Donald W. Black

Common variants on chromosome 6p22.1 are associated with schizophrenia

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

Identification of loci associated with schizophrenia by genome-wide association and follow-up

We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10−5 in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 × 10−4), and the overall pattern of replication was unlikely to occur by chance (P = 9 × 10−8). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 × 10−7) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 × 10−9).

A Family Study of Obsessive-Compulsive Disorder

First-degree relatives of probands with obsessive-compulsive disorder (OCD) (n = 32) and psychiatrically normal controls (n = 33) were blindly interviewed with the use of the Diagnostic Interview Schedule. The morbidity risk for anxiety disorders was increased among the relatives of obsessional subjects compared with that for the relatives of controls, but the risk for OCD was not. Risk for a more broadly defined OCD (including relatives with obsessions and compulsions not meeting criteria for OCD) was increased among the parents of obsessional subjects but not among the parents of controls (16% vs 3%). The findings suggest that an anxiety disorder diathesis is transmitted in families with OCD, but that its expression within these families is variable. The findings also support the current practice of classifying OCD as an anxiety disorder.

Copy Number Variants in Schizophrenia: Confirmation of Five Previous Findings and New Evidence for 3q29 Microdeletions and VIPR2 Duplications

OBJECTIVE To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.

Internet addiction: definition, assessment, epidemiology and clinical management.

Internet addiction is characterized by excessive or poorly controlled preoccupations, urges or behaviours regarding computer use and internet access that lead to impairment or distress. The condition has attracted increasing attention in the popular media and among researchers, and this attention has paralleled the growth in computer (and Internet) access.Prevalence estimates vary widely, although a recent random telephone survey of the general US population reported an estimate of 0.3–0.7%.The disorder occurs worldwide, but mainly in countries where computer access and technology are widespread. Clinical samples and a majority of relevant surveys report a male preponderance. Onset is reported to occur in the late 20s or early 30s age group, and there is often a lag of a decade or more from initial to problematic computer usage.Internet addiction has been associated with dimensionally measured depression and indicators of social isolation. Psychiatric co-morbidity is common, particularly mood, anxiety, impulse control and substance use disorders. Aetiology is unknown, but probably involves psychological, neurobiological and cultural factors.There are no evidence-based treatments for internet addiction. Cognitive behavioural approaches may be helpful. There is no proven role for psychotropic medication. Marital and family therapy may help in selected cases, and online self-help books and tapes are available. Lastly, a self-imposed ban on computer use and Internet access may be necessary in some cases.

Comparison of One-Year Efficacy and Safety of Atorvastatin Versus Lovastatin in Primary Hypercholesterolemia

This double-blind study to evaluate long-term efficacy and safety of atorvastatin was performed in 31 community- and university-based research centers in the USA to directly compare a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (reductase inhibitor) to an accepted drug of this class in patients with moderate hypercholesterolemia. Participants remained on a cholesterol-lowering diet throughout the study. One thousand forty-nine patients were randomized to receive atorvastatin 10 mg, lovastatin 20 mg, or placebo. At 16 weeks the placebo group was randomized to either atorvastatin or lovastatin treatment. At 22 weeks, patients who had not met low-density lipoprotein (LDL) cholesterol target levels doubled the dose of reductase inhibitor. Efficacy evaluation was mean percent change from baseline in LDL cholesterol, triglycerides, total cholesterol, high-density-lipoprotein cholesterol, and apolipoprotein B (apoB). Safety profiles as determined by change from baseline in laboratory evaluations, ophthalmologic parameters, and reporting of adverse events were similar for the 2 reductase inhibitors. After 52 weeks, the atorvastatin group maintained a significantly greater reduction in LDL cholesterol (-37% vs -29%), triglyceride (-16% vs -8%), total cholesterol (-27% vs -21%), and apoB (-30% vs -22%) (p <0.05). More patients receiving atorvastatin achieved LDL cholesterol target levels than did lovastatin patients (78% vs 63%, respectively), particularly those with coronary heart disease (37% vs 11%, respectively). Atorvastatin is highly effective and well tolerated in patients with primary hypercholesterolemia with no increased risk of adverse events.

Systems Training for Emotional Predictability and Problem Solving (STEPPS) for Outpatients With Borderline Personality Disorder: A Randomized Controlled Trial and 1-Year Follow-Up

OBJECTIVE Systems Training for Emotional Predictability and Problem Solving (STEPPS) is a 20-week manual-based group treatment program for outpatients with borderline personality disorder that combines cognitive behavioral elements and skills training with a systems component. The authors compared STEPPS plus treatment as usual with treatment as usual alone in a randomized controlled trial. METHOD Subjects with borderline personality disorder were randomly assigned to STEPPS plus treatment as usual or treatment as usual alone. Total score on the Zanarini Rating Scale for Borderline Personality Disorder was the primary outcome measure. Secondary outcomes included measures of global functioning, depression, impulsivity, and social functioning; suicide attempts and self-harm acts; and crisis utilization. Subjects were followed 1 year posttreatment. A linear mixed-effects model was used in the analysis. RESULTS Data pertaining to 124 subjects (STEPPS plus treatment as usual [N=65]; treatment as usual alone [N=59]) were analyzed. Subjects assigned to STEPPS plus treatment as usual experienced greater improvement in the Zanarini Rating Scale for Borderline Personality Disorder total score and subscales assessing affective, cognitive, interpersonal, and impulsive domains. STEPPS plus treatment as usual also led to greater improvements in impulsivity, negative affectivity, mood, and global functioning. These differences yielded moderate to large effect sizes. There were no differences between groups for suicide attempts, self-harm acts, or hospitalizations. Most gains attributed to STEPPS were maintained during follow-up. Fewer STEPPS plus treatment as usual subjects had emergency department visits during treatment and follow-up. The discontinuation rate was high in both groups. CONCLUSIONS STEPPS, an adjunctive group treatment, can deliver clinically meaningful improvements in borderline personality disorder-related symptoms and behaviors, enhance global functioning, and relieve depression.

Compulsive buying. Demography, phenomenology, and comorbidity in 46 subjects.

Compulsive buying has been generally ignored in the psychiatric literature, although it is apparently frequent, underrecognized, and can lead to severe financial and legal consequences for its sufferers. The current investigation was designed to assess the overall life-style and problems of subjects identified as compulsive shoppers. Forty-six compulsive buyers were assessed for comorbid psychiatric disorders with the Diagnostic Interview Schedule, the Structured Interview for DSM-III-R Personality Disorders, and a semistructured interview to assess buying behavior. The typical shopper was a 31-year-old female who had developed compulsive buying at age 18 years. Subjects spent their money on clothing, shoes, and records/compact discs. The average debt load accrued was

A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients witb hypercholesterolemia☆

5,422 out of an average yearly income of

Genomewide Linkage Scan of 409 European-Ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

23,443. More than two-thirds met lifetime criteria for a major (Axis I) mental disorder, most commonly anxiety, substance abuse, and mood disorders. Nearly 60% were found to meet criteria for a DSM-III-R personality disorder, most commonly the obsessive-compulsive, borderline, and avoidant types. The authors conclude that compulsive buying is a definable clinical syndrome which can cause its sufferers significant distress and is associated with significant psychiatric comorbidity.