Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

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A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

Aims To prepare for DSM-V, the structure of DSM-IV alcohol dependence and abuse criteria and a proposed additional criterion, at-risk drinking, require study in countries with low per-capita consumption, and comparison of current and lifetime results within the same sample. We investigated DSM-IV Alcohol Use Disorder (AUD) criteria in Israel, where per-capita alcohol consumption is low. Methods Household residents selected from the Israeli population register (N=1,338) were interviewed with the AUDADIS. Item Response Theory analyses were conducted using MPlus, and diagnostic thresholds examined with the kappa statistic. Results Dependence and abuse criteria fit a unidimensional model interspersed across the severity continuum, for both current and lifetime timeframes. Legal problems were rare and did not improve model fit. Weekly at-risk drinking reflected greater severity than in U.S. samples. When dependence and abuse criteria were combined, a diagnostic threshold of ≥3 criteria produced the best agreement with DSM-IV diagnoses (kappa>0.80). Conclusion Consistent with other studies, alcohol dependence and abuse criteria reflected a latent variable representing a single AUD. Results suggested little effect in removing legal problems and little gained by adding weekly at-risk drinking. Results contribute to knowledge about AUD criteria by examining them in a low-consumption country.

Chronic CR-PTSD may be associated with increased circulatory level of neuroactive steroids with inhibitory activity at the GABA(A) receptors. Neurosteroid-induced decreased GABAergic tone may be relevant to the symptomatology and pathophysiology of chronic PTSD, as well as to the frequent co-morbidity of PTSD with depression and anxiety disorders.

Aims Evidence-based changes planned for DSM-5 substance use disorders (SUDs) include combining dependence and three of the abuse criteria into one disorder and adding a criterion indicating craving. Because DSM-IV did not include a category for nicotine abuse, little empirical support is available for aligning the nicotine use disorder criteria with the DSM-5 criteria for other SUDs. Design Latent variable analyses, likelihood ratio tests (LRT) and bootstrap tests were used to explore the unidimensionality, psychometric properties and information of the nicotine criteria. Setting, Participants A sample of household residents selected from the Israeli population register yielded 727 lifetime cigarette smokers. Measurements DSM-IV nicotine dependence criteria and proposed abuse and craving criteria, assessed with a structured interview. Findings Three abuse criteria (hazardous use, social/interpersonal problems, and neglect roles) were prevalent among smokers, formed a unidimensional latent trait with nicotine dependence criteria, were intermixed with dependence criteria across the severity spectrum, and significantly increased the diagnostic information over the dependence-only model. LRT results also supported including the abuse criteria (Χ²₃=259.63, p<0.0001). A craving criterion was shown to fit well with the other criteria. Conclusion Similar to findings from research on other substances, nicotine dependence, abuse, and craving criteria formed a single factor. The results support alignment of nicotine criteria with those for alcohol and drug use disorders in DSM-5.

Attention deficit hyperactivity disorder (ADHD) may be associated with a dysregulation of the catecholaminergic and serotonergic systems. Furthermore, ADHD is frequently complicated by aggressive impulsive behaviour, which is suggested to be related to low serum cholesterol levels. We examined the relationship between blood serotonin, norepinephrine, dopa and lipid levels and the degree of hyperactivity, impulsiveness, lack of concentration, and aggressiveness in boys with ADHD of low and high severity as determined by a specially designed formulated scale based on the DSM-IV criteria for ADHD. No differences were noted between the groups in any of the peripheral biological parameters except blood serotonin, for which a tendency (P=0.08) towards lower levels was observed in the children with more severe disorder. We conclude that children with severe ADHD may have a different serotonin turnover compared to children with mild ADHD. These results may have implications for our understanding of the pathogenesis of ADHD, at least the more severe type.

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