Practitioner Review: Pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: Clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in children and youth with autism spectrum disorder(ASD). The aim of this systematic review and meta-analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD and (b) distil findings for clinical translation. METHODS: We searched electronic databases and clinical trial registries (1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants (methylphenidate or amphetamines), atomoxetine, alpha-2 adrenergic receptor agonists, antipsychotics, tricyclic antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed medications, or behavioral therapies. Data were pooled using a random-effects model. RESULTS: Twenty-five studies (4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included. Methylphenidate reduced hyperactivity (parent-rated: standardized mean difference [SMD] = -.63, 95%CI = -.95,-.30; teacher-rated: SMD = -.81, 95%CI = -1.43,-.19) and inattention (parent-rated: SMD = -.36, 95%CI = -.64,-.07; teacher-rated: SMD = -.30, 95%CI = -.49,-.11). Atomoxetine reduced inattention (parent-rated: SMD = -.54, 95%CI = -.98,-.09; teacher/investigator-rated: SMD = -0.38, 95%CI = -0.75, -0.01) and parent-rated hyperactivity (parent-rated: SMD = -.49, 95%CI = -.76,-.23; teacher-rated: SMD = -.43, 95%CI = -.92, .06). Indirect evidence for significant reductions in hyperactivity with second-generation antipsychotics was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a nonsignificant elevated risk of dropout due to adverse events. CONCLUSIONS: Direct pooled evidence supports the efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/efficacy data and lack of data evaluating long-term continuation is undertaken to help guide clinical decision-making regarding treatment of co-occurring ADHD symptoms in children and youth with ASD.

Implementation and evaluation of a curriculum on the assessment and treatment of disruptive behaviour disorders.

Disruptive behaviour disorders (DBDs)-which can include or be comorbid with disorders such as attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder and disruptive mood dysregulation disorder-are commonly seen in paediatric practice. Given increases in the prescribing of atypical antipsychotics for children and youth, it is imperative that paediatric trainees in Canada receive adequate education on the optimal treatment of DBDs. We describe the development, dissemination, and evaluation of a novel paediatric resident curriculum for the assessment and treatment of DBDs in children and adolescents. Pre-post-evaluation of the curriculum showed improved knowledge in participants.

I Am Your Father.

In this narrative medicine essay, a child psychiatrist is left with no choice but to sit with his 6-year-old son after all his child-behavior strategies failed to jolt the child out of his meltdown, sparked by a long line for a Star Wars ride at a Disney park.

Practitioner Review: On the trustworthiness of clinical practice guidelines - a systematic review of the quality of methods used to develop guidelines in child and youth mental health.

BACKGROUND: Numerous practice guidelines (PGs) relevant to child and youth mental health (CYMH) are available, but their quality is uncertain. We used systematic review methodology to identify the methods employed to develop PGs in CYMH and assess whether they align with international quality standards. METHODS: We used prespecified inclusion criteria to search for CYMH PGs (2009-2014) in journals of professional associations or websites of organizations who produce or house PGs. Eligible PGs and organization websites were screened to identify PG development methods. Two reviewers assessed the alignment of the PG development methods with PG quality criteria using the Appraisal of Guidelines for Research and Evaluation (AGREE II) domains and Institute of Medicine (IOM) standards. RESULTS: Five sets of eligible development methods were identified in 70 eligible PGs. Three sets adhered to all (National Institute for Health and Care Excellence; Scottish Intercollegiate Guidelines Network) or most (U.S. Preventive Services Task Force) AGREE II domains and IOM standards, and were used to develop 31.4% of PGs. The two remaining sets of development methods had important weaknesses (e.g. lack of mandatory rigorous systematic reviews, multidisciplinary development groups, or transparent conflict of interest methods) and were associated with 21.4% of PGs. No development methods could be identified in 40.0% of PGs; ineligible development methods were referenced in 7.1% of PGs. CONCLUSIONS: Up to 69% of available CYMH PGs may have been developed using methods that do not align with AGREE II quality criteria or IOM standards. The quality of available CYMH PGs needs to be assessed, and strategies designed to guide practitioners to high quality PGs and facilitate adherence by PG developers to international quality standards are needed.

The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine.

OBJECTIVE: Children with attention-deficit hyperactivity disorder (ADHD) may have oppositional behaviour, conduct problems, and aggression. These symptoms vary in severity, and may be related to a comorbid diagnosis of oppositional defiant disorder (ODD) or conduct disorder (CD). Critical evaluation of the efficacy of ADHD medications may guide the clinician regarding the usefulness of medications for these symptoms. METHOD: We performed a systematic review and meta-analysis of psychostimulants, alpha-2 agonists, and atomoxetine for oppositional behaviour, conduct problems, and aggression in youth with ADHD, ODD, and CD. The quality of evidence for medications was rated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Two systematic reviews and 20 randomized controlled trials were included. There is high-quality evidence that psychostimulants have a moderate-to-large effect on oppositional behaviour, conduct problems, and aggression in youth with ADHD, with and without ODD or CD. There is very-low-quality evidence that clonidine has a small effect on oppositional behaviour and conduct problems in youth with ADHD, with and without ODD or CD. There is moderate-quality evidence that guanfacine has a small-to-moderate effect on oppositional behaviour in youth with ADHD, with and without ODD. There is high-quality evidence that atomoxetine has a small effect on oppositional behaviour in youth with ADHD, with and without ODD or CD. CONCLUSIONS: Evidence indicates that psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit.

The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 2: antipsychotics and traditional mood stabilizers.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are among the most common psychiatric diagnoses in childhood. Aggression and conduct problems are a major source of disability and a risk factor for poor long-term outcomes. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) of antipsychotics, lithium, and anticonvulsants for aggression and conduct problems in youth with ADHD, ODD, and CD. Each medication was given an overall quality of evidence rating based on the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Eleven RCTs of antipsychotics and 7 RCTs of lithium and anticonvulsants were included. There is moderate-quality evidence that risperidone has a moderate-to-large effect on conduct problems and aggression in youth with subaverage IQ and ODD, CD, or disruptive behaviour disorder not otherwise specified, with and without ADHD, and high-quality evidence that risperidone has a moderate effect on disruptive and aggressive behaviour in youth with average IQ and ODD or CD, with and without ADHD. Evidence supporting the use of haloperidol, thioridazine, quetiapine, and lithium in aggressive youth with CD is of low or very-low quality, and evidence supporting the use of divalproex in aggressive youth with ODD or CD is of low quality. There is very-low-quality evidence that carbamazepine is no different from placebo for the management of aggression in youth with CD. CONCLUSION: With the exception of risperidone, the evidence to support the use of antipsychotics and mood stabilizers is of low quality.

Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder.

OBJECTIVE: To develop evidence-based guidelines on pharmacotherapy for severe disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), or conduct disorder (CD). The guidelines assume that psychosocial interventions have been pursued but did not achieve sufficient improvement. METHOD: A multidisciplinary consensus group used the Grading of Recommendations Assessment, Development and Evaluation approach for rating evidence quality and for grading recommendations. We conducted a systematic review of medications studied in placebo-controlled trials for treating disruptive and aggressive behaviour in children and adolescents with ADHD, ODD, or CD. We followed consensus procedures to make 1 of 4 recommendations for each medication: strong, in favour (↑↑); conditional, in favour (↑?); conditional, against (↓?); and strong, against (↓↓). RESULTS: For children and adolescents with disruptive or aggressive behaviour associated with ADHD, psychostimulants received a strong recommendation in favour of use, while atomoxetine and alpha-2 agonists received a conditional recommendation in favour of use. If these patients do poorly with ADHD medications, the medication with the most evidence is risperidone. Risperidone also has the most evidence for treating disruptive or aggressive behaviour in the absence of ADHD. However, given risperidone's major adverse effects, it received only a conditional recommendation in favour of use. We recommended against using quetiapine, haloperidol, lithium, or carbamazepine because of the poor quality of evidence and their major adverse effects. CONCLUSION: When severe disruptive or aggressive behaviour occurs with ADHD, medications for ADHD should be used first. Other medications have major adverse effects and, with the exception of risperidone, very limited evidence to support their use.

Uncovering the complexity of Tourette syndrome, little by little.

The aetiology of Tourette syndrome is highly complex and still poorly understood. In this issue, using data from a large, prospective, population-based cohort of children, Mathews et al examine associations of pre- and perinatal exposures with Tourette syndrome and other chronic tic disorders. Their work illustrates the importance of environmental factors in the aetiology of neuropsychiatric conditions and the value of replication in science.

Case Report: Defining Applicant Attributes to Be Prioritized in the Selection of Child and Adolescent Psychiatry Subspecialty Residents at the University of Toronto.

Background/Objectives: The child and adolescent psychiatry (CAP) subspecialty training program at the University of Toronto was among the first fully accredited CAP programs in Canada. As one of Canada's largest CAP subspecialty programs, we attract many excellent applicants annually. While objectivity and transparency in the selection of candidates have been valued, it was unclear which applicant attributes should be prioritized. This quality improvement project was undertaken to identify the key applicant attributes that should be prioritized for admission to the program. Materials/Methods: An initial list of attributes was compiled by project team members and feedback solicited. Through iterative design, this list was categorized into "end products," "branding attributes" and "generic attributes." The "end products" were removed as these represented outputs of training rather than attributes on which applicant selection should be based. Subsequent steps involved only the "branding" and "generic" attributes. A consensus-building exercise led to the creation of two short-lists of five attributes within each category. Finally, a paired-comparison forced choice methodology was used to determine the ranking of these attributes in order of importance when assessing applicants. Results: The final lists of "generic" and "branding" attributes developed through a consensus-building exercise are presented in rank order based on the paired-comparison methodology. The overall response rate for the forced choice electronic survey was 49% of faculty and learners. Conclusions/Discussion: This project used an iterative process of consensus building & pairwise comparison to prioritize key attributes for assessing trainee selection to the program. Going forward, these attributes will be incorporated into the file review and interview portions of our admissions process. In addition to emphasizing these priority attributes in admissions, there are implications for other aspects of the program including curriculum and faculty development, as well as guiding the overall mission and vision for the Division. A similar process could be undertaken by other training programs seeking to identify priority attributes for admission to their programs.

Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study.

BACKGROUND: Children with Tourette syndrome generally experience improvement of tics by age 18 years, but psychosocial and comorbidity outcomes at this age are unclear. AIMS: To compare psychosocial outcomes and lifetime comorbidity rates in older adolescents with Tourette syndrome and controls. We hypothesised a priori that individuals with Tourette syndrome would have lower Children's Global Assessment Scale (CGAS) scores. METHOD: A total of 65 individuals with Tourette syndrome, identified in childhood, and 65 matched community controls without tic or obsessive-compulsive disorder (OCD) symptoms were assessed around 18 years of age regarding psychosocial functioning and lifetime psychiatric disorders. RESULTS: Compared with controls, individuals with Tourette syndrome had substantially lower CGAS scores (P = 10(-8)) and higher rates of attention-deficit hyperactivity disorder (ADHD), major depression, learning disorder and conduct disorder (P< or =0.01). In the participants with Tourette syndrome, poorer psychosocial outcomes were associated with greater ADHD, OCD and tic severity. CONCLUSIONS: Clinically ascertained children with Tourette syndrome typically have impaired psychosocial functioning and high comorbidity rates in late adolescence.

Deep brain stimulation for Gilles de la Tourette syndrome in children and youth: a meta-analysis with individual participant data.

Objective: Gilles de la Tourette syndrome (GTS) is a disorder characterized by motor and vocal tics. Although by definition the onset of GTS is before age 18 years, clinical trials of deep brain stimulation (DBS) have been conducted only in adults. Using individual participant data (IPD) meta-analysis methodology, the current study investigated the safety and efficacy of DBS as a treatment for GTS in children and youth. Methods: A systematic review with no date or language restrictions was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Three electronic databases were searched: PubMed, EMBASE, and Web of Science. From 843 articles screened, the IPD of 58 children and youth (ages 12­21 years) extracted from 21 articles were collected and analyzed. A mixed-effects univariable analysis followed by multivariable hierarchical regression was performed using change in the Yale Global Tic Severity Scale (YGTSS) score as the primary outcome and reported measures of comorbidities as secondary outcomes. Results: The authors' results showed an average improvement of 57.5% ± 24.6% across studies on the YGTSS. They also found that comorbid depression and stimulation pulse width each correlated negatively with outcome (p < 0.05). In patients with less severe GTS, greater improvements were evident following thalamic stimulation. More than one-quarter (n = 16, 27.6%) of participants experienced side effects, the majority of which were minor. Conclusions: DBS in the pediatric population may be an effective option with a moderate safety profile for treatment of GTS in carefully selected children and youth. Large, prospective studies with long-term follow-up are necessary to understand how DBS influences tic symptoms and may alter the natural course of GTS in children.

Ferritin levels and their association with regional brain volumes in Tourette's syndrome.

OBJECTIVE: A previous small study showed lower serum ferritin levels in subjects with Tourette's syndrome than in healthy subjects. The authors measured peripheral iron indices in a large group of Tourette's syndrome and comparison subjects and explored associations of ferritin levels with regional brain volumes. METHOD: Ferritin was measured in 107 children and adults (63 Tourette's syndrome, 44 comparison); serum iron was measured in 73 (41 Tourette's syndrome, 32 comparison). Magnetic resonance imaging scans were used to measure volumes of the basal ganglia and cortical gray matter. RESULTS: Ferritin and serum iron were significantly lower in the Tourette's syndrome subjects, although still within the normal range. No association was found between tic severity and either iron index. In the Tourette's syndrome subjects, ferritin did not correlate significantly with caudate volume but did correlate positively with putamen volume. In the comparison subjects, ferritin correlated inversely with caudate volume but did not correlate significantly with putamen volume. Irrespective of diagnosis, ferritin correlated positively with volumes of the sensorimotor, midtemporal, and subgenual cortices. CONCLUSIONS: The lower peripheral ferritin and iron levels in persons with Tourette's syndrome are consistent with findings in other movement disorders and suggest that lower iron availability may have a causal role in the pathophysiology of tic disorders. Lower iron stores may contribute to hypoplasia of the caudate and putamen, increasing vulnerability to developing tics or to having more severe tics. Lower iron stores may also contribute to smaller cortical volumes and consequently to reduced inhibitory control of tics.

Increased number of subcortical hyperintensities on MRI in children and adolescents with Tourette's syndrome, obsessive-compulsive disorder, and attention deficit hyperactivity disorder.

OBJECTIVE: To investigate whether cerebral hyperintensities on T2-weighted magnetic resonance images (MRI) are associated with childhood neuropsychiatric disorders. METHOD: The authors compared the frequency of cortical and subcortical cerebral hyperintensities in 100 children and adolescents with Tourette's syndrome, obsessive-compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD) and 32 healthy comparison subjects. RESULTS: The frequency of cerebral hyperintensities was significantly higher in subjects with Tourette's syndrome, OCD, or ADHD than in healthy comparison subjects; each diagnostic group seemed to contribute to this effect. Among the patient groups, the likelihood of detecting cerebral hyperintensities in the subcortex (primarily the basal ganglia and thalamus) was significantly greater than in the cortex. CONCLUSIONS: A childhood diagnosis of Tourette's syndrome, OCD, or ADHD significantly increased the likelihood of detecting cerebral hyperintensities, particularly in the subcortex, supporting the notion that subcortical injury may play a role in the pathophysiology of these conditions.

The pharmacoepidemiology of selective serotonin reuptake inhibitors for children and adolescents in Canada from 2005 to 2009: a database analysis.

OBJECTIVE: The aim of this study was to describe the frequency and trends in prescriptions and recommendations for selective serotonin reuptake inhibitors (SSRIs) for mental health disorders in children and adolescents in Canada from 2005 to 2009. METHOD: Data were extracted from databases supplied by IMS Brogan (IMS), a proprietary source of pharmacoepidemiologic data. Analyses were performed to obtain descriptive statistics on SSRI prescriptions dispensed, SSRI drug recommendation frequency, reasons for drug recommendations (therapeutic indication), and median duration of use of SSRIs in Canadian children. Canadian census data were used to assess whether changes in SSRI use were related to changes in the number of children in Canada over the time period studied. RESULTS: SSRI prescriptions written by pediatricians increased by 39 %, while SSRI drug recommendations by all specialists for children and adolescents increased by 44 % over the 5-year interval. Over the 5-year period studied, fluoxetine was the most commonly recommended and dispensed SSRI. The use of escitalopram has increased while the use of paroxetine has declined. Between 2005 and 2009, the two most common therapeutic indications for SSRI recommendations were mood disorder (50 %) and anxiety disorder (25 %). Median treatment duration was less than 1 year, with duration generally increasing with patient age. CONCLUSIONS: The increase in use of SSRIs in Canadian children and adolescents from 2005 to 2009 suggests that the effects of public health warnings concerning suicidal thinking and behavior associated with these drugs are now dissipating. This may be attributable to the FDA's pediatric approvals for fluoxetine and escitalopram, the growing comfort of clinicians with using SSRIs in children, limited availability of psychosocial treatments, and the influence of marketing. The use of paroxetine has continued to decline, likely because of specific warnings directed toward this agent and limited evidence supporting its efficacy.