No NRG1 V266L in Chinese patients with schizophrenia.

NRG1 is one of the best-supported schizophrenia (SZ) susceptibility genes. A NRG1 V266L missense mutation has been found to be associated with SZ in several populations. V266L is not in linkage disequilibrium with any of the SZ-associated NRG1 haplotypes described thus far, and may represent an independent SZ susceptibility locus within NRG1 gene. V266 is a highly conserved residue and its substitution is predicted to have a deleterious effect on the protein. As there are no data for V266L in Chinese, and given the potential relevance of this mutation, we investigated the V266L prevalence in 270 Chinese patients with schizophrenia and 270 ethnically matched controls. V266L was found neither in patients nor in controls. Lack of replication of an association across populations may be because of the differences in linkage disequilibrium structure or allele frequencies. Some true associations may not be replicated regardless of the sample size of the study.

Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.

Chromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-Mb high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-Mb region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ErbB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia.

Meta-regression analysis using latitude as moderator of paternal age related schizophrenia risk: high ambient temperature induced de novo mutations or is it related to the cold?

While the season of birth, latitude and first admission effects suggest higher risk of schizophrenia with cold climate, the high ambient temperature induced de novo mutation hypothesis suggests the opposite. We conducted a systematic review and meta-analysis (4 case-control studies and 5 cohort studies). We used annual mean daily temperature and latitude of study sites as direct and indirect measures of ambient temperature respectively. Using case-control studies conducted in the Northern hemisphere for meta-regression, high latitude and low ambient temperature were found to increase paternal age related schizophrenia risk significantly. More research is needed to support the de novo mutation hypothesis.

An association study of RGS4 polymorphisms with clinical phenotypes of schizophrenia in a Chinese population.

The regulator of G-protein signaling 4 (RGS4) has been suggested as a candidate gene for schizophrenia. However, following an initial positive report, subsequent association studies between RGS4 and schizophrenia have yielded inconclusive results. Also, few studies have investigated the association of RGS4 polymorphisms with the phenotypic subgroups of schizophrenia. To further clarify the role of RGS4 in this disease, we performed a case-control study (504 cases and 531 controls of Han Chinese descent) to examine the association of RGS4 with schizophrenia and with clinical and neurocognitive profiles. The four markers (SNPs 1, 4, 7, and 18) implicated in the original association study were genotyped. We detected significant association of four-marker haplotypes with schizophrenia (UNPHASED: global P = 0.037; PHASE: global P = 0.048). The haplotype G-G-G-G, which was implicated in at least three previous studies, was the major risk haplotype (UNPHASED: P = 0.019; PHASE: P = 0.010). Regarding the clinical phenotypes, the Wechsler Adult Intelligence Test (WAIS) information subtest score was associated with SNP4 genotypes (P = 0.001). PANSS total and global psychopathology scores were also associated with SNP4, but may not reliably reflect the general severity of disease as the scores may be affected by confounders like medication response. Our study provides further support for a role of RGS4 in the pathogenesis of schizophrenia. We identified G-G-G-G as the risk haplotype in our Chinese sample. The association with information subtest score suggests an effect of RGS4 on premorbid functioning, which may be related to neurodevelopmental processes. Further independent studies are required to verify our findings.

Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis.

OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of atomoxetine in children and adolescents. MATERIALS AND METHODS: We searched for studies published between 1985 and 2006 through Medline, PubMed, PsychInfo and Cochrane Central Register of Controlled Trials (CENTRAL 2006 Issue 3) using keywords related to atomoxetine and attention-deficit/hyperactivity disorder (ADHD) and scanned though reference lists. We included nine randomized placebo-controlled trials (atomoxetine:placebo = 1,150:678). RESULTS: Atomoxetine was superior (p < 0.01) to placebo in reducing ADHD symptoms across different scales (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Conners' Parent and Teacher Rating Scales-Revised:Short Form, Clinical Global Impression-Severity) rated by different raters (parent, teacher, clinician). The number-needed-to-treat (NNTs) for treatment response and relapse prevention were 3.43 (95% CI, 2.79-4.45) and 10.30 (95% CI, 5.89-40.62), respectively. High baseline ADHD symptoms (p = 0.02) was associated with greater reduction in ADHD symptoms, whereas male gender (p = 0.02), comorbid oppositional defiant disorder (ODD) status (p = 0.01) and ADHD hyperactive/impulsive subtype (p = 0.01) were associated with smaller reductions. The commonest adverse events were gastrointestinal [appetite decrease, number-needed-to-harm (NNH) = 8.81; abdominal pain, NNH = 22.48; vomiting, NNH = 29.96; dyspepsia, NNH = 49.38] and sleep related (somnolence, NNH = 19.41). Young age (p = 0.03) and high baseline hyperactive/impulsive symptoms (p < 0.01) were associated with more adverse events, whereas ADHD inattentive subtype (p = 0.04) was associated with less adverse events. Quality of life using Child Health Questionnaire (CHQ) improved (p < 0.01) with atomoxetine treatment. Both ADHD and ODD symptoms (p < 0.01) were reduced in comorbid ADHD+ODD, and ODD status was not associated with more adverse events. Efficacy and side effects were not altered by comorbid general anxiety disorder or major depression. CONCLUSIONS: Atomoxetine is efficacious in reducing ADHD symptoms. It may have a role in treating comorbid ODD or depression, and probably in comorbid anxiety.

A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention deficit hyperactivity disorder.

The association between the 10-repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05-1.30, chi-square = 8.11, df = 1, P = 0.004), but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphism in the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.

The components of executive functioning in a cohort of patients with chronic schizophrenia: a multiple single-case study design.

We examined the fractionation of executive functioning performance in ninety patients with schizophrenia, who were tested for initiation, sustained attention, switching/flexibility, attention allocation and impulsivity/disinhibition. The participants were also given tests of general intelligence and memory. We analysed the executive functioning performance of individual patients against normative data from our laboratory, and summary scores for all of the executive functioning components were computed. For each component, participants were classified as having impairment with a test performance of 1.5 standard deviations or more from the norm of the corresponding test. Of all of the participants, 27.8% (n=25) demonstrated poor performance in all of the components, and 5.6 % (n=5) exhibited intact or fair performance in all of the components. Furthermore, 18.9% (n=17) showed intact or fair performance in one component, 16.7% (n=15) in two components, 21.1% (n=19) in three components and 10% (n=9) in four components. The groups did not differ in education, gender or duration of illness, but the group that showed impaired performance in all of the components demonstrated the most severe psychotic symptoms after controlling for background intelligence, age and medication. The differential breakdown for the executive functioning performance across the participants suggests that the fractionation of central executive functioning occurs in schizophrenia.

Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study.

We observed that a number of patients with severe acute respiratory syndrome (SARS) developed affective psychosis during the acute phase of their illness. We reviewed all SARS-related psychiatric consultations in Hong Kong and investigated the risk factors for psychosis among patients with SARS in a matched case-control study. Patients with SARS-related psychosis received higher total doses of steroids and had higher rates of family history of psychiatric illness. The findings of the present study suggest that steroid toxicity, personal vulnerability, and, probably, psychosocial stressors jointly contributed to the development of psychosis in patients with SARS.

A comparison between schizophrenia patients and healthy controls on the expression of attentional blink in a rapid serial visual presentation (RSVP) paradigm.

The expression of attentional blink (AB) in 24 schizophrenia inpatients was compared to 22 healthy subjects in a dual-target rapid serial visual presentation (RSVP) paradigm in which a sequence of discrete stimuli was presented in rapid succession. Correct identification of the first target led to poorer detection of the second one when they were interspersed by distractors. This second-target deficit constitutes the AB effect, which is most pronounced between 200 and 500 ms after the offset of the first target stimulus and steadily decays as the number of intervening distractors increases. Despite relatively poor performance in terms of target identification within RSVP streams, schizophrenia patients expressed an AB effect that was as clear as that seen in healthy subjects. Moreover, there was evidence for an enhanced AB effect in schizophrenia patients. This outcome contrasts with the robust finding that schizophrenia patients are attenuated in the expression of prepulse inhibition, another paradigm believed to assess attentional control. The present results add to the extensive literature on the nature and specification of attentional dysfunction implicated in schizophrenia.