Ronald Y.L. Chen

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.

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

ObjectivesThe objective of this study was to evaluate the efficacy and safety of atomoxetine in children and adolescents.Materials and methodsWe 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).ResultsAtomoxetine 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.ConclusionsAtomoxetine is efficacious in reducing ADHD symptoms. It may have a role in treating comorbid ODD or depression, and probably in comorbid anxiety.

The impact of family experience on the duration of untreated psychosis (DUP) in Hong Kong

BackgroundPrevious family experience of psychotic illness may play an important role in whether and when a patient seeks help in first-episode psychosis. This study investigated the relationship between family experience of psychosis and the duration of untreated psychosis in a prospective sample of first-episode psychosis patients in Hong Kong. We also studied the effects of pre-morbid adjustment, educational level, living alone, and mode of onset as potential determinants of the duration of untreated psychosis (DUP).MethodsA total of 131 first-episode psychosis patients in Hong Kong were recruited in a study of the DUP and related factors. The Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS) was used to measure the DUP and to provide a structured assessment of family history, educational level, household arrangement, and mode of onset.ResultsPrevious family experience of psychiatric illness (the presence of another family member who has been receiving psychiatric treatment) and an acute mode of onset were significant predictors of a shorter DUP. Educational level had a modest effect on its own, but was not significant in the binary logistic regression model. Living alone had a moderate effect size, but was non-significant, possibly because of the small proportion of single-person households in the sample. The symptom profile, pre-morbid adjustment, and other demographic factors were not significantly related to the DUP.ConclusionIn addition to the mode of onset, previous family experience plays an important role in the presentation of early psychosis. Educational efforts that target the family should be an important part of any strategy for the early detection of psychosis.

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.

Progressive deterioration of soft neurological signs in chronic schizophrenic patients.

Objective: Neurological signs are found to be increased in schizophrenia in cross‐sectional studies. Whether they progress with time is an important issue in addressing the course of the illness.

No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients.

Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. One possible explanation for such discrepancy is disease heterogeneity due to the current limitations in the diagnosis of schizophrenia. We conducted a case-control study of the T102C polymorphism with detailed characterisation of the clinical phenotypes to investigate the possible association with schizophrenia not only at the diagnostic level, but also with reference to other clinical phenotypes potentially related to serotonin dysfunction. Four hundred and seventy-one biologically unrelated schizophrenic patients and 523 unrelated healthy controls of Han Chinese descent in Hong Kong were compared for genotypes and allele frequencies of the T102C polymorphism by PCR amplification and restriction analysis. No evidence of association was detected at the diagnostic level and various clinical phenotypes. However, we found a trend association with small effect size between genotype 102T/102C and patients with better verbal fluency and less motor co-ordination soft neurological signs. There is a need for future large-scale studies on the possible associations between genetic polymorphisms and neurocognitive function impairments in schizophrenia.

Stroop interference and facilitation effects in first-episode schizophrenic patients

In the Stroop test, interference occurs in naming the print color of a word when the word is itself the name of another color. Facilitation occurs when the word is the same as the print color. Previous studies on selective attention in schizophrenia using the Stroop interference effects have yielded contradicting results. Constraints included limited sample size and the recruitment of medicated chronic patients. We studied the Stroop interference and facilitation effects in a relatively large sample of first-episode schizophrenic patients (n=56), a substantial proportion of whom were medication-naïve (n=30) at the time of initial testing. We have also carried out longitudinal follow-up assessments when patients reached a clinically stable state, as well as 4months after recovery from the episode. We found that the Stroop interference effect was not increased in first-episode schizophrenic patients, whether medication-naïve or not. This effect did not change over the follow-up period. In addition, we detected an increase in Stroop facilitation effect in medicated schizophrenic patients, but only in the initial assessment soon after they had received medication. After sustained treatment, the increase in facilitation was normalized. These observations supported previous findings of a normal Stroop interference effect amongst schizophrenic patients. The increased facilitation effect for patients in their early phase of treatment (but not later) may represent an acute effect of anti-psychotic medication. Its nature and significance require further investigation.

Prefrontal neuropsychological impairment and illness duration in schizophrenia: a study of 204 patients in Hong Kong.

Previous studies investigating the progression of neuropsychological impairment in schizophrenia have yielded conflicting results. We compared prefrontal neuropsychological function and other cognitive performance in a larger sample of schizophrenic patients with different duration of illness. The inclusion of a normal control group also allowed the effect of age to be taken into account. Performance in the Wisconsin Card Sorting Test (WCST) and semantic fluency were both impaired at an early stage in the illness and did not significantly deteriorate as the illness duration increased. Against this background there was preliminary evidence for deterioration in verbal memory function. The data support a lack of progression in prefrontal dysfunction and in most other cognitive domains.

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.

Positional Pathway Screen of wnt Signaling Genes in Schizophrenia: Association with DKK4

BACKGROUND Wnt signaling has been implicated in schizophrenia from studies of gene expression in patients, from an understanding of the function of reported susceptibility genes and from experimental studies of psychoactive drugs. This diverse evidence suggests that wnt signaling genes, defined as pathway participants, modifiers or targets, are good candidates as susceptibility factors. METHODS We performed a combined positional and candidate association screen by identifying known wnt signaling genes in regions linked to schizophrenia. In a staged study we examined over 50 single nucleotide polymorphisms (SNPs) in 28 wnt signaling genes, first in trios of Chinese origin and then in a case-control series from Hong Kong. RESULTS In both sets, Dickkopf 4 (DKK4) was associated with schizophrenia - with an odds ratio of 3.9 (p < .01, CI = 1.3-11.1) in the combined sample. CONCLUSIONS As DKK family members have previously been found to show altered expression in schizophrenia brain and to bind to neuregulin, this finding suggests that DKK4 may play a role in schizophrenia pathogenesis.