Maternal anxiety, depression and sleep disorders before and during pregnancy, and preschool ADHD symptoms in the NINFEA birth cohort study.

AIMS.: Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. Within the context of a mother-child cohort, we examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms. METHODS.: The study included 3634 singletons from the Italian NINFEA (Nascita e INFanzia: gli Effetti dell'Ambiente') cohort. Maternal doctor-diagnosed anxiety, depression and sleep disorders before and during pregnancy were assessed from the questionnaires completed during pregnancy and 6 months after delivery. Mothers rated child ADHD symptoms at 4 years of age, according to the Diagnostic and Statistical Manual of Mental Disorders. Hyperactive-impulsive (ADHD-H), inattentive (ADHD-I) and total ADHD scores were analysed in the models adjusted for child's gender, first-born status, maternal age, education, alcohol consumption and smoking during pregnancy. RESULTS.: The total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3-27.9%), sleep disorders (35.7%; 95% CI 10.7-66.5%) and depression (17.5%; 95% CI 3.2-33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period. CONCLUSIONS.: Maternal anxiety, depression and sleep disorders are associated with a relative increase in the number of ADHD-H, ADHD-I and total ADHD symptoms in preschoolers.

Bilateral Striatal Necrosis after Sydenham's Chorea in a 7-Year-Old Boy: A 2-Year Follow-Up.

Child bilateral striatal necrosis (BSN) is a rare and etiologically heterogeneous condition. An association with group A streptococcus (GAS) infection was previously reported in two cases of BSN in infancy and early childhood. We here report on a 7-year-old boy who developed chorea and dystonia 20 days after symptomatic recovery from Sydenham's chorea. Repeated brain magnetic resonance imaging scans, obtained before, soon after the onset of the post-Sydenham symptoms, and 1 year later were consistent with an evolution from bilateral striatal microbleeding to necrosis, and consequently reduced basal ganglia volume and enlargement of the frontal horns. No support was found for other possible autoimmune, infectious, metabolic, toxic or genetic etiologies for BSN. Prednisone treatment was instituted and continued for 1 year. Two years after the onset of the post-Sydenham symptoms, the child, although much improved, still has generalized dystonic-choreic movements. This case confirms and extends into school age, the link between GAS and BSN.

Prevalence of severe ADHD: an epidemiological study in the Italian regions of Tuscany and Latium.

BACKGROUND: The rate with which attention deficit/hyperactivity disorder (ADHD) is diagnosed varies widely across countries, suggesting that cultural factors influence the clinical interpretation of child behaviour. This study estimated the point prevalence of severe ADHD among elementary and middle-school Italian children. METHOD: An epidemiological sample of 2016 children attending 2nd-8th grade in the Italian regions of Tuscany and Latium was selected based on census distribution of the school-age population. Teachers completed the Italian version of the ADHD Rating Scale for Teachers (SDAI). For children with at least six inattention symptoms and/or at least six hyperactivity/impulsivity symptoms rated 'very often' by the teachers, the parents completed the Italian ADHD Rating Scale for Parents (SDAG). Children with documented ADHD symptoms at both school and home received a complete psychiatric interview with the Kiddie Schedule for Affective Disorders and Schizophrenia-present and lifetime version (K-SADS-PL). RESULTS: Of the 1887 assessed children, 4.45% (95% CI 3.58-5.51) met the ADHD cut-off on teacher ratings, 1.43% (0.96-2.12) had ADHD symptoms endorsed by both teacher and parent, and 1.32% (0.87-1.97) were further confirmed by the psychiatric evaluation. The male:female ratio was 7:1. The inattentive type accounted for about half of the ADHD cases. CONCLUSIONS: When applying stringent criteria for both severity and pervasiveness of symptoms, it is estimated that about 1.3% of the Italian elementary and middle-school children suffer from severe ADHD.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

Prevention and treatment of child and adolescent depression: challenges and opportunities.

OBJECTIVE: To examine the current theoretical rationale and empirical evidence for preventing and treating major depressive disorder in childhood and adolescence. METHODS: Selective review of recent controlled investigations on the efficacy and safety of preventive and treatment interventions. RESULTS: Even more than in adults, pediatric clinical trials in depression are dominated by symptomatic improvement with non-specific clinical contact (on average, 50% 'placebo response'). The additional benefit of specific psychotherapeutic or pharmacological treatment is on average modest. Antidepressant medication is effective in speeding up improvement, but more than a third of patients do not reach full remission even after prolonged treatment. The advantage of routinely combining medication with cognitive-behavioral therapy (CBT) is unclear. Depressed suicidal adolescents can benefit from CBT and medications. CBT can protect high-risk youths from developing a depressive episode. CONCLUSIONS: Effective interventions to prevent and treat depression in youth exist, but their therapeutic benefit appears to be, on average, small, possibly due to the clinical heterogeneity subsumed under the current diagnostic construct of depressive disorder. More specifically, targeted interventions tailored to individual clinical and biological characteristics may result in greater effectiveness and overall efficiency.

Behavioural and temperamental characteristics of children and adolescents suffering from primary headache.

To examine indices of behavioural and emotional problems and temperamental traits in clinically referred children and adolescents suffering from tension headache or migraine. Headache in childhood and adolescence (<18 years) has been associated with the presence of behavioural and emotional difficulties, but limited data are available on the relationship between these problems and different types of headache. Clinically referred children and adolescents (N=114), 6-16 years of age, suffering from primary headache according to the diagnostic criteria of the International Headache Society, 47 with tension-type headache (TH) and 67 with migraine (M), and 36 normal controls without headache (NC) were assessed using the Parent Child Behaviour Checklist (CBCL), Children's Depression Inventory (CDI), Multidimensional Anxiety Scale for Children (MASC), Conner's Parent Rating Scale (CPRS), and Emotionality-Activity-Sociability-Shyness Scale (EAS). Psychological and personality self-rating assessments were obtained also on the children's parents and siblings. Although most headache patients had scores within the normative non-pathological range, both TH and M patients had higher CBCL total, internalizing, and externalizing scores than NC (P<0.001), and TH patients had higher scores than M patients. TH and M had higher CDI and MASC scores than NC (P<0.05), with no difference between the headache groups. TH patients had higher Emotionality and Shyness scores, and lower Sociability scores than M patients. Clinically referred children and adolescents with TH and M had higher scores of behavioural and emotional symptoms, both of internalizing and externalizing type, than normal peers. The TH group had greater psychological and temperamental difficulties than the M group.

Psychopharmacology for young children: clinical needs and research opportunities.

In response to concerns about the increasing use of psychotropic medications in preschoolers, the National Institute of Mental Health and the Food and Drug Administration convened a workshop in October 2000 to examine the current state of knowledge regarding psychopharmacology for young children and discuss a variety of topics relevant to research in this age group, including safety, efficacy, investigational methods, and ethical aspects. The meeting gathered researchers, practitioners, ethicists, industry staff, and family and patient representatives. Efficacy and safety of psychotropics have not been systematically evaluated in preschoolers. The major limitation to this research is the diagnostic uncertainty surrounding most manifestations of psychopathology in early childhood. Research in developmental psychopathology is needed to clarify diagnosis and provide sensitive and specific methods for clinical trials. Possible approaches to expanding the research basis of this area of clinical practice, including a recently started study of methylphenidate in preschoolers, are reported here.

Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States.

BACKGROUND: There have been no previous nationally representative estimates of the prevalence of mental disorders and drug use among adults receiving care for human immunodeficiency virus (HIV) disease in the United States. It is also not known which clinical and sociodemographic factors are associated with these disorders. SUBJECTS AND METHODS: We enrolled a nationally representative probability sample of 2864 adults receiving care for HIV in the United States in 1996. Participants were administered a brief structured psychiatric instrument that screened for psychiatric disorders (major depression, dysthymia, generalized anxiety disorders, and panic attacks) and drug use during the previous 12 months. Sociodemographic and clinical factors associated with screening positive for any psychiatric disorder and drug dependence were examined in multivariate logistic regression analyses. RESULTS: Nearly half of the sample screened positive for a psychiatric disorder, nearly 40% reported using an illicit drug other than marijuana, and more than 12% screened positive for drug dependence during the previous 12 months. Factors independently associated with screening positive for a psychiatric disorder included number of HIV-related symptoms, illicit drug use, drug dependence, heavy alcohol use, and being unemployed or disabled. Factors independently associated with screening positive for drug dependence included having many HIV-related symptoms, being younger, being heterosexual, having frequent heavy alcohol use, and screening positive for a psychiatric disorder. CONCLUSIONS: Many people infected with HIV may also have psychiatric and/or drug dependence disorders. Clinicians may need to actively identify those at risk and work with policymakers to ensure the availability of appropriate care for these treatable disorders.

Use of mental health and substance abuse treatment services among adults with HIV in the United States.

BACKGROUND: The need for mental health and substance abuse services is great among those with human immunodeficiency virus (HIV), but little information is available on services used by this population or on individual factors associated with access to care. METHODS: Data are from the HIV Cost and Services Utilization Study, a national probability survey of 2864 HIV-infected adults receiving medical care in the United States in 1996. We estimated 6-month use of services for mental health and substance abuse problems and examined socioeconomic, HIV illness, and regional factors associated with use. RESULTS: We estimated that 61.4% of 231 400 adults under care for HIV used mental health or substance abuse services: 1.8% had hospitalizations, 3.4% received residential substance abuse treatment, 26.0% made individual mental health specialty visits, 15.2% had group mental health treatment, 40.3% discussed emotional problems with medical providers, 29.6% took psychotherapeutic medications, 5.6% received outpatient substance abuse treatment, and 12.4% participated in substance abuse self-help groups. Socioeconomic factors commonly associated with poorer access to health services predicted lower likelihood of using mental health outpatient care, but greater likelihood of receiving substance abuse treatment services. Those with less severe HIV illness were less likely to access services. Persons living in the Northeast were more likely to receive services. CONCLUSIONS: The magnitude of mental health and substance abuse care provided to those with known HIV infection is substantial, and challenges to providers should be recognized. Inequalities in access to care are evident, but differ among general medical, specialty mental health, and substance abuse treatment sectors.

Advances in paediatric neuropsychopharmacology: an overview.

This Special Section of Int J Neuropsychopharmacol highlights current progress in paediatric neuropsychopharmacology. Combining critical reviews and, in some cases, new data, specific topics include: biological findings in major depression, sleep dysregulation in depressed youth, cardiovascular and ventilatory dysregulation in panic disorder, paediatric autoimmune neuropsychiatric disorder associated with strep (PANDAS), age of onset as a subtype marker in tic and obsessive--compulsive disorders (OCD), functional and pharmaconeuroanatomy of OCD and the behavioural pharmacokinetics of methylphenidate. In this introductory section, these articles are placed in the context of the state-of-the field and, more specifically, within the framework of recent NIMH initiatives in paediatric neuropsychopharmacology.

Long-term effects of stimulant medications on the brain: possible relevance to the treatment of attention deficit hyperactivity disorder.

In spite of extensive data supporting the short-term efficacy and safety of stimulant medications in the treatment of children with attention deficit hyperactivity disorder (ADHD), only limited information is available on the long-term effects of these drugs. On one hand, it is unclear whether treatment of ADHD with amphetamine-like stimulant medications for extended periods of time during child development can carry negative consequences, as manifested by an increase in use of illicit drugs, higher incidence of mania, psychosis, or other manifestations of psychopathology. On the other hand, it is not known whether the beneficial effects of stimulants extend beyond acute symptomatic relief and affect important outcome variables, such as later psychopathology, educational achievement, antisocial behavior, and social or occupational status. Data from naturalistic follow-up of clinical samples are limited by lack of appropriate controls and self-selection biases that are difficult to determine and control. These studies have reached conflicting conclusions, although most of them found no lasting negative effects of chronic stimulant treatment. Studies in animals, mainly in rodents, indicate that repeated exposure to stimulants leads to behavioral sensitization to the psychomotor effects of these medications. Extrapolation of these data to therapeutic use in humans is difficult given interspecies differences and the relatively high doses and parenteral route of administration usually employed in animals. This report is based on the proceedings of a workshop organized by the National Institute of Mental Health in December 1999 to discuss possible research approaches to studying the long-term effects of stimulants in children with ADHD. Both clinical and basic neuroscience data are reviewed, and opportunities for future research are highlighted.

Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers.

In 1992, the National Institute of Mental Health and 6 teams of investigators began a multisite clinical trial, the Multimodal Treatment of Attention-Deficit Hyperactivity Disorder (MTA) study. Five hundred seventy-nine children were randomly assigned to either routine community care (CC) or one of three study-delivered treatments, all lasting 14 months. The three MTA treatments-monthly medication management (usually methylphenidate) following weekly titration (MedMgt), intensive behavioral treatment (Beh), and the combination (Comb)-were designed to reflect known best practices within each treatment approach. Children were assessed at four time points in multiple outcome. Results indicated that Comb and MedMgt interventions were substantially superior to Beh and CC interventions for attention-deficit hyperactivity disorder symptoms. For other functioning domains (social skills, academics, parent-child relations, oppositional behavior, anxiety/depression), results suggested slight advantages of Comb over single treatments (MedMgt, Beh) and community care. High quality medication treatment characterized by careful yet adequate dosing, three times daily methylphenidate administration, monthly follow-up visits, and communication with schools conveyed substantial benefits to those children that received it. In contrast to the overall study findings that showed the largest benefits for high quality medication management (regardless of whether given in the MedMgt or Comb group), secondary analyses revealed that Comb had a significant incremental effect over MedMgt (with a small effect size for this comparison) when categorical indicators of excellent response and when composite outcome measures were used. In addition, children with parent-defined comorbid anxiety disorders, particularly those with overlapping disruptive disorder comorbidities, showed preferential benefits to the Beh and Comb interventions. Parental attitudes and disciplinary practices appeared to mediate improved response to the Beh and Comb interventions.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

ADHD comorbidity findings from the MTA study: comparing comorbid subgroups.

OBJECTIVES: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. METHOD: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7-9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. RESULTS: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. CONCLUSIONS: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.