Attention-deficit/hyperactivity disorder and dopamine receptor D4 (DRD4) exon 3 variable number of tandem repeats (VNTR) 2-repeat allele.

To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.

Genetic Overlap Between Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in SHANK2 Gene.

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap. Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old. Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2/SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 (OR = 0.762, permuted p = 0.0376), rs7106631 (OR = 0.720, permuted p = 0.0034), and rs9888288 (OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings. Conclusion: SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children.

Are psychiatric comorbidities and associated cognitive functions related to treatment response to methylphenidate in boys with attention-deficit/hyperactivity disorder?

BACKGROUND: Methylphenidate (MPH) has been found to be an effective medication for attention-deficit/hyperactivity disorder (ADHD). However, there are neither consistent nor sufficient findings on whether psychiatric comorbidities and associated cognitive functions of ADHD are related to treatment response to MPH in ADHD children. OBJECTIVES: This study investigated whether psychiatric comorbidities, IQ, and neurocognitive deficits are related to treatment response to MPH in ADHD children. In some ways, it is preferable to have a drug that the effectiveness of which to a disorder is not affected by its associated cognitive functions and psychiatric comorbidities. On the other hand, it is likely that the baseline symptom severity of ADHD is associated with the effectiveness of MPH treatment on the symptoms post treatment. METHODS: A total of 149 Chinese boys (aged 6-12 years) with ADHD, combined type, and normal IQ participated in this study. Assessment of ADHD symptom severity was conducted pre and post MPH treatment, while assessment of psychiatric comorbidities, IQ, and neurocognitive deficits was performed in a non-medicated condition. Treatment response was defined as the ADHD symptom severity post MPH treatment. RESULTS: Results indicated that MPH treatment was effective, significantly improving the ADHD condition. Yet, comorbid disorders, IQ, and neurocognitive deficits were not related to MPH treatment response on ADHD symptoms. These findings indicated that the effectiveness of MPH was not affected by psychiatric comorbidities and associated cognitive functions of ADHD. Instead, as expected, it was the baseline symptom severity that was mainly related to the treatment response, ie, the milder the baseline condition, the better the treatment response. CONCLUSION: The current findings positively endorse the widespread clinical use of MPH for treating ADHD. It improves the behavioral symptoms of ADHD regardless of varying psychiatric comorbidities, IQ, and neurocognitive deficits.

Family-based association study of DRD4 gene in methylphenidate-responded Attention Deficit/Hyperactivity Disorder.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Age-related grey matter volume correlates of response inhibition and shifting in attention-deficit hyperactivity disorder.

BACKGROUND: Children with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age. AIMS: To map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes. METHOD: Attention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). Voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age. RESULTS: Individuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age-dependent. CONCLUSIONS: Our evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.

Prevalence of DSM-IV disorders in Chinese adolescents and the effects of an impairment criterion: a pilot community study in Hong Kong.

PURPOSE: To provide preliminary prevalence estimates of common DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-4th Edition) disorders in a sample of Hong Kong Chinese adolescents. METHODS: 541 Chinese adolescents were recruited from Grades 7, 8 and 9 of 28 mainstream high schools in Hong Kong (mean age=13.8 years; SD=1.2). The adolescents and their parents were separately administered the Youth and Parent versions of DISC-IV (Diagnostic Interview Schedule for Children-Version 4), respectively. RESULTS: Based upon both symptom and impairment criteria, as required by DSM-IV, the overall prevalence estimate of DSM-IV disorders in our sample of Chinese adolescents was 16.4%. Estimates for such individual disorders/diagnostic groupings as anxiety disorders, depressive disorders, attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), and substance use disorders were 6.9, 1.3, 3.9, 6.8, 1.7, and 1.1%, respectively. These rates were largely compatible with those reported in previous studies with perhaps lower rates of generalized anxiety disorder (GAD), depressive disorders, CD, and substance use disorders, but a higher rate of ODD. The rate of ADHD was somewhat higher, but this might reflect the current DSM-IV diagnostic practice. The rate of anxiety disorders was not as high as predicted from some previous questionnaire surveys. The application of an impairment criterion had discernible impacts on prevalence estimates, greater on anxiety and substance use disorders, but smaller on depressive and disruptive behavior disorders. There was a lack of gender difference in rates of ODD and CD. DISCUSSION AND CONCLUSION: While the findings reported here are broadly compatible with those of other studies, there may be cross-cultural differences in rates of some individual disorders, e.g., GAD, depressive disorders, ODD, CD, and substance use disorders, as well as in gender difference regarding rates of ODD and CD. However, exact comparison between studies is confounded by methodological differences in sample characteristics, measures, and case definition. Standardization of methodology in epidemiological surveys should allow more precise identification of any within- or between-culture variations in prevalence estimation.

Risk factors for suicide in the immediate post-discharge period.

BACKGROUND: Suicide risk is highest in the first few months following psychiatric in-patient care. Most data on post-discharge suicides have come from Western countries. Many studies collected cases of suicide over a long post-discharge period and did not focus on this high-risk period. This study aims to describe the characteristics and examine the risk factors of suicides occurring in the immediate post-discharge period in Hong Kong. METHODS: A case-control study based on discharged patients from all psychiatric hospitals/units in Hong Kong in 1997-1999. Suicides occurring within 60 days of discharge from psychiatric hospitals (N = 97) were ascertained by record linkage with Coroner's court data. Controls were matched for age, gender, diagnoses, discharge hospitals, and dates of discharge. Possible risk factors were extracted from in- and out-patient records, and were identified by conditional logistic regression. RESULTS: The commonest diagnosis and suicide method were schizophrenia and falling from a height, respectively. There were no significant case-control differences in the drug treatment received. Risk factors for suicides were: previous deliberate self-harm (OR = 2.3, 95% CI = 1.07-5.05), admission for deliberate self-harm (OR = 3.2, 95% CI = 1.3-7.8), compulsory admission (OR = 3.1, 95% CI = 1.1-8.7), living alone (OR = 5.8, 95% CI = 1.4-23), work stresses (OR = 5.4, 95% CI = 1.5-18) and being out of contact (OR = 7.9, 95% CI = 1.87-33). The overall number of risk factors had greater screening efficacy for suicide than any single factor. CONCLUSIONS: Vulnerable (previous suicidality) and uncooperative (compulsory admission and out of contact) patients who live alone and are exposed to work stresses are prone to immediate post-discharge suicide. Thorough treatment of the circumstances leading to the index admissions, management of work stresses, improved engagement in follow-up care and systematic assessment of suicide risk are indicated.

Mapping brain structure in attention deficit-hyperactivity disorder: a voxel-based MRI study of regional grey and white matter volume.

The neuroanatomical basis of attention deficit-hyperactivity disorder (ADHD) is postulated to involve brain circuitry responsible for attention and executive function. Relatively new automated methods of MRI analysis allow rapid examination of each volume element (voxel) of whole brain, therefore we planned a comprehensive quantitative examination of brain anatomy in children with ADHD using voxel-based methods. We aimed to quantify whole brain, global tissue class and regional grey and white matter volume differences in 28 male children with ADHD and 31 closely matched controls. Since ADHD is often complicated by comorbid oppositional defiant disorder (ODD) and conduct disorder (CD), we also conducted post-hoc analyses of subgroups of children with ADHD with and without these comorbidities. Significant regional deficits in ADHD were observed within a predominantly right-sided frontal-pallidal-parietal grey matter network and bilateral white matter tracts. Post-hoc comparisons suggested that comorbid ODD or CD did not greatly alter the extent of regional pathology in ADHD. The exceptions being cerebellar and striatal volume deficits which were significantly greater in children with ADHD plus comorbidities, but not those with ADHD alone, compared to controls. Overall, restricted structural brain abnormalities caused by ADHD were localized to brain systems known to be necessary for attention and executive function.

Duration of hospitalization and post discharge suicide.

A retrospective cohort of discharged patients from all public psychiatric hospitals in Hong Kong (1997-1999) was linked to suicide data from Coroner's court. Patients hospitalized shorter than 15 days had significantly lower suicide rates than longer stay patients. The results were fairly consistent across immediate/late post discharge periods, gender, age, diagnoses, and narrow/wide definitions of suicide. This finding was opposite of what has been reported in the literature. Short hospitalization carried different suicide risks in different service settings.

The test-retest reliability and screening efficiency of DISC Predictive Scales-version 4.32 (DPS-4.32) with Chinese children/youths.

INTRODUCTION: The DISC Predictive Scales-4.32 (DPS-4.32) were short-forms of the Diagnostic Interview Schedule for Children-IV (DISC-IV). METHOD: The psychometric properties of DPS-4.32 were tested on two Chinese samples: a clinic sample of 83 children/youths, and a community sample of 541 youths. RESULTS: Both Parent and Youth DPS-4.32 exhibited good-to-excellent test-retest reliability. Their screening efficiency was examined respectively against DSM-IV diagnoses of the full-length Parent and Youth DISC-IV. Results indicated large AUCs (Area under Receiver-Operating Characteristic Curve), as well as high sensitivity, specificity, and negative predictive values, supporting the capability of DPS-4.32 to differentiate cases from noncases. CONCLUSION: DPS-4.32 held promise as efficient short-forms of DISC-IV, screening DSM-IV diagnoses. They were also applicable to the Chinese population, demonstrating their cross-cultural applicability.

Test-retest reliability of the Chinese version of the Diagnostic Interview Schedule for Children-Version 4 (DISC-IV).

BACKGROUND: Despite the huge youth population, there is a lack of psychiatric diagnostic instruments with reported psychometric properties in Chinese. This study reports the development of the Chinese version of DISC-IV and examines its test-retest reliability. METHOD: Seventy-eight parents and 79 youths (mean age 13.1 years) attending child psychiatric clinics were interviewed twice using the Chinese DISC-IV (Diagnostic Interview Schedule for Children-IV) about 22 days apart. RESULTS: The kappa coefficients were good to excellent for obsessive compulsive disorder (OCD) (both youth (Y) and parent (P) versions), major depressive disorder (MDD) (P), attention deficit hyperactivity disorder (ADHD) (P); fair for anxiety disorder (P), oppositional defiant disorder (ODD) (P, Y), MDD (Y); but poor for anxiety disorder (Y) and ADHD (Y). Parent informants had better test-retest reliability than youth informants. CONCLUSIONS: The Chinese DISC-IV had comparable test-retest reliability with the original English version.

Psychiatric care of suicides in Hong Kong.

BACKGROUND: Though psychiatric patients have high suicidal risks, relatively little is known about the pattern of psychiatric care they received, especially in a non-Western setting. METHODS: Territory-wide record linkage study of computerised psychiatric records of suicide cases according to coroner's verdicts. RESULTS: Only 1/4 of the suicide population received psychiatric care in Hong Kong. These patient suicides differed from general population suicide in the distribution of sex, age, and suicide methods. Suicides are more common during the periods of in-patient care and immediately post discharge. Among these patient suicides, recent contacts with psychiatrists before their lethal acts were common. LIMITATIONS: Proportion of patients that received psychiatric care could be underestimates because private psychiatric patients and persons who immigrated were not counted. No clinical data are available from the record linkage. CONCLUSIONS: A wider coverage of psychiatric care to the suicidal population is required through improved accessibility and public health education. A smooth transition of care after discharge, active case tracing, and improved in-patient care should be considered.

The suicide risk of discharged psychiatric patients.

BACKGROUND: The suicide risk of psychiatric patients fluctuated along the course of their illness and was found to be high in the immediate post-discharge period in some settings. The epidemiology and psychiatric services for the suicide population in Hong Kong have differed from those of the West (i.e., low youth suicide rate, high elderly suicide rate, high female/male ratio, and heavily government-subsidized psychiatric service). This study examined the suicide rates within a year of discharge from psychiatric inpatient care in Hong Kong. METHOD: Discharges from all psychiatric hospitals or psychiatric wards in general hospitals in Hong Kong from 1997 through 1999 were followed up for suicides (ICD-9, E950-E959) and "undetermined" causes of deaths (E980-E989) by record linkage with the Coroner's Court until their deaths or Dec. 31, 2000. The suicide rates (/1000 person-years at risk) and standardized mortality ratios (SMRs; assigning a value of 1 to the same age- and sex-specific suicide rates in the general population) were calculated. RESULTS: 21,921 patients (aged over 15 years) were discharged from psychiatric hospitals from 1997 through 1999. Two hundred eighty patients committed suicide within 1 year of discharge; 85 suicides (30%) occurred within 28 days after discharge. The SMRs for suicide in the first 28 days after discharge were 178 (95% CI = 132 to 235) for females and 113 (95% CI = 86 to 147) for males. These rates were 4.0 (95% CI = 2.7 to 5.6) times higher for females and 4.6 (95% CI = 3.2 to 6.3) times higher for males than the rate in the rest of the year. Young adults had higher SMRs than the elderly. No specific diagnoses had higher suicidal risk than others. Calculations including undetermined causes of deaths (N = 53) gave similar results. CONCLUSION: The immediate post-discharge period carries a high risk of suicide for psychiatric patients. The high-risk groups are young adults and females. No diagnosis appears to carry a particularly high risk.