The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children.

OBJECTIVE: The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. METHODS: This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified. RESULTS: Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69nmol/g cre. vs. 186.84nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95µg/g cre. vs. 16.55µg/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24-0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13-1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12-65.04). CONCLUSION: This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Risk of stroke among patients with post-traumatic stress disorder: nationwide longitudinal study.

BACKGROUND: Previous evidence has shown positive associations between post-traumatic stress disorder (PTSD) and hypertension, dyslipidaemia and diabetes mellitus, which are all risk factors for stroke, but the role of PTSD in the subsequent development of stroke is still unknown. AIMS: To investigate the temporal association between PTSD and the development of stroke. METHOD: Identified from the Taiwan National Health Insurance Research Database, 5217 individuals aged ≥18 years, with PTSD but with no history of stroke, and 20 868 age- and gender-matched controls were enrolled between 2002 and 2009, and followed up until the end of 2011 to identify the development of stroke. RESULTS: Individuals with PTSD had an increased risk of developing any stroke (hazard ratio (HR) 3.37, 95% CI 2.44-4.67) and ischaemic stroke (HR = 3.47, 95% CI 2.23-5.39) after adjusting for demographic data and medical comorbidities. Sensitivity tests showed consistent findings (any stroke HR = 3.02, 95% CI 2.13-4.28; ischaemic stroke HR = 2.89, 95% CI 1.79-4.66) after excluding the first year of observation. CONCLUSIONS: Individuals with PTSD have an increased risk of developing any stroke and ischaemic stroke. Further studies are required to investigate the underlying mechanisms.

Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study.

OBJECTIVES: Previous studies have found that attention-deficit hyperactivity disorder (ADHD) in childhood and adolescence is associated with an increased risk of major depression and bipolar disorder in later life. However, the effect of ADHD comorbidity on the diagnostic conversion to bipolar disorder among patients with major depression is still uncertain. METHODS: Using the Taiwan National Health Insurance Research Database, 58,023 subjects < 30 years of age who had major depression with (n = 1,193) or without (n = 56,830) ADHD comorbidity between the years 2000 and 2008 were enrolled in our study. Subjects who developed bipolar disorder during the follow-up to the end of 2011 were identified. RESULTS: Adolescents and young adults who had major depression with ADHD comorbidity had an increased incidence of subsequent bipolar disorder (18.9% versus 11.2%, p < 0.001) compared to those without ADHD. Cox regression analysis showed that ADHD comorbidity was an independent risk factor (hazard ratio = 1.50, 95% confidence interval 1.30-1.72) predicting subsequent bipolar disorder among those with major depression, adjusting for demographic data and psychiatric comorbidities. CONCLUSIONS: Patients with comorbid diagnoses of major depression and ADHD had an increased risk of diagnostic conversion to bipolar disorder compared to those who had major depression alone. Further studies would be required to validate this finding and to investigate the possible underlying mechanisms.

A double-blind, randomized comparison study of efficacy and safety of intramuscular olanzapine and intramuscular haloperidol in patients with schizophrenia and acute agitated behavior.

Studies of intramuscular (IM) olanzapine in Asian and Taiwanese populations are limited. This study examined the efficacy and safety of IM olanzapine in Taiwanese patients with schizophrenia and acute agitated behavior.This was a multicenter, double-blind, randomized, parallel study comparing the efficacy and safety of 10 mg/d IM olanzapine (n = 25) against 7.5 mg/d haloperidol (n = 24). The primary objective was to assess the change of agitation from baseline to 2 hours after the first IM injection on the Positive and Negative Symptom Scale-Excited Component Scale.The changes of Positive and Negative Symptom Scale-Excited Component Scale score from baseline to 2 hours after the first IM injection did not show statistically significant difference between study groups (olanzapine -9.0 ± 5.7, haloperidol -7.9 ± 4.0, P = 0.254). Both groups reported insomnia as the most common treatment-emergent adverse event, and no serious adverse event was reported.Intramuscular olanzapine and IM haloperidol are similarly effective antipsychotic agents in treating agitated symptoms in Taiwanese patients with schizophrenia. Both IM olanzapine and IM haloperidol were proven to be safe and well tolerated, which also provided alternative options in the treatment of patients with schizophrenia with agitation.

Risk of epilepsy among patients with atopic dermatitis: a nationwide longitudinal study.

OBJECTIVE: Both atopic dermatitis and epilepsy have been regarded as chronic inflammatory diseases. However, their association has yet to be investigated. METHODS: Using the Taiwan National Health Insurance Research Database, 35,312 patients with atopic dermatitis but without a history of epilepsy, and 35,312 age-/gender-matched controls were enrolled between 1998 and 2008, and followed to the end of 2011 to identify the development of epilepsy. RESULTS: Subjects with atopic dermatitis had a higher incidence of developing epilepsy (0.94 vs. 0.27/1,000 person-years, p < 0.001) than the control group. The Cox regression model showed that atopic dermatitis increased the risk of developing epilepsy (hazard ratio [HR] 2.91, 95% confidence interval [CI] 2.23-3.82) after adjusting for demographic data and medical comorbidities. Sensitivity tests showed consistent findings (HR 2.32, 95% CI 1.68-2.96) after excluding the first year of observation. In addition, asthma (HR 1.34, 95% CI 1.04-1.72) and allergic rhinitis (HR 1.34, 95% CI 1.04-1.73) were related to the risk of epilepsy. SIGNIFICANCE: Subjects with atopic dermatitis were associated with an increased risk of developing epilepsy in later life. Further studies would be needed to investigate the underlying mechanisms.

Association between maternal behavior in infancy and adult mental health: a 30-year prospective study.

BACKGROUND: Existing theories suggest that the mother-infant relationship has a potentially significant effect on long-term adult mental health, but there are few empirical data to support this view. Even fewer prior studies have examined the specific dynamics of the mother-infant relationship and their association with adult mental health. METHODS: A total of 1752 inner-city infants born between 1960 and 1965 were followed prospectively as a part of the Collaborative Perinatal Project (CPP) and the Johns Hopkins Pathways to Adulthood Study. Multiple observations of development and an extensive adult interview were performed. Maternal behavior was observed and systematically rated at the infant's 4-month pediatric neurological evaluation and at 8 months by a developmental psychologist. Factor analysis was used to organize the maternal behavior variables into different types of dysfunctional mother-infant relationships. Adult mental health was assessed at the follow-up interview, when the infant had reached the age of 27-33 years, by the General Health Questionnaire (GHQ) and self-perception of current mental health. RESULTS: There was a significant association between unsupportive maternal behavior at 8 months and subsequent poor adult mental health (Fisher's exact test, p=0.026). There was no association between overly involved maternal behavior and poor mental health as an adult. After adjustment for potential confounding variables, the elevated rates of poor adult mental health in children of mothers who exhibited unsupportive maternal behavior at 8 months persisted (OR=1.41 [95% CI=1.00-1.97], p<0.05). CONCLUSION: Infants who experience unsupportive maternal behavior at 8 months have an increased risk for developing psychological sequelae later in life.

The use of sertraline to treat an adolescent of dystonia comorbid with major depressive disorder with psychotic features.

Dystonia is characterized by sustained or intermittent involuntary muscle contractions. Psychiatric symptoms are essential non-motor features of dystonia, and higher risks of depressive and anxiety disorders have been reported. The precedence of psychiatric to motor symptoms in some patients and the dopaminergic and serotonergic system involvement in both the motor and psychiatric aspects suggest these psychiatric disorders may be intrinsic to the neurobiology of dystonia. Nevertheless, psychiatric comorbidities are often construed as secondary reactions to motor disabilities and the negative bio-psycho-social impacts of dystonia, leading to underdiagnosis and undertreatment. Research on antidepressant use in dystonia is scarce, especially in children and adolescents. This report presents a 17-year-old female with dystonia comorbid with depression with psychotic features, whose motor symptoms improved but psychiatric symptoms persisted with dopaminergic pharmacotherapy. Sertraline was finally added 5 years after the onset and successfully managed her psychotic depression without worsening motor symptoms. Early detection, prompt diagnosis, and timely holistic treatment with dopaminergic agents, antidepressants, and psychosocial interventions are critical for the mental health of dystonia patients.

Attention deficit hyperactivity disorder, tic disorder, and allergy: is there a link? A nationwide population-based study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and tic disorder usually co-occur in the same individuals, but the underlying mechanisms remain unclear. Previous evidence has shown that a frequent coexistence of allergic diseases was noted in patients with ADHD or tic disorder. We attempted to investigate the possible link among ADHD, tic disorder, and various allergic diseases. METHODS: Utilizing the Taiwan National Health Insurance Research Database from 1996 to 2010, 5,811 patients with ADHD alone, 1,816 patients with tic disorder alone, and 349 patients with dual diagnoses of ADHD and tic disorder were identified and compared with age-/gender-matched controls (1:4) in an investigation of the association among ADHD, tic disorder, and allergic diseases. RESULTS: Patients with dual diagnoses of ADHD and tic disorder had a significantly higher prevalence of allergic diseases and psychiatric comorbidities, including allergic rhinitis (43% vs. 28.4% vs. 33.6% vs. 19.7%, p < 0.001), asthma (27.5% vs. 17.2% vs. 18.2% vs. 11.9%, p < 0.001), atopic dermatitis (10.6% vs. 8.4% vs. 7.0 vs. 5.9%, p < 0.001), allergic conjunctivitis (55.6% vs. 34.7% vs. 43.5% vs. 26.3%, p < 0.001), obsessive compulsive disorder (4.0% vs. 1.3% vs. 2.0% vs. 0.1%, p < 0.001), and anxiety disorder (22.1% vs. 18.0% vs. 6.0% vs. 0.5%, p < 0.001) than the ADHD alone group, the tic alone group, and the control group. Furthermore, ADHD patients with more allergic diseases (≥ 3 comorbidities: OR: 3.73, 95% CI: 2.65~5.25; 2 comorbidities: OR: 2.52, 95% CI: 1.82~3.47; 1 comorbidity: OR: 1.87, 95% CI: 1.41~2.49) exhibited an increased risk of tic disorder compared with ADHD patients without allergic disease. CONCLUSION: A significant association among ADHD, tic disorder, and allergic diseases was noted in our study. The results may inspire further studies to clarify the underlying mechanisms and help us understand more about the complex etiology of ADHD, tic disorder, and their co-occurrence.

Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study.

BACKGROUND: Previous cross-sectional studies have suggested an association between asthma and attention-deficit/hyperactivity disorder (ADHD), but the temporal relationship was not determined. Using a nationwide population-based prospective case-control cohort study (1:4, age-/gender-matched), we hypothesized that asthma in infanthood or early childhood would increase the risk of ADHD in later life. METHODS: In all, 2,294 children with asthma and 9,176 controls aged between 0 and 3 years in 2000 were included in our study. Cases of ADHD that occurred to the end of follow-up (31 December 2010) were identified. RESULTS: Children with asthma had a higher incidence of developing ADHD (7% vs. 4.6%, p < .001) than control cohort during the follow-up period. After adjusting for age at enrollment, gender, level of urbanization, and comorbid allergic diseases (allergic rhinitis and atopic dermatitis), children with asthma had an elevated risk (HR: 1.31, 95% CI: 1.07-1.59) of developing ADHD compared with control group. DISCUSSION: Our prospective study supported a temporal relationship between asthma and ADHD. Asthma in very early life increased the risk of developing ADHD during the school years. Further studies are required to investigate whether the prompt treatment of asthma and comorbid allergic diseases could prevent the development of ADHD or decrease ADHD symptoms.