An integrated program of computer-presented and physical cognitive training exercises for children with attention-deficit/hyperactivity disorder.

BACKGROUND: This study integrated an experimental medicine approach and a randomized cross-over clinical trial design following CONSORT recommendations to evaluate a cognitive training (CT) intervention for attention deficit hyperactivity disorder (ADHD). The experimental medicine approach was adopted because of documented pathophysiological heterogeneity within the diagnosis of ADHD. The cross-over design was adopted to provide the intervention for all participants and make maximum use of data. METHODS: Children (n = 93, mean age 7.3 +/- 1.1 years) with or sub-threshold for ADHD were randomly assigned to CT exercises over 15 weeks, before or after 15 weeks of treatment-as-usual (TAU). Fifteen dropped out of the CT/TAU group and 12 out of the TAU/CT group, leaving 66 for cross-over analysis. Seven in the CT/TAU group completed CT before dropping out making 73 available for experimental medicine analyses. Attention, response inhibition, and working memory were assessed before and after CT and TAU. RESULTS: Children were more likely to improve with CT than TAU (27/66 v. 13/66, McNemar p = 0.02). Consistent with the experimental medicine hypotheses, responders improved on all tests of executive function (p = 0.009-0.01) while non-responders improved on none (p = 0.27-0.81). The degree of clinical improvement was predicted by baseline and change scores in focused attention and working memory (p = 0.008). The response rate was higher in inattentive and combined subtypes than hyperactive-impulsive subtype (p = 0.003). CONCLUSIONS: Targeting cognitive dysfunction decreases clinical symptoms in proportion to improvement in cognition. Inattentive and combined subtypes were more likely to respond, consistent with targeted pathology and clinically relevant heterogeneity within ADHD.

Interrupted Time Series of User-centered Clinical Decision Support Implementation for Emergency Department-initiated Buprenorphine for Opioid Use Disorder.

OBJECTIVES: Adoption of emergency department (ED) initiation of buprenorphine (BUP) for opioid use disorder (OUD) into routine emergency care has been slow, partly due to clinicians' unfamiliarity with this practice and perceptions that it is complicated and time-consuming. To address these barriers and guide emergency clinicians through the process of BUP initiation, we implemented a user-centered computerized clinical decision support system (CDS). This study was conducted to assess the feasibility of implementation and to evaluate the preliminary efficacy of the intervention to increase the rate of ED-initiated BUP. METHODS: An interrupted time series study was conducted in an urban, academic ED from April 2018 to February 2019 (preimplementation phase), March 2019 to August 2019 (implementation phase), and September 2019 to December 2019 (maintenance phase) to study the effect of the intervention on adult ED patients identified by a validated electronic health record (EHR)-based computable phenotype consisting of structured data consistent with potential cases of OUD who would benefit from BUP treatment. The intervention offers flexible CDS for identification of OUD, assessment of opioid withdrawal, and motivation of readiness to start treatment and automates EHR activities related to ED initiation of BUP (including documentation, orders, prescribing, and referral). The primary outcome was the rate of ED-initiated BUP. Secondary outcomes were launch of the intervention, prescription for naloxone at ED discharge, and referral for ongoing addiction treatment. RESULTS: Of the 141,041 unique patients presenting to the ED over the preimplementation and implementation phases (i.e., the phases used in primary analysis), 906 (574 preimplementation and 332 implementation) met OUD phenotype and inclusion criteria. The rate of BUP initiation increased from 3.5% (20/574) in the preimplementation phase to 6.6% (22/332) in the implementation phase (p = 0.03). After the temporal trend of the number of physician's with X-waiver training and other covariates were adjusted for, the relative risk of BUP initiation rate was 2.73 (95% confidence interval [CI] = 0.62 to 12.0, p = 0.18). Similarly, the number of unique attendings who initiated BUP increased modestly 7/53 (13.0%) to 13/57 (22.8%, p = 0.10) after offering just-in-time training during the implementation period. The rate of naloxone prescribed at discharge also increased (6.5% preimplementation and 11.5% implementation; p < 0.01). The intervention received a system usability scale score of 82.0 (95% CI = 76.7 to 87.2). CONCLUSION: Implementation of user-centered CDS at a single ED was feasible, acceptable, and associated with increased rates of ED-initiated BUP and naloxone prescribing in patients with OUD and a doubling of the number of unique physicians adopting the practice. We have implemented this intervention across several health systems in an ongoing trial to assess its effectiveness, scalability, and generalizability.

Progress Report on EMBED: A Pragmatic Trial of User-Centered Clinical Decision Support to Implement EMergency Department-Initiated BuprenorphinE for Opioid Use Disorder.

Buprenorphine (BUP) can safely and effectively reduce craving, overdose, and mortality rates in people with opioid use disorder (OUD). However, adoption of ED-initiation of BUP has been slow partly due to physician perception this practice is too complex and disruptive. We report progress of the ongoing EMBED (EMergency department-initiated BuprenorphinE for opioid use Disorder) project. This project is a five-year collaboration across five healthcare systems with the goal to develop, integrate, study, and disseminate user-centered Clinical Decision Support (CDS) to promote the adoption of Emergency Department (ED)-initiation of buprenorphine/naloxone (BUP) into routine emergency care. Soon to enter its third year, the project has already completed multiple milestones to achieve its goals including (1) user-centered design of the CDS prototype, (2) integration of the CDS into an automated electronic health record (EHR) workflow, (3) data coordination including derivation and validation of an EHR-based computable phenotype, (4) meeting all ethical and regulatory requirements to achieve a waiver of informed consent, (5) pilot testing of the intervention at a single site, and (6) launching a parallel group-randomized 18-month pragmatic trial in 20 EDs across 5 healthcare systems. Pilot testing of the intervention in a single ED was associated with increased rates of ED-initiated BUP and naloxone prescribing and a doubling of the number of unique physicians adopting the practice. The ongoing multi-center pragmatic trial will assess the intervention's effectiveness, scalability, and generalizability with a goal to shift the emergency care paradigm for OUD towards early identification and treatment. TRIAL REGISTRATION: Clinicaltrials.gov # NCT03658642.

Maternal perceptions of father involvement among refugee and disadvantaged families in Beirut, Lebanon.

The role of fathers in (co-)parenting their children among refugee and disadvantaged families in low and middle-income countries (LMICs) remains poorly understood. This study sought to examine the associations among mothers' perceptions of their husband's involvement (hereafter referred to as paternal involvement), and her perceptions of her own well-being and a number of other variables, as well as observed mother-child interactions in families living in refugee and disadvantaged communities in Beirut, Lebanon. We analyzed baseline data from 104 mother-child dyads (mean age of children = 4.34 years; range = 2.05 to 7.93 years of age) who participated in a randomized controlled trial aimed at evaluating the impact of the Mother-Child Education Program in Beirut. In addition to the mother's perception of paternal involvement and the videotaped mother-child interactions, data were collected concerning the mother's well-being and her level of social support, as well as her level of stress as a parent and the way her children were disciplined in the family. Mother-child pairs were videotaped while completing a puzzle together and dyadic interactions were coded. Path analysis showed that paternal involvement was significantly associated with a higher level of maternal well-being and lower distress levels. In addition, higher levels of maternal distress were associated with higher levels of harsh discipline and parenting stress. Correlation analysis showed that higher perceptions of paternal involvement were associated with more positive affect displayed by the child, more positive regard for the child, and better mother-child synchrony during the dyadic interactions. Limitations include the cross-sectional design and the modest sample size, which hinder causal inferences and generalizability of the findings. These preliminary findings suggest that higher levels of paternal involvement may have an impact on markers of maternal mental health and positive mother-child interactions in families living in disadvantaged communities or humanitarian settings. Paternal involvement should be considered when designing and implementing parenting programs in LMICs.

Effects of the Mother-Child Education Program on Parenting Stress and Disciplinary Practices Among Refugee and Other Marginalized Communities in Lebanon: A Pilot Randomized Controlled Trial.

OBJECTIVE: Few randomized controlled trials (RCTs) have explored the implementation and impact of early childhood parenting education programs in very fragile contexts and humanitarian settings. We tested the effects of a group-based intervention, the Mother-Child Education Program (MOCEP), on parenting stress and practices among two refugee communities and one other marginalized community in Beirut, Lebanon. METHOD: A pilot wait-list RCT was conducted to assess the program's impact on maternal, child (average age: 4 years), and dyadic outcomes. A total of 106 mother-child dyads were randomly assigned to either the intervention group (n = 53) or the wait-list control group (n = 53). Analysis was conducted by modified intention-to-treat and supplemental analyses through multiple imputation of missing post-intervention data. RESULTS: Forty families (38%) withdrew early from the study. After completing the program, mothers in the intervention group showed a reduction in their harsh parenting practices, as indexed by the Disciplinary Style Questionnaire (Cohen's d = -0.76, 95% CI = -1.24, -0.27) and in their level of parenting stress, as indexed by the Parenting Stress Index-Short Form (PSI-SF; Cohen's d = -0.90, 95% CI = -1.39, -0.40). Exploratory but underpowered analyses of dyadic interactions revealed reductions in the PSI were associated with a reduction in harsh parenting after the intervention. However, we did not detect any positive impact on behavioral or emotional outcomes among the children. CONCLUSION: Our analyses suggest that MOCEP had a positive impact on disciplinary practices and parenting stress in a context of high fragility, but that broader effects on maternal and child outcomes may be dependent on program attendance and the availability of other services. We discuss implications of this pilot study for practice and research of a largely unexplored area of program evaluation. CLINICAL TRIAL REGISTRATION INFORMATION: Mother and Child Education Program in Palestinian Refugee Camps; https://clinicaltrials.gov; NCT02402556.

A Randomized Controlled Trial of an Integrated Brain, Body, and Social Intervention for Children With ADHD.

Objective: This study evaluated the efficacy of an Integrated Brain, Body, and Social (IBBS) intervention for children with ADHD. Treatment consisted of computerized cognitive remediation training, physical exercises, and a behavior management strategy. Method: Ninety-two children aged 5 to 9 years with ADHD were randomly assigned to 15 weeks of IBBS or to treatment-as-usual. Primary outcome measures included blinded clinician ratings of ADHD symptoms and global clinical functioning. Secondary outcome measures consisted of parent and teacher ratings of ADHD and neurocognitive tests. Results: No significant treatment effects were found on any of our primary outcome measures. In terms of secondary outcome measures, the IBBS group showed significant improvement on a verbal working memory task; however, this result did not survive correction for multiple group comparisons. Conclusion: These results suggest that expanding cognitive training to multiple domains by means of two training modalities does not lead to generalized improvement of ADHD symptomatology.

Implementation Evaluation of the Mother-Child Education Program Among Refugee and Other Vulnerable Communities in Lebanon.

Despite the knowledge that quality early childhood development programs, including those that target parental knowledge and behaviors, are essential for ameliorating the negative effects of early-life adversity, robust analyses of their implementation and impact in highly vulnerable settings are scarce. To address this knowledge gap, we conducted a pilot wait-list randomized controlled trial (RCT) to assess the impact and the process of implementing and evaluating the Mother-Child Education Program (MOCEP) among refugee families and one low-income community in Beirut, Lebanon. This paper focuses on the analysis of MOCEP's implementation (i.e., key enablers of and barriers to the application and evaluation of the program). Our analysis suggests that, despite multiple challenges, implementation and robust evaluations of early childhood parenting programs in fragile contexts are feasible and urgently needed. This study illustrates how implementation evaluations are a key component of RCTs and crucial to identifying strategies to optimize program uptake and maximize impact.

Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections.

OBJECTIVE: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are hypothesized to occur as a result of cross-reactive antibodies produced in response to group A streptococcal infections. Previous research suggests that immunomodulatory therapies, such as intravenous immunoglobulin (IVIG), may lead to rapid and sustained symptom improvement in patients with PANDAS. METHOD: A total of 35 children meeting criteria for PANDAS and moderate to severe obsessive-compulsive disorder (OCD) were enrolled in a randomized-entry, double-blind, placebo-controlled, 6-week trial of IVIG (1 g/kg/day on 2 consecutive days), followed by optional open-label treatment for nonresponders, with follow-up at 12 and 24 weeks. Primary outcome measures were the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impressions-Improvement (CGI-I) rating. "Responders" were defined, a priori, by a ≥ 30% decrease in CY-BOCS total score, and a "much" or "very much" improved rating on CGI-I. RESULTS: During the double-blind phase, the mean decrease in CY-BOCS score was 24% ± 31% in the IVIG group (n = 17) and 12% ± 27% in the placebo group (n = 18), with six responders in the IVIG group (35%) versus four (22%) in the placebo group; these differences were not statistically significant. Twenty-four participants met criteria for nonresponse to double-blind infusion and received open-label IVIG at week 6. Among all participants, the mean CY-BOCS improvement from baseline was 55% ± 33% at week 12 and 62% ± 33% at week 24. CONCLUSION: IVIG was safe and well tolerated. Between-group differences were smaller than anticipated, and the double-blind comparison failed to demonstrate superiority of IVIG over placebo. The observed open-label improvements indicate that future trials would benefit from larger sample sizes designed in part to aid in the identification of biomarkers predictive of a positive response to immunotherapy. Future investigations focused on the natural history of PANDAS are also warranted. Clinical trial registration information-Intravenous Immunoglobulin for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections); http://clinicaltrials.gov/; NCT01281969ZIAMH002666.

Randomized Sham Controlled Double-blind Trial of Repetitive Transcranial Magnetic Stimulation for Adults With Severe Tourette Syndrome.

BACKGROUND: A small proportion of individuals with Tourette syndrome (TS) have a lifelong course of illness that fails to respond to conventional treatments. Open label studies have suggested that low frequency (1-Hz) repetitive transcranial magnetic stimulation (rTMS) targeting the supplementary motor area (SMA) may be effective in reducing tic severity. OBJECTIVE/HYPOTHESIS: To examine the efficacy of rTMS over the SMA for TS in a randomized double-blind sham-controlled trial (RCT). METHODS: We conducted a two-site RCT-rTMS with 20 adults with severe TS for 3 weeks. Treatment consisted of 15 sessions (1-Hz; 30 min; 1800 pulses per day) of active or sham rTMS at 110% of the motor threshold over the SMA. A subsequent 3 week course of active rTMS treatment was offered. RESULTS: Of the 20 patients (16 males; mean age of 33.7 ± 12.2 years), 9 received active and 11 received sham rTMS. After 3 weeks, patients receiving active rTMS showed on average a 17.3% reduction in the YGTSS total tic score compared to a 13.2% reduction in those receiving sham rTMS, resulting in no statistically significant reduction in tic severity (P = 0.27). An additional 3 week open label active treatment for those patients (n = 7) initially randomized to active rTMS resulted in a significant overall 29.7% reduction in tic severity compared to baseline (P = 0.04). CONCLUSION: This RCT did not demonstrate efficacy of 3-week SMA-targeted low frequency rTMS in the treatment of severe adult TS. Further studies using longer or alternative stimulation protocols are warranted.

Gene variants associated with antisocial behaviour: a latent variable approach.

OBJECTIVE: The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. METHODS: Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. RESULTS: Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour. CONCLUSIONS: This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a 'shared' variance across genetic risk alleles associated with complex neuropsychiatric dimensional phenotypes using relatively small numbers of well-characterized research participants.

Tourette syndrome in youth with and without obsessive compulsive disorder and attention deficit hyperactivity disorder.

Chronic tic disorders (TD) are consistently found to have high rates of comorbidity with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). The purpose of this study is to compare the severity of TD only to TD with comorbid OCD or ADHD based on severity of tics, measures of psychopathology and additional comorbid diagnoses. Baseline data from 158 youth with a chronic TD who participated in two longitudinal studies were examined. Fifty-three percent (N = 85) of the youth also met criteria for a diagnosis of OCD, 38.6 % (n = 61) met criteria for ADHD and 24.1 % (N = 38) met criteria for both. Measures of interest addressed severity of tics, symptoms of anxiety, depression, ADHD, psychosocial stress, global functioning and the presence of comorbid diagnoses. Youth with comorbid TD and OCD were characterized by more severe tics, increased levels of depressive and anxious symptoms, heightened psychosocial stress and poorer global functioning. Youth with comorbid TD and ADHD did not differ from those with TD alone on measures of tic severity, but experienced greater psychosocial stress and poorer global functioning. Subjects with comorbid TD and OCD had more internalizing disorders than those without OCD, while those with comorbid ADHD were more likely to meet criteria for oppositional defiant disorder. TD with OCD is a more severe subtype of TD than TD without OCD. TD with ADHD is associated with higher psychosocial stress and more externalizing behaviors. Further research is needed into the underlying relationships between these closely associated conditions.

Risperidone-related improvement of irritability in children with autism is not associated with changes in serum of epidermal growth factor and interleukin-13.

Risperidone has been shown to improve serious behavioral problems in children with autism. Here we asked whether risperidone-associated improvement was related to changes in concentrations of inflammatory molecules in the serum of these subjects. Seven molecules were identified as worthy of further assessment by performing a pilot analysis of 31 inflammatory markers in 21 medication-free subjects with autism versus 15 healthy controls: epidermal growth factor (EGF), interferon-γ (IFN-γ), interleukin (IL)-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), IL-1 and IL-1-receptor antagonist. Serum concentrations of these markers were then established in a different set of subjects that participated in a double-blind, clinical trial and an expanded group of healthy subjects. In the first analysis, samples obtained from subjects with autism at baseline visits were compared to visits after 8-week treatment with placebo (n=37) or risperidone (n=40). The cytokine concentrations remained stable over the 8-week period for both risperidone and placebo groups. In the second analysis, we explored further the differences between medication-free subjects with autism (n=77) and healthy controls (recruited independently; n=19). Serum levels of EGF were elevated in subjects with autism (median=103 pg/mL, n=75) in comparison to healthy controls (75 pg/mL, n=19; p<0.05), and levels of IL-13 were decreased in autism (median=0.8 pg/mL, n=77) in comparison to controls (9.8 pg/mL, n=19; p=0.0003). These changes did not correlate with standardized measures used for a diagnosis of autism. In summary, risperidone-induced clinical improvement in subjects with autism was not associated with changes in the serum inflammatory markers measured. Whether altered levels of EGF and IL-13 play a role in the pathogenesis or phenotype of autism requires further investigation.

Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study.

OBJECTIVE: The objective of this blinded, prospective, longitudinal study was to determine whether new group A ß hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD: Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS: No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS: This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.

Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD.

OBJECTIVE: Exposure to heavy maternal cigarette smoking in pregnancy and severe maternal psychosocial stress during pregnancy appear to be important risk factors for the development of ADHD. This study aimed to determine whether these perinatal risk factors were associated with neuropsychological deficits commonly seen in ADHD. METHOD: We examined the effect of these two risk factors on measures of attentional control, motor inhibition, visual-motor integration, and fine motor coordination in a group of 81 children with ADHD, aged from 8 to 18 years. The neuropsychological battery included the Connors' Continuous Performance Test (CPT), the Stroop Color-Word Interference Test, the Beery Visual-Motor Integration Test, and the Purdue Pegboard Test. RESULTS: Heavy maternal smoking during pregnancy was associated with slower reaction times (p < .002), and reaction time variability (p < .007) on the CPT. CONCLUSIONS: This study suggests a persistent negative effect of heavy prenatal maternal smoking on attentional control in children with ADHD. Future studies should examine the neurobiological basis and determine the degree to which inherited genetic susceptibility factors contribute to this finding.

Severe psychosocial stress and heavy cigarette smoking during pregnancy: an examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome.

Attention-deficit/hyperactivity disorder (ADHD) is frequently diagnosed in children with Tourette syndrome (TS). The basis for this co-occurrence is uncertain. This study aimed to determine if specific pre- and perinatal risk factors, including heavy maternal smoking and severe psychosocial stress during pregnancy, were associated with one or both disorders, or neither. We compared maternal report data on pre- and perinatal risk factors on 222 children between the ages of 7 and 18 years including 45 individuals with TS alone, 52 individuals with ADHD alone, 60 individuals with condition of comorbid TS + ADHD, and 65 unaffected control children. Pre- and perinatal histories as well as psychiatric assessments were performed using standardized questionnaires and semi-structured interviews with the mothers and children. Logistic regression was used to determine the odds ratio for each variable of interest. Compared to the mothers of unaffected control children, the mothers of children with ADHD alone reported higher rates of heavy smoking (>10 cigarettes per day) during pregnancy and higher levels of severe psychosocial stress during pregnancy (OR = 13.5, p < 0.01 and OR = 6.8, p < 0.002, respectively). The TS + ADHD and the TS alone patients also had higher rates heavy maternal smoking and high levels of psychosocial stress compared to the control children, but these differences failed to reach statistical significance (heavy smoking: OR = 8.5, p < 0.052, OR = 4.6, p < 0.19, respectively; severe psychosocial stress: OR = 3.1, p < 0.07, OR = 2.6, p < 0.11, respectively). Heavy maternal smoking and severe levels psychosocial stress during pregnancy were independently associated with a diagnosis of ADHD. TS patients also had higher rates of these risk factors, but the ORs failed to reach statistical significance. Efforts are needed to reduce the frequency of these risk factors in high-risk populations. Future studies, using genetically sensitive designs, are also needed to sort out the causal pathways.

Streptococcal upper respiratory tract infections and psychosocial stress predict future tic and obsessive-compulsive symptom severity in children and adolescents with Tourette syndrome and obsessive-compulsive disorder.

BACKGROUND: One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity. METHODS: Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity. RESULTS: Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity. CONCLUSIONS: Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

Children with Tourette's syndrome may suffer immunoglobulin A dysgammaglobulinemia: preliminary report.

BACKGROUND: 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). METHODS: 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). RESULTS: 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). CONCLUSIONS: At least some TS/OCD patients may suffer IgA dysgammaglobulinemia, possibly rendering the children more prone to URTI.

Neuropsychiatric disorders associated with streptococcal infection: a case-control study among privately insured children.

OBJECTIVE: To assess whether antecedent streptococcal infection(s) increase the risk of subsequent diagnosis of obsessive-compulsive disorder (OCD), Tourette syndrome (TS), other tic disorders, attention-deficit/hyperactivity disorder (ADHD), or major depressive disorder (MDD) in a national sample of privately insured children. METHOD: Using health insurance claims data, we compared the prior year's occurrence of streptococcal infection in children ages 4 to 13 years with OCD, TS, or tic disorder newly diagnosed between January 1998 and December 2004 to that of a cohort of matched controls. Conditional logistic regression models were used to determine the association of prior streptococcal sore throat or scarlet fever with a diagnosis of OCD, TS, or tic disorder. We repeated the analyses for two other infectious diseases (otitis media and sinusitis) and one noninfectious condition (migraine). We also investigated the potential specificity of this association by performing similar analyses focused on newly diagnosed ADHD and newly diagnosed MDD. RESULTS: Subjects with newly diagnosed OCD, TS, or tic disorder were more likely than controls to have had a diagnosis of streptococcal infection in the previous year (odds ratio 1.54, 95% confidence interval 1.29-2.15). Prior streptococcal infection was also associated with incident diagnoses of ADHD (odds ratio 1.20, 95% confidence interval 1.06-1.35) and MDD (odds ratio 1.63, 95% confidence interval 1.12-2.30). CONCLUSIONS: These findings provide epidemiologic evidence that some pediatric-onset neuropsychiatric disorders, including OCD, tic disorders, ADHD, and MDD, may be temporally related to prior streptococcal infections. Whether this is the result of a nonspecific stress response or secondary to an activation of the immune system remains to be determined.

Psychosocial stress predicts future symptom severities in children and adolescents with Tourette syndrome and/or obsessive-compulsive disorder.

BACKGROUND: The goals of this prospective longitudinal study were to monitor levels of psychosocial stress in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared to healthy control subjects and to examine the relationship between measures of psychosocial stress and fluctuations in tic, obsessive-compulsive (OC), and depressive symptom severity. METHODS: Consecutive ratings of tic, OC and depressive symptom severity were obtained for 45 cases and 41 matched healthy control subjects over a two-year period. Measures of psychosocial stress included youth self-report, parental report, and clinician ratings of long-term contextual threat. Structural equation modeling for unbalanced repeated measures was used to assess the temporal sequence of psychosocial stress with the severity of tic, OC and depressive symptoms. RESULTS: Subjects with TS and OCD experienced significantly more psychosocial stress than did the controls. Estimates of psychosocial stress were predictive of future depressive symptoms. Current levels of psychosocial stress were also a significant predictor of future OC symptom severity, but not vice versa. Current OC symptom severity was a predictor of future depressive symptom severity, but not vice versa. Current levels of psychosocial stress and depression were independent predictors of future tic severity, even after controlling for the effect of advancing chronological age. CONCLUSIONS: The impact of antecedent psychosocial adversity is greater on future depressive symptoms than for tic and/or OC symptoms. Worsening OC symptoms are also a predictor of future depressive symptoms. Advancing chronological age is robustly associated with reductions in tic severity.

Effects of short- and long-term risperidone treatment on prolactin levels in children with autism.

BACKGROUND: The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS: Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS: Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS: Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.