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Attention deficit hyperactivity disorder, tic disorder, and allergy: Is there a link? A nationwide population-based study
Journal of Child Psychology and Psychiatry
Abstract
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.
... Allergic rhinitis is one of the most common allergic diseases and one of the most common non-communicable diseases worldwide, which can coincide with other diseases, such as tic disorders [1,2]. ...
... 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association classifies Neurologic tic into three distinct conditions: Tourette syndrome, Persistent (Chronic) Motor or Vocal Tic Disorder, and provisional (transient) tic disorder [4,5]. Several studies have reported a connection between allergic conditions and tic disorders [2,6,7]. The etiology of tic disorders is complex and may be due to the interaction of genetic, environmental, immunological, and hormonal factors [8]. ...
... The severity of allergic rhinitis is also considered a factor that could play a role in the association of AR and tic disorders [14]. Previous research has suggested [2,6,7] that allergic rhinitis can affect people simultaneously with tic disorder in children and adolescents. The chronicity of patients' symptoms leads to changes in their behavior and quality of life, which in turn causes neurological and psychological disorders in the long run. ...
Background
Allergic rhinitis is the most common allergic disease. It can accompany psychological disorders such as tic disorders due to the prolonged course of the symptoms of allergic rhinitis. This pioneer case-control study aims to investigate tic disorders in children and adolescents under 18 years of age diagnosed with allergic rhinitis.
Method
The case group in this study consisted of patients who had both allergic rhinitis and tic disorders. Patients with allergic rhinitis without tic disorders were also enrolled as the control group with matched gender and age. Demographic characteristics, tic classifications, and contributing factors for allergic rhinitis and tic disorders were studied among the cases. Tic disorders were evaluated using DSM-5 criteria for the classification of tic disorders.
Results
47 patients in the case group and 47 patients in the control group were included in this study. 53.2% and 46.8% were males and females in the case group, respectively. The mean age of the patients was 10.46 ± 3.97 years old. Sound tics were more common among the patients compared to motor tics. Patients with concomitant AR and tic disorders had more days per week with AR symptoms (P-value ≤ 0.001; OR (every day vs. three days a week = 11.02(2.98, 40.76))). Most patients with sound tick were women (p: 0.026), and most patients with motion tic were in the Provisional tic disorder group (p: 0.001). The history of infantile eczema was seen more in patients without sound tic (p: 0.025), and otitis media was significantly less common among patients with sound tics (p: 0.026). Provisional tic disorder was the most common class among the patients. In the case group (coexistence between allergic rhinitis and tic) compared to the control group, patients had significantly more days with AR symptoms per week.
Conclusion
This preliminary study indicates that Provisional tic disorder was the most common classification of tic among patients with allergic rhinitis, especially in patients with motor tics. Asthma in motor tics, a history of food allergy in infancy, and a history of infantile eczema were also common among patients with vocal tics. Also, patients with allergic rhinitis and tic had more severe disease (more symptoms per week) than those with rhinitis alone. These findings emphasize the association of tic disorders with immunological pathways.
... [3] Several studies reported that children with allergic diseases had a higher risk of developing ADHD, with academic and behavioral problems exhibiting as hyperactive and impulsive behaviors. [2,[4][5][6][7][8][9] Early respiratory allergy symptoms and food allergy independently and synergistically contributed to an increased ADHD risk. [10] In an analysis of 19 US population-based surveys, attention deficit (AD) alone, asthma alone, and AR alone were each significantly associated with ADHD, and the combination of AD and asthma further increased ADHD risk. ...
... [2] Several possible mechanisms and factors may elucidate the link between allergic diseases and neurobehavioral disorders. [2,5,10] First, inflammation and immunologic dysregulation may play synergistic roles in increasing the risk of ADHD in allergic diseases. [2,29] Immaturity of the immune system during early life stages leads to exposure to high levels of proinflammatory cytokines among allergic children. ...
BACKGROUND: Over the last decades, the hypothesis that an allergic response could lead to the development of attention-deficit/hyperactivity disorder (ADHD) was raised and clinical studies investigated the co-existence of both. These studies had shown that allergic diseases and neurobehavioral disorders were concurrent and could be associated with genetic factors, neuroimmunity and microbial dysbiosis. To date, this was the first study in the Philippines to evaluate the prevalence and association of allergic diseases, its severity and ADHD symptoms. OBJECTIVE: The objective of this study was to determine the association of allergic diseases and ADHD symptoms among children aged 6–12 years based on parental report using the Filipino version of the Vanderbilt ADHD Parent Rating Scale. METHODS: School-aged children between 6 and 12 years with physician diagnosed allergies (bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, drug allergy, food allergy and/or acute or chronic urticaria) were randomly selected. Skin prick test (SPT) to aeroallergens was done. The parents completed the Filipino version of the Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS), a screening tool for ADHD. RESULTS: Among the 415 patients, 135 (32.5%) of them screened positive for ADHD symptoms. Upon assessment of the Vanderbilt parent rating subscale responses, 13.49% of the children were categorized as predominantly inattentive subtype, 6.02% as predominantly hyperactive/impulsive subtype and 13.01% as combined inattention/hyperactivity. Three hundred and seventy six (91%) children were diagnosed with asthma. Among these asthmatics, 119 (32%) had ADHD symptoms with the following subtypes – predominantly inattentive subtype (13.56%), predominantly hyperactive/impulsive subtype (5.05%) and combined inattention/hyperactivity (13.03%). Combined inattention/hyperactivity subtype had a significant proportion of severe asthmatics, as compared to mild or moderate asthma (p value = 0.026). Furthermore, 389 (94%) children were diagnosed with allergic rhinitis. Among these patients, 130 (33%) had ADHD symptoms with the following subtypes – predominantly inattentive subtype (13.62%), predominantly hyperactive/impulsive subtype (6.43%) and combined inattention/hyperactivity (13.37%). However, evidence was not sufficient to demonstrate an association between ADHD subtypes and allergic rhinitis severity. Lastly, 206 (50%) children were diagnosed with atopic dermatitis. Among these patients, 71 (34%) had ADHD symptoms with the following subtypes – predominantly inattentive subtype (14.56%), predominantly hyperactive/impulsive subtype (4.85%) and combined inattention/hyperactivity (15.05%). However, there was insufficient evidence to demonstrate a link between ADHD subtypes and atopic dermatitis severity. CONCLUSION: Children with allergies, especially those with severe asthma, are more likely to have ADHD symptoms. Key words: attention deficit hyperactivity disorder, allergic disease, allergic sensitization, asthma
... [1][2][3][4] Recent reports suggest that TDs in children may also be associated with headaches, infections, and allergies. [5][6][7] The prevalence of headache is reported to be 10.0%-17.8% in school age children. The prevalence may increase with age with a peak in early adolescence, reaching to 27.0%-32.0%. ...
... [21] In a recent study, it was suggested that this relationship extended to TDs in general and comorbid ADHD may further elevate the risk. [6] Similar to those studies we found that children with TDs have elevated odds of atopy and drug allergies and that this extended to their mothers. ...
Objective: This study aimed to evaluate primary headache disorders and other
causative comorbidities (e.g., epilepsy, atopic disorders, recurrent abdominal pain,
motion sickness, and headache) in children with tic disorders (TDs) and their
mothers.
Materials and Methods: In a multi‑center, cross‑sectional, familial
association study using case–control design, youth (between 7 and 17 years) with
TDs (TD, as per Diagnostic and Statistical Manual of Mental Disorders‑5 criteria)
and age‑ and sex‑matched healthy controls and their mothers were evaluated in
the aspect of functional syndromes spectrum including migraine, epilepsy, atopic
disorders, motion sickness, and recurrent abdominal pain.
Results: Seventy‑nine
youth with TD and 101 controls were included. Causative comorbidities, other than
epilepsy and motion sickness were more common in children with TD with an odds
ratio (OR) of 2.1 (atopy) and 3.9 (food allergy). Specifically, recurrent abdominal
pain and migraine were found in 36.7% and 31.7% of children (vs. 18.8% and
16.8% of controls, ORs 2.5 and 2.3, respectively). Mothers of youth with TDs also
have higher rates of atopy, drug allergy and allergic dermatitis (ORs; 3.8, 3.2 and
2.1; respectively).
Conclusion: Results of recent studies suggest a possible link
between atopic disorders, migraine, recurrent abdominal pain and TDs. Our results
contribute to those studies and suggest that this relationship may extend to the
mothers of children as well.
... The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to diagnose diseases during the study period. The NHIRD has been used extensively in epidemiologic studies in Taiwan [7][8][9]26]. VGHTPE institutional review board approved the study protocol and waived the requirement for informed consent, because this investigation used de-identified data and no human subjects contact was required (2018-07-016AC). ...
Although several studies have examined a diagnostic conversion from major depressive disorder (MDD) to bipolar disorder (BD), only a few studies specifically focused on adolescents and young adults who are at the peak ages of BD onset. Data from participants (N = 130,793) aged 10–29 years who were diagnosed with MDD were extracted from the Taiwan National Health Insurance Research Database. We applied demographic analyses, survival analysis, Aalen Johansen curves, and Cox regression, investigating the diagnostic conversion rate and factors that were most or less predictive of conversion. Among the adolescents and young adults with MDD, the number of participant conversion subsample is 14,187 and the conversion rate was 13.80% (95% confidence interval: 13.54–14.06%) during the 11-year follow-up. The conversion rate was highest in the first year (4.50%; 4.39–4.61%) and decreased over time. The significant predictors were younger age of diagnosis with MDD (p < 0.001), moderate and high antidepressant resistance (p < 0.001), obesity (p < 0.001), psychiatric comorbidities (attention-deficit/hyperactivity disorder, substance use disorder, and cluster B and C personality disorder, all p < 0.001), a family history of mental disorders (schizophrenia and mood disorders, all p < 0.05), lower monthly income (p < 0.001), and more mental health visits to the clinic each year (p < 0.001). A composite of demographic characteristics, antidepressant resistance, physical and psychiatric comorbidities, and family history significantly predicted diagnostic conversion from MDD to BD (area under the curve = 0.795, p < 0.001). Compared to adult population, the adolescents and young adults had different factors that were most or less predictive of conversion, which warrants further investigation.
... Patel et [42] al.'s analysis of 87,053,155 children and adults found a relationship between vitiligo and ADHD (OR = 2.59, 95%CI, 1.92-3.49). One Taiwanese research [43] in 2013 discovered a connection between AT diseases and ankylosing spondylitis with ADHD. It has been reported that family history of type 1 diabetes [44], rheumatoid arthritis [45], multiple sclerosis [45], systemic lupus erythematosus [46] increase the ADHD risk. ...
Background
Observational studies suggest a connection between autoimmune diseases (AD) and attention deficit hyperactivity disorder (ADHD). Nevertheless, the causality between AD and ADHD is yet to be determined. Therefore, we're employing a twin-sample analysis on Mendelian randomization, with a view to exploring the causality between ADHD and 19 AD.
Method
We evaluated the total statistics of the latest Genome-Wide Association Studies (GWAS) for ADHD2022 (38691 cases, 186843 controls) and 19 common ADs, including Autoimmune thyroiditis, Type 1 diabetes, Celiac disease, Vitamin B12 deficiency anemia, Idiopathic thrombocytopenic purpura, multiple sclerosis, Graves' disease, Sjogren's syndrome, Iridocyclitis, Ulcerative colitis, Crohn's disease, Psoriasis, Alopecia areata, Vitiligo, Rheumatoid arthritis (RA), Myasthenia gravis, Systemic sclerosis, Systemic lupus erythematosus, Ankylosing spondylitis. These summary statistics originated in publicly assessible, relatively large-scale GWAS meta-analyses conducted to date. The causality between ADHD and 19 ADs using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. Cochran's Q statistic was adopted, for the purpose of measuring the heterogeneity of the instrumental variable (IV).
Result
The result indicate that ADHD potentially increases the risk of vitiligo (IVW OR = 2.385, 95%CI, 1.054–5.398, P = 3.69e-02) and suggests an association between ADHD and increased hazard of rheumatoid arthritis (IVW OR = 1.092, 95%CI, 1.009–1.182, P = 2.94e-02). However, no other significant causal relationships were observed in our analyses.
Conclusion
In this research, the causalities between ADHD and 19 ADs were comprehensively assessed. Besides, it was identified genetic evidence suggesting possible causalities between ADHD and vitiligo along with rheumatoid arthritis in European populations.
... The Institutional Review Board of Taipei Veterans General Hospital approved the study protocol [2018-07-016 AC] and waived the requirement for informed consent because de-identified data were used in this study and no participants were actively enrolled. NHIRD has been used in numerous epidemiological studies in Taiwan (Chen et al., 2013;Cheng et al., 2018;Hsu et al., 2023;Zhang et al., 2021). ...
... Yuce et al. [8] found that the incidence of tic disorders was significantly higher in patients with allergic diseases, and speculated that allergic diseases and tic disorders shared the same immunological pathogenesis. Chen [9] found that patients with ADHD + tic disorder, ADHD alone, and tic disorder alone were more likely to have allergic diseases than control group. They reckoned that the altered immune reaction and dysregulated cytokine secretion may be the common pathway among those distinct diseases. ...
Objective
The study was to investigate serum total IgE levels and the distribution of specific IgE types in children aged 6–9 years with tic disorder, in order to provide knowledge for diagnosis and treatment of children with tic disorder.
Methods
Total serum IgE levels were detected by enzyme-linked immunosorbent assay (ELISA). Specific IgE levels in 72 children with tic disorder and normal 31 children were detected by EUROblot, respectively.
Results
The total serum IgE level of children with tic disorder aged 6–9 years was significantly higher than those of children in control group. Specific IgE distribution in tic disorder group was observed increased mainly including inhaled mugwort, dust mite combination 1 (house dust mite/dust mite), mold combination (penicillium point/mycobacteria/Aspergillus fumigatus/streptomyces), cockroaches in Germany respectively, and also food freshwater fish combination 1 (salmon/sea bass/carp), marine fish combination 1 (cod/lobster/scallop), egg white, and crab, while elevated specific IgE of normal children group was mainly food-based (egg white, milk, and soybean). The significant different specific IgE between two groups was dust mite combination 1 (house dust mite/dust mite) (P < 0.05).
Conclusion
The total serum IgE level of children with tic disorder aged 6–9 years was significantly increased, which may be related to the disease. Specific IgE in children with tic disorder was mainly inhalation allergens, especially dust mite combination 1 (house dust mite/dust mite), which should be avoided in clinical diagnosis and daily life.
... The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan [30][31][32][33][34]. Institutional Review Board of Taipei Veterans General Hospital approved the study protocol and waived the requirement for informed consent since this investigation used de-identified data and no human subjects contact was required. ...
Although a growing number of studies have investigated the relationship between psychosocial factors and periodontitis, studies investigating the association between bipolar disorder (BD) and periodontitis are lacking. Using the Taiwan National Health Insurance Research Database, 4251 adolescents with BD and 17,004 age- and sex-matched controls were included. They were followed up from enrollment to the end of 2011 or death. Periodontitis was diagnosed during the follow-up. Cox regression analysis indicated that adolescents with BD had a higher risk of periodontitis (hazard ratio [HR]: 2.96, 95% confidence interval [CI] 2.77–3.17) than did controls. Subanalyses stratified by sex revealed a higher risk of periodontitis in male (HR: 2.83, 95% CI 2.56–3.14) and female (HR: 3.01, 95% CI 2.74–3.30) adolescents with BD than their respective controls. The long-term use of mood stabilizers was associated with a higher risk of periodontitis (HR: 1.19, 95% CI 1.06–1.35) in the BD cohort. Our study highlighted an increased risk of periodontitis in adolescents with BD compared with controls during the follow-up. We recommend that more attention should be paid to the prevention of periodontitis in adolescents with BD, especially those who are female or receiving mood stabilizers.
... The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan [22][23][24][25]. The study was approved by the Institutional Review Board at Taipei Veterans General Hospital (protocol number = 2018-07-016AC and date of approval = July 23, 2021) with the waiver of the requirement for any informed consent. ...
Background: Increasing studies have supported the relationship between pain disorders and treatment-resistant depression (TRD) or chronic pain disorders may possibly impact the clinical characteristics of major depressive disorder (MDD). Thus, this linkage has been seen as a potential clinical marker to predict diagnostic conversion to bipolar disorder (BD) among patients with MDD. Methods: With the Taiwan National Health Insurance Research Database, we enrolled 4,760 adolescent and young adult patients with TRD, 19,040 counterparts with antidepressant-responsive depression, and 19,040 age-/sex-/residence-/family income-matched controls. Then, we followed up on their conversion from MDD to BD from enrollment to the end of 2011. Results: The incidence of diagnostic progression from MDD to BD was significantly higher in the TRD group than the non-TRD group (30.5% versus 10.6%, p < 0.001). Logistic regression analysis with adjustment of demographic characteristics showed that the TRD group had the highest risks of previous migraine, tension headache, fibromyalgia, peripheral neuropathy, dysmenorrhea, and irritable bowel syndrome, followed by the non-TRD group, and then the control group (p < 0.05). In further analysis of those data stratified by diagnostic progression to BD, we found no consistent results among different subgroups. Conclusion: Clinicians should be aware of the higher risk of developing TRD in depressive patients with comorbid pain disorders such as migraine, tension headache, fibromyalgia, peripheral neuropathy, dysmenorrhea, and irritable bowel syndrome. Besides, we found no consistent results in predicting diagnostic conversion from MDD to BD when the rôle of these pain disorders was evaluated.
... The diagnostic codes used in the present study were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in numerous epidemiologic studies in Taiwan [7][8][9]22]. ...
This longitudinal study aimed to investigate the risk of subsequent autoimmune disease in patients with post-traumatic stress disorder (PTSD) in Asian population. Between 2002 and 2009, we enrolled 5273 patients with PTSD and 1:4 matched controls from the National Health Insurance Database of Taiwan, and followed up the patients until December 31, 2011, or death. The investigated autoimmune diseases included thyroiditis, lupus, rheumatic arthritis, inflammatory bowel disease, Sjogren’s syndrome, dermatomyositis, and polymyositis. The Cox regression model was used to estimate the risk of developing autoimmune diseases, with adjustment for demographics and psychiatric and medical comorbidities. Furthermore, we examined the psychiatric clinics utility of patients with PTSD indicating the severity of PTSD in association with autoimmune diseases. After adjusting for confounders, patients with PTSD had a 2.26-fold higher risk of developing any autoimmune diseases (reported as hazard ratios with 95% confidence intervals: 1.82–2.80) than the controls. For specific autoimmune diseases, patients with PTSD had a 2.70-fold higher risk (1.98–3.68) of thyroiditis, a 2.95-fold higher risk (1.20–7.30) of lupus, and a 6.32-fold higher risk (3.44–11.60) of Sjogren’s syndrome. Moreover, the PTSD severity was associated with the risk of autoimmune diseases in a dose-dependent manner. The patient with the highest psychiatric clinics utility was associated with an 8.23-fold higher risk (6.21–10.90) of any autoimmune diseases than the controls. Patients with PTSD had an increased risk of autoimmune diseases, and such risk was associated with the severity of PTSD in a dose-dependent manner. However, the present study did not provide a direct effect between PTSD and autoimmune diseases, but rather an association. Further studies are warranted to examine the underlying pathophysiological mechanisms.
... Symptoms of ADHD typically begin during early childhood and are characterized by impaired attention, increased impulsivity, and motor hyperactivity [2]. While the onset of symptoms typically occurs at a young age, symptoms often persist into adulthood [3]. Although psychiatric comorbidity among patients with ADHD has been very well documented [4], few large systematic studies had assessed the link between ADHD and somatic comorbidities [5]. ...
Background:
The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and type 2 diabetes mellitus (T2D) and its cardiovascular outcomes have not been sufficiently studied.
Methods:
2,986 adults with T2D from the Joslin Diabetes Center at Upstate Medical University were assessed for ADHD-like symptoms, executive dysfunction, and emotional control using the Adult Self-Report Scale V1.1 (ASRS) expanded version. Surveys were sent electronically, and clinical data were obtained from the electronic medical record. Pearson chi-square test was used for categorical variables association. When ASRS scores were the dependent variable, negative binomial regression correcting for demographic variables that were associated with the ASRS scores was used.
Results:
155 (49.2%) of respondents met DSM-5 criteria for ADHD using the ASRS scores; Only ten (3.6%) of respondents had an ICD10 diagnosis of ADHD in their medical record; Forty-three (13.7%) had either a diagnosis of ADHD in the medical history or were taking medications used by people with ADHD. Higher levels of ADHD-like symptoms were found in patients with T2D compared with population norms. There was a modest association of the ASRS executive dysfunction subscale with overall cardiovascular comorbidities (p = 0.03). However, the p-value did not survive the multiple testing correction. Both ADHD-like symptoms and symptoms associated with emotional control, however, were not associated with specific cardiovascular diseases, hypertension, or with HbA1c, LDL-cholesterol, triglycerides, ALT, creatinine, or eGFR.
Conclusion:
Our results suggest that adults with T2D attending a tertiary care diabetes clinic are at risk for having ADHD-like symptoms, highlighting the importance of screening for ADHD symptoms in this specialty setting and referring undiagnosed adult patients for further assessment and treatment of ADHD. Larger studies are needed to clarify the relationship between ADHD-like symptoms, executive dysfunction, and emotional control with diabetic control and comorbidities.
... The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan (Chen et al., 2015;Chen et al., 2013;Cheng et al., 2018;Liang et al., 2020). This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (2018-07-016AC). ...
Background:
Whether response to antidepressants is related to the risk of developing type 2 diabetes mellitus (T2DM) in adolescents with depression remains unknown.
Methods:
This study used the Taiwan National Health Insurance Research Database to enroll 1739 adolescents with antidepressant-resistant depression, 6956 with antidepressant-responsive depression, and 6956 controls between 2001 and 2010, with an end-of-2011 follow-up. Physician-diagnosed T2DM was identified at follow-up. T2DM-related risk factors, namely hypertension, dyslipidemia, and obesity, were assessed and controlled for as confounding factors.
Results:
Adolescents with antidepressant-resistant depression (hazard ratio [HR], 95 % confidence interval [CI]: 4.62, 2.75-7.75) and those with antidepressant-responsive depression (HR, 95 % CI: 3.06, 1.98-4.72) had a higher risk of developing T2DM at follow-up than did the control group. Those with antidepressant-resistant depression were more likely to receive a diagnosis of T2DM (HR, 95 % CI: 1.51, 1.04-2.19) later in life than were those with antidepressant-responsive depression.
Discussion:
Clinicians should closely monitor factors related to T2DM, such as fasting blood sugar, in high-risk populations, especially in adolescents with antidepressant-resistant depression.
... The NHIRD has been used extensively in a multitude of epidemiological studies conducted in Taiwan. [20][21][22][23] This study was approved by the relevant institutional review board. ...
PURPOSE
Evidence suggests an increased long-term risk of major psychiatric disorders (MPDs) in childhood and adolescent cancer survivors (CACSs). However, definitive conclusions regarding such associations and whether such associations vary for different types of cancers remain unclear.
METHODS
Using a nationwide data set from 2001 to 2011, we enrolled CACSs and likewise randomly selected individuals without cancer from the general population (1:10 ratio) who were matched to the CACSs with regard to demographic data. We investigated eight organ system–related cancers. The primary outcomes were the risks of seven MPD diagnoses: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder.
RESULTS
CACSs (n = 5,121; mean age = 9.08 years) showed increased risks of six MPD diagnoses than controls (n = 51,210), with results as follows (in descending order): ASD (hazard ratio [HR], 10.42; associated 95% CI, 4.58 to 23.69), ADHD (HR, 6.59; 95% CI, 4.91 to 8.86), BD (HR, 2.93; 95% CI, 1.26 to 6.80), MDD (HR, 1.88; 95% CI, 1.26 to 2.79), OCD (HR, 3.37; 95% CI, 1.33 to 8.52), and post-traumatic stress disorder (HR, 6.10; 95% CI, 1.46 to 25.54). CACSs also showed earlier ages at diagnoses of ADHD, schizophrenia, MDD, and OCD than controls. The risks of MPD diagnoses vary according to specific cancer types/categories. Brain cancer and lymphatic/hematopoietic tissue cancer were associated with the greatest number of MPD diagnoses (ie, each was associated with six diagnoses). In addition, ASD and ADHD were associated with most organ system–related cancers (ie, each was associated with five categories).
CONCLUSION
We found that CACSs were at higher risks of MPD diagnoses than controls. Follow-up care should include psychosocial interventions focusing on early signs of mental health problems and early interventions in this high-risk group.
... The diagnostic codes used in the NHIRD are based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan (Chen et al., 2015(Chen et al., , 2013Cheng et al., 2018;Liang et al., 2020b). This study was approved by the Institutional Review Board of Taipei Veterans General Hospital, and the need for written informed consent was waived for this population-based database study. ...
Whether a history of premenstrual dysphoric disorder (PMDD) is associated with a subsequent risk of major affective disorders remains unclear. This study aimed to examine the risk of unipolar depression and bipolar disorder in women with PMDD compared with those without PMDD. This study used data from the Taiwan National Health Insurance Research Database. Women who were diagnosed with PMDD and had no history of any major affective disorder were included. The controls were women without PMDD matched for demographics and physical and psychiatric comorbidities. Cox regression was used to estimate the risk of unipolar depression and bipolar disorder. We included 8222 women with PMDD and 32,888 matched controls. After adjusting for potential confounders, we found that the women with PMDD were associated with a higher risk of unipolar depression [hazard ratio (HR) 2.58; 95% confidence interval (CI), 2.23-2.98] and bipolar disorder (HR 2.50; 95% CI 1.62-3.88) than the controls. The PMDD group had a younger age at the diagnosis of unipolar depression (37.11 vs 41.59 years) and bipolar disorder (35.59 vs 42.02 years, p=0.002), and shorter duration between enrollment and onset of unipolar depression (2.97 vs 5.33 years, p<0.001) and bipolar disorder (3.05 vs 5.57 years, p<0.001). Our results showed a strong association between PMDD and major affective disorders. Healthcare workers should be aware of patients with PMDD and the risk of developing major affective mental disorders.
... (3) Direct evidence of pro-inflammatory overactivity in the brain in TD and ADHD is modest and limited and (4) hyper-reactivity of systemic immune pathways and neuro-inflammation may contribute to natural fluctuations of the core behavioral features of TD and ADHD. However, data and a specific comment on TD + ADHD co-occurrence is missing, although Chen et al. [44] reported on a Taiwan National Health Insurance research database (n = 5811 ADHD-only, n = 1816 TD-only, n = 349 TD + ADHD) that patients with TD + ADHD had a significantly higher prevalence of allergic diseases than (in decreasing order) ADHD-only, TD-only, and controls, suggesting that ADHD is the essential factor. ...
Background:
The co-existence of tic disorders and attention-deficit/hyperactivity disorder (TD + ADHD) has proven to be highly important in daily clinical practice. The factor ADHD is not only associated with further comorbidities, but also has a long-term negative psychosocial effect, while the factor TD is usually less disturbing for the major part of the patients. It remains unclear how far this is related to a different neurobiological background of the associated disorders or whether TD + ADHD reflects a common one.
Objective:
This review provides an update on the neurobiological background of TD + ADHD in order to better understand and treat this clinical problem, while clarifying whether an additive model of TD + ADHD holds true and should be used as a basis for further clinical recommendations.
Method:
A comprehensive research of the literature was conducted and analyzed, including existing clinical guidelines for both TD and ADHD. Besides genetical and environmental risk factors, brain structure and functions, neurophysiological processes and neurotransmitter systems were reviewed.
Results:
Only a limited number of empirical studies on the neurobiological background of TD and ADHD have taken the peculiarity of co-existing TD + ADHD into consideration, and even less studies have used a 2 × 2 factorial design in order to disentangle the impact/effects of the factors of TD versus those of ADHD. Nevertheless, the assumption that TD + ADHD can best be seen as an additive model at all levels of investigation was strengthened, although some overlap of more general, disorder non-specific aspects seem to exist.
Conclusion:
Beyond stress-related transdiagnostic aspects, separate specific disturbances in certain neuronal circuits may lead to disorder-related symptoms inducing TD + ADHD in an additive way. Hence, within a classificatory categorical framework, the dimensional aspects of multilevel diagnostic-profiling seem to be a helpful precondition for personalized decisions on counselling and disorder-specific treatment in TD + ADHD.
... When older, they may engage in risky behaviors, including substance abuse and delinquency. Moreover, other conditions such as conduct disorder, anxiety, depression, oppositional defiant disorder, and obsessive disorder can accompany ADHD (1,(5)(6)(7). ...
Air pollution is considered a risk factor for several diseases, particularly respiratory and cardiovascular diseases. However, the effects of air pollution on neurobehavioral disorders have not been confirmed as of yet. Thus, the aim of this study was to determine whether there was an association between seven air pollutants and ADHD medication administration (ADHD‑MA) in Pennsylvania‑located elementary schools over a 3‑year period. An ecological study design involving records of 168,825 children from elementary schools in 49 Pennsylvania counties was used. The number of children with ADHD‑MA was extracted from an online software specifically designed for allowing nurses to record health conditions in schools. Daily measurements of air pollutants were obtained from the U.S Environmental Protection Agency. The differences in the number of ADHD‑MA among the four seasons, for all years, were statistically significant (P<0.001). Three air pollutants (SO2, CO, and PM2.5) were significantly associated with ADHD‑MA; no interactions among air pollutants were significant. Air pollution was thus likely associated with ADHD‑MA. Prospective epidemiological and biomedical studies should next examine the molecular relationship between air pollution and ADHD symptoms.
... In Taiwan, the NHIRD has provided valuable information in various epidemiologic studies. [19][20][21] The validity of diagnoses based on ICD-9-CM coding in the NHIRD had been assessed by several validation studies. 22 Inclusion criteria of patients with ASD We recruited an ASD cohort if they were adolescents aged 10-19 years and young adults aged 20-29 years with a diagnosis of ASD (ICD-9-CM code: 299) made by board-certified psychiatrists at least twice based on the comprehensive interview and ICD-9-CM between 1 January 2001, and 31 December 2010, and without a previous diagnosis of schizophrenia (ICD-9-CM code: 295) before the enrollment. ...
Aims:
Previous studies have suggested an increased risk of developing schizophrenia later in life in children with ASD. This study aims to investigate the diagnosis stability and the potential predictors for progression to schizophrenia in autism spectrum disorder (ASD).
Methods:
We recruited 11,170 adolescents (10-19 years) and young adults (20-29 years) with ASD between 2001 and 2010. They were followed up to the end of 2011 to identify newly diagnosed schizophrenia. The Kaplan-Meier method and Cox regression with age as a time scale were employed to estimate incidence rates and the significance of candidate predictors.
Results:
The progression rate from ASD to schizophrenia was10.26%for 10 years of follow-up. Among 860 progressors, 580 (67.44%)occurred within the first 3 years after a diagnosis of ASD.The identified predictors were age (reported as hazard ratio with 95% confidence interval: 1.13; 1.11-1.15), depressive disorder (1.36; 1.09-1.69), alcohol use disorder (3.05; 2.14-4.35),substance use disorder (1.91; 1.18-3.09),cluster A personality disorder (2.95; 1.79-4.84), cluster B personality disorder (1.86; 1.05-3.28),and a family history of schizophrenia (2.12; 1.65-2.74).
Conclusion:
More than two-thirds of the progressors developed schizophrenia within the first 3 years. Demographic characteristics, physical and psychiatric comorbidities, and psychiatric family history were significant predictors of progression. This article is protected by copyright. All rights reserved.
... This nested case-control study used data from the Taiwan NHIRD from January 1998 to December 2013. The details of the NHIRD have been described in our previous research [22][23][24][25]. Briefly, the National Health Research Institute audits and releases the NHIRD for scientific and study purposes. ...
Background:
To investigate the association between proton pump inhibitor (PPI) exposure and a risk of type 2 diabetes mellitus (T2DM) among patients with upper gastrointestinal disease (UGID).
Method:
We conducted a case-control study from Taiwan's National Health Insurance Research Database between 1998 and 2013. A total of 20,940 patients with T2DM and 20,940 controls were included. The dose of PPIs was categorized according to the cumulative defined daily dose (cDDD). The risk of T2DM was assessed using conditional logistic regression analysis.
Result:
Compared with cDDD ≤ 30, higher dosage of PPI exposure was associated with an increased risk of T2DM development: cDDD 31-120 (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.13-1.26); cDDD 121-365 (OR: 1.26, 95% CI: 1.19-1.33); and cDDD > 365 (OR: 1.34, 95% CI: 1.23-1.46). Subgroup analysis of individual PPI showed that pantoprazole (OR: 1.14, 95% CI: 1.07-1.21), lansoprazole (OR: 1.08, 95% CI: 1.03-1.12), and omeprazole (OR: 1.11, 95% CI: 1.06-1.16) have a significantly higher risk of T2DM development.
Conclusions:
A dose-dependent increased risk of T2DM was found among patients with UGID using higher doses of PPIs compared with those with lower doses of these drugs. Further studies are necessary to investigate the underlying pathophysiology of PPIs and T2DM.
... Some studies in children suggest possible relationships between TS and allergic diseases, such that more research is warranted to clarify the specific nature of these relationships (e.g., longitudinal relationship between variables, whether it is correlational, causal). Given that the neural basis of TDs are relatively understood, it will be important to understand whether and precisely how gut microbiota might impact relevant circuitry, as well as whether altered microbiota precede or are followed by the emergence of TD symptoms (22)(23)(24). The gut microbiota of allergic and non-allergic infants shows significant differences during the first year of life (25,26). ...
Object
To investigate the distribution characteristics of gut microbiota in children with tic disorder (TD) and the possible role of these characteristics in the pathogenesis of TD.
Methods
The medical records of 28 children with TD treated at Wuxi Children's Hospital from January 1 to October 31, 2020, and 21 age-matched healthy children (controls) were included. The relative quantification of bacterial taxa was performed using 16S ribosomal RNA gene amplicon sequencing.
Results
There was no significant difference in the alpha diversity of gut microbiota between the TD and control groups. Analyses of beta diversity were able to differentiate the TD patients from the healthy controls based on their gut microbiota. At the phylum level, the two groups were mainly composed of four phyla, Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. There were significant differences in Firmicutes and Actinobacteria between the two groups ( P <0.05). At the level of genera, the abundance of Bifidobacterium and Collinsella reduced while that of Ruminococcaceae unclassified, Prevotella, Faecalibacterium, Coprobacillus , and Odoribacter increased in the TD group compared to that in the control group. The intergroup differences were significant ( P < 0.05).
Conclusion
The abnormal composition of gut microbiota in children with TD suggests that the change in gut microbiota may play an important role in TD development.
... The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to diagnosing diseases during the study period. The NHIRD has been used extensively in epidemiologic studies in Taiwan [15][16][17][18]. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital. ...
Evidence suggests a continuity between obsessive–compulsive disorder (OCD) and schizophrenia. However, the factors that may predict diagnostic progression from OCD to schizophrenia remain unclear. A total of 35,255 adolescents and adults with OCD (ICD-9-CM code: 300.3) were enrolled between 2001 and 2010 and followed up at the end of 2011 for the identification of de novo schizophrenia (ICD-9-CM code: 295). The Kaplan–Meier method was used to estimate incidence rates, and the Cox regression was used to determine the significance of candidate predictors. At the end of the 11-year follow-up period, the crude cumulative progression rate from OCD to schizophrenia was 6%, and the estimated progression rate totaled 7.80%. Male sex (hazard ratio: 1.23), obesity (1.77), autism spectrum disorder (1.69), bipolar disorder (1.69), posttraumatic stress disorder (1.65), cluster A personality disorder (2.50), and a family history of schizophrenia (2.57) also were related to an elevated likelihood of subsequent progression to schizophrenia in patients with OCD. Further study is necessary to elucidate the exact pathomechanisms underlying diagnostic progression to schizophrenia in patients with OCD.
... The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes are used for disease diagnosis. The NHIRD has been used extensively in many epidemiologic studies in Taiwan (Chen et al., 2013(Chen et al., , 2016Cheng et al., 2018). ...
Objective
Studies have suggested that impaired sensory processing is a shared characteristic of autism spectrum disorder (ASD) and migraine. However, the association between ASD and migraine remains unclear.
Methods
We examined 18,035 children and adolescents with ASD and 18,035 age- and sex-matched controls whose data were recorded in the Taiwan National Health Insurance Research Database between 2001 and 2011. We monitored the individuals until the end of 2011 and identified those who developed migraine during the follow-up period.
Results
After adjustment for medical and psychiatric comorbidities, children and adolescents with ASD had a significantly higher risk of developing migraine than did those without ASD (hazard ratio [HR]: 2.71, 95 % confidence interval [CI]: 1.63–4.51). Sensitivity analysis after the exclusion of the first year of the observation period (HR: 2.31, 95 % CI: 1.38–3.89) or medical and psychiatric comorbidities (HR: 2.38, 95 % CI: 1.11–5.15) revealed comparable between-group results.
Conclusions
Children and adolescents with ASD were more likely to develop migraine later in life compared with those without ASD. ASD is an independent risk factor for migraine, regardless of the psychiatric and medical comorbidities involved. Research on the mechanisms underlying the association between ASD and migraine is warranted.
... purposes (Chen et al., 2015b;Chen et al., 2013a;Cheng et al., 2018;Chu et al., 2018;Huang et al., 2021;Kuo et al., 2020;Liang et al., 2020). We adopted the specialized dataset of psychiatric disorders from the Taiwan NHIRD from the years between 2000 and 2011. ...
Objective: We investigated the diagnostic progression to bipolar disorder (BD) among adolescents and young adults with attention-deficit/hyperactivity disorder (ADHD).
Methods: Using the Taiwan National Health Insurance Research Database, we enrolled adolescents and young adults aged 10–29 years with ADHD between January 1, 2001, and December 31, 2010, who were followed up until December 31, 2011, to determine progression to BD. Cox regression analysis was used to examine candidate risk and protective factors.
Results: At the 11-year follow-up, the progression rate from ADHD to BD was 5.12%. Of the participants who progressed, 62.16% (322/518) progressed within the first 3 years. Risk factors for progression were as follows: older age (hazard ratio [HR], 1.058; 95% confidence interval [CI], 1.033–1.084), comorbidity with autistic spectrum disorder (HR, 1.839; 95% CI, 1.415–2.391), disruptive behavior disorder (HR, 1.434; 95% CI, 1.132–1.816), intelligence disability (HR, 1.744; 95% CI, 1.399–2.176), depressive disorder (HR, 1.978; 95% CI, 1.577–2.482), alcohol use disorder (HR, 1.705; 95% CI, 1.057–2.751), cluster A (HR, 2.508; 95% CI, 1.167–5.391) or B (HR, 2.718; 95% CI, 1.974–3.741) personality disorder, and a family history of BD (HR, 2.618; 95% CI, 1.823–3.758) Identified protective factors were male sex (HR, 0.771; 95% CI, 0.630–0.943) and cluster C personality disorder (HR, 0.278; 95% CI, 0.086–0.898).
Conclusion: The study demonstrated the specific risk and protective factors for BD progression among adolescents and young adults with ADHD. It is important for clinician and mental health care providers to recognize identified factors to focus on early detection and prompt intervention.
... The NHIRD has been used extensively in many epidemiologic studies in Taiwan. 11,[18][19][20] This study was approved by the Institutional Review Board of Taipei Veterans General Hospital. ...
Background: The association between postpartum depression and postpartum psychosis and subsequent maternal and offspring mental disorders in Western countries has been established; however, whether the relationship can be generalized to the Asian population is unknown.
Methods: Using the Taiwan National Health Insurance Research Database, this study enrolled 933,745 mother-infant pairs who delivered their first child and had no history of severe mental illness before childbirth from 2001 to 2010. Postpartum depression and postpartum psychosis were assessed in 3 periods between childbirth and 3, 6, or 12 months after childbirth. Subsequent maternal schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM code: 296 except 296.2x, 296.3x, 296.9x, and 296.82), and depressive disorder (ICD-9-CM codes: 296.2x, 296.3x, 300.4, and 311) and offspring autism spectrum disorder (ASD; ICD-9-CM code: 299) and attention-deficit/hyperactivity disorder (ADHD; ICD-9-CM code: 314) were identified during the follow-up period to the end of 2011.
Results: Both postpartum depression and postpartum psychosis were found to be related to increased risks of schizophrenia, bipolar disorder, and depressive disorder in mothers, with hazard ratios (HRs) ranging between 8.80 (95% CI, 7.95-9.74) and 63.96 (95% CI, 50.39-81.18). Children exposed to maternal postpartum depression and psychosis were more likely to develop ADHD. Only postpartum depression was related to the likelihood of offspring ASD.
Conclusions: Per these findings, we clinicians and health care providers should closely monitor the mental health condition of postpartum women and their children.
... These authors found a higher risk of allergic rhinitis, asthma, dermatitis, and conjunctivitis in patients with TS; however, there were no more details on the possible susceptibility of patients with TS to allergic mechanisms. 22 A preliminary study carried out in Turkey found associations between allergic diseases and TS and/or OCD and discovered different associations between various allergic diseases (rhinitis or eczema) and neuropsychiatric disorders (TD or OCD). 16 Recently, we have found that children with TD seek help at outpatient clinics for complaints such as blinking of the eyes, wrinkling of the nose, and hawking (clearing the throat). ...
Tic disorders (TD) are childhood-onset neurological disorders. Immune system dysregulation has been postulated to play a role in TD, and its mechanisms likely involve dysfunctional neural-immune cross-talk, which ultimately leads to altered maturation of the brain pathways that control different TD clinical manifestations and behavioral and emotional damages. Clinical studies have demonstrated an association between TD and allergies and overactive immune responses at a systemic level. In this study, the Yale Global Tic Severity Scale was taken as a global measure of tic severity. Compared with the control group, the group of children with TD plus allergic diseases displayed significantly increased Yale total scores (p<0.05), which suggests that children with TD plus allergic diseases have heavier tic symptoms. Both motor and vocal tic scores are higher in the group of children with TD plus allergy compared with the control group. We counted immune cell subpopulations using FACS. T lymphocyte subset comparison of CD3, CD4, CD8, and CD4:CD8 expression ratios revealed that the level of CD3, CD4, and CD4:CD8 in children with TD plus allergic diseases was significantly lower than those of children with TD without allergic diseases. These differences were statistically significant (p<0.05) and suggest that children with TD plus allergic diseases have imbalanced T lymphocyte subsets. We concluded that allergy increased the severity of TD through an imbalance in cellular immunity. Studies need to be done to show whether treatment of allergic symptoms leads to a decrease in TD manifestations.
... The NHIRD has been used extensively in epidemiological studies in Taiwan. [5][6][7][8] This study was approved by the Institutional Review Board of Taipei Veterans General Hospital. ...
Background and Purpose
Patients with obsessive-compulsive disorder (OCD) tend to be comorbid with stroke-related risk factors, including obesity, hypertension, and diabetes. However, the temporal association between OCD and subsequent stroke risk is unclear.
Methods
Using data collected between 2001 and 2010 by Taiwan’s National Health Insurance Research Database, 28 064 adult patients with OCD (International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM ] code: 300.3) and 28 064 age-, sex-, and comorbidity-matched controls were included in this study. Patients who developed ischemic ( ICD-9-CM codes: 433, 434, and 435) and hemorrhagic ( ICD-9-CM codes: 430, 431, and 432) stroke during follow-up (from enrollment to end of 2011) were identified. Moreover, medications used for treating OCD were assessed.
Results
Patients with OCD (hazard ratio [HR], 3.02 [95% CI, 1.91–4.77]), especially middle-aged (HR, 2.66 [95% CI, 1.34–5.29]) and elderly adults (HR, 3.46 [95% CI, 1.70–7.05]), had an elevated risk of developing ischemic stroke during the follow-up period compared with non-OCD controls. The cumulative HR of hemorrhagic stroke did not differ (HR, 0.87 [95% CI, 0.42–1.80]) between the OCD and non-OCD groups. In patients with OCD, both short- (HR, 1.69 [95% CI, 0.74–3.88]; HR, 0.31 [95% CI, 0.05–1.95]) and long-term use (HR, 1.37 [95% CI, 0.60–3.16]; HR, 0.90 [95% CI, 0.22–3.76]) of OCD medications were not correlated with ischemic and hemorrhagic stroke compared with nonuse.
Conclusions
Clinicians should closely monitor cerebrovascular disease and related risks in patients with OCD. The pathomechanism of OCD with an increased risk of ischemic stroke warrants further investigation.
... Nevertheless, the human MHCI region on chromosome 6 has been implicated as a susceptibility locus for ADHD (Willcutt et al., 2002). In addition, ADHD and autoimmune diseases such as asthma and atopic dermatitis have often been found as complications in the same individuals (Chen et al., 2013). Our results revealed a direct link between MHCI, a key player in the immune system, and three major symptoms of ADHD by establishing a plausible mouse model of ADHD and potentially provide a novel landmark in the pathogenesis of the disorder. ...
Inappropriate synaptic development has been proposed as a potential mechanism of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD). Major histocompatibility complex class I (MHCI), an immunity-associated molecule expressed by neurons in the brain, regulates synaptic development; however, the involvement of MHCI in these disorders remains elusive. We evaluated whether functional MHCI deficiency induced by β2m-/-Tap1-/- double-knockout in mice leads to abnormalities akin to those seen in neurodevelopmental disorders. We found that functional MHCI deficiency induced locomotor hyperactivity, motor impulsivity, and attention deficits, three major symptoms of ADHD. In contrast, these mice showed normal spatial learning, behavioral flexibility, social behavior, and sensorimotor integration. In the analysis of the dopamine system, upregulation of dopamine D1 receptor (D1R) expression in the nucleus accumbens and a greater locomotor response to D1R agonist SKF 81297 were found in the functional MHCI-deficient mice. Low-dose methylphenidate, used for the treatment of ADHD patients, alleviated the three behavioral symptoms and suppressed c-Fos expression in the D1R-expressing medium spiny neurons of the mice. These findings reveal an unexpected role of MHCI in three major symptoms of ADHD and may provide a novel landmark in the pathogenesis of ADHD.
... The NHIRD has been used extensively in many epidemiologic studies in Taiwan. [7][8][9][10] This study was approved by the Institutional Review Board of Taipei Veterans General Hospital. ...
Background
The effect of relative age on the diagnoses of attention deficit hyperactivity disorder (ADHD), disruptive behavior disorder (DD), anxiety disorder, and depressive disorder and the prescription for ADHD and antidepressant medications remains unclear.
Aim
To clarify the impact of relative age in a school year with the diagnoses of ADHD, DD, anxiety disorder and depressive disorder and the prescription for ADHD and antidepressant medications.
Methods
The annual cutoff birthdate for entry to school in Taiwan is August 31. The Taiwan National Health Insurance Research Database was used to enroll 9,548,393 children and adolescents aged 3–17 years during the study period (September 1, 2001, to August 31, 2011). The poisson regression model was performed to examine the likelihood of receiving diagnoses of ADHD, DD, anxiety disorder, and depressive disorder, as well as the prescription of ADHD and antidepressant medications among children born in August (the youngest) and September (the oldest).
Results
Both boys and girls born in August had a higher risk of being diagnosed as having ADHD (odds ratio [OR] = boys: 1.65, girls: 1.80), DD (1.29, 1.45), anxiety disorder (1.49, 1.33), and depressive disorder (1.10, 1.10). Furthermore, children born in August were more likely to be prescribed ADHD medication (1.71, 1.72) and antidepressants (1.18, 1.09) compared with those born in September.
Discussion
Relative age, as an indicator of neurocognitive maturity, is a critical factor for the likelihood of being diagnosed as having ADHD, DD, anxiety disorder, and depressive disorder among children and adolescents.
... The income-related insured amount was defined by the monthly income of the insured family and was divided into three levels: ≤ 15,840 new Taiwan dollar (NTD), 15,841-25,000 NTD, and > 25,000 NTD. The NHIRD has been used extensively in many epidemiologic studies in Taiwan [12][13][14][15]. Finally, in Taiwan, kindergarten education is for children aged between 3 and 5 years; primary school education is for those aged between 6 and 11 years; secondary school education is for those aged 12 and 17 years. ...
Background
The annual cut-off birthdate for entry into school in Taiwan is August 31. Thus, children and adolescents born in August are typically the youngest in their grades. The potential effect of relative age on the diagnosis of autism spectrum disorder (ASD) remains uncertain.MethodsA total of 9,548,393 individuals aged 3–17 years during the study period (from September 1, 2001, to August 31, 2011) identified from the Taiwan National Health Insurance Research Database were enrolled into our study. Logistic regression analysis was used to examine the likelihood of receiving ASD diagnosis for those who were born in August (the youngest) compared with those who were born in September (the oldest).ResultsBoth boys and girls born in August had a higher likelihood of being diagnosed with ASD (odds ratio [OR]: 1.24, 95% confidence interval [CI]: 1.16–1.32; OR: 1.23, 95% CI 1.06–1.42) than did those born in September. Sensitivity analysis conducted over different periods revealed consistent findings.DiscussionRelative age, as an indicator of neurocognitive maturity, is a crucial contributor to the risk of being diagnosed with ASD among children and adolescents. Our findings highlight the importance of considering the age of a child within a grade when diagnosing ASD.
... Moreover, the authors reported that the risk for TS increased with the number of allergies and with age. In another register-based study from Taiwan (Chen et al., 2013), 1816 cases of tic disorders only, 5811 cases of ADHD only, 349 cases with comorbid tics and ADHD, and 31,904 controls were compared on the diagnoses of allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis. The OR for any allergic diseases in the cases with tic disorders only, compared to controls, was 2.88, which was significantly higher than the odds for allergic diseases in the ADHD only (OR = 1.64). ...
Current knowledge on the general somatic health and causes of death in Tourette syndrome and chronic tic disorder is very limited. Here, we review the available literature on the topic, while highlighting strengths and weaknesses of the studies conducted to date. These previous works have suggested associations between Tourette syndrome and chronic tic disorder and a range of health conditions, including autoimmune disorders, common allergies and respiratory diseases, sleep difficulties, and metabolic and cardiovascular outcomes. Additionally, the risk of mortality in tic disorders might be higher than that of the general population, but specific causes of death have rarely been studied, except for substance use-related deaths and suicide, which are significantly higher in individuals with Tourette syndrome and chronic tic disorder. Many of these emerging findings require replication and extension but, taken together, they suggest that that it might be sensible to monitor the general health and suicide risk of individuals with Tourette syndrome or chronic tic disorder across the lifespan. We suggest further avenues for research on this topic.
... This is similar with the finding that the association of SHS with hand eczema was stronger among occupational workers than the general population 10 . Except behavioral factors, ADHD is associated with atopic and allergic diseases according to population-based studies 26,27 , possibly through immunological mechanisms involving IgE hypersecretion, increased eosinophilic activity, and T helper 2 cytokine over-secretion 16 . Our finding, however, did not support the mediation effect of ADHD in the association linking SHS and eczema. ...
Smoking has been identified as a risk factor for atopic dermatitis and hand eczema, but less is known about the association of exposure to second-hand smoke (SHS) with hand eczema. The study aimed to investigate the association of SHS exposure with hand eczema and atopic dermatitis in a group of adolescents. We conducted a cross-sectional study among first-year college students. SHS exposure was measured by a self-administered questionnaire. Skin diseases were diagnosed by dermatologists in the field survey. Mixed models were used to estimate the associations. A total of 20,129 participants that underwent skin examination and a questionnaire survey were included in the analyses. The prevalence rates of atopic dermatitis and hand eczema were 3.86% and 3.35%, respectively. Crude and adjusted estimates consistently showed that exposure to SHS was significantly associated with atopic dermatitis and hand eczema in a dose–response manner. Attention deficit/hyperactivity disorder mediated minimal or no effect of SHS on hand eczema and atopic dermatitis. Subgroup analysis by type of hand eczema, and sensitivity analysis by excluding data with center effect showed consistent results. Exposure to SHS is an independent but modifiable risk factor for hand eczema and atopic dermatitis in adolescents.
... On the other hand, an association between TS and allergies is supported by a more conspicuous body of evidence. Retrospective, case-control population studies of Taiwanese national health insurance datasets (150,151) reported higher risk of conjunctivitis, rhinitis, asthma, and atopic dermatitis in individuals diagnosed with TS. A higher age-and sex-adjusted comorbidity rate for asthma in TS was also documented through the Canadian Community Health Survey (152). ...
Objective: The goal of this article is to review the past decade's literature and provide a critical commentary on the involvement of immunological mechanisms in normal brain development, as well as its role in the pathophysiology of Tourette syndrome, other Chronic tic disorders (CTD), and related neuropsychiatric disorders including Obsessive-compulsive disorder (OCD) and Attention deficit hyperactivity disorder (ADHD).
Methods: We conducted a literature search using the Medline/PubMed and EMBASE electronic databases to locate relevant articles and abstracts published between 2009 and 2020, using a comprehensive list of search terms related to immune mechanisms and the diseases of interest, including both clinical and animal model studies.
Results: The cellular and molecular processes that constitute our “immune system” are crucial to normal brain development and the formation and maintenance of neural circuits. It is also increasingly evident that innate and adaptive systemic immune pathways, as well as neuroinflammatory mechanisms, play an important role in the pathobiology of at least a subset of individuals with Tourette syndrome and related neuropsychiatric disorders In the conceptual framework of the holobiont theory, emerging evidence points also to the importance of the “microbiota-gut-brain axis” in the pathobiology of these neurodevelopmental disorders.
Conclusions: Neural development is an enormously complex and dynamic process. Immunological pathways are implicated in several early neurodevelopmental processes including the formation and refinement of neural circuits. Hyper-reactivity of systemic immune pathways and neuroinflammation may contribute to the natural fluctuations of the core behavioral features of CTD, OCD, and ADHD. There is still limited knowledge of the efficacy of direct and indirect (i.e., through environmental modifications) immune-modulatory interventions in the treatment of these disorders. Future research also needs to focus on the key molecular pathways through which dysbiosis of different tissue microbiota influence neuroimmune interactions in these disorders, and how microbiota modification could modify their natural history. It is also possible that valid biomarkers will emerge that will guide a more personalized approach to the treatment of these disorders.
... The NHIRD has been used extensively in many epidemiologic studies in Taiwan. [23][24][25][26] Inclusion criteria for the unaffected siblings of patients with MDD and the control group Individuals who were born before 1990 and had the siblings with MDD (ICD-9-CM codes: 296.2x, 296.3x) but had no personal diagnosis of severe mental disorders (ICD-9-CM codes: 295, 296, 297) at any time were enrolled as the study group. The age-, sex-, income-, level-of-urbanization-and birth-time-matched (1:4) control group was randomly identified after eliminating the study cases, those who had been given a diagnosis of severe mental disorders at any time, and those with any sibling with severe mental disorders. ...
Studies have suggested an association between metabolic and cerebrocardiovascular diseases and major depressive disorder (MDD). However, the risk of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD remains uncertain. Using the Taiwan National Health Insurance Research Database, 22,438 unaffected siblings of patients with MDD and 89,752 age-/sex-matched controls were selected and followed up from 1996 to the end of 2011. Individuals who developed metabolic and cerebrocardiovascular diseases during the follow-up period were identified. Compared with the controls, the unaffected siblings of patients with MDD had a higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), and obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic stroke (0.6% vs. 0.4%, p < 0.005) and ischemic heart disease (2.1% vs. 1.7%, p < 0.001). Logistic regression analyses revealed that the unaffected siblings of patients with MDD were more likely to develop hypertension, dyslipidemia, ischemic stroke, and ischemic heart diseases during the follow-up period than the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases. Additional studies are required to investigate the shared pathophysiology of MDD and metabolic and cerebrocardiovascular diseases.
... The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to diagnosing diseases during the study period. The NHIRD has been used extensively in many epidemiologic studies in Taiwan (Chen et al., 2013(Chen et al., , 2016Cheng et al., 2018). This study protocol was reviewed and approved by the Institutional Review Board of Taipei Veterans General Hospital. ...
Background
Whether the first-degree relatives (FDRs) of patients with obsessive-compulsive disorder (OCD) have an increased risk of the major psychiatric disorders, namely schizophrenia, bipolar disorder, OCD, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), remains unclear.
Methods
Using the Taiwan National Health Insurance Research Database with the whole population sample size ( n = 23 258 175), 89 500 FDRs, including parents, offspring, siblings, and twins, of patients with OCD were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with OCD.
Results
FDRs of patients with OCD had higher RRs of major psychiatric disorders, namely OCD (RR 8.11, 95% confidence interval (CI) 7.68–8.57), bipolar disorder (RR 2.85, 95% CI 2.68–3.04), MDD (RR 2.67, 95% CI 2.58–2.76), ASD (RR 2.38, 95% CI 2.10–2.71), ADHD (RR 2.19, 95% CI 2.07–2.32), and schizophrenia (RR 1.97, 95% CI 1.86–2.09), compared with the total population. Different familial kinships of FDRs, such as parents, offspring, siblings, and twins consistently had increased risks for these disorders. In addition, a dose-dependent relationship was found between the numbers of OCD probands and the risk of each major psychiatric disorder.
Conclusions
The FDRs, including parents, offspring, siblings, and twins, of patients with OCD have a higher risk of OCD, schizophrenia, bipolar disorder, MDD, ADHD, and ASD. The familial co-aggregation of OCD with OCD and other major psychiatric disorders was existent in a dose-dependent manner. Given the increased risks of psychiatric disorders, medical practitioners should closely monitor the mental health of the FDRs of patients with OCD.
... The diagnostic codes used are based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in numerous epidemiologic studies in Taiwan [9][10][11][12][13]. ...
Objective: We intended to investigate the risk of developing migraine among patients with posttraumatic stress disorder (PTSD). Methods: With the Taiwan's National Health Insurance Research Database, we examined 5,644 patients with PTSD and 22,576 age- and sex-matched controls between 2002 and 2009 and followed them to the end of 2011. Individuals who developed migraine during the follow-up period were identified. Results: Patients with PTSD had a significantly higher incidence of developing migraine (5.74 vs. 1.22 per 1,000 person-years, p < 0.001) during the follow-up period than the controls. We did Cox regression analysis with adjustments of demographic data and medical comorbidities and found that patients with PTSD were more likely to develop migraine (hazard ratio [HR] = 3.83, 95% confidence interval [CI] = 2.82–5.20) than the control group. Sensitivity analyses after excluding the 1st year (HR = 2.89; 95% CI = 2.04–4.08) or the first 3 years (HR = 2.07; 95% CI = 1.32–3.24) of observation showed consistent findings. Moreover, a high frequency of psychiatric clinics visiting for PTSD was associated with an increased risk of developing migraine. Conclusion: Patients with PTSD had a higher risk of migraine than the controls. The symptom severity of PTSD may be associated with an increased risk of migraine. Further studies are required to investigate the underlying pathophysiology between PTSD and migraine.
Background.
Numerous investigations have examined the potential link between allergic rhinitis and attention deficit hyperactivity disorder. However, there are studies that show no association between the two diseases. The connection between these two conditions remains inconclusive. This study aimed to conduct a meta-analysis exploring the correlation between AR and ADHD.
Methods.
We conducted systematic searches of the MEDLINE, EMBASE, Cochrane Library, ERIC, PubMed, Web of Science, and CINAHL databases, up to the year 2023. Subsequently, we conducted a meta-analysis using R 4.2.2, where we computed the pooled Odds Ratio with a 95% Confidence Interval to assess the relationship between AR and ADHD within studies exhibiting similar characteristics. Statistical heterogeneity was evaluated by computing the value using the Cochrane Intervention Manual's guidelines. Additionally, subgroup analyses were conducted by stratifying the study population according to gender, age, etc. Sensitivity analysis was performed by systematically removing individual studies.
Results.
In this systematic review, we incorporated 12 eligible studies, collectively encompassing a sample size of 530,360 participants. Within the included studies, heterogeneity was observed, and the utilization of a random-effects model demonstrated a noteworthy correlation between children with ADHD and the presence of AR. Similarly, children with AR exhibited a significant correlation with the occurrence of ADHD. We also found some relationships in subgroup analyses.
Conclusion.
A substantial correlation is evident between AR and ADHD in children and adolescents. AR may potentially contribute as a risk factor for the onset of ADHD, and conversely, ADHD may heighten the likelihood of developing AR.
Background:
Congenital cleft lip and palate (CCLP) may be associated with major psychiatric disorders, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and major depressive disorder.
Methods:
From the Taiwan National Health Insurance Research Database, 1,158 children and adolescents with CCLP and 11,580 age/sex-matched controls without CCLP were included in this study between 2001 and 2010; they were followed up until the end of 2011 to identify the aforementioned major psychiatric disorders.
Results:
After adjustment for age, sex, income, residence, and family history, the Cox regression model revealed a positive relationship of CCLP with subsequent schizophrenia (hazard ratio [HR]: 7.60, 95% confidence interval [CI]: 2.03-28.54), ASD (HR: 6.03, 95% CI: 1.76-20.61), and ADHD (HR: 7.33, 95% CI: 5.01-10.73).
Discussion:
These findings suggest that clinicians should be attentive to the presence or emergence of mental health conditions in patients with CCLP. Further studies are necessary to investigate the pathogenesis between CCLP and major psychiatric disorders.
Background: Proton-pump inhibitors (PPI) are among the most widely used drugs worldwide. However, the association between PPI use and the risk of asthma remains unclear. Objective: To investigate the association between PPI use and subsequent asthma risk. Methods: We included participants from the Taiwan National Health Insurance Research Database between 1999 and 2013. Patients who used PPIs and experienced new-onset asthma (n = 20,344) were assigned to the case cohort and matched in a 1:1 ratio with controls who did not subsequently develop asthma. PPI use was defined as > 30 cumulative defined daily doses (cDDD); non-PPI use was defined as ≤ 30 cDDDs. The Charlson Comorbidity Index (CCI) score was used for clinical prognosis and comorbidity adjustment. Multivariate Cox regression models were used for the calculation of adjusted odds ratios (OR). Results: There was a significant and dose-dependent association between PPI use and the risk of developing asthma. The adjusted ORs were 1.24 (95% confidence interval [CI], 1.15-1.33), 1.39 (95% CI, 1.28-1.50), and 1.61 (95% CI, 1.43-1.81) for the male subject with 31-120 cDDDs, 120-365 cDDDs, and >365 cDDDs, respectively, compared with PPI nonusers. Men were at higher risk of developing asthma with longer PPI use compared with women. Stratified analyses based on the PPI type showed that exposure to lansoprazole, pantoprazole, omeprazole, and esomeprazole was associated with subsequent asthma risk. Conclusion: Extended use of PPIs was found to be linked to an increased risk of asthma development. This association remained consistent across different age groups, sexes, demographic factors, indications for PPI use, CCI scores, and other atopic diseases. However, further prospective studies are required to elucidate the causal mechanisms involved.
Background:
People with autism spectrum disorder (ASD) may have poor oral health status because they often experience challenges with daily oral hygiene and have inadequate access to oral health care services. This study explored periodontitis risk in adolescents with ASD compared with those who did not have a diagnosis of ASD.
Methods:
Data from 2001 through December 31, 2011 from the Taiwan National Health Insurance Research Database on 3,473 adolescents with ASD and 34,730 age- and sex-matched people who did not have a diagnosis of ASD were obtained, and subsequent periodontitis was identified from enrollment through December 31, 2011.
Results:
Adolescents with ASD (hazard ratio, 2.01; 95% CI, 1.84 to 2.20) were more likely to develop periodontitis at follow-up than those who did not have a diagnosis of ASD. Findings remained consistent in subanalyses stratified by sex and intellectual disability. People with ASD had periodontitis onset at an earlier mean (SD) age than those who did not have a diagnosis of ASD (17.97 [3.12] vs 21.86 [2.28] years; P < .001).
Conclusions:
ASD is an independent risk factor for subsequent periodontitis development.
Practical implications:
Oral health should be closely monitored in adolescents with ASD. Future investigation of the common pathogenesis between periodontitis and ASD is warranted.
Resumo:
Um controlo metabólico adequado durante a infância e adolescência é importante para prevenir as complicações associadas à Diabetes mellitus tipo 1 (DM1). Vários estudos demonstraram a relação entre fatores biopsicossociais, adesão à terapêutica e controlo metabólico. Objetivo: Avaliar a influência de fatores psicossociais e clínicos no controlo metabólico na DM1 em idade pediátrica. Métodos: Estudo retrospetivo e descritivo dos diabéticos tipo 1 seguidos em consulta, tendo sido feita a comparação de variáveis psicossociais e clínicas em 3 grupos de acordo com HbA1c mediana: A) ≤7,5%, B) 7,6 a 8,9% e C) ≥9%. Resultados: 71 doentes, idade mediana 15 anos, mediana de HbA1c 8,6%. A literacia paterna, o aproveitamento escolar, a avaliação do risco social, a falha na medição da glicémia ou na administração de insulina, a ausência de contagem de hidratos de carbono, o absentismo às consultas e a taxa de internamentos foram fatores que apresentaram diferença estatística entre os 3 grupos de estudo. Conclusões: Verificou-se que alguns dos fatores psicossociais e clínicos avaliados se relacionam com incumprimento terapêutico e agravamento do controlo metabólico.
Tourette syndrome (TS) is now recognized as a common neurodevelopmental disorder affecting children and adults. It has gained increasingly public awareness and scientific interest worldwide. Knowledge of its clinical presentation and available treatment approaches has increased dramatically over the last two decades. Tourette Syndrome offers a unique, comprehensive, and up-to-date overview of TS. The volume highlights the latest findings regarding clinical presentation, underlying genetic, epigenetic, immunological, and neurobiological causal mechanisms, and state-of-the-art therapies. Importantly, in this digital world of ours and given the ongoing pandemic, this volume also provides a detailed review of the latest available multifaceted and multidisciplinary treatment options including psychoeducational and cognitive-behavioral interventions, many of which can now be accessed online. More than 50 leading scientists and expert clinicians from across the globe authored the chapters. Readers can also access videotaped presentations recorded by several of these scholars. Fortunately, several of these presentations include individuals with TS and related conditions who have graciously volunteered to discuss their life’s journey. This volume is a useful source for a wide audience of scholars and clinicians, all of whom will have access to what is known so far on TS and related conditions within their area of expertise. It provides readers an opportunity to expand and update their knowledge base in other areas of science and advocacy. Families and health professionals will also have access to updates from a broad range of advocacy associations and organizations all around the world that are dedicated to improving lives of individuals with TS.
Tourette syndrome (TS) is now recognized as a common neurodevelopmental disorder affecting children and adults. It has gained increasingly public awareness and scientific interest worldwide. Knowledge of its clinical presentation and available treatment approaches has increased dramatically over the last two decades. Tourette Syndrome offers a unique, comprehensive, and up-to-date overview of TS. The volume highlights the latest findings regarding clinical presentation, underlying genetic, epigenetic, immunological, and neurobiological causal mechanisms, and state-of-the-art therapies. Importantly, in this digital world of ours and given the ongoing pandemic, this volume also provides a detailed review of the latest available multifaceted and multidisciplinary treatment options including psychoeducational and cognitive-behavioral interventions, many of which can now be accessed online. More than 50 leading scientists and expert clinicians from across the globe authored the chapters. Readers can also access videotaped presentations recorded by several of these scholars. Fortunately, several of these presentations include individuals with TS and related conditions who have graciously volunteered to discuss their life’s journey. This volume is a useful source for a wide audience of scholars and clinicians, all of whom will have access to what is known so far on TS and related conditions within their area of expertise. It provides readers an opportunity to expand and update their knowledge base in other areas of science and advocacy. Families and health professionals will also have access to updates from a broad range of advocacy associations and organizations all around the world that are dedicated to improving lives of individuals with TS.
Background
Few studies have reported an association between atopic dermatitis and cognitive impairment in children. Therefore, we evaluated the association between atopic dermatitis (AD) and neurodevelopmental dysfunction in children.
Methods
We analyzed 2,395,966 children born between 2008 and 2012 in Korea. All data were acquired from the databases of the Korean National Health Insurance System. AD was defined as five or more diagnoses before age 24 months. The outcome was suspected neurodevelopmental dysfunction in the gross motor skill, fine motor skill, cognition, language, sociality, and self-care domains of the Korean Developmental Screening Test for Infants and Children at age 6 years. The positive control outcome was defined as attention deficit hyperactive disorder (ADHD). The associations were assessed using ordinal logistic regression, adjusting for asthma and allergic rhinitis.
Results
Among the eligible children, 89,452 and 30,557 were allocated to the control and AD groups, respectively. In the weighted data, the AD group showed a higher risk of suspected neurodevelopmental dysfunction in the total score (weighted adjusted odds ratio [95% CI] 1.10 [1.05–1.16]), gross motor skills (1.14 [1.04–1.25]), and fine motor skills (1.15 [1.06–1.25]) than the control group. The AD with steroids or hospitalization groups showed an increased risk of suspected neurodevelopmental dysfunction. In addition, the AD group showed a significant association with mental retardation, psychological development disorder, and behavioral and emotional disorders as well as ADHD.
Conclusions
AD before age 2 years may be associated with an increased risk of neurodevelopmental dysfunction including gross and fine motor skills in the young childhood period.
Objective:
Several small-scale studies have suggested a biological link between obsessive-compulsive disorder (OCD) and Parkinson's disease (PD). However, the temporal association of OCD and subsequent PD remained unclear.
Methods:
Here, we used Taiwan National Health Insurance Research Database and included the data of 28,722 patients with OCD (ICD-9-CM code: 300.3) and 287,220 matched controls between 2001 and 2009. They were followed until the end of 2011 to identify diagnosis of new-onset PD (ICD-9-CM code: 332.0). The frequency of psychiatric outpatient visits for OCD per year (<5, 5-10, and > 10) was identified as a proxy of OCD severity.
Results:
Using the stratified Cox regression model, the hazard ratio (HR) of developing PD among patients with OCD was 2.70 [95% confidence interval (95% CI): 1.74-4.18] compared with matched controls. Among patients with OCD, those with >10/year psychiatric outpatient visits for OCD (HR: 3.18, 95% CI: 2.06-4.93) were more likely to develop PD during the follow-up period compared with those with <5/year psychiatric outpatient visits for OCD.
Conclusion:
OCD was found to be an independent risk factor for PD. The mechanisms underlying the temporal association between OCD and subsequent PD require further investigation.
Objective:
To clarify patterns of comorbid atopic disorders in children with tic disorders compared to controls, and to evaluate whether medications commonly used for treatment of tics and attention deficit hyperactivity disorder (ADHD) are associated with differing risks of atopy.
Background:
Inflammatory mechanisms are increasingly recognized as playing a role in a range of neuropsychiatric disorders. The association between tic disorders, ADHD, obsessive-compulsive disorder (OCD) and atopic disorders is uncertain.
Methods:
We performed a retrospective cohort study using the global electronic health records database TriNetX. Using odds ratios, we compared the risk of atopy in children with tic disorder (n = 4508), ADHD (n = 83,569), and/or OCD (n = 1555) to controls (n = 758 290). To analyze the risk of developing atopy with use of different medications commonly prescribed to treat tics and ADHD, we performed a separate analysis including children with tic disorder, ADHD, and/or OCD who had initiated treatment with one of these medications. Binary logistic regression controlling for age and sex was used to calculate odds ratios.
Results:
Children with tic disorder, ADHD, or OCD were more likely than controls to have comorbid atopy. Children who had taken clonidine, guanfacine, methylphenidate, or dexmethylphenidate were more likely to develop an atopic disorder than controls.
Conclusions:
Our study suggests a link between atopic disorders and tic disorders, ADHD, and OCD. Although the underlying mechanism for this association remains unclear, medication use may play a role.
Background
: The temporal association between type 1 diabetes mellitus (T1DM) and major psychiatric disorders, including schizophrenia, major affective disorder, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD), remains elusive.
Methods
: The specialized databases of catastrophic diseases and mental disorders and the longitudinal health insurance database of Taiwan National Health Insurance Research Database were used in current study. A total of 6,226 patients with T1DM and 62,260 age- and sex-matched controls were recruited between 2001 and 2010 and were followed until the end of 2011 for the identification of diagnoses of schizophrenia (International Classification of Clinical Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code: 295), bipolar disorder (ICD-9-CM codes: 296 except 296.2x, 296.3x, 296.9x, and 296.82), major depressive disorder (ICD-9-CM codes: 296.2x and 296.3x), ASD (ICD-9-CM code: 299), and ADHD (ICD-9-CM code: 314).
Results
: Cox regression analysis revealed increased hazard ratios of schizophrenia (12.28), bipolar disorder (13.80), major depressive disorder (10.41), ASD (14.52), and ADHD (8.19) in patients with T1DM compared with controls.
Discussion
: Our findings indicate the importance of clinicians closely monitoring the mental health condition of children, adolescents, and adults with T1DM. Additional studies should be conducted to elucidate the definite pathomechanisms of comorbidities between T1DM and major psychiatric disorders.
This systematic review aims to 1) explore the association between tic disorders (TD) and allergic diseases (AD), 2) judge whether patients with a diagnosis of TD are prone to suffer from a specific AD, by compiling the literature and analyzing the evidence. A literature search was conducted in PubMed and Embase database on February 24, 2021. The inclusion criteria for the literature were all comparative studies that reported TD patients were diagnosed with allergic illness as well. We identified that TD is positively associated with asthma, allergic rhinitis and allergic conjunctivitis, respectively. Especially, provisional tic disorder (PTD) patients might be more likely to suffer from these three AD, although it is still difficult to accurately predict which specific AD is prone to be accompanied by a specific TD. Shared genetic and etiological factors are suggested responsible for the AD-TD association. Large prospective cohort studies in future might shed light on a deep understanding of the relationship between immune disorders and tics.
Background:
Proton pump inhibitors (PPIs) are among the most widely used drugs. Little is known about the association between PPI use and risk of psoriasis.
Objective:
To investigate the association between PPI use and subsequent psoriasis risk.
Methods:
We included participants from the Taiwan National Health Insurance Research Database. Patients with PPI use and an incidence of psoriasis (n = 5,756) were assigned to the case cohort and 1:1 matched to controls. PPI use was defined as >30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as ≤30 cDDDs. Logistic regression was used for the analyses.
Results:
There was a significant association between PPI use and psoriasis risk. The confounder-adjusted odd ratios (95% confidence interval [CI]) were 1.52 (1.31-1.76) and 1.54 (1.22-1.93) for patients with 120-365 cDDDs and >365 cDDDs, respectively, compared with PPI nonusers. Stratified analyses based on PPI type showed that exposure to lansoprazole (OR, 1.25; 95% CI, 1.11-1.41) was associated with subsequent psoriasis risk.
Conclusions:
PPI use might be associated with an increased risk of developing psoriasis or as an epiphenomenon. Further prospective studies are needed to elucidate the association and underlying mechanisms.
Autism Spectrum Disorder (ASD) is a huge spectrum covering a wide variation in the type and severity of symptoms people experience. Every individual on the autism spectrum is distinctive and their needs will be reflected differently. The chapter begins with describing medical definitions of ASD and discusses the challenges faced by students with ASD, their peers, family and their teachers. It points out the barriers that this groups of students face due to the lack of understanding and skills to help them at school.
Background
Studies have indicated that parental depression was slightly related to the increased risk of offspring attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the association between exposure to parental depression at different neurodevelopmental stages (i.e., perinatal or postnatal period) and subsequent ADHD and ASD development remained uncertain.
Method
708515 children born between 2001 and 2008 were screened for ADHD and ASD based on ICD-9-CM codes of 314 and 299 given by psychiatrists from their birth to the end of 2011. Paternal and maternal depression was separately assessed during five periods, namely those before pregnancy (pre-pregnancy), during pregnancy (perinatal), and <1, 1–3, and >3 years after childbirth (postnatal). Cox regression analyses were performed.
Results
Both paternal and maternal depression occurring in the pre-pregnancy, perinatal and postnatal periods were significantly associated with subsequent ADHD and ASD in the offspring, with hazard ratios between 1.42 (95% confidence interval [CI]: 1.35-1.49) and 2.25 (2.09-2.41). The chronicity and additive effect of paternal and maternal depression were related to increased risks of offspring ADHD and ASD. The effects of maternal depression were stronger than the effects of paternal depression for offspring ADHD (HR: 1.35, 95% CI: 1.27-1.45) and ASD (HR: 1.23, 95% CI: 1.05-1.46) risks.
Conclusion
Both paternal depression and maternal depression in the pre-pregnancy, perinatal and postnatal periods increases offspring ADHD and ASD risks, and these risks increase further with increases in the duration of parental depression and with the additive effect of parental and maternal depression.
Attention deficit hyperactivity disorder (ADHD) is increasingly recognized as a common disorder not only in children, but also in the adult population. Similarly, asthma also has a substantial prevalence among adults. Previous studies concerning a potential relationship between ADHD and asthma have not presented consistent results.
A cross-sectional study of 594 adult patients diagnosed with ADHD, compared with 719 persons from the general population. Information was collected between 1997 and 2005 using auto-questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including asthma, and work status.
The prevalence of asthma was significantly higher in the ADHD patient group compared to the controls, 24.4% vs. 11.3% respectively (OR = 2.54, 95% CI 1.89-3.44), and controls with asthma scored higher on ratings of both past and present symptoms of ADHD. Female ADHD patients had a significantly higher prevalence of asthma compared to male ADHD patients (30.9% vs. 18.2%, OR = 2.01, CI 1.36-2.95), but in controls a slight female preponderance was not statistically significant. In both ADHD patients and controls, having asthma was associated with an increased prevalence of symptoms of mood- and anxiety disorders.
The present findings point to a co-morbidity of ADHD and asthma, and these patients may represent a clinical and biological subgroup of adult patients with ADHD.
The aim of the present study was to investigate the effect of both tic disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) on attentional functions. N=96 children and adolescents participated in the study, including n=21 subjects with TD, n=23 subjects with ADHD, n=25 subjects with TD+ADHD, and n=27 controls. Attentional performance was tested based on four computerized attention tasks (sustained attention, divided attention, go/nogo and set shifting). The effect of TD as well as ADHD on attentional performance was tested using a 2 × 2 factorial approach. A diagnosis of TD had no negative impact on attentional functions but was associated with improved performance in the set shifting task. By contrast, regardless of a diagnosis of TD, subjects with ADHD were found to perform worse in the sustained attention, divided attention and go/nogo task. No interaction effect between the factors TD and ADHD was revealed for any of the attention measures. Our results add to findings from other areas of research, showing that in subjects with TD and ADHD, ADHD psychopathology is often the main source of impairment, whereas a diagnosis of TD has little or no impact on neuropsychological performance in most cases and even seems to be associated with adaptive mechanisms.
Obsessive-compulsive disorder (OCD) and related conditions including Tourette's disorder (TD) are chronic, relapsing disorders of unknown etiology associated with marked impairment and disability. Associated immune dysfunction has been reported and debated in the literature since the late 80s. The immunologic culprit receiving the most interest has been Group A Streptococcus (GAS), which began to receive attention as a potential cause of neuropsychiatric symptoms, following the investigation of the symptoms reported in Sydenham's chorea (SC) and rheumatic fever, such as motor tics, vocal tics, and both obsessive-compulsive and attention deficit/hyperactivity symptoms. Young children have been described as having a sudden onset of these neuropsychiatric symptoms temporally associated with GAS, but without supporting evidence of rheumatic fever. This presentation of OCD and tics has been termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS). Of note, SC, OCD, and TD often begin in early childhood and share common anatomic areas--the basal ganglia of the brain and the related cortical and thalamic sites--adding support to the possibility that these disorders might share a common immunologic and/or genetic vulnerability. Relevant manuscripts were identified through searches of the PsycINFO and MedLine databases using the following keywords: OCD, immune, PANDAS, Sydenham chorea, Tourette's disorder Group A Streptococcus. Articles were also identified through reference lists from research articles and other materials on childhood OCD, PANDAS, and TD between 1966 and December 2010. Considering the overlap of clinical and neuroanatomic findings among these disorders, this review explores evidence regarding the immunobiology as well as the relevant clinical and therapeutic aspects of TD, OCD, and PANDAS.
Children with attention-deficit/hyperactivity disorder (ADHD) show a marked temporal variability in their display of symptoms and neuropsychological performance. This could be explained in terms of an impaired glial supply of energy to support neuronal activity.
We pursued one test of the idea with measures of a neurotrophin reflecting glial integrity (S100B) and the influences of 8 cytokines on the metabolism of amino-acids, and of tryptophan/kynurenine to neuroprotective or potentially toxic products that could modulate glial function. Serum samples from 21 medication-naïve children with ADHD, 21 typically-developing controls, 14 medicated children with ADHD and 7 healthy siblings were analysed in this preliminary exploration of group differences and associations.
There were no marked group differences in levels of S100B, no major imbalance in the ratios of pro- to anti-inflammatory interleukins nor in the metabolism of kynurenine to toxic metabolites in ADHD. However, four trends are described that may be worthy of closer examination in a more extensive study. First, S100B levels tended to be lower in ADHD children that did not show oppositional/conduct problems. Second, in medicated children raised interleukin levels showed a trend to normalisation. Third, while across all children the sensitivity to allergy reflected increased levels of IL-16 and IL-10, the latter showed a significant inverse relationship to measures of S100B in the ADHD group. Fourthly, against expectations healthy controls tended to show higher levels of toxic 3-hydroxykynurenine (3 HK) than those with ADHD.
Thus, there were no clear signs (S100B) that the glial functions were compromised in ADHD. However, other markers of glial function require examination. Nonetheless there is preliminary evidence that a minor imbalance of the immunological system was improved on medication. Finally, if lower levels of the potentially toxic 3 HK in ADHD children were confirmed this could reflect a reduction of normal pruning processes in the brain that would be consistent with delayed maturation (supported here by associations with amino-acid metabolism) and a reduced metabolic source of energy.
Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.
Cytokines have emerged in the past two decades as some of the most extensively studied peptide molecules contributing to the pathophysiology of many diseases. As a result of these translational efforts, discovery of drugs aimed at reducing damage caused by cytokines has been accomplished for some conditions. The characterization of the role of cytokines in the pathophysiology of neuropsychiatric disorders is still in its infancy. This article highlights the growing correlation of brain cytokine levels with corresponding psychiatric symptoms, known as cytokine-induced sickness behavior, comprising increased sleep, decreased appetite, decreased sexual drive, and overwhelming fatigue frequently combined with fever.
Tourette syndrome (TS) has a multifactorial etiology, in which genetic, environmental, immunological and hormonal factors interact to establish vulnerability. This review: (i) summarizes research exploring the exposure of TS patients to immune-activating environmental factors, and (ii) focuses on recent findings supporting a role of the innate and adaptive immune systems in the pathogenesis of TS and related disorders. A higher exposure prior to disease onset to group A beta-haemolytic streptococcal (GABHS) infections in children with tics and obsessive-compulsive (OC) symptoms has been documented, although their influence upon the course of disease remains uncertain. Increased activation of immune responses in TS is suggested by changes in gene expression profiles of peripheral immune cells, relative frequency of lymphocyte subpopulations, and synthesis of immune effector molecules. Increased activity of cell-mediated mechanisms is suggested by the increased expression of genes controlling natural killer and cytotoxic T cells, increased plasma levels of some pro-inflammatory cytokines which correlate with disease severity, and increased synthesis of antineuronal antibodies. Important methodological differences might account for some inconsistency among results of studies addressing autoantibodies in TS. Finally, a general predisposition to autoimmune responses in TS patients is indicated by the reduced frequency of regulatory T cells, which induce tolerance towards self-antigens. Although the pathogenic role of immune activation in TS has not been definitively proven, a pathophysiological model is proposed to explain the possible effect of immunity upon dopamine transmission regulation and the generation of tics.
Attention deficit/hyperactivity disorder (ADHD) is often present in patients with post-streptococcal neuropsychiatric disorders such as Sydenham's chorea and PANDAS, in which anti-basal ganglia antibodies (ABGA) have been frequently found. Our study investigates the hypothesis that pharyngeal group A beta-hemolytic streptococcus (GABHS) infections and serum ABGA are more frequent in children with ADHD non-comorbid (nc-ADHD) with obsessive-compulsive disorder or tics than in controls. We compared 22 children with nc-ADHD (DSM-IV-TR) and 22 healthy controls matched by age, gender and season of sample collection, for the frequency of recent GABHS infection and the presence of ABGA. Eleven out of 22 children (51%) with nc-ADHD showed evidence of GABHS infection compared to three out of 22 (14%) controls (P = 0.007). We found positive ABGA in one ADHD subject (4%) and in one control (4%). This preliminary study indicates that frequency of ABGA in children with nc-ADHD does not differ from that in matched controls, despite the fact that our ADHD patients had had more recent GABHS infections than the controls. This suggests that ABGA do not have a role in the pathogenesis of nc-ADHD.
This study examines the possible relationship existing between the HLA-DR gene and attention deficit hyperactivity disorder (ADHD) and/or mental retardation (MR). The diagnosis of ADHD and mental retardation were established through clinical interviews with the parents, children and teachers, according to the criteria in DSM-IV. HLA-DRB1 genotyping was performed both by polymerase chain reaction-sequence specific primers (PCR-SSP) and by sequence based typing (SBT) in a cohort of 81 affected children and a sample of 100 healthy controls. Here, we report a positive association of HLA-DR4 with ADHD but not with MR. The study adds confirmation to the role of the HLA-DRB1 in the etiology of some types of childhood neuropsychiatric illnesses.
HLA A, B, C and DR were typed in 73 Korean patients with Tourette disorder meeting the diagnostic criteria of DSM III-R and compared with 291 normal subjects. Relatively higher frequencies were found in HLA A11 and A26(10) with lower incidences in HLA A24(9) and B13. A family history of tic disorders was associated with a lower frequency of HLA A24(9).
Empirical studies suggest that allergies play an etiological role in a small subgroup of children who suffer from attention deficit-hyperactivity disorder (ADHD). Research indicates that allergic reactions results in cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic/adrenergic activity play a causal role in manic and depressive behaviors. It is hypothesized that allergic reactions engender cholinergic/adrenergic activity imbalances in the central nervous system, leading to poorly regulated arousal levels and ADHD behaviors in some children.
The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS).
The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities.
The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure.
The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.
Objective: The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A β-hemolytic streptococcal [GABHS]) infections (PANDAS). Method: The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. Results: The children’s symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean=6.3 years, SD=2.7, for tics; mean=7.4 years, SD=2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional labi...
This comprehensive account of the genetic and environmental factors that cause atopic dermatitis reconciles two hypotheses concerning the origin of the disease - IgE-mediated sensitization, or an intrinsic defect in epithelial cells that causes dysfunction of the skin barrier - with evidence that both mechanisms contribute. Clinical implications are discussed.
Background: To evaluate associations between attention-deficit/hyperactivity disorder (ADHD) and comorbid psychiatric disorders using research-identified incident cases of ADHD and population-based controls.
Methods: Subjects included a birth cohort of all children born 1976–1982 remaining in Rochester, MN after age five (n = 5,718). Among them we identified 379 ADHD incident cases and 758 age-gender matched non-ADHD controls, passively followed to age 19 years. All psychiatric diagnoses were identified and abstracted, but only those confirmed by qualified medical professionals were included in the analysis. For each psychiatric disorder, cumulative incidence rates for subjects with and without ADHD were estimated using the Kaplan–Meier method. Corresponding hazard ratios (HR) were estimated using Cox models adjusted for gender and mother’s age and education at the subject’s birth. The association between ADHD and the likelihood of having an internalizing or externalizing disorder was summarized by estimating odds ratios (OR).
Results: Attention-deficit/hyperactivity disorder was associated with a significantly increased risk of adjustment disorders (HR = 3.88), conduct/oppositional defiant disorder (HR = 9.54), mood disorders (HR = 3.67), anxiety disorders (HR = 2.94), tic disorders (HR = 6.53), eating disorders (HR = 5.68), personality disorders (HR = 5.80), and substance-related disorders (HR = 4.03). When psychiatric comorbidities were classified on the internalization-externalization dimension, ADHD was strongly associated with coexisting internalizing/externalizing (OR = 10.6), or externalizing-only (OR = 10.0) disorders.
Conclusion: This population-based study confirms that children with ADHD are at significantly increased risk for a wide range of psychiatric disorders. Besides treating the ADHD, clinicians should identify and provide appropriate treatment for psychiatric comorbidities.
Background:
Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD.
Objective:
The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD.
Study design:
This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7-day post-treatment follow-up phase. Efficacy and safety assessments were performed.
Setting:
The study was conducted at 37 study centres in the US from April 2009 through January 2010.
Participants:
Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled.
Intervention:
Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day.
Main outcome measure:
The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings.
Results:
430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p=0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p<0.005). Secondary efficacy assessments demonstrated a similar pattern with a non-significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively.
Conclusion:
Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD.
Clinical trial registration number:
NCT00880217.
Background:
Post-infectious autoimmunity has been implicated in pathogenesis of Tourette's syndrome (TS) but no evidence of inflammation in central nervous system has been reported yet. We evaluated the expression of genes encoding selected inflammatory factors in post-mortem specimen of adult TS patients: interferon-γ (a cytokine released from CD8 and Thelper 1 CD4 subset of T lymphocytes), interleukin-2 (IL-2, a growth factor derived from T lymphocytes), interleukin-1 β (a cytokine involved in initiation of inflammation), monocyte chemotactic factor -1 (MCP-1, a marker of chronic inflammation) and CD45 (pan-leukocytic marker). For validation purposes, we determined expression of three genes that were previously reported to be elevated in post-mortem specimen of other TS cases: protein tyrosine phosphatase receptor-N (PTPR-N), PTPR-U and recoverin.
Methods:
Total RNA was isolated from formalin fixed brain tissue sections of basal ganglia area from four patients with TS and four control subjects, and real-time reverse transcription-polymerase chain reaction analysis was employed to quantitatively evaluate gene expression of the selected genes.
Results:
Significantly increased expression of MCP-1, IL-2 and PTPR-N was observed in TS cases (6.5-fold, 2.3-fold and 16.1-fold increase, respectively, p<0.05).
Conclusions:
Elevated expression of MCP-1 and IL-2 supports the possibility of chronic inflammatory processes in the basal ganglia. Replication of elevated expression of PTPR-N in TS specimen suggests that pathway(s) involving this molecule may be important in TS pathogenesis.
Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes.
We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated.
While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10(-4) - 1.6 × 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes.
We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration.
The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3‐autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3‐receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3‐receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1‐{3‐[3‐(4‐chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake‐promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder.
LINKED ARTICLES
This review is dedicated to the memory of Sir James Black who recently passed away and whose achievements in classical pharmacology and drug design have been examples to the author throughout his career. BJP published an issue in 2010 on Analytical Receptor Pharmacology in Drug Discovery, which was dedicated to the memory of Sir James Black. To view this issue visit http://dx.doi.org/10.1111/bph.2010.161.issue‐6 In 2009 BJP published a Histamine themed issue. To view this issue visit http://dx.doi.org/10.1111/bph.2009.157.issue‐1
Tourette's disorder (TD) frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). While the relationship between TD and OCD suggests that they share etiological factors, the exact relationship between TD and ADHD is less clear. The goal of the current analyses was to understand better the familial relationship between DSM-IV ADHD and TD. Direct interview diagnostic data from a case-control study of 692 relatives of 75 comorbid TD and ADHD (TD + ADHD), 74 TD without ADHD (TD Only), 41 ADHD without TD (ADHD Only), and 49 control probands were analyzed. Hierarchical loglinear modeling was used to explore association patterns between TD, ADHD, and OCD or sub-clinical OCD (OCD/OCDsub) diagnoses among the 190 affected probands and their 538 relatives. The presence of OCD or OCDsub diagnosis in a proband was associated with a significantly increased risk of comorbid TD + ADHD in his/her relatives. The finding of an association between TD, ADHD and a proband OCD/OCDsub diagnosis was unexpected. The current results suggest that TD, ADHD, and OCD symptoms have overlapping neurobiology when occurring in families of TD and/or ADHD probands.
Linkage between allergy and increased immune response activation in Tourette syndrome (TS) has been reported. We performed a matched case-control study to evaluate correlation between allergic diseases and TS.
Data in this case-control study were from the Taiwan National Health Insurance Research Database. The sample comprised 845 2- to 18-year-old patients with newly diagnosed TS in 2003–2007 and 3378 controls frequency matched with cases on age, sex, and urbanization level. Unconditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of the association between allergic disease (e.g., allergic rhinitis, atopic dermatitis, asthma, and allergic conjunctivitis), the number of allergic comorbidities, and TS.
The majority (76.0%) of incident TS cases were boys; the 4 allergic diseases strongly correlated with higher risk of TS. In a model simultaneously considering all 4 allergic diseases, subjects with allergic rhinitis showed double the risk of TS (adjusted OR = 2.18, 95%CI 1.83–2.59; p < 0.0001); adjusted ORs were 1.82, 1.61, and 1.33, respectively, for asthma (95% CI 1.47–2.24; p < 0.0001), dermatitis (95%CI 1.32–1.95; p < 0.0001), and allergic conjunctivitis (95% CI 1.13–1.57; p < 0.001). Risk increased with number of comorbidities (p < 0.0001); this association was positively modified by age (p < 0.0001).
Our data showed significant correlation between allergic diseases and TS. Risk also increased with number of allergic comorbidities and with age. Further studies on the mechanism of neuroimmunology of TS are required.
Tourette syndrome (TS) is a neuropsychiatric disorder with a genetic component that is highly comorbid with obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). However, the genetic relations between these disorders have not been clearly elucidated. This study examined the familial relations among TS, OCD, and ADHD in a large sample of TS families.
Parent-offspring concordance of TS, OCD, and ADHD was examined in 952 individuals from 222 TS-affected sib-pair families originally collected for genetic studies using logistic regression with generalized estimating equations to control for correlated data. Variance components methods were used to estimate the heritability and genetic and environmental correlations among TS, OCD, and ADHD. Bilineal families where both parents had TS or OCD were excluded.
OCD and ADHD were highly heritable in these TS families. There were significant genetic correlations between TS and OCD and between OCD and ADHD, but not between TS and ADHD. In addition, significant environmental correlations were found between TS and ADHD and between OCD and ADHD. Parental OCD + ADHD was associated with offspring OCD + ADHD.
This study provides further evidence for a genetic relation between TS and OCD and suggests that the observed relation between TS and ADHD may due in part be to a genetic association between OCD and ADHD and in part due to shared environmental factors.
H(3) antagonists increase the release of brain histamine, acetylcholine, noradrenaline, and dopamine, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine supports the effect on attention and vigilance, but histamine also modulates other cognitive domains such as short-term and long-term memory. A number of H(3) antagonists, including 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride (BF2.649), (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), MK-0249 (structure not yet disclosed), JNJ-17216498 (structure not yet disclosed), and ABT-288 (structure not yet disclosed), have advanced to the clinical area for the potential treatment of human cognitive disorders. H(3) antagonists exhibited wake-promoting effects in humans and efficacy in narcoleptic patients, indicating target engagement, but some of them were not efficacious in patients suffering from attention-deficit hyperactivity disorder and schizophrenic patients. Preclinical studies have also shown that H(3) antagonists activate intracellular signaling pathways that may improve cognitive efficacy and disease-modifying effects in Alzheimer's disease. Ongoing clinical studies will be able to determine the utility of H(3) antagonists for the treatment of cognitive disorders in humans.
To cite this article: Schmitt J, Buske-Kirschbaum A, Roessner V. Is atopic disease a risk factor for attention-deficit/hyperactivity disorder? A systematic review. Allergy 2010; 65: 1506–1524.
The increase in prevalence and burden of atopic diseases, i.e. eczema, rhinitis, and asthma over the past decades was paralleled by a worldwide increase in attention-deficit/hyperactivity disorder (ADHD) diagnoses. We systematically reviewed epidemiologic studies investigating the relationship between atopic diseases and ADHD. Electronic literature search in PubMed and PsycINFO (until 02/2010) supplemented by handsearch yielded 20 relevant studies totaling 170 175 individuals. Relevant data were abstracted independently by two reviewers. Six studies consistently reported a positive association between eczema and ADHD with one study suggesting effect modification by sleeping problems. Twelve studies consistently found a positive association between asthma and ADHD, which, however, appeared to be at least partly explained (confounded) by concurrent or previous eczema. Rhinitis and serum-IgE level were not related to ADHD symptomatology. We conclude that not atopic disease in general, but rather that eczema appears to be independently related to ADHD. Conclusions about temporality and whether the observed association constitutes a causal relationship are impossible, as most studies were cross-sectional (n = 14; 70%) or case–control studies without incident exposure measurement (n = 5; 25%). Another methodological concern is that the criteria to define atopic disease and ADHD were inadequate in most studies. A failure to adjust for confounders in the majority of studies was an additional limitation so that meta-analysis was not indicated. Future interdisciplinary high-quality prospective research is needed to better understand the mechanisms underlying the relationship between eczema and ADHD and to eventually establish targeted preventive and treatment strategies.
Histamine H(3) receptor (H(3)R) antagonists/inverse agonists can be therapeutically useful in the treatment of various CNS, metabolic syndrome and allergic disorders, and constitute an attractive target in the search for new drugs. However, several drug candidates have been rejected because of unwanted effects. There is, therefore, a strong need to develop new H(3)R ligands.
A review was conducted of recent advances in the search for H(3)R antagonists/inverse agonists as reflected by patent applications/patents over the last 3 years.
A total of around 100 patent applications/patents along with selected peer-reviewed publications are surveyed. These involve antagonists/inverse agonists of H(3)R, which the authors have divided into five groups. The above-mentioned compounds were evaluated for their potential utility in the treatment of narcolepsy, attention deficit hyperactivity disorder, epilepsy, Alzheimer's disease, schizophrenia, obesity and neuropathic pain.
Several H(3)R antagonists/inverse agonists appear to be promising drug candidates, including at least 15 compounds undergoing evaluation in clinical development. Especially interesting is pitolisant, which is progressing through to Phase III clinical trials.
Dysregulation of the immune system may play a role in tic disorders. We screened for immune disturbances by investigating serum levels of cytokines and soluble adhesion molecules in patients with a tic disorder.
Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, soluble IL-2 receptor (sIL2R), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, soluble vascular cell adhesion molecule-1 (sVCAM-1), and intercellular adhesion molecule-1 (sICAM-1) of 66 children and adolescents with a tic disorder and 71 healthy volunteers were compared. We also addressed possible relations between concentrations of the immune markers and severity of tics and comorbid obsessive-compulsive symptoms.
Median serum concentrations did not differ significantly between patients and healthy subjects. Serum IL-2 concentrations were positively associated with tic severity ratings; serum IL-12 concentrations negatively with severity ratings of obsessive-compulsive symptoms.
These preliminary findings do not reveal major immune activation in children with a tic disorder but may suggest more subtle disturbances related to disease expression.
Coexistence of tics and attention-deficit/hyperactivity disorder (ADHD) has important clinical and scientific implications. Existing data on the co-occurrence of tic disorders, Tourette Syndrome (TS), and ADHD are largely derived from small-scale studies in selected samples and therefore heterogeneous. The Nordbaden project captures the complete outpatient claims data of more than 2.2 million persons, representing 82% of the regional population in 2003. Based upon the number of diagnosed cases of tic disorders, TS, and ADHD, we determined 12-months administrative prevalence rates as well as rates of co-occurrence. Both tic disorders and ADHD were diagnosed most often in the age group 7-12 years (any tic disorder: 0.8%; ADHD: 5.0%). With increasing age, the administrative prevalence difference in favor of males disappeared, with tic disorders being somewhat more frequently reported in females than males in the age groups above 30 years. The highest rate of ADHD co-occurring with tic disorders was found in adolescents (age 13-18 years, 15.1%). Tic disorders were observed in 2.3% of patients with ADHD. Administrative prevalence rates of tic disorders and TS were substantially lower compared to rates found in community-based epidemiological studies, suggesting that a large number of cases remain undetected and untreated under present conditions of routine outpatient care.
Postinfectious autoimmunity has been implicated in Tourette's syndrome and obsessive-compulsive disorder (TS/OCD), whereas increased frequency of upper respiratory tract infections (URTI) in TS/OCD patients suggests immune deficiency. We hypothesized that antineuronal antibodies may be elevated in patients (reflecting autoimmune processes), and levels of total immunoglobulins (Igs) may be decreased (reflecting immune deficiency).
We analyzed plasma of TS/OCD patients (n = 24) and healthy age- and sex-matched control subjects (n = 22) by enzyme-linked immunosorbent assay (ELISA) for the levels of total and specific IgG, IgM, and IgA against antigens previously identified in multiple sclerosis (myelin basic protein and myelin-associated glycoprotein) and Sydenham's chorea (ganglioside-GM1, lysoganglioside, and tubulin).
Total IgA was decreased in TS/OCD patients (median 115 mg/100 mL) compared with control subjects (141 mg/100 mL; p = .02). Specific IgA against all antigens, except tubulin were also decreased in the patients (MPB 0 vs. 13 [ELISA units [EU]; myelin-associated glycoprotein 29 vs. 44 EU, p = .04; ganglioside GM1 21 vs. 35 EU, p = .01; lysoganglioside 44 vs. 56 EU, p = .03; tubulin 44 vs. 44 EU, p = .8). The levels of total IgA and anti-myelin basic protein (MBP) IgA were significantly lower in the subgroup of pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS) cases (n = 10) than in non-PANDAS cases (n = 9; total IgA 98 mg/100 mL vs. 133 mg/mL, p = .03; anti-MBP IgA 1 vs. 6 EU, p = .03) or healthy control subjects (total IgA 141 mg/100 mL, p = .02; anti-MBP IgA 13 EU, p = .005).
At least some TS/OCD patients may suffer IgA dysgammaglobulinemia, possibly rendering the children more prone to URTI.
Individuals with Tourette syndrome (TS) often display comorbid symptoms of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as well as externalizing and internalizing behaviors. This study was aimed to examine the impacts of tic severity, ADHD symptoms, and OCD on internalizing (e.g., anxiety) and externalizing (e.g., aggression) psychopathology.
Using linear regressions, we examined how tics, ADHD, and OCD symptoms predicted the externalization and internalization behaviors measured by the Child Behavior Checklist in a clinical sample of children and adolescents with TS. In addition, Child Behavior Checklist scales were compared among children with TS without ADHD, TS and ADHD, ADHD without TS, and unaffected control group.
In the TS group, externalizing behaviors were predicted by tic severity, inattention, and hyperactivity/impulsivity but not by OCD symptoms, whereas internalizing behaviors were predicted by inattention and OCD symptoms but not by tic severity or hyperactivity/impulsivity. Comparison among different clinical groups revealed main effects of TS and ADHD on both externalizing and internalizing behaviors.
These findings suggest that tics, ADHD, and OCD symptoms differentially explain the variance in externalizing and internalizing behavioral problems in individuals with TS. In addition, the data support the notion that TS is itself a risk factor for behavioral problems, mandating that children with TS even without ADHD and OCD still need to be assessed and treated for psychopathology.
Tourette syndrome (TS) is a heritable neuropsychiatric disorder that presents in childhood with a constellation of motor and non-motor symptoms. The defining feature of the disorder is the presence of brief, stereotyped, motor or vocal behaviours called tics. Although tics are themselves voluntary, they are typically performed secondary to involuntary sensory symptoms or irresistible urges. TS is therefore said to be a disorder of human volition that likely represents a general failure of inhibition. It shares many features with obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and impulse control disorder with which it is also commonly associated. Much of the anatomic substrate for TS probably lies in the circuits that connect multiple areas of cortex with the basal ganglia and thalamus to subserve motivation, inhibition of behaviour, planning of motor acts and detection of threats. To date, pathological studies of TS have been very few and the number of subjects evaluated too small to reliably elucidate the nature and significance of several reported abnormalities. However, evidence derived from both pharmacological trials and selected functional imaging studies suggests that disturbances of the dopaminergic and serotonergic neurotransmitter systems play a key role in the pathogenesis of TS. At the same time, multiple studies have demonstrated reciprocal interactions between the serotonin and dopamine systems of the brain. This information, when placed in the context of the observed functional imaging abnormalities, may generate further insights into the pathophysiology of TS.
Self-report data were gathered from a national sample of over two hundred Canadian Tourette Syndrome (TS) patients. Included was previous use of stimulant medication and prior extended use of antihistamines for allergies or sinus condition. Patients were also asked information on Tourette Syndrome-precipitated hospitalization or boarding school placement, the type of physician treating them and on a five-point scale their level of satisfaction with their medical care. Results indicate that over 20% of TS patients have used stimulant medications and 30% have used antihistamine for extended periods. Many patients have spent time in psychiatric settings and most are under the care of psychiatrist or neurologist. Approximately 40% of TS patients reported being satisfied to very satisfied with the medical care they were receiving, and 20% having mixed feelings. Few patients receiving medical care were dissatisfied with their treatment.
Four patients with Tourette's syndrome who presented in an allergist's office are described. The diagnostic criteria, presentation of Tourette's syndrome, and current therapy are discussed. All four patients had increased serum IgE levels and positive skin tests. Symptoms of Tourette patients may mimic allergy or present combined with allergic illness.
Five kindreds with multiple individuals manifesting Tourette syndrome (TS) or related abnormal movements were evaluated for linkage between TS and HLA-A, B, C and DR antigens. Families were selected to have a constellation of affected individuals which gave the appearance of transmission of a major susceptibility gene. All kindreds had at least two clearly affected first or second degree relatives. Although developmental neurobehavioral disorders are candidates for showing a relationship to specific tissue antigens, we found no evidence for a close linkage between a gene locus determining susceptibility to TS and the HLA loci.
In this paper we evaluate the association between asthma and attention-deficit hyperactivity disorder (ADHD), addressing issues of comorbidity and familiality by formulating and testing competing hypotheses.
Subjects were 6- to 17-year-old boys with DSM-III-R ADHD (N = 140) and normal controls (N = 120) and their first-degree relatives. Information on asthma was obtained from the mothers in a standardized manner blind to the proband's clinical status.
The risk for asthma did not meaningfully differ between ADHD and control children. Relatives of ADHD probands with and without asthma were at significantly greater risk for ADHD than relatives of normal controls. In contrast, the risk for asthma was significantly elevated only among relatives of children with ADHD plus asthma.
These findings argue against a substantial etiological or pathophysiological relationship between the two conditions but suggest that ADHD and asthma are independently transmitted in families. Thus, the observation of ADHD symptoms in an asthmatic child should not be dismissed out of hand as being a consequence of asthma since many asthmatic ADHD children may actually have ADHD.
The objective was to determine whether a relationship exists among the complement C4B gene, a DR region gene and attention deficit hyperactivity disorder (ADHD). Thirty-one subjects with ADHD, their mothers, all but 5 of their fathers, and 90 normal subjects living in northern Utah were studied. DR and C4B typing were performed by serologic HLA typing techniques and the DNA methods PCR-RFLP. The alleles of 2 genes, the null allele of the C4B gene and the beta 1 allele of the DR gene, encode for products involved in immune function and regulation. Each of these alleles was found to be significantly associated with ADHD. Moreover, approximately 55% of the ADHD subjects carried both of these alleles on 1 of their chromosomes, compared to only 8% of normal controls. Genes related to the immune system may be associated with development of the symptoms of ADHD.
This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.
Sydenham’s chorea (SC) is a manifestation of post-streptococcal autoimmunity. Following infection of a susceptible individual with an appropriate strain of Group A beta-hemolytic streptococcus (GABHS), anti-strep antibodies are generated. SC is presumably due to the recognition by certain anti-strep antibodies of autoantigens present in the basal ganglia, and subsequent antibody-antigen binding1. The production of antibodies is a complex cascade of events which involve T cells; antigen presenting cells (APC) of various sorts; B cells; and a variety of soluble mediators which regulate cellular function and influence isotype and subclass of the antibodies produced2. We have sought to examine the role of T cell and APC derived cytokines in SC.
Tourette's syndrome is a relatively common disorder that may present as a spectrum that can include both motor and behavioral features.
We report four patients referred to allergists to rule out atopy as a reason fro their presumed respiratory symptoms who were subsequently found to have Tourette's syndrome. A review of the literature was also performed using Medline.
The symptoms of Tourette's syndrome may overlap those associated with allergy involving the respiratory tract. There is little published information on the association of Tourette's syndrome with atopy.
Allergists should be aware of Tourette's syndrome and the variable clinical spectrum of this disorder as Tourette's syndrome patients may be referred prior to the diagnosis of Tourette's syndrome.
There are mixed research results in the literature regarding a possible association between Attention Deficit Hyperactivity Disorder (ADHD) and atopic disorders. If such an association were supported, the implications for underlying pathophysiology would be significant. We evaluated level of atopic responsiveness (based on IgE-mediated response to skin prick tests) in 312 referrals to a pediatric allergist. Based on the atopy code, children were categorized as non-atopic, or moderately or severely atopic. Parents completed the Child Behavior Checklist (CBCL). Univariate analyses on the eight CBCL subscales revealed no differences between the atopic groups. Our results do not support an association between IgE-Mediated atopic responsiveness and ADHD, but they do not rule out an association between allergic symptoms and ADHD based on some other mechanism.
In our clinical practice, we often encounter signs and symptoms of allergy, such as rhinitis and asthma, in patients with Tourette's syndrome (TS). Some of the allergic manifestations are similar to the oral tics or motor tics found in TS patients. To clarify the association between TS and allergy, we evaluated 72 consecutive patients with TS from 1 September 1996 through 31 August 1997. The diagnosis of TS was based on the Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria. Sixty-five boys and 7 girls, 4 to 17 years old (9.4 +/- 3.1 yr) were evaluated using the Multiple Allergens Simultaneous Tests (MAST) for the detection of total and specific immunoglobulin. Forty-five patients had positive results, of whom 41 (56.9%) had clinical evidence of allergy. The prevalence of allergy in the local population as reported by The International Study of Asthma and Allergy in Childhood Taiwan Group (1994) was 44.3% (33.5% with allergic rhinitis and 10.8% with asthma). These subjects served as controls. Comparing the number of patients with clinical evidence of allergy in the MAST positive group (56.9%) of TS patients with the control group (44.3%), the difference was significant++ (p < 0.05). The prevalence of allergy in TS patients in our study was significantly higher than in the general population. TS had an association with allergy.
The occurrence of myelitis with atopic diathesis (atopic myelitis) affecting young adults has recently been noted in Japan. The disease preferentially affects the posterior column of the cervical spinal cord, as shown clinically and by MRI. It is characterized by hyperIgEaemia and the presence of mite antigen-specific IgE. The spinal cord lesions have been shown to be eosinophilic inflammation on biopsy and thus an allergic mechanism is thought to be operative in this condition. In addition, we also found that Hirayama disease, juvenile muscular atrophy of the distal upper extremity, is also associated with airway allergy such as allergic rhinitis and atopic asthma. In children, poliomyelitislike illness after acute asthma attacks is well known as Hopkins syndrome. Moreover, by the prospective study of the history of allergic disorders in common neurologic diseases, an association between spinal progressive muscular atrophy (SPMA) and asthma as well as between myelitis and atopic dermatitis has been demonstrated. These observations strongly suggest a link between atopic diathesis and spinal cord damage. Central nervous system damage associated with atopic diathesis may be classified into two types; eosinophilic myelitis preferentially affecting the cervical spinal cord and lower motor neuron damage, such as Hopkins syndrome, Hirayama disease and SPMA. The former is typically associated with atopic dermatitis while the latter, with airway allergy.
As our knowledge of Gilles de la Tourette's syndrome increases, so does our appreciation for the pathogenic complexity of this disorder and the challenges associated with its treatment. Advances in the neurosciences have led to new models of pathogenesis, whereas clinical studies have reinvigorated early hypotheses. The interdependent roles of genes and environment in disease formation have yet to be fully elucidated. Results of epidemiological studies have prompted debate on how best to characterise and diagnose this disorder. Absence of ideal anti-tic drugs, combined with knowledge that uncomplicated cases of childhood Tourette's syndrome frequently have a favourable outcome, has led to striking changes in care and treatment of patients. This seminar focuses on these changing views and offers a new perspective on our understanding of the pathogenesis of Tourette's syndrome and on principles for treatment of patients with this disorder.
Despite long-standing clinical concerns, relatively little is known about the comorbidity between attention-deficit/hyperactivity disorder (ADHD) and tic disorders. Therefore, we examined tic disorders in an ongoing prospective follow-up study of male subjects with ADHD, a sample unselected for any comorbid disorder.
One hundred twenty-eight male children and adolescents with ADHD and 110 male controls were comprehensively evaluated at baseline and 4 years later. We characterized tic disorders along with a wide range of neuropsychiatric correlates, including other comorbid disorders and indices of psychosocial function in multiple domains (school, cognitive, social, and family).
Compared with controls, subjects with ADHD showed more tic disorders at baseline and more new onsets were reported at follow-up. Attention-deficit/hyperactivity disorder and tic disorders appeared to be independent in course: in contrast to low rates of ADHD remission, tic disorders mostly remitted. The age-adjusted rate of ADHD remission was 20% and that of tic remission, 65%. Tic disorders had little effect on the psychosocial functioning of subjects with ADHD.
These findings suggest that comorbidity with a tic disorder has a limited effect on ADHD outcome. However, because of the relatively small sample of subjects with tic disorders, our conclusions should be considered preliminary until confirmed in larger studies of medicated and unmedicated children with ADHD with and without tic disorders.
The recognition of the five criteria for PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) by Swedo et al established a homogenous subgroup of children with childhood onset obsessive-compulsive disorder (OCD) and/or tic disorders. The five clinical characteristics that define the PANDAS subgroup are the presence of OCD and/or tic disorder, prepubertal age of onset, abrupt onset and relapsing-remitting symptom course, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and a temporal association between symptom exacerbations and a Group-A beta-hemolytic streptococcal (GAS) infection. These five criteria have been used for the purpose of systematic research on the phenomenology and unique therapies for the PANDAS subgroup as well as studies of the pathophysiology of post-streptococcal OCD and tic disorders. The etiology of OCD and tics in the PANDAS subgroup is unknown, but is theorized to occur as a result of post-streptococcal autoimmunity in a manner similar to that of Sydenham's chorea. The working hypothesis for the pathophysiology begins with a GAS infection in a susceptible host that incites the production of antibodies to GAS that crossreact with the cellular components of the basal ganglia, particularly in the caudate nucleus and putamen. The obsessions, compulsions, tics, and other neuropsychiatric symptoms seen in these children are postulated to arise from an interaction of these antibodies with neurons of the basal ganglia.