be based on a lack of understanding of the amount of risk conferred to family members by reported gene variants. Providing public discussions for placing these risks in perspective should be the responsibility of researchers. Open public discussion of the ethical and social uses of the information gained from psychiatric genetic research and its limitations is encouraged., ((c) 2005 Wiley-Liss, Inc.)

Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates., (Copyright 2005 Wiley-Liss, Inc.)

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness., ((c) 2004 Wiley-Liss, Inc.)

Protocadherin X and Protocadherin Y (PCDHX and PCDHY) are cell-surface adhesion molecules expressed predominantly in the brain. The PCDHX/Y gene-pair was generated by an X-Y translocation approximately 3 million years ago (MYA) that gave rise to the Homo sapiens-specific region of Xq21.3 and Yp11.2 homology. Genes within this region are expected to code for sexually dimorphic human characteristics, including, for example, cerebral asymmetry a dimension of variation that has been suggested is relevant to psychosis. We examined differences in patients with schizophrenic or schizoaffective psychosis in the genomic sequence of PCDHX and PCDHY in coding and adjacent intronic sequences using denaturing high performance liquid chromatography (DHPLC). Three coding variants were detected in PCDHX and two in PCDHY. However, neither the coding variants nor the intronic polymorphisms could be related to psychosis within families. Low sequence variation suggests selective pressure against sequence change in modern humans in contrast to the structural chromosomal and sequence changes including fixed X-Y differences that occurred in this region earlier in hominid evolution. Our findings exclude sequence variation in PCDHX/Y as relevant to the aetiology of psychosis. However, we note the unusual status of this region with respect to X-inactivation. Further investigation of the epigenetic control of PCDHX/Y in relation to psychosis is warranted., (Copyright 2004 Wiley-Liss, Inc.)

The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia., (Copyright 2003 Wiley-Liss, Inc.)